Effect of exenatide, sitagliptin, or glimepiride on β-cell secretory capacity in early type 2 diabetes

Abstract

Objective: Agents that augment GLP-1 effects enhance glucose-dependent β-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on β-cell secretory capacity, an in vivo measure of functional β-cell mass, early in the course of T2D.

Research design and methods: We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIRarg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIRpot]), and 340 mg/dL (maximum arginine-induced insulin release [AIRmax]) hyperglycemic clamp conditions, in which AIRmax provides the β-cell secretory capacity.

Results: The change in AIRpot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIRmax (P = 0.1). Within each group, the primary outcome measure, AIRmax, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGRmin) was also increased with glimepiride treatment (P < 0.05), and the change in AGRmin trended higher with glimepiride than with exenatide (P = 0.06).

Conclusions: After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional β-cell mass as measured by β-cell secretory capacity, whereas glimepiride appeared to enhance β- and α-cell secretion.

Figure 1

Subject characteristics over the 6-month study period. Means ± SE of weight, fasting capillary glucose as determined by glucometer readings, and HbA_1c in each group. Also shown for the glimepiride group is the average dose at each monthly visit. Changes in weight over time were not significantly different across the three groups [F(12, 222) = 1.1013; P = 0.4]. Average capillary glucose was significantly different [F(12, 204) = 2.53; P < 0.01] when comparing across all three groups. HbA_1c was different by trend [F(4, 74) = 2.28; P < 0.1] when comparing across all three groups. *P < 0.05 when comparing Δ from baseline within each group at each time point.