SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Abstract

IntroductionIn women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM.MethodsThe SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals.Trial registration numberNTR6134; Pre-results.

Metformin for pregnancy and beyond: the pros and cons

“…Compared to metformin glyburide is associated with higher rates of neonatal hypoglycaemia and macrosomia. 32,33 The upcoming SUGAR-DIP trial 34 will evaluate if glyburide has any potential as an additive agent in sequential therapy for the treatment of GDM.…”

Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis

“…7 14-27 Yet, some have reported that metformin increased the risk of preterm birth compared with insulin, 7 while others found a decreased risk of pregnancy-induced hypertension, 20 27 neonatal death or serious comorbidity 14 with metformin compared with insulin or other oral hypoglycaemic drugs. Ongoing trials which are sufficiently powered, such as the SUGAR-DIP trial 28 which aims to recruit 810 women with GDM, should be able to shed some light on the impact of metformin on some of these pregnancy outcomes.…”