Efficacy of vildagliptin for prevention of postpartum diabetes in women with a recent history of insulin-requiring gestational diabetes: A phase II, randomized, double-blind, placebo-controlled study

Abstract

Objective: Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes.

Methods: Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT).

Results: Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events.

Conclusions: The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and β-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602.

Keywords: Dipeptidyl peptidase-4 inhibitor; Gestational diabetes mellitus; Life-style; Postpartum diabetes; Prevention; Randomized controlled trial.

Figure 1

Cumulative probability of developing postpartum diabetes according to the 1997 ADA criteria (A) and 2012 ADA criteria (B) in women with a recent history of insulin-requiring GDM treated with 50 mg vildagliptin or placebo twice daily.

Figure 2

Cumulative probability of developing postpartum impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) in women with a recent history of insulin-requiring GDM treated with 50 mg vildagliptin or placebo twice daily.

Figure 3

Markers of β-cell function (A) and insulin resistance (B) in women with a recent history of insulin-requiring GDM treated with 50 mg vildagliptin or placebo twice daily. The markers of β-cell function were measured at baseline/screening and up to 36 months after randomization. Results are shown as the median (interquartile range). OGTT = oral glucose tolerance test; SMC = standard meal challenge. HOMA-IR = homeostatic model assessment of insulin resistance; ISI = insulin-sensitivity index.

Figure 4

Other efficacy measures (glucose, HbA1c, GLP-1, GIP, BMI, waist-to-hip ratio, and blood pressure) in women with a recent history of insulin-requiring GDM treated with 50 mg vildagliptin or placebo twice daily. The efficacy variables were measured at baseline/screening and up to 36 months after randomization. Results are shown as the median (interquartile range). AUC = area under the curve; GIP = glucose-dependent insulinotropic polypeptide GLP-1 = glucagon-like peptide-1; HbA1c = hemoglobin A1c; OGTT = oral glucose tolerance test; SMC = standard meal challenge. HbA1c is expressed in %: 6.2% convert to 44 mmol/mol and 5.1% convert to 31 mmol/mol. BMI = body mass index.