One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial

Abstract

Objective: Traditional blood glucose-lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in beta-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp-derived measures of beta-cell function, glycemic control, and body weight.

Research design and methods: Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). beta-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety.

Results: Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09-2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: -0.8 +/- 0.1 and -0.7 +/- 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference -4.6 kg, P < 0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy.

Conclusions: Exenatide significantly improves beta-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, beta-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

Figure 1

Protocol flow chart and baseline characteristics of the study population. Data represent means ± SEM.

Figure 2

Time course for A1C (A) and fasting plasma glucose (B). SMBG concentrations before (C) and after (D) 52 weeks of treatment. Changes in body weight (E) and insulin sensitivity were measured as the M value (F). Data are means ± SEM. ●, exenatide; ○, insulin glargine; ■, pretreatment; □, 52 weeks on-drug; ▨, 4 weeks off-drug. Vertical black line at 52 weeks represents cessation of study medication. BB, before breakfast; AB, after breakfast; BL, before lunch; AL, after lunch; BD, before dinner; AD, after dinner; BT, bedtime.

Figure 3

C-peptide concentrations during hyperglycemic clamp and ratio to pretreatment in the exenatide (A and C)- and insulin glargine (B and D)-treated group. Data represent mean ± SEM in A and B and geometric mean ± SEM in C and D. AIR_arg, C-peptide response to arginine at 15 mmol/l glucose concentration; 1st phase, first-phase C-peptide response to glucose; 2nd phase, second-phase C-peptide response to glucose. See research design and methods for calculations of β-cell function measures. ●, ■, pretreatment; ○, □, 52-weeks on-drug; ■, ▨, 4 weeks off-drug.