The goals of therapy for type 1 or type 2 diabetes mellitus (DM) are to (1) eliminate symptoms related to hyperglycemia, (2) reduce or eliminate the long-term microvascular and macrovascular complications of DM (Chap. 398), and (3) allow the patient to achieve as normal a lifestyle as possible. To reach these goals, the physician should identify a target level of glycemic control for each patient, provide the patient with the educational and pharmacologic resources necessary to reach this level, and monitor/treat DM-related complications. Symptoms of diabetes usually resolve when the plasma glucose is <11.1 mmol/L (200 mg/dL), and thus most DM treatment focuses on achieving the second and third goals. This chapter first reviews the ongoing treatment of diabetes in the outpatient setting and then discusses the treatment of severe hyperglycemia, as well as the treatment of diabetes in hospitalized patients.
The care of an individual with either type 1 or type 2 DM requires a multidisciplinary team. Central to the success of this team are the patient’s participation, input, and enthusiasm, all of which are essential for optimal diabetes management. Members of the health care team include the primary care provider and/or the endocrinologist or diabetologist, a certified diabetes educator, a nutritionist, a psychologist, and/or social worker. In addition, when the complications of DM arise, subspecialists (including ophthalmologists, neurologists, podiatrists, nephrologists, transplant surgeons, cardiologists, and cardiovascular surgeons) with experience in DM-related complications are essential.
ONGOING ASPECTS OF COMPREHENSIVE DIABETES CARE
A number of names are sometimes applied to different approaches to diabetes care, such as intensive insulin therapy, intensive glycemic control, and “tight control.” The current chapter, and other sources, uses the term comprehensive diabetes care to emphasize the fact that optimal diabetes therapy involves more than plasma glucose management and medications. Although glycemic control is central to optimal diabetes therapy, comprehensive diabetes care of both type 1 and type 2 DM should also detect and manage DM-specific complications (Chap. 398), and modify risk factors for DM-associated diseases. The key elements of comprehensive diabetes care are summarized in Table 397-1. The morbidity and mortality of DM can be greatly reduced by timely and consistent surveillance, including the detection, prevention, and management of DM-related complications (Table 397-1 and Chap. 398). Such screening procedures are indicated for all individuals with DM, but many individuals with diabetes do not receive these or comprehensive diabetes care. In addition to the physical aspects of DM, social, family, financial, cultural, and employment-related issues may impact diabetes care. The treatment goals for patients with diabetes summarized in Table 397-2 should be individualized. The prevention and treatment of clinically significant hypoglycemia (<3.0 mmol/L or 54 mg/dL) is discussed in Chap. 399. The International Diabetes Federation (IDF), recognizing that resources available for diabetes care vary widely throughout the world, has issued guidelines for “recommended care” (a well-developed service base and with health care funding systems consuming a significant part of their national wealth), “limited care” (health care settings with very limited resources), and “comprehensive care” (health care settings with considerable resources). This chapter provides guidance for this comprehensive level of diabetes care.
TABLE 397-1Guidelines for Ongoing, Comprehensive Medical Care for Patients with Diabetes ||Download (.pdf) TABLE 397-1 Guidelines for Ongoing, Comprehensive Medical Care for Patients with Diabetes
Individualized glycemic goal and therapeutic plan
Self-monitoring of blood glucose (individualized frequency)
HbA1c testing (2–4 times/year)
Lifestyle management in the care of diabetes, including:
Diabetes-self-management education and support
Psychosocial care, including evaluation for depression, anxiety
Detection, prevention, or management of diabetes-related complications, including:
Diabetes-related eye examination (annual or biannual; Chap. 398)
Diabetes-related foot examination (1–2 times/year by provider; daily by patient; Chap. 398)
Diabetes-related neuropathy examination (annual; Chap. 398)
Diabetes-related kidney disease testing (annual; Chap. 398)
Manage or treat diabetes-relevant conditions, including:
Blood pressure (assess quarterly; Chap. 398)
Lipids (annual; Chap. 398)
Consider antiplatelet therapy (Chap. 398)
Influenza/pneumococcal/hepatitis B immunizations (Chap. 4)
TABLE 397-2Treatment Goals for Adults with Diabetesa ||Download (.pdf) TABLE 397-2 Treatment Goals for Adults with Diabetesa
|Index ||Goal |
|Glycemic controlb || |
| HbA1c ||<7.0%c |
| Preprandial capillary plasma glucose ||4.4–7.2 mmol/L (80–130 mg/dL) |
| Postprandial capillary plasma glucosed ||<10.0 mmol/L (<180 mg/dL) |
|Blood pressure ||<140/90 mmHge |
LIFESTYLE MANAGEMENT IN DIABETES CARE
The patient with type 1 or type 2 DM should receive education about nutrition, exercise, psychosocial support, care of diabetes during illness, and medications to lower the plasma glucose. The American Diabetes Association (ADA) uses the term “Lifestyle Management” to refer to aspects of diabetes care, including: (1) diabetes self-management education (DSME) and diabetes self-management support (DSMS); (2) nutrition therapy; and (3) psychosocial care. Along with improved compliance, patient education allows individuals with DM to assume greater responsibility for his/her care. Patient education should be viewed as a continuing process with regular visits for reinforcement; it should not be a process that is completed after one or two visits to a nurse educator or nutritionist. DSME and DSMS are ways to improve the patient’s knowledge, skills, and abilities necessary for diabetes self-care and should also emphasize psychosocial issues and emotional well-being. More frequent contact between the patient and the diabetes management team (e.g., electronic, telephone) improves glycemic control.
Diabetes Self-Management Education and Support
The diabetes educator is a health care professional (nurse, dietician, or pharmacist) with specialized patient education skills who is certified in diabetes education (e.g., American Association of Diabetes Educators). Education topics important for optimal diabetes self-care include self-monitoring of blood glucose (SMBG); urine ketone monitoring (type 1 DM); insulin administration; guidelines for diabetes management during illnesses; prevention and management of hypoglycemia (Chap. 399); foot and skin care; diabetes management before, during, and after exercise; and risk factor-modifying activities. The focus is providing patient-centered, individualized education.
Medical nutrition therapy (MNT) is a term used by the ADA to describe the optimal coordination of caloric intake with other aspects of diabetes therapy (insulin, exercise, and weight loss). Primary measures of MNT are directed at preventing or delaying the onset of type 2 DM in high-risk individuals (obese or with prediabetes) by promoting weight reduction. Medical treatment of obesity is a rapidly evolving area and is discussed in Chap. 395. Secondary measures of MNT are directed at improving glycemic control. Tertiary measures of MNT are directed at managing diabetes-related complications (cardiovascular disease [CVD], nephropathy). Although the recommendations for all three types of MNT overlap, this chapter emphasizes secondary measures of MNT. Pharmacologic approaches that facilitate weight loss and metabolic surgery should be considered in selected patients (Chaps. 394 and 395).
In general, the components of optimal MNT are similar for individuals with type 1 or type 2 DM and similar to those for the general population—high quality, nutrient-dense without a specific focus on composition (Mediterranean, dietary approaches to stop hypertension, etc.; Table 397-3). Historically, nutrition education imposed restrictive, complicated regimens on the patient. Current practices have greatly changed, although many patients and health care providers still view the diabetic diet as monolithic and static. There is not a specific diet for individuals with diabetes, certainly not a one diet for everyone. For example, MNT now includes foods with some sucrose and seeks to modify other risk factors such as hyperlipidemia and hypertension. Using the glycemic index, an estimate of the postprandial rise in the blood glucose when a certain amount of that food is consumed, may reduce postprandial glucose excursions and improve glycemic control.
TABLE 397-3Nutritional Recommendations for Adults with Diabetes or Prediabetesa ||Download (.pdf) TABLE 397-3 Nutritional Recommendations for Adults with Diabetes or Prediabetesa
General dietary guidelines
Vegetable, fruits, whole grains, legumes, low-fat dairy products in food higher in fiber and lower in glycemic content
Fat in diet (optimal % of diet is not known; should be individualized)
Carbohydrate in diet (optimal % of diet is not known; should be individualized)
Monitor carbohydrate intake in regard to calories
Sucrose-containing foods may be consumed with adjustments in insulin dose, but minimize intake
Estimate grams of carbohydrate in diet (type 1 DM)
Consider using glycemic index to predict how consumption of a particular food may affect blood glucose
Fructose preferred over sucrose
Protein in diet (optimal % of diet is not known; should be individualized)
Reduced-calorie and nonnutritive sweeteners may be useful
Routine supplements of vitamins, antioxidants, or trace elements not supported by evidence
Sodium intake as advised for general population
The goal of MNT in type 1 DM is to coordinate and match the caloric intake, both temporally and quantitatively, with the appropriate amount of insulin. MNT in type 1 DM and SMBG should be integrated to define the optimal insulin regimen. The ADA encourages patients and providers to use carbohydrate counting to estimate the nutrient content of a meal or snack. Based on the patient’s estimate of the carbohydrate content of a meal, an insulin-to-carbohydrate ratio determines the bolus insulin dose for a meal or snack. MNT must be flexible enough to allow for exercise, and the insulin regimen must allow for deviations in caloric intake. An important component of MNT in type 1 DM is to minimize the weight gain often associated with intensive insulin therapy.
The goals of MNT in type 2 DM should focus on weight loss and address the greatly increased prevalence of cardiovascular risk factors (hypertension, dyslipidemia, obesity) and disease in this population. The majority of these individuals are obese, and weight loss is strongly encouraged. Hypocaloric diets and modest weight loss (5–7%) often result in rapid and dramatic glucose lowering in individuals with new-onset type 2 DM. MNT for type 2 DM should emphasize modest caloric reduction and increased physical activity. Weight loss and exercise improve insulin sensitivity.
Fasting for religious reasons, such as during Ramadan, presents a challenge for individuals with diabetes, especially those taking medications to lower the plasma glucose. Under IDF-issued guidelines on fasting, individuals are risk-stratified as those who can safely fast with medical evaluation and supervision and those in whom fasting is not advised.
Exercise has multiple positive benefits including cardiovascular risk reduction, reduced blood pressure, maintenance of muscle mass, reduction in body fat, and weight loss. For individuals with type 1 or type 2 DM, exercise is also useful for lowering plasma glucose (during and following exercise) and increasing insulin sensitivity. In patients with diabetes, the ADA recommends 150 min/week (distributed over at least 3 days) of moderate aerobic physical activity with no gaps longer than 2 days. Resistance exercise, flexibility and balance training, and reduced sedentary behavior throughout the day are advised.
Despite its benefits, exercise presents challenges for individuals with DM because they lack the normal glucoregulatory mechanisms (normally, insulin falls and glucagon rises during exercise). Skeletal muscle is a major site for metabolic fuel consumption in the resting state, and the increased muscle activity during vigorous, aerobic exercise greatly increases fuel requirements. Individuals with type 1 DM are prone to either hyperglycemia or hypoglycemia during exercise, depending on the preexercise plasma glucose, the circulating insulin level, and the level of exercise-induced catecholamines. If the insulin level is too low, the rise in catecholamines may increase the plasma glucose excessively, promote ketone body formation, and possibly lead to ketoacidosis. Conversely, if the circulating insulin level is excessive, this relative hyperinsulinemia may reduce hepatic glucose production (decreased glycogenolysis, decreased gluconeogenesis) and increase glucose entry into muscle, leading to hypoglycemia.
To avoid exercise-related hyper- or hypoglycemia, individuals with type 1 DM should (1) monitor blood glucose before, during, and after exercise; (2) delay exercise if blood glucose is >14 mmol/L (250 mg/dL) and ketones are present; (3) if the blood glucose is <5.6 mmol/L (100 mg/dL), ingest carbohydrate before exercising; (4) monitor glucose during exercise and ingest carbohydrate to prevent hypoglycemia; (5) decrease insulin doses (based on previous experience) before and after exercise and inject insulin into a nonexercising area; and (6) learn individual glucose responses to different types of exercise. In individuals with type 2 DM, exercise-related hypoglycemia is less common but can occur in individuals taking either insulin or insulin secretagogues. Untreated proliferative retinopathy is a relative contraindication to vigorous exercise, because this may lead to vitreous hemorrhage or retinal detachment (Chap. 398).
Because the individual with DM faces challenges that affect many aspects of daily life, psychosocial assessment and support are a critical part of comprehensive diabetes care. Patients should view themselves as essential members of the diabetes care team and not as someone who is cared for by the diabetes management team. Even with considerable effort, normoglycemia can be an elusive goal, and solutions to worsening glycemic control may not be easily identifiable. Depression, anxiety, or “Diabetes Distress,” defined by the ADA as “…negative psychological reactions related to emotional burdens…in having to manage a chronic disease like diabetes, should be recognized and may require the care of a mental health specialist.” Emotional stress may provoke a change in behavior so that individuals no longer adhere to a dietary, exercise, or therapeutic regimen. The individual with DM must accept that he or she may develop complications related to DM. Eating disorders, including binge eating disorders, bulimia, and anorexia nervosa, appear to occur more frequently in individuals with type 1 or type 2 DM.
MONITORING THE LEVEL OF GLYCEMIC CONTROL
Optimal monitoring of glycemic control involves plasma glucose measurements by the patient and an assessment of long-term control by the providers on the diabetes management team (measurement of hemoglobin A1c [HbA1c] and review of the patient’s SMBG). These measurements are complementary: the patient’s measurements provide a picture of short-term glycemic control, whereas the HbA1c reflects average glycemic control over the previous 2–3 months.
Self-Monitoring of Blood Glucose
SMBG is the standard of care in diabetes management and allows the patient to monitor his or her blood glucose at any time. In SMBG, a small drop of blood and an easily detectable enzymatic reaction allow measurement of the capillary plasma glucose. Many glucose monitors can rapidly and accurately measure glucose (calibrated to provide plasma glucose value even though blood glucose is measured) in small amounts of blood (3–10 μL) obtained from the fingertip; alternative testing sites (e.g., forearm) are less reliable. By combining glucose measurements with diet and exercise history, and medication changes, the diabetes management team and patient can improve the treatment program.
The frequency of SMBG measurements must be individualized and adapted to address the goals of diabetes care. Individuals with type 1 DM or individuals with type 2 DM taking multiple insulin injections each day should routinely measure their plasma glucose three or more times per day (some measure >10 times/day) to estimate and select mealtime boluses of short-acting insulin and to modify long-acting insulin doses. Most individuals with type 2 DM require less frequent monitoring, although the optimal frequency of SMBG has not been clearly defined. Individuals with type 2 DM who are taking insulin should use SMBG more frequently than those on oral agents. Individuals with type 2 DM who are on oral medications should use SMBG as a means of assessing the efficacy of their medication and the impact of dietary choices and exercise. Because plasma glucose levels fluctuate less in these individuals, one or fewer SMBG measurements per day may be sufficient. Most measurements in individuals with type 1 or type 2 DM should be performed prior to a meal and supplemented with postprandial measurements to assist in reaching postprandial glucose targets (Table 397-2).
Devices for continuous glucose monitoring (CGM) usually do not replace the need for traditional glucose measurements and require calibration by SMBG. These rapidly evolving technologies require substantial expertise on the part of the diabetes management team and the patient. Current CGM systems measure the glucose in interstitial fluid, which is in equilibrium with the plasma glucose. These devices provide useful short-term information about the patterns of glucose changes as well as an enhanced ability to detect hypoglycemic episodes. Alerts and alarms (vibration, sound) can notify the patient if the glucose is rising or falling rapidly, or is predicted to cross a hyper- or hypoglycemic threshold. Clinical experience with these devices in type 1 DM is growing rapidly, especially in individuals who have not achieved glycemic targets, those with hypoglycemia unawareness to decrease the frequency of serious hypoglycemia (especially nocturnal hypoglycemia), and those desiring more frequent glycemic feedback. The combination of an insulin-infusion device (discussed below) and a CGM are currently open-loop, meaning the patient must adjust the insulin-infusion device, but closed-loop systems (insulin-infusion device automatically adjusted by algorithm) may soon be entering clinical practice; one system that adjusts the basal rate has been recently approved by the U.S. Food and Drug Administration (FDA).
Assessment of Long-Term Glycemic Control
Measurement of glycated hemoglobin (HbA1c) is the standard method for assessing long-term glycemic control. When plasma glucose is consistently elevated, there is an increase in nonenzymatic glycation of hemoglobin; this alteration reflects the glycemic history over the previous 2–3 months, because erythrocytes have an average life span of 120 days (glycemic level in the preceding month contributes about 50% to the HbA1c value). Measurement of HbA1c at the “point of care” allows for more rapid feedback and may therefore assist in adjustment of therapy.
HbA1c should be measured in all individuals with DM during their initial evaluation and as part of their comprehensive diabetes care. As the primary predictor of long-term complications of DM, the HbA1c should mirror, to a certain extent, the short-term measurements of SMBG. These two measurements are complementary in that recent intercurrent illnesses may impact the SMBG measurements but not the HbA1c. Likewise, postprandial and nocturnal hyperglycemia may not be detected by the SMBG of fasting and preprandial capillary plasma glucose but will be reflected in the HbA1c. The HbA1c is an “average” and thus does not detect glycemic variability in the way SMBG and CGM can. In standardized assays, the HbA1c approximates the following mean plasma glucose values: an HbA1c of 6% = 7.0 mmol/L (126 mg/dL), 7% = 8.6 mmol/L (154 mg/dL), 8% = 10.2 mmol/L (183 mg/dL), 9% = 11.8 mmol/L (212 mg/dL), 10% = 13.4 mmol/L (240 mg/dL), 11% = 14.9 mmol/L (269 mg/dL), and 12% = 16.5 mmol/L (298 mg/dL). However, there is interindividual variability in the HbA1c to mean glucose relationship, and in African-Americans the HbA1c is on average 0.4% higher than in Caucasians for the same mean glucose. Clinical conditions leading to abnormal RBC parameters such as hemoglobinopathies, anemias, reticulocytosis, transfusions, and uremia may alter the HbA1c result. In patients achieving their glycemic goal, the ADA recommends measurement of the HbA1c at least twice per year. More frequent testing (every 3 months) is warranted when glycemic control is inadequate or when therapy has changed. Laboratory standards for the HbA1c test have been established and should be correlated to the reference assay of the Diabetes Control and Complications Trial (DCCT). The degree of glycation of other proteins, such as albumin, or measurement of 1,5-anhydroglucitol can be used as an alternative indicator of glycemic control when the HbA1c is inaccurate. The fructosamine assay (measuring glycated albumin) reflects the glycemic status over the prior 2 weeks.
PHARMACOLOGIC TREATMENT OF DIABETES
Comprehensive care of type 1 and type 2 DM requires an emphasis on nutrition, exercise, and monitoring of glycemic control but also usually involves glucose-lowering medication(s). This chapter discusses classes of such medications but does not describe every glucose-lowering agent available worldwide. The initial step is to select an individualized, glycemic goal for the patient.
ESTABLISHMENT OF TARGET LEVEL OF GLYCEMIC CONTROL
Because the complications of DM are related to glycemic control, normoglycemia or near-normoglycemia is the desired, but often elusive, goal for most patients. Normalization or near-normalization of the plasma glucose for long periods of time is extremely difficult, as demonstrated by the DCCT and United Kingdom Prospective Diabetes Study (UKPDS). Regardless of the level of hyperglycemia, improvement in glycemic control will lower the risk of diabetes-specific complications, most notably the microvascular complications (Chap. 398).
The target for glycemic control (as reflected by the HbA1c) must be individualized, and the goals of therapy should be developed in consultation with the patient after considering a number of medical, social, and lifestyle issues. The ADA calls this a patient-centered approach, and other organizations such as the IDF and American Association of Clinical Endocrinologists (AACE) also suggest an individualized glycemic goal. Important factors to consider include the patient’s age and ability to understand and implement a complex treatment regimen, presence and severity of complications of diabetes, known CVD, ability to recognize hypoglycemic symptoms, presence of other medical conditions or treatments that might affect survival or the response to therapy, lifestyle and occupation (e.g., possible consequences of experiencing hypoglycemia on the job), and level of support available from family and friends.
In general, the ADA suggests that the goal is to achieve an HbA1c as close to normal as possible without significant hypoglycemia. In most individuals, the target HbA1c should be <7% (Table 397-2) with a more stringent target ≤6.5% for some patients. With modern implementation of intensive insulin therapy for type 1 DM, the level of HbA1c is no longer inversely related to the frequency and severity of hypoglycemia as seen in the DCCT; nevertheless, it may still be appropriate to set a higher HbA1c target <7.5 or 8% for patients with impaired awareness of hypoglycemia. A higher HbA1c goal may also be appropriate for the very young or old or in individuals with limited life span or comorbid conditions. For example, an appropriate HbA1c goal in elderly individuals with multiple, chronic illnesses and impaired activities of daily living might be 8.0 or 8.5%.
More stringent glycemic control (HbA1c of ≤6%) is not beneficial, and may be detrimental, in patients with type 2 DM and a high risk of CVD. Large clinical trials (UKPDS, Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], Veterans Affairs Diabetes Trial [VADT]; Chap. 398) have examined glycemic control in type 2 DM in individuals with low risk of CVD, with high risk of CVD, or with established CVD and have found that more intense glycemic control is not beneficial and, in some patient populations, may have a negative impact on some outcomes. These divergent outcomes stress the need for individualized glycemic goals based on the following general guidelines: (1) early in the course of type 2 diabetes when the CVD risk is lower, improved glycemic control likely leads to improved cardiovascular outcome, but this benefit may occur more than a decade after the period of improved glycemic control; (2) intense glycemic control in individuals with established CVD or at high risk for CVD is not advantageous, and may be deleterious, over a follow-up of 3–5 years; (3) hypoglycemia in such high-risk populations (elderly, CVD) should be avoided; and (4) improved glycemic control reduces microvascular complications of diabetes (Chap. 398) even if it does not improve macrovascular complications like CVD.
The ADA recommendations for fasting and bedtime glycemic goals and HbA1c targets are summarized in Table 397-2. The goal is to design and implement insulin regimens that mimic physiologic insulin secretion. Because individuals with type 1 DM partially or completely lack endogenous insulin production, administration of basal insulin is essential for regulating glycogen breakdown, gluconeogenesis, lipolysis, and ketogenesis (i.e., largely fine-tuning hepatic and adipose metabolism). Likewise, insulin replacement for meals should be appropriate for the carbohydrate intake and promote normal glucose utilization and storage.
Intensive insulin therapy has the goal of achieving near-normal glycemia. This approach requires multiple resources, including thorough and continuing patient education, comprehensive recording of plasma glucose measurements and nutrition intake by the patient, and a variable insulin regimen that matches carbohydrate intake and insulin dose. Insulin regimens include multiple-component insulin regimens, multiple daily injections (MDIs), or continuous subcutaneous (SC) insulin infusion (CSII) (each discussed below).
The benefits of intensive insulin therapy and improved glycemic control include a reduction in the acute metabolic and chronic microvascular complications of DM. From a psychological standpoint, the patient experiences greater control over his or her diabetes and often notes an improved sense of well-being, greater flexibility in the timing and content of meals, and the capability to alter insulin dosing with exercise. In addition, intensive insulin therapy prior to and during pregnancy reduces the risk of fetal malformations and morbidity. Intensive insulin therapy is encouraged in newly diagnosed patients with type 1 DM because it may prolong the period of C-peptide production, which may result in better glycemic control and a reduced risk of serious hypoglycemia. Although intensive management confers impressive benefits, it is also accompanied by significant personal and financial costs and is therefore not appropriate for all individuals.
Current insulin preparations are generated by recombinant DNA technology and consist of the amino acid sequence of human insulin or variations thereof. In the United States, most insulin is formulated as U-100 (100 units/mL); short-acting insulin formulated as U-200 (200 units/mL; lispro) and long-acting as U-300 (300 units/mL; glargine) are available in order to limit injection volumes for patients with high insulin requirements. Regular insulin formulated as U-500 (500 units/mL) is sometimes used in patients with severe insulin resistance. Human insulin has been formulated with distinctive pharmacokinetics (regular and neutral protamine Hagedorn [NPH] insulin have the native insulin amino acid sequence) or genetically modified to alter insulin absorption and hence insulin action. Insulins can be classified as short-acting or long-acting (Table 397-4). For example, one short-acting insulin formulation, insulin lispro, is an insulin analogue in which the 28th and 29th amino acids (lysine and proline) on the insulin B chain have been reversed by recombinant DNA technology. Insulin aspart and insulin glulisine are genetically modified insulin analogues with properties similar to lispro. A biosimilar version of lispro has been approved. All three of these insulin analogues have full biologic activity but less tendency for self-aggregation, resulting in more rapid absorption and onset of action and a shorter duration of action. These characteristics are particularly advantageous for allowing entrainment of insulin injection and action to rising plasma glucose levels following meals. The shorter duration of action also appears to be associated with a decreased number of hypoglycemic episodes, primarily because the decay of insulin action corresponds to the decline in plasma glucose after a meal. Thus, insulin aspart, lispro, or glulisine is preferred over regular insulin for prandial coverage in many patients. Insulin glargine is a long-acting biosynthetic human insulin that differs from normal insulin in that asparagine is replaced by glycine at amino acid 21, and two arginine residues are added to the C terminus of the B chain, leading to the formation of microprecipitates at physiologic pH in subcutaneous tissue. Compared to NPH insulin, the onset of insulin glargine action is later, the duration of action is longer (~24 h), and there is a less pronounced peak. A lower incidence of hypoglycemia, especially at night, has been reported with insulin glargine when compared to NPH insulin. A biosimilar version is now available. Insulin detemir has a fatty acid side chain that reversibly binds to albumin and prolongs its action by slowing absorption and catabolism, but its duration of action may only reach 12–20 h. Twice-daily injections of glargine, or especially detemir, are sometimes required to provide optimal 24-h coverage. Because of modification and extension of the carboxy-terminal terminus of the B chain, insulin degludec forms multihexamers in subcutaneous tissue and binds albumin, prolonging its duration of action (>42 h); it provides similar glycemic control as glargine but with less frequent nocturnal and severe hypoglycemia.
TABLE 397-4Properties of Insulin Preparationsa ||Download (.pdf) TABLE 397-4 Properties of Insulin Preparationsa
| ||Time of Action |
|Preparation ||Onset, h ||Peak, h ||Effective Duration, h |
| Aspart ||<0.25 ||0.5–1.5 ||2–4 |
| Glulisine ||<0.25 ||0.5–1.5 ||2–4 |
| Lisprof ||<0.25 ||0.5–1.5 ||2–4 |
| Regularg ||0.5–1.0 ||2–3 ||3–6 |
| Inhaled human insulin ||0.5–1.0 ||2–3 ||3 |
| Degludec ||1–9 ||—c ||42d |
| Detemir ||1–4 ||—c ||12–24d |
| Glarginef ||2–4 ||—c ||20–24 |
| NPH ||2–4 ||4–10 ||10–16 |
|Examples of insulin combinationse |
| 75/25–75% protamine lispro, 25% lispro ||<0.25 ||Dualf ||10–16 |
| 70/30–70% protamine aspart, 30% aspart ||<0.25 ||Dualf ||15-18 |
| 50/50–50% protamine lispro, 50% lispro ||<0.25 ||Dualf ||10–16 |
| 70/30–70% NPH, 30% regular ||0.5–1 ||Dualf ||10–16 |
|Combination of long-acting insulin and GLP-1 receptor agonist ||See text || || |
Basal insulin requirements are provided by long-acting insulin formulations (NPH insulin, insulin glargine, insulin detemir, or insulin degludec). These are usually prescribed with short-acting insulin in an attempt to mimic physiologic insulin release with meals. Although mixing of NPH and short-acting insulin formulations is common practice, this mixing may alter the insulin absorption profile (especially the short-acting insulins). For example, lispro absorption is delayed by mixing with NPH. The alteration in insulin absorption when the patient mixes different insulin formulations should not prevent mixing insulins. However, the following guidelines should be followed: (1) mix the different insulin formulations in the syringe immediately before injection (inject within 2 min after mixing); (2) do not store insulin as a mixture; (3) follow the same routine in terms of insulin mixing and administration to standardize the physiologic response to injected insulin; and (4) do not mix insulin glargine, detemir, or degludec with other insulins. The miscibility of some insulins allows for the production of combination insulins that contain 70% NPH and 30% regular (70/30), or equal mixtures of NPH and regular (50/50). By including the insulin analogue mixed with protamine, several additional combinations have a short-acting and long-acting profile (Table 397-4). Although more convenient for the patient (only two injections/day), combination insulin formulations do not allow independent adjustment of short-acting and long-acting activity. Several insulin formulations are available as insulin “pens,” which are more convenient for some patients. Other novel insulins, such as one with a duration of action of several days, are in development. Insulin delivery by inhalation to provide meal-time insulin is approved, but not widely used. Prior to its use, the forced expiratory volume in one second (FEV1) should be measured. Inhaled insulin can cause bronchospasm and cough and should be not be in individuals with lung disease or who smoke. Long-acting insulin/glucagon-like peptide-1 (GLP-1) receptor agonist combinations in fixed doses (degludec + liraglutide or glargine + lixisenatide) have recently become available, are effective, and are not associated with weight gain.
Representations of the various insulin regimens that may be used in type 1 DM are illustrated in Fig. 397-1. Although the insulin profiles are depicted as “smooth,” symmetric curves, there is considerable patient-to-patient variation in the peak and duration. In all regimens, long-acting insulins (NPH, glargine, detemir, or degludec) supply basal insulin, whereas regular, insulin aspart, glulisine, or lispro provide prandial insulin. Short-acting insulin analogues should be injected just before (<10 min) and regular insulin 30–45 min prior to a meal. Sometimes short-acting insulin analogues are injected just after a meal (gastroparesis, unpredictable food intake).
Representative insulin regimens for the treatment of diabetes. For each panel, the y-axis shows the amount of insulin effect and the x-axis shows the time of day. B, breakfast; HS, bedtime; L, lunch; S, supper. *Lispro, glulisine, or insulin aspart can be used. The time of insulin injection is shown with a vertical arrow. The type of insulin is noted above each insulin curve. A. Multiple-component insulin regimen consisting of long-acting insulin (degludec, determir, or glargine) to provide basal insulin coverage and three shots of glulisine, lispro, or insulin aspart to provide glycemic coverage for each meal. B. Injection of two shots of long-acting insulin (NPH) and short-acting insulin analogue (glulisine, lispro, insulin aspart [solid red line], or regular insulin [green dashed line]). Some deliver the second dose of NPH at bedtime or also use a short-acting insulin at lunch. Only one formulation of short-acting insulin is used. C. Insulin administration by insulin infusion device is shown with the basal insulin and a bolus injection at each meal. The basal insulin rate is decreased during the evening and increased slightly prior to the patient awakening in the morning. Glulisine, lispro, or insulin aspart is used in the insulin infusion device. (Part C adapted from FR Kaufman: Medical Management of Type 1 Diabetes, 6th ed. American Diabetes Association, Alexandria, VA, 2012.)
A shortcoming of current insulin regimens is that injected insulin immediately enters the systemic circulation, whereas endogenous insulin is secreted into the portal venous system. Thus, exogenous insulin administration exposes the liver to subphysiologic insulin levels. No insulin regimen reproduces the precise insulin secretory pattern of the pancreatic islet. However, the most physiologic regimens entail more frequent insulin injections, greater reliance on short-acting insulin, and more frequent capillary plasma glucose measurements (or by CGM). In general, individuals with type 1 DM require 0.4–1 units/kg per day of insulin divided into multiple doses, with ~50% of the insulin given as basal insulin.
MDI regimens refer to the combination of basal insulin and bolus insulin (preprandial short-acting insulin). The timing and dose of short-acting, preprandial insulin are altered to accommodate the SMBG results, anticipated food intake, and physical activity. Such regimens offer the patient with type 1 DM more flexibility in terms of lifestyle and the best chance for achieving near normoglycemia. One such regimen, shown in Fig. 397-1A, consists of basal insulin with glargine, detemir, or degludec and preprandial lispro, glulisine, or insulin aspart. The insulin aspart, glulisine, or lispro dose is based on individualized algorithms that integrate the preprandial glucose and the anticipated carbohydrate intake. To determine the meal component of the preprandial insulin dose, the patient uses an insulin-to-carbohydrate ratio (a common ratio for type 1 DM is 1 unit/10–15 g of carbohydrate, but this must be determined for each individual). To this insulin, dose is added the supplemental or correcting insulin based on the preprandial blood glucose (one formula uses 1 unit of insulin for every 2.7 mmol/L [50 mg/dL] over the preprandial glucose target; another formula uses [body weight in kg] × [blood glucose – desired glucose in mg/dL]/1500). Such calculations must be adjusted based on each individual’s sensitivity to insulin. An alternative multiple-component insulin regimen consists of bedtime NPH insulin, a small dose of NPH insulin at breakfast (20–30% of bedtime dose), and preprandial short-acting insulin. Other variations of this regimen are in use but have the disadvantage that NPH has a significant peak, making hypoglycemia more common. Frequent SMBG (≥4 times per day) is essential for these types of insulin regimens, although less frequent SMBG may be acceptable when used together with CGM.
In the past, one commonly used regimen consisted of twice-daily injections of NPH mixed with a short-acting insulin before the morning and evening meals (Fig. 397-1B). Such regimens usually prescribe two-thirds of the total daily insulin dose in the morning (with about two-thirds given as long-acting insulin and one-third as short-acting) and one-third before the evening meal (with approximately one-half given as long-acting insulin and one-half as short-acting). The drawback to such a regimen is that it forces a rigid schedule on the patient, in terms of daily activity and the content and timing of meals. Moreover, if the patient’s meal pattern or content varies or if physical activity is increased, hyperglycemia or hypoglycemia may result. Moving the long-acting insulin from before the evening meal to bedtime may avoid nocturnal hypoglycemia and provide more insulin as glucose levels rise in the early morning as growth hormone and cortisol secretion peak (so-called dawn phenomenon). The insulin dose in such regimens should be adjusted based on SMBG results with the following general assumptions: (1) the fasting glucose is primarily determined by the prior evening long-acting insulin; (2) the prelunch glucose is a function of the morning short-acting insulin; (3) the presupper glucose is a function of the morning long-acting insulin; and (4) the bedtime glucose is a function of the presupper, short-acting insulin. This is not an optimal regimen for the patient with type 1 DM, but is sometimes used for patients with insulin-requiring type 2 DM.
CSII is a very effective insulin regimen for the patient with type 1 DM (Fig. 397-1C). To the basal insulin infusion, a preprandial insulin (“bolus”) is delivered by the insulin infusion device based on instructions from the patient, who uses an individualized algorithm incorporating the preprandial plasma glucose and anticipated carbohydrate intake. These sophisticated devices can accurately deliver small doses of insulin (microliters per hour) and have several advantages: (1) multiple basal infusion rates can be programmed to accommodate nocturnal versus daytime basal insulin requirement; (2) basal infusion rates can be altered during periods of exercise; (3) different waveforms of insulin infusion with meal-related bolus allow better matching of insulin depending on meal composition; and (4) programmed algorithms consider ongoing action of prior insulin administration and blood glucose values in calculating the insulin dose. These devices require instruction by a health professional with considerable experience with insulin infusion devices and very frequent patient interactions with the diabetes management team. Insulin infusion devices present unique challenges, such as infection at the infusion site, unexplained hyperglycemia because the infusion set becomes obstructed, or diabetic ketoacidosis (DKA) if the insulin infusion device becomes disconnected. Because most physicians use lispro, glulisine, or insulin aspart in CSII, the extremely short half-life of these insulins quickly leads to insulin deficiency if the delivery system is interrupted. Essential to the safe use of infusion devices is thorough patient education, frequent SMBG (or by CGM), and a backup safety plan in the event of insulin infusion device failure. CGM sensor-augmented insulin infusion devices integrate the information from the CGM to inform insulin delivery. Currently, sensor communicating functions can interrupt basal insulin delivery during hypoglycemia (threshold suspension) or when hypoglycemia is anticipated (predictive suspension [not available in the United States]), which may be particularly useful for addressing nocturnal hypoglycemia. A partial closed-loop system has recently become available that combines patient-directed preprandial boluses with automated adjustment of between meal and basal insulin delivery based on CGM. Clinical experience with closed-loop systems is limited but increasing.
Other Agents That Improve Glucose Control
The role of amylin, a 37-amino-acid peptide co-secreted with insulin from pancreatic beta cells, in normal glucose homeostasis is uncertain. However, based on the rationale that patients who are insulin deficient are also amylin deficient, an analogue of amylin (pramlintide) was created and found to reduce postprandial glycemic excursions in type 1 and type 2 diabetic patients taking insulin. Pramlintide injected just before a meal slows gastric emptying and suppresses glucagon but does not alter insulin levels. Pramlintide is approved for insulin-treated patients with type 1 and type 2 DM. Addition of pramlintide produces a modest reduction in the HbA1c and seems to dampen meal-related glucose excursions. In type 1 DM, pramlintide is started as a 15-μg SC injection before each meal and titrated up to a maximum of 30–60 μg as tolerated. In type 2 DM, pramlintide is started as a 60-μg SC injection before each meal and may be titrated up to a maximum of 120 μg. The major side effects are nausea and vomiting, and dose escalations should be slow to limit these side effects. Because pramlintide slows gastric emptying, it may influence absorption of other medications and should not be used in combination with other drugs that slow gastrointestinal (GI) motility. The short-acting insulin given before the meal should initially be reduced to avoid hypoglycemia and then titrated as the effects of the pramlintide become evident. Because pramlintide suppresses glucagon, it may worsen hypoglycemia recovery and should not be used in patients with hypoglycemia unawareness.
The goals of glycemia-controlling therapy for type 2 DM are similar to those in type 1 DM. Whereas glycemic control tends to dominate the management of type 1 DM, the care of individuals with type 2 DM must also include attention to the treatment of conditions associated with type 2 DM (e.g., obesity, hypertension, dyslipidemia, CVD) and detection/management of DM-related complications (Fig. 397-2; Chap. 398). Reduction in cardiovascular risk is of paramount importance because this is the leading cause of mortality in these individuals.
Essential elements in comprehensive care of type 2 diabetes.
Type 2 DM management should begin with MNT (discussed above). An exercise regimen to increase insulin sensitivity and promote weight loss should also be instituted. Pharmacologic approaches to the management of type 2 DM include oral glucose-lowering agents, insulin, and other agents that improve glucose control; most physicians and patients prefer oral glucose-lowering agents as the initial choice. Any therapy that improves glycemic control reduces “glucose toxicity” to beta cells and may improve endogenous insulin secretion. However, type 2 DM is a progressive disorder and ultimately requires multiple therapeutic agents and often insulin in most patients.
Advances in the therapy of type 2 DM have generated oral glucose-lowering agents that target different pathophysiologic processes in type 2 DM. Based on their mechanisms of action, glucose-lowering agents are subdivided into agents that increase insulin secretion, reduce glucose production, increase insulin sensitivity, enhance GLP-1 action, or promote urinary excretion of glucose (Table 397-5). Glucose-lowering agents other than insulin (with the exception of amylin analogue) are ineffective in type 1 DM and should not be used for glucose management of severely ill individuals with type 2 DM. Insulin is sometimes the initial glucose-lowering agent in type 2 DM.
TABLE 397-5Agents Used for Treatment of Type 1 or Type 2 Diabetes ||Download (.pdf) TABLE 397-5 Agents Used for Treatment of Type 1 or Type 2 Diabetes
| ||Mechanism of Action ||Examplesa ||HbA1c Reduction (%)b ||Agent-Specific Advantages ||Agent-Specific Disadvantages ||Contraindications |
|Oral || || || || || || |
|Biguanidesc* ||↓ Hepatic glucose production ||Metformin ||1–2 ||Weight neutral, do not cause hypoglycemia, inexpensive, extensive experience, ↓ CV events ||Diarrhea, nausea, lactic acidosis, vitamin B12 deficiency ||Renal insufficiency (see text for GFR <45 mL/min), CHF, radiographic contrast studies, hospitalized patients, acidosis |
|α-Glucosidase inhibitorsc** ||↓ GI glucose absorption ||Acarbose, miglitol, voglibose ||0.5–0.8 ||Reduce postprandial glycemia ||GI flatulence, liver function tests ||Renal/liver disease |
|Dipeptidyl peptidase IV inhibitorsc*** ||Prolong endogenous GLP-1 action; ↑ Insulin, ↓ glucagon ||Alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin ||0.5–0.8 ||Well tolerated, do not cause hypoglycemia ||Angioedema/urticarial and immune-mediated dermatologic effects ||Reduced dose with renal disease |
|Insulin secretagogues: Sulfonylureasc* ||↑ Insulin secretion ||Glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glyburide, glyclopyramide ||1–2 ||Short onset of action, lower postprandial glucose, inexpensive ||Hypoglycemia, weight gain ||Renal/liver disease |
|Insulin secretagogues: Nonsulfonylureasc*** ||↑ Insulin secretion ||Mitiglinide nateglinide, repaglinide ||0.5–1.0 ||Short onset of action, lower postprandial glucose ||Hypoglycemia ||Renal/liver disease |
|Sodium-glucose cotransporter 2 inhibitors*** ||↑ renal glucose excretion ||Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin ||0.5–1.0 ||do not cause hypoglycemia, ↓ weight and BP; see text for CVD effect ||Urinary and genital infections, polyuria, dehydration, exacerbate tendency to hyperkalemia and DKA; see text ||Moderate renal insufficiency, insulin-deficient DM |
|Thiazolidinedionesc*** ||↓ Insulin resistance, ↑ glucose utilization ||Pioglitazone, rosiglitazone ||0.5–1.4 ||Lower insulin requirements ||Peripheral edema, CHF, weight gain, fractures, macular edema ||CHF, liver disease |
|Parenteral || || || || || || |
|Amylin agonistsc,d*** ||Slow gastric emptying, ↓ glucagon ||Pramlintide ||0.25–0.5 ||Reduce postprandial glycemia, weight loss ||Injection, nausea, ↑ risk of hypoglycemia with insulin ||Agents that also slow GI motility |
|GLP-1 receptor agonistsc*** ||↑ Insulin, ↓ glucagon, slow gastric emptying, satiety ||Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide ||0.5–1.0 ||Weight loss, do not cause hypoglycemia; see text for CVD effect ||Injection, nausea, ↑ risk of hypoglycemia with insulin secretagogues ||Renal disease, agents that also slow GI motility; medullary carcinoma of thyroid, pancreatic disease |
|Insulinc,d**** ||↑ Glucose utilization, ↓ hepatic glucose production, and other anabolic actions ||See text and Table 397-4 ||Not limited ||Known safety profile ||Injection, weight gain, hypoglycemia || |
|Medical nutrition therapy and physical activityc* ||↓ Insulin resistance, ↑ insulin secretion ||Low-calorie, low-fat diet, exercise ||1–3 ||Other health benefits ||Compliance difficult, long-term success low || |
Metformin, representative of this class of agents, reduces hepatic glucose production and improves peripheral glucose utilization slightly (Table 397-5). Metformin activates AMP-dependent protein kinase and enters cells through organic cation transporters (polymorphisms of these may influence the response to metformin). Recent evidence indicates that metformin’s mechanism for reducing hepatic glucose production is to antagonize glucagon’s ability to generate cAMP in hepatocytes. Metformin reduces fasting plasma glucose (FPG) and insulin levels, improves the lipid profile, and promotes modest weight loss. An extended-release form is available and may have fewer GI side effects (diarrhea, anorexia, nausea, metallic taste). Because of its relatively slow onset of action and GI symptoms with higher doses, the initial dose should be low and then escalated every 1–2 weeks based on SMBG measurements to a maximally tolerated dose of 2000 mg daily. Metformin is effective as monotherapy and can be used in combination with other oral agents or with insulin. Long-term use is associated with reduced micro- and probably macrovascular complications, but the data are less conclusive for macrovascular complications. The major toxicity of metformin, lactic acidosis, is very rare and can be prevented by careful patient selection. Vitamin B12 levels are lower during metformin treatment and should be monitored. Metformin should not be used in patients with moderate renal insufficiency (glomerular filtration rate [GFR] <45 mL/min), any form of acidosis, unstable congestive heart failure (CHF), liver disease, or severe hypoxemia. The National Institute for Health and Clinical Excellence in the United Kingdom suggests that metformin may be safe at a GFR >30 mL/min, with a reduced dose when the GFR is <45 mL/min. Metformin should be discontinued in hospitalized patients, in patients who can take nothing orally, and in those receiving radiographic contrast material. Insulin should be used until metformin can be restarted.
INSULIN SECRETAGOGUES—AGENTS THAT AFFECT THE ATP-SENSITIVE K+ CHANNEL
Insulin secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell (Chap. 396). These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years) who have residual endogenous insulin production. First-generation sulfonylureas (chlorpropamide, tolazamide, tolbutamide) have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions, and are no longer used. Second-generation sulfonylureas have a more rapid onset of action and better coverage of the postprandial glucose rise, but the shorter half-life of some agents may require more than once-a-day dosing. Sulfonylureas reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1- to 2-week intervals based on SMBG. In general, sulfonylureas increase insulin acutely and thus should be taken shortly before a meal; with chronic therapy, though, the insulin release is more sustained. Long-term use is associated with reduced micro- and macrovascular complications. Glimepiride and glipizide can be given in a single daily dose and are preferred over glyburide, especially in the elderly. Repaglinide, nateglinide, and mitiglinide are not sulfonylureas but also interact with the ATP-sensitive potassium channel. Because of their short half-life, these agents are given immediately before each meal to reduce meal-related glucose excursions.
Insulin secretagogues, especially the longer acting ones, have the potential to cause hypoglycemia, especially in elderly individuals. Hypoglycemia is usually related to delayed meals, increased physical activity, alcohol intake, or renal insufficiency. Individuals who ingest an overdose of some agents develop prolonged and serious hypoglycemia and should be monitored closely in the hospital (Chap. 399). Most sulfonylureas are metabolized in the liver to compounds (some of which are active) that are cleared by the kidney. Thus, their use in individuals with significant hepatic or renal dysfunction is not advisable. Weight gain, a common side effect of sulfonylurea therapy, results from the increased insulin levels and improvement in glycemic control. Some sulfonylureas have significant drug interactions with alcohol and some medications including warfarin, aspirin, ketoconazole, α-glucosidase inhibitors, and fluconazole. A related isoform of ATP-sensitive potassium channels is present in the myocardium and the brain. All of these agents except glyburide have a low affinity for this isoform. Despite concerns that this agent might affect the myocardial response to ischemia and observational studies suggesting that sulfonylureas increase cardiovascular risk, studies have not shown an increased cardiac mortality with glyburide or other agents in this class.
INSULIN SECRETAGOGUES—AGENTS THAT ENHANCE GLP-1 RECEPTOR SIGNALING
“Incretins” amplify glucose-stimulated insulin secretion (Chap. 396). Agents that either act as a GLP-1 receptor agonist or enhance endogenous GLP-1 activity are approved for the treatment of type 2 DM (Table 397-5). Agents in this class do not cause hypoglycemia because of the glucose-dependent nature of incretin-stimulated insulin secretion (unless there is concomitant use of an agent that can lead to hypoglycemia—sulfonylureas, etc.). GLP-1 receptor agonists increase glucose-stimulated insulin secretion, suppress glucagon, and slow gastric emptying. These agents do not promote weight gain; in fact, most patients experience modest weight loss and appetite suppression. Short-acting GLP-1 receptor agonists are exenatide and lixisenatide. Long-acting GLP-1 receptor agonists include liraglutide, exenatide, albiglutide, dulaglutide, and lixisenatide. Short-acting GLP-1 receptor agonists provide mostly postprandial coverage whereas the long-acting GLP-1 receptor agonists reduce both the postprandial and fasting glucose.
For example, exenatide, a synthetic version of a peptide initially identified in the saliva of the Gila monster (exendin-4), is an analogue of GLP-1. Unlike native GLP-1, which has a half-life of ~2 min, differences in the exenatide amino acid sequence render it resistant to the enzyme that degrades GLP-1 (dipeptidyl peptidase IV [DPP-IV]). Thus, exenatide has prolonged GLP-1-like action and binds to GLP-1 receptors found in islets, the GI tract, and the brain. Liraglutide, another GLP-1 receptor agonist, is almost identical to native GLP-1 except for an amino acid substitution and addition of a fatty acyl group (coupled with a γ-glutamic acid spacer) that promote binding to albumin and plasma proteins and prolong its half-life. Higher doses of liraglutide than used for glucose-lowering effects have been approved for weight loss therapy for obesity. Liraglutide treatment has also been associated with a decrease in CVD events in patients with type 2 DM and established CVD and with lower rates of diabetic kidney disease. In a similar patient population, semaglutide treatment was associated with fewer CVD events and reduced diabetic kidney disease, but with an increased rate of retinopathy-related complications. Whether the effect on CVD is a drug class effect is not clear as other GLP-1 receptor agonists have not reduced CVD events. Treatment with these agents should start at a low dose to minimize initial side effects (nausea being the limiting one). GLP-1 receptor agonists can be used as combination therapy with metformin, sulfonylureas, and thiazolidinediones. Some patients taking insulin secretagogues may require a reduction in those agents to prevent hypoglycemia. The major side effects are nausea, vomiting, and diarrhea. Some formulations carry a black box warning from the FDA because of an increased risk of thyroid C-cell tumors in rodents and are contraindicated in individuals with medullary carcinoma of the thyroid, multiple endocrine neoplasia, or pancreatic disease. Because GLP-1 receptor agonists slow gastric emptying, they may influence the absorption of other drugs. Whether GLP-1 receptor agonists enhance beta cell survival or promote beta cell proliferation in humans as in rodents is not known, but these agents do not appear to alter the natural history of type 2 DM.
DPP-IV inhibitors inhibit degradation of native GLP-1 and thus enhance the incretin effect. DPP-IV, which is widely expressed on the cell surface of endothelial cells and some lymphocytes, degrades a wide range of peptides (not GLP-1 specific). DPP-IV inhibitors promote insulin secretion in the absence of hypoglycemia or weight gain and appear to have a preferential effect on postprandial blood glucose. The levels of GLP-1 action in the patient are greater with the GLP-1 receptor agonists than with DPP-IV inhibitors. DPP-IV inhibitors are used either alone or in combination with other oral agents in type 2 DM. Reduced doses should be given to patients with renal insufficiency. There is conflicting evidence concerning a potentially increased risk for acute pancreatitis with GLP-1 receptor agonists and DPP-IV inhibitors, although initial concerns about possible premalignant lesions appear to be unfounded. For now, it is reasonable to avoid these agents in patients with pancreatic disease or with other significant risk factors for acute pancreatitis (e.g., heavy alcohol use, severely elevated serum triglycerides, hypercalcemia).
α-Glucosidase inhibitors reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion (Table 397-5). Postprandial hyperglycemia, secondary to impaired hepatic and peripheral glucose disposal, contributes significantly to the hyperglycemic state in type 2 DM. These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen. Therapy should be initiated at a low dose with the evening meal and increased to a maximal dose over weeks to months. The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to the large bowel and can be reduced somewhat by gradual upward dose titration. α-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia. Simultaneous treatment with bile acid resins and antacids should be avoided. These agents should not be used in individuals with inflammatory bowel disease, gastroparesis, or a serum creatinine >177 μmol/L (2 mg/dL). This class of agents is not as potent as other oral agents in lowering the HbA1c but is unique because it reduces the postprandial glucose rise. If hypoglycemia from other diabetes treatments occurs while taking these agents, the patient should consume glucose because the degradation and absorption of complex carbohydrates will be retarded.
Thiazolidinediones (Table 397-5) reduce insulin resistance by binding to the peroxisome proliferator-activated receptor γ (PPAR-γ) nuclear receptor (which forms a heterodimer with the retinoid X receptor). The PPAR-γ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues. Agonists of this receptor regulate a large number of genes, promote adipocyte differentiation, reduce hepatic fat accumulation, and promote fatty acid storage. Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance. Although direct comparisons are not available, the two currently available thiazolidinediones appear to have similar efficacy. The prototype of this class of drugs, troglitazone, was withdrawn from the U.S. market after reports of hepatotoxicity and an association with an idiosyncratic liver reaction that sometimes led to hepatic failure. Although rosiglitazone and pioglitazone do not appear to induce the liver abnormalities seen with troglitazone, the FDA recommends measurement of liver function tests prior to initiating therapy. Modestly increased transaminase levels related to underlying fatty liver disease should not preclude treatment as these levels may improve with thiazolidinediones due to a reduction in hepatic fat content.
Rosiglitazone raises low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides slightly. Pioglitazone raises HDL to a greater degree and LDL a lesser degree but lowers triglycerides. The clinical significance of the lipid changes with these agents is not known and may be difficult to ascertain because most patients with type 2 DM are also treated with a statin.
Thiazolidinediones are associated with weight gain (2–3 kg), a small reduction in the hematocrit, and a mild increase in plasma volume. Peripheral edema and CHF are more common in individuals treated with these agents. These agents are contraindicated in patients with liver disease or CHF (class III or IV). The FDA has issued an alert that rare patients taking these agents may experience a worsening of diabetic macular edema. An increased risk of fractures has been noted in postmenopausal women taking these agents. Thiazolidinediones have been shown to induce ovulation in premenopausal women with polycystic ovary syndrome. Women should be warned about the risk of pregnancy because the safety of thiazolidinediones in pregnancy is not established.
Concerns about increased cardiovascular risk associated with rosiglitazone led to considerable restrictions on its use and to the FDA issuing a “black box” warning in 2007. However, based on new information, the FDA has revised its guidelines and categorizes rosiglitazone similar to other drugs for type 2 DM. According to a recent FDA pronouncement, pioglitazone may be associated with an increased risk of bladder cancer. In one study, pioglitazone lowered the risk for recurrent stroke or myocardial infarction in insulin-resistant individuals without diabetes who had a prior stroke or transient ischemic attack.
Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors
These agents (Table 397-5) lower the blood glucose by selectively inhibiting this co-transporter, which is expressed almost exclusively in the proximal, convoluted tubule in the kidney. This inhibits glucose reabsorption, lowers the renal threshold for glucose, and leads to increased urinary glucose excretion. Thus, the glucose-lowering effect is insulin independent and not related to changes in insulin sensitivity or secretion. The loss of urinary glucose may promote modest weight reduction. Since these agents also impair proximal reabsorption of sodium, their use is associated with a diuretic effect and 3–6 mm Hg reduction in systolic blood pressure. Due to the increased urinary glucose, urinary and genital mycotic infections are more common in both men and women, and the diuretic effect can lead to reduced intravascular volume and acutely impaired kidney function. Inhibition of SGLT2 on the alpha cell may lead to increased glucagon and consequently liver production of glucose and ketones. Euglycemic DKA may occur during illness or when ongoing glucosuria masks stress-induced requirements for insulin. These agents should not be prescribed for patients with type 1 DM or pancreatogenic forms of DM associated with insulin deficiency. Empagliflozin and canagliflozin reduces CVD events and all cause cardiovascular mortality in patients with type 2 DM and established CVD, the risk for nephropathy, and the rate of hospitalization for CHF. A possible increased risk of bladder cancer has been seen with dapagliflozin; canagliflozin is associated with an increased risk of leg and foot amputation and bone fractures.
OTHER THERAPIES FOR TYPE 2 DM
Evidence indicates that bile acids, by signaling through nuclear receptors, may have a role in metabolism. Bile acid metabolism is abnormal in type 2 DM. The bile acid–binding resin colesevelam has been approved for the treatment of type 2 DM (already approved for treatment of hypercholesterolemia). Because bile acid–binding resins are minimally absorbed into the systemic circulation, how bile acid–binding resins lower blood glucose is not known. The most common side effects are GI (constipation, abdominal pain, and nausea). Bile acid–binding resins can increase plasma triglycerides and should be used cautiously in patients with a tendency for hypertriglyceridemia. The role of this class of drugs in the treatment of type 2 DM is not yet defined.
A formulation of the dopamine receptor agonist bromocriptine (Cycloset) has been approved by the FDA for the treatment of type 2 DM. However, its role in the treatment of type 2 DM is uncertain.
INSULIN THERAPY IN TYPE 2 DM
Insulin should be considered as part of the initial therapy in type 2 DM, particularly in lean individuals or those with severe weight loss, in individuals with underlying renal or hepatic disease that precludes oral glucose-lowering agents, or in individuals who are hospitalized or acutely ill. Insulin therapy is ultimately required by a substantial number of individuals with type 2 DM because of the progressive nature of the disorder and the relative insulin deficiency that develops in patients with long-standing diabetes. Both physician and patient reluctance often delay the initiation of insulin therapy, but glucose control and patient well-being are improved by insulin therapy in patients who have not reached glycemic targets.
Because endogenous insulin secretion continues and is capable of providing some coverage of mealtime caloric intake, insulin is usually initiated in a single dose of long-acting insulin (0.2–0.4 U/kg per day), given in the evening or just before bedtime (NPH, glargine, detemir, or degludec). Because fasting hyperglycemia and increased hepatic glucose production are prominent features of type 2 DM, bedtime insulin is more effective in clinical trials than a single dose of morning insulin. Glargine given at bedtime has less nocturnal hypoglycemia than NPH insulin. Some physicians prefer a relatively low, fixed starting dose of long-acting insulin (5–15 units) or a weight-based dose (0.1 units/kg). The insulin dose may then be adjusted in 10% increments as dictated by SMBG results. Both morning and bedtime long-acting insulin may be used in combination with oral glucose-lowering agents. Initially, basal insulin may be sufficient, but often prandial insulin coverage with multiple insulin injections is needed as diabetes progresses (see insulin regimens used for type 1 DM). Other insulin formulations that have a combination of short-acting and long-acting insulin (Table 397-4) are sometimes used in patients with type 2 DM because of convenience but do not allow independent adjustment of short-acting and long-acting insulin dose and often do not achieve the same degree of glycemic control as basal/bolus regimens. In selected patients with type 2 DM, insulin-infusion devices may be considered.
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
The level of hyperglycemia and the patient’s individualized goal (see “Establishment of Target Level of Glycemic Control”) should influence the initial choice of therapy. Assuming that maximal benefit of MNT and increased physical activity has been realized, patients with mild hyperglycemia (FPG <7.0–11.0 mmol/L [126–199 mg/dL]) often respond well to a single, oral glucose-lowering agent, while those with moderate hyperglycemia (FPG 11.1–13.9 mmol/L [200–250 mg/dL]) will usually require more than one oral agent or insulin. Patients with more severe hyperglycemia (FPG >13.9 mmol/L [250 mg/dL]) may respond partially but are unlikely to achieve normoglycemia with oral therapy. Insulin can be used as initial therapy in individuals with severe hyperglycemia (FPG <13.9–16.7 mmol/L [250–300 mg/dL]) or in those who are symptomatic from the hyperglycemia. This approach is based on the rationale that more rapid glycemic control will reduce “glucose toxicity” to the islet cells, improve endogenous insulin secretion, and possibly allow oral glucose-lowering agents to be more effective. If this occurs, the insulin may be discontinued.
Insulin secretagogues, biguanides, α-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists, DPP-IV inhibitors, SLGT2 inhibitors, and insulin are approved for monotherapy of type 2 DM. Although each class of oral glucose-lowering agents has advantages and disadvantages (Table 397-5), certain generalizations apply: (1) insulin secretagogues, biguanides, GLP-1 receptor agonists, and thiazolidinediones improve glycemic control to a similar degree (1–2% reduction in HbA1c) and are more effective than α-glucosidase inhibitors, DPP-IV inhibitors, and SLGT2 inhibitors; (2) assuming a similar degree of glycemic improvement, the clinical advantage of one class of drugs is not clear; any therapy that improves glycemic control is likely beneficial; (3) insulin secretagogues, GLP-1 receptor agonists, DPP-IV inhibitors, α-glucosidase inhibitors, and SLGT2 inhibitors begin to lower the plasma glucose immediately, whereas the glucose-lowering effects of the biguanides and thiazolidinediones are delayed by weeks; (4) not all agents are effective in all individuals with type 2 DM; (5) biguanides, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, thiazolidinediones, and SLGT2 inhibitors do not directly cause hypoglycemia; (6) most individuals will eventually require treatment with more than one class of oral glucose-lowering agents or insulin, reflecting the progressive nature of type 2 DM; and (7) durability of glycemic control is slightly less for sulfonylureas compared to metformin or thiazolidinediones.
Considerable clinical experience exists with metformin and sulfonylureas because they have been available for several decades. It is assumed that the α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, thiazolidinediones, and SLGT2 inhibitors will reduce DM-related complications by improving glycemic control, but long-term data are not yet available. The thiazolidinediones are theoretically attractive because they target a fundamental abnormality in type 2 DM, namely insulin resistance.
Treatment algorithms by several professional societies (ADA/European Association for the Study of Diabetes [EASD], IDF, AACE) suggest metformin as initial therapy because of its efficacy, known side effect profile, and low cost (Fig. 397-3). Metformin’s advantages are that it promotes mild weight loss, lowers insulin levels, and improves the lipid profile slightly. Based on SMBG results and the HbA1c, the dose of metformin should be increased until the glycemic target is achieved or maximum dose is reached.
Glycemic management of type 2 diabetes. See text for discussion of treatment of severe hyperglycemia or symptomatic hyperglycemia. Agents that can be combined with metformin include insulin secretagogues, thiazolidinediones, α-glucosidase inhibitors, DPP-IV inhibitors, GLP-1 receptor agonists, SLGT2 inhibitors, and insulin. HbA1c, hemoglobin HbA1c.
COMBINATION THERAPY WITH GLUCOSE-LOWERING AGENTS
A number of combinations of therapeutic agents are successful in type 2 DM metformin + second oral agent, metformin + GLP-1 receptor agonist, metformin + insulin, or combinations of a long-acting insulin and a GLP-1 receptor agonist. Because mechanisms of action of the first and second agents should be different, the effect on glycemic control is usually additive. There are little data to support the choice of one combination over another combination. Based on recent demonstrations of a beneficial cardiovascular effect in certain individuals with type 2 DM and CVD, or at high-risk of CVD, empagliflozin, canagliflozin, and liraglutide should now be considered in these populations. Medication costs vary considerably (Table 397-5), and this often factors into medication choice. Several fixed-dose combinations of oral agents are available, but evidence that they are superior to titration of single agent to a maximum dose and then addition of a second agent is lacking. If adequate control is not achieved with the combination of two agents (based on reassessment of the HbA1c every 3 months), a third oral agent, GLP-1 receptor agonist, or basal insulin should be added (Fig. 397-3). Treatment approaches vary considerably from country to country. For example, α-glucosidase inhibitors are used commonly in South Asian patients (Indian), but infrequently in the United States or Europe. Whether this reflects an underlying difference in the disease or physician preference is not clear.
Treatment with insulin often becomes necessary as type 2 DM enters the phase of relative insulin deficiency and is signaled by inadequate glycemic control with one or two oral glucose-lowering agents. Insulin alone or in combination should be used in patients who fail to reach glycemic targets. For example, a single dose of long-acting insulin at bedtime is often effective in combination with metformin. As endogenous insulin production falls further, multiple injections of long-acting and short-acting insulin regimens are necessary to control postprandial glucose excursions. These insulin regimens are identical to the long-acting and short-acting combination regimens discussed above for type 1 DM, although usually at higher doses given insulin resistance. Weight gain and hypoglycemia are the major adverse effects of insulin therapy. The daily insulin dose required can become quite large (1–2 units/kg per day) as endogenous insulin production falls and insulin resistance persists. Individuals who require >1 unit/kg per day of long-acting insulin should be considered for combination therapy with metformin or a thiazolidinedione. The addition of metformin or a thiazolidinedione can reduce insulin requirements in some individuals with type 2 DM, while maintaining or even improving glycemic control. Insulin plus a thiazolidinedione promotes weight gain and is associated with peripheral edema. Addition of a thiazolidinedione to a patient’s insulin regimen may necessitate a reduction in the insulin dose to avoid hypoglycemia. Patients requiring large doses of insulin (>200 units/day) can be treated with a more concentrated form of insulin.
Whole pancreas transplantation can normalize glucose control in type 1 DM and when performed simultaneously with or after kidney transplantation can prolong the life of the kidney transplant by offering protection against recurrent diabetic nephropathy. Pancreatic islet transplantation is available as a less invasive form of beta cell replacement therapy for type 1 DM, but remains investigational in the United States. Due to the risks associated with chronic immunosuppression, whole pancreas and pancreatic islet transplantation may be considered for patients with severe metabolic instability or already requiring immunosuppression in support of a kidney or other organ transplant. Patients with chronic pancreatitis and preserved islet function who require pancreatectomy for pain relief may benefit from autologous islet transplantation as this may prevent or ameliorate postsurgical DM.
Metabolic (also referred to as bariatric) surgery for obese individuals with type 2 DM has shown considerable promise, sometimes with dramatic resolution of the diabetes or major reductions in the needed dose of glucose-lowering therapies (Chap. 395). Several large, non-randomized clinical trials have demonstrated a much greater efficacy of metabolic surgery compared to medical management in the treatment of type 2 DM and may be considered in individuals with T2DM and a BMI >30 kg/m2. The ADA clinical guidelines state that metabolic surgery should be considered in individuals with type 2 DM and a body mass index >30 kg/m2 if hyperglycemia is inadequately controlled despite optimal medical therapy.
Many individuals with long-standing type 1 DM still produce very small amounts of insulin or have insulin-positive cells within the pancreas. This suggests that beta cells may slowly regenerate but are quickly destroyed by the autoimmune process. Particularly early in the disease course, efforts to suppress the autoimmune process and allow for beta cell regeneration are being tested at the time of diagnosis of type 1 DM, and for prevention in autoantibody-positive individuals at Stages 1 and 2 of type 1 DM (417-6). Closed-loop insulin infusion devices that infuse the appropriate amount of insulin in response to changing glucose levels are progressing rapidly. Bi-hormonal infusion devices that deliver both insulin and glucagon are under development. New therapies under evaluation or development for type 2 DM include activators of glucokinase, inhibitors of 11 β-hydroxysteroid dehydrogenase-1, GPR40 agonists, and agents to reduce inflammation.
Because whole pancreas and pancreatic islet transplantation are both limited by organ availability from deceased donors, stem cell-derived islet cells and xenogeneic sources of islets may eventually allow for a limitless supply of insulin-producing cells for transplantation.
ADVERSE EFFECTS OF THERAPY FOR DM
As with any therapy, the benefits of efforts directed toward glycemic control must be balanced against the risks of treatment (Table 397-5). Side effects of intensive treatment include an increased frequency of serious hypoglycemia, weight gain, increased economic costs, and greater demands on the patient. In the DCCT, quality of life was very similar in the intensive and standard therapy groups. The most serious complication of therapy for DM is hypoglycemia, and its treatment with oral glucose or glucagon injection is discussed in Chap. 399. Severe, recurrent hypoglycemia warrants examination of treatment regimen and glycemic goal for the individual patient. Weight gain occurs with most (insulin, insulin secretagogues, thiazolidinediones) but not all (metformin, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors) therapies. The weight gain is partially due to the anabolic effects of insulin and the reduction in glucosuria. As a result of concerns about CV safety of diabetes therapies, the FDA requires information about the cardiovascular safety profile as part of its evaluation of new medications for type 2 DM.
ACUTE DISORDERS RELATED TO SEVERE HYPERGLYCEMIA
Individuals with type 1 or type 2 DM and severe hyperglycemia (>13.9 mmol/L [250 mg/dL]) should be assessed for clinical stability, including mentation and hydration. Depending on the patient and the rapidity and duration of the severe hyperglycemia, an individual may require more intense and rapid therapy to lower the blood glucose. However, many patients with poorly controlled diabetes and hyperglycemia have few symptoms. The physician should assess if the patient is stable or if DKA or a hyperglycemic hyperosmolar state (HHS) should be considered. Ketones, an indicator of DKA, should be measured in individuals with type 1 DM when the plasma glucose is >13.9 mmol/L (250 mg/dL), during a concurrent illness, or with symptoms such as nausea, vomiting, or abdominal pain. Blood measurement of β-hydroxybutyrate is preferred over urine testing with nitroprusside-based assays that measure only acetoacetate and acetone.
DKA and HHS are acute, severe disorders directly related to diabetes. DKA was formerly considered a hallmark of type 1 DM, but also occurs in individuals with type 2 DM who can sometimes subsequently be treated with oral glucose-lowering agents (usually obese individuals of Hispanic or African-American descent). HHS is primarily seen in individuals with type 2 DM. Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and acid-base abnormalities. DKA and HHS exist along a continuum of hyperglycemia, with or without ketosis. The metabolic similarities and differences in DKA and HHS are highlighted in Table 397-6. Both disorders are associated with potentially serious complications if not promptly diagnosed and carefully treated.
TABLE 397-6Laboratory Values in Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS) (Representative Ranges at Presentation) ||Download (.pdf) TABLE 397-6 Laboratory Values in Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS) (Representative Ranges at Presentation)
| ||DKA ||HHS |
|Glucose,a mmol/L (mg/dL) ||13.9–33.3 (250–600) ||33.3–66.6 (600–1200) |
|Sodium, meq/L ||125–135 ||135–145 |
|Potassiuma,b ||Normal to ↑ ||Normal |
|Magnesiuma ||Normal ||Normal |
|Chloridea ||Normal ||Normal |
|Phosphatea,b ||Normal ||Normal |
|Creatinine ||Slightly ↑ ||Moderately ↑ |
|Osmolality (mosm/mL) ||300–320 ||330–380 |
|Plasma ketonesa ||++++ ||+/– |
|Serum bicarbonate,a meq/L ||<15 ||Normal to slightly ↓ |
|Arterial pH ||6.8–7.3 ||>7.3 |
|Arterial PCO2,a mmHg ||20–30 ||Normal |
|Anion gapa(Na – [Cl + HCO3]) ||↑ ||Normal to slightly ↑ |
The symptoms and physical signs of DKA are listed in Table 397-7 and usually develop over 24 h. DKA may be the initial symptom complex that leads to a diagnosis of type 1 DM, but more frequently, it occurs in individuals with established diabetes. Nausea and vomiting are often prominent, and their presence in an individual with diabetes warrants laboratory evaluation for DKA. Abdominal pain may be severe and can resemble acute pancreatitis or ruptured viscus. Hyperglycemia leads to glucosuria, volume depletion, and tachycardia. Hypotension can occur because of volume depletion in combination with peripheral vasodilatation. Kussmaul respirations and a fruity odor on the patient’s breath (secondary to metabolic acidosis and increased acetone) are classic signs of the disorder. Lethargy and central nervous system depression may evolve into coma with severe DKA but should also prompt evaluation for other reasons for altered mental status (e.g., infection, hypoxemia). Cerebral edema, an extremely serious complication of DKA, is seen most frequently in children. Signs of infection, which may precipitate DKA, should be sought on physical examination, even in the absence of fever. Tissue ischemia (heart, brain) can also be a precipitating factor. Omission of insulin because of an eating disorder, mental health disorders, or an unstable psychosocial environment may sometimes be a factor precipitating DKA.
TABLE 397-7Manifestations of Diabetic Ketoacidosis ||Download (.pdf) TABLE 397-7 Manifestations of Diabetic Ketoacidosis
Shortness of breath
Inadequate insulin administration
Infarction (cerebral, coronary, mesenteric, peripheral)
Tachypnea/Kussmaul respirations/respiratory distress
Abdominal tenderness (may resemble acute pancreatitis or surgical abdomen)
Lethargy/obtundation/cerebral edema/possibly coma
DKA results from relative or absolute insulin deficiency combined with counterregulatory hormone excess (glucagon, catecholamines, cortisol, and growth hormone). Both insulin deficiency and glucagon excess, in particular, are necessary for DKA to develop. The decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis, and ketone body formation in the liver, as well as increases in substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver. Markers of inflammation (cytokines, C-reactive protein) are elevated in both DKA and HHS.
The combination of insulin deficiency and hyperglycemia reduces the hepatic level of fructose-2,6-bisphosphate, which alters the activity of phosphofructokinase and fructose-1,6-bisphosphatase. Glucagon excess decreases the activity of pyruvate kinase, whereas insulin deficiency increases the activity of phosphoenolpyruvate carboxykinase. These changes shift the handling of pyruvate toward glucose synthesis and away from glycolysis. The increased levels of glucagon and catecholamines in the face of low insulin levels promote glycogenolysis. Insulin deficiency also reduces levels of the GLUT4 glucose transporter, which impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose metabolism.
Ketosis results from a marked increase in free fatty acid release from adipocytes, with a resulting shift toward ketone body synthesis in the liver. Reduced insulin levels, in combination with elevations in catecholamines and growth hormone, increase lipolysis and the release of free fatty acids. Normally, these free fatty acids are converted to very low-density lipoprotein (VLDL) in the liver. However, in DKA, hyperglucagonemia alters hepatic metabolism to favor ketone body formation, through activation of the enzyme carnitine palmitoyltransferase I. This enzyme is crucial for regulating fatty acid transport into the mitochondria, where beta oxidation and conversion to ketone bodies occur. At physiologic pH, ketone bodies exist as ketoacids, which are neutralized by bicarbonate. As bicarbonate stores are depleted, metabolic acidosis ensues. Increased lactic acid production also contributes to the acidosis. The increased free fatty acids increase VLDL-triglyceride production. VLDL clearance is also reduced because the activity of insulin-sensitive lipoprotein lipase in muscle and fat is decreased.
DKA is often precipitated by increased insulin requirements, as occurs during a concurrent illness (Table 397-7). Failure to augment insulin therapy often compounds the problem. Complete omission or inadequate administration of insulin by the patient or health care team (in a hospitalized patient with type 1 DM) may precipitate DKA. Patients using insulin-infusion devices with short-acting insulin may develop DKA, because even a brief interruption in insulin delivery (e.g., mechanical malfunction) quickly leads to insulin deficiency.
Laboratory Abnormalities and Diagnosis
The timely diagnosis of DKA is crucial and allows for prompt initiation of therapy. DKA is characterized by hyperglycemia (serum glucose > 13.9 mmol/L [250 mg/dL], ketosis, and metabolic acidosis (serum bicarbonate <15 mmol/L with increased anion gap) along with a number of secondary metabolic derangements (Table 397-6). Occasionally, the serum glucose is only minimally elevated, and may even be normal (euglycemic DKA). This has been noted in individuals treated with SGLT2 inhibitors. Arterial pH ranges between 6.8 and 7.3, depending on the severity of the acidosis. Despite a total-body potassium deficit, the serum potassium at presentation may be mildly elevated, secondary to the acidosis and volume depletion. Total-body stores of sodium, chloride, phosphorus, and magnesium are also reduced in DKA but are not accurately reflected by their levels in the serum because of hypovolemia and hyperglycemia. Elevated blood urea nitrogen (BUN) and serum creatinine levels reflect intravascular volume depletion. Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are commonly found as well. Hyperamylasemia may suggest a diagnosis of pancreatitis, especially when accompanied by abdominal pain. However, in DKA the amylase is usually of salivary origin and thus is not diagnostic of pancreatitis. Serum lipase should be obtained if pancreatitis is suspected.
The measured serum sodium is reduced as a consequence of the hyperglycemia (1.6-mmol/L [1.6-meq] reduction in serum sodium for each 5.6-mmol/L [100-mg/dL] rise in the serum glucose). A normal serum sodium in the setting of DKA indicates a more profound water deficit. In “conventional” units, the calculated serum osmolality (2 × [serum sodium + serum potassium] + plasma glucose [mg/dL]/18 + BUN/2.8) is mildly to moderately elevated, although to a lesser degree than that found in HHS (see below).
In DKA, the ketone body, β-hydroxybutyrate, is synthesized at a threefold greater rate than acetoacetate; however, acetoacetate is preferentially detected by a commonly used ketosis detection reagent (nitroprusside). Serum ketones are present at significant levels (usually positive at serum dilution of ≥1:8). The nitroprusside tablet, or stick, is often used to detect urine ketones; certain medications such as captopril or penicillamine may cause false-positive reactions. Serum or plasma assays for β-hydroxybutyrate are preferred because they more accurately reflect the true ketone body level.
The metabolic derangements of DKA exist along a spectrum, beginning with mild acidosis with moderate hyperglycemia evolving into more severe findings. The degree of acidosis and hyperglycemia do not necessarily correlate closely because a variety of factors determine the level of hyperglycemia (oral intake, urinary glucose loss). Ketonemia is a consistent finding in DKA and distinguishes it from simple hyperglycemia. The differential diagnosis of DKA includes starvation ketosis, alcoholic ketoacidosis (bicarbonate usually >15 meq/L), and other forms of increased anion-gap acidosis (Chap. 51).
TREATMENT Diabetic Ketoacidosis
The management of DKA is outlined in Table 397-8. After initiating IV fluid replacement and insulin therapy, the agent or event that precipitated the episode of DKA should be sought and aggressively treated. If the patient is vomiting or has altered mental status, a nasogastric tube should be inserted to prevent aspiration of gastric contents. Central to successful treatment of DKA is careful monitoring and frequent reassessment to ensure that the patient and the metabolic derangements are improving. A comprehensive flow sheet should record chronologic changes in vital signs, fluid intake and output, and laboratory values as a function of insulin administered.
After the initial bolus of normal saline, replacement of the sodium and free water deficit is carried out over the next 24 h (fluid deficit is often 3–5 L). When hemodynamic stability and adequate urine output are achieved, IV fluids should be switched to 0.45% saline depending on the calculated volume deficit. The change to 0.45% saline helps to reduce the trend toward hyperchloremia later in the course of DKA. Alternatively, initial use of lactated Ringer’s IV solution may reduce the hyperchloremia that commonly occurs with normal saline.
A bolus of IV (0.1 units/kg) short-acting regular insulin is usually administered immediately (Table 397-8), and subsequent treatment should provide continuous and adequate levels of circulating insulin. IV administration is usually preferred (0.1 units/kg of regular insulin per hour) because it ensures rapid distribution and allows adjustment of the infusion rate as the patient responds to therapy. DKA can also be treated with SC short-acting insulin analogues. IV regular insulin should be continued until the acidosis resolves and the patient is metabolically stable. As the acidosis and insulin resistance associated with DKA resolve, the insulin infusion rate can be decreased (to 0.02–0.1 units/kg per hour). Long-acting insulin, in combination with SC short-acting insulin, should be administered as soon as the patient resumes eating, because this facilitates transition to an outpatient insulin regimen and reduces length of hospital stay. It is crucial to continue the insulin infusion until adequate insulin levels are achieved by administering long-acting insulin by the SC route. Even relatively brief periods of inadequate insulin administration in this transition phase may result in DKA relapse.
Hyperglycemia usually improves at a rate of 4.2–5.6 mmol/L (50–100 mg/dL) per hour as a result of insulin-mediated glucose disposal, reduced hepatic glucose release, and rehydration. The latter reduces catecholamines, increases urinary glucose loss, and expands the intravascular volume. The decline in the plasma glucose within the first 1–2 h may be more rapid and is mostly related to volume expansion. When the plasma glucose reaches 11.1–13.9 mmol/L (200–250 mg/dL), glucose should be added to the 0.45% saline infusion to maintain the plasma glucose in the 8.3–11.1 mmol/L (150–200 mg/dL) range, and the insulin infusion should be continued at a lower rate to inhibit ketogenesis. More rapid correction of the serum glucose can precipitate the development of cerebral edema. Ketoacidosis begins to resolve as insulin reduces lipolysis, increases peripheral ketone body use, suppresses hepatic ketone body formation, and promotes bicarbonate regeneration. However, the acidosis and ketosis resolve more slowly than hyperglycemia. As ketoacidosis improves, β-hydroxybutyrate is converted to acetoacetate. Ketone body levels may appear to increase if measured by laboratory assays that use the nitroprusside reaction, which only detects acetoacetate and acetone. The improvement in acidosis and anion gap, a result of bicarbonate regeneration and decline in ketone bodies, is reflected by a rise in the serum bicarbonate level and the arterial pH. Depending on the rise of serum chloride, the anion gap (but not bicarbonate) will normalize. A hyperchloremic acidosis (serum bicarbonate of 15–18 mmol/L [15–18 meq/L]) often follows successful treatment and gradually resolves as the kidneys regenerate bicarbonate and excrete chloride.
Potassium stores are depleted in DKA (estimated deficit 3–5 mmol/kg [3–5 meq/kg]). During treatment with insulin and fluids, various factors contribute to the development of hypokalemia. These include insulin-mediated potassium transport into cells, resolution of the acidosis (which also promotes potassium entry into cells), and urinary loss of potassium salts of organic acids. Thus, potassium repletion should commence as soon as adequate urine output and a normal serum potassium are documented. If the initial serum potassium level is elevated, then potassium repletion should be delayed until the potassium falls into the normal range. Inclusion of 20–40 meq of potassium in each liter of IV fluid is reasonable, but additional potassium supplements may also be required. To reduce the amount of chloride administered, potassium phosphate or acetate can be substituted for the chloride salt. The goal is to maintain the serum potassium at >3.5 mmol/L (3.5 meq/L).
Despite a bicarbonate deficit, bicarbonate replacement is not usually necessary. In fact, theoretical arguments suggest that bicarbonate administration and rapid reversal of acidosis may impair cardiac function, reduce tissue oxygenation, and promote hypokalemia. The results of most clinical trials do not support the routine use of bicarbonate replacement, and one study in children found that bicarbonate use was associated with an increased risk of cerebral edema. However, in the presence of severe acidosis (arterial pH <7.0), the ADA advises bicarbonate (50 mmol [meq/L] of sodium bicarbonate in 200 mL of sterile water with 10 meq/L KCl per hour for 2 h until the pH is >7.0). Hypophosphatemia may result from increased glucose usage, but randomized clinical trials have not demonstrated that phosphate replacement is beneficial in DKA. If the serum phosphate is <0.32 mmol/L (1 mg/dL), then phosphate supplement should be considered and the serum calcium monitored. Hypomagnesemia may develop during DKA therapy and may also require supplementation.
With appropriate therapy, the mortality rate of DKA is low (<1%) and is related more to the underlying or precipitating event, such as infection or myocardial infarction. Venous thrombosis, upper GI bleeding, and acute respiratory distress syndrome occasionally complicate DKA. The major nonmetabolic complication of DKA therapy is cerebral edema, which most often develops in children as DKA is resolving. The etiology of and optimal therapy for cerebral edema are not well established, but overreplacement of free water and rapid normalization of serum glucose should be avoided.
Following treatment, the physician and patient should review the sequence of events that led to DKA to prevent future recurrences. Foremost is patient education about the symptoms of DKA, its precipitating factors, and the management of diabetes during a concurrent illness. During illness or when oral intake is compromised, patients should (1) frequently measure the capillary blood glucose; (2) measure urinary ketones when the serum glucose is >13.7 mmol/L (250 mg/dL); (3) drink fluids to maintain hydration; (4) continue or increase insulin; and (5) seek medical attention if dehydration, persistent vomiting, or uncontrolled hyperglycemia develop. Using these strategies, early DKA can be prevented or detected and treated appropriately on an outpatient basis.
TABLE 397-8Management of Diabetic Ketoacidosis ||Download (.pdf) TABLE 397-8 Management of Diabetic Ketoacidosis
Confirm diagnosis (↑ plasma glucose, positive serum ketones, metabolic acidosis).
Admit to hospital; intensive care setting may be necessary for frequent monitoring or if pH <7.00 or unconscious.
Serum electrolytes (K+, Na+, Mg2+, Cl–, bicarbonate, phosphate)
Acid-base status—pH, HCO3–, PCO2, β-hydroxybutyrate
Renal function (creatinine, urine output)
Replace fluids: 2–3 L of 0.9% saline over first 1–3 h (10–20 mL/kg per hour); subsequently, 0.45% saline at 250–500 mL/h; change to 5% glucose and 0.45% saline at 150–250 mL/h when plasma glucose reaches 250 mg/dL (13.9 mmol/L).
Administer short-acting regular insulin: IV (0.1 units/kg), then 0.1 units/kg per hour by continuous IV infusion; increase two- to threefold if no response by 2–4 h. If the initial serum potassium is <3.3 mmol/L (3.3 meq/L), do not administer insulin until the potassium is corrected.
Assess patient: What precipitated the episode (noncompliance, infection, trauma, pregnancy, infarction, cocaine)? Initiate appropriate workup for precipitating event (cultures, CXR, ECG).
Measure capillary glucose every 1–2 h; measure electrolytes (especially K+, bicarbonate, phosphate) and anion gap every 4 h for first 24 h.
Monitor blood pressure, pulse, respirations, mental status, fluid intake and output every 1–4 h.
Replace K+: 10 meq/h when plasma K+ <5.0–5.2 meq/L (or 20–30 meq/L of infusion fluid), ECG normal, urine flow and normal creatinine documented; administer 40–80 meq/h when plasma K+ <3.5 meq/L or if bicarbonate is given. If initial serum potassium is >5.2 mmol/L (5.2 meq/L), do not supplement K+ until the potassium is corrected.
See text about bicarbonate or phosphate supplementation.
Continue above until patient is stable, glucose goal is 8.3–11.1 mmol/L (150–200 mg/dL), and acidosis is resolved. Insulin infusion may be decreased to 0.02–0.1 units/kg per hour.
Administer long-acting insulin as soon as patient is eating. Allow for a 2–4 hour overlap in insulin infusion and SC long-acting insulin injection.
HYPERGLYCEMIC HYPEROSMOLAR STATE
The prototypical patient with HHS is an elderly individual with type 2 DM, with a several-week history of polyuria, weight loss, and diminished oral intake that culminates in mental confusion, lethargy, or coma. The physical examination reflects profound dehydration and hyperosmolality and reveals hypotension, tachycardia, and altered mental status. Notably absent are symptoms of nausea, vomiting, and abdominal pain and the Kussmaul respirations characteristic of DKA. HHS is often precipitated by a serious, concurrent illness such as myocardial infarction or stroke. Sepsis, pneumonia, and other serious infections are frequent precipitants and should be sought. In addition, a debilitating condition (prior stroke or dementia) or social situation that compromises water intake usually contributes to the development of the disorder.
Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS. Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle (see above discussion of DKA). Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion, which is exacerbated by inadequate fluid replacement. The absence of ketosis in HHS is not understood. Presumably, the insulin deficiency is only relative and less severe than in DKA. Lower levels of counterregulatory hormones and free fatty acids have been found in HHS than in DKA in some studies. It is also possible that the liver is less capable of ketone body synthesis or that the insulin/glucagon ratio does not favor ketogenesis.
Laboratory Abnormalities and Diagnosis
The laboratory features in HHS are summarized in Table 397-6. Most notable are the marked hyperglycemia (plasma glucose may be >55.5 mmol/L [1000 mg/dL]), hyperosmolality (>350 mosmol/L), and prerenal azotemia. The measured serum sodium may be normal or slightly low despite the marked hyperglycemia. The corrected serum sodium is usually increased (add 1.6 meq to measured sodium for each 5.6-mmol/L [100-mg/dL] rise in the serum glucose). In contrast to DKA, acidosis and ketonemia are absent or mild. A small anion-gap metabolic acidosis may be present secondary to increased lactic acid. Moderate ketonuria, if present, is secondary to starvation.
TREATMENT Hyperglycemic Hyperosmolar State
Volume depletion and hyperglycemia are prominent features of both HHS and DKA. Consequently, therapy of these disorders shares several elements (Table 397-8). In both disorders, careful monitoring of the patient’s fluid status, laboratory values, and insulin infusion rate is crucial. Underlying or precipitating problems should be aggressively sought and treated. In HHS, fluid losses and dehydration are usually more pronounced than in DKA due to the longer duration of the illness. The patient with HHS is usually older, more likely to have mental status changes, and more likely to have a life-threatening precipitating event with accompanying comorbidities. Even with proper treatment, HHS has a substantially higher mortality rate than DKA (up to 15% in some clinical series).
Fluid replacement should initially stabilize the hemodynamic status of the patient (1–3 L of 0.9% normal saline over the first 2–3 h). Because the fluid deficit in HHS is accumulated over a period of days to weeks, the rapidity of reversal of the hyperosmolar state must balance the need for free water repletion with the risk that too rapid a reversal may worsen neurologic function. If the serum sodium is >150 mmol/L (150 meq/L), 0.45% saline should be used. After hemodynamic stability is achieved, the IV fluid administration is directed at reversing the free water deficit using hypotonic fluids (0.45% saline initially, then 5% dextrose in water [D5W]). The calculated free water deficit (which averages 9–10 L) should be reversed over the next 1–2 days (infusion rates of 200–300 mL/h of hypotonic solution). Potassium repletion is usually necessary and should be dictated by repeated measurements of the serum potassium. In patients taking diuretics, the potassium deficit can be quite large and may be accompanied by magnesium deficiency. Hypophosphatemia may occur during therapy and can be improved by using KPO4 and beginning nutrition.
As in DKA, rehydration and volume expansion lower the plasma glucose initially, but insulin is also required. A reasonable regimen for HHS begins with an IV insulin bolus of 0.1 unit/kg followed by IV insulin at a constant infusion rate of 0.1 unit/kg per hour. If the serum glucose does not fall, increase the insulin infusion rate by twofold. As in DKA, glucose should be added to IV fluid when the plasma glucose falls to 11.1–13.9 mmol/L (200–250 mg/dL), and the insulin infusion rate should be decreased to 0.02–0.1 unit/kg per hour. The insulin infusion should be continued until the patient has resumed eating and can be transferred to a SC insulin regimen. The patient should be discharged from the hospital on insulin, although some patients can later switch to oral glucose-lowering agents.
MANAGEMENT OF DIABETES IN A HOSPITALIZED PATIENT
Virtually all medical and surgical subspecialties are involved in the care of hospitalized patients with diabetes. Hyperglycemia, whether in a patient with known diabetes or in someone without known diabetes, appears to be a predictor of poor outcome in hospitalized patients. General anesthesia, surgery, infection, or concurrent illness raises the levels of counterregulatory hormones (cortisol, growth hormone, catecholamines, and glucagon) and cytokines that may lead to transient insulin resistance and hyperglycemia. These factors increase insulin requirements by increasing glucose production and impairing glucose utilization and thus may worsen glycemic control. The concurrent illness or surgical procedure may lead to variable insulin absorption and also prevent the patient with DM from eating normally and, thus, may promote hypoglycemia. Glycemic control should be assessed on admission using the HbA1c. Electrolytes, renal function, and intravascular volume status should be assessed as well. The high prevalence of CVD in individuals with DM (especially in type 2 DM) may necessitate preoperative cardiovascular evaluation (Chap. 398).
The goals of diabetes management during hospitalization are near-normoglycemia, avoidance of hypoglycemia, and transition back to the outpatient diabetes treatment regimen. Upon hospital admission, frequent glycemic monitoring should begin, as should planning for diabetes management after discharge. Glycemic control appears to improve the clinical outcomes in a variety of settings, but optimal glycemic goals for the hospitalized patient are incompletely defined. In a number of cross-sectional studies of patients with diabetes, a greater degree of hyperglycemia was associated with worse cardiac, neurologic, and infectious outcomes. In some studies, patients who do not have preexisting diabetes but who develop modest blood glucose elevations during their hospitalization appear to benefit from achieving near-normoglycemia using insulin treatment. However, a large randomized clinical trial (Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation [NICE-SUGAR]) of individuals in the intensive care unit (ICU) (most of whom were receiving mechanical ventilation) found an increased mortality rate and a greater number of episodes of severe hypoglycemia with very strict glycemic control (target blood glucose of 4.5–6 mmol/L or 81–108 mg/dL) compared to individuals with a more moderate glycemic goal (target blood glucose of <10 mmol/L or 180 mg/dL). Currently, most data suggest that very strict blood glucose control in acutely ill patients likely worsens outcomes and increases the frequency of hypoglycemia. The ADA suggests the following glycemic goals for hospitalized patients: (1) in critically or non-critically ill patients: glucose of 7.8–10.0 mmol/L or 140–180 mg/dL; (2) in selected patients: glucose of 6.1–7.8 mmol/L or 110–140 mg/dL with avoidance of hypoglycemia.
Critical aspects for optimal diabetes care in the hospital include the following. (1) A hospital-wide system approach to treatment of hyperglycemia and prevention of hypoglycemia is needed. Inpatient diabetes management teams consisting of nurse practitioners and physicians are increasingly common. (2) Diabetes treatment plans should focus on the transition from the ICU and the transition from the inpatient to outpatient setting. (3) Adjustment of the discharge treatment regimen of patients whose diabetes was poorly controlled on admission (as reflected by the HbA1c) is important.
The physician caring for an individual with diabetes in the perioperative period, during times of infection or serious physical illness, or simply when the patient is fasting for a diagnostic procedure must monitor the plasma glucose vigilantly, adjust the diabetes treatment regimen, and provide glucose infusion as needed. Hypoglycemia is frequent in hospitalized patients, and many of these episodes are avoidable. Hospital systems should have a diabetes management protocol to avoid inpatient hypoglycemia. Measures to reduce or prevent hypoglycemia include frequent glucose monitoring and anticipating potential modifications of insulin/glucose administration because of changes in the clinical situation or treatment (e.g., tapering of glucocorticoids) or interruption of enteral or parenteral infusions or PO intake.
Depending on the severity of the patient’s illness and the hospital setting, the physician can use either an insulin infusion or SC insulin. Insulin infusions are preferred in the ICU or in a clinically unstable setting because the half-life of the infused insulin is quite short (minutes). The absorption of SC insulin may be variable in such situations. Insulin infusions can also effectively control plasma glucose in the perioperative period and when the patient is unable to take anything by mouth. Regular insulin is used rather than insulin analogues for IV insulin infusion because it is less expensive and equally effective. The physician must consider carefully the clinical setting in which an insulin infusion will be used, including whether adequate ancillary personnel are available to monitor the plasma glucose frequently and whether they can adjust the insulin infusion rate to maintain the plasma glucose within the optimal range. Insulin-infusion algorithms should integrate the insulin sensitivity of the patient, frequent blood glucose monitoring, and the trend of changes in the blood glucose to determine the insulin-infusion rate. Insulin-infusion algorithms jointly developed and implemented by nursing and physician staff are advised. Because of the short half-life of IV regular insulin, it is necessary to administer long-acting insulin prior to discontinuation of the insulin infusion (2–4 h before the infusion is stopped) to avoid a period of insulin deficiency.
In patients who are not critically ill or not in the ICU, basal or “scheduled” insulin is provided by SC, long-acting insulin supplemented by prandial and/or “corrective” insulin using a short-acting insulin (insulin analogues preferred). The use of “sliding scale,” short-acting insulin alone, where no insulin is given unless the blood glucose is elevated, is inadequate for inpatient glucose management and should not be used. The short-acting, preprandial insulin dose should include coverage for food consumption (based on anticipated carbohydrate intake) plus a corrective or supplemental insulin based on the patient’s insulin sensitivity and the blood glucose. For example, if the patient is thin (and likely insulin-sensitive), a corrective insulin supplement might be 1 unit for each 2.7 mmol/L (50 mg/dL) over the glucose target. If the patient is obese and insulin-resistant, then the insulin supplement might be 2 units for each 2.7 mmol/L (50 mg/dL) over the glucose target. It is critical to individualize the regimen and adjust the basal or “scheduled” insulin dose frequently, based on the corrective insulin required. A consistent carbohydrate-controlled diabetes meal plan for hospitalized patients provides a predictable amount of carbohydrate for a particular meal each day (but not necessarily the same amount for breakfast, lunch, and supper) and avoids concentrated sweets. Individuals with type 1 DM who are undergoing general anesthesia and surgery or who are seriously ill should receive continuous insulin, either through an IV insulin infusion, their insulin infusion device, or by SC administration of a reduced dose of long-acting insulin. Short-acting insulin alone is insufficient. Prolongation of a surgical procedure or delay in the recovery room is not uncommon and may result in periods of insulin deficiency leading to DKA. Insulin infusion is the preferred method for managing patients with type 1 DM over a prolonged (several hours) perioperative period or when serious concurrent illness is present (0.5–1.0 units/h of regular insulin). If the diagnostic or surgical procedure is brief (<2 h), a reduced dose of SC insulin may suffice (20–50% basal reduction, with short-acting bolus insulin withheld or reduced). This approach prevents interruption of insulin infusion device therapy, or for MDI, facilitates the transition back to long-acting insulin after the procedure. The blood glucose should be monitored frequently during the illness or in the perioperative period.
Individuals with type 2 DM can be managed with either an insulin infusion or SC long-acting insulin (20–50% reduction depending on clinical setting) plus preprandial, short-acting insulin. Oral glucose-lowering agents should be discontinued upon admission and are not useful in regulating the plasma glucose in clinical situations where the insulin requirements and glucose intake are changing rapidly. Moreover, these oral agents may be dangerous if the patient is fasting (e.g., hypoglycemia with sulfonylureas) or at risk for declining kidney function due to, for example, radiographic contrast media or unstable CHF (lactic acidosis with metformin). Once clinically stable, oral glucose-lowering agents may be resumed in anticipation of discharge.
SPECIAL CONSIDERATIONS IN DM
TOTAL PARENTERAL NUTRITION (TPN)
TPN greatly increases insulin requirements (See also Chap. 328). In addition, individuals not previously known to have DM may become hyperglycemic during TPN and require insulin treatment. IV insulin infusion is the preferred treatment for hyperglycemia, and rapid titration to the required insulin dose is done most efficiently using a separate insulin infusion. After the total insulin dose has been determined, a proportion of this insulin may be added directly to the TPN solution to cover the nutritional requirements for insulin, and adjusted based on the need for modified dosing of short-acting insulin. Total enteral nutrition (TEN) also increases insulin requirements and may lead to or worsen hyperglycemia. Hyperglycemia may be limited by using high protein formulations, but often requires insulin treatment. Short- or intermediate (i.e., NPH)-acting insulins should be used to cover bolus or continuous enteral feeding to minimize the risk for hypoglycemia should the TEN be interrupted or held. Patients with insulin deficiency (type 1 DM and pancreatogenic DM) should also receive long-acting insulin (0.1–0.2 units/kg per day) to cover basal insulin requirements should the TPN or TEN be interrupted or cycled.
Glucocorticoids increase insulin resistance, decrease glucose utilization, increase hepatic glucose production, and impair insulin secretion. These changes lead to a worsening of glycemic control in individuals with DM and may precipitate hyperglycemia in other individuals. If new-onset hyperglycemia remains during chronic treatment with supraphysiologic doses of glucocorticoid (>5 mg of prednisone or equivalent), the DM may be called “steroid-induced diabetes.” The effects of glucocorticoids on glucose homeostasis are dose-related, usually reversible, and most pronounced in the postprandial period. If the FPG is near the normal range, oral diabetes agents (e.g., sulfonylureas, metformin) may be sufficient to reduce hyperglycemia. If the FPG is >11.1 mmol/L (200 mg/dL), oral agents are usually not efficacious, and insulin therapy is required. Short-acting insulin may be sufficient alone or together with long-acting insulin in order to control postprandial glucose excursions.
DIABETES MANAGEMENT IN OLDER ADULTS
Diabetes is very common in older adults, being present in ~25% of individuals over the age of 65. Increasingly, individuals with many years of type 1 DM are part of the patient population. As discussed above, individualized therapeutic goals and modalities in older adults should consider biologic age, other comorbidities and risk factors (hypertension, CV disease, etc.), neurocognitive and physical functional status, living arrangements, social support, and other medications. For example, the HbA1c goal for a highly functional 80-year-old should be different than that for an individual with diabetes in long-term care (skilled nursing facilities). In the former, the HbA1c goal (<7.5%) and selected therapies may be similar to younger individuals whereas in an individual with complex/poor health or cognitive impairment, an HbA1c goal of <8.5% would be reasonable. Critical to diabetes management in all older individuals is the avoidance of hypoglycemia, which can worsen underlying cognitive impairment or CV disease. Thus, medications that can cause hypoglycemia (insulin secretagogues, insulin) should be used carefully. In choosing medications for diabetes, the adverse effects (Table 397-5) should be considered (especially heart failure, renal insufficiency, etc.). Hypertension and dyslipidemia should be treated in elderly individuals with diabetes since there is clear benefit of blood pressure control with the benefit for lipid-lowering medications being less clearly demonstrated.
Reproductive capacity in either men or women with DM appears to be normal. Menstrual cycles may be associated with alterations in glycemic control in women with DM. Pregnancy is associated with marked insulin resistance; the increased insulin requirements often precipitate DM and lead to the diagnosis of gestational diabetes mellitus (GDM). Glucose, which at high levels is a teratogen to the developing fetus, readily crosses the placenta, but insulin does not. Thus, hyperglycemia from the maternal circulation may stimulate insulin secretion in the fetus. The anabolic and growth effects of insulin may result in macrosomia. GDM complicates ~7% (range 1–14%) of pregnancies. The incidence of GDM is greatly increased in certain ethnic groups, including African Americans and Latinas, consistent with a similar increased risk of type 2 DM. Current recommendations advise screening for glucose intolerance between weeks 24 and 28 of pregnancy in women not known to have diabetes. Therapy for GDM is similar to that for individuals with pregnancy-associated diabetes and involves MNT and insulin, if hyperglycemia persists. Oral glucose-lowering agents are not approved for use during pregnancy, but studies using metformin or glyburide have shown efficacy and have not found toxicity. With current practices, the morbidity and mortality rates of the mother with GDM and the fetus are not different from those in the nondiabetic population. Individuals who develop GDM are at marked increased risk for developing type 2 DM in the future and should be screened periodically for DM (see screening recommendations in Chap. 396). Most individuals with GDM revert to normal glucose tolerance after delivery, but some will continue to have overt diabetes or impairment of glucose tolerance after delivery. In addition, children of women with GDM appear to be at risk for obesity and glucose intolerance and have an increased risk of diabetes beginning in the later stages of adolescence.
Pregnancy in individuals with known DM requires meticulous planning and adherence to strict treatment regimens. Intensive insulin therapy and near-normalization of the HbA1c (<6.5%) are essential for individuals with existing DM who are planning pregnancy. Consideration should be given to insulin infusion and CGM devices that may help to improve glycemic control prior to conception since the most crucial period of glycemic control is soon after fertilization. The risk of fetal malformations is increased 4–10 times in individuals with uncontrolled DM at the time of conception, and normal plasma glucose during the preconception period and throughout the periods of organ development in the fetus should be the goal, with more frequent monitoring of HbA1c every 2 months throughout gestation.
Lipodystrophy, or the loss of subcutaneous fat tissue, may be generalized in certain genetic conditions such as leprechaunism, or acquired as part of an autoimmune disorder. Generalized lipodystrophy is associated with leptin deficiency and severe insulin resistance and is often accompanied by acanthosis nigricans, hepatic steatosis, and severe hypertriglyceridemia. Recombinant human leptin (metreleptin) may allow for the achievement of metabolic control in generalized lipodystrophy, but is associated with the development of neutralizing antibodies and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).
Protease Inhibitors and Lipodystrophy
Protease inhibitors used in the treatment of HIV disease (Chap. 197) have been associated with a centripetal accumulation of fat (visceral and abdominal area), accumulation of fat in the dorsocervical region, loss of extremity fat, decreased insulin sensitivity (elevations of the fasting insulin level and reduced glucose tolerance on IV glucose tolerance testing), and dyslipidemia. Although many aspects of the physical appearance of these individuals resemble Cushing’s syndrome, increased cortisol levels do not account for this appearance. The possibility remains that this is related to HIV infection by some undefined mechanism, because some features of the syndrome were observed before the introduction of protease inhibitors. Therapy for HIV-related lipodystrophy is not well established.
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