The significant increase in the prevalence of diabetes, particularly in younger populations, makes the need for new, more effective therapies crucial. Several new medications currently undergoing clinical studies may have significant impact for the treatment of diabetes. This article is the first of a 2-part series that looks at some of the potential therapies for patients with diabetes.
One new class of drugs that shows early promising results is the incretin mimetics. Incretins are endogenous hormones that are secreted from the gastrointestinal tract during food intake. They stimulate insulin secretion in response to glucose absorption. Two incretin hormones, glucose-dependent insulinotropic peptide and glucagonlike peptide-1 (GLP-1), have been identified. In addition to increasing insulin levels, GLP-1 also is thought to suppress glucagon production.
Exenatide is the first incretin mimetic to undergo phase 3 clinical trials. The compound was originally isolated from the salivary venom of a South American lizard. Three studies, both 30 weeks in length, show a significant reduction in hemoglobin A1C (HbA1C ) in patients unable to obtain adequate blood glucose control with metformin therapy alone or with the addition of sulfonylureas. One study included 336 patients who had not achieved control on a minimum of 1500 mg/day of metformin for at least 3 months. Patients received either 5 or 10 μg of exenatide or placebo injected subcutaneously twice daily. The average baseline A1C level was 8.2%. Of the patients who received 10 μg twice daily, 46% who completed the study achieved an A1C of<7%. Additionally, the 10-μg-treatment group experienced an average weight loss of 2.8 kg (6.2 lb).
Another study included 773 patients who had not obtained adequate control on combination metformin/ sulfonylurea therapy. Thirty-four percent of the patients who completed the study in the 10-μg-treatment group achieved an A1C reading of<7%. The average reduction in HbA1C over placebo was 1%. The most common adverse effect reported in all studies was nausea.
Combining results from the studies, the incidence of nausea was 45% to 49% in the 10-μg-treatment group, compared with 21% to 23% in the placebo group. The overall dropout rate due to nausea was 3% in the 10-μg group, 1% in the 5-μg group, and 0% in the placebo group. In the exenatide-plus-metformin/sulfonylurea study, mild-to-moderate hypoglycemia occurred in 27.8% and 19.2% of patients in the 10- and 5-μg treatment groups, respectively, compared with 12.6% of patients receiving placebo.
One potential clinical advantage to consider with exenatide is weight loss. With several current therapies availableincluding sulfonylureas, meglitinides, insulin, and thiazolidinediones patients with diabetes often experience the frustration of weight gain. With exenatide, the combination of dose-dependent reductions in A1C and dose-dependent weight loss may be a motivating factor for patients to want to gain better control of their diabetes.
Another advantage seen with exenatide was improvement in pancreatic beta cell function. Beta cell function improvement was assessed using Homeostatic Model Assessment and reductions in the proinsulin/insulin ratio. The major disadvantage is that the drug is administered by injection only. Development is under way to produce a longer-acting form of the drug that could be injected once weekly or once monthly. Other incretin mimetics, such as liraglutide, also are in development and show early promising results.
Diabetes affects approximately 18 million people in the United States. Disease-related complicationssuch as kidney failure, retinopathy, and neuropathyoccur more frequently in diabetics who do not achieve adequate reductions in their A1C level. Incretin mimetics are likely to be an important new therapeutic category to improve diabetic outcomes.
Other new therapies that can help patients achieve these goals will be a welcome addition to the currently available modalities. The second part of this series will focus on other advances in diabetic therapy, including inhaled insulin.
Dr. Brian is a clinical specialist with Cornerstone Health Care, High Point, NC.