ESSENTIALS OF DIAGNOSIS
Type 1 diabetes
Polyuria, polydipsia, and weight loss associated with random plasma glucose of 200 mg/dL (11.1 mmol/L) or more.
Plasma glucose of 126 mg/dL (7.0 mmol/L) or more after an overnight fast, documented on more than one occasion.
Ketonemia, ketonuria, or both.
Islet autoantibodies are frequently present.
Type 2 diabetes
Many patients are over 40 years of age and obese.
Polyuria and polydipsia. Ketonuria and weight loss generally are uncommon at time of diagnosis. Candidal vaginitis in women may be an initial manifestation. Many patients have few or no symptoms.
Plasma glucose of 126 mg/dL or more after an overnight fast on more than one occasion. Two hours after 75 g oral glucose, diagnostic values are 200 mg/dL (11.1 mmol) or more.
HbA1c 6.5% or more.
Hypertension, dyslipidemia, and atherosclerosis are often associated.
An estimated 29.1 million people (9.3%) in the United States have diabetes mellitus, of which approximately 1.25 million have type 1 diabetes and most of the rest have type 2 diabetes. A third group designated as “other specific types” by the American Diabetes Association (ADA) (Table 27–1) number only in the thousands. Among these are the rare monogenic defects of either B cell function or of insulin action, primary diseases of the exocrine pancreas, endocrinopathies, and medication-induced diabetes. Updated information about the prevalence of diabetes in the United States is available from the Centers for Disease Control and Prevention (http://www.cdc.gov/diabetes/pubs/estimates.htm#prev).
Table 27–1.Other specific types of diabetes mellitus. |Favorite Table|Download (.pdf) Table 27–1. Other specific types of diabetes mellitus.
Genetic defects of pancreatic B cell function
MODY 1 (HNF-4alpha); rare
MODY 2 (glucokinase); less rare
MODY 3 (HNF-1alpha); accounts for two-thirds of all MODY
MODY 4 (PDX1); very rare
MODY 5 (HNF-1beta); very rare
MODY 6 (neuroD1); very rare
Genetic defects in insulin action
Type A insulin resistance
Diseases of the exocrine pancreas
Drug- or chemical-induced diabetes
Other genetic syndromes (Down, Klinefelter, Turner, others) sometimes associated with diabetes
Classification & Pathogenesis
Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either a deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate for the resistance.
A. Type 1 Diabetes Mellitus
This form of diabetes is due to pancreatic islet B cell destruction predominantly by an autoimmune process in over 95% of cases (type 1A) and idiopathic in less than 5% (type 1B). The rate of pancreatic B cell destruction is quite variable, being rapid in some individuals and slow in others. Type 1 diabetes is usually associated with ketosis in its untreated state. It occurs at any age but most commonly arises in children and young adults with a peak incidence before school age and again at around puberty. It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic B cells fail to respond to all insulinogenic stimuli. Exogenous insulin is therefore required to reverse the catabolic state, prevent ketosis, reduce the hyperglucagonemia, and reduce blood glucose.
1. Immune-mediated type 1 diabetes mellitus (type 1A)
The highest incidence of immune-mediated type 1 diabetes mellitus is in Scandinavia and northern Europe, where the annual incidence is as high as 40 per 100,000 children aged 14 years or younger in Finland, 31 per 100,000 in Sweden, 22 per 100,000 in Norway, and 20 per 100,000 in England. The annual incidence of type 1 diabetes decreases across the rest of Europe to 11 per 100,000 in Greece and 9 per 100,000 in France. Surprisingly, the island of Sardinia has as high an annual incidence as Finland (40 per 100,000) even though in the rest of Italy, including the island of Sicily, it is only 11 per 100,000 per year. In the United States, the annual incidence of type 1 diabetes averages 16 per 100,000, with higher rates in states more densely populated with persons of Scandinavian descent such as Minnesota. Worldwide, the lowest incidence of type 1 diabetes (less than 1 case per 100,000 per year) is in China and parts of South America. The global incidence of type 1 diabetes is increasing (approximately 3% each year). In Europe, the highest annual incidence increase was seen in low prevalence countries in Eastern Europe, especially Romania and Poland. Changes in environmental factors most likely explain this increased incidence.
Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental factors. Genes that are related to the HLA locus contribute about 40% of the genetic risk. About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4, compared with 45–50% of white controls. HLA-DQ genes are even more specific markers of type 1 susceptibility, since a particular variety (HLA-DQB1*0302) is found in the DR4 patients with type 1, while a “protective” gene (HLA-DQB1*0602) is often present in the DR4 controls. The other important gene that contributes to about 10% of the genetic risk is found at the 5′ polymorphic region of the insulin gene. This polymorphic region affects the expression of the insulin gene in the thymus and results in depletion of insulin-specific T lymphocytes. In linkage studies, 16 other genetic regions of the human genome have been identified as being important to pathogenesis. Many of the genes linked to these additional loci play important roles in the function and regulation of the immune response. Mutations in genes associated with T cell tolerance can also cause autoimmune diabetes. The autoimmune regulatory gene (AIRE) product regulates the expression of several proteins in the thymus causing the deletion of self-reactive T cells. Type 1 diabetes mellitus as well as other autoimmune disorders (autoimmune polyglandular syndrome 1) develop in 20% of individuals with homozygote mutations in AIRE. FOXP3, an X chromosome gene, encodes a transcription factor required for the formation of regulatory T cells. Mutations in FOXP3 lead to very early type 1 diabetes mellitus and other autoimmune endocrinopathies (immunodysregulation polyendocrinopathy enteropathy X-linked [IPEX] syndrome). Most patients with type 1 diabetes mellitus have circulating antibodies to islet cells (ICA), glutamic acid decarboxylase 65 (GAD65), insulin (IAA), tyrosine phosphatase IA2 (ICA-512), and zinc transporter 8 (ZnT8) at the time the diagnosis is made (Table 27–2). These antibodies facilitate screening for an autoimmune cause of diabetes, particularly screening siblings of affected children, as well as adults with atypical features of type 2 diabetes mellitus. Screening with GAD65, ICA-512, IAA, and ZnT8 autoantibodies may identify about 98% of people who have an autoimmune basis for their beta cell loss. Antibody levels decline with increasing duration of disease. Also, low levels of anti-insulin antibodies develop in almost all patients once they are treated with insulin.
Table 27–2.Diagnostic sensitivity and specificity of autoimmune markers in patients with newly diagnosed type 1 diabetes mellitus. |Favorite Table|Download (.pdf) Table 27–2. Diagnostic sensitivity and specificity of autoimmune markers in patients with newly diagnosed type 1 diabetes mellitus.
| ||Sensitivity ||Specificity |
|ICA antibody ||44–100% ||96% |
|Glutamic acid decarboxylase (GAD65) ||70–90% ||99% |
|Insulin (IAA) ||40–70% ||99% |
|Tyrosine phosphatase (IA-2) ||50–70% ||99% |
|Zinc transporter 8 (ZnT8) ||50–70% ||99% |
Family members of diabetic probands are at increased lifetime risk for developing type 1 diabetes mellitus. A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child’s father has it. The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic proband. If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%. The highest risk is for identical twins, where the concordance rate is 25–50%.
Some patients with a milder expression of type 1 diabetes mellitus initially retain enough B cell function to avoid ketosis, but as their B cell mass diminishes later in life, dependence on insulin therapy develops. Islet cell antibody surveys among northern Europeans indicate that up to 15% of “type 2” diabetic patients may actually have this mild form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA). Evidence for environmental factors playing a role in the development of type 1 diabetes include the observation that the disease is more common in Scandinavian countries and becomes progressively less frequent in countries nearer and nearer to the equator. Also, the risk for type 1 diabetes increases when individuals who normally have a low risk emigrate to the Northern Hemisphere. For example, Pakistani children born and raised in Bradford, England have a higher risk for developing type 1 diabetes compared with children who lived in Pakistan all their lives.
Which environmental factor is responsible for the increased risk is not known. There have been a number of different hypotheses including infections with certain viruses (mumps, rubella, Coxsackie B4) and consumption of cow’s milk. Also, in developed countries, childhood infections have become less frequent and so perhaps the immune system becomes dysregulated with development of autoimmunity and conditions such as asthma and diabetes. This theory is referred to as the hygiene hypothesis. Part of the difficulty in determining the causative environmental factor is that autoimmune injury is initiated many years before the clinical presentation of diabetes.
2. Idiopathic type 1 diabetes mellitus (type 1B)
Approximately 5% of subjects have no evidence of pancreatic B cell autoimmunity to explain their insulinopenia and ketoacidosis. This subgroup has been classified as “idiopathic type 1 diabetes” and designated as “type 1B.” Although only a minority of patients with type 1 diabetes fall into this group, most of these individuals are of Asian or African origin. About 4% of the West Africans with ketosis-prone diabetes are homozygous for a mutation in PAX-4 (Arg133Trp)—a transcription factor that is essential for the development of pancreatic islets.
B. Type 2 Diabetes Mellitus
This represents a heterogeneous group of conditions that used to occur predominantly in adults, but it is now more frequently encountered in children and adolescents. More than 90% of all diabetic persons in the United States are included under this classification. Circulating endogenous insulin is sufficient to prevent ketoacidosis but is inadequate to prevent hyperglycemia in the face of increased needs owing to tissue insensitivity (insulin resistance).
Genetic and environmental factors combine to cause both the insulin resistance and the beta cell loss. Most epidemiologic data indicate strong genetic influences, since in monozygotic twins over 40 years of age, concordance develops in over 70% of cases within a year whenever type 2 diabetes develops in one twin. So far, more than 30 genetic loci have been associated with an increased risk of type 2 diabetes. A significant number of the identified loci appear to code for proteins that have a role in beta cell function or development. One of the genetic loci with the largest risk effect is TCF7L2. This gene codes for a transcription factor involved in the WNT signaling pathway that is required for normal pancreatic development. Alleles at other genetic loci (CDKAL1, SLC30A8, HHEX-IDE, CDKN2A/B, KCNJ11, and IGF2BP2) are thought to affect insulin secretion. Two loci (FTO and MC4R) affect fat mass and obesity risk. The PPARG locus has been implicated in insulin resistance. The loci identified to date still explain only some of the heritable risk for diabetes; clearly, other loci remain to be discovered.
Early in the disease process, hyperplasia of pancreatic B cells occurs and probably accounts for the fasting hyperinsulinism and exaggerated insulin and proinsulin responses to glucose and other stimuli. With time, chronic deposition of amyloid in the islets may combine with inherited genetic defects progressively to impair B cell function.
Obesity is the most important environmental factor causing insulin resistance. The degree and prevalence of obesity varies among different racial groups with type 2 diabetes. While obesity is apparent in no more than 30% of Chinese and Japanese patients with type 2, it is found in 60–70% of North Americans, Europeans, or Africans with type 2 and approaches 100% of patients with type 2 among Pima Indians or Pacific Islanders from Nauru or Samoa.
Visceral obesity, due to accumulation of fat in the omental and mesenteric regions, correlates with insulin resistance; subcutaneous abdominal fat seems to have less of an association with insulin insensitivity. There are many patients with type 2 diabetes who, while not overtly obese, have increased visceral fat; they are termed the “metabolically obese.” Exercise may affect the deposition of visceral fat as suggested by CT scans of Japanese wrestlers, whose extreme obesity is predominantly subcutaneous. Their daily vigorous exercise program prevents accumulation of visceral fat, and they have normal serum lipids and euglycemia despite daily intakes of 5000–7000 kcal and development of massive subcutaneous obesity.
A number of mechanisms may operate to cause the insulin resistance associated with obesity. Free fatty acid levels are increased in obesity, and their oxidation by skeletal muscle leads to a decrease in insulin-mediated glucose disposal, that is, insulin resistance. Adipocytes secrete molecules (adipokines) that can affect insulin signaling. Examples include adiponectin, which enhances insulin action, and resistin, which impairs insulin action; abnormal levels of these types of molecules in obesity may contribute to the development of resistance. Macrophages and other immune cells in adipose tissue are activated in response to an increase in adipocyte lipid stores. They release a variety of molecules, including tissue necrosis factor alpha and interleukin-6, that impair insulin signaling.
Hyperglycemia per se can impair insulin action by causing accumulation of hexosamines in muscle and fat tissue and by inhibiting glucose transport (acquired glucose toxicity). Correction of hyperglycemia reverses this acquired insulin resistance.
C. Other Specific Types of Diabetes Mellitus
1. Maturity-onset diabetes of the young (MODY)
This subgroup is a relatively rare monogenic disorder characterized by non–insulin-dependent diabetes with autosomal dominant inheritance and an age at onset of 25 years or younger. Patients are nonobese, and their hyperglycemia is due to impaired glucose-induced secretion of insulin. Six types of MODY have been described (Table 27–1). Except for MODY 2, in which a glucokinase gene is defective, all other types involve mutations of a nuclear transcription factor that regulates islet gene expression.
The enzyme glucokinase is a rate-limiting step in glycolysis and determines the rate of adenosine triphosphate (ATP) production from glucose and the insulin secretory response in the beta cell. MODY 2, due to glucokinase mutations, is usually quite mild, associated with only slight fasting hyperglycemia and few if any microvascular diabetic complications. It generally responds well to hygienic measures or low doses of oral hypoglycemic agents. MODY 3, due to mutations in hepatic nuclear factor 1 alpha is the most common form, accounting for two-thirds of all MODY cases. Initially, patients with MODY 3 are responsive to sulfonylurea therapy but the clinical course is of progressive beta cell failure and eventual need for insulin therapy. Mutations in both alleles of glucokinase present with more severe neonatal diabetes. Mutation in one allele of the pancreatic duodenal homeobox 1 (PDX1) causes diabetes usually at a later age (~ 35 years) than other forms of MODY; mutations in both alleles of PDX1 causes pancreatic agenesis.
2. Diabetes due to mutant insulins or insulin receptors
Less than 10 families have been described with a subtype of nonobese type 2 diabetes from mutant insulins. Since affected individuals were heterozygous and possessed one normal insulin gene, diabetes was mild, did not appear until middle age, and showed autosomal dominant genetic transmission. There is generally no evidence of clinical insulin resistance, and these patients respond well to standard therapy. Defects in one of their insulin receptor genes have been found in more than 40 people with diabetes, and most have extreme insulin resistance associated with acanthosis nigricans (Figure 27–1). In very rare instances when both insulin receptor genes are abnormal, newborns present with a leprechaun-like phenotype and seldom live through infancy.
Acanthosis nigricans of the nape of the neck, with typical dark and velvety appearance. (Used, with permission, from Umesh Masharani, MB, BS, MRCP (UK).)
3. Diabetes mellitus associated with a mutation of mitochondrial DNA
Since sperm do not contain mitochondria, only the mother transmits mitochondrial genes to her offspring. Diabetes due to mutations of mitochondrial DNA occurs in less than 2% of patients with diabetes. The most common cause is the A3243G mutation in the gene coding for the tRNA (Leu, UUR). Diabetes occurs even when a small percentage of the mitochondria in the cell carry the mutation; the heteroplasmy levels in the leukocytes range from 1% to 40%. Diabetes usually develops in these patients in their late 30s, and characteristically, they also have hearing loss (maternally inherited diabetes and deafness [MIDD]). In some patients, the beta cell failure can be rapidly progressive and patients require insulin soon after diagnosis. Other patients can be managed by diet or oral agents for a while but most eventually require insulin. MIDD patients are not usually overweight; they resemble patients with type 1 diabetes mellitus but without evidence for autoimmunity.
Wolfram syndrome is an autosomal recessive neurodegenerative disorder first evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD. It is due to mutations in a gene named WFS1, which encodes a 100.3 KDa transmembrane protein localized in the endoplasmic reticulum. The WFS1 protein forms part of the unfolding protein response and helps protect the beta cells from endoplasmic reticulum stress and apoptosis especially during periods of high insulin demand. Diabetes develops in mice with mutated form of this protein; and isolated islets from these mice show impairment in insulin secretion to glucose stimulus and increased apoptosis. The diabetes mellitus usually presents in the first decade together with the optic atrophy. Cranial diabetes insipidus and sensorineural deafness develop during the second decade in 60–75% of patients. Ureterohydronephrosis, neurogenic bladder, cerebellar ataxia, peripheral neuropathy, and psychiatric illness develop later in many patients.
5. Autosomal recessive syndromes
Homozygous mutations in a number of pancreatic transcription factors, NEUROG3, PTF1A, RFX6, and GLI-similar 3 (GLIS3), cause neonatal or childhood diabetes. Homozygous PTF1A mutations result in absent pancreas and cerebellar atrophy; NEUROG3 mutations cause severe malabsorption and diabetes before puberty. Homozygous mutations in RFX6 cause the Mitchell-Riley syndrome characterized by absence of all islet cell types apart from pancreatic polypeptide cells, hypoplasia of the pancreas and gallbladder, and intestinal atresia. GLIS3 gene plays a role in transcription of insulin gene, and homozygous mutations cause neonatal diabetes and congenital hypothyroidism. The gene EIF2AK3 encodes PKR-like ER kinase (PERK), which controls one of the pathways of the unfolded protein response. Absence of PERK leads to inadequate response to ER stress and accelerated beta cell apoptosis. Patients with mutation in this gene have neonatal diabetes, epiphyseal dysplasia, developmental delay, and hepatic and renal dysfunction (Wolcott-Rallison syndrome).
6. Diabetes mellitus secondary to other causes
Endocrine tumors secreting growth hormone, glucocorticoids, catecholamines, glucagon, or somatostatin can cause glucose intolerance (Table 27–3). In the first four of these situations, peripheral responsiveness to insulin is impaired. With excess of glucocorticoids, catecholamines, or glucagon, increased hepatic output of glucose is a contributory factor; in the case of catecholamines, decreased insulin release is an additional factor in producing carbohydrate intolerance, and with somatostatin, inhibition of insulin secretion is the major factor. Diabetes mainly occurs in individuals with underlying defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is resolved.
Table 27–3.Secondary causes of hyperglycemia. |Favorite Table|Download (.pdf) Table 27–3. Secondary causes of hyperglycemia.
Hyperglycemia due to tissue insensitivity to insulin
Hormonal tumors (acromegaly, Cushing syndrome, glucagonoma, pheochromocytoma)
Pharmacologic agents (corticosteroids, sympathomimetic drugs, niacin)
Liver disease (cirrhosis, hemochromatosis)
Muscle disorders (myotonic dystrophy)
Adipose tissue disorders (lipodystrophy, truncal obesity)
Insulin receptor disorders (acanthosis nigricans syndromes, leprechaunism)
Hyperglycemia due to reduced insulin secretion
Hormonal tumors (somatostatinoma, pheochromocytoma)
Pancreatic disorders (pancreatitis, hemosiderosis, hemochromatosis)
Pharmacologic agents (thiazide diuretics, phenytoin, pentamidine, calcineurin inhibitors)
High-titer anti-insulin receptor antibodies that inhibit insulin binding cause a clinical syndrome characterized by severe insulin resistance, glucose intolerance or diabetes mellitus, and acanthosis nigricans. These patients usually have other autoimmune disorders. There are reports of spontaneous remission or remission with cytotoxic therapy.
Many medications are associated with carbohydrate intolerance or frank diabetes (Table 27–3). The medications act by decreasing insulin secretion or by increasing insulin resistance or both. Cyclosporine and tacrolimus impair insulin secretion; sirolimus principally increases insulin resistance. These agents contribute to the development of new-onset diabetes after transplantation. Corticosteroids increase insulin resistance but may also have an effect on beta cell function; in a case control study and a large population cohort study, oral corticosteroids doubled the risk for development of diabetes. Thiazide diuretics and beta-blockers modestly increase the risk for diabetes. Treating the hypokalemia due to thiazides may reverse the hyperglycemia. Atypical antipsychotics, particularly olanzapine and clozapine, have been associated with increased risk of glucose intolerance. These medications cause weight gain and insulin resistance but may also impair beta cell function; an increase in rates of diabetic ketoacidosis has been reported.
Chronic pancreatitis or subtotal pancreatectomy reduces the number of functioning B cells and can result in a metabolic derangement very similar to that of genetic type 1 diabetes except that a concomitant reduction in pancreatic A cells may reduce glucagon secretion so that relatively lower doses of insulin replacement are needed.
Insulin Resistance Syndrome (Syndrome X; Metabolic Syndrome)
Twenty-five percent of the general nonobese, nondiabetic population has insulin resistance of a magnitude similar to that seen in type 2 diabetes. These insulin-resistant nondiabetic individuals are at much higher risk for developing type 2 diabetes than insulin-sensitive persons. In addition to diabetes, these individuals have a cluster of abnormalities termed syndrome X or metabolic syndrome that significantly increases their risk of atherosclerotic disease: elevated plasma triglycerides and small, dense, low-density lipoproteins (LDL); lower high-density lipoproteins (HDLs); higher blood pressure; hyperuricemia; abdominal obesity; prothrombotic state with increased levels of plasminogen activator inhibitor type 1 (PAI-1); and proinflammatory state.
It has been postulated that hyperinsulinemia and insulin resistance play a direct role in these metabolic abnormalities, but supportive evidence is inconclusive. Although hyperinsulinism and hypertension often coexist in whites, that is not the case in blacks or Pima Indians. Moreover, patients with hyperinsulinism due to insulinoma are not hypertensive, and there is no fall in blood pressure after surgical removal of the insulinoma restores normal insulin levels. The main value of grouping these disorders as a syndrome, however, is to remind clinicians that the therapeutic goals are not only to correct hyperglycemia but also to manage the elevated blood pressure and dyslipidemia that result in increased cerebrovascular and cardiac morbidity and mortality in these patients.
American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care. 2016 Jan;39(Suppl):S1–119.
DM. Diabetes: advances in diagnosis and treatment. JAMA. 2015 Sep 8;314(10):1052–62. Erratum in: JAMA. 2015 Dec 22–29;314(24):2693.
et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010 Apr;53(4):600–5.
et al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet. 2014 Mar 22;383(9922):1084–94.
The principal clinical features of the two major types of diabetes mellitus are listed for comparison in eTable 27–1.
eTable 27–1.Clinical features of diabetes at diagnosis. |Favorite Table|Download (.pdf) eTable 27–1. Clinical features of diabetes at diagnosis.
| ||Type 1 Diabetes ||Type 2 Diabetes |
|Polyuria and thirst ||++ ||+ |
|Weakness or fatigue ||++ ||+ |
|Polyphagia with weight loss ||++ ||– |
|Recurrent blurred vision ||+ ||++ |
|Vulvovaginitis or pruritus ||+ ||++ |
|Peripheral neuropathy ||+ ||++ |
|Nocturnal enuresis ||++ ||– |
|Often asymptomatic ||– ||++ |
Patients with type 1 diabetes have a characteristic symptom complex. An absolute deficiency of insulin results in accumulation of circulating glucose and fatty acids, with consequent hyperosmolality and hyperketonemia.
Patients with type 2 diabetes may or may not have characteristic features. The presence of obesity or a strongly positive family history for mild diabetes suggests a high risk for the development of type 2 diabetes.
A characteristic symptom complex of hyperosmolality and hyperketonemia from the accumulation of circulating glucose and fatty acids typically presents in patients with type 1 diabetes who have an absolute deficiency of insulin. Increased urination and thirst are consequences of osmotic diuresis secondary to sustained hyperglycemia. The diuresis results in a loss of glucose as well as free water and electrolytes in the urine. Blurred vision often develops as the lenses are exposed to hyperosmolar fluids.
Weight loss despite normal or increased appetite is a common feature of type 1 when it develops subacutely. The weight loss is initially due to depletion of water, glycogen, and triglycerides; thereafter, reduced muscle mass occurs as amino acids are diverted to form glucose and ketone bodies.
Lowered plasma volume produces symptoms of postural hypotension. Total body potassium loss and the general catabolism of muscle protein contribute to the weakness.
Paresthesias may be present at the time of diagnosis, particularly when the onset is subacute. They reflect a temporary dysfunction of peripheral sensory nerves, which clears as insulin replacement restores glycemic levels closer to normal, suggesting neurotoxicity from sustained hyperglycemia.
When absolute insulin deficiency is of acute onset, the above symptoms develop abruptly. Ketoacidosis exacerbates the dehydration and hyperosmolality by producing anorexia and nausea and vomiting, interfering with oral fluid replacement.
The patient’s level of consciousness can vary depending on the degree of hyperosmolality. When insulin deficiency develops relatively slowly and sufficient water intake is maintained, patients remain relatively alert and physical findings may be minimal. When vomiting occurs in response to worsening ketoacidosis, dehydration progresses and compensatory mechanisms become inadequate to keep serum osmolality below 320–330 mOsm/L. Under these circumstances, stupor or even coma may occur. The fruity breath odor of acetone further suggests the diagnosis of diabetic ketoacidosis.
Hypotension in the recumbent position is a serious prognostic sign. Loss of subcutaneous fat and muscle wasting are features of more slowly developing insulin deficiency. In occasional patients with slow, insidious onset of insulin deficiency, subcutaneous fat may be considerably depleted.
While increased urination and thirst may be presenting symptoms in some patients with type 2 diabetes, many other patients have an insidious onset of hyperglycemia and are asymptomatic initially. This is particularly true in obese patients, whose diabetes may be detected only after glycosuria or hyperglycemia is noted during routine laboratory studies. Occasionally, when the disease has been occult for some time, patients with type 2 diabetes may have evidence of neuropathic or cardiovascular complications at the time of presentation. Chronic skin infections are common. Generalized pruritus and symptoms of vaginitis are frequently the initial complaints of women. Diabetes should be suspected in women with chronic candidal vulvovaginitis as well as in those who have delivered babies larger than 9 lb (4.1 kg) or have had polyhydramnios, preeclampsia, or unexplained fetal losses. Balanoposthitis (inflammation of the foreskin and glans in uncircumcised males) may occur.
Many patients with type 2 diabetes are overweight or obese. Even those who are not significantly obese often have characteristic localization of fat deposits on the upper segment of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. This centripetal fat distribution is characterized by a high waist circumference; a waist circumference larger than 40 inches (102 cm) in men and 35 inches (88 cm) in women is associated with an increased risk of diabetes. Some patients may have acanthosis nigricans, which is associated with significant insulin resistance; the skin in the axilla, groin, and back of neck is hyperpigmented and hyperkeratotic (Figure 27–1). Mild hypertension is often present in obese patients with diabetes. Eruptive xanthomas on the flexor surface of the limbs and on the buttocks and lipemia retinalis due to hyperchylomicronemia can occur in patients with uncontrolled type 2 diabetes who also have a familial form of hypertriglyceridemia.
Hyperglycemic hyperosmolar coma can also be present; in these cases, patients are profoundly dehydrated, hypotensive, lethargic or comatose but without Kussmaul respirations.
A specific and convenient method to detect glucosuria is the paper strip impregnated with glucose oxidase and a chromogen system (Clinistix, Diastix), which is sensitive to as little as 100 mg/dL (5.5 mmol) glucose in urine. Diastix can be directly applied to the urinary stream, and differing color responses of the indicator strip reflect glucose concentration.
A normal renal threshold for glucose as well as reliable bladder emptying is essential for interpretation.
Nondiabetic glycosuria (renal glycosuria) is a benign asymptomatic condition wherein glucose appears in the urine despite a normal amount of glucose in the blood, either basally or during a glucose tolerance test. Its cause may vary from mutations in the SGLT2 gene coding for sodium-glucose transporter 2 (familial renal glycosuria) to one associated with dysfunction of the proximal renal tubule (Fanconi syndrome, chronic kidney disease), or it may merely be a consequence of the increased load of glucose presented to the tubules by the elevated glomerular filtration rate (GFR) during pregnancy. As many as 50% of pregnant women normally have demonstrable sugar in the urine, especially during the third and fourth months. This sugar is practically always glucose except during the late weeks of pregnancy, when lactose may be present.
2. Urine and blood ketones
Qualitative detection of ketone bodies can be accomplished by nitroprusside tests (Acetest or Ketostix). Although these tests do not detect beta-hydroxybutyric acid, which lacks a ketone group, the semiquantitative estimation of ketonuria thus obtained is nonetheless usually adequate for clinical purposes. Many laboratories measure beta-hydroxybutyric acid, and there are meters available (Precision Xtra; Nova Max Plus) for patient use that measures beta-hydroxybutyric acid levels in capillary glucose samples. Beta-hydroxybutyrate levels greater than 0.6 mmol/L require evaluation. Patients with levels greater than 3.0 mmol/L, equivalent to very large urinary ketones, require hospitalization.
3. Plasma or serum glucose
Plasma or serum from venous blood samples has the advantage over whole blood of providing values for glucose that are independent of hematocrit and that reflect the glucose concentration to which body tissues are exposed. Venous samples should be collected in tubes containing sodium fluoride to prevent glycolysis, placed on ice and the plasma separated from cells within 60 minutes. In the absence of fluoride, the rate of disappearance of glucose in presence of blood cells has been reported to be approximately 10 mg/dL/h (0.56 mmol/L). The glucose concentration is 10–15% higher in plasma or serum than in whole blood because structural components of blood cells are absent. A plasma glucose level of 126 mg/dL (7 mmol/L) or higher on more than one occasion after at least 8 hours of fasting is diagnostic of diabetes mellitus (Table 27–4). Fasting plasma glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) are associated with increased risk of diabetes (impaired fasting glucose tolerance).
Table 27–4.Criteria for the diagnosis of diabetes. |Favorite Table|Download (.pdf) Table 27–4. Criteria for the diagnosis of diabetes.
| ||Normal Glucose Tolerance ||Impaired Glucose Tolerance ||Diabetes Mellitus2 |
|Fasting plasma glucose mg/dL (mmol/L) ||< 100 (5.6) ||100–125
(5.6–6.9) ||≥ 126
|Two hours after glucose load1 mg/dL (mmol/L) ||< 140 (7.8) ||≥ 140–199
(7.8–11.0) ||≥ 200
|HbA1c (%) ||< 5.7 ||5.7–6.4 ||≥ 6.5 |
4. Oral glucose tolerance test
If the fasting plasma glucose level is less than 126 mg/dL (7 mmol/L) when diabetes is nonetheless suspected, then a standardized oral glucose tolerance test may be done (Table 27–4). In order to optimize insulin secretion and effectiveness, especially when patients have been on a low-carbohydrate diet, a minimum of 150–200 g of carbohydrate per day should be included in the diet for 3 days preceding the test. The patient should eat nothing after midnight prior to the test day. On the morning of the test, adults are then given 75 g of glucose in 300 mL of water; children are given 1.75 g of glucose per kilogram of ideal body weight. The glucose load is consumed within 5 minutes. The test should be performed in the morning because there is some diurnal variation in oral glucose tolerance, and patients should not smoke or be active during the test.
Blood samples for plasma glucose are obtained at 0 and 120 minutes after ingestion of glucose. An oral glucose tolerance test is normal if the fasting venous plasma glucose value is less than 100 mg/dL (5.6 mmol/L) and the 2-hour value falls below 140 mg/dL (7.8 mmol/L). A fasting value of 126 mg/dL (7 mmol/L) or higher or a 2-hour value of greater than 200 mg/dL (11.1 mmol/L) is diagnostic of diabetes mellitus. Patients with 2-hour value of 140–199 mg/dL (7.8–11.1 mmol/L) have impaired glucose tolerance. False-positive results may occur in patients who are malnourished, bedridden, or afflicted with an infection or severe emotional stress.
5. Glycated hemoglobin (hemoglobin A1) measurements
Hemoglobin becomes glycated by ketoamine reactions between glucose and other sugars and the free amino groups on the alpha and beta chains. Only glycation of the N-terminal valine of the beta chain imparts sufficient negative charge to the hemoglobin molecule to allow separation by charge dependent techniques. These charge separated hemoglobins are collectively referred to as hemoglobin A1 (HbA1). The major form of HbA1 is hemoglobin A1c (HbA1c) where glucose is the carbohydrate. HbA1c comprises 4–6% of total hemoglobin A1. The remaining HbA1 species contain fructose-1,6 diphosphate (HbA1a1); glucose-6-phosphate (HbA1a2); and unknown carbohydrate moiety (HbA1b). HbA1c is abnormally elevated in diabetic persons with chronic hyperglycemia. Methods for measuring HbA1c include electrophoresis, cation-exchange chromatography, boronate affinity chromatography, and immunoassays. Office-based immunoassays using capillary blood give a result in about 9 minutes and this allows for nearly immediate feedback to the patients regarding their glycemic control.
Since glycohemoglobins circulate within red blood cells whose life span lasts up to 120 days, they generally reflect the state of glycemia over the preceding 8–12 weeks, thereby providing an improved method of assessing diabetic control. The HbA1c value, however, is weighted to more recent glucose levels (previous month) and this explains why significant changes in HbA1c are observed with short-term (1 month) changes in mean plasma glucose levels. Measurements should be made in patients with either type of diabetes mellitus at 3- to 4-month intervals. In patients monitoring their own blood glucose levels, HbA1c values provide a valuable check on the accuracy of monitoring. In patients who do not monitor their own blood glucose levels, HbA1c values are essential for adjusting therapy. There is a linear relationship between the HbA1c and the average glucose levels in the previous 3 months. In a study using a combination of intermittent seven-point capillary blood glucose profiles (preprandial, postprandial, and bedtime) and intermittent continuous glucose monitoring data, the change in glucose values was 28.7 mg/dL for every 1% change in HbA1c. Substantial individual variability exists, however, between HbA1c and mean glucose concentration. For HbA1c values between 6.9% and 7.1%, the glucose levels ranged from 125 mg/dL to 205 mg/dL (6.9–11.4 mmol/L; 95% CIs). For HbA1c of 6%, the mean glucose levels ranged from 100 mg/dL to 152 mg/dL (5.5–8.5 mmol/L); and for 8% they ranged from 147 mg/dL to 217 mg/dL (8.1–12.1 mmol/L). For this reason, caution should be exercised in estimating average glucose levels from measured HbA1c.
The accuracy of HbA1c values can be affected by hemoglobin variants or traits; the effect depends on the specific hemoglobin variant or derivative and the specific assay used. Immunoassays that use an antibody to the glycated amino terminus of beta globin do not recognize the terminus of the gamma globin of hemoglobin F. In patients with high levels of hemoglobin F, immunoassays give falsely low values of HbA1c. Cation-exchange chromatography separates hemoglobin species by charge differences. Hemoglobin variants that co-elute with HbA1c can lead to an overestimation of the HbA1c value. Chemically modified derivatives of hemoglobin such as carbamoylation (in end-stage chronic kidney disease) or acetylation (high-dose aspirin therapy) can similarly co-elute with HbA1c by some assay methods. The National Glycohemoglobin Standardization Program website (www.ngsp.org) has information on the impact of frequently encountered hemoglobin variants and traits on the results obtained with the commonly used HbA1c assays.
Any condition that shortens erythrocyte survival or decreases mean erythrocyte age (eg, recovery from acute blood loss, hemolytic anemia) will falsely lower HbA1c irrespective of the assay method used. Intravenous iron and erythropoietin therapy for treatment of anemia in chronic kidney disease also falsely lower HbA1c levels. Alternative methods such as fructosamine should be considered for these patients. Vitamins C and E are reported to falsely lower test results possibly by inhibiting glycation of hemoglobin. Conditions that increase erythrocyte survival such as splenectomy for hereditary spherocytosis will falsely raise HbA1c levels. Iron deficiency anemia is also associated with higher HbA1c levels.
HbA1c is endorsed by the ADA as a diagnostic test for type 1 and type 2 diabetes (Table 27–4). A cutoff value of 6.5% was chosen because the risk for retinopathy increases substantially above this value. The advantages of using the HbA1c to diagnose diabetes is that there is no need to fast; it has lower intraindividual variability than the fasting glucose test and the oral glucose tolerance test; and it provides an estimate of glucose control for the preceding 2–3 months. People with HbA1c levels of 5.7–6.4% should be considered at high risk for developing diabetes (prediabetes). The diagnosis should be confirmed with a repeat HbA1c test, unless the patient is symptomatic with plasma glucose levels greater than 200 mg/dL (11.1 mmol/L). This test is not appropriate to use in populations with high prevalence of hemoglobinopathies or in conditions with increased red cell turnover. Also, the testing is performed using a National Glycohemoglobin Standardization Program (NGSP) certified method and standardized to the Diabetes Control and Complication Trial assay. In the European Union, the tests are standardized to the International Federation of Clinical Chemistry (IFCC), which defines HbA1c as mmol glycated hexapeptide per mol (glycated and nonglycated hexapeptides) and reported as mmol HbA1c/mol Hb. The conversion factor for NGSP and IFCC results is NGSP (USA) result = (0.09148*IFCC result) + 2.152. There is worldwide consensus that HbA1c should be reported in both NGSP (%) and IFCC (mmol/mol) units.
Serum fructosamine is formed by nonenzymatic glycosylation of serum proteins (predominantly albumin). Since serum albumin has a much shorter half-life than hemoglobin, serum fructosamine generally reflects the state of glycemic control for only the preceding 1–2 weeks. Reductions in serum albumin (eg, nephrotic state, protein-losing enteropathy, or hepatic disease) will lower the serum fructosamine value. When abnormal hemoglobins or hemolytic states affect the interpretation of glycohemoglobin or when a narrower time frame is required, such as for ascertaining glycemic control at the time of conception in a diabetic woman who has recently become pregnant, serum fructosamine assays offer some advantage. Normal values vary in relation to the serum albumin concentration and are 200–285 mcmol/L when the serum albumin level is 5 g/dL. HbA1c values and serum fructosamine are highly correlated. Serum fructosamine levels of 300, 367, and 430 mcmol/L approximate to HbA1c values of 7%, 8%, and 9%, respectively. Substantial individual variability exists, though, when estimating the likely HbA1c value from the fructosamine measurement.
7. Self-monitoring of blood glucose
Capillary blood glucose measurements performed by patients themselves, as outpatients, are extremely useful. In type 1 patients in whom “tight” metabolic control is attempted, they are indispensable. There are several paper strip (glucose oxidase, glucose dehydrogenase, or hexokinase) methods for measuring glucose on capillary blood samples. A reflectance photometer or an amperometric system is then used to measure the reaction that takes place on the reagent strip. A large number of blood glucose meters are now available. All are accurate, but they vary with regard to speed, convenience, size of blood samples required, reporting capability, and cost. Popular models include those manufactured by LifeScan (One Touch), Bayer Corporation (Breeze, Contour), Roche Diagnostics (Accu-Chek), Sanofi Aventis (iBGStar), and Abbott Laboratories (Precision, FreeStyle). These blood glucose meters are relatively inexpensive, ranging from $50 to $100 each. Test strips remain a major expense, costing about $.25 to $1.50 apiece. Each glucose meter also comes with a lancet device and disposable 26- to 33-gauge lancets. Most meters can store from 100 to 1000 glucose values in their memories and have capabilities to download the values into a computer spreadsheet for review by the patients and their health care team. iBGStar is a glucose meter that connects directly to the iPhone. Some meters are designed to communicate with a specific insulin pump. Contour Next Link meter, for example, communicates with the MiniMed Medtronic pump). The accuracy of data obtained by home glucose monitoring does require education of the patient in sampling and measuring procedures as well as in properly calibrating the instruments.
The clinician should be aware of the limitations of the self-monitoring glucose systems. The strips have limited lifespans and improper storage (high temperature; open vial) can affect their function. Patients should also be advised not to use expired strips. Some of the older meters require input of a code for each batch of strips and failure to enter the code can result in misleading results. The newer meters no longer require this step. Increases or decreases in hematocrit can decrease or increase the measured glucose values. The mechanism underlying this effect is not known but presumably it is due to the impact of red cells on the diffusion of plasma into the reagent layer. Meters and the test strips are calibrated over the glucose concentrations ranging from 60 mg/dL (3.3 mmol/L) to 160 mg/dL (8.9 mmol/L) and the accuracy is not as good for higher and lower glucose levels. When the glucose is less than 60 mg/dL (3.3 mmol/L), the difference between the meter and the laboratory value may be as much as 20%. Glucose oxidase–based amperometric systems underestimate glucose levels in the presence of high oxygen tension. This may be important in the critically ill who are receiving supplemental oxygen; under these circumstances, a glucose dehydrogenase–based system may be preferable. Glucose-dehydrogenase pyrroloquinoline quinone (GDH-PQQ) systems may report falsely high glucose levels in patients who are receiving parenteral products containing nonglucose sugars such as maltose, galactose, or xylose or their metabolites. Some meters have been approved for measuring glucose in blood samples obtained at alternative sites such as the forearm and thigh. There is, however, a 5- to 20-minute lag in the glucose response on the arm with respect to the glucose response on the finger. Forearm blood glucose measurements could therefore result in a delay in detection of rapidly developing hypoglycemia. Impaired circulation to the fingers (for example, in patients with Raynaud disease) will artificially lower finger-stick glucose measurements (pseudohypoglycemia).
8. Continuous glucose monitoring systems
A number of continuous glucose monitoring systems are available for clinical use. The systems manufactured by Medtronic Minimed, DexCom systems, and Abbott Diagnostics (outside the United States), involve inserting a subcutaneous sensor (rather like an insulin pump cannula) that measures glucose concentrations in the interstitial fluid for 3–7 days. The MiniMed system can only be used in conjunction with the Minimed pump and the glucose data are displayed on the screen of the pump. The DexCom system transmits glucose data wirelessly to a separate pager-like device with a screen. The DexCom system also has the option of displaying data on smart phones or smart watches or on the screens of several insulin pumps. The systems allow the patient to set “alerts” for low and high glucose values and rate of change of glucose levels. Patients still have to calibrate the devices with periodic fingerstick glucose levels, and since there are concerns regarding reliability, it is still necessary to confirm the displayed glucose level with a fingerstick glucose before making interventions such as injecting extra insulin or eating extra carbohydrates. A 6-month randomized controlled study of type 1 patients showed that adults (25 years and older) using these systems had improved glycemic control without an increase in the incidence of hypoglycemia. A randomized controlled study of continuous glucose monitoring during pregnancy showed improved glycemic control in the third trimester, lower birth weight, and reduced risk of macrosomia. The individual glucose values are not that critical—what matters is the direction and the rate at which the glucose is changing, allowing the user to take corrective action. The wearer also gains insight into the way particular foods and activities affect their glucose levels. The other main benefit is the low glucose alert warning. The MiniMed insulin pump can be programmed to automatically suspend insulin delivery for up to 2 hours when the glucose levels on its continuous glucose monitoring device falls to a preset level and the patient does not respond to the alert. This insulin suspension feature has been shown to reduce the amount of time patients are in the hypoglycemic range at night. Many of these systems are covered by insurance. The initial cost is about $800 to $1000, and the sensor, which has to be changed every 3 to 7 days, costs $35 to $60; the out-of-pocket expense of about $4000 annually.
There is great interest in using the data obtained from these continuous glucose monitoring systems to automatically deliver insulin by continuous subcutaneous insulin infusion pump. Algorithms have been devised to link continuous glucose monitoring to insulin delivery. These closed loop systems (artificial pancreas) have been shown in short-term clinical studies to improve nighttime glucose control and reduce the risk of nocturnal hypoglycemia.
9. Lipoprotein abnormalities in diabetes
Circulating lipoproteins are just as dependent on insulin as is the plasma glucose. In type 1 diabetes, moderately deficient control of hyperglycemia is associated with only a slight elevation of LDL cholesterol and serum triglycerides and little if any change in HDL cholesterol. Once the hyperglycemia is corrected, lipoprotein levels are generally normal. However, in patients with type 2 diabetes, a distinct “diabetic dyslipidemia” is characteristic of the insulin resistance syndrome. Its features are a high serum triglyceride level (300–400 mg/dL [3.4–4.5 mmol/L]), a low HDL cholesterol (less than 30 mg/dL [0.8 mmol/L]), and a qualitative change in LDL particles, producing a smaller dense particle whose membrane carries supranormal amounts of free cholesterol. These smaller dense LDL particles are more susceptible to oxidation, which renders them more atherogenic. Since a low HDL cholesterol is a major feature predisposing to macrovascular disease, the term “dyslipidemia” has preempted the term “hyperlipidemia,” which mainly denoted the elevated triglycerides. Measures designed to correct the obesity and hyperglycemia, such as exercise, diet, and hypoglycemic therapy, are the treatment of choice for diabetic dyslipidemia, and in occasional patients in whom normal weight was achieved, all features of the lipoprotein abnormalities cleared. Since primary disorders of lipid metabolism may coexist with diabetes, persistence of lipid abnormalities after restoration of normal weight and blood glucose should prompt a diagnostic workup and possible pharmacotherapy of the lipid disorder. Chapter 28 discusses these matters in detail.
et al. Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial. Lancet Diabetes Endocrinol. 2015 Jan;3(1):17–26.
et al. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan: executive summary. Endocr Pract. 2011 Mar–Apr;17(2):287–302.
et al. Implications of using hemoglobin A1C for diagnosing diabetes mellitus. Am J Med. 2011 May;124(5):395–401.
et al. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. BMJ. 2011 Jul 7; 343:d3805.
et al. Home use of an artificial beta cell in Type 1 diabetes. N Engl J Med. 2015 Nov 26;373(22):2129–40.
et al. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med. 2012 Sep 4;157(5):336–47.
Clinical Trials in Diabetes
Findings of the Diabetes Complications and Control Trial (DCCT) and of the United Kingdom Prospective Diabetes Study (UKPDS), have confirmed the beneficial effects of improved glycemic control in both type 1 and type 2 diabetes.
The Diabetes Control and Complications Trial, a long-term therapeutic study involving 1441 patients with type 1 diabetes mellitus, reported that “near” normalization of blood glucose resulted in a delay in the onset and a major slowing of the progression of established microvascular and neuropathic complications of diabetes during a follow-up period of up to 10 years. Multiple insulin injections (66%) or insulin pumps (34%) were used in the intensively treated group, who were trained to modify their therapy in response to frequent glucose monitoring. The conventionally treated groups used no more than two insulin injections, and clinical well-being was the goal with no attempt to modify management based on HbA1c determinations or the glucose results.
In half of the patients, a mean hemoglobin A1c of 7.2% (normal: less than 6%) and a mean blood glucose of 155 mg/dL (8.6 mmol/L) were achieved using intensive therapy, while in the conventionally treated group HbA1c averaged 8.9% with an average blood glucose of 225 mg/dL (12.5 mmol/L). Over the study period, which averaged 7 years, there was an approximately 60% reduction in risk between the two groups in regard to diabetic retinopathy, nephropathy, and neuropathy. The intensively treated group also had a nonsignificant reduction in the risk of macrovascular disease of 41% (95% CI, –10 to 68). Intensively treated patients had a threefold greater risk of serious hypoglycemia as well as a greater tendency toward weight gain. However, there were no deaths definitely attributable to hypoglycemia in any persons in the DCCT study, and no evidence of posthypoglycemic cognitive damage was detected.
Subjects participating in the DCCT study were subsequently enrolled in a follow-up observational study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Even though the between-group differences in mean HbA1c narrowed over 4 years, the group assigned to intensive therapy had a lower risk of retinopathy at 4 years, microalbuminuria at 7 to 8 years, and impaired GFR (less than 60 mL/min/1.73 m2) at 22 years of continued study follow-up. Moreover, by the end of the 11-year follow-up period, the intensive therapy group had significantly reduced their risk of any cardiovascular disease events by 42% (95% CI, 9% to 23%; P = 0.02). Thus, it seems that the benefits of good glucose control persist even if control deteriorates at a later date.
The general consensus of the ADA is that intensive insulin therapy associated with comprehensive self-management training should become standard therapy in patients with type 1 diabetes mellitus after the age of puberty. Exceptions include those with advanced chronic kidney disease and the elderly, since in these groups the detrimental risks of hypoglycemia outweigh the benefits of tight glycemic control.
Diabetes Prevention Trial-1, a multicenter study, was designed to determine whether the development of type 1 diabetes mellitus could be prevented or delayed by immune intervention therapy. Daily low-dose insulin injections were administered for up to 8 years in first-degree relatives of type 1 diabetic patients who were selected as being at high risk for development of type 1 diabetes because of detectable islet cell antibodies and reduced early-insulin release. Unfortunately, this immune intervention failed to prevent the onset of type 1 diabetes compared with a randomized untreated group. A related study using oral insulin in lower risk first-degree relatives who have islet cell antibodies but whose early insulin release remains intact also failed to show an effect on the onset of type 1 diabetes. After an average of 4.3 years of observation, type 1 diabetes developed in about 35% of persons in both the oral insulin and the placebo groups.
At the time of diagnosis of type 1 diabetes, patients still have significant B cell function. This explains why soon after diagnosis patients go into a partial clinical remission ("honeymoon") requiring little or no insulin. This clinical remission is short-lived, however, and eventually patients lose all B cell function and have more labile glucose control. Attempts have been made to prolong this partial clinical remission using immunomodulatory agents. The CD3 complex is the major signal transducing element of the T cell receptor and the anti-CD3 antibodies are believed to modulate the autoimmune response by selectively inhibiting the pathogenic T cells or by inducing regulatory T cells. Phase I/II and II/III clinical trials using the humanized monoclonal antibodies against CD3, hOKT3gamma (Ala-Ala) (teplizumab) and ChAglyCD3 (otelixizumab) delayed but did not completely arrest the decline in insulin production in patients with newly diagnosed type 1 diabetes. A study using anti-CD3 antibody prior to clinical onset of diabetes is also under consideration. These and other approaches that selectively modulate the autoimmune T cell response hold promise that type 1 diabetes may eventually be preventable without prolonged immunosuppression.
The Diabetes Prevention Program was aimed at discovering whether treatment with either diet and exercise or metformin could prevent the onset of type 2 diabetes in people with impaired glucose tolerance; 3234 overweight men and women aged 25–85 years with impaired glucose tolerance participated in the study. Intervention with a low-fat diet and 150 minutes of moderate exercise (equivalent to a brisk walk) per week reduced the risk of progression to type 2 diabetes by 71% compared with a matched control group. Participants taking 850 mg of metformin twice a day reduced their risk of developing type 2 diabetes by 31%, but this intervention was relatively ineffective in those who were either less obese or in the older age group.
With the demonstration that intervention can be successful in preventing progression to diabetes in these subjects, a recommendation has been made to change the terminology from the less comprehensible “impaired glucose tolerance” to “prediabetes.” The latter is a term that the public can better understand and thus respond to by implementing healthier diet and exercise habits.
The Kumamoto study involved a relatively small number of patients with type 2 diabetes (n = 110) who were nonobese and only slightly insulin-resistant, requiring less than 30 units of insulin per day for intensive therapy. Over a 6-year period, it was shown that intensive insulin therapy, achieving a mean HbA1c of 7.1%, significantly reduced microvascular end points compared with conventional insulin therapy achieving a mean HbA1c of 9.4%. Cardiovascular events were neither worsened nor improved by intensive therapy, and weight changes were likewise not influenced by either form of treatment.
The Veterans Administration Cooperative Study involved 153 obese men who were moderately insulin-resistant and who were monitored for only 27 months. Intensive insulin treatment resulted in mean HbA1c differences from conventional insulin treatment (7.2% versus 9.5%) that were comparable to those reported from the Kumamoto Study. However, a difference in cardiovascular outcome in this study has prompted some concern. While conventional insulin therapy resulted in 26 total cardiovascular events, there were 35 total cardiovascular events in the intensively treated group. This difference in the relatively small population was not statistically significant, but when the total events were broken down to major events (myocardial infarction, stroke, cardiovascular death, heart failure, or amputation), the 18 major events in the group treated intensively with insulin were reported to be statistically greater (P = 0.04) than the ten major events occurring with conventional treatment. While this difference may be a chance consequence of studying too few patients for too short a time, it raises the possibility that insulin-resistant patients with visceral obesity and long-standing type 2 diabetes may develop a greater risk of serious cardiovascular mishap when intensively treated with high doses of insulin. At the end of the study, 64% of the intensively treated group were either receiving (1) an average of 113 units of insulin per day when only two injections per day were used or (2) a mean dosage of 133 units per day when multiple injections were used. Unfortunately, the UKPDS, which did not discern any effect of intensive therapy on cardiovascular outcomes, does not resolve the concern generated by the Veterans Administration Study since their patient population consisted of newly diagnosed diabetic patients in whom the obese subgroup seemed to be less insulin-resistant, requiring a median insulin dose for intensive therapy of only 60 units per day by the twelfth year of the study.
The United Kingdom Prospective Diabetes Study, a multicenter study, was designed to establish, in type 2 diabetic patients, whether the risk of macrovascular or microvascular complications could be reduced by intensive blood glucose control with oral hypoglycemic agents or insulin and whether any particular therapy was of advantage. A total of 3867 patients aged 25–65 years with newly diagnosed diabetes were recruited between 1977 and 1991, and studied over 10 years. The median age at baseline was 54 years; 44% were overweight (more than 120% over ideal weight); and baseline HbA1c was 9.1%. Therapies were randomized to include a control group on diet alone and separate groups intensively treated with either insulin or sulfonylurea (chlorpropamide, glyburide, or glipizide). Metformin was included as a randomization option in a subgroup of 342 overweight or obese patients, and much later in the study an additional subgroup of both normal-weight and overweight patients who were responding unsatisfactorily to sulfonylurea therapy were randomized to either continue on their sulfonylurea therapy alone or to have metformin combined with it. Subsequently, an additional modification was made to evaluate whether tight control of blood pressure with stepwise antihypertensive therapy would prevent macrovascular and microvascular complications in 758 hypertensive patients among this UKPDS population compared with 390 of them whose blood pressure was treated less intensively. The tight control group was randomly assigned to treatment with either an angiotensin-converting enzyme (ACE) inhibitor (captopril) or a beta-blocker (atenolol). Both medications were stepped up to maximum dosages of 100 mg/day and then, if blood pressure remained higher than the target level of less than 150/85 mm Hg, more medications were added in the following stepwise sequence: a diuretic, slow-release nifedipine, methyldopa, and prazosin—until the target level of tight control was achieved. In the control group, hypertension was conventionally treated to achieve target levels less than 180/105 mm Hg, but these patients were not prescribed either ACE inhibitors or beta-blockers.
Intensive treatment with either sulfonylureas, metformin, combinations of those two, or insulin achieved mean HbA1c levels of 7%. This level of glycemic control decreased the risk of microvascular complications (retinopathy and nephropathy) in comparison with conventional therapy (mostly diet alone), which achieved mean levels of HbA1c of 7.9%. Weight gain occurred in intensively treated patients except when metformin was used as monotherapy. No adverse cardiovascular outcomes were noted regardless of the therapeutic agent. In the overweight or obese subgroup, metformin therapy was more beneficial than diet alone in reducing the number of cases that progressed to diabetes as well as decreasing the number of patients who suffered myocardial infarctions and strokes. Hypoglycemic reactions occurred in the intensive treatment groups, but only one death from hypoglycemia was documented during 27,000 patient-years of intensive therapy.
Tight control of blood pressure (median value 144/82 mm Hg vs 154/87 mm Hg) substantially reduced the risk of microvascular disease and stroke but not myocardial infarction. In fact, reducing blood pressure by this amount had substantially greater impact on microvascular outcomes than that achieved by lowering HbA1c from 7.9% to 7%. An epidemiologic analysis of the UKPDS data did show that every 10 mm Hg decrease in updated mean systolic blood pressure was associated with 11% reduction in risk for myocardial infarction. More than half of the patients needed two or more medications for adequate therapy of their hypertension, and there was no demonstrable advantage of angiotensin-converting enzyme (ACE) inhibitor therapy over therapy with beta-blockers with regard to diabetes end points. Use of a calcium channel blocker added to both treatment groups appeared to be safe over the long term in this diabetic population despite some controversy in the literature about its safety in patients with diabetes.
Like the DCCT trialists, the UKPDS researchers performed post-trial monitoring to determine whether there were long-term benefits of having been in the intensively treated glucose and blood pressure arms of the study. The between-group differences in HbA1c were lost within the first year of follow-up, but the reduced risk (24%, P = 0.001) of development or progression of microvascular complications in the intensively treated group persisted for 10 years. The intensively treated group had significantly reduced risk of myocardial infarction (15%, P = 0.01) and death from any cause (13%, P = 0.007) during the follow-up period. The subgroup of overweight or obese subjects who were initially randomized to metformin therapy showed sustained reduction in risk of myocardial infarction and death from any cause in the follow-up period. The between-group blood pressure differences disappeared within 2 years of the end of the trial. Unlike the sustained benefits seen with glucose control, there were no sustained benefits from having been in the more tightly controlled blood pressure group. Both blood pressure groups were at similar risk for microvascular events and diabetes-related end points during the follow-up period.
Thus, the follow-up of the UKPDS type 2 diabetes cohort showed that, as in type 1 diabetes, the benefits of good glucose control persist even if control deteriorates at a later date. Blood pressure benefits, however, last only as long as the blood pressure is well controlled.
Findings from the UKPDS support that glycemic control to levels of HbA1c to 7% show benefit in reducing total diabetes end points, including a 25% reduction in microvascular disease as compared with HbA1c levels of 7.9%. This reassures those who have questioned whether the value of intensive therapy, so convincingly shown by the DCCT in type 1 diabetes, can safely be extrapolated to older patients with type 2 diabetes. It also argues against the concept of a "threshold" of glycemic control since in this group there was a benefit from this modest reduction of HbA1c below 7.9% whereas in the DCCT a threshold was suggested in that further benefit was less apparent at HbA1c levels below 8%.
Because of the complexity of the overall design in which many of the original therapy groups received additional medications to achieve glycemic goals but remained assigned to their group, statistical analysis may have been compromised by these multiple crossovers. For instance, in the diet group that was used as a control for all the drug treatment groups, only 58% of their total "patient-years" were actually drug-free while the remainder consisted of nonintensive therapy with various hypoglycemic drug regimens to avoid unacceptable hyperglycemia. This probably partly explains why the mean HbA1c for this group was as low as 7.9% on "diet alone" therapy for over 10 years. In view of these crossovers within treatment groups, caution is suggested regarding several subgroup analyses that are controversial. These include the implication that metformin was superior to insulin or sulfonylureas in reducing diabetes-related end points in obese patients compared with diet therapy even though all three treatment groups achieved the same degree of glycemic control. Conversely, the finding of excess mortality in the subgroup of patients receiving combination therapy with metformin and sulfonylureas need not necessarily preclude this combination in patients doing poorly on sulfonylureas alone, although it certainly indicates a need for clarification of this important question.
Probably the most striking implication of the UKPDS is the benefit to the hypertensive type 2 diabetic patient of intensive control of blood pressure. There was no demonstrable advantage of ACE inhibitor therapy on outcome despite a number of short-term reports in smaller populations, which have implied that these drugs have special efficacy in reducing glomerular pressure beyond their general antihypertensive effects. Moreover, slow-release nifedipine showed no evidence of cardiac toxicity in this study despite some previous reports claiming that calcium channel blockers may be hazardous in patients with diabetes. Finally, the greater benefit in diabetes end points from antihypertensive than from antihyperglycemic treatments may be that the difference between the mean blood pressures achieved (144/82 mm Hg versus 154/87 mm Hg) is therapeutically more influential than the slight difference in HbA1c (7% versus 7.9%). Greater hyperglycemia in the control group would most likely have rectified this discrepancy in outcomes.
The Steno-2 study was designed in 1990 to validate the efficacy of targeting multiple concomitant risk factors (diet, smoking cessation, exercise, and pharmacologic interventions) for both microvascular and macrovascular disorders in type 2 diabetes. A prospective, randomized, open, blinded end point design was used where 160 patients with type 2 diabetes and microalbuminuria were assigned to conventional therapy with their general practitioner or to intensive care at the Steno Diabetes Center. The intensively treated group had stepwise introduction of lifestyle and pharmacologic interventions aimed at keeping glycated hemoglobin less than 6.5%, blood pressure lower than 130/80 mm Hg; total cholesterol under 175 mg/dL (4.5 mmol/L), and triglycerides less than 150 mg/dL (1.7 mmol/L). All the intensively treated group received ACE inhibitors and if intolerant, an angiotensin II-receptor blocker. The lifestyle component of intensive intervention included reduction in dietary fat intake to less than 30% of total calories; smoking cessation program; light to moderate exercise; daily vitamin-mineral supplement of vitamin C, E, and chromium picolinate. Initially, aspirin was only given as secondary prevention to patients with a history of ischemic cardiovascular disease; later, all patients received aspirin. After a mean follow-up of 7.8 years, cardiovascular events (eg, myocardial infarction, angioplasties, coronary bypass grafts, strokes, amputations, vascular surgical interventions) developed in 44% of patients in the conventional arm and only in 24% in the intensive multifactorial arm—about a 50% reduction. Rates of nephropathy, retinopathy, and autonomic neuropathy were also lower in the multifactorial intervention arm by 62% and 63%, respectively.
The persons who participated in this trial were subsequently enrolled in an observational follow-up study for an average of 5.5 years. Even though the significant differences in glycemic control and levels of risk factors of cardiovascular disease between the groups had disappeared by the end of the follow-up period, the interventional group continued to have a lower risk of retinal photocoagulation, renal failure, cardiovascular end points, and cardiovascular mortality.
The data from the UKPDS and this study provide support for guidelines recommending vigorous treatment of concomitant microvascular and cardiovascular risk factors in patients with type 2 diabetes.
The ACCORD study was a randomized controlled study designed to determine whether normal HbA1c levels would reduce the risk of cardiovascular events in middle-aged or older individuals with type 2 diabetes. About 35% of the 10,251 recruited subjects had established cardiovascular disease at study entry. The intensive arm of the study was discontinued after 3.5 years of follow-up because of more unexplained deaths in the intensive arm when compared with the control arm (22%, P = 0.020). Analysis of the data at time of discontinuation showed that the intensively treated group (mean HbA1c 6.4%) had a 10% reduction in cardiovascular event rate compared with the standard treated group (mean HbA1c 7.5%), but this difference was not statistically significant.
The ADVANCE trial randomly assigned 11,140 patients with type 2 diabetes to standard or intensive glucose control. The primary outcomes were major macrovascular cardiovascular events (nonfatal myocardial infarction or stroke or death from cardiovascular causes) or microvascular events. Overall, one-third (32%) of the subjects had established cardiovascular disease at study entry. After a median follow-up of 5 years, there was a nonsignificant reduction (6%) in major macrovascular event rate in the intensively treated group (mean HbA1c 6.5%) compared with the standard therapy group (HbA1c 7.3%).
The Veteran Administration Diabetes Trial (VADT) randomly assigned 1791 patients (97% men) from age 50 to 69 years with type 2 diabetes to standard or intensive glucose control. The primary outcome was a composite of myocardial infarction, death from cardiovascular causes, heart failure, vascular surgery, inoperable coronary artery disease, and amputation for gangrene. All the patients had optimized blood pressure and lipid levels. After a median follow-up of 5.6 years, there was no significant difference in the primary cardiovascular outcome in the intensively treated group (HbA1c 6.9%) compared with the standard therapy (HbA1c 8.4%). Within this larger study, there was an embedded study evaluating the impact of the intensive therapy on patients who were subcategorized as having low, moderate, and high coronary calcium scores on CT scans. Patients with low coronary calcium score showed a reduced number of cardiovascular events with intensive therapy.
Results from three subsequent trials, the ACCORD, ADVANCE, and VADT, do not provide support for the hypothesis that near-normal glucose control in patients with type 2 diabetes will reduce cardiovascular events. It is, however, important not to over-interpret the results of these three studies. The results do not exclude the possibility that cardiovascular benefits might accrue with longer duration of near-normal glucose control. In the UKPDS, risk reductions for myocardial infarction and death from any cause were only observed during 10 years of post-trial follow-up. Specific subgroups of type 2 diabetic patients may also have different outcomes. The ACCORD, ADVANCE, and VADT studies recruited patients who had diabetes for 8–10 years and one-third of them already had established cardiovascular disease. Patients in the UKPDS, in contrast, had newly diagnosed diabetes and only 7.5% had a history of macrovascular disease. It is possible that the benefits of tight glycemic control on macrovascular events are attenuated in patients with longer duration of diabetes or with established vascular disease. Specific therapies used to lower glucose may also affect cardiovascular event rate or mortality. Severe hypoglycemia occurred more frequently in the intensively treated groups of the ACCORD, ADVANCE, and VADT studies; the ACCORD investigators were not able to exclude undiagnosed hypoglycemia as a potential cause for the increased death rate in the intensive treatment group.
A formal meta-analysis performed of the raw trial data from the ACCORD, ADVANCE, VADT, and UKPDS studies found that allocation to more intensive glucose control reduced the risk of myocardial infarction by 15% (hazard ratio 0.85, 95% CI 0.76–0.94). This benefit occurred in patients who did not have preexisting macrovascular disease.
ACCORD Study Group; Gerstein
et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545–59.
ADVANCE Collaborative Group; Patel
et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560–72.
Diabetes Prevention Trial—Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002 May 30;346(22):1685–91.
et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129–39.
et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008 Feb 7;358(6):580–91.
et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577–89.
et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25):2643–53.
et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA. 2015 Jan 6;313(1):45–53.
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977–86.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998 Sep 12;352(9131):837–53.
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998 Sep 12;317(7160):703–13.
A well-balanced, nutritious diet remains a fundamental element of therapy. There is no specific recommendation on the percentage of calories that should come from carbohydrate, protein, and fat. The macronutrient proportions should be individualized based on the patient’s eating patterns, preferences, and metabolic goals. In general, most patients with diabetes consume about 45% of their total daily calories in the form of carbohydrates, 25–35% in the form of fat, and 10–35% in the form of protein. In patients with type 2 diabetes, limiting the carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. A Mediterranean-style eating pattern (a diet supplemented with walnuts, almonds, hazelnuts, and olive oil) has been shown to improve glycemic control and lower combined endpoints for cardiovascular events and stroke. In those patients with obesity and type 2 diabetes, weight reduction by caloric restriction is an important goal of the diet (see Chapter 29). Patients with type 1 diabetes or type 2 diabetes who take insulin should be taught “carbohydrate counting,” so they can administer their insulin bolus for each meal based on its carbohydrate content.
The current recommendations for saturated fats and dietary cholesterol intake for people with diabetes are the same as for the general population. Saturated fats should be limited to less than 10% of daily calories and dietary cholesterol intake should be less than 300 mg/day. For those patients with kidney disease, dietary protein should be maintained at the recommended daily allowance of 0.8g/kg/day. Exchange lists for meal planning can be obtained from the American Diabetes Association and its affiliate associations or from the American Dietetic Association (http://www.eatright.org), 216 W. Jackson Blvd., Chicago, IL 60606 (312-899-0040).
Plant components such as cellulose, gum, and pectin are indigestible by humans and are termed dietary “fiber.” Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit and may have beneficial effects on colonic function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal, or apple skin, tend to retard nutrient absorption rates so that glucose absorption is slower and hyperglycemia may be slightly diminished. Although its recommendations do not include insoluble fiber supplements such as added bran, the ADA recommends food such as oatmeal, cereals, and beans with relatively high soluble fiber content as staple components of the diet in diabetics. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.
The glycemic index of a carbohydrate containing food is determined by comparing the glucose excursions after consuming 50 g of test food with glucose excursions after consuming 50 g of reference food (white bread):
Eating low glycemic index foods results in lower glucose levels after meals. Low glycemic index foods have values of 55 or less and include many fruits, vegetables, grainy breads, pasta, and legumes. High glycemic index foods have values of 70 or greater and include baked potato, white bread, and white rice. Glycemic index is lowered by presence of fats and protein when food is consumed in a mixed meal. Even though it may not be possible to accurately predict the glycemic index of a particular food in the context of a meal, it is reasonable to choose foods with low glycemic index.
3. Artificial and other sweeteners
Saccharin (Sweet ‘N Low), sucralose (Splenda), acesulfame potassium (Sweet One), and rebiana (Truvia) are “artificial” sweeteners that can be used in cooking and baking. Aspartame (NutraSweet) lacks heat stability, so it cannot be used in cooking. None of these sweeteners raise blood glucose levels.
Fructose represents a “natural” sugar substance that is a highly effective sweetener, induces only slight increases in plasma glucose levels, and does not require insulin for its metabolism. However, because of potential adverse effects of large amounts of fructose on raising serum cholesterol, triglycerides, and LDL cholesterol, it does not have any advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.
Sugar alcohols, also known as polyols or polyalcohol, are commonly used as sweeteners and bulking agents. They occur naturally in a variety of fruits and vegetables but are also commercially made from sucrose, glucose, and starch. Examples are sorbitol, xylitol, mannitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates (HSH). They are not as easily absorbed as sugar, so they do not raise blood glucose levels as much. Therefore, sugar alcohols are often used in food products that are labeled as “sugar free,” such as chewing gum, lozenges, hard candy, and sugar-free ice cream. However, if consumed in large quantities, they will raise blood glucose and can cause bloating and diarrhea.
B. Medications for Treating Hyperglycemia
The medications for treating type 2 diabetes are listed in Table 27–5. They fall into several categories: (1) Medications that primarily stimulate insulin secretion by binding to the sulfonylurea receptor: Sulfonylureas remain the most widely prescribed medications for treating hyperglycemia. The meglitinide analog repaglinide and the D-phenylalanine derivative nateglinide also bind the sulfonylurea receptor and stimulate insulin secretion. (2) Medications that primarily lower glucose levels by their actions on the liver, muscle, and adipose tissue: Metformin works in the liver. The thiazolidinediones appear to have their main effect on skeletal muscle and adipose tissue. (3) Medications that principally slow intestinal absorption of glucose: The alpha-glucosidase inhibitors acarbose and miglitol are such currently available therapies. (4) Medications that mimic incretin effect or prolong incretin action: Glucagon-like peptide 1 (GLP1) receptor agonists and DPP 4 inhibitors fall into this category. (5) Medications that inhibit reabsorption of filtered glucose in the kidney: The sodium-glucose co-transporter inhibitors dapagliflozin and canagliflozin are two such agents. (6) Others: Pramlintide lowers glucose by suppressing glucagon and slowing gastric emptying. The mechanisms by which bromocriptine and colesevelam lower glucose levels have not been defined. The medications are discussed in detail below. A framework for planning treatment using medications from these six categories is offered later in this chapter.
Table 27–5.Drugs for treatment of type 2 diabetes mellitus. |Favorite Table|Download (.pdf) Table 27–5. Drugs for treatment of type 2 diabetes mellitus.
|Drug ||Tablet Size ||Daily Dose ||Duration of Action |
|Acetohexamide (Dymelor) ||250 and 500 mg ||0.25–1.5 g as single dose or in two divided doses ||8–24 hours |
|Chlorpropamide (Diabinese) ||100 and 250 mg ||0.1–0.5 g as single dose ||24–72 hours |
|Gliclazide (not available in United States) ||80 mg ||40–80 mg as single dose; 160–320 mg as divided dose ||12 hours |
|Glimepiride (Amaryl) ||1, 2, and 4 mg ||1–4 mg once a day is usual dose; 8 mg once a day is maximal dose ||Up to 24 hours |
|Glipizide || || || |
| (Glucotrol) ||5 and 10 mg ||2.5–40 mg as a single dose or in two divided doses 30 minutes before meals ||6–12 hours |
| (Glucotrol XL) ||2.5, 5, and 10 mg ||2.5 to 10 mg once a day is usual dose; 20 mg once a day is maximal dose ||Up to 24 hours |
|Glyburide || || || |
| (Dia Beta, Micronase) ||1.25, 2.5, and 5 mg ||1.25–20 mg as single dose or in two divided doses ||Up to 24 hours |
| (Glynase) ||1.5, 3, and 6 mg ||1.5–12 mg as single dose or in two divided doses ||Up to 24 hours |
|Tolazamide (Tolinase) ||100, 250, and 500 mg ||0.1–1 g as single dose or in two divided doses ||Up to 24 hours |
|Tolbutamide (Orinase) ||250 and 500 mg ||0.5–2 g in two or three divided doses ||6–12 hours |
|Meglitinide analogs |
|Mitiglinide (available in Japan) ||5 and 10 mg ||5 or 10 mg three times a day before meals ||2 hours |
|Repaglinide (Prandin) ||0.5, 1, and 2 mg ||0.5 to 4 mg three times a day before meals ||3 hours |
|D-Phenylalanine derivative |
|Nateglinide (Starlix) ||60 and 120 mg ||60 or 120 mg three times a day before meals ||1.5 hours |
|Metformin (Glucophage) ||500, 850, and 1000 mg ||1–2.5 g; 1 tablet with meals two or three times daily ||7–12 hours |
|Extended-release metformin (Glucophage XR) ||500 and 750 mg ||500–2000 mg once a day ||Up to 24 hours |
|Pioglitazone (Actos) ||15, 30, and 45 mg ||15–45 mg daily ||Up to 24 hours |
|Rosiglitazone (Avandia) ||2, 4, and 8 mg ||4–8 mg daily (can be divided) ||Up to 24 hours |
|Alpha-glucosidase inhibitors |
|Acarbose (Precose) ||50 and 100 mg ||25–100 mg three times a day just before meals ||4 hours |
|Miglitol (Glyset) ||25, 50, and 100 mg ||25–100 mg three times a day just before meals ||4 hours |
|Voglibose (not available in United States) ||0.2 and 0.3 mg ||0.2–0.3 mg three times a day just before meals ||4 hours |
|GLP-1 receptor agonists |
|Exenatide (Byetta) ||1.2 mL and 2.4 mL prefilled pens containing 5 mcg and 10 mcg (subcutaneous injection) ||5 mcg subcutaneously twice a day within 1 hour of breakfast and dinner. Increase to 10 mcg subcutaneously twice a day after about a month. Do not use if calculated creatinine clearance is < 30 mL/min. ||6 hours |
|Exenatide, long-acting release (Byetta LAR, Bydureon) ||2 mg (powder) ||Suspend in provided diluent and inject subcutaneously. ||1 week |
|Liraglutide (Victoza) ||Pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg ||0.6 mg subcutaneously once a day (starting dose). Increase to 1.2 mg after a week if no adverse reactions. Dose can be further increased to 1.8 mg, if necessary. ||24 hours |
|Albiglutide (Tanzeum) ||30, 50 mg single dose pen (powder) ||Mix with diluent and inject subcutaneously. 30 mg is usual dose. Dose can be increased to 50 mg if necessary. ||1 week |
|Dulaglutide (Trulicity) ||0.75, 1.5 mg single dose pen or prefilled syringe ||0.75 mg subcutaneously. Dose can be increased to 1.5 mg if necessary. ||1 week |
|DPP-4 inhibitors |
|Alogliptin (Nesina) ||6.25, 12.5, and 25 mg ||25 mg once daily; dose is 12.5 mg daily if calculated creatinine clearance is 30–59 mL/min and 6.25 mg daily if clearance < 30 mL/min. ||24 hours |
|Saxagliptin (Onglyza) ||2.5 and 5 mg ||2.5 mg or 5 mg once daily. Use 2.5 mg dose if calculated creatinine clearance is ≤ 50 mL/min or if also taking drugs that are strong CYP3A4/5 inhibitors such as ketoconazole. ||24 hours |
|Sitagliptin (Januvia) ||25, 50, and 100 mg ||100 mg once daily is usual dose; dose is 50 mg once daily if calculated creatinine clearance is 30 to 50 mL/min and 25 mg once daily if clearance is < 30 mL/min. ||24 hours |
|Vildagliptin (Galvus) (not available in United States) ||50 mg ||50 mg once or twice daily. Contraindicated in patients with calculated creatinine clearance ≤ 60 mL/min or AST/ALT three times upper limit of normal. ||24 hours |
|Linagliptin (Tradjenta) ||5 mg ||5 mg daily ||24 hours |
|SGLT2 inhibitors |
|Canagliflozin (Invokana) ||100 and 300 mg || |
100 mg daily is usual dose. Do not use if eGFR < 45 mL/min/1.72 m2.
300 mg dose can be used if normal eGFR, resulting in lowering the HbA1c an additional ~ 0.1–0.25%.
|24 hours |
|Dapagliflozin (Farxiga) ||5 and 10 mg ||10 mg daily. Use 5 mg dose in hepatic failure. ||24 hours |
|Empagliflozin (Jardiance) ||10 and 25 mg ||10 mg daily. 25 mg dose can be used if necessary. ||24 hours |
|Bromocriptine (Cycloset) ||0.8 mg ||0.8 mg daily. Increase weekly by 1 tablet until maximal tolerated dose of 1.6–4.8 mg daily. ||24 hours |
|Colesevelam (Welchol) ||625 mg ||3 tablets twice a day ||24 hours |
|Pramlintide (Symlin) ||5 mL vial containing 0.6 mg/mL; also available as prefilled pens. Symlin pen 60 or Symlin pen 120 (subcutaneous injection) ||For insulin-treated type 2 patients, start at 60 mcg dose three times a day (10 units on U100 insulin syringe). Increase to 120 mcg three times a day (20 units on U100 insulin syringe) if no nausea for 3–7 days. Give immediately before meal. ||2 hours |
| || ||For type 1 patients, start at 15 mcg three times a day (2.5 units on U100 insulin syringe) and increase by increments of 15 mcg to a maximum of 60 mcg three times a day, as tolerated. || |
| || ||To avoid hypoglycemia, lower insulin dose by 50% on initiation of therapy. || |
1. Medications that primarily stimulate insulin secretion by binding to the sulfonylurea receptor on the beta cell
The primary mechanism of action of the sulfonylureas is to stimulate insulin release from pancreatic B cells. Specific receptors on the surface of pancreatic B cells bind sulfonylureas in the rank order of their insulinotropic potency (glyburide with the greatest affinity and tolbutamide with the least affinity). It has been shown that activation of these receptors closes potassium channels, resulting in depolarization of the B cell. This depolarized state permits calcium to enter the cell and actively promote insulin release.
Sulfonylureas are used in patients with type 2 but not type 1 diabetes, since these medications require functioning pancreatic B cells to produce their effect on blood glucose. Sulfonylureas are metabolized by the liver and apart from acetohexamide, whose metabolite is more active than the parent compound, the metabolites of all the other sulfonylureas are weakly active or inactive. The metabolites are excreted by the kidney and, in the case of the second-generation sulfonylureas, partly excreted in the bile. Sulfonylureas are generally contraindicated in patients with severe liver or kidney impairment. Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in less than 0.1% of users.
(1) First-generation sulfonylureas (tolbutamide, tolazamide, acetohexamide, chlorpropamide)
Tolbutamide is rapidly oxidized in the liver to inactive metabolites, and its approximate duration of effect is relatively short (6–10 hours). Tolbutamide is probably best administered in divided doses (eg, 500 mg before each meal and at bedtime); however, some patients require only one or two tablets daily with a maximum dose of 3000 mg/day. Because of its short duration of action, which is independent of kidney function, tolbutamide is relatively safe to use in kidney impairment. Prolonged hypoglycemia has been reported rarely with tolbutamide, mostly in patients receiving certain antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal medications to treat candidiasis. These medications apparently compete with tolbutamide for oxidative enzyme systems in the liver, resulting in maintenance of high levels of unmetabolized, active sulfonylurea in the circulation.
Tolazamide, acetohexamide, and chlorpropamide are rarely used. Chlorpropamide has a prolonged biologic effect, and severe hypoglycemia can occur especially in the elderly as their renal clearance declines with aging. Its other side effects include alcohol-induced flushing and hyponatremia due to its effect on vasopressin secretion and action.
(2) Second-generation sulfonylureas (glyburide, glipizide, gliclazide, glimepiride)
Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times more potent than tolbutamide. These medications should be used with caution in patients with cardiovascular disease or in elderly patients, in whom prolonged hypoglycemia would be especially dangerous.
The usual starting dose of glyburide is 2.5 mg/day, and the average maintenance dose is 5–10 mg/day given as a single morning dose; maintenance doses higher than 20 mg/day are not recommended. Some reports suggest that 10 mg is a maximum daily therapeutic dose, with 15–20 mg having no additional benefit in poor responders and doses over 20 mg actually worsening hyperglycemia. A “Press Tab” formulation of “micronized” glyburide—easy to divide in half with slight pressure if necessary—is available. Glyburide is metabolized in the liver into products with hypoglycemic activity, which probably explains why assays specific for the unmetabolized compound suggest a plasma half-life of only 1–2 hours, yet the biologic effects of glyburide are clearly persistent 24 hours after a single morning dose in diabetic patients. Glyburide is unique among sulfonylureas in that it not only binds to the pancreatic B cell membrane sulfonylurea receptor but also becomes sequestered within the B cell. This may also contribute to its prolonged biologic effect despite its relatively short circulating half-life.
Glyburide has few adverse effects other than its potential for causing hypoglycemia, which at times can be prolonged. Flushing has rarely been reported after ethanol ingestion. It does not cause water retention, as chlorpropamide does, but rather slightly enhances free water clearance. Glyburide should not be used in patients with liver failure and chronic kidney disease because of the risk of hypoglycemia. Elderly patients are at particular risk for hypoglycemia even with relatively small daily doses.
The recommended starting dose of glipizide is 5 mg/day, with up to 15 mg/day given as a single daily dose before breakfast. When higher daily doses are required, they should be divided and given before meals. The maximum dose recommended by the manufacturer is 40 mg/d, although doses above 10–15 mg probably provide little additional benefit in poor responders and may even be less effective than smaller doses. For maximum effect in reducing postprandial hyperglycemia, glipizide should be ingested 30 minutes before meals, since rapid absorption is delayed when the medication is taken with food.
At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy should therefore not be used in patients with liver failure. Because of its lower potency and shorter duration of action, it is preferable to glyburide in elderly patients and for those patients with kidney disease. Glucotrol-XL provides extended release of glipizide during transit through the gastrointestinal tract with greater effectiveness in lowering prebreakfast hyperglycemia than the shorter-duration immediate-release standard glipizide tablets. However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over glyburide.
Gliclazide (not available in the United States) is another intermediate duration sulfonylurea with a duration of action of about 12 hours. The recommended starting dose is 40–80 mg/day with a maximum dose of 320 mg. Doses of 160 mg and above are given as divided doses before breakfast and dinner. The medication is metabolized by the liver; the metabolites and conjugates have no hypoglycemic effect. An extended release preparation is available.
Glimepiride has a long duration of effect with a half-life of 5 hours allowing once or twice daily dosing. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound. A single daily dose of 1 mg/day has been shown to be effective, and the maximal recommended dose is 8 mg. It is completely metabolized by the liver to relatively inactive metabolic products.
Repaglinide is structurally similar to glyburide but lacks the sulfonic acid-urea moiety. It acts by binding to the sulfonylurea receptor and closing the adenosine triphosphate (ATP)-sensitive potassium channel. It is rapidly absorbed from the intestine and then undergoes complete metabolism in the liver to inactive biliary products, giving it a plasma half-life of less than 1 hour. The medication therefore causes a brief but rapid pulse of insulin. The starting dose is 0.5 mg three times a day 15 minutes before each meal. The dose can be titrated to a maximum daily dose of 16 mg. Like the sulfonylureas, repaglinide can be used in combination with metformin. Hypoglycemia is the main side effect. In clinical trials, when the medication was compared with a long-duration sulfonylurea (glyburide), there was a trend toward less hypoglycemia. Like the sulfonylureas, repaglinide causes weight gain. Metabolism is by cytochrome P450 3A4 isoenzyme, and other medications that induce or inhibit this isoenzyme may increase or inhibit (respectively) the metabolism of repaglinide. The medication may be useful in patients with kidney impairment or in the elderly.
Mitiglinide is a benzylsuccinic acid derivative that binds to the sulfonylurea receptor and is similar to repaglinide in its clinical effects. It is approved for use in Japan.
c. d-Phenylalanine derivative
Nateglinide stimulates insulin secretion by binding to the sulfonylurea receptor and closing the ATP-sensitive potassium channel. This compound is rapidly absorbed from the intestine, reaching peak plasma levels within 1 hour. It is metabolized in the liver and has a plasma half-life of about 1.5 hours. Like repaglinide, it causes a brief rapid pulse of insulin, and when given before a meal it reduces the postprandial rise in blood glucose. For most patients, the recommended starting and maintenance dose is 120 mg three times a day before meals. Use 60 mg in patients who have mild elevations in HbA1c. Like the other insulin secretagogues, its main side effects are hypoglycemia and weight gain.
2. Medications that primarily lower glucose levels by their actions on the liver, muscle, and adipose tissue
Metformin (1,1-dimethylbiguanide hydrochloride) is used, either alone or in conjunction with other oral agents or insulin, in the treatment of patients with type 2 diabetes.
Metformin’s therapeutic effects primarily derive from the increasing hepatic adenosine monophosphate-activated protein kinase activity, which reduces hepatic gluconeogenesis and lipogenesis. Metformin is a substrate for organic cation transporter 1, which is abundantly expressed in hepatocytes and in the gut.
Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins or metabolized, being excreted unchanged by the kidneys.
Metformin is the first-line therapy for patients with type 2 diabetes. The current recommendation is to start this medication at diagnosis. A side benefit of metformin therapy is its tendency to improve both fasting and postprandial hyperglycemia and hypertriglyceridemia in obese patients with diabetes without the weight gain associated with insulin or sulfonylurea therapy. Metformin is ineffective in patients with type 1 diabetes. Patients with chronic kidney disease should not be given this medication because failure to excrete it would produce high blood and tissue levels of metformin that could stimulate lactic acid overproduction. In the United States, metformin use is not recommended at or above a serum creatinine level of 1.4 mg/dL in women and 1.5 mg/dL in men. In the United Kingdom, the recommendations are to review metformin use when the serum creatinine exceeds 130 mcmol/L (1.5 mg/dL) or the estimated glomerular filtration rate (eGFR) falls below 45 mL/min per 1.73 m2. The medication should be stopped if the serum creatinine exceeds 150 mcmol/L (1.7mg/dL) or the eGFR is below 30 mL/min per 1.73 m2. Patients with liver failure or persons with excessive alcohol intake should not receive this medication—lactic acid production from the gut and other tissues, which rises during metformin therapy, could result in lactic acidosis when defective hepatocytes cannot remove the lactate or when alcohol-induced reduction of nucleotides interferes with lactate clearance.
The maximum dosage of metformin is 2550 mg, although little benefit is seen above a total dose of 2000 mg. It is important to begin with a low dose and increase the dosage very gradually in divided doses—taken with meals—to reduce minor gastrointestinal upsets. A common schedule would be one 500 mg tablet three times a day with meals or one 850 mg or 1000 mg tablet twice daily at breakfast and dinner. Up to 2000 mg of the extended-release preparation can be given once a day. Lower doses should be used in patients with eGFRs between 30 and 45 mL/min per 1.73 m2.
The most frequent side effects of metformin are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal discomfort, diarrhea), which occur in up to 20% of patients. These effects are dose-related, tend to occur at onset of therapy, and often are transient. However, in 3–5% of patients, therapy may have to be discontinued because of persistent diarrheal discomfort. In a retrospective analysis, it has been reported that patients switched from immediate-release metformin to comparable dose of extended-release metformin experienced fewer gastrointestinal side effects.
Hypoglycemia does not occur with therapeutic doses of metformin, which permits its description as a “euglycemic” or “antihyperglycemic” medication rather than an oral hypoglycemic agent. Dermatologic or hematologic toxicity is rare. Metformin interferes with the calcium dependent absorption of vitamin B12-intrinsic complex in the terminal ileum; vitamin B12 deficiency can occur after many years of metformin use. Periodic screening with vitamin B12 levels should be considered, especially in patients with peripheral neuropathy or if a macrocytic anemia develops. Increased intake of dietary calcium may prevent the metformin-induced B12 malaborption.
Lactic acidosis has been reported as a side effect but is uncommon with metformin in contrast to phenformin. While therapeutic doses of metformin reduce lactate uptake by the liver, serum lactate levels rise only minimally if at all, since other organs such as the kidney can remove the slight excess. However, if tissue hypoxia occurs, the metformin-treated patient is at higher risk for lactic acidosis due to compromised lactate removal. Similarly, when kidney function deteriorates, affecting not only lactate removal by the kidney but also metformin excretion, plasma levels of metformin rise far above the therapeutic range and block hepatic uptake enough to provoke lactic acidosis without associated increases in lactic acid production. Almost all reported cases have involved persons with associated risk factors that should have contraindicated its use (kidney, liver, or cardiorespiratory insufficiency; alcoholism; advanced age). Acute kidney injury can occur rarely in certain patients receiving radiocontrast agents. Metformin therapy should therefore be temporarily halted on the day of radiocontrast administration and restarted a day or two later after confirmation that renal function has not deteriorated.
Two medications of this class, rosiglitazone and pioglitazone, are available for clinical use. These medications sensitize peripheral tissues to insulin. They bind a nuclear receptor called peroxisome proliferator-activated receptor gamma (PPAR-gamma) and affect the expression of a number of genes. Observed effects of thiazolidinediones include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased hepatic glucose output, increased adiponectin and decreased release of resistin from adipocytes, and increased differentiation of preadipocytes into adipocytes. They have also been demonstrated to decrease levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, and interleukin 6. Like the biguanides, this class of medications does not cause hypoglycemia.
Both rosiglitazone and pioglitazone are effective as monotherapy and in combination with sulfonylureas or metformin or insulin, lowering HbA1c by 1–2%. When used in combination with insulin, they can result in a 30–50% reduction in insulin dosage, and some patients can come off insulin completely. The dosage of rosiglitazone is 4–8 mg daily and of pioglitazone, 15–45 mg daily, and the medications do not have to be taken with food. Rosiglitazone is primarily metabolized by the CYP 2C8 isoenzyme and pioglitazone is metabolized by CYP 2C8 and CYP 3A4.
The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia. Patients inadequately managed on sulfonylureas can do well on a combination of sulfonylurea and rosiglitazone or pioglitazone. About 25% of patients in clinical trials fail to respond to these medications, presumably because they are significantly insulinopenic.
These medications have some additional effects apart from glucose lowering. Rosiglitazone therapy is associated with increases in total cholesterol, LDL cholesterol (15%), and HDL cholesterol (10%). There is a reduction in free fatty acids of about 8–15%. The changes in triglycerides were generally not different from placebo. Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL cholesterol (15%) but did not cause a consistent change in total cholesterol and LDL cholesterol levels. A prospective randomized comparison of the metabolic effects of pioglitazone and rosiglitazone on patients who had previously taken troglitazone (now withdrawn from the US market) showed similar effects on HbA1c and weight gain. Pioglitazone-treated persons, however, had lower total cholesterol, LDL cholesterol, and triglycerides when compared with rosiglitazone-treated persons. Small prospective studies have demonstrated that treatment with these medications leads to improvements in the biochemical and histologic features of nonalcoholic fatty liver disease. The thiazolidinediones also may limit vascular smooth muscle proliferation after injury, and there are reports that pioglitazone can reduce neointimal proliferation after coronary stent placement. In one double-blind, placebo-controlled study, rosiglitazone was shown to be associated with a decrease in the ratio of urinary albumin to creatinine excretion.
Safety concerns and some troublesome side effects have emerged about this class of medications that significantly limit their use. A meta-analysis of 42 randomized clinical trials with rosiglitazone suggested that this medication increases the risk of angina pectoris or myocardial infarction. A meta-analysis of clinical trials with pioglitazone did not show similar findings. Although conclusive data were lacking, the European Medicines Agency suspended the use of rosiglitazone in Europe. In the United States, the FDA established a restricted distribution program. A subsequent large prospective clinical trial (the RECORD study) failed to confirm the meta-analysis finding and the restrictions were lifted in the United States. It is unlikely, however, that there is going to be a resurgence in its use and pioglitazone is likely to remain the preferred agent.
Edema occurs in about 3–4% of patients receiving monotherapy with rosiglitazone or pioglitazone. The edema occurs more frequently (10–15%) in patients receiving concomitant insulin therapy and may result in heart failure. The medications are contraindicated in diabetic individuals with New York Heart Association class III and IV cardiac status. Thiazolidinediones have also been reported as being associated with new onset or worsening macular edema. Apparently, this is a rare side effect, and most of these patients also had peripheral edema. The macular edema resolved or improved once the medication was discontinued.
In experimental animals, rosiglitazone stimulates bone marrow adipogenesis at the expense of osteoblastogenesis resulting in a decrease in bone density. An increase in fracture risk in women (but not men) has been reported with both rosiglitazone and pioglitazone. The fracture risk is in the range of 1.9 per 100 patient-years with the thiazolidinedione compared to 1.1 per 100 patient years on comparison treatment. In at least one study of rosiglitazone, the fracture risk was increased in premenopausal as well as postmenopausal women.
Other side effects include anemia, which occurs in 4% of patients treated with these medications; it may be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs, especially when the medication is combined with a sulfonylurea or insulin. Some of the weight gain is fluid retention, but there is also an increase in total fat mass. Initial reports in male rats and humans raised concern about bladder tumors. A 10-year observational cohort study of patients taking pioglitazone, however, failed to find an association with bladder cancer. Reassuringly, a large multipopulation pooled analysis (1.01 million persons over 5.9 million person years) also failed to find an association between cumulative exposure of pioglitazone or rosiglitazone and incidence of bladder cancer.
Troglitazone, the first medication in this class to go into widespread clinical use, was withdrawn from clinical use because of medication-associated fatal liver failure. Although rosiglitazone and pioglitazone have not been reported to cause liver injury, the FDA recommends that they should not be used in patients with clinical evidence of active liver disease or pretreatment elevation of the alanine aminotransferase (ALT) level that is 2.5 times greater than the upper limit of normal. Obviously, caution should be used in initiation of therapy in patients with even mild ALT elevations. Liver biochemical tests should be performed prior to initiation of treatment and periodically thereafter.
3. Medications that affect absorption of glucose
Alpha-glucosidase inhibitors competitively inhibit the alpha-glucosidase enzymes in the gut that digest dietary starch and sucrose. Two of these medications—acarbose and miglitol—are available for clinical use in the United States. Voglibose, another alpha-glucosidase inhibitor is available in Japan, Korea, and India. Acarbose and miglitol are potent inhibitors of glucoamylase, alpha-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase. Acarbose binds 1000 times more avidly to the intestinal disaccharidases than do products of carbohydrate digestion or sucrose. A fundamental difference between acarbose and miglitol is in their absorption. Acarbose has the molecular mass and structural features of a tetrasaccharide, and very little (about 2%) crosses the microvillar membrane. Miglitol, however, has a structural similarity with glucose and is absorbable. Both medications delay the absorption of carbohydrate and lower postprandial glycemic excursion.
The recommended starting dose of acarbose is 50 mg twice daily, gradually increasing to 100 mg three times daily. For maximal benefit on postprandial hyperglycemia, acarbose should be given with the first mouthful of food ingested. In diabetic patients, it reduces postprandial hyperglycemia by 30–50%, and its overall effect is to lower the HbA1c by 0.5–1%.
The principal adverse effect, seen in 20–30% of patients, is flatulence. This is caused by undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends to discourage excessive carbohydrate consumption and promotes improved compliance of type 2 patients with their diet prescriptions. When acarbose is given alone, there is no risk of hypoglycemia. However, if combined with insulin or sulfonylureas, it might increase the risk of hypoglycemia from these agents. A slight rise in hepatic aminotransferases has been noted in clinical trials with acarbose (5% versus 2% in placebo controls, and particularly with doses greater than 300 mg/day). The levels generally return to normal on stopping the medication.
In the UKPDS, approximately 2000 patients on diet, sulfonylurea, metformin, or insulin therapy were randomized to acarbose or placebo therapy. By 3 years, 60% of the patients had discontinued the medication, mostly because of gastrointestinal symptoms. If one looked only at the 40% who remained on the medication, they had a 0.5% lower HbA1c compared with placebo.
Miglitol is similar to acarbose in terms of its clinical effects. It is indicated for use in diet- or sulfonylurea-treated patients with type 2 diabetes. Therapy is initiated at the lowest effective dosage of 25 mg three times a day. The usual maintenance dose is 50 mg three times a day, although some patients may benefit from increasing the dose to 100 mg three times a day. Gastrointestinal side effects occur as with acarbose. The medication is not metabolized and is excreted unchanged by the kidney. Theoretically, absorbable alpha-glucosidase inhibitors could induce a deficiency of one or more of the alpha-glucosidases involved in cellular glycogen metabolism and biosynthesis of glycoproteins. This does not occur in practice because, unlike the intestinal mucosa, which sees a high concentration of the medication, the blood level is 200-fold to 1000-fold lower than the concentration needed to inhibit intracellular alpha-glucosidases. Miglitol should not be used in end-stage chronic kidney disease, when its clearance would be impaired.
Oral glucose provokes a threefold to fourfold higher insulin response than an equivalent dose of glucose given intravenously. This is because the oral glucose causes a release of gut hormones, principally glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP1), that amplify the glucose-induced insulin release. This “incretin effect” of GLP-1 secretion (but not GIP1 secretion) is reduced in patients with type 2 diabetes and when GLP-1 is infused in patients with type 2 diabetes, it stimulates insulin secretion and lowers glucose levels. GLP-1, unlike the sulfonylureas, has only a modest insulin stimulatory effect at normoglycemic concentrations. This means that GLP-1 has a lower risk for hypoglycemia than the sulfonylureas.
In addition to its insulin stimulatory effect, GLP-1 also has a number of other pancreatic and extrapancreatic effects. It suppresses glucagon secretion and so may ameliorate the hyperglucagonemia that is present in people with diabetes and improve postprandial hyperglycemia. GLP-1 preserves islet integrity and reduces apoptotic cell death of human islet cells in culture. In mice, streptozotocin-induced apoptosis is significantly reduced by coadministration of exendin-4 or exenatide, a GLP-1 receptor agonist. GLP-1 acts on the stomach delaying gastric emptying; the importance of this effect on glucose lowering is illustrated by the observation that antagonizing the deceleration of gastric emptying markedly reduces the glucose lowering effect of GLP-1. GLP-1 receptors are present in the central nervous system and may play a role in the anorectic effect of the drugs. Intracerebroventricular administration of GLP-1 in wild type mice, but not in GLP-1 receptor knockout mice, inhibits feeding. Type 2 diabetic patients undergoing GLP-1 infusion are less hungry; it is unclear whether this is mainly due to a deceleration of gastric emptying or whether there is a central nervous system effect as well.
a. GLP-1 receptor agonists
GLP-1 is rapidly proteolyzed by dipeptidyl peptidase 4 (DPP-4) and by other enzymes, such as endopeptidase 24.11, and is also cleared rapidly by the kidney. As a result, GLP-1’s half-life is only 1–2 minutes. The native peptide, therefore, cannot be used therapeutically and the approach taken has been to develop metabolically stable analogs or derivatives of GLP-1 that are not subject to the same enzymatic degradation or renal clearance. Four GLP-1 receptor agonists, exenatide, liraglutide, albiglutide, and dulaglutide are available for clinical use.
Exenatide (Exendin 4) is a GLP-1 receptor agonist isolated from the saliva of the Gila monster (a venomous lizard) that is more resistant to DPP-4 action and cleared by the kidney. Its half-life is 2.4 hours, and its glucose lowering effect is about 6 hours. Exenatide is dispensed as two fixed-dose pens (5 mcg and 10 mcg). It is injected 60 minutes before breakfast and before dinner. Patients with type 2 diabetes should be prescribed the 5 mcg pen for the first month and, if tolerated, the dose can then be increased to 10 mcg twice a day. The medication is not recommended in patients with GFR less than 30 mL/min. In clinical trials, adding exenatide therapy to patients with type 2 diabetes already taking metformin or a sulfonylurea, or both, further lowered the HbA1c value by 0.4% to 0.6% over a 30-week period. These patients also experienced a weight loss of 3–6 pounds. Exenatide LAR is a once weekly preparation that is dispensed as a powder (2 mg). It is suspended in the provided diluent just prior to injection. In comparative clinical trials, the long-acting drug lowers the HbA1c level a little more than the twice daily drug. Low-titer antibodies against exenatide develop in over one-third (38%) of patients, but the clinical effects are not attenuated. High-titer antibodies develop in a subset of patients (~6%), and in about half of these cases, an attenuation of glycemic response has been seen.
Liraglutide is a soluble fatty acid acylated GLP-1 analog (with replacement of lysine with arginine at position 34 and the attachment of a C16 acyl chain to a lysine at position 26). The fatty-acyl GLP-1 retains affinity for GLP-1 receptors but the addition of the C16 acyl chain allows for noncovalent binding to albumin, both hindering DPP-4 access to the molecule and contributing to a prolonged half-life and duration of action. The half-life is approximately 12 hours, allowing the medication to be injected once a day. The dosing is initiated at 0.6 mg daily, increased after 1 week to 1.2 mg daily. Some patients may benefit from increasing the dose to 1.8 mg. In clinical trials lasting 26 and 52 weeks, adding liraglutide to the therapeutic regimen (metformin, sulfonylurea, thiazolidinedione) of patients with type 2 diabetes further lowered the HbA1c value. Depending on the dose and design of the study, the HbA1c decline was in the range of 0.6% to 1.5%. The patients had sustained weight loss of 1–6 pounds. Liraglutide at a dose of 3 mg daily has been approved for weight loss.
Albiglutide is a human GLP-1 dimer fused to human albumin. It is rendered resistant to DPP-4 action by a glycine substitution for alanine at position 8. The half-life of albiglutide is about 5 days and a steady state is reached after 4–5 weeks of once weekly administration. The usual dose is 30 mg weekly by subcutaneous injection. The dose can be increased to 50 mg weekly if necessary. The pen contains a lyophilized powder that is reconstituted just prior to administration. Albiglutide monotherapy and combination therapy lowers HbA1c by about 0.8%. Weight loss is much less than with exenatide and liraglutide.
Dulaglutide consists of two GLP-1 analog molecules covalently linked to an Fc fragment of human IgG4. The GLP-1 molecule has amino acid substitutions that resist DPP-4 action. The half-life of dulaglutide is about 5 days. The usual dose is 0.75 mg weekly by subcutaneous injection. The maximum recommended dose is 1.5 mg weekly. Dulaglutide monotherapy and combination therapy lowers HbA1c by about 0.7% to 1.6%. Weight loss ranged from 2 pounds to 7 pounds.
The most frequent adverse reactions of the GLP1 receptor agonists are nausea (11–40%), vomiting (4–13%), and diarrhea (9–17%). The reactions are more frequent at the higher doses. Albiglutide tends to have the lowest rates of these reactions. In clinical trials about 1–5% of participants withdrew from the studies because of the gastrointestinal symptoms.
All the GLP-1 receptor agonists are associated with increased risk of pancreatitis. The FDA reported 30 postmarketing reports of acute pancreatitis in patients taking exenatide. The pancreatitis was severe (hemorrhagic or necrotizing) in 6 instances, and 2 of these patients died. In the liraglutide, albiglutide, and dulaglutide clinical trials, there were 13, 6, and 5 cases of pancreatitis in the drug-treated groups versus 1, 2, and 1 case(s) in the comparator groups, respectively. This translates to about 1.4–2.2 vs 0.6–0.9 cases of pancreatitis per 1000 patient years. Patients taking GLP-1 receptor agonists should be advised to seek immediate medical care if they experience unexplained persistent severe abdominal pain.
There have been rare reports of acute kidney injury in patients taking exenatide. Some of these patients had preexisting kidney disease, and others had one or more risk factors for kidney disease. A number of the patients reported nausea, vomiting, and diarrhea, and it is possible that these side effects caused volume depletion and contributed to the development of the kidney injury. For this reason, the GLP-1 receptors agonists should be prescribed cautiously in patients with kidney impairment.
GLP-1 receptor agonists stimulate C-cell neoplasia and cause medullary thyroid carcinoma in rats. Human C-cells express very few GLP1-receptors, and the relevance to human therapy is unclear. The medications, however, should not be used in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) syndrome type 2.
An alternate approach to the use of GLP-1 receptor agonists is to inhibit the enzyme DPP-4 and prolong the action of endogenously released GLP-1 and GIP. Four oral DPP-4 inhibitors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are available in the United States for the treatment of type 2 diabetes. An additional DPP-4 inhibitor, vildagliptin, is available in Europe.
Sitagliptin, when used in clinical trials alone and in combination with metformin and pioglitazone, improved HbA1c from 0.5% to 1.4%. The usual dose of sitagliptin is 100 mg once daily, but the dose is reduced to 50 mg daily if the calculated creatinine clearance is 30–50 mL/min and to 25 mg for clearances less than 30 mL/min. Unlike exenatide, sitagliptin does not cause nausea or vomiting. It also does not result in weight loss. The main adverse effect appears to be a predisposition to nasopharyngitis or upper respiratory tract infection. A small increase in neutrophil count of ~200 cells/mcL has also occurred. Since its FDA approval and clinical use, there have been reports of serious allergic reactions to sitagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. There have also been reports of pancreatitis (88 cases including 2 cases of hemorrhagic or necrotizing pancreatitis). The frequency of these events is unclear. A number of neuropeptides, growth factors, cytokines, and chemokines are potential DPP-4 substrates; DPP-4 inhibitors prolong the actions of neuropeptide Y and substance P. It is unknown whether the effects of DPP-4 inhibitors on the actions of neuropeptide Y and substance P over a long-term period will have negative consequences.
Saxagliptin, when added to the therapeutic regimen (metformin, sulfonylurea, thiazolidinedione) of patients with type 2 diabetes, further lowered the HbA1c value by about 0.7–0.9%. The dose is 2.5 mg or 5 mg orally once a day. The 2.5-mg dose should be used in patients with calculated creatinine clearance less than 50 mL/min. It lowers HbA1c by about 0.6% when added to metformin or glyburide or thiazolidine in various 24-week clinical trials. The medication does not cause weight gain or loss. The main adverse reactions were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. There is also small reversible dose-dependent reduction in absolute lymphocyte count, which remains within normal limits. Hypersensitivity reactions, such as urticaria and facial edema, occurred in 1.5% of patients taking the medication compared with 0.4% receiving placebo. The metabolism of saxagliptin is by CYP3A4/5; thus, strong inhibitors or inducers of CYP3A4/5 will affect the pharmacokinetics of saxagliptin and its active metabolite. Saxagliptin may increase the risk of heart failure. In a post marketing study of 16,492 type 2 diabetes patients, there were 289 cases of heart failure in the saxagliptin group (3.5%) and 228 cases in the placebo group (2.8%)—a hazard ratio of 1.27. Patients at the highest risk for failure were those who had a history of heart failure or had elevated levels of N-terminal of the prohormone brain natriuretic peptide (NT-pBNP) or had kidney impairment.
Alogliptin lowers HbA1c by about 0.5–0.6% when added to metformin, sulfonylurea, or pioglitazone. The usual dose is 25 mg orally daily. The 12.5-mg dose is used in patients with calculated creatinine clearance of 30 to 60 mLs/min; and 6.25 mg for clearance less than 30 mL/min. In clinical trials, pancreatitis occurred in 11 of 5902 patients on alogliptin (0.2%) and in 5 of 5183 patients receiving all comparators (<0.1%). There have been reports of hypersensitivity reactions (anaphylaxis, angioedema, Stevens-Johnson syndrome). Cases of hepatic failure have been reported but it is unclear if alogliptin was the cause. The medication, however, should be discontinued in the event of liver failure.
In a large post-marketing study, alogliptin, like saxagliptin, was associated with a slightly increased rate of heart failure.
Linagliptin lowers HbA1c by about 0.4–0.6% when added to metformin, sulfonylurea, or pioglitazone. The dose is 5 mg orally daily, and, since it is primarily excreted unmetabolized via the bile, no dose adjustment is needed in patients with renal failure. The adverse reactions include nasopharyngitis and hypersensitivity reactions (urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity). In one study, there were eight cases of pancreatitis in 4687 patients exposed to drug (4311 patient years) with 0 cases in 1183 patients receiving placebo (433 patient years).
Vildagliptin lowers HbA1c by about 0.5–1% when added to the therapeutic regimen of patients with type 2 diabetes. The dose is 50 mg once or twice daily. Adverse reactions include upper respiratory tract infections, nasopharyngitis, dizziness, and headache. Rare cases of hepatic dysfunction, including hepatitis, have been reported. Liver function testing is recommended quarterly during the first year of use and periodically thereafter. Animal studies using much higher doses of DPP-4 inhibitors and GLP1-receptor agonists than are used in humans caused expansion of pancreatic ductal glands and generation of premalignant pancreatic intraepithelial (PanIN) lesions that have the potential to progress to pancreatic adenocarcinoma. There is, however, currently no evidence that these drugs cause pancreatic cancer in humans.
5. Sodium-glucose co-transporter 2 inhibitors
Glucose is freely filtered by the renal glomeruli and is reabsorbed in the proximal tubules by the action of sodium-glucose co-transporters (SGLT). Sodium-glucose co-transporter 2 (SGLT2) accounts for about 90% of glucose reabsorption and its inhibition causes glycosuria in people with diabetes, lowering plasma glucose levels. The SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin are approved for clinical use in the United States.
Canagliflozin reduces the threshold for glycosuria from a plasma glucose threshold of ~180 mg/dL to 70–90 mg/dL. It has been shown to reduce HbA1c by 0.6–1% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of 2–5 kg. The usual dose is 100 mg daily but up to 300 mg daily can be used in patients with normal kidney function.
Dapagliflozin is an SGLT2 inhibitor that has been shown to reduce HbA1c levels by 0.5–0.8% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of about 2–4 kg. The usual dose is 10 mg daily but 5 mg daily is the recommended initial dose in patients with hepatic failure.
Empagliflozin reduces HbA1c by 0.5–0.7% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of about 2–3 kg. The usual dosage is 10 mg daily but a higher dose of 25 mg daily can be used. In a postmarketing multinational study of 7020 patients with type 2 diabetes with known cardiovascular disease, the addition of empagliflozin was associated with a lower primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio 0.86, P = 0.04). The mechanisms regarding the benefit remain unclear. Weight loss, lower blood pressure, and diuresis may have played a role since there were fewer deaths from heart failure in the treated group whereas the rates of myocardial infarction were unaltered. Additional studies with empagliflozin and other SGLT2 inhibitors are needed to confirm this result.
As might be expected, the efficacy of the SGLT2 inhibitors is reduced in chronic kidney disease. They can also increase creatinine and decrease eGFR, especially in patients with kidney impairment. Canagliflozin is contraindicated in patients with eGFR less than 45 mL/min/1.73 m2. The main side effects are increased incidence of genital mycotic infections and urinary tract infections affecting ~8–9% of patients. There have also been reports of cases of pyelonephritis and septicemia requiring hospitalization. The glycosuria can cause intravascular volume contraction and hypotension.
Canagliflozin has been reported to cause a decrease in bone mineral density at the lumbar spine and the hip. In a pooled analysis of eight clinical trials (mean duration 68 weeks), a 30% increase in fractures was observed in patients taking canagliflozin. It is likely that the effect on the bones is a class effect and not restricted to canagliflozin. All the SGLT2 inhibitors cause a modest increase in LDL cholesterol levels (3–8%). Also, in clinical trials, patients taking dapagliflozin had higher rates of breast cancer (nine cases vs none in comparator arms) and bladder cancer (10 cases vs 1 in placebo arm). These cancer rates exceeded the expected rates in age-matched reference diabetes population.
Cases of diabetic ketoacidosis have been reported with off-label use of SGLT2 inhibitors in patients with type 1 diabetes. Type 1 patients are taught to give less insulin if their glucose levels are not elevated. SGLT2 inhibitors lower glucose levels by changing the renal threshold and not by insulin action. Type 1 patients taking an SGLT2 inhibitor, because the glucose levels are not elevated, may either withhold or reduce their insulin doses to such a degree as to induce ketoacidoisis. SGLT2 inhibitors should not be used in patients with type 1 diabetes and in those patients labelled as having type 2 diabetes but who are very insulin deficient and ketosis-prone.
Pramlintide is a synthetic analog of islet amyloid polypeptide (IAPP or amylin). When given subcutaneously, it delays gastric emptying, suppresses glucagon secretion, and decreases appetite. It is approved for use both in type 1 diabetes and in insulin-treated type 2 diabetes. In 6-month clinical studies with type 1 and insulin-treated type 2 patients, those taking the medication had an approximately 0.4% reduction in HbA1c and about 1.7 kg weight loss compared with placebo. The HbA1c reduction was sustained for 2 years but some of the weight was regained. The medication is given by injection immediately before the meal. Hypoglycemia can occur, and it is recommended that the short-acting or premixed insulin doses be reduced by 50% when the medication is started. Since the medication slows gastric emptying, recovery from hypoglycemia can be a problem because of delay in absorption of fast-acting carbohydrates. Nausea was the other main side effect, affecting 30–50% of persons but tended to improve with time. In patients with type 1 diabetes, the initial dose of pramlintide is 15 mcg before each meal and titrated up by 15 mcg increments to a maintenance dose of 30 mcg or 60 mcg before each meal. In patients with type 2 diabetes, the starting dose is 60 mcg premeals increased to 120 mcg in 3 to 7 days if no significant nausea occurs.
Bromocriptine, a dopamine 2 receptor agonist, has been shown to modestly lower HbA1c by 0.1–0.5% when compared to baseline and 0.4–0.5% compared to placebo. The tablet dose is 0.8 mg and the daily dose is 2 (1.6 g) to 6 (4.8 mg) tablets as tolerated. Common side effects are nausea, vomiting, dizziness, and headache.
Colesevelam, the bile acid sequesterant, when added to metformin or sulfonylurea or insulin lowered HbA1c 0.3– 0.4 % when compared to baseline and 0.5–0.6% compared to placebo. HbA1c lowering, however, was not observed in a single monotherapy clinical trial comparing colesevelam to placebo. Colesevelam use is associated with ~20% increase in triglyceride levels. Other adverse effects include constipation and dyspepsia.
With their modest glucose lowering and significant side effects, using bromocriptine or colesevelam to treat diabetes is not recommended.
7. Medication combinations
Several medication combinations are available in different dose sizes, including glyburide and metformin (Glucovance); glipizide and metformin (Metaglip); repaglinide and metformin (Prandi-Met); rosiglitazone and metformin (Avandamet); pioglitazone and metformin (ACTOplusMet); rosiglitazone and glimepiride (Avandaryl); pioglitazone and glimepiride (Duetact); sitagliptin and metformin (Janumet); saxagliptin and metformin XR (Kombiglyze XR); linagliptin and metformin (Jentadueto); alogliptin and metformin (Kazano); alogliptin and pioglitazone (Oseni); dapagliflozin and metformin (Xigduo); canagliflozin and metformin (Invokamet); empagliflozin and metformin (Synjardy); and empagliflozin and linagliptin (Glyxambi). These medication combinations, however, limit the clinician’s ability to optimally adjust dosage of the individual medications and for that reason are not recommended.
8. Safety of the antihyperglycemic agents
The UKPDS has put to rest previous concerns regarding the safety of sulfonylureas. It did not confirm any cardiovascular hazard among over 1500 patients treated intensively with sulfonylureas for over 10 years, compared with a comparable number who received either insulin or diet therapy. Analysis of a subgroup of obese patients receiving metformin also showed no hazard and even a slight reduction in cardiovascular deaths compared with conventional therapy.
The currently available thiazolidinediones have not to date exhibited the idiosyncratic hepatotoxicity seen with troglitazone. However, these drugs can precipitate heart failure and should not be used in patients with New York Heart Association class III and IV cardiac status. Lactic acidosis from metformin (see above) is quite rare and probably not a major problem with its use in the absence of major risk factors such as impaired kidney or liver function or conditions predisposing to hypoxia.
Insulin is indicated for type 1 diabetes as well as for type 2 diabetic patients with insulinopenia whose hyperglycemia does not respond to diet therapy either alone or combined with other hypoglycemic medications.
With the development of highly purified human insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site. However, the problem of achieving optimal insulin delivery remains unsolved with the present state of technology. It has not been possible to reproduce the physiologic patterns of intraportal insulin secretion with subcutaneous injections of short-acting or longer-acting insulin preparations. Even so, with the help of appropriate modifications of diet and exercise and careful monitoring of capillary blood glucose levels at home, it has often been possible to achieve acceptable control of blood glucose by using various mixtures of short- and longer-acting insulins injected at least twice daily or portable insulin infusion pumps.
1. Characteristics of available insulin preparations
Commercial insulin preparations differ with respect to the time of onset and duration of their biologic action (Table 27–6).
Table 27–6.Summary of bioavailability characteristics of the insulins. |Favorite Table|Download (.pdf) Table 27–6. Summary of bioavailability characteristics of the insulins.
|Insulin Preparations ||Onset of Action ||Peak Action ||Effective Duration |
|Insulins lispro, aspart, glulisine ||5–15 minutes ||1–1.5 hours ||3–4 hours |
|Human regular ||30–60 minutes ||2 hours ||6–8 hours |
|Human NPH ||2–4 hours ||6–7 hours ||10–20 hours |
|Insulin glargine ||0.5–1 hour ||Flat ||~24 hours |
|Insulin detemir ||0.5–1 hour ||Flat ||17 hours |
|Insulin degludec ||0.5–1.5 hours ||Flat ||More than 42 hours |
|Technosphere inhaled insulin ||5–15 minutes ||1 hour ||3 hours |
Human insulin is dispensed as either regular (R) or NPH (N) formulations. Six analogs of human insulin—three rapidly acting (insulin lispro, insulin aspart, insulin glulisine) and three long-acting (insulin glargine, insulin detemir, and insulin degludec)—are approved by the FDA for clinical use (Table 27–7). Animal insulins are no longer available in the United States. All currently available insulins contain less than 10 ppm of proinsulin and are labeled as “purified.” These purified insulins preserve their potency, so that refrigeration is recommended but not crucial. During travel, reserve supplies of insulin can be readily transported for weeks without losing potency if protected from extremes of heat or cold. All the insulins in the United States are available in a concentration of 100 units/mL (U100) and dispensed in 10 mL vials or 0.3 mL cartridges or prefilled disposable pens. Several insulins are available at higher concentrations: insulin glargine, 300 units/mL (U300); insulin degludec, 200 units/mL (U200); insulin lispro, 200 units/mL (U200); and regular insulin, 500 units/mL (U500).
Table 27–7.Insulin preparations available in the United States.1 |Favorite Table|Download (.pdf) Table 27–7. Insulin preparations available in the United States.1
Rapidly acting human insulin analogs
Insulin lispro (Humalog, Lilly)
Insulin aspart (Novolog, Novo Nordisk)
Insulin glulisine (Apidra, Sanofi Aventis)
Short-acting regular insulin
Regular insulin (Lilly, Novo Nordisk)
Technosphere inhaled regular insulin (Afrezza)
NPH insulin (Lilly, Novo Nordisk)
70% NPH/30% regular (70/30 insulin—Lilly, Novo Nordisk)
70% NPL/25% insulin lispro (Humalog Mix 75/25—Lilly)
50% NPL/50% insulin lispro (Humalog Mix 50/50—Lilly)
70% insulin aspart protamine/30% insulin aspart (Novolog Mix 70/30—Novo Nordisk)
70% insulin degludec/30 insulin aspart (Ryzodeg, Novo Nordisk)
Long-acting human insulin analogs
Insulin glargine (Lantus (U100), Toujeo (U300), Sanofi Aventis; Basaglar (U100), Lilly)
Insulin detemir (Levemir, Novo Nordisk)
Insulin degludec (Tresiba, Novo Nordisk)
The short-acting preparations are regular insulin and the rapidly acting insulin analogs (Table 27–7; eFigure 27–1). They are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. The long-acting preparations are NPH insulin and the long-acting insulin analogs. NPH insulin is dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer. The long-acting insulin analogs are also dispensed as clear solutions; insulin glargine is at acidic pH and insulin detemir is at neutral pH. The rapidly acting insulin analogs and the long-acting insulins are designed for subcutaneous administration, while regular insulin can also be given intravenously.
Extent and duration of action of various types of insulin–euglycemic hyperinsulinemic clamps in normal volunteers. A: Intermediate neutral protamine Hagedorn (NPH) insulin and long-acting insulin analogs. B: Regular insulin and rapidly acting insulin analogs.
a. Short-acting insulin preparations
Regular insulin is a short-acting soluble crystalline zinc insulin whose effect appears within 30 minutes after subcutaneous injection and lasts 5–7 hours when usual quantities are administered. Intravenous infusions of regular insulin are particularly useful in the treatment of diabetic ketoacidosis and during the perioperative management of patients with diabetes who require insulin. Regular insulin is indicated when the subcutaneous insulin requirement is changing rapidly, such as after surgery or during acute infections—although the rapidly acting insulin analogs may be preferable in these situations.
For markedly insulin-resistant persons who would otherwise require large volumes of insulin solution, a U500 preparation of human regular insulin is available in a 10 mL vial. Since a U500 syringe is not available, when U500 insulin is required in cases of severe insulin resistance, a U100 insulin syringe or tuberculin syringe must be used to measure doses. The clinician should carefully note dosages in both units and volume to avoid overdosage. The U500 preparation is much more expensive and is rarely needed.
(2) Rapidly acting insulin analogs
Insulin lispro (Humalog), is an insulin analog where the proline at position B28 is reversed with the lysine at B29. Insulin aspart (Novolog), is a single substitution of proline by aspartic acid at position B28. In insulin glulisine (Apidra) the asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid. These three analogs have less of a tendency to form hexamers, in contrast to human insulin. When injected subcutaneously, the analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as soon as 1 hour—in contrast to regular human insulin, whose hexamers require considerably more time to dissociate and become absorbed. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with the circulating half-life, or with their immunogenicity, which are all identical with those of human regular insulin.
Clinical trials have demonstrated that the optimal times of preprandial subcutaneous injection of comparable doses of the rapidly acting insulin analogs and of regular human insulin are 20 minutes and 60 minutes, respectively, before the meal. While this more rapid onset of action has been welcomed as a great convenience by diabetic patients who object to waiting as long as 60 minutes after injecting regular human insulin before they can begin their meal, patients must be taught to ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia during the meal. Another desirable feature of rapidly acting insulin analogs is that their duration of action remains at about 4 hours irrespective of dosage. This contrasts with regular insulin, whose duration of action is prolonged when larger doses are used.
The rapidly acting analogs are also commonly used in pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, persons using insulin lispro had lower HbA1c values and improved postprandial glucose control with the same frequency of hypoglycemia. In the event of pump failure, however, users of the rapidly acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.
While insulin aspart has been approved for intravenous use (eg, in hyperglycemic emergencies), there is no advantage in using insulin aspart over regular insulin by this route. A U200 concentration of insulin lispro is available in a disposable prefilled pen. The only advantage of the U200 over the U100 insulin lispro preparation is that it delivers the same dose in half the volume.
b. Long-acting insulin preparations
(1) NPH (neutral protamine Hagedorn or isophane) insulin
NPH is an intermediate-acting insulin whose onset of action is delayed by combining 2 parts soluble crystalline zinc insulin with 1 part protamine zinc insulin. This produces equivalent amounts of insulin and protamine, so that neither is present in an uncomplexed form (“isophane”).
Its onset of action is delayed to 2–4 hours, and its peak response is generally reached in about 6–7 hours. Because its duration of action is often less than 24 hours (with a range of 10–20 hours), most patients require at least two injections daily to maintain a sustained insulin effect. Occasional vials of NPH insulin have tended to show unusual clumping of their contents or "frosting" of the container, with considerable loss of bioactivity. This instability is rare and occurs less frequently if NPH human insulin is refrigerated when not in use and if bottles are discarded after 1 month of use.
In this insulin, the asparagine at position 21 of the insulin A chain is replaced by glycine and two arginines are added to the carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule closer to neutral making it more soluble in an acidic environment. In contrast, human insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin, which, when injected into the neutral pH environment of the subcutaneous tissue, forms microprecipitates that slowly release the insulin into the circulation. It lasts for about 24 hours without any pronounced peaks and is given once a day to provide basal coverage. This insulin cannot be mixed with the other human insulins because of its acidic pH. When this insulin was given as a single injection at bedtime to type 1 patients in clinical trials, fasting hyperglycemia was better controlled with less nocturnal hypoglycemia when compared to NPH insulin.
In one clinical trial involving type 2 patients, insulin glargine was associated with a slightly higher progression of retinopathy when compared with NPH insulin. The frequency was 7.5% with the analog and 2.7% with the NPH. However, this observation was not confirmed in a 5-year open-label prospective study of 1024 persons randomized to NPH or insulin glargine. Insulin glargine has a sixfold greater affinity for IGF-1 receptor compared with the human insulin and there has been concern that long-term use of insulin glargine might increase cancer risk. An observational study from Germany of 127,031 patients who had exposure to regular insulin, short-acting insulin analogs, and insulin glargine reported a strong correlation between increased insulin dose and cancer risk. Moreover, insulin glargine, dose for dose, appeared to carry a higher risk of cancer than regular insulin. Subsequent epidemiologic studies, however, failed to confirm this observation. A more concentrated form of insulin glargine (U300) is available as an insulin pen. In pharmacodynamic studies in type 1 patients, the U300 compared to the U100 preparation had approximately 5 hours longer duration of action. In clinical trials in type 1 patients, U300 use did not result in better control or reduce the rates of hypoglycemia. Although limited clinical data suggest that insulin glargine is safe in pregnancy, it is not approved for this use.
In this insulin analog, the threonine at position B30 has been removed and a 14-C fatty acid chain (tetradecanoic acid) is attached to the lysine at position 29 by acylation. The fatty acid chain makes the molecule more lipophilic than native insulin and the addition of zinc stabilizes the molecule and leads to formation of hexamers. Its prolonged action is due to dihexamerization and binding of hexamers and dimers to albumin at the injection site as well as binding of the monomer via its fatty acid side chain to albumin in the circulation. The affinity of insulin detemir is fourfold to fivefold lower than that of human soluble insulin and therefore the U100 formulation of insulin detemir has an insulin concentration of 2400 nmol/mL compared with 600 nmol/mL for NPH. The duration of action for insulin detemir is about 17 hours at therapeutically relevant doses. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. It has been approved for use during pregnancy. This insulin has been reported to have lower within-subject pharmacodynamic variability compared with NPH insulin and insulin glargine. In vitro studies do not suggest any clinically relevant albumin binding interactions between insulin detemir and fatty acids or protein-bound medications. Since there is a vast excess (~400,000) of albumin binding sites available in plasma per insulin detemir molecule, it is unlikely that hypoalbuminemic disease states affect the ratio of bound to free insulin detemir.
In this insulin analog, the threonine at position B30 has been removed, and the lysine at position B29 is conjugated to hexdecanoic acid via a gamma-L-glutamyl spacer. In the vial, in the presence of phenol and zinc, the insulin is in the form of dihexamers but when injected subcutaneously, it self associates into large multihexameric chains consisting of thousands of dihexamers. The chains slowly dissolve in the subcutaneous tissue and insulin monomers are steadily released into the systemic circulation. The half-life of the insulin is 25 hours. Its onset of action is in 30–90 minutes and its duration of action is more than 42 hours. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. Insulin degludec is available in two concentrations, U100 and U200, and dispensed in prefilled disposable pens.
c. Mixed insulin preparations
Patients with type 2 diabetes can sometimes achieve reasonable glucose control with just pre-breakfast and pre-supper injections of mixtures of short acting and NPH insulins. The regular insulin or rapidly acting insulin analog is withdrawn first, then the NPH insulin and then injected immediately. Stable premixed insulins (70% NPH and 30% regular) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or impairment of manual dexterity. Premixed preparations of insulin lispro and NPH insulins are unstable. An exchange of insulin lispro occurs with the human insulin in the protamine complex. Consequently, the soluble component becomes over time a mixture of regular and insulin lispro at varying ratios. In an attempt to remedy this, an intermediate insulin composed of isophane complexes of protamine with insulin lispro was developed called NPL (neutral protamine lispro). This insulin has the same duration of action as NPH insulin. Premixed combinations of NPL and insulin lispro (75% NPL/25% insulin lispro mixture [Humalog Mix 75/25] and 50% NPL/50% insulin lispro mixture [Humalog Mix 50/50]) are available for clinical use. Similarly, a 70% insulin aspart protamine/30% insulin aspart (NovoLog Mix 70/30) is available. The main advantages of these mixtures are that they can be given within 15 minutes of starting a meal and they are superior in controlling the postprandial glucose rise after a carbohydrate rich meal. These benefits have not translated into improvements in HbA1c levels when compared with the usual 70% NPH/30% regular mixture. The longer-acting insulin analogs, insulin glargine and insulin detemir, cannot be mixed with either regular insulin or the rapidly acting insulin analogs. Insulin degludec, however, can be mixed and is available as 70% insulin degludec/30% insulin aspart and is injected once or twice a day.
3. Methods of insulin administration
a. Insulin syringes and needles
Plastic disposable syringes are available in 1 mL, 0.5 mL, and 0.3 mL sizes. The “low-dose” 0.3 mL syringes are popular, because many patients with diabetes do not take more than 30 units of insulin in a single injection except in rare instances of extreme insulin resistance. Three lengths of needles are available: 6 mm, 8 mm, and 12.7 mm. Long needles are preferable in obese patients to reduce variability of insulin absorption. The needles are of 28, 30, and 31 gauges. The 31 gauge needles are almost painless. “Disposable” syringes may be reused until blunting of the needle occurs (usually after three to five injections). Sterility adequate to avoid infection with reuse appears to be maintained by recapping syringes between uses. Cleansing the needle with alcohol may not be desirable since it can dissolve the silicone coating and can increase the pain of skin puncturing.
Any part of the body covered by loose skin can be used, such as the abdomen, thighs, upper arms, flanks, and upper buttocks. Preparation with alcohol is not required prior to injection as long as the skin is clean. Rotation of sites is recommended to avoid delayed absorption when fibrosis or lipohypertrophy occurs from repeated use of a single site. However, considerable variability of absorption rates from different sites, particularly with exercise, may contribute to the instability of glycemic control in certain type 1 patients if injection sites are rotated too frequently in different areas of the body. Consequently, it is best to limit injection sites to a single region of the body and rotate sites within that region. The abdomen is recommended for subcutaneous injections, since regular insulin has been shown to absorb more rapidly from there than from other subcutaneous sites. The effect of anatomic regions appears to be much less pronounced with the analog insulins.
b. Insulin pen injector devices
Insulin pens eliminate the need for carrying insulin vials and syringes. Cartridges of insulin lispro and insulin aspart are available for reusable pens (Eli Lilly, Novo Nordisk, and Owen Mumford). Disposable prefilled pens are also available for insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin glargine, insulin degludec, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, 50% NPL/50% insulin lispro, 70% insulin aspart protamine/30% insulin aspart, and 70% insulin degludec/30% insulin aspart. Pen needles are available in 29, 31, and 32 gauges and 4, 5, 6, 8, and 12.7 mm lengths (Novofine; BD).
In the United States, Medtronic Mini-Med, Animas, Insulet, Roche, and Tandem make battery operated continuous subcutaneous insulin infusion (CSII) pumps. These pumps are small (about the size of a pager) and very easy to program. They offer many features, including the ability to set a number of different basal rates throughout the 24 hours and to adjust the time over which bolus doses are given. They also are able to detect pressure build-up if the catheter is kinked. The catheter connecting the insulin reservoir to the subcutaneous cannula can be disconnected, allowing the patient to remove the pump temporarily (eg, for bathing). Ominpod (Insulet Corporation) is an insulin infusion system in which the insulin reservoir and infusion set are integrated into one unit (pod), so there is no catheter (electronic patch pump). The pod, placed on the skin, delivers subcutaneous basal and bolus insulin based on wirelessly transmitted instructions from a personal digital assistant. The great advantage of continuous subcutaneous insulin infusion (CSII) is that it allows for establishment of a basal profile tailored to the patient. The patient therefore is able to eat with less regard to timing because the basal insulin infusion should maintain constant blood glucose between meals. Also the ability to adjust the basal insulin infusion makes it easier for the patient to manage glycemic excursions that occur with exercise. The pumps also have software that can assist the patient to calculate boluses based on glucose reading and carbohydrates to be consumed. They keep track of the time elapsed since last insulin bolus and the patient is reminded of this when he or she attempts to give additional correction bolus before the effect of the previous bolus has worn off (“insulin on board” feature). This feature reduces the risk of overcorrecting and subsequent hypoglycemia.
CSII therapy is appropriate for patients with type 1 diabetes who are motivated, mechanically inclined, educated about diabetes (diet, insulin action, treatment of hypoglycemia and hyperglycemia), and willing to monitor their blood glucose four to six times a day. Known complications of CSII include ketoacidosis, which can occur when insulin delivery is interrupted, and skin infections. Another disadvantage is its cost and the time demanded of the clinician and staff in initiating therapy.
V-go (Valeritas) is a mechanical patch pump designed specifically for people with type 2 diabetes who employ a basal/bolus insulin regimen. The device is preset to deliver one of three fixed and flat basal rates (20, 30, or 40 units) for 24 hours (at which point it must be replaced) and there is a button that delivers two units per press to help cover meals.
The dry-powder formulation of recombinant human regular insulin that is delivered by inhalation (technosphere insulin, Afrezza) is approved for use in adults with diabetes. Pharmacokinetic studies show that technosphere insulin is rapidly absorbed with peak insulin levels reached in 12–15 minutes and declining to baseline in 3 hours. Pharmacodynamic studies show that median time to maximum effect with inhaled insulin is approximately 1 hour and declines to baseline by about 3 hours. In contrast, the median time to maximum effect with subcutaneous insulin lispro is about 2 hours and declines to baseline by 4 hours. In clinical trials, technosphere insulin combined with basal insulin was as effective in glucose lowering as rapid-acting insulin analogs combined with basal insulin. It is formulated as a single-use, color-coded cartridge delivering 4, 8, or 12 units immediately before the meal. The manufacturer provides a dose conversion table; patients injecting up to 4 units of rapid-acting insulin analog should use the 4-unit cartridge. Those injecting 5 to 8 units should use the 8-unit cartridge. If the dose is 9–12 units of rapid-acting insulin premeal then one 4-unit cartridge and one 8-unit cartridge or one 12-unit cartridge should be used. The inhaler is about the size of a referee’s whistle.
The most common adverse reaction of the inhaled insulin was a cough affecting about 27% of patients. A small decrease in pulmonary function (forced expiratory volume in 1 second [FEV1]) was seen in the first 3 months of use, which persisted over 2 years of follow-up. Inhaled insulin is contraindicated in smokers and patients with chronic lung disease, such as asthma and chronic obstructive pulmonary disease. Spirometry should be performed to identify potential lung disease prior to initiating therapy. During the clinical trials, there were two cases of lung cancer in patients who were taking inhaled insulin and none in the comparator-treated patients. All the patients in whom lung cancer developed had a history of prior cigarette smoking. There were also two cases of squamous cell carcinoma of the lung in nonsmokers exposed to inhaled insulin; these cases occurred after completion of the clinical trials. Cases of lung cancer were also reported in cigarette smokers using a previously available inhaled insulin preparation (Exubera). The incidence rate in the Exubera treated group was 0.13 per 1000 patient years and 0.03 per 1000 patient years in the comparator-treated group.
1. Pancreas transplantation
All uremic patients with type 1 diabetes who are candidates for a kidney transplant should be considered potential candidates for a pancreas transplant. Eligibility criteria include age younger than 55 and minimal cardiovascular risk. Contraindications include noncorrectable coronary artery disease, extensive peripheral vascular disease, and significant obesity (weight greater than 100 kg). The pancreas transplant may occur at the same time as kidney transplant or after kidney transplant. Patients undergoing simultaneous pancreas and kidney transplantation have an 83% chance of pancreatic graft survival at 1 year and 69% at 5 years. Solitary pancreatic transplantation in the absence of a need for kidney transplantation is considered only in those rare patients who do not respond to all other insulin therapeutic approaches and who have frequent severe hypoglycemia or who have life-threatening complications related to their lack of metabolic control. Pancreas transplant alone graft survival is 78% at 1 year and 54% at 5 years.
Total pancreatectomy is curative for severe pain syndrome associated with chronic pancreatitis. The pancreatectomy, however, results in surgical diabetes. Harvesting islets from the removed pancreas and autotransplanting them into the liver (via portal vein) can prevent the development of diabetes or result in “mild” diabetes (partial islet function) that is easier to manage. Since the islets are autologous no immunosuppression is required. The number of islets transplanted is the main predictor of insulin independence.
People with type 1 diabetes can become insulin independent after receiving islets isolated from a donor pancreas (alloislet transplant). The islets are infused into the portal vein using a percutaneous transhepatic approach, and they lodge in the liver releasing insulin in response to physiologic stimuli. Long-term immunosuppression is necessary to prevent allograft rejection and to suppress the autoimmune process that led to the disease in the first place. Insulin independence for more than 5 years has been demonstrated in patients who got anti-CD3 antibody or anti-thymocyte globulin induction immunosuppression and calcineurin inhibitors, mTor inhibitors, and mycophenolate mofetil as maintenance immunosuppression. Islet cell transplant trials with different kinds and combinations of immunosuppressive agents are currently underway. One major limitation is the need for more than one islet infusion to achieve insulin independence. This is because of significant loss of islets during isolation and the period prior to engraftment. Alloislet transplantation is currently an experimental procedure and widespread application will depend on improving insulin independence rates with one infusion and also demonstrating that the long-term outcomes are as good as those of pancreas transplant alone.
et al. The role of kidney in glucose homeostasis—SGLT2 inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharmacol. 2013 Sep;6(5):519–39.
et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011 May 3;154(9):602–13. Erratum in: Ann Intern Med. 2011 Jul 5;155(1):67–8.
et al. New long-acting insulin analogs: from clamp studies to clinical practice. Diabetes Care. 2015 Apr;38(4):541–3.
et al. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care. 2013 Jul;36(7):2118–25.
et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012 Oct 18;2(5).
RW. The current state of pancreas transplantation. Nat Rev Endocrinol. 2013 Sep;9(9):555–62.
et al. Transplantation: sustained benefits of islet transplants for T1DM. Nat Rev Endocrinol. 2015 Oct;11(10):572–4.
et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012 Mar 12;344:e1369.
et al. The role of the kidney and SGLT2 inhibitors in type 2 diabetes. Can J Diabetes. 2015 Dec;39(Suppl 5):S167–75.
MA. A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes Care. 2013 Jul;36(7):2126–32.
et al. An overview of new GLP-1 receptor agonists for type 2 diabetes. Expert Opin Investig Drugs. 2016 Feb;25(2):145–58.
Steps in the Management of the Diabetic Patient
A. Diagnostic Examination
An attempt should be made to characterize the diabetes as type 1 or type 2, based on the clinical features present and on whether or not ketonuria accompanies the glycosuria. Features that suggest end-organ insulin insensitivity to insulin, such as visceral obesity, acanthosis nigricans, or both, must be identified. The family history should document not only the incidence of diabetes in other members of the family but also the age at onset, association with obesity, the need for insulin, and whether there were complications. For the occasional patient, measurement of GAD65, IAA, ICA 512, and zinc transporter 8 antibodies can help distinguish between type 1 and type 2 diabetes. Many patients with newly diagnosed type 1 diabetes still have significant endogenous insulin production, and C peptide levels do not reliably distinguish between type 1 and type 2 diabetes. Other factors that increase cardiac risk, such as smoking history, presence of hypertension or hyperlipidemia, or oral contraceptive pill use, should be recorded.
Laboratory diagnosis of diabetes should document fasting plasma glucose levels above 126 mg/dL (7 mmol/L) or postprandial values consistently above 200 mg/dL (11.1 mmol/L) or HbA1c of at least 6.5% and whether ketonuria accompanies the glycosuria. An HbA1c measurement is also useful for assessing the effectiveness of future therapy. Baseline values include fasting plasma triglycerides, total cholesterol and HDL-cholesterol, electrocardiography, kidney function studies, peripheral pulses, and neurologic, podiatric, and ophthalmologic examinations to help guide future assessments.
B. Patient Education (Self-Management Training)
Since diabetes is a lifelong disorder, education of the patient and the family is probably the most important obligation of the clinician who provides initial care. The best persons to manage a disease that is affected so markedly by daily fluctuations in environmental stress, exercise, diet, and infections are the patients themselves and their families. The “teaching curriculum” should include explanations by the clinician or nurse of the nature of diabetes and its potential acute and chronic hazards and how they can be recognized early and prevented or treated. Self-monitoring of blood glucose should be emphasized, especially in insulin-requiring diabetic patients, and instructions must be given on proper testing and recording of data.
Patients taking insulin should have an understanding of the actions of basal and bolus insulins. They should be taught to determine whether the basal dose is appropriate and how to adjust the rapidly acting insulin dose for the carbohydrate content of a meal. Patients and their families and friends should be taught to recognize signs and symptoms of hypoglycemia and how to treat low glucose reactions. Strenuous exercise can precipitate hypoglycemia, and patients must therefore be taught to reduce their insulin dosage in anticipation of strenuous activity or to take supplemental carbohydrate. Injection of insulin into a site farthest away from the muscles most involved in the exercise may help ameliorate exercise-induced hypoglycemia, since insulin injected in the proximity of exercising muscle may be more rapidly mobilized. Exercise training also increases the effectiveness of insulin and insulin doses should be adjusted accordingly. Infections can cause insulin resistance, and patients should be instructed on how to manage the hyperglycemia with supplemental rapidly acting insulin.
The targets for blood glucose control should be elevated appropriately in elderly patients since they have the greatest risk if subjected to hypoglycemia and the least long-term benefit from more rigid glycemic control. Advice on personal hygiene, including detailed instructions on foot and dental care, should be provided. All infections (especially pyogenic ones) provoke the release of high levels of insulin antagonists, such as catecholamines or glucagon, and thus bring about a marked increase in insulin requirements. Patients who are taking oral agents may decompensate and temporarily require insulin. Patients should be told about community agencies, such as Diabetes Association chapters, that can serve as a continuing source of instruction.
Finally, vigorous efforts should be made to persuade patients with newly diagnosed diabetes who smoke to give up the habit, since large vessel peripheral vascular disease and debilitating retinopathy are less common in nonsmoking diabetic patients.
Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient. However, certain general principles of management can be outlined for hyperglycemic states of different types.
Traditional once- or twice-daily insulin regimens are usually ineffective in type 1 patients without residual endogenous insulin. In these patients, information and counseling based on the findings of the DCCT (see above) should be provided about the advantages of taking multiple injections of insulin in conjunction with self-blood glucose monitoring. If near-normalization of blood glucose is attempted, at least four measurements of capillary blood glucose and three or four insulin injections are necessary.
A combination of rapidly acting insulin analogs and long-acting insulin analogs allows for more physiologic insulin replacement. The rapidly acting insulin analogs have been advocated as a safer and much more convenient alternative to regular human insulin for preprandial use. In a study comparing regular insulin with insulin lispro, daily insulin doses and HbA1c levels were similar, but insulin lispro improved postprandial control, reduced hypoglycemic episodes, and improved patient convenience compared with regular insulin. However, because of their relatively short duration (no more than 3–4 hours), the rapidly acting insulin analogs need to be combined with longer-acting insulins to provide basal coverage and avoid hyperglycemia prior to the next meal. In addition to carbohydrate content of the meal, the effect of simultaneous fat ingestion must also be considered a factor in determining the rapidly acting insulin analog dosage required to control the glycemic increment during and just after the meal. With low-carbohydrate content and high-fat intake, there is an increased risk of hypoglycemia from insulin lispro within 2 hours after the meal. Table 27–8 illustrates a regimen with a rapidly acting insulin analog and insulin detemir or insulin glargine that might be appropriate for a 70-kg person with type 1 diabetes eating meals providing standard carbohydrate intake and moderate to low fat content.
Table 27–8.Examples of intensive insulin regimens using rapidly acting insulin analogs (insulin lispro, aspart, or glulisine) and insulin detemir, or insulin glargine or degludec in a 70-kg man with type 1 diabetes.1–3 |Favorite Table|Download (.pdf) Table 27–8. Examples of intensive insulin regimens using rapidly acting insulin analogs (insulin lispro, aspart, or glulisine) and insulin detemir, or insulin glargine or degludec in a 70-kg man with type 1 diabetes.1–3
| ||Pre-Breakfast ||Pre-Lunch ||Pre-Dinner ||At Bedtime |
|Rapidly acting insulin analog ||5 units ||4 units ||6 units || |
|Insulin detemir ||6–7 units || || ||8–9 units |
|OR || || || || |
|Rapidly acting insulin analog ||5 units ||4 units ||6 units ||— |
|Insulin glargine or degludec || ||— || ||15–16 units |
Insulin glargine is usually given once in the evening to provide 24-hour coverage. This insulin cannot be mixed with any of the other insulins and must be given as a separate injection. There are occasional patients in whom insulin glargine does not seem to last for 24 hours, and in such cases it needs to be given twice a day. As shown, insulin detemir may also need to be given twice a day to get adequate 24-hour basal coverage. Alternatively, small doses of NPH (~3–4 units) can be given with each meal to provide daytime basal coverage with a larger dose at night. Unlike the long-acting insulin analogs, NPH can be mixed in the same syringe as the insulin lispro, insulin aspart, and insulin glulisine.
Continuous subcutaneous insulin infusion (CSII) by portable battery-operated “open loop” devices currently provides the most flexible approach, allowing the setting of different basal rates throughout the 24 hours and permitting patients to delay or skip meals and vary meal size and composition. The dosage is usually based on providing 50% of the estimated insulin dose as basal and the remainder as intermittent boluses prior to meals. For example, a 70-kg man requiring 35 units of insulin per day may require a basal rate of 0.7 units per hour throughout the 24 hours with the exception of 3 am to 8 am, when 0.8 units per hour might be appropriate (given the “dawn phenomenon”—reduced tissue sensitivity to insulin between 5 am and 8 am). The meal bolus would depend on the carbohydrate content of the meal and the premeal blood glucose value. One unit per 15 g of carbohydrate plus 1 unit for 50 mg/dL (2.8 mmol/L) of blood glucose above a target value (eg, 120 mg/dL [6.7 mmol/L]) is a common starting point. Further adjustments to basal and bolus dosages would depend on the results of blood glucose monitoring. The majority of patients use the rapidly acting insulin analogs in the pumps. One of the more difficult therapeutic problems in managing patients with type 1 diabetes is determining the proper adjustment of insulin dose when the prebreakfast blood glucose level is high. Occasionally, the prebreakfast hyperglycemia is due to the Somogyi effect, in which nocturnal hypoglycemia leads to a surge of counterregulatory hormones to produce high blood glucose levels by 7 am. However, a more common cause for prebreakfast hyperglycemia is the waning of circulating insulin levels by the morning. Also, the dawn phenomenon is present in as many as 75% of type 1 patients and can aggravate the hyperglycemia.
The diagnosis of the cause of prebreakfast hyperglycemia can be facilitated by self-monitoring of blood glucose at 3 am in addition to the usual bedtime and 7 am measurements (Table 27–9). This is required for only a few nights, and when a particular pattern emerges from monitoring blood glucose levels overnight, appropriate therapeutic measures can be taken. The Somogyi effect can be treated by eliminating the dose of intermediate insulin at dinnertime and giving it at a lower dosage at bedtime or by supplying more food at bedtime. When a waning insulin level is the cause, then either increasing the evening dose or shifting it from dinnertime to bedtime (or both) can be effective. A bedtime dose either of insulin glargine or insulin detemir provides more sustained overnight insulin levels than human NPH and may be effective in managing refractory prebreakfast hyperglycemia. If this fails, insulin pump therapy may be required.
Table 27–9.Prebreakfast hyperglycemia: Classification by blood glucose and insulin levels. |Favorite Table|Download (.pdf) Table 27–9. Prebreakfast hyperglycemia: Classification by blood glucose and insulin levels.
| ||Blood Glucose (mg/dL) [mmol/L] ||Free Immunoreactive Insulin (microunit/mL) |
|10:00 PM ||3:00 AM ||7:00 AM ||10:00 PM ||3:00 AM ||7:00 AM |
|Somogyi effect ||90  ||40 [2.2] ||200 [11.1] ||High ||Slightly high ||Normal |
|Dawn phenomenon ||110 [6.1] ||110 [6.1] ||150 [8.3] ||Normal ||Normal ||Normal |
|Waning of insulin dose plus dawn phenomenon ||110 [6.1] ||190 [10.6] ||220 [12.2] ||Normal ||Low ||Low |
|Waning of insulin dose plus dawn phenomenon plus Somogyi effect ||110 [6.1] ||40 [2.2] ||380 [21.1] ||High ||Normal ||Low |
Therapeutic recommendations are based on the relative contributions of beta cell insufficiency and insulin insensitivity in individual patients. The possibility that the individual patient has a specific etiologic cause for their diabetes should always be considered, especially when the patient does not have a family history of type 2 diabetes or does not have any evidence of central obesity or insulin resistance. Such patients should be evaluated for other types of diabetes such as LADA or MODY. Patients with LADA should be prescribed insulin when the disease is diagnosed and treated like patients with type 1 diabetes. It is also important to note that many patients with type 2 diabetes mellitus have a progressive loss of beta cell function and will require additional therapeutic interventions with time.
One of the primary modes of therapy in the obese patient with type 2 diabetes is weight reduction. Normalization of glycemia can be achieved by weight loss and improvement in tissue sensitivity to insulin. A combination of caloric restriction, increased exercise, and behavior modification is required if a weight reduction program is to be successful. Understanding the risks associated with the diagnosis of diabetes may motivate the patient to lose weight.
For selected patients, medical or surgical options for weight loss should be considered. Orlistat, phentermine/topiramate, lorcaserin, naltrexone/extended-release bupropion, and high-dose liraglutide (3 mg daily) are weight loss medications approved for use in combination with diet and exercise (see Chapter 29).
Orlistat (Xenical) is a reversible inhibitor of gastric and pancreatic lipases and prevents the hydrolysis and absorption of dietary triglycerides. It is available over-the-counter and in prescription strength. In 1-year studies in obese patients with type 2 diabetes, those taking orlistat had lost more weight, had lower HbA1c values, and had improved lipid profiles. The main adverse reactions were gastrointestinal, with oily spotting, oily stool, flatus, and fecal urgency and frequency. Malabsorption of fat-soluble vitamins also occurs, and patients should take a multivitamin tablet containing fat-soluble vitamins at least 2 hours before or 2 hours after the administration of orlistat. Cases of severe liver injury have been reported with this medication, although a cause and effect relationship has not been established.
Phentermine is a sympathomimetic amine stimulating release of norepinephrine from the hypothalamus. Topiramate is primarily used as an anticonvulsant, but it also appears to reduce appetite. In a 56-week phase 3 study, an extended-release preparation of phentermine/topiramate (Qsymia) together with diet and lifestyle intervention resulted in 10 kg weight loss (9.8%) compared to 1.4 kg (1.2%) with placebo. As might be expected, the diabetes subgroup on active therapy had greater reductions in HbA1c levels; and fewer patients with prediabetes on active therapy progressed to diabetes. The adverse events are consistent with those of the constituent drugs. The most common adverse reactions were paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Topiramate can worsen depression and increase risk of suicidal thoughts. It is also teratogenic and the FDA has required the manufacturer to conduct a risk evaluation and mitigation strategy (REMS). The medication is only available through specialty mail-order pharmacies.
Lorcaserin (Belviq) is a 5-hydroxytryptamine receptor subtype 2C (5-HT2C) agonist. This receptor subclass regulates mood and appetite. In a 52-week study, patients taking lorcaserin had a 8.1 kg weight loss (8.2%) compared to 3.2 kg placebo group (3.3%). The main adverse reactions were headache and nausea. Fenfluramine, an agonist for the 5-HT2B receptor, was associated with serotonin-related cardiac valvulopathy. Activation of the 5-HT2C receptor, however, does not appear to be associated with valvulopathy. Sibutramine, a combined serotonin-norepinephrine reuptake inhibitor, was moderately effective in promoting weight loss, but it was withdrawn from the US market because of its association with increased cardiovascular risk.
Naltrexone is an antagonist at mu- and kappa-opioid receptors and is used in the treatment of alcohol and opioid dependence. Bupropion is a partial agonist at the mu-opioid receptor, an antagonist at the kappa-opioid receptor and a partial agonist at the nociception receptor; it is used to treat depression, seasonal affective disorder, and as an aid to stop smoking. Naltrexone/extended-release bupropion (Contrave) together with diet and exercise in patients with diabetes resulted in 2% more weight loss than placebo at 1 year of study. The weight loss with the medication was greater in the study of obese people without diabetes (4.1%). Serious neuropsychiatric events and seizures have been reported in patients taking bupropion. Naltrexone should not be given to patients receiving long-term opioid therapy. Naltrexone/extended bupropion should be discontinued if the patient needs opioid therapy and lower doses of opioids may be needed.
Liraglutide 3 mg (Saxenda) is a GLP-1 receptor agonist. The 0.6–1.8 mg dose has been approved for the treatment of type 2 diabetes and is associated with modest weight loss. The 3-mg dose has been approved for weight loss in combination with diet and exercise. In nondiabetic obese persons, liraglutide together with diet and exercise resulted in 4.5% more weight loss than placebo at 1 year of treatment. In a study of people with diabetes, the average weight loss with the medication was 3.7% compared to placebo at 1 year. Common adverse reactions include nausea, vomiting, and diarrhea. Serious side effects include pancreatitis. The medication should not be used in patients with MEN 2 or personal or family history of medullary thyroid cancer.
Bariatric surgery (Roux-en-Y, gastric banding, gastric sleeve, biliopancreatic diversion/duodenal switch) typically results in substantial weight loss and improvement in glucose levels. A meta-analysis examining the impact of bariatric surgery on patients with diabetes and BMI of 40 kg/m2 or greater noted that 82% of patients had resolution of clinical and laboratory manifestations of diabetes in the first 2 years after surgery and 62% remained free of diabetes more than 2 years after surgery. The improvement was most marked in the procedure that caused the greatest weight loss (biliopancreatic diversion/duodenal switch). There was, however, a high attrition of patients available for follow-up, and there was little information about different ethnic types. Weight regain does occur after bariatric surgery, and it can be expected that 20–25% of the lost weight will be regained over 10 years. The impact of this weight gain on diabetes recurrence depends principally on the degree of beta cell dysfunction. Also anatomic changes imposed by malabsorptive surgery can result in protein malnutrition, vitamin and mineral deficiencies. Clinically significant deficiencies in calcium; folic acid; iron; and vitamins D, B12, A, and K are common. Thus, patients undergoing malabsorptive procedures require lifelong supplementation and monitoring by a team familiar with possible deficiencies. Both early and late dumping symptoms can also occur.
Nonobese patients with type 2 diabetes frequently have increased visceral adiposity—the so-called metabolically obese normal weight patient. There is less emphasis on weight loss, but exercise remains an important aspect of treatment.
b. Glucose lowering agents
Figure 27–2 outlines the treatment approach based on the consensus algorithm proposed by the American Diabetes Association and the European Association for the Study of Diabetes. The current recommendation is to start metformin therapy at diagnosis and not wait to see whether the patient can achieve target glycemic control with weight management and exercise. See discussion of the individual medications, above. Metformin is advantageous because, apart from lowering glucose without the risk of hypoglycemia, it also lowers serum triglycerides and promotes some modest weight loss. In the UKPDS study, metformin use in the obese participants was associated with reduction in risk of cardiovascular events. The medication, however, cannot be used in patients with end-stage renal disease, and sometimes gastrointestinal side effects develop at even the lowest doses and persist over time. Under these circumstances the choice of the initial agent depends on a number of factors, including comorbid conditions, adverse reactions to the medications, ability of the patient to monitor for hypoglycemia, medication cost, and patient and clinician preferences. Pioglitazone improves peripheral insulin resistance and lowers glucose without causing hypoglycemia. Troublesome adverse reactions include weight gain, fluid retention and heart failure, increased fracture risk in women, and possible increased risk of bladder cancer. Pioglitazone is contraindicated in patients with active liver disease and in patients with liver enzymes are 2.5 times or more the upper limit of normal. The alpha-glucosidase inhibitors (acarbose, miglitol) have modest glucose lowering effects and have gastrointestinal side effects. The GLP-1 receptor agonists (eg, exenatide or liraglutide) have a lower risk of hypoglycemia than the sulfonylureas and they promote weight loss; however, they need to be given by injection. These agents cause nausea, may cause pancreatitis, and are contraindicated in patients with gastroparesis. The DPP-4 inhibitors (eg, sitagliptin) also have a low risk of hypoglycemia, and they do not cause nausea or vomiting. They can also be used in patients with kidney impairment. There are, however, reports of serious allergic reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome. There is also concern that they may, like the GLP-1 receptor agonists, cause pancreatitis. The SGLT2 inhibitors (eg, canagliflozin) lower fasting and postprandial glucose levels. They also have a low risk of hypoglycemia, promote weight loss, and lower blood pressure levels. They increase the risk for mycotic genital infections and urinary tract infections, however. They can cause volume depletion and are less effective in patients with kidney disease.
Algorithm for the treatment of type 2 diabetes based on the 2012 and 2015 recommendations of the consensus panel of the American Diabetes Association/European Association for the Study of Diabetes.
When diabetes is not well controlled with initial therapy (usually metformin), then a second agent should be added. Sulfonylureas have been available for many years and their use in combination with metformin is well established. They do, however, have the propensity of causing hypoglycemia and weight gain. In patients who experience hyperglycemia after a carbohydrate-rich meal (such as dinner), a short-acting secretagogue (repaglinide or nateglinide) before meals may suffice to get the glucose levels into the target range. Patients with severe insulin resistance may be candidates for pioglitazone. Patients who are very concerned about weight gain may benefit from a trial of GLP-1 receptor agonist or DPP-4 inhibitor or SGLT2 inhibitor. If two agents are inadequate, then a third agent is added, although data regarding efficacy of such combined therapy are limited.
When the combination of oral agents (and injectable GLP-1 receptor agonists) fail to achieve euglycemia in patients with type 2 diabetes, then insulin treatment should be instituted. Various insulin regimens may be effective. One proposed regimen is to continue the oral combination therapy and then simply add a bedtime dose of NPH or long-acting insulin analog (insulin glargine or insulin detemir) to reduce excessive nocturnal hepatic glucose output and improve fasting glucose levels. If the patient does not achieve target glucose levels during the day, then daytime insulin treatment can be initiated. A convenient insulin regimen under these circumstances is a split dose of 70/30 NPH/regular mixture (or Humalog Mix 75/25 or NovoLogMix 70/30) before breakfast and before dinner. If this regimen fails to achieve satisfactory glycemic goals or is associated with unacceptable frequency of hypoglycemic episodes, then a more intensive regimen of multiple insulin injections can be instituted as in patients with type 1 diabetes. Metformin principally reduces hepatic glucose output, and it is reasonable to continue with this medication when insulin therapy is instituted. Pioglitazone, which improves peripheral insulin sensitivity, can be used together with insulin but this combination is associated with more weight gain and peripheral edema. The sulfonylureas also continue to be of benefit. There is limited information on the benefits of continuing the GLP1-receptor agonists or the DPP-4 inhibitors or the SGLT2 inhibitors once insulin therapy is initiated. Weight-reducing interventions should continue even after initiation of insulin therapy and may allow for simplification of the therapeutic regimen in the future.
D. Acceptable Levels of Glycemic Control
A reasonable aim of therapy is to approach normal glycemic excursions without provoking severe or frequent hypoglycemia. Criteria for “acceptable” control includes the following: (1) blood glucose levels of 90–130 mg/dL (5–7.2 mmol/L) before meals and after an overnight fast, (2) levels no higher than 180 mg/dL (10 mmol/L) 1 hour after meals and 150 mg/dL (8.3 mmol/L) 2 hours after meals, and (3) HbA1c levels less than 7% for nonpregnant adults. Less stringent HbA1c goals may be appropriate in children, those with a history of severe hypoglycemia, limited life expectancy, and advanced microvascular and macrovascular disease. In the elderly frail patient, an HbA1c target of approximately 8% (preprandial blood glucose levels in the range of the 150–159 mg/dL) may be reasonable although formal evidence is lacking. The UKPDS study demonstrated that blood pressure control was as significant or more significant than glycemic control in patients with type 2 diabetes regarding the prevention of microvascular as well as macrovascular complications.
et al. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010 Nov;95(11):4823–43.
et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015 Jan;38(1):140–9.
et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012 Apr 26;366(17):1577–85.
et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009 Jan;32(1):193–203.
et al. Intensive insulin therapy in patients with type 1 diabetes mellitus. Endocrinol Metab Clin North Am. 2012 Mar;41(1):89–104.
et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013 Aug 20;159(4):262–74.
et al; American Diabetes Association. Physical activity/exercise and diabetes. Diabetes Care. 2004 Jan;27(Suppl 1):S58–62.
E. Complications of Insulin Therapy
Hypoglycemic reactions are the most common complications that occur in patients with diabetes who are treated with insulin. The signs and symptoms of hypoglycemia may be divided into those resulting from stimulation of the autonomic nervous system and those from neuroglycopenia (insufficient glucose for normal central nervous system function). When the blood glucose falls to around 54 mg/dL (3 mmol/L), the patient starts to experience both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger) nervous system symptoms. If these autonomic symptoms are ignored and the glucose levels fall further (to around 50 mg/dL [2.8 mmol/L]), then neuroglycopenic symptoms appear, including irritability, confusion, blurred vision, tiredness, headache, and difficulty speaking. A further decline in glucose can then lead to loss of consciousness or even a seizure. With repeated episodes of hypoglycemia, there is adaptation, and autonomic symptoms do not occur until the blood glucose levels are much lower and so the first symptoms are often due to neuroglycopenia. This condition is referred to as “hypoglycemic unawareness.” It has been shown that hypoglycemic unawareness can be reversed by keeping glucose levels high for a period of several weeks. Except for sweating, most of the sympathetic symptoms of hypoglycemia are blunted in patients receiving beta-blocking agents. Though not absolutely contraindicated, these medications must be used with caution in patients with diabetes who require insulin, and beta-1-selective blocking agents are preferred.
Hypoglycemia can occur in patient taking sulfonylureas, repaglinide, and nateglinide, particularly if the patient is elderly, has kidney or liver disease, or is taking certain other medications that alter metabolism of the sulfonylureas (eg, phenylbutazone, sulfonamides, or warfarin). It occurs more frequently with the use of long-acting sulfonylureas than when shorter-acting agents are used. Otherwise, hypoglycemia in insulin-treated patients with diabetes occurs as a consequence of three factors: behavioral issues, impaired counterregulatory systems, and complications of diabetes.
Behavioral issues include injecting too much insulin for the amount of carbohydrates ingested. Drinking alcohol in excess, especially on an empty stomach, can also cause hypoglycemia. In patients with type 1 diabetes, hypoglycemia can occur during or even several hours after exercise, and so glucose levels need to be monitored and food and insulin adjusted. Some patients do not like their glucose levels to be high, and they treat every high glucose level aggressively. These individuals who “stack” their insulin—that is, give another dose of insulin before the first injection has had its full action—can develop hypoglycemia.
Counterregulatory issues resulting in hypoglycemia include impaired glucagon response, sympatho-adrenal responses, and cortisol deficiency. Patients with diabetes of greater than 5 years duration lose their glucagon response to hypoglycemia. As a result, they are at a significant disadvantage in protecting themselves against falling glucose levels. Once the glucagon response is lost, their sympatho-adrenal responses take on added importance. Unfortunately, aging, autonomic neuropathy, or hypoglycemic unawareness due to repeated low glucose levels further blunts the sympatho-adrenal responses. Occasionally, Addison disease develops in persons with type 1 diabetes mellitus; when this happens, insulin requirements fall significantly, and unless insulin dose is reduced, recurrent hypoglycemia will develop.
Complications of diabetes that increase the risk for hypoglycemia include autonomic neuropathy, gastroparesis, and end-stage chronic kidney disease. The sympathetic nervous system is an important system alerting the individual that the glucose level is falling by causing symptoms of tachycardia, palpitations, sweating, and tremulousness. Failure of the sympatho-adrenal responses increases the risk of hypoglycemia. In addition, in patients with gastroparesis, if insulin is given before a meal, the peak of insulin action may occur before the food is absorbed causing the glucose levels to fall. Finally, in end-stage chronic kidney disease, hypoglycemia can occur presumably because of decreased insulin clearance as well as loss of renal contribution to gluconeogenesis in the postabsorptive state.
To prevent and treat insulin-induced hypoglycemia, the diabetic patient should carry glucose tablets or juice at all times. For most episodes, ingestion of 15 grams of carbohydrate is sufficient to reverse the hypoglycemia. The patient should be instructed to check the blood glucose in 15 minutes and treat again if the glucose level is still low. A parenteral glucagon emergency kit (1 mg) should be provided to every patient with diabetes who is receiving insulin therapy. Family or friends should be instructed how to inject it subcutaneously or intramuscularly into the buttock, arm, or thigh in the event that the patient is unconscious or refuses food. The medication can occasionally cause vomiting, and the unconscious patient should be turned on his or her side to protect the airway. The glucagon mobilizes glycogen from the liver, raising the blood glucose by about 36 mg/dL (2 mmol/L) in about 15 minutes. After the patient recovers consciousness, additional oral carbohydrate should be given. People with diabetes receiving hypoglycemic medication therapy should also wear an identification MedicAlert bracelet or necklace or carry a card in his or her wallet (1-800-ID-ALERT, www.medicalert.org).
Medical personnel treating severe hypoglycemia can give 50 mL of 50% glucose solution by rapid intravenous infusion. If intravenous access is not available, 1 mg of glucagon can be injected intramuscularly.
2. Immunopathology of insulin therapy
At least five molecular classes of insulin antibodies are produced during the course of insulin therapy in diabetes, including IgA, IgD, IgE, IgG, and IgM. With the switch to human and purified pork insulin, the various immunopathologic syndromes such as insulin allergy, immune insulin resistance, and lipoatrophy have become quite rare since the titers and avidity of these induced antibodies are generally quite low.
Insulin allergy, or immediate-type hypersensitivity, is a rare condition in which local or systemic urticaria is due to histamine release from tissue mast cells sensitized by adherence of anti-insulin IgE antibodies. In severe cases, anaphylaxis results. When only human insulin has been used from the onset of insulin therapy, insulin allergy is exceedingly rare. Antihistamines, corticosteroids, and even desensitization may be required, especially for systemic hypersensitivity. There have been case reports of successful use of insulin lispro in those rare patients who have a generalized allergy to human insulin or insulin resistance due to a high titer of insulin antibodies.
b. Immune insulin resistance
A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a small extent develops in most insulin-treated patients. With the old animal insulins, a high titer of circulating antibodies sometimes developed, resulting in extremely high insulin requirements—often more than 200 units daily. This is now rarely seen with the switch to human or highly purified pork insulins and has not been reported with the analogs.
Atrophy of subcutaneous fatty tissue leading to disfiguring excavations and depressed areas may rarely occur at the site of injection (eFigure 27–2). This complication results from an immune reaction, and it has become rarer with the development of human and highly purified insulin preparations. Lipohypertrophy, on the other hand, is a consequence of the pharmacologic effects of insulin being deposited in the same location repeatedly (eFigure 27–3). It can occur with purified insulins as well. Rotation of injection sites will prevent lipohypertrophy. There is a case report of a patient who had intractable lipohypertrophy with human insulin but no longer had the problem when he switched to insulin lispro.
Subcutaneous atrophy from insulin injections. (Courtesy of Elliot Joslin Research Laboratories and Diabetes Foundation, Boston, Massachusetts.)
Lipohypertrophy in a man 22 years of age who had been taking insulin for 2 years. (Courtesy of Elliot Joslin Research Laboratories and Diabetes Foundation, Boston, Massachusetts.)
PE. Elimination of hypoglycemia from the lives of people affected by diabetes. Diabetes. 2011 Jan;60(1):24–7.
PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013 Jul 25;369(4):362–72.
Chronic Complications of Diabetes
Late clinical manifestations of diabetes mellitus include a number of pathologic changes that involve small and large blood vessels, cranial and peripheral nerves, the skin, and the lens of the eye. These lesions lead to hypertension, end-stage chronic kidney disease, blindness, autonomic and peripheral neuropathy, amputations of the lower extremities, myocardial infarction, and cerebrovascular accidents. These late manifestations correlate with the duration of the diabetic state subsequent to the onset of puberty. In type 1 diabetes, end-stage chronic kidney disease develops in up to 40% of patients, compared with less than 20% of patients with type 2 diabetes. Proliferative retinopathy ultimately develops in both types of diabetes but has a slightly higher prevalence in type 1 patients (25% after 15 years’ duration). In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death, whereas patients with type 2 diabetes are more likely to have macrovascular diseases leading to myocardial infarction and stroke as the main causes of death. Cigarette use adds significantly to the risk of both microvascular and macrovascular complications in diabetic patients.
Premature cataracts occur in diabetic patients and seem to correlate with both the duration of diabetes and the severity of chronic hyperglycemia. Nonenzymatic glycosylation of lens protein is twice as high in diabetic patients as in age-matched nondiabetic persons and may contribute to the premature occurrence of cataracts.
There are two main categories of diabetic retinopathy: nonproliferative and proliferative (see Chapter 7) (eFigures 27–4 and 27–5). Diabetic macular edema can occur at any stage. Nonproliferative (“background”) retinopathy represents the earliest stage of retinal involvement by diabetes and is characterized by such changes as microaneurysms, dot hemorrhages, exudates, and retinal edema. During this stage, the retinal capillaries leak proteins, lipids, or red cells into the retina. When this process occurs in the macula (clinically significant macular edema), the area of greatest concentration of visual cells, there is interference with visual acuity; this is the most common cause of visual impairment in patients with type 2 diabetes. The prevalence of nonproliferative retinopathy in patients with type 2 diabetes is 60% after 16 years.
Nonproliferative diabetic retinopathy with intraretinal hemorrhages, microaneurysms, cotton wool spots and hard exudates. (Used, with permission, from Drs. Bernard Dolan and Andrew Mick, San Francisco VA Medical Center, San Francisco.)
Proliferative diabetic retinopathy with neovascularization of the disk and preretinal hemorrhage. Fluorescein angiogram demonstrates leakage from the neovascularization. (Used, with permission, from Drs. Bernard Dolan and Andrew Mick, San Francisco VA Medical Center, San Francisco.)
Proliferative retinopathy involves the growth of new capillaries and fibrous tissue within the retina and into the vitreous chamber. It is a consequence of small vessel occlusion, which causes retinal hypoxia; this in turn stimulates new vessel growth. New vessel formation may occur at the optic disk or elsewhere on the retina. Prior to proliferation of new capillaries, a preproliferative phase often occurs in which arteriolar ischemia is manifested as cotton-wool spots (small infarcted areas of retina). Vision is usually normal until vitreous hemorrhage or retinal detachment occurs.
Proliferative retinopathy can occur in both types of diabetes but is more common in type 1, developing about 7–10 years after onset of symptoms, with a prevalence of 25% after 15 years’ duration. Proliferative retinopathy is a leading cause of blindness in the United States, particularly since it increases the risk of retinal detachment. Vision-threatening retinopathy virtually never appears in type 1 patients in the first 3–5 years of diabetes or before puberty. Up to 20% of patients with type 2 diabetes have retinopathy at the time of diagnosis, because many were probably diabetic for an extensive period of time before diagnosis. Annual consultation with an ophthalmologist should be arranged for patients who have had type 1 diabetes for more than 3–5 years and for all patients with type 2 diabetes. Chapter 7 describes the treatment of retinopathy and macular edema. Patients with any macular edema, severe nonproliferative retinopathy, or any proliferative retinopathy require the care of an ophthalmologist. Extensive "scatter" xenon or argon photocoagulation and focal treatment of new vessels reduce severe visual loss in those cases in which proliferative retinopathy is associated with recent vitreous hemorrhages or in which extensive new vessels are located on or near the optic disk. Macular edema, which is more common than proliferative retinopathy in patients with type 2 diabetes (up to 20% prevalence), has a guarded prognosis, but it has also responded to scatter therapy with improvement in visual acuity if detected early. Injection of bevacizumab (Avastin), an anti-vascular endothelial growth factor (anti-VEGF), into the eye has been shown to stop the growth of the new blood vessels in diabetic eye disease. Avoiding tobacco use and correction of associated hypertension are important therapeutic measures in the management of diabetic retinopathy. There is no contraindication to using aspirin in patients with proliferative retinopathy.
Glaucoma occurs in approximately 6% of persons with diabetes. It is responsive to the usual therapy for open-angle disease. Neovascularization of the iris in patients with diabetes can predispose to closed-angle glaucoma, but this is relatively uncommon except after cataract extraction, when growth of new vessels has been known to progress rapidly, involving the angle of the iris and obstructing outflow.
As many as 4000 cases of end-stage chronic kidney disease occur each year among diabetic people in the United States (eFigure 27–6). This is about one-third of all patients being treated for end-stage chronic kidney disease and represents a considerable national health expense.
Development of renal failure in type 1 diabetes. (Reproduced, with permission, from Omachi R. The pathogenesis and prevention of diabetic nephropathy. West J Med. 1986;145:222.)
The cumulative incidence of nephropathy differs between the two major types of diabetes. Patients with type 1 diabetes have a 30–40% chance of having nephropathy after 20 years—in contrast to the much lower frequency in type 2 diabetes patients, in whom only about 15–20% develop clinical kidney disease. However, since there are many more individuals affected with type 2 diabetes, end-stage chronic kidney disease is much more prevalent in type 2 than in type 1 diabetes in the United States and especially throughout the rest of the world. Improved glycemic control and more effective therapeutic measures to correct hypertension—and with the beneficial effects of ACE inhibitors—can reduce the development of end-stage chronic kidney disease among patients with diabetes.
Diabetic nephropathy is initially manifested by proteinuria; subsequently, as kidney function declines, urea and creatinine accumulate in the blood. Sensitive radioimmunoassay methods detect small amounts of urinary albumin—in contrast to the less sensitive dipstick strips, whose minimal detection limit is 0.3–0.5%. Conventional 24-hour urine collections, in addition to being inconvenient for patients, also show wide variability of albumin excretion, since several factors such as sustained erect posture, dietary protein, and exercise tend to increase albumin excretion rates. For these reasons, an albumin-creatinine ratio in an early morning spot urine collected upon awakening is preferable. In the early morning spot urine, a ratio of albumin (mcg/L) to creatinine (mg/L) of less than 30 mcg/mg creatinine is normal, and a ratio of 30–300 mcg/mg creatinine suggests abnormal microalbuminuria. At least two early morning spot urine collections over a 3- to 6-month period should be abnormal before a diagnosis of microalbuminuria is justified. Short-term hyperglycemia, exercise, urinary tract infections, heart failure, and acute febrile illness can cause transient albuminuria and so testing for microalbuminuria should be postponed until resolution of these problems.
Subsequent end-stage chronic kidney disease can be predicted by persistent urinary albumin excretion rates exceeding 30 mcg/mg creatinine. Glycemic control as well as a protein diet of 0.8 g/kg/day may reduce both the hyperfiltration and the elevated microalbuminuria in patients in the early stages of diabetes and those with incipient diabetic nephropathy. Antihypertensive therapy also decreases microalbuminuria. Evidence from some studies—but not the UKPDS—supports a specific role for ACE inhibitors in reducing intraglomerular pressure in addition to their lowering of systemic hypertension. An ACE inhibitor (captopril, 50 mg twice daily) in normotensive diabetic patients impedes progression to proteinuria and prevents the increase in albumin excretion rate. Since microalbuminuria has been shown to correlate with elevated nocturnal systolic blood pressure, it is possible that “normotensive” diabetic patients with microalbuminuria have slightly elevated systolic blood pressure during sleep, which is lowered during antihypertensive therapy. This action may contribute to the reported efficacy of ACE inhibitors in reducing microalbuminuria in “normotensive” patients.
If treatment is inadequate, then the disease progresses with proteinuria of varying severity occasionally leading to nephrotic syndrome with hypoalbuminemia, edema, and an increase in circulating LDL cholesterol, as well as progressive azotemia. In contrast to all other kidney disorders, the proteinuria associated with diabetic nephropathy does not diminish with progressive end-stage chronic kidney disease (patients continue to excrete 10–11 g daily as creatinine clearance diminishes). As end-stage chronic kidney disease progresses, there is an elevation in the renal threshold at which glycosuria appears (see Chapter 22).
Patients with diabetic nephropathy should be evaluated and monitored by a nephrologist. There has been gradual improvement in quality of life of diabetic patients receiving dialysis but mortality remains higher than in nondiabetic patients. During 5 years of follow-up in a European registry study, the mortality rate in people with diabetes receiving dialysis was 226.9 deaths/1000 patient years whereas the rate was 151.4 deaths/1000 patients years in people receiving dialysis who did not have diabetes. Diabetic nephropathy accounts for about 20% of kidney transplantations performed annually in the United States.
Diabetic neuropathies are the most common complications of diabetes affecting up to 50% of older patients with type 2 diabetes.
a. Distal symmetric polyneuropathy
This is the most common form of diabetic peripheral neuropathy where loss of function appears in a stocking-glove pattern and is due to an axonal neuropathic process. Longer nerves are especially vulnerable, hence the impact on the foot (eFigure 27–7). Both motor and sensory nerve conduction is delayed in the peripheral nerves, and ankle jerks may be absent.
Distal symmetric polyneuropathy. Although interosseous muscle wasting often occurs more typically in the feet than in the hands, it is often more dramatic and more evident to the clinician when it occurs in the hands. Although the condition is usually an asymptomatic sign of diabetic neuropathy, the weakness that results from muscle wasting may impair the patient's ability to hold onto objects and may cause motor impairment. (Used, with permission, from Upjohn Co. Teaching Slides, Scope R Publications.)
Sensory involvement usually occurs first and is generally bilateral, symmetric, and associated with dulled perception of vibration, pain, and temperature. The pain can range from mild discomfort to severe incapacitating symptoms. The sensory deficit may eventually be of sufficient degree to prevent patients from feeling pain. Patients who have a sensory neuropathy should therefore be examined with a 5.07 Semmes-Weinstein filament and those who cannot feel the filament must be considered at risk for unperceived neuropathic injury.
The denervation of the small muscles of the foot results in clawing of the toes and displacement of the submetatarsal fat pads anteriorly. These changes, together with the joint and connective tissue changes, alter the biomechanics of the foot and increase plantar pressures. This combination of decreased pain threshold, abnormally high foot pressures, and repetitive stress (such as from walking) can lead to calluses and ulcerations in the high-pressure areas such as over the metatarsal heads (Figure 27–3). Peripheral neuropathy, autonomic neuropathy, and trauma also predisposes to the development of Charcot arthropathy. An acute case of Charcot foot arthropathy presents with pain and swelling, and if left untreated, leads to a “rocker bottom” deformity and ulceration. The early radiologic changes show joint subluxation and periarticular fractures. As the process progresses, there is frank osteoclastic destruction leading to deranged and unstable joints particularly in the midfoot. Not surprisingly, the key issue for the healing of neuropathic ulcers in a foot with good vascular supply is mechanical unloading. In addition, any infection should be treated with debridement and appropriate antibiotics; healing duration of 8–10 weeks is typical. Occasionally, when healing appears refractory, platelet-derived growth factor (becaplermin [Regranex]) should be considered for local application. A post-marketing epidemiologic study showed increased cancer deaths in patients who had used three or more tubes of becaplermin on their leg or feet ulcers, resulting in a “black box” warning on the medication label. Once ulcers are healed, therapeutic footwear is key to preventing recurrences. Custom molded shoes are reserved for patients with significant foot deformities. Other patients with neuropathy may require accommodative insoles that distribute the load over as wide an area as possible. Patients with foot deformities and loss of their protective threshold should get regular care from a podiatrist. Patients should be educated on appropriate footwear and those with loss of their protective threshold should be instructed to inspect their feet daily for reddened areas, blisters, abrasions, or lacerations.
Diabetic foot ulcer over head of first metatarsal (arrow). (Used, with permission, from Dean SM, Satiani B, Abraham WT. Color Atlas and Synopsis of Vascular Diseases. McGraw-Hill, 2014.)
In some patients, hypersensitivity to light touch and occasionally severe “burning” pain, particularly at night, can become physically and emotionally disabling. Nortriptyline or desipramine in doses of 25–150 mg/day orally may provide dramatic relief for pain from diabetic neuropathy, often within 48–72 hours. This rapid response is in contrast to the 2 or 3 weeks required for an antidepressive effect. Patients often attribute the benefit to having a full night’s sleep. Mild to moderate morning drowsiness is a side effect that generally improves with time or can be lessened by giving the medication several hours before bedtime. This medication should not be continued if improvement has not occurred after 5 days of therapy. Amitriptyline, 25–75 mg orally at bedtime can also be used but has more anticholinergic effects. Tricyclic antidepressants, in combination with the phenothiazine, fluphenazine, have been shown in two studies to be efficacious in painful neuropathy, with benefits unrelated to relief of depression. Gabapentin (900–1800 mg orally daily in three divided doses) has also been shown to be effective in the treatment of painful neuropathy and should be tried if the tricyclic medications prove ineffective. Pregabalin, a congener of gabapentin, has been shown in an 8-week study to be more effective than placebo in treating painful diabetic peripheral neuropathy. However, this medication was not compared with an active control. Also, because of its abuse potential, it has been categorized as a schedule V controlled substance. Duloxetine (60–120 mg), a serotonin and norepinephrine reuptake inhibitor, has been approved for the treatment of painful diabetic neuropathy. In clinical trials, this medication reduced the pain sensitivity score by 40–50%. Capsaicin, a topical irritant, has been found to be effective in reducing local nerve pain; it is dispensed as a cream (Zostrix 0.025%, Zostrix-HP 0.075%) to be rubbed into the skin over the painful region two to four times daily. Gloves should be used for application since hand contamination could result in discomfort if the cream comes in contact with eyes or sensitive areas such as the genitalia. Application of a 5% lidocaine patch over an area of maximal pain has been reported to be of benefit. It is approved for treatment of postherpetic neuralgia and is in clinical trials for the treatment of painful diabetic neuropathy.
Diabetic neuropathic cachexia is a syndrome characterized by a symmetric peripheral neuropathy associated with profound weight loss (up to 60% of total body weight) and painful dysesthesias affecting the proximal lower limbs, the hands, or the lower trunk. Treatment is usually with insulin and analgesics. The prognosis is generally good, and patients typically recover their baseline weight with resolution of the painful sensory symptoms within 1 year.
b. Isolated peripheral neuropathy
Involvement of the distribution of only one nerve (“mononeuropathy”) or of several nerves (“mononeuropathy multiplex”) is characterized by sudden onset with subsequent recovery of all or most of the function. This neuropathology has been attributed to vascular ischemia or traumatic damage. Cranial and femoral nerves are commonly involved, and motor abnormalities predominate. The patient with cranial nerve involvement usually has diplopia and single third, fourth, or sixth nerve weakness on examination but the pupil is spared. A full recovery of function occurs in 6–12 weeks. Diabetic amyotrophy presents with onset of severe pain in the front of the thigh. Within a few days or weeks of the onset of pain, weakness and wasting of the quadriceps develops. As the weakness appears, the pain tends to improve. Management includes analgesia and improved diabetes control. The symptoms improve over 6–18 months.
Neuropathy of the autonomic system occurs principally in patients with diabetes of long duration. It affects many diverse visceral functions including blood pressure and pulse, gastrointestinal activity, bladder function, and erectile dysfunction. Treatment is directed specifically at each abnormality.
Involvement of the gastrointestinal system may be manifested by nausea, vomiting, postprandial fullness, reflux or dysphagia, constipation or diarrhea (or both), and fecal incontinence. Gastroparesis should be considered in type 1 diabetic patients in whom unexpected fluctuations and variability in their blood glucose levels develops after meals. Radioisotope studies show marked delay in gastric emptying. Metoclopramide has been of some help in treating diabetic gastroparesis. It is a dopamine antagonist that has central antiemetic effects as well as a cholinergic action to facilitate gastric emptying. It is given in a dose of 10 mg orally three or four times a day, 30 minutes before meals and at bedtime. Drowsiness, restlessness, fatigue, and lassitude are common adverse effects. Tardive dyskinesia and extrapyramidal effects can occur, especially when used for longer than 3 months, and the FDA has cautioned against the long-term use of metoclopramide.
Erythromycin appears to bind to motilin receptors in the stomach and has been found to improve gastric emptying over the short term in doses of 250 mg three times daily, but its effectiveness seems to diminish over time. In selected patients, injections of botulinum toxin into the pylorus can reduce pylorus sphincter resistance and enhance gastric emptying. Gastric electrical stimulation has been reported to improve symptoms and quality of life indices in patients with gastroparesis refractory to pharmacologic therapy.
Diarrhea associated with autonomic neuropathy has occasionally responded to broad-spectrum antibiotic therapy (such as rifaximin, metronidazole, amoxicillin/clavulanate, ciprofloxacin, or doxycycline), although it often undergoes spontaneous remission. Refractory diabetic diarrhea is often associated with impaired sphincter control and fecal incontinence. Therapy with loperamide, 4–8 mg daily, or diphenoxylate with atropine, two tablets up to four times a day, may provide relief. In more severe cases, tincture of paregoric or codeine (60 mg tablets) may be required to reduce the frequency of diarrhea and improve the consistency of the stools. Clonidine has been reported to lessen diabetic diarrhea; however, its usefulness is limited by its tendency to lower blood pressure in these patients who already have autonomic neuropathy, resulting in orthostatic hypotension. Constipation usually responds to stimulant laxatives such as senna.
Incomplete emptying of the bladder can sometimes occur. Bethanechol in doses of 10–50 mg orally three times a day has occasionally improved emptying of the atonic urinary bladder. Catheter decompression of the distended bladder has been reported to improve its function, and considerable benefit has been reported after surgical severing of the internal vesicle sphincter.
Use of Jobst fitted stockings, tilting the head of the bed, and arising slowly from the supine position can be helpful in treating symptoms of orthostatic hypotension. When such measures are inadequate, then treatment with fludrocortisone 0.1–0.2 mg orally daily can be considered. This medication, however, can result in supine hypertension and hypokalemia. Midodrine (10 mg orally three times a day), an alpha-agonist, can also be used.
Erectile dysfunction can result from neurologic, psychological or vascular causes, or a combination of these causes. There are medical, mechanical, and surgical treatments available for treatment of erectile dysfunction. Penile erection depends on relaxation of the smooth muscle in the arteries of the corpus cavernosum, and this is mediated by nitric oxide-induced cyclic 3′,5′-guanosine monophosphate (cGMP) formation. cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors impair the breakdown of cGMP and improve the ability to attain and maintain an erection. Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) have been shown in placebo-controlled clinical trials to improve erections in response to sexual stimulation. The recommended dose of sildenafil for most patients is one 50-mg tablet taken approximately 1 hour before sexual activity. The peak effect is at 1.5–2 hours, with some effect persisting for 4 hours. Patients with diabetes mellitus using sildenafil reported 50–60% improvement in erectile function. The maximum recommended dose is 100 mg. The recommended dose of both vardenafil and tadalafil is 10 mg. The doses may be increased to 20 mg or decreased to 5 mg based on efficacy and side effects. Tadalafil has been shown to improve erectile function for up to 36 hours after dosing. Low doses are available for daily use. In clinical trials, only a few adverse effects have been reported—transient mild headache, flushing, dyspepsia, and some altered color vision. Priapism can occur with these medications, and patients should be advised to seek immediate medical attention if an erection persists for longer than 4 hours. These phosphodiesterase type 5 (PDE5) inhibitors potentiate the hypotensive effects of nitrates and their use is contraindicated in patients who are concurrently using organic nitrates in any form. Caution is advised for men who have suffered a heart attack, stroke, or life-threatening arrhythmia within the previous 6 months; men who have resting hypotension or hypertension; and men who have a history of heart failure or have unstable angina. Rarely, a decrease in vision or permanent visual loss has been reported after PDE5 inhibitor use.
Intracorporeal injection of vasoactive medications causes penile engorgement and erection. Medications most commonly used include papaverine alone, papaverine with phentolamine, and alprostadil (prostaglandin E1). Alprostadil injections are relatively painless, but careful instruction is essential to prevent local trauma, priapism, and fibrosis. Intraurethral pellets of alprostadil avoid the problem of injection of the medication.
External vacuum therapy (Erec-Aid System) is a nonsurgical treatment consisting of a suction chamber operated by a hand pump that creates a vacuum around the penis. This draws blood into the penis to produce an erection that is maintained by a specially designed tension ring inserted around the base of the penis and which can be kept in place for up to 20–30 minutes. While this method is generally effective, its cumbersome nature limits its appeal.
Surgical implants of penile prostheses remain an option for those patients in whom the nonsurgical approaches are ineffective.
D. Cardiovascular Complications
Microangiopathy occurs in the heart and may explain the etiology of congestive cardiomyopathies in diabetic patients who do not have demonstrable coronary artery disease. More commonly, however, heart disease in patients with diabetes is due to coronary atherosclerosis. Myocardial infarction is three to five times more common in diabetic patients and is the leading cause of death in patients with type 2 diabetes. Cardiovascular disease risk is increased in patients with type 1 diabetes as well, although the absolute risk is lower than in patients with type 2 diabetes. Premenopausal women who normally have lower rates of coronary artery disease lose this protection once diabetes develops. The increased risk in patients with type 2 diabetes reflects the combination of hyperglycemia, hyperlipidemia, abnormalities of platelet adhesiveness, coagulation factors, hypertension, oxidative stress, and inflammation. Large intervention studies of risk factor reduction in diabetes are lacking, but it is reasonable to assume that reducing these risk factors would have a beneficial effect. Lowering LDL cholesterol reduces first events in patients without known coronary disease and secondary events in patients with known coronary disease. These intervention studies included some patients with diabetes, and the benefits of LDL cholesterol lowering was apparent in this group. The National Cholesterol Education Program clinical practice guidelines have designated diabetes as a coronary risk equivalent and have recommended that patients with diabetes should have an LDL cholesterol goal of less than 100 mg/dL (2.6 mmol/L). Lowering LDL cholesterol to 70 mg/dL (1.8 mmol/L) may have additional benefit and is a reasonable target for most patients with type 2 diabetes who have multiple risk factors for cardiovascular disease.
The ADA also recommends lowering systolic blood pressure to less than 140 mm Hg and diastolic pressure to less than 90 mm Hg in patients with diabetes. The systolic target of 130 mm Hg or less and diastolic of 80 mm Hg or less is recommended for the younger patient if it can be achieved without undue treatment burden. The Systolic Blood Pressure Intervention Trial (SPRINT) reported that treating to a systolic blood pressure of less than 120 mm Hg reduced cardiovascular events by 25% and death from cardiovascular causes by 43% during 3.26 years of follow-up. People with diabetes, however, were excluded from this study, and it is unclear if the results are applicable to this population. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized 33,357 persons (age 55 years and older) with hypertension and at least one other coronary artery disease risk factor to receive treatment with chlorthalidone, amlodipine, or lisinopril. Chlorthalidone appeared to be superior to amlodipine and lisinopril in lowering blood pressure, reducing the incidence of cardiovascular events, tolerability, and cost. The study included 12,063 individuals with type 2 diabetes. The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9297 high-risk patients who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor to receive ramipril or placebo for a mean of 5 years. Treatment with ramipril resulted in a 25% reduction of the risk of myocardial infarction, stroke, or death from cardiovascular disease. The mean difference between the placebo and ramipril group was 2.2 mm Hg systolic and 1.4 mm Hg diastolic blood pressure. The reduction in cardiovascular event rate remained significant after adjustment for this small difference in blood pressure. The mechanism underlying this protective effect of ramipril is unknown. Patients with type 2 diabetes who already have cardiovascular disease or microalbuminuria should be considered for treatment with an ACE inhibitor. More clinical studies are needed to address the question of whether patients with type 2 diabetes who do not have cardiovascular disease or microalbuminuria would specifically benefit from ACE inhibitor treatment.
Aspirin at a dose of 81–325 mg daily is effective in reducing cardiovascular morbidity and mortality in patients who have a history of myocardial infarction or stroke (secondary prevention). It is unclear if aspirin prevents primary cardiovascular events in people with diabetes. The current recommendation is to give aspirin to people with diabetes who have a greater than 10% 10-year risk of cardiovascular events. Typically, this includes most diabetic men aged 50 years or older and diabetic women aged 60 years or older with one or more additional risk factors (smoking, hypertension, dyslipidemia, family history of premature cardiovascular disease, or albuminuria). Contraindications for aspirin therapy are patients with aspirin allergy, bleeding tendency, recent gastrointestinal bleeding, or active hepatic disease. Based on the Early Treatment Diabetic Retinopathy Study (ETDRS), there does not appear to be a contraindication to aspirin use to achieve cardiovascular benefit in diabetic patients who have proliferative retinopathy. Aspirin also does not seem to affect the severity of vitreous/preretinal hemorrhages or their resolution.
2. Peripheral vascular disease
Atherosclerosis is markedly accelerated in the larger arteries. It is often diffuse, with localized enhancement in certain areas of turbulent blood flow, such as at the bifurcation of the aorta or other large vessels. Clinical manifestations of peripheral vascular disease include ischemia of the lower extremities, erectile dysfunction, and intestinal angina.
The incidence of gangrene of the feet in patients with diabetes is 30 times that in age-matched controls. The factors responsible for its development, in addition to peripheral vascular disease, are small vessel disease, peripheral neuropathy with loss of both pain sensation and neurogenic inflammatory responses, and secondary infection. In two-thirds of patients with ischemic gangrene, pedal pulses are not palpable. In the remaining one-third who have palpable pulses, reduced blood flow through these vessels can be demonstrated by plethysmographic or Doppler ultrasound examination. Prevention of foot injury is imperative. Agents that reduce peripheral blood flow such as tobacco should be avoided. Control of other risk factors such as hypertension is essential. Beta-blockers are relatively contraindicated because of presumed negative peripheral hemodynamic consequences but data that support this are lacking. Cholesterol-lowering agents are useful as adjunctive therapy when early ischemic signs are detected and when dyslipidemia is present. Patients should be advised to seek immediate medical care if a diabetic foot ulcer develops. Improvement in peripheral blood flow with endarterectomy and bypass operations is possible in certain patients.
E. Skin and Mucous Membrane Complications
Chronic pyogenic infections of the skin may occur, especially in poorly controlled diabetic patients. Candidal infection can produce erythema and edema of intertriginous areas below the breasts, in the axillas, and between the fingers. It causes vulvovaginitis in women with chronically uncontrolled diabetes who have persistent glucosuria and is a frequent cause of pruritus. While antifungal creams containing miconazole or clotrimazole offer immediate relief of vulvovaginitis, recurrence is frequent unless glucosuria is reduced.
In some patients with type 2 diabetes, poor glycemic control can cause a severe hypertriglycemia, which can present as eruptive cutaneous xanthomas and pancreatitis. The skin lesions appear as yellow morbilliform eruptions 2–5 mm in diameter with erythematous areolae. They occur on extensor surfaces (elbows, knees, buttocks) and disappear after triglyceride levels are reduced.
Necrobiosis lipoidica diabeticorum is usually located over the anterior surfaces of the legs or the dorsal surfaces of the ankles (eFigure 27–8). They are oval or irregularly shaped plaques with demarcated borders and a glistening yellow surface and occur in women two to four times more frequently than in men. Pathologically, the lesions show degeneration of collagen, granulomatous inflammation of subcutaneous tissues and blood vessels, capillary basement membrane thickening and obliteration of vessel lumina. The condition is associated with type 1 diabetes, although it can occur in patients with type 2 diabetes, and also in patients without diabetes. First-line therapy includes topical and subcutaneous corticosteroids. Improving glycemic control may help the condition.
Necrobiosis lipoidica diabeticorum.
“Shin spots” are not uncommon in adults with diabetes. They are brownish, rounded, painless atrophic lesions of the skin in the pretibial area.
F. Bone and Joint Complications
Long-standing diabetes can cause progressive stiffness of the hand secondary to contracture and tightening of skin over the joints (diabetic cheiroarthropathy), frozen shoulder (adhesive capsulitis), carpal tunnel syndrome, and Dupuytren contractures. These complications are believed to be due to glycosylation of collagen and perhaps other proteins in connective tissue. There may also be an inflammatory component.
Data on bone mineral density and fracture risk in people with diabetes are contradictory. Patients with type 2 diabetes do appear to be at increased risk for nonvertebral fractures. Women with type 1 diabetes have an increased risk of fracture when compared with women without diabetes. Other factors, such as duration of diabetes, and diabetes complications, such as neuropathy and kidney disease, likely affect both the bone mineral density and fracture risk.
Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of the anterior longitudinal ligaments of the spine and various extraspinal ligaments. It causes stiffness and decreased range of spinal motion. The peripheral joints most commonly affected are the metacarpophalangeal joints, elbows, and shoulders. Diabetes, obesity, hypertension, and dyslipidemia are risk factors for this condition.
Hyperuricemia and acute and tophaceous gout are more common in type 2 diabetes.
Bursitis, particularly of the shoulders and hips, occurs more frequently than expected in patients with diabetes.
et al. Diabetic foot ulcers: part I. Pathophysiology and prevention. J Am Acad Dermatol. 2014 Jan;70(1):1.e1–18.
et al. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012 Jun;11(6):521–34.
et al. Diabetes mellitus and peripheral vascular disease: diagnosis and management. Clin Podiatr Med Surg. 2014 Jan;31(1):11–26.
et al. Systemic medical management of diabetic retinopathy. Middle East Afr J Ophthalmol. 2013 Oct–Dec;20(4):301–8.
et al. The diabetic neuropathies: practical and rational therapy. Semin Neurol. 2012 Jul;32(3):196–203.
et al. The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res. 2016 Mar;51:156–86.
et al; Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010 Oct;33(10):2285–93.
et al. Current concepts in the management of diabetic nephropathy. Neth J Med. 2013 Nov;71(9):448–58.
et al; SPRINT research group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015 Nov 26;373(22):2103–16.
A. Diabetes Management in the Hospital
Most patients with diabetes are hospitalized for reasons other than their diabetes. Indeed, up to 10–15% of all hospitalized patients have diabetes. Audits suggest that as many as a 30% of these hospitalized patients have inappropriate management of their diabetes, with such errors as being given metformin where contraindicated, failure to act on high blood glucose levels, omission of diabetes medication, no record of diabetes complications, and inappropriate insulin management or blood glucose monitoring. It is challenging using outpatient oral therapies or insulin regimens in the hospital because patients are not eating as usual; they are often fasting for procedures; clinical events increase adverse reactions associated with diabetes medicines, eg, thiazolidinediones can cause fluid retention and worsen heart failure; metformin should not be used in patients with significant chronic kidney or liver disease, or those getting contrast for radiographic studies. Subcutaneous or intravenous insulin therapy is frequently substituted for other diabetes medicines because the insulin dose can be adjusted to match changing inpatient needs and it is safe to use insulin in patients with heart, kidney, and liver disease.
Surgery represents a stress situation during which most of the insulin antagonists (eg, catecholamines, growth hormone, and corticosteroids) are mobilized. In the diabetic patient, this can lead to a worsening of hyperglycemia and perhaps even ketoacidosis. The aim of medical management of people with diabetes during the perioperative period is to minimize these stress-induced changes. Recommendations for management depend both on the patient’s usual diabetic regimen and on the type of surgery (major or minor) to be done (see also Chapter 3).
For people with diabetes controlled with diet alone, no special precautions must be taken unless diabetic control is markedly disturbed by the procedure. If this occurs, small doses of short-acting insulin as needed will correct the hyperglycemia.
Patients taking oral agents should not take them on the day of surgery. If there is significant hyperglycemia, small doses of short-acting insulin are given as needed. If this approach does not provide adequate control, an insulin infusion should be started in the manner indicated below. The oral agents can be restarted once the patient is eating normally after the operation. It is important to order a postoperative serum creatinine level to ensure adequate kidney function prior to restarting metformin therapy.
Patients taking insulin represent the only serious challenge to management of diabetes when surgery is necessary. However, with careful attention to changes in the clinical or laboratory picture, glucose control can be managed successfully. The protocol used to control the glucose depends on the kind of diabetes (type 1 or type 2); whether it is minor surgery (lasting less than 2 hours and patient eating afterwards) or major surgery (lasting more than 2 hours, with invasion of a body cavity, and patient not eating afterwards); and the preoperative insulin regimen (basal bolus or premixed insulin twice a day or premeal bolus only or regular insulin before meals and NPH at bedtime). Patients with type 1 diabetes must be receiving some insulin to prevent the development of diabetic ketoacidosis. Many patients with type 2 diabetes who are taking insulin do well perioperatively without insulin for a few hours. Ideally, patients with diabetes should undergo surgery early in the morning. Table 27–10 summarizes the approach for these patients.
Table 27–10.Recommendations for management of insulin-treated diabetes during surgery. |Favorite Table|Download (.pdf) Table 27–10. Recommendations for management of insulin-treated diabetes during surgery.
|Type of Diabetes ||Minor Surgical Procedures (< 2 hours; eating afterwards) ||Major Surgical Procedures (> 2 hours; invasion of body cavity; not eating immediately after recovery) |
|Type 2: Patients taking basal bolus insulin regimen; twice daily premixed insulin ||No insulin on the day of operation. Start 5% dextrose infusion; monitor fingerstick blood glucose and give subcutaneous short-acting insulin every 4 or 6 hours ||Same regimen as minor procedure. If control is not satisfactory, then intravenous insulin infusion |
|Type 1: Patients taking basal bolus insulin regimen or using insulin pump ||Patients using pump should discontinue the pump the evening before procedure and given 24-hour basal insulin. On day of procedure, start 5% dextrose; monitor blood glucose and give subcutaneous short-acting insulin every 4 or 6 hours ||Initiate insulin infusion on morning of procedure and transition back to usual regimen when eating |
One insulin infusion method adds 10 units of regular insulin to 1 L of 5% dextrose in 0.45% saline, and this is infused intravenously at a rate of 100–180 mL/h. This gives the patient 1–1.8 units of insulin per hour which, except in the most severe cases, generally keeps the blood glucose within the range of 100–250 mg/dL (5.5–13.9 mmol/L). The infusion may be continued for several days, if necessary. Perioperatively, plasma glucose or blood glucose should be determined every 2–4 hours to be sure metabolic control is adequate. If it is not, adjustments in the ratio of insulin to dextrose in the intravenous solution can be made.
An alternative method consists of separate infusions of insulin and glucose delivered by pumps to permit independent adjustments of each infusion rate, depending on hourly variation of blood glucose values. There are a number of different algorithms available for insulin infusions (see http://www.hospitalmedicine.org).
After surgery, when the patient has resumed an adequate oral intake, subcutaneous administration of insulin can be resumed and intravenous administration of insulin and dextrose can be stopped 30 minutes after the first subcutaneous dose. Insulin needs may vary in the first several days after surgery because of continuing postoperative stresses and because of variable caloric intake. In this situation, multiple doses of short-acting insulin plus some long-acting basal insulin, guided by blood glucose determinations, can keep the patient in acceptable metabolic control.
In the intensive care units (ICUs), glucose levels are controlled most frequently using insulin infusions. Patients receiving total parenteral nutrition can have insulin added to the bag. Standard total parenteral nutrition contains 25% dextrose so an infusion rate of 50 mL/h delivers 12.5 g of dextrose per hour.
On the general surgical and medical wards, most patients are treated with subcutaneous insulin regimens. Limited cross-sectional and prospective studies suggest that the best glucose control is achieved on a combination of basal and bolus regimen with 50% of daily insulin needs provided by intermediate- or long-acting insulins. Standardized order sets can reduce errors, and they often include algorithms for recognition and treatment of hypoglycemia (see http://ucsfinpatientdiabetes.pbworks.com for examples).
The morbidity and mortality in diabetic patients is twice that of nondiabetic patients. Those with new-onset hyperglycemia (ie, those without a preadmission diagnosis of diabetes) have even higher mortality—almost eightfold that of nondiabetic patients in one study. These observations have led to the question of whether tight glycemic control in the hospital improves outcomes.
A prospective trial in surgical ICU patients (Leuven 1 study) reported that starting insulin therapy in ICU patients with blood glucose levels greater than 110 mg/dL [6.1 mmol/L]) reduced mortality and morbidity. Only a small number of persons in this study (204 of 1548) had a diagnosis of diabetes preoperatively, and so this study suggests that controlling hyperglycemia per se (independent of a diagnosis of diabetes) was beneficial. The benefits, however, were principally seen in patients who were in the ICU for longer than 5 days, and it is unclear whether the benefits also apply to most surgical patients who stay in the ICU for only 1 to 2 days.
The same investigators performed a similar prospective trial among 1200 medical ICU patients (Leuven 2 study) and reported that aggressive treatment of hyperglycemia reduced morbidity (decreased acquired kidney injury and increased early weaning from mechanical ventilation) but not mortality. Again, as in the surgical ICU study, only a small number of persons (16.9%) had a diagnosis of diabetes at admission.
The findings of the Leuven studies, however, have not been confirmed by other prospective studies. Two other ICU-based studies (Glucontrol and VISEP) that attempted to confirm the findings were unable to do so. Both studies were stopped prematurely, however. The Glucontrol study was stopped because an interim analysis (falsely) suggested increased mortality in the test group; and the VISEP study was stopped because of seven-fold increase in hypoglycemic events in the intensively treated group. A large multicenter, multinational study (NICE-SUGAR) recruited 6104 surgical and medical ICU patients with hyperglycemia (20% had diabetes) and randomized them to tight control (blood glucose levels of 81–108 mg/dL [4.5–6 mmol/L]) or less tight control (glucose levels less than 180 mg/dL [10 mmol/L]). The tight group achieved blood glucose levels of 115 ± 18 mg/dL (6.4 ± 1.0 mmol/L) and the conventional group, 144 ± 23 mg/dL (8 ± 1.3 mmol/L). There were more deaths (829 versus 751 deaths) in the tight glucose control group compared with the less tight glucose control group (P = 0.02). The excess deaths in the intensive group were due to cardiovascular events. The intensively treated group also had more cases of severe hypoglycemia (206 versus 15 cases).
A study on tight intraoperative glycemic control during cardiac surgery also failed to show any benefit; if anything, the intensively treated group had more events. The United Kingdom Glucose Insulin in Stroke Trial (GIST-UK) failed to show beneficial effect of tight glycemic control in stroke patients; however, the investigators acknowledged that, because of slow recruitment, the study was underpowered.
Thus, based on the evidence available, ICU patients with diabetes and new-onset hyperglycemia with blood glucose levels above 180 mg/dL (10 mmol/L) should be treated with insulin, aiming for target glucose levels between 140 mg/dL (7.8 mmol/L) and 180 mg/dL (10 mmol/L). In the ICU setting, aiming for blood glucose levels close to 100 mg/dL (5.6 mmol/L) is not beneficial and may even be harmful. When patients leave the ICU, target glucose values between 100 mg/dL (5.6 mmol/L) and 180 mg/dL (10 mmol/L) may be appropriate, although this view is based on clinical observations rather than conclusive evidence.
B. Pregnancy and the Diabetic Patient
Tight glycemic control with normal HbA1c levels is very important during pregnancy. Early in pregnancy, poor control increases the risk of spontaneous abortion and congenital malformations. Late in pregnancy, poor control can result in polyhydramnios, preterm labor, stillbirth, and fetal macrosomia with its associated problems. Diabetes complications can impact both maternal and fetal health. Diabetic retinopathy can first develop during pregnancy or retinopathy that is already present can worsen. Diabetic women with microalbuminuria can have worsening albuminuria during pregnancy and are at higher risk for preeclampsia. Patients who have preexisting kidney failure (prepregnancy creatinine clearance less than 80 mL/min) are at high risk for further decline in kidney function during the pregnancy, and this may not reverse after delivery. Diabetic gastroparesis can severely exacerbate the nausea and vomiting of pregnancy and some patients may require fluid and nutritional support.
Although there is evidence that glyburide is safe during pregnancy, the current practice is to control diabetes with insulin therapy. Every effort should be made, utilizing multiple injections of insulin or a continuous infusion of insulin by pump, to maintain near-normalization of fasting and preprandial blood glucose values while avoiding hypoglycemia.
Regular and NPH insulin and the insulin analogs lispro, aspart, and detemir are labeled pregnancy category B. Insulin glargine, glulisine, and degludec are labeled category C because of lack of clinical safety data. A small study using insulin glargine in 32 pregnancies did not reveal any problems.
Unless there are fetal or maternal complications, diabetic women should be able to carry the pregnancy to full-term, delivering at 38 to 41 weeks. Induction of labor before 39 weeks may be considered if there is concern about increasing fetal weight. See Chapter 19 for further details.
et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013 Nov;98(11):4227–49.
et al. Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med. 2011 Feb 15;154(4):268–82.
et al. Critique of normoglycemia in intensive care evaluation: survival using glucose algorithm regulation (NICE-SUGAR)—a review of recent literature. Curr Opin Clin Nutr Metab Care. 2010 Mar;13(2):211–4.
The DCCT showed that the previously poor prognosis for as many as 40% of patients with type 1 diabetes is markedly improved by optimal care. DCCT participants were generally young and highly motivated and were cared for in academic centers by skilled diabetes educators and endocrinologists who were able to provide more attention and services than are usually available. Improved training of primary care providers may be beneficial.
For type 2 diabetes, the UKPDS documented a reduction in microvascular disease with glycemic control, although this was not apparent in the obese subgroup. Cardiovascular outcomes were not improved by glycemic control, although antihypertensive therapy showed benefit in reducing the number of adverse cardiovascular complications as well as in reducing the occurrence of microvascular disease among hypertensive patients. In patients with visceral obesity, successful management of type 2 diabetes remains a major challenge in the attempt to achieve appropriate control of hyperglycemia, hypertension, and dyslipidemia. Once safe and effective methods are devised to prevent or manage obesity, the prognosis of type 2 diabetes with its high cardiovascular risks should improve considerably.
In addition to poorly understood genetic factors relating to differences in individual susceptibility to development of long-term complications of hyperglycemia, it is clear that in both types of diabetes, the diabetic patient’s intelligence, motivation, and awareness of the potential complications of the disease contribute significantly to the ultimate outcome.
All patients should receive self-management education when diabetes is diagnosed and at intervals thereafter. The instructional team must include a registered dietitian and registered nurse; they must be Certified Diabetes Educators (CDEs).
Patients with type 1 diabetes should be referred to an endocrinologist for comanagement with a primary care provider.
Patients with type 2 diabetes should be referred to an endocrinologist if treatment goals are not met or if the patient requires an increasingly complex regimen to maintain glycemic control.
Patients with type 2 diabetes should be referred to an ophthalmologist or optometrist for a dilated eye examination when the diabetes is diagnosed, and patients with type 1 diabetes should be referred 5 years after the diagnosis is made.
Patients with peripheral neuropathy, especially those with loss of protective threshold (unable to detect 5.07 Semmes-Weinstein filament) or structural foot problems, should be referred to a podiatrist.
Referrals to other specialists may be required for management of chronic complications of diabetes.
American Diabetes Association. Standards of Medical Care in Diabetes—2015. Diabetes Care. 2015 Jan;38(Suppl 1):S11–90.