Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes

Abstract

Objective: We previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure.

Research design and methods: Sixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI).

Results: At 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ± 0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (-7.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and -0.99 ± 0.65, respectively; P = 0.028).

Conclusions: EXE and GLAR sustained HbA(1c) over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health.

Trial registration: ClinicalTrials.gov NCT00097500.

Figures

Figure 1

Protocol flowchart and baseline characteristics of the study population. Data are mean ± SD.

Figure 2

Time course for HbA1c (A), fasting plasma glucose (B), and change in body weight (C). Data are mean (SEM). ○ = EXE; ● = GLAR. Vertical hatched lines at weeks 52, 64, and 168 represent cessation and restart of study medication.

Figure 3

β-Cell function parameters during 3 years of EXE (n = 16) and GLAR (n = 20) treatment. Serum C-peptide concentrations during hyperglycemic clamp are shown at week 0 (A), week 52 (B), week 56 (C), and week 172 (D). ○ = EXE; ● = GLAR. β-Cell secretory capacity ratio-to-pretreatment is shown in the EXE- (E) and GLAR-treated (F) groups. ■ = week 0 (pretreatment); ▦ = week 52 (on-drug); ▤ = week 56 (off-drug); □ = week 172 (off-drug). Mean DI the EXE- and GLAR-treated group (G). ■ = EXE week 0 (pretreatment); □ = EXE week 172 (off-drug); ● = GLAR week 0 (pretreatment); ○ = GLAR week 172 (off-drug). DI change from pretreatment (H). □ = EXE; ■ = GLAR. Data are mean (SEM) in A–D and G–H; geometric mean (SEM) in E–F. AIRarg, C-peptide response to arginine at 15 mmol/L glucose concentration; AIRgluc and 1st phase, first-phase C-peptide response to glucose; 2nd phase, second-phase C-peptide response to glucose. See Research Design and Methods section for calculations of β-cell function measures.