Glibenclamide and metfoRmin versus stAndard care in gEstational diabeteS (GRACES): a feasibility open label randomised trial

Abstract

Background: Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM.

Methods: We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks' gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic control, participant satisfaction and clinical outcomes.

Results: Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n = 13) or metformin and insulin (n = 10). Mean (SD) recruitment rate was 0.39 (0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6-90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic control to metformin and glibenclamide, with fewer blood glucose readings <3.5 mmol/l (median [IQR] difference/woman/week of treatment 0.58 [0.03-1.87]).

Conclusions: A large randomised controlled trial comparing glibenclamide or insulin in combination with metformin for women with GDM would be feasible but is unlikely to be worthwhile, given the poorer glycaemic control with glibenclamide and metformin in this pilot study. The combination of metformin and glibenclamide should be reserved for women with GDM with true needle phobia or inability to use insulin therapy.

Trial registration: www.clinicaltrials.gov registration number:NCT02080377 February 11th 2014.

Keywords: Feasibility; Gestational diabetes; Glibenclamide; Metformin; Patient preference.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Scotland A Research Ethics Committee (reference number:13/SS/0223) and the Medicines and Healthcare products Regulatory Agency (EudraCT number:2013–004706-25) and was registered with clinical trials.gov (registration number:NCT02080377). The trial was overseen by a Trial Steering Committee and an independent Data Monitoring Committee. All participants gave written informed consent.

Consent for publication

Not applicable.

Competing interests

Professor Norman reports grants from Chief Scientist Office, Scottish Government, grants from Tommy’s, during the conduct of the study; other from GSK, grants from NIHR, MRC, SANDs, outside the submitted work. Prof Strachan reports personal fees from Novo Nordisk, personal fees from Eisai, personal fees from Astra Zeneca, outside the submitted work. Dr. Lindsay reports personal fees from Eli Lilly ltd, personal fees from Novo Nordisk ltd, outside the submitted work. Associate Professor Edmund Juszczak reports grants from Chief Scientist Office, Scottish Government Health & Social Care Directorates during the conduct of the study. None of the other authors have any conflicts of interest to declare.

Glibenclamide and the comparator insulin were supplied through the hospital pharmacies. Neither the funder nor the supplier of drugs had any role in study design, data collection, data analysis, data interpretation or writing of the report. The joint study sponsor in terms of the EU Clinical Trials Directive was the University of Edinburgh and NHS Lothian and had no role in analysis of the data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The views expressed in this publication are those of the author(s) and not necessarily those of the Chief Scientist Office, Scotland and Tommy’s.

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Figures

Fig. 1

CONSORT flow chart

Fig. 2

Fasting and post-prandial home blood glucose readings in women with GDM treated with metformin and randomised to glibenclamide (G1-13 Panels a and c) or insulin (I 1-10 Panels b and d)