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

ObjectiveWomen 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.MethodsWomen 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).ResultsBetween 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.ConclusionsThe 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.govNCT01018602.

Effects of treatment with metformin and/or sitagliptin on beta‐cell function and insulin resistance in prediabetic women with previous gestational diabetes

“…In a phase II trial, administration of the dipeptidyl-peptidase-4 (DPP-4) inhibitor vildagliptin to women within the first year after delivery did not reduce the risk of postpartum diabetes, although some improvements in beta-cell function and insulin sensitivity were noted. 15 Co-administration of a DPP-4 inhibitor with MET may simultaneously address these key homeostatic mechanisms, as has been recently suggested in a study performed in women with prior GDM and residual impaired glucose tolerance (IGT). 16 In order to gain more detailed insights into the potential modifying effect on insulin secretion and insulin sensitivity of the combination treatment, we explored the effect of 16 weeks of therapy with sitagliptin (SITA) and MET monotherapy as well as in combination in women with recent GDM and impaired glucose regulation (IGR).…”

“…More scarce is information about a potential beneficial effect in sustaining beta‐cell function. In a phase II trial, administration of the dipeptidyl‐peptidase‐4 (DPP‐4) inhibitor vildagliptin to women within the first year after delivery did not reduce the risk of postpartum diabetes, although some improvements in beta‐cell function and insulin sensitivity were noted …”

The life course perspective of gestational diabetes: An opportunity for the prevention of diabetes and heart disease in women

“…In a study of 40 women with previous GDM, the combination of metformin and the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin yielded improvement in beta-cell function and insulin sensitivity after 16-weeks (compared to baseline), 74 while a placebo-controlled trial in 113 women found that the DPP-4 inhibitor vildagliptin did not reduce the risk of diabetes in this patient population. 75 In addition, a study of 49 women reported that the combination of metformin and the sodium glucose co-transporter-2 (SGLT-2) inhibitor dapagliflozin reduced weight and improved cardiometabolic risk factors after 24-weeks. 76 Recognizing the limitations of this literature, we are currently conducting a double-blind, placebo-controlled RCT to evaluate the impact of the SGLT-2 inhibitor empagliflozin on beta-cell function and glucose tolerance over 1 year in women with recent GDM (ClinicalTrials.Gov NCT03215069).…”

Incretins as a Potential Treatment Option for Gestational Diabetes Mellitus

“…Hummel et al [ 64 ] assessed the effectiveness of vildagliptin for the prevention of postpartum diabetes in women with a recent history of insulin-requiring GDM. The study included 113 women—58 received vildagliptin and 55 placebo pills.…”

“…However, the researchers were unable to demonstrate an advantage of taking vildagliptin over a placebo in terms of reducing the risk of postpartum diabetes. Moreover, indicators related to insulin resistance, glucose control, or pancreatic β-cell function were not significantly different between the two groups [ 64 ].…”