Pharmacologic Treatments—Incretin Mimetics, DPP-4 Inhibitors

Oral Abstracts
Reported by Joelle Escoffery, PhD

In this session, several new therapeutic approaches to the treatment of type 2 diabetes were addressed.

Vilsboll and colleagues reported on the efficacy and safety of treatment with the GLP-1 analogue liraglutide. In this 14-week study, patients treated with either diet or a single oral antidiabetic agent were randomized to receive either a placebo or 1 of 3 doses of liraglutide (0.65 mg, 1.25 mg, or 1.9 mg) after a 4-week wash-out period. Results demonstrated a significant effect on glycemic control (P<.001 for all treatment groups vs placebo) and weight reduction (P = .039 for the 1.9 mg dose vs placebo). Approximately half of patients achieved A1C <7%. No minor or major hypoglycemic events were observed. The most frequent adverse events were GI in nature and decreased over the course of treatment. Four patients (3 receiving liraglutide and 1 receiving placebo) withdrew from the study. In short, liraglutide monotherapy was effective and generally well tolerated.

Linnebjerg and colleagues reported on the first study to directly quantify the effect of exenatide on gastric emptying. In this 3-period, single-blind crossover study, 17 patients with type 2 diabetes received exenatide (5 mcg or 10 mcg) or placebo administered as a twice-daily subcutaneous injection for each of the 3 5-day periods. Immediately following the morning dose on the last day of a period, patients consumed a 450 kcal breakfast that included 99 mTc-labeled eggs and 111 In labeled water. Endpoints of interest included plasma exenatide, serum glucose, insulin, self-reported appetite, and gastric emptying. Compared with placebo, exenatide reduced postprandial glucose excursions and slowed gastric emptying in a dose-dependent fashion. Although exenatide did not reduce self-reported perceptions of hunger, food intake was reduced.

Data on the safety and efficacy of exenatide in conjunction with thiazolidenedione (TZD) therapy were presented by Dr Zinnman. In this study, patients not reaching glycemic goals despite treatment with TZD alone or with TZD and metformin combination therapy were randomly assigned to either placebo or exenatide (5 mcg for 4 weeks then increased to 10 mcg) injections BID for 16 weeks. Exenatide therapy decreased A1C by 0.8%, and 16% of exenatide-treated subjects met their treatment goal of A1C <7%. Both fasting and postprandial glycemic levels and weight were decreased compared with placebo. The most frequent adverse event reported in this study was nausea, and no differences in hypoglycemia incidence were observed between the groups. In conclusion, exenatide is an effective adjunctive therapy for patients on TZD or TZD and metformin combination therapy who are not meeting glycemic targets.

Wajcberg and colleagues examined the contribution of glucagon suppression to improvements in postprandial hyperglycemia among patients taking exenatide. In this study, 6 patients with type 2 diabetes participated in 3 meal-tolerance tests under conditions of 1) saline infusion, 2) exenatide infusion, and 3) exenatide plus glucagon infusion. Plasma glucose, insulin, and glucagon secretion were measured, as well as endogenous glucose production, oral glucose appearance, and splanchnic glucose uptake. Glucagon levels did not change in control subjects but were reduced among patients treated with exenatide. Patients who received the exenatide plus glucagon infusion showed glucagon levels comparable to control patients. There was a significant increase in insulin levels seen with exenatide treatment (both with and withouth glucagon) as well as a decrease in plasma glucose levels (seen with exenatide only). Oral glucose appearance was reduced in exenatide patients compared with control patients, but was not affected in patients receiving exenatide and glucagon. Endogenous glucose production was reduced among patients receiving only exenatide, and that effect was partially attenuated in the group receiving exenatide and glucagon. In conclusion, exenatide reduces postprandial hyperglycemia by reducing the rate of glucose appearance. The effect of exenatide on the suppression of endogenous glucose production is attributable to both enhanced insulin secretion and suppressed glucagon secretion.

The efficacy and durability of the oral dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin was addressed by Dejager and colleagues in a 52-week, double-blind study. Patients were randomly assigned to 2000 mg daily metformin or 100 mg daily vildagliptin (50 mg bid). Both groups achieved a decrease in A1C that was sustained for the duration of the study (1% in the vildagliptin group and 1.4% in the metformin group). Vildagliptin was associated with weight maintenance, and metformin was associated with modest weight gain. The incidence of gastrointestinal side effects was higher among metformin-treated patients. In conclusion, vildagliptin is effective for the treatment of type 2 diabetes over a period of a year, and it is well tolerated. 

An additional study testing the efficacy of vildagliptin was presented by Garber and colleagues. In this study, metformin-treated patients were randomized to receive vildagliptin (50 mg qd or bid) or placebo. There was an A1C decrease of 0.7% in the 50 mg qd group, and an A1C decrease of 1.1% in the 50 mg bid group. No weight gain was observed in any of the 3 groups, and there was no significant difference among the 3 groups in terms of side effects. In conclusion, vildagliptin in conjunction with metformin is effective and well tolerated.

Ballas and colleagues presented data on the ability of vildagliptin to suppress endogenous glucose production and improve ß-cell function in patients with type 2 diabetes. In this study, 16 patients with type 2 diabetes participated. Patients received 100 mg vildagliptin or placebo followed by a meal tolerance test administered half an hour later. Treatment with vildagliptin suppressed endogenous glucose production, whereas rates of glucose disposal were comparable between the groups. Treatment with vildagliptin also increased insulin secretion and decreased glucagon secretion. The decline in endogenous glucose production was associated with the decrease in plasma glucose seen during the 14-hour period following the meal tolerance test.