A well-balanced, nutritious diet remains a fundamental element of therapy. There is no specific recommendation on the percentage of calories that should come from carbohydrate, protein, and fat. The macronutrient proportions should be individualized based on the patient’s eating patterns, preferences, and metabolic goals. In general, most patients with diabetes consume about 45% of their total daily calories in the form of carbohydrates, 25–35% in the form of fat, and 10–35% in the form of protein. In patients with type 2 diabetes, limiting the carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. A Mediterranean-style eating pattern (a diet supplemented with walnuts, almonds, hazelnuts, and olive oil) has been shown to improve glycemic control and lower combined endpoints for cardiovascular events and stroke. In those patients with obesity and type 2 diabetes, weight reduction by caloric restriction is an important goal of the diet (see Chapter 29). Patients with type 1 diabetes or type 2 diabetes who take insulin should be taught “carbohydrate counting,” so they can administer their insulin bolus for each meal based on its carbohydrate content.
The current recommendations for saturated fats and dietary cholesterol intake for people with diabetes are the same as for the general population. Saturated fats should be limited to less than 10% of daily calories and dietary cholesterol intake should be less than 300 mg/day. For those patients with kidney disease, dietary protein should be maintained at the recommended daily allowance of 0.8 g/kg/day. Exchange lists for meal planning can be obtained from the American Diabetes Association and its affiliate associations or from the American Dietetic Association (http://www.eatright.org), 216 W. Jackson Blvd., Chicago, IL 60606 (312-899-0040).
Plant components such as cellulose, gum, and pectin are indigestible by humans and are termed dietary “fiber.” Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit and may have beneficial effects on colonic function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal, or apple skin, tend to retard nutrient absorption rates so that glucose absorption is slower and hyperglycemia may be slightly diminished. Although its recommendations do not include insoluble fiber supplements such as added bran, the ADA recommends food such as oatmeal, cereals, and beans with relatively high soluble fiber content as staple components of the diet in diabetics. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.
The glycemic index of a carbohydrate containing food is determined by comparing the glucose excursions after consuming 50 g of test food with glucose excursions after consuming 50 g of reference food (white bread):
Eating low glycemic index foods results in lower glucose levels after meals. Low glycemic index foods have values of 55 or less and include many fruits, vegetables, grainy breads, pasta, and legumes. High glycemic index foods have values of 70 or greater and include baked potato, white bread, and white rice. Glycemic index is lowered by the presence of fats and protein when food is consumed in a mixed meal. Even though it may not be possible to accurately predict the glycemic index of a particular food in the context of a meal, it is reasonable to choose foods with low glycemic index.
3. Artificial and other sweeteners
Saccharin (Sweet N Low), sucralose (Splenda), acesulfame potassium (Sweet One), and rebiana (Truvia) are “artificial” sweeteners that can be used in cooking and baking. Aspartame (NutraSweet) lacks heat stability, so it cannot be used in cooking. None of these sweeteners raise blood glucose levels.
Fructose represents a “natural” sugar substance that is a highly effective sweetener, induces only slight increases in plasma glucose levels, and does not require insulin for its metabolism. However, because of potential adverse effects of large amounts of fructose on raising serum cholesterol, triglycerides, and LDL cholesterol, it does not have any advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.
Sugar alcohols, also known as polyols or polyalcohol, are commonly used as sweeteners and bulking agents. They occur naturally in a variety of fruits and vegetables but are also commercially made from sucrose, glucose, and starch. Examples are sorbitol, xylitol, mannitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates (HSH). They are not as easily absorbed as sugar, so they do not raise blood glucose levels as much. Therefore, sugar alcohols are often used in food products that are labeled as “sugar free,” such as chewing gum, lozenges, hard candy, and sugar-free ice cream. However, if consumed in large quantities, they will raise blood glucose and can cause bloating and diarrhea.
B. Medications for Treating Hyperglycemia
The medications for treating type 2 diabetes are listed in Table 27–5. They fall into several categories: (1) Medications that primarily stimulate insulin secretion by binding to the sulfonylurea receptor: Sulfonylureas remain the most widely prescribed medications for treating hyperglycemia. The meglitinide analog repaglinide and the D-phenylalanine derivative nateglinide also bind the sulfonylurea receptor and stimulate insulin secretion. (2) Medications that primarily lower glucose levels by their actions on the liver, muscle, and adipose tissue: Metformin works in the liver. The thiazolidinediones appear to have their main effect on skeletal muscle and adipose tissue. (3) Medications that principally slow intestinal absorption of glucose: The alpha-glucosidase inhibitors acarbose and miglitol are such currently available therapies. (4) Medications that mimic incretin effect or prolong incretin action: Glucagon-like peptide 1 (GLP1) receptor agonists and DPP 4 inhibitors fall into this category. (5) Medications that inhibit reabsorption of filtered glucose in the kidney: The sodium-glucose co-transporter inhibitors dapagliflozin and canagliflozin are two such agents. (6) Others: Pramlintide lowers glucose by suppressing glucagon and slowing gastric emptying. The mechanisms by which bromocriptine and colesevelam lower glucose levels have not been defined. The medications are discussed in detail below. A framework for planning treatment using medications from these six categories is offered later in this chapter.
Table 27–5.Drugs for treatment of type 2 diabetes mellitus. ||Download (.pdf) Table 27–5. Drugs for treatment of type 2 diabetes mellitus.
|Drug ||Tablet Size ||Daily Dose ||Duration of Action |
|Acetohexamide (Dymelor) (not available in United States) ||250 and 500 mg ||0.25–1.5 g as single dose or in two divided doses ||8–24 hours |
|Chlorpropamide (Diabinese) ||100 and 250 mg ||0.1–0.5 g as single dose ||24–72 hours |
|Gliclazide (not available in United States) ||80 mg ||40–80 mg as single dose; 160–320 mg as divided dose ||12 hours |
|Glimepiride (Amaryl) ||1, 2, and 4 mg ||Usual dose: 1–4 mg once daily; maximal dose: 8 mg once daily ||Up to 24 hours |
|Glipizide || || || |
| (Glucotrol) ||5 and 10 mg ||2.5–40 mg as a single dose or in two divided doses 30 minutes before meals ||6–12 hours |
| (Glucotrol XL) ||2.5, 5, and 10 mg ||Usual dose: 2.5–10 mg once daily; maximal dose: 20 mg once daily ||Up to 24 hours |
|Glyburide || || || |
| (Dia Beta, Micronase) ||1.25, 2.5, and 5 mg ||1.25–20 mg as single dose or in two divided doses ||Up to 24 hours |
| (Glynase) ||1.5, 3, and 6 mg ||1.5–12 mg as single dose or in two divided doses ||Up to 24 hours |
|Tolazamide (Tolinase) ||100, 250, and 500 mg ||0.1–1 g as single dose or in two divided doses ||Up to 24 hours |
|Tolbutamide (Orinase) ||250 and 500 mg ||0.5–2 g in two or three divided doses ||6–24 hours |
|Meglitinide Analogs |
|Mitiglinide (available in Japan) ||5 and 10 mg ||5 or 10 mg three times daily before meals ||2 hours |
|Repaglinide (Prandin) ||0.5, 1, and 2 mg ||0.5 to 4 mg three times daily before meals ||3 hours |
|d-Phenylalanine Derivative |
|Nateglinide (Starlix) ||60 and 120 mg ||60 or 120 mg three times daily before meals ||4 hours |
|Metformin (Glucophage)1 ||500, 850, and 1000 mg ||1–2.5 g; 1 tablet with meals two or three times daily ||4 hours |
|Metformin, extended release (Glucophage XR)1 ||500, 750, and 1000 mg ||500–2000 mg once daily ||Up to 24 hours |
|Pioglitazone (Actos) ||15, 30, and 45 mg ||15–45 mg daily ||Up to 24 hours |
|Rosiglitazone (Avandia) ||2, 4, and 8 mg ||4–8 mg daily (can be divided) ||Up to 24 hours |
|Alpha-Glucosidase Inhibitors |
|Acarbose (Precose) ||25, 50, and 100 mg ||25–100 mg three times daily just before meals ||4 hours |
|Miglitol (Glyset) ||25, 50, and 100 mg ||25–100 mg three times daily just before meals ||4 hours |
|Voglibose (not available in United States) ||0.2 and 0.3 mg ||0.2–0.3 mg three times daily just before meals ||4 hours |
|GLP-1 Receptor Agonists |
|Dulaglutide (Trulicity) ||0.75-, 1.5-mg single-dose pen or prefilled syringe ||0.75 mg subcutaneously once weekly. Dose can be increased to 1.5 mg if necessary. ||1 week |
|Exenatide (Byetta) ||1.2 mL and 2.4 mL prefilled pens delivering 5 mcg and 10 mcg doses || |
5 mcg subcutaneously twice daily within 1 hour of breakfast and dinner. Increase to 10 mcg subcutaneously twice daily after about a month
AVOID if eGFR < 30 mL/min/1.73 m2
|6 hours |
|Exenatide, long-acting release (Byetta LAR, Bydureon) ||2 mg (powder) ||Suspend in provided diluent and inject subcutaneously. ||1 week |
|Liraglutide (Victoza) ||Prefilled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg ||0.6 mg subcutaneously once daily (starting dose). Increase to 1.2 mg after a week if no adverse reactions. Dose can be further increased to 1.8 mg, if necessary. ||24 hours |
|Lixisenatide (Adlyxin, Lyxumia) ||3-mL prefilled pens delivering 10- or 20-mcg doses ||10 mcg daily. Increase to 20 mcg daily after 2 weeks. ||24 hours |
|Semaglutide (Ozempic, Rybelsus) || |
Prefilled pens delivering 0.25 mg or 0.5 mg
1-, 3-,7-, and 14-mg tablets
0.25 mg weekly for 1 month and increase to 0.5 mg weekly if no adverse reactions. Dose can be further increased to 1 mg weekly.
Take fasting daily with water and wait 30 min to eat. Start at 3 mg for 1 month and then increase to 7 mg. Dose can be further increased to 14 mg.
|DPP-4 Inhibitors |
|Alogliptin (Nesina) ||6.25, 12.5, and 25 mg ||25 mg once daily; eGFR 30–59 mL/min/1.73 m2: 12.5 mg daily; eGFR < 30 mL/min/1.73 m2: 6.25 mg daily. ||24 hours |
|Linagliptin (Tradjenta) ||5 mg ||5 mg daily ||24 hours |
|Saxagliptin (Onglyza) ||2.5 and 5 mg ||2.5 mg or 5 mg once daily. eGFR ≤ 50 mL/min/1.73 m2 or if also taking drugs that are strong CYP3A4/5 inhibitors such as ketoconazole: 2.5 mg daily. ||24 hours |
|Sitagliptin (Januvia) ||25, 50, and 100 mg ||100 mg once daily; eGFR 30–50 mL/min/1.73 m2: 50 mg once daily; eGFR < 30 mL/min: 25 mg once daily ||24 hours |
|Vildagliptin (Galvus) (not available in United States) ||50 mg || |
50 mg once or twice daily.
AVOID if eGFR ≤ 60 mL/min/1.73 m2 or AST/ALT three times upper limit of normal
|24 hours |
|SGLT2 Inhibitors |
|Canagliflozin (Invokana) ||100 and 300 mg || |
Usual dose: 100 mg daily. 300-mg dose can be used if normal eGFR, resulting in lowering the HbA1c an additional ~ 0.1–0.25%.
AVOID if eGFR < 45 mL/min/1.73 m2.
|24 hours |
|Dapagliflozin (Farxiga) ||5 and 10 mg ||10 mg daily. ||24 hours |
|Empagliflozin (Jardiance) ||10 and 25 mg ||10 mg daily. 25-mg dose can be used if necessary. ||24 hours |
|Ertugliflozin (Steglatro) ||5 and 15 mg ||5 mg daily. 15 mg dose can be used if necessary ||24 hours |
|Bromocriptine (Cycloset) ||0.8 mg ||0.8 mg daily. Increase weekly by 1 tablet until maximal tolerated dose of 1.6–4.8 mg daily. ||24 hours |
|Colesevelam (Welchol) ||625 mg ||3 tablets twice daily ||24 hours |
|Pramlintide (Symlin) ||5-mL vial containing 0.6 mg/mL; also available as prefilled pens. Symlin pen 60 or Symlin pen 120 || |
For insulin-treated type 2 patients, start at 60-mcg dose subcutaneously three times daily (10 units on U100 insulin syringe). Increase to 120 mcg three times daily (20 units on U100 insulin syringe) if no nausea for 3–7 days. Give immediately before meal.
For type 1 patients, start at 15 mcg three times daily (2.5 units on U100 insulin syringe) and increase by increments of 15 mcg to a maximum of 60 mcg three times daily, as tolerated.
To avoid hypoglycemia, lower insulin dose by 50% on initiation of therapy.
|2 hours |
1. Medications that primarily stimulate insulin secretion by binding to the sulfonylurea receptor on the beta cell
The primary mechanism of action of the sulfonylureas is to stimulate insulin release from pancreatic B cells. Specific receptors on the surface of pancreatic B cells bind sulfonylureas in the rank order of their insulinotropic potency (glyburide with the greatest affinity and tolbutamide with the least affinity). It has been shown that activation of these receptors closes potassium channels, resulting in depolarization of the B cell. This depolarized state permits calcium to enter the cell and actively promote insulin release.
Sulfonylureas are used in patients with type 2 but not type 1 diabetes, since these medications require functioning pancreatic B cells to produce their effect on blood glucose. Sulfonylureas are metabolized by the liver and apart from acetohexamide, whose metabolite is more active than the parent compound, the metabolites of all the other sulfonylureas are weakly active or inactive. The metabolites are excreted by the kidney and, in the case of the second-generation sulfonylureas, partly excreted in the bile.
Hypoglycemia is a common adverse reaction with the sulfonylureas. Weight gain is also common, especially in the first year of use. The mechanisms of the weight gain include improved glucose control and increased food intake in response to hypoglycemia.
Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in less than 0.1% of users.
Tolbutamide is probably best administered in divided doses (eg, 500 mg before each meal and at bedtime); however, some patients require only one or two tablets daily with a maximum dose of 3000 mg/day. Because of its short duration of action (about 6–10 hours, which is independent of kidney function), tolbutamide is relatively safe to use in kidney disease. Prolonged hypoglycemia has been reported rarely with tolbutamide, mostly in patients receiving antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal medications to treat candidiasis. These medications apparently compete with tolbutamide for oxidative enzyme systems in the liver, resulting in maintenance of high levels of unmetabolized, active sulfonylurea in the circulation.
Tolazamide, acetohexamide, and chlorpropamide are rarely used. Chlorpropamide has a prolonged biologic effect, and severe hypoglycemia can occur especially in older adults as their renal clearance declines with aging. Its other side effects include alcohol-induced flushing and hyponatremia due to its effect on vasopressin secretion and action.
Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times more potent than tolbutamide. These medications should be used with caution in patients with cardiovascular disease or in elderly patients, in whom prolonged hypoglycemia would be especially dangerous.
The usual starting dose of glyburide is 2.5 mg/day, and the average maintenance dose is 5–10 mg/day given as a single morning dose; maintenance doses higher than 20 mg/day are not recommended. Some reports suggest that 10 mg is a maximum daily therapeutic dose, with 15–20 mg having no additional benefit in poor responders and doses over 20 mg actually worsening hyperglycemia. A “Press Tab” formulation of “micronized” glyburide—easy to divide in half with slight pressure if necessary—is available. Glyburide is metabolized in the liver and the metabolic products of glyburide have hypoglycemic activity. This probably explains why assays specific for the unmetabolized compound suggest a plasma half-life of only 1–2 hours, yet the biologic effects of glyburide are clearly persistent 24 hours after a single morning dose in diabetic patients. Glyburide is unique among sulfonylureas in that it not only binds to the pancreatic B cell membrane sulfonylurea receptor but also becomes sequestered within the B cell. This may also contribute to its prolonged biologic effect despite its relatively short circulating half-life.
Glyburide has few adverse effects other than its potential for causing hypoglycemia, which at times can be prolonged. Flushing has rarely been reported after ethanol ingestion. It does not cause water retention, as chlorpropamide does, but rather slightly enhances free water clearance. Glyburide should not be used in patients with liver failure and chronic kidney disease because of the risk of hypoglycemia. Elderly patients are at particular risk for hypoglycemia even with relatively small daily doses.
The recommended starting dose of glipizide is 5 mg/day, with up to 15 mg/day given as a single daily dose before breakfast. When higher daily doses are required, they should be divided and given before meals. The maximum dose recommended by the manufacturer is 40 mg/d, although doses above 10–15 mg probably provide little additional benefit in poor responders and may even be less effective than smaller doses. For maximum effect in reducing postprandial hyperglycemia, glipizide should be ingested 30 minutes before meals, since rapid absorption is delayed when the medication is taken with food.
At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy should therefore not be used in patients with liver failure. Because of its lower potency and shorter duration of action, it is preferable to glyburide in elderly patients and for those patients with kidney disease. Glucotrol-XL provides extended release of glipizide during transit through the gastrointestinal tract with greater effectiveness in lowering prebreakfast hyperglycemia than the shorter-duration immediate-release standard glipizide tablets. However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over glyburide.
Gliclazide (not available in the United States) is another intermediate duration sulfonylurea with a duration of action of about 12 hours. The recommended starting dose is 40–80 mg/day with a maximum dose of 320 mg. Doses of 160 mg and above are given as divided doses before breakfast and dinner. The medication is metabolized by the liver; the metabolites and conjugates have no hypoglycemic effect. An extended release preparation is available.
Glimepiride has a long duration of effect with a half-life of 5 hours allowing once or twice daily dosing. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound. A single daily dose of 1 mg/day has been shown to be effective, and the maximal recommended dose is 8 mg. It is completely metabolized by the liver to relatively inactive metabolic products.
Repaglinide is structurally similar to glyburide but lacks the sulfonic acid-urea moiety. It acts by binding to the sulfonylurea receptor and closing the adenosine triphosphate (ATP)-sensitive potassium channel. It is rapidly absorbed from the intestine and then undergoes complete metabolism in the liver to inactive biliary products, giving it a plasma half-life of less than 1 hour. The medication therefore causes a brief but rapid pulse of insulin. The starting dose is 0.5 mg three times a day 15 minutes before each meal. The dose can be titrated to a maximum daily dose of 16 mg. Like the sulfonylureas, repaglinide can be used in combination with metformin. Hypoglycemia is the main side effect. In clinical trials, when the medication was compared with a long-duration sulfonylurea (glyburide), there was a trend toward less hypoglycemia. Like the sulfonylureas, repaglinide causes weight gain. Metabolism is by cytochrome P450 3A4 isoenzyme, and other medications that induce or inhibit this isoenzyme may increase or inhibit (respectively) the metabolism of repaglinide. The medication may be useful in patients with kidney impairment or in older adults.
Mitiglinide is a benzylsuccinic acid derivative that binds to the sulfonylurea receptor and is similar to repaglinide in its clinical effects. It is approved for use in Japan.
C. D-PHENYLALANINE DERIVATIVE
Nateglinide stimulates insulin secretion by binding to the sulfonylurea receptor and closing the ATP-sensitive potassium channel. It is rapidly absorbed from the intestine, reaching peak plasma levels within 1 hour. It is metabolized in the liver and has a plasma half-life of about 1.5 hours. Like repaglinide, it causes a brief rapid pulse of insulin, and when given before a meal it reduces the postprandial rise in blood glucose. For most patients, the recommended starting and maintenance dose is 120 mg three times a day before meals. Use 60 mg in patients who have mild elevations in HbA1c. Like the other insulin secretagogues, its main side effects are hypoglycemia and weight gain.
2. Medications that primarily lower glucose levels by their actions on the liver, muscle, and adipose tissue
Metformin is the first-line therapy for patients with type 2 diabetes. It can be used alone or in conjunction with other oral agents or insulin in the treatment of patients with type 2 diabetes. It is ineffective in patients with type 1 diabetes.
Metformin’s therapeutic effects primarily derive from the increasing hepatic adenosine monophosphate-activated protein kinase activity, which reduces hepatic gluconeogenesis and lipogenesis. Metformin is a substrate for organic cation transporter 1, which is abundantly expressed in hepatocytes and in the gut. Metformin has a half-life of 1.5–3 hours and is not bound to plasma proteins or metabolized, being excreted unchanged by the kidneys.
The current recommendation is to start metformin at diagnosis. A side benefit of metformin therapy is its tendency to improve both fasting and postprandial hyperglycemia and hypertriglyceridemia in obese patients with diabetes without the weight gain associated with insulin or sulfonylurea therapy. Patients with chronic kidney disease should not be given this medication because failure to excrete it would produce high blood and tissue levels of metformin that could stimulate lactic acid overproduction. In the United States, metformin use is not recommended at or above a serum creatinine level of 1.4 mg/dL in women and 1.5 mg/dL in men. In the United Kingdom, the recommendations are to review metformin use when the serum creatinine exceeds 130 mcmol/L (1.5 mg/dL) or the estimated glomerular filtration rate (eGFR) falls below 45 mL/min/1.73 m2. The medication should be stopped if the serum creatinine exceeds 150 mcmol/L (1.7 mg/dL) or the eGFR is below 30 mL/min/1.73 m2. Patients with liver failure or persons with excessive alcohol intake should not receive this medication because of the risk of lactic acidosis.
The maximum dosage of metformin is 2550 mg, although little benefit is seen above a total dose of 2000 mg. It is important to begin with a low dose and increase the dosage very gradually in divided doses—taken with meals—to reduce minor gastrointestinal upsets. A common schedule would be one 500-mg tablet three times a day with meals or one 850- or 1000-mg tablet twice daily at breakfast and dinner. Up to 2000 mg of the extended-release preparation can be given once a day. Lower doses should be used in patients with eGFRs between 30 and 45 mL/min/1.73 m2 and in the elderly who are at higher risk for acute kidney injury from reduced renal functional reserve.
The most frequent side effects of metformin are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal discomfort, diarrhea), which occur in up to 20% of patients. These effects are dose-related, tend to occur at onset of therapy, and often are transient. However, in 3–5% of patients, therapy may have to be discontinued because of persistent diarrheal discomfort. Patients switching from immediate-release metformin to comparable dose of extended-release metformin may experience fewer gastrointestinal side effects. At the time of this publication in June, 2020, five companies had withdrawn metformin from the market because of contamination with N-nitrosodimethylamine. Other companies do not appear to have a problem with contamination and continue to manufacture metformin.
Hypoglycemia does not occur with therapeutic doses of metformin, which permits its description as a “euglycemic” or “antihyperglycemic” medication rather than an oral hypoglycemic agent. Dermatologic or hematologic toxicity is rare. Metformin interferes with the calcium dependent absorption of vitamin B12-intrinsic complex in the terminal ileum; vitamin B12 deficiency can occur after many years of metformin use. Periodic screening with vitamin B12 levels should be considered, especially in patients with peripheral neuropathy or if a macrocytic anemia develops. Increased intake of dietary calcium may prevent the metformin-induced B12 malaborption.
Lactic acidosis has been reported as a side effect but is uncommon with metformin in contrast to phenformin. While therapeutic doses of metformin reduce lactate uptake by the liver, serum lactate levels rise only minimally if at all, since other organs such as the kidney can remove the slight excess. However, if tissue hypoxia occurs, the metformin-treated patient is at higher risk for lactic acidosis due to compromised lactate removal. Similarly, when kidney function deteriorates, affecting not only lactate removal by the kidney but also metformin excretion, plasma levels of metformin rise far above the therapeutic range and block hepatic uptake enough to provoke lactic acidosis without associated increases in lactic acid production. Almost all reported cases have involved persons with associated risk factors that should have contraindicated its use (kidney, liver, or cardiorespiratory insufficiency and alcoholism). Acute kidney injury can occur rarely in certain patients taking metformin who receive radiocontrast agents. Metformin therapy should therefore be temporarily halted on the day of radiocontrast administration and restarted a day or two later after confirmation that kidney function has not deteriorated.
Two medications of this class, rosiglitazone and pioglitazone, are available for clinical use. These medications sensitize peripheral tissues to insulin. They bind the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma) and affect the expression of a number of genes. Observed effects of thiazolidinediones include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased hepatic glucose output, increased adiponectin and decreased release of resistin from adipocytes, and increased differentiation of preadipocytes into adipocytes. They have also been demonstrated to decrease levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, and interleukin 6. Like the biguanides, this class of medications does not cause hypoglycemia.
Both rosiglitazone and pioglitazone are effective as monotherapy and in combination with sulfonylureas or metformin or insulin, lowering HbA1c by 1–2%. When used in combination with insulin, they can result in a 30–50% reduction in insulin dosage, and some patients can come off insulin completely. The oral dosage of rosiglitazone is 4–8 mg daily and of pioglitazone, 15–45 mg daily, and the medications do not have to be taken with food. Rosiglitazone is primarily metabolized by the CYP 2C8 isoenzyme and pioglitazone is metabolized by CYP 2C8 and CYP 3A4.
The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia. Patients inadequately managed on sulfonylureas can do well on a combination of sulfonylurea and rosiglitazone or pioglitazone. About 25% of patients in clinical trials fail to respond to these medications, presumably because they are significantly insulinopenic.
These medications have some additional effects apart from glucose lowering. Rosiglitazone therapy is associated with increases in total cholesterol, LDL cholesterol (15%), and HDL cholesterol (10%). There is a reduction in free fatty acids of about 8–15%. The changes in triglycerides are generally not different from placebo. Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL cholesterol (15%) but did not cause a consistent change in total cholesterol and LDL cholesterol levels. A prospective randomized comparison of the metabolic effects of pioglitazone and rosiglitazone on patients who had previously taken troglitazone (now withdrawn from the US market) showed similar effects on HbA1c and weight gain. Small prospective studies have demonstrated that treatment with these medications leads to improvements in the biochemical and histologic features of nonalcoholic fatty liver disease. The thiazolidinediones also may limit vascular smooth muscle proliferation after injury, and there are reports that pioglitazone can reduce neointimal proliferation after coronary stent placement. In one double-blind, placebo-controlled study, rosiglitazone was shown to be associated with a decrease in the ratio of urinary albumin to creatinine excretion.
Safety concerns and some troublesome side effects limit the use of this class of medication. Rosiglitazone use declined when a meta-analysis of 42 randomized clinical trials suggested that this medication increases the risk of angina pectoris or myocardial infarction; the European Medicines Agency suspended the use of rosiglitazone in Europe. In the United States, the FDA established a restricted distribution program. A subsequent large prospective clinical trial (the RECORD study) failed to confirm the meta-analysis finding and the restrictions were lifted in the United States.
Edema occurs in about 3–4% of patients receiving monotherapy with rosiglitazone or pioglitazone. The edema occurs more frequently (10–15%) in patients receiving concomitant insulin therapy and may result in heart failure. The medications are contraindicated in diabetic individuals with New York Heart Association class III and IV cardiac status. Thiazolidinediones have also been reported as being associated with new onset or worsening macular edema. Apparently, this is a rare side effect, and most of these patients also had peripheral edema. The macular edema resolved or improved once the medication was discontinued.
Troglitazone, the first medication in this class, was withdrawn from clinical use because of medication-associated fatal liver failure. Although rosiglitazone and pioglitazone have not been reported to cause liver injury, the FDA recommends that they should not be used in patients with clinical evidence of active liver disease or pretreatment elevation of the alanine aminotransferase (ALT) level that is 2.5 times greater than the upper limit of normal. Caution should be used in initiation of therapy in patients with even mild ALT elevations. Liver biochemical tests should be performed on all patients prior to initiation of treatment and periodically thereafter.
In experimental animals, rosiglitazone stimulates bone marrow adipogenesis at the expense of osteoblastogenesis resulting in a decrease in bone density. An increase in fracture risk in women (but not men) has been reported with both rosiglitazone and pioglitazone. The fracture risk is in the range of 1.9 per 100 patient-years with the thiazolidinedione as opposed to 1.1 per 100 patient-years on comparison treatment. In at least one study of rosiglitazone, the fracture risk was increased in premenopausal as well as postmenopausal women.
Other side effects include anemia, which occurs in 4% of patients treated with these medications; it may be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs, especially when the medication is combined with a sulfonylurea or insulin. Some of the weight gain is fluid retention, but there is also an increase in total fat mass. Clinical studies have reported conflicting results regarding an association of bladder cancer with pioglitazone use. A 10-year observational cohort study of patients taking pioglitazone failed to find an association with bladder cancer. A large multipopulation pooled analysis (1.01 million persons over 5.9 million person-years) also failed to find an association between cumulative exposure of pioglitazone or rosiglitazone and incidence of bladder cancer. Another population-based study, however, generating 689,616 person-years of follow-up did find that pioglitazone but not rosiglitazone was associated with an increased risk of bladder cancer.
3. Medications that affect absorption of glucose
Alpha-glucosidase inhibitors competitively inhibit the alpha-glucosidase enzymes in the gut that digest dietary starch and sucrose. Two of these medications—acarbose and miglitol—are available for clinical use in the United States. Voglibose, another alpha-glucosidase inhibitor is available in Japan, Korea, and India. Acarbose and miglitol are potent inhibitors of glucoamylase, alpha-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase. Acarbose binds 1000 times more avidly to the intestinal disaccharidases than do products of carbohydrate digestion or sucrose. A fundamental difference between acarbose and miglitol is in their absorption. Acarbose has the molecular mass and structural features of a tetrasaccharide, and very little (about 2%) crosses the microvillar membrane. Miglitol, however, has a structural similarity with glucose and is absorbable. Both medications delay the absorption of carbohydrate and lower postprandial glycemic excursion.
The recommended starting dose of acarbose is 50 mg orally twice daily, gradually increasing to 100 mg three times daily. For maximal benefit on postprandial hyperglycemia, acarbose should be given with the first mouthful of food ingested. In diabetic patients, it reduces postprandial hyperglycemia by 30–50%, and its overall effect is to lower the HbA1c by 0.5–1%.
The principal adverse effect, seen in 20–30% of patients, is flatulence. This is caused by undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends to discourage excessive carbohydrate consumption and promotes improved compliance of type 2 patients with their diet prescriptions. When acarbose is given alone, there is no risk of hypoglycemia. However, if combined with insulin or sulfonylureas, it might increase the risk of hypoglycemia from these agents. A slight rise in hepatic aminotransferases has been noted in clinical trials with acarbose (5% vs 2% in placebo controls, and particularly with doses greater than 300 mg/day). The levels generally return to normal on stopping the medication.
In the UKPDS, approximately 2000 patients on diet, sulfonylurea, metformin, or insulin therapy were randomized to acarbose or placebo therapy. By 3 years, 60% of the patients had discontinued the medication, mostly because of gastrointestinal symptoms. If one looked only at the 40% who remained on the medication, they had a 0.5% lower HbA1c compared with placebo.
Miglitol is similar to acarbose in terms of its clinical effects. It is indicated for use in diet- or sulfonylurea-treated patients with type 2 diabetes. Therapy is initiated at the lowest effective dosage of 25 mg orally three times a day. The usual maintenance dose is 50 mg three times a day, although some patients may benefit from increasing the dose to 100 mg three times a day. Gastrointestinal side effects occur as with acarbose. The medication is not metabolized and is excreted unchanged by the kidney. Theoretically, absorbable alpha-glucosidase inhibitors could induce a deficiency of one or more of the alpha-glucosidases involved in cellular glycogen metabolism and biosynthesis of glycoproteins. This does not occur in practice because, unlike the intestinal mucosa, which sees a high concentration of the medication, the blood level is 200-fold to 1000-fold lower than the concentration needed to inhibit intracellular alpha-glucosidases. Miglitol should not be used in end-stage chronic kidney disease, when its clearance would be impaired.
Oral glucose provokes a threefold to fourfold higher insulin response than an equivalent dose of glucose given intravenously. This is because the oral glucose causes a release of gut hormones, principally glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP1), that amplify the glucose-induced insulin release. This “incretin effect” of GLP-1 secretion (but not GIP1 secretion) is reduced in patients with type 2 diabetes and when GLP-1 is infused in patients with type 2 diabetes, it stimulates insulin secretion and lowers glucose levels. GLP-1, unlike the sulfonylureas, has only a modest insulin stimulatory effect at normoglycemic concentrations. This means that GLP-1 has a lower risk for hypoglycemia than the sulfonylureas.
In addition to its insulin stimulatory effect, GLP-1 also has a number of other pancreatic and extrapancreatic effects. It suppresses glucagon secretion and so may ameliorate the hyperglucagonemia that is present in people with diabetes and improve postprandial hyperglycemia. GLP-1 preserves islet integrity and reduces apoptotic cell death of human islet cells in culture. In mice, streptozotocin-induced apoptosis is significantly reduced by coadministration of exendin-4 or exenatide, a GLP-1 receptor agonist. GLP-1 acts on the stomach delaying gastric emptying; the importance of this effect on glucose lowering is illustrated by the observation that antagonizing the deceleration of gastric emptying markedly reduces the glucose lowering effect of GLP-1. GLP-1 receptors are present in the central nervous system and may play a role in the anorectic effect of the drugs. Intracerebroventricular administration of GLP-1 in wild type mice, but not in GLP-1 receptor knockout mice, inhibits feeding. Type 2 diabetic patients undergoing GLP-1 infusion are less hungry; it is unclear whether this is mainly due to a deceleration of gastric emptying or whether there is a central nervous system effect as well.
A. GLP-1 RECEPTOR AGONISTS
GLP-1’s half-life is only 1–2 minutes. It is rapidly proteolyzed by dipeptidyl peptidase 4 (DPP-4) and by other enzymes, such as endopeptidase 24.11, and is also cleared quickly by the kidney. The native peptide, therefore, cannot be used therapeutically. Five GLP-1 receptor agonists with longer half-lives, exenatide, liraglutide, dulaglutide, lixisenatide, and semaglutide, are available for clinical use.
Exenatide (Exendin 4) is a GLP-1 receptor agonist isolated from the saliva of the Gila monster (a venomous lizard) that is more resistant to DPP-4 action and cleared by the kidney. Its half-life is 2.4 hours, and its glucose lowering effect is about 6 hours. Exenatide is dispensed as two fixed-dose pens (5 mcg and 10 mcg). It is injected 60 minutes before breakfast and before dinner. Patients with type 2 diabetes should be prescribed the 5 mcg pen for the first month and, if tolerated, the dose can then be increased to 10 mcg twice a day. The medication is not recommended in patients with eGFR less than 30 mL/min/1.73 m2. In clinical trials, adding exenatide therapy to patients with type 2 diabetes already taking metformin or a sulfonylurea, or both, further lowered the HbA1c value by 0.4% to 0.6% over a 30-week period. These patients also experienced a weight loss of 3–6 pounds. Exenatide LAR is a once-weekly preparation that is dispensed as a powder (2 mg). It is suspended in the provided diluent just prior to injection. In comparative clinical trials, the long-acting drug lowers the HbA1c level a little more than the twice daily drug. Low-titer antibodies against exenatide develop in over one-third (38%) of patients, but the clinical effects are not attenuated. High-titer antibodies develop in a subset of patients (~6%), and in about half of these cases, an attenuation of glycemic response has been seen.
Liraglutide is a soluble fatty acid acylated GLP-1 analog. There is replacement of lysine with arginine at position 34 and the attachment of a C16 acyl chain to a lysine at position 26. The fatty-acyl GLP-1 retains affinity for GLP-1 receptors but the addition of the C16 acyl chain allows for noncovalent binding to albumin, both hindering DPP-4 access to the molecule and contributing to a prolonged half-life and duration of action. The half-life is approximately 12 hours, allowing the medication to be injected once a day. The dosing is initiated at 0.6 mg daily, increased after 1 week to 1.2 mg daily. Some patients may benefit from increasing the dose to 1.8 mg. In clinical trials lasting 26 and 52 weeks, adding liraglutide to the therapeutic regimen (metformin, sulfonylurea, thiazolidinedione) of patients with type 2 diabetes further lowered the HbA1c value. Depending on the dose and design of the study, the HbA1c decline was in the range of 0.6% to 1.5%. The patients had sustained weight loss of 1–6 pounds. Liraglutide at a dose of 3 mg daily has been approved for weight loss.
In a postmarketing multinational study of 9340 patients with type 2 diabetes with known cardiovascular disease, the addition of liraglutide was associated with a lower primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio 0.87, P = 0.01). Patients taking liraglutide had lower HbA1c levels, weight loss of 2.3 kg, lower systolic blood pressure, and fewer episodes of severe hypoglycemia.
Dulaglutide consists of two GLP-1 analog molecules covalently linked to an Fc fragment of human IgG4. The GLP-1 molecule has amino acid substitutions that resist DPP-4 action. The half-life of dulaglutide is about 5 days. The usual dose is 0.75 mg weekly by subcutaneous injection. The maximum recommended dose is 1.5 mg weekly. Dulaglutide monotherapy and combination therapy lowers HbA1c by about 0.7% to 1.6%. Weight loss ranged from 2 pounds to 7 pounds.
Lixisenatide is a synthetic analog of exendin 4 (deletion of a proline and addition of 6 lysines to the C-terminal region) with a half-life of 3 hours. It is dispensed as two fixed-dose pens (10 mcg and 20 mcg). The 10-mcg dose is injected once daily before breakfast for the first 2 weeks, and if tolerated, the dose is then increased to 20 mcg daily. Its clinical effect is about the same as exenatide with HbA1c lowering in the 0.4–0.6% range. Weight loss ranges from 2 pounds to 6 pounds. Antibodies to lixisenatide occur frequently (70%) and ~2.4% with the highest antibody titers have attenuated glycemic response.
Semaglutide is a synthetic analog of GLP-1 with a drug half-life of about 1 week. It has an alpha-aminoisobutyric acid substitution at position 8 that makes the molecule resistant to DPP4 action and a C-18 fatty di-acid chain attached to lysine at position 26 that binds to albumin, which accounts for the drug’s long half-life. Semaglutide is dispensed as two pens: one pen delivers a 0.25-mg or 0.5-mg dose and the other pen delivers a 1-mg dose. The recommended dosing is 0.25 mg weekly for 4 weeks and if tolerated the dose is then increased to 0.5 mg per week. The 1-mg per week dose can provide additional glucose lowering effect. Semaglutide monotherapy and combination therapy lowers HbA1c from 1.5% to 1.8%. An increase in diabetic retinopathy was observed in the semaglutide treated group in one of the clinical trials. It is thought that this might have been secondary to the rapid glucose lowering with the drug.
Semaglutide is an oral medication; the patient must take it fasting with a glass of water and then wait half an hour before eating, drinking, or taking other medicines. Semaglutide is co-formulated with sodium N-[8 (2-hydroxylbenzoyl) amino] caprylate (SNAC), which results in a complex that is more lipophilic and resistant to proteolysis. The recommended starting dose is 3 mg daily for the first month and increased to 7–14 mg daily as tolerated and as needed for glucose control.
The most frequent adverse reactions of the GLP-1 receptor agonists are nausea (11–40%), vomiting (4–13%), and diarrhea (9–17%). The reactions are more frequent at the higher doses. In clinical trials about 1–5% of participants withdrew from the studies because of the gastrointestinal symptoms.
The GLP-1 receptor agonists have been associated with increased risk of pancreatitis. The pancreatitis was severe (hemorrhagic or necrotizing) in 6 instances, and 2 of these patients died. In the liraglutide and dulaglutide clinical trials, there were 13 and 5 cases of pancreatitis in the drug-treated groups versus 1 and 1 case in the comparator groups, respectively. This translates to about 1.4–2.2 vs 0.6–0.9 cases of pancreatitis per 1000 patient-years. Patients taking GLP-1 receptor agonists should be advised to seek immediate medical care if they experience unexplained persistent severe abdominal pain.
There have been rare reports of acute kidney injury in patients taking exenatide. Some of these patients had preexisting kidney disease, and others had one or more risk factors for kidney disease. A number of the patients reported nausea, vomiting, and diarrhea, and it is possible that these side effects caused volume depletion and contributed to the development of the kidney injury. For this reason, the GLP-1 receptors agonists should be prescribed cautiously in patients with kidney impairment. Liraglutide, semaglutide, and dulaglutide are metabolized by proteolysis and are preferred choices in patients with kidney failure.
GLP-1 receptor agonists stimulate C-cell neoplasia and cause medullary thyroid carcinoma in rats. Human C-cells express very few GLP-1 receptors, and the relevance to human therapy is unclear. The medications, however, should not be used in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) syndrome type 2.
An alternate approach to the use of GLP-1 receptor agonists is to inhibit the enzyme DPP-4 and prolong the action of endogenously released GLP-1 and GIP. Four oral DPP-4 inhibitors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are available in the United States for the treatment of type 2 diabetes. An additional DPP-4 inhibitor, vildagliptin, is available in Europe. Other DPP-4 inhibitors—gemigliptin, anagliptin, teneligliptin, trelagliptin, omarigliptin, evogliptin, and gosogliptin—have been approved outside the United States and European Union (Korea, India, Thailand, Japan, Russia, and several South American countries).
Sitagliptin, when used alone or in combination with other diabetes medications, lowers HbA1c by approximately 0.5%. The usual dose of sitagliptin is 100 mg once daily, but the dose is reduced to 50 mg daily if the calculated creatinine clearance is 30–50 mL/min and to 25 mg for clearances less than 30 mL/min. Saxagliptin, when added to the therapeutic regimen (metformin, sulfonylurea, thiazolidinedione) of patients with type 2 diabetes, further lowered the HbA1c value by about 0.7–0.9%. The dose is 2.5 mg or 5 mg orally once a day. The 2.5-mg dose should be used in patients with eGFR less than 50 mL/min/1.73 m2.
Alogliptin lowers HbA1c by about 0.5–0.6% when added to metformin, sulfonylurea, or pioglitazone. The usual dose is 25 mg orally daily. The 12.5-mg dose is used in patients with eGFR of 30–60 mL/min/1.73 m2; and 6.25 mg for clearance less than 30 mL/min/1.73 m2. Linagliptin lowers HbA1c by about 0.4–0.6% when added to metformin, sulfonylurea, or pioglitazone. The dose is 5 mg orally daily, and since, it is primarily excreted unmetabolized via the bile, no dose adjustment is needed in patients with kidney disease. Vildagliptin lowers HbA1c by about 0.5–1% when added to the therapeutic regimen of patients with type 2 diabetes. The dose is 50 mg once or twice daily.
The main adverse effect of DPP-4 inhibitors appears to be a predisposition to nasopharyngitis or upper respiratory tract infection. Hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin conditions (such as Stevens-Johnson syndrome), have been reported. There have also been reports of pancreatitis, but the frequency of the event is unclear. Cases of liver failure have been reported with the use of alogliptin, but it is uncertain if alogliptin was the cause. The medication, however, should be discontinued in the event of liver failure. Rare cases of hepatic dysfunction, including hepatitis, have been reported with the use of vildagliptin; and liver biochemical testing is recommended quarterly during the first year of use and periodically thereafter. Saxagliptin may increase the risk of heart failure. In a post-marketing study of 16,492 patients with type 2 diabetes, heart failure occurred in 3.5% in the saxagliptin group and 2.8% in the placebo group (hazard ratio 1.27). Patients with the highest risk of heart failure were those who had a history of heart failure or had elevated levels of N-terminal of the prohormone B-type natriuretic peptide (NT-pBNP) or had kidney impairment. In a large post-marketing study, alogliptin, like saxagliptin, was associated with a slightly increased rate of heart failure. The FDA has issued a warning that the DPP-4 inhibitors can occasionally cause joint pains that resolve after stopping the drug.
5. Sodium-glucose co-transporter 2 inhibitors
Glucose is freely filtered by the kidney glomeruli and is reabsorbed in the proximal tubules by the action of sodium-glucose co-transporters (SGLT). Sodium-glucose co-transporter 2 (SGLT2) accounts for about 90% of glucose reabsorption and its inhibition causes glycosuria in people with diabetes, lowering plasma glucose levels. The oral SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are approved for clinical use in the United States. These agents reduce the threshold for glycosuria from a plasma glucose threshold of about a 180 mg/dL to about 40 mg/dL; and lower HbA1c by 0.5–1% when used alone or in combination with other oral agents or insulin. The efficacy is higher at higher HbA1c levels when more glucose is excreted as a result of SGLT2 inhibition. The loss of calories results in modest weight loss of 2–5 kg.
The usual dose of canagliflozin is 100 mg daily but up to 300 mg daily can be used in patients with normal kidney function. The dose of dapagliflozin is 10 mg daily but 5 mg daily is the recommended initial dose in patients with hepatic failure. The usual dosage of empagliflozin is 10 mg daily but a higher dose of 25 mg daily can be used. The recommended starting dose of ertugliflozin is 5 mg, but the dose can be increased to 15 mg daily if additional glucose lowering is needed.
In a postmarketing multinational study of 7020 patients with type 2 diabetes with known cardiovascular disease, the addition of empagliflozin was associated with a lower primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio 0.86, P = 0.04). The mechanisms regarding the benefit remain unclear. Weight loss, lower blood pressure, and diuresis may have played a role since there were fewer deaths from heart failure in the treated group whereas the rates of myocardial infarction were unaltered. A similar multinational study was performed with the addition of canagliflozin. This was a study of 10,142 patients with type 2 diabetes with known or at increased risk for cardiovascular disease. The canagliflozin treated group had a lower primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio 0.86, P = 0.02). In a 2019 heart failure study of 4744 patients with NYHA class II, III, IV heart failure and ejection fraction of less 40%, dapagliflozin reduced the cumulative incidence of worsening heart failure or cardiovascular death (hazard ratio 0.74, P < 0.001). Forty-two percent of the patients had diabetes; the findings in patients with and without diabetes were the same. Both empagliflozin and canagliflozin show benefit in terms of progression of albuminuria and kidney injury, possibly by lowering glomerular hyperfiltration. In a 2019 multinational study of 4401 patients with type 2 diabetes and albuminuric chronic kidney disease (eGFR 30–89 mL/min/1.73 m2 with albumin [mg] to creatinine [g] ratio > 300 to 5000) and taking an ACE inhibitor or angiotensin receptor blocker, canagliflozin reduced the risk of end-stage renal disease, the doubling of serum creatinine, and of renal death.
As might be expected, the efficacy of the SGLT2 inhibitors is reduced in chronic kidney disease. They can also increase creatinine and decrease eGFR, especially in patients with kidney impairment. Their use is generally not recommended in patients with eGFR less than 45 mL/min/1.73 m2 and are contraindicated in patients with eGFR less than 30 mL/min/1.73 m2. The main side effects are increased incidence of genital mycotic infections and urinary tract infections affecting ~8–9% of patients. Cases of necrotizing fasciitis of the perineum (Fournier gangrene) have been reported. There have also been reports of cases of pyelonephritis and septicemia requiring hospitalization. The glycosuria can cause intravascular volume contraction and hypotension.
The multinational study with canagliflozin showed an increased risk of amputations, especially of the toes (hazard ratio 1.97). This finding has not been observed in other studies using this drug or with the other SGLT2 inhibitors.
Canagliflozin has been reported to cause a decrease in bone mineral density at the lumbar spine and the hip. In a pooled analysis of eight clinical trials (mean duration 68 weeks), a 30% increase in fractures was observed in patients taking canagliflozin. It is likely that the effect on the bones is a class effect and not restricted to canagliflozin. All the SGLT2 inhibitors cause a modest increase in LDL cholesterol levels (3–8%). Also, in clinical trials, patients taking dapagliflozin had higher rates of breast cancer (nine cases vs none in comparator arms) and bladder cancer (10 cases vs 1 in placebo arm). These cancer rates exceeded the expected rates in age-matched reference diabetes population.
Cases of DKA have been reported with off-label use of SGLT2 inhibitors in patients with type 1 diabetes. Type 1 patients are taught to give less insulin if their glucose levels are not elevated. SGLT2 inhibitors lower glucose levels by changing the renal threshold and not by insulin action. Type 1 patients taking an SGLT2 inhibitor, because the glucose levels are not elevated, may either withhold or reduce their insulin doses to such a degree as to induce ketoacidosis. SGLT2 inhibitors should not be used in patients with type 1 diabetes and in those patients labeled as having type 2 diabetes but who are very insulin deficient and ketosis-prone.
Pramlintide is a synthetic analog of islet amyloid polypeptide (IAPP or amylin). When given subcutaneously, it delays gastric emptying, suppresses glucagon secretion, and decreases appetite. It is approved for use both in type 1 diabetes and in insulin-treated type 2 diabetes. In 6-month clinical studies with type 1 and insulin-treated type 2 patients, those taking the medication had an approximately 0.4% reduction in HbA1c and about 1.7 kg weight loss compared with placebo. The HbA1c reduction was sustained for 2 years but some of the weight was regained. The medication is given by injection immediately before the meal. Hypoglycemia can occur, and it is recommended that the short-acting or premixed insulin doses be reduced by 50% when the medication is started. Since the medication slows gastric emptying, recovery from hypoglycemia can be a problem because of delay in absorption of fast-acting carbohydrates. Nausea is the other main side effect, affecting 30–50% of persons, but tends to improve with time. In patients with type 1 diabetes, the initial dose of pramlintide is 15 mcg before each meal and titrated up by 15-mcg increments to a maintenance dose of 30 mcg or 60 mcg before each meal. In patients with type 2 diabetes, the starting dose is 60 mcg premeals increased to 120 mcg in 3 to 7 days if no significant nausea occurs.
Bromocriptine, a dopamine 2 receptor agonist, has been shown to modestly lower HbA1c by 0.1–0.5% when compared to baseline and 0.4–0.5% compared to placebo. Common side effects are nausea, vomiting, dizziness, and headache.
Colesevelam, the bile acid sequestrant, when added to metformin or sulfonylurea or insulin, lowered HbA1c 0.3–0.4% when compared to baseline and 0.5–0.6% compared to placebo. HbA1c lowering, however, was not observed in a single monotherapy clinical trial comparing colesevelam to placebo. Colesevelam use is associated with ~20% increase in triglyceride levels. Other adverse effects include constipation and dyspepsia.
With their modest glucose lowering and significant side effects, using bromocriptine or colesevelam to treat diabetes is not recommended.
7. Medication combinations
Several medication combinations are available in different dose sizes, including glyburide and metformin (Glucovance); glipizide and metformin (Metaglip); repaglinide and metformin (Prandi-Met); rosiglitazone and metformin (Avandamet); pioglitazone and metformin (ACTOplusMet); rosiglitazone and glimepiride (Avandaryl); pioglitazone and glimepiride (Duetact); sitagliptin and metformin (Janumet); saxagliptin and metformin XR (Kombiglyze XR); linagliptin and metformin (Jentadueto); alogliptin and metformin (Kazano); alogliptin and pioglitazone (Oseni); dapagliflozin and metformin (Xigduo); canagliflozin and metformin (Invokamet); empagliflozin and metformin (Synjardy); empagliflozin and linagliptin (Glyxambi); ertugliflozin and metformin (Segluormet); ertugliflozin and sitagliptin (Steglujan); insulin degludec and liraglutide (Xultophy); and insulin glargine and lixisenatide (Soliqua). These medication combinations, however, limit the clinician’s ability to optimally adjust dosage of the individual medications and for that reason are not recommended.
8. Safety of the antihyperglycemic agents
The UKPDS has put to rest previous concerns regarding the safety of sulfonylureas. It did not confirm any cardiovascular hazard among over 1500 patients treated intensively with sulfonylureas for over 10 years, compared with a comparable number who received either insulin or diet therapy. Analysis of a subgroup of obese patients receiving metformin also showed no hazard and even a slight reduction in cardiovascular deaths compared with conventional therapy.
The currently available thiazolidinediones have not to date exhibited the idiosyncratic hepatotoxicity seen with troglitazone. However, these drugs can precipitate heart failure and should not be used in patients with New York Heart Association class III and IV cardiac status. Lactic acidosis from metformin is quite rare and probably not a major problem with its use in the absence of major risk factors such as impaired kidney or liver function or conditions predisposing to hypoxia.
Insulin is indicated for type 1 diabetes as well as for type 2 diabetic patients with insulinopenia whose hyperglycemia does not respond to diet therapy either alone or combined with other hypoglycemic medications.
With the development of highly purified human insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site. However, the problem of achieving optimal insulin delivery remains unsolved with the present state of technology. It has not been possible to reproduce the physiologic patterns of intraportal insulin secretion with subcutaneous injections of short-acting or longer-acting insulin preparations. Even so, with the help of appropriate modifications of diet and exercise and careful monitoring of capillary blood glucose levels at home, it has often been possible to achieve acceptable control of blood glucose by using various mixtures of short- and longer-acting insulins injected at least twice daily or portable insulin infusion pumps.
1. Characteristics of available insulin preparations
Human insulin is dispensed as either regular (R) or NPH (N) formulations. Six analogs of human insulin—three rapidly acting (insulin lispro, insulin aspart, insulin glulisine) and three long-acting (insulin glargine, insulin detemir, and insulin degludec)—are approved by the FDA for clinical use. Commercial insulin preparations differ with respect to the time of onset and duration of their biologic action (Table 27–6). All currently available insulins contain less than 10 ppm of proinsulin and are labeled as “purified.” These purified insulins preserve their potency, so that refrigeration is recommended but not crucial. During travel, reserve supplies of insulin can be readily transported for weeks without losing potency if protected from extremes of heat or cold. All the insulins in the United States are available in a concentration of 100 units/mL (U100) and dispensed in 10-mL vials or 0.3-mL cartridges or prefilled disposable pens. Several insulins are available at higher concentrations: insulin glargine, 300 units/mL (U300); insulin degludec, 200 units/mL (U200); insulin lispro, 200 units/mL (U200); and regular insulin, 500 units/mL (U500).
Table 27–6.Summary of bioavailability characteristics of the insulins. ||Download (.pdf) Table 27–6. Summary of bioavailability characteristics of the insulins.
|Insulin Preparations ||Onset of Action ||Peak Action ||Effective Duration |
|Insulins lispro, aspart,1 glulisine ||5–15 minutes ||1–1.5 hours ||3–4 hours |
|Human regular ||30–60 minutes ||2 hours ||6–8 hours |
|Human NPH ||2–4 hours ||6–7 hours ||10–20 hours |
|Insulin glargine ||0.5–1 hour ||Flat ||~24 hours |
|Insulin detemir ||0.5–1 hour ||Flat ||17 hours |
|Insulin degludec ||0.5–1.5 hours ||Flat ||More than 42 hours |
|Technosphere inhaled insulin ||5–15 minutes ||1 hour ||3 hours |
The short-acting preparations are regular insulin and the rapidly acting insulin analogs (Table 27–7; eFigure 27–1). They are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. The long-acting preparations are NPH insulin and the long-acting insulin analogs. NPH insulin is dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer. The long-acting insulin analogs are also dispensed as clear solutions; insulin glargine is at acidic pH and insulin detemir is at neutral pH. See Table 27–7. The rapidly acting insulin analogs and the long-acting insulins are designed for subcutaneous administration, while regular insulin can also be given intravenously.
Table 27–7.Insulin preparations available in the United States.1 ||Download (.pdf) Table 27–7. Insulin preparations available in the United States.1
Rapidly acting human insulin analogs
Insulin lispro (Humalog, Lilly; Admelog, Sanofi)
Insulin aspart (Novolog, FiAsp, Novo Nordisk)
Insulin glulisine (Apidra, Sanofi Aventis)
Short-acting regular insulin
Regular insulin (Lilly, Novo Nordisk)
Technosphere inhaled regular insulin (Afrezza)
NPH insulin (Lilly, Novo Nordisk)
70% NPH/30% regular (70/30 insulin—Lilly, Novo Nordisk)
70% NPL/25% insulin lispro (Humalog Mix 75/25—Lilly)
50% NPL/50% insulin lispro (Humalog Mix 50/50—Lilly)
70% insulin aspart protamine/30% insulin aspart (Novolog Mix 70/30—Novo Nordisk)
70% insulin degludec/30 insulin aspart (Ryzodeg, Novo Nordisk)
Long-acting human insulin analogs
Insulin glargine (Lantus (U100), Toujeo (U300), Sanofi Aventis; Basaglar (U100), Lilly)
Insulin detemir (Levemir, Novo Nordisk)
Insulin degludec (Tresiba, Novo Nordisk)
Extent and duration of action of various types of insulin–euglycemic hyperinsulinemic clamps in normal volunteers. A: Intermediate neutral protamine Hagedorn (NPH) insulin and long-acting insulin analogs. B: Regular insulin and rapidly acting insulin analogs.
A. SHORT-ACTING INSULIN PREPARATIONS
Regular insulin is a short-acting soluble crystalline zinc insulin whose effect appears within 30 minutes after subcutaneous injection and lasts 5–7 hours when usual quantities are administered. Intravenous infusions of regular insulin are particularly useful in the treatment of DKA and during the perioperative management of patients with diabetes who require insulin. For markedly insulin-resistant persons who would otherwise require large volumes of insulin solution, a U500 preparation of human regular insulin is available both in a vial form and a disposable pen. A U500 insulin syringe should be used if the vial form is dispensed. U500 regular insulin is much more expensive than the U100 concentration and is rarely needed.
(2) Rapidly acting insulin analogs
Insulin lispro (Humalog, Admelog) is an insulin analog where the proline at position B28 is reversed with the lysine at B29. Insulin aspart (Novolog) is a single substitution of proline by aspartic acid at position B28. In insulin glulisine (Apidra) the asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid. These three analogs have less of a tendency to form hexamers, in contrast to human insulin. When injected subcutaneously, the analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as soon as 1 hour—in contrast to regular human insulin, whose hexamers require considerably more time to dissociate and become absorbed. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with the circulating half-life, or with their immunogenicity, which are all identical with those of human regular insulin. An insulin aspart formulation (FiAsp) that contains niacinamide (vitamin B3) has a more rapid initial absorption and its onset of action is about 10 minutes faster than the standard insulin aspart formulation. Because of this more rapid onset of action, the 1-hour (but not 2-hour) postprandial glucose excursions are lower compared to the standard formulation.
Clinical trials have demonstrated that the optimal times of preprandial subcutaneous injection of comparable doses of the rapidly acting insulin analogs and of regular human insulin are 20 minutes and 60 minutes, respectively, before the meal. The quicker onset of action with the rapidly acting insulin analogs allows the patient to inject insulin just before eating rather than wait for 60 minutes as needed for regular insulin. Another desirable feature of rapidly acting insulin analogs is that their duration of action remains at about 4 hours for most commonly used dosages. This contrasts with regular insulin, whose duration of action is significantly prolonged when larger doses are used.
The rapidly acting analogs are commonly used in pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, persons using insulin lispro had lower HbA1c values and improved postprandial glucose control with the same frequency of hypoglycemia. In the event of pump failure, however, users of the rapidly acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.
While insulin aspart has been approved for intravenous use (eg, in hyperglycemic emergencies), there is no advantage in using insulin aspart over regular insulin by this route. A U200 concentration of insulin lispro is available in a disposable prefilled pen. The only advantage of the U200 over the U100 insulin lispro preparation is that it delivers the same dose in half the volume.
B. LONG-ACTING INSULIN PREPARATIONS
(1) NPH (neutral protamine Hagedorn or isophane) insulin
NPH is an intermediate-acting insulin whose onset of action is delayed to 2–4 hours, and its peak response is generally reached in about 6–7 hours. The onset of action is delayed by combining 2 parts soluble crystalline zinc insulin with 1 part protamine zinc insulin. This produces equivalent amounts of insulin and protamine, so that neither is present in an uncomplexed form (“isophane”). Because its duration of action is often less than 24 hours (with a range of 10–20 hours), most patients require at least two injections daily to maintain a sustained insulin effect. Occasional vials of NPH insulin have tended to show unusual clumping of their contents or “frosting” of the container, with considerable loss of bioactivity. This instability is rare and occurs less frequently if NPH human insulin is refrigerated when not in use and if bottles are discarded after 1 month of use.
In this insulin, the asparagine at position 21 of the insulin A chain is replaced by glycine and two arginines are added to the carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule closer to neutral making it more soluble in an acidic environment. In contrast, human insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin, which, when injected into the neutral pH environment of the subcutaneous tissue, forms microprecipitates that slowly release the insulin into the circulation. This insulin lasts for about 24 hours without any pronounced peaks and is given once a day to provide basal coverage. This insulin cannot be mixed with the other human insulins because of its acidic pH. When this insulin was given as a single injection at bedtime to type 1 patients in clinical trials, fasting hyperglycemia was better controlled with less nocturnal hypoglycemia when compared to NPH insulin.
In one clinical trial involving type 2 patients, insulin glargine was associated with a slightly higher progression of retinopathy when compared with NPH insulin. The frequency was 7.5% with the analog and 2.7% with the NPH. However, this observation was not confirmed in a 5-year open-label prospective study of 1024 persons randomized to NPH or insulin glargine. Insulin glargine has a sixfold greater affinity for IGF-1 receptor compared with the human insulin and there has been concern that long-term use of insulin glargine might increase cancer risk. An observational study from Germany of 127,031 patients who had exposure to regular insulin, short-acting insulin analogs, and insulin glargine reported a strong correlation between increased insulin dose and cancer risk. Moreover, insulin glargine, dose for dose, appeared to carry a higher risk of cancer than regular insulin. Subsequent epidemiologic studies, however, failed to confirm this observation. A more concentrated form of insulin glargine (U300) is available as an insulin pen. In pharmacodynamic studies in type 1 patients, the U300 compared to the U100 preparation had approximately 5 hours longer duration of action. In clinical trials in type 1 patients, U300 use did not result in better control or reduce the rates of hypoglycemia. Although limited clinical data suggest that insulin glargine is safe in pregnancy, it is not approved for this use.
In this insulin analog, the threonine at position B30 has been removed and a 14-C fatty acid chain (tetradecanoic acid) is attached to the lysine at position 29 by acylation. The fatty acid chain makes the molecule more lipophilic than native insulin and the addition of zinc stabilizes the molecule and leads to formation of hexamers. Its prolonged action is due to dihexamerization and binding of hexamers and dimers to albumin at the injection site as well as binding of the monomer via its fatty acid side chain to albumin in the circulation. The affinity of insulin detemir is fourfold to fivefold lower than that of human soluble insulin and therefore the U100 formulation of insulin detemir has an insulin concentration of 2400 nmol/mL compared with 600 nmol/mL for NPH. The duration of action for insulin detemir is about 17 hours at therapeutically relevant doses. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. It has been approved for use during pregnancy. This insulin has been reported to have lower within-subject pharmacodynamic variability compared with NPH insulin and insulin glargine. In vitro studies do not suggest any clinically relevant albumin binding interactions between insulin detemir and fatty acids or protein-bound medications. Since there is a vast excess (∼400,000) of albumin binding sites available in plasma per insulin detemir molecule, it is unlikely that hypoalbuminemic disease states affect the ratio of bound to free insulin detemir.
In this insulin analog, the threonine at position B30 has been removed, and the lysine at position B29 is conjugated to hexdecanoic acid via a gamma-L-glutamyl spacer. In the vial, in the presence of phenol and zinc, the insulin is in the form of dihexamers but when injected subcutaneously, it self associates into large multihexameric chains consisting of thousands of dihexamers. The chains slowly dissolve in the subcutaneous tissue and insulin monomers are steadily released into the systemic circulation. The half-life of insulin degludec is 25 hours. Its onset of action is in 30–90 minutes and its duration of action is more than 42 hours. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. Insulin degludec is available in two concentrations, U100 and U200, and dispensed in prefilled disposable pens.
C. MIXED INSULIN PREPARATIONS
Patients with type 2 diabetes can sometimes achieve reasonable glucose control with just prebreakfast and predinner injections of mixtures of short acting and NPH insulins. The regular insulin or rapidly acting insulin analog is withdrawn first, then the NPH insulin and then injected immediately. Stable premixed insulins (70% NPH and 30% regular) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or impairment of manual dexterity (Table 27–7). Premixed preparations of insulin lispro and NPH insulins are unstable; stability is achieved by replacing the NPH insulin with NPL (neutral protamine lispro). This insulin has the same duration of action as NPH insulin. Premixed combinations of NPL and insulin lispro (75% NPL/25% insulin lispro mixture [Humalog Mix 75/25] and 50% NPL/50% insulin lispro mixture [Humalog Mix 50/50]) are available for clinical use. Similarly, a 70% insulin aspart protamine/30% insulin aspart (NovoLog Mix 70/30) is available. The main advantages of these mixtures are that they can be given within 15 minutes of starting a meal and they are superior in controlling the postprandial glucose rise after a carbohydrate rich meal. These benefits have not translated into improvements in HbA1c levels when compared with the usual 70% NPH/30% regular mixture. The longer-acting insulin analogs, insulin glargine and insulin detemir, cannot be mixed with either regular insulin or the rapidly acting insulin analogs. Insulin degludec, however, can be mixed and is available as 70% insulin degludec/30% insulin aspart and is injected once or twice a day.
3. Methods of insulin administration
A. INSULIN SYRINGES AND NEEDLES
Plastic disposable syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes. The “low-dose” 0.3-mL syringes are popular because many patients with diabetes do not take more than 30 units of insulin in a single injection except in rare instances of extreme insulin resistance. Three lengths of needles are available: 6 mm, 8 mm, and 12.7 mm. Long needles are preferable in obese patients to reduce variability of insulin absorption. The needles are of 28, 30, and 31 gauges. The 31-gauge needles are almost painless. “Disposable” syringes may be reused until blunting of the needle occurs (usually after three to five injections). Sterility adequate to avoid infection with reuse appears to be maintained by recapping syringes between uses. Cleansing the needle with alcohol may not be desirable since it can dissolve the silicone coating and can increase the pain of skin puncturing.
Any part of the body covered by loose skin can be used, such as the abdomen, thighs, upper arms, flanks, and upper buttocks. Preparation with alcohol is not required prior to injection as long as the skin is clean. Rotation of sites is recommended to avoid delayed absorption when fibrosis or lipohypertrophy occurs from repeated use of a single site. Regular insulin is absorbed more rapidly when injected in the deltoid or abdomen compared to thighs and buttocks. Exercise can increase absorption when the injection site is adjacent to the exercise muscle. For most patients, the abdomen is the recommend region for injection because it provides adequate area in which to rotate sites. The effect of anatomic regions appears to be much less pronounced with the analog insulins.
C. INSULIN PEN INJECTOR DEVICES
Insulin pens eliminate the need for carrying insulin vials and syringes. Cartridges of insulin lispro and insulin aspart are available for reusable pens (Novo Nordisk, and Owen Mumford). Disposable prefilled pens are also available for regular insulin (U100 and U500), insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin glargine, insulin degludec, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, 50% NPL/50% insulin lispro, 70% insulin aspart protamine/30% insulin aspart, and 70% insulin degludec/30% insulin aspart. Pen needles are available in 29, 31, and 32 gauges and 4-, 5-, 6-, 8-, and 12.7-mm lengths (Novofine; BD).
In the United States, Medtronic Mini-Med, Insulet, and Tandem make battery operated continuous subcutaneous insulin infusion (CSII) pumps. These pumps are small (about the size of a pager) and easy to program. They offer many features, including the ability to set a number of different basal rates throughout the 24 hours and to adjust the time over which bolus doses are given. They also are able to detect pressure build-up if the catheter is kinked. The catheter connecting the insulin reservoir to the subcutaneous cannula can be disconnected, allowing the patient to remove the pump temporarily (eg, for bathing). Ominpod (Insulet Corporation) is an insulin infusion system in which the insulin reservoir and infusion set are integrated into one unit (pod), so there is no catheter (electronic patch pump). The pod, placed on the skin, delivers subcutaneous basal and bolus insulin based on wirelessly transmitted instructions from a personal digital assistant. The great advantage of continuous subcutaneous insulin infusion (CSII) is that it allows for establishment of a basal profile tailored to the patient allowing for better overnight and between meals glucose control. The ability to adjust the basal insulin infusion makes it easier for the patient to manage glycemic excursions that occur with exercise. The pumps have software that can assist the patient to calculate boluses based on glucose reading and carbohydrates to be consumed. They keep track of the time elapsed since the last insulin bolus; the patient is reminded of this when he or she attempts to give additional correction bolus before the effect of the previous bolus has worn off (“insulin on board” feature). This feature reduces the risk of overcorrecting and subsequent hypoglycemia.
CSII therapy is appropriate for patients with type 1 diabetes who are motivated, mechanically inclined, educated about diabetes (diet, insulin action, treatment of hypoglycemia and hyperglycemia), and willing to monitor their blood glucose four to six times a day. Known complications of CSII include ketoacidosis, which can occur when insulin delivery is interrupted, and skin infections. Another disadvantage is its cost and the time needed of the clinician and staff to initiate therapy. Almost all patients use rapid-acting insulin analogs in their pumps.
V-go (Valeritas) is a mechanical patch pump designed specifically for people with type 2 diabetes who use a basal/bolus insulin regimen. The device is preset to deliver one of three fixed and flat basal rates (20, 30, or 40 units) for 24 hours (at which point it must be replaced) and there is a button that delivers two units per press to help cover meals.
Algorithms have been devised to use glucose data from the continuous glucose monitoring systems to automatically deliver insulin by continuous subcutaneous insulin infusion pump. These closed loop systems (artificial pancreas) have been shown in clinical studies to improve nighttime glucose control, modestly lower HbA1c levels, and reduce the risk of nocturnal hypoglycemia. The MiniMed 670 G and the Tandem Control-IQ, have been approved for clinical use. The MiniMed 670 G closed loop system uses glucose data from a sensor to automatically adjust basal insulin doses every 5 minutes, targeting a sensor glucose level of 120 mg/dL (6.7 mmol/L). Insulin delivery is suspended when the sensor glucose level falls below or is predicted to fall below target level. The glucose target can be adjusted up to 150 mg/dL (8.3 mmol/L) for physical activity. The Tandem Control-IQ targets a sensor glucose level of 112.5 mg/dL (6.25 mmol/L). The patient is still responsible for bolusing insulin for meals and snacks. There are also Do-It-Yourself closed loop systems using free open source software. One such system, called the “Loop,” uses the Dexcom G6 sensor, the iPhone, and the Omnipod insulin pump. The “Loop” controller is downloaded on to the iPhone, and it uses the Dexcom G6 sensor glucose measurements (also on the iPhone) to automatically adjust basal insulin delivery on the Omnipod pump. Increasing numbers of type 1 patients use these Do-It-Yourself systems, but they are not approved for use by the FDA. Successful use, however, requires the patient to be proficient at using both the insulin pump and continuous glucose monitor. The systems are expensive; the insulin pump, which needs to be replaced every 4 years, costs about $6000 and the pump supplies are $1500 per year. The continuous glucose monitoring system costs approximately $4000 per year.
Technosphere insulin (Afrezza) is a dry-powder formulation of recombinant human regular insulin that can be inhaled. It consists of 2- to 2.5-mcm crystals of the excipient fumaryl diketopiperazine that provide a large surface area for adsorption of proteins like insulin. The technosphere insulin is rapidly absorbed with peak insulin levels reached in 12–15 minutes and declining to baseline in 3 hours; the median time to maximum effect with inhaled insulin is approximately 1 hour and declines to baseline by about 3 hours. In contrast, the median time to maximum effect with subcutaneous insulin lispro is about 2 hours and declines to baseline by 4 hours. In clinical trials, technosphere insulin combined with basal insulin was as effective in glucose lowering as rapid-acting insulin analogs combined with basal insulin. It is formulated as a single-use, color-coded cartridge delivering 4, 8, or 12 units immediately before the meal. The manufacturer provides a dose conversion table; patients injecting up to 4 units of rapid-acting insulin analog should use the 4-unit cartridge. Those injecting 5 to 8 units should use the 8-unit cartridge. If the dose is 9–12 units of rapid-acting insulin premeal then one 4-unit cartridge and one 8-unit cartridge or one 12-unit cartridge should be used. The inhaler is about the size of a referee’s whistle.
The most common adverse reaction of the inhaled insulin is a cough, affecting about 27% of patients. A small decrease in pulmonary function (forced expiratory volume in 1 second [FEV1]) is seen in the first 3 months of use, which persists over 2 years of follow-up. Inhaled insulin is contraindicated in patients who smoke and in those with chronic lung disease, such as asthma and chronic obstructive pulmonary disease. Spirometry should be performed to identify potential lung disease prior to initiating therapy. During clinical trials, there were two cases of lung cancer in patients who were taking inhaled insulin and none in the comparator-treated patients. All the patients in whom lung cancer developed had a history of prior cigarette smoking. There were also two cases of squamous cell carcinoma of the lung in nonsmokers exposed to inhaled insulin; these cases occurred after completion of the clinical trials. Cases of lung cancer were also reported in cigarette smokers using a previously available inhaled insulin preparation (Exubera). The incidence rate in the Exubera treated group was 0.13 per 1000 patient-years and 0.03 per 1000 patient-years in the comparator-treated group.
1. Pancreas transplantation
All patients with end-stage kidney disease and type 1 diabetes who are candidates for a kidney transplant should be considered potential candidates for a pancreas transplant. Eligibility criteria include age younger than 55 and minimal cardiovascular risk. Contraindications include noncorrectable coronary artery disease, extensive peripheral vascular disease, and significant obesity (weight greater than 100 kg). The pancreas transplant may occur at the same time as kidney transplant or after kidney transplant. Patients undergoing simultaneous pancreas and kidney transplantation have an 83% chance of pancreatic graft survival at 1 year and 69% at 5 years. Solitary pancreatic transplantation in the absence of a need for kidney transplantation is considered only in those rare patients who do not respond to all other insulin therapeutic approaches and who have frequent severe hypoglycemia, or who have life-threatening complications related to their lack of metabolic control. Solitary pancreas transplant graft survival is 78% at 1 year and 54% at 5 years.
Total pancreatectomy is curative for severe pain syndrome associated with chronic pancreatitis. The pancreatectomy, however, results in surgical diabetes. Harvesting islets from the removed pancreas and autotransplanting them into the liver (via portal vein) can prevent the development of diabetes or result in “mild” diabetes (partial islet function) that is easier to manage. Since the islets are autologous no immunosuppression is required. The number of islets transplanted is the main predictor of insulin independence.
People with type 1 diabetes can become insulin independent after receiving islets isolated from a donor pancreas (alloislet transplant). The islets are infused into the portal vein using a percutaneous transhepatic approach, and they lodge in the liver releasing insulin in response to physiologic stimuli. Long-term immunosuppression is necessary to prevent allograft rejection and to suppress the autoimmune process that led to the disease in the first place. Insulin independence for more than 5 years has been demonstrated in patients who got anti-CD3 antibody or anti-thymocyte globulin induction immunosuppression and calcineurin inhibitors, mTor inhibitors, and mycophenolate mofetil as maintenance immunosuppression. One major limitation is the need for more than one islet infusion to achieve insulin independence. This is because of significant loss of islets during isolation and the period prior to engraftment. Widespread alloislet transplantation will depend on improving insulin independence rates with one infusion and also demonstrating that the long-term outcomes are as good as those of pancreas transplant alone.
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