Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial

Denice S. Feig, Lois E. Donovan, Bernard Zinman, J. J. Sanchez, Elizabeth Asztalos, Edmond A. Ryan, George I. Fantus, Eileen Hutton, Anthony B. Armson, Lorraine L. Lipscombe, David Simmons, Jon F.R. Barrett, Paul J. Karanicolas, Siobhan Tobin, H. David McIntyre, Simon Yu Tian, George Tomlinson, Kellie E. Murphy, Denice Feig, Diane DonatShital Gandhi, Barbara Cleave, Vivian Zhou, Effie Viguiliouk, Debbie Fong, Michele Strom, Melissa Deans, Aarthi Kamath, Ariane Godbout, Florence Weber, Michele Mahone, Bi Lan Wo, Marie Josee Bedard, Melanie Robinson, Sylvie Daigle, Sophie Leblanc, Sora Ludwig, Sherri Pockett, Laurie Slater, Lois Donovan, Carolyn Oldford, Catherine Young, Heidi Virtanen, Abhay Lodha, Stephanie Cooper, Jennifer Yamamoto, Claire Gougeon, Cheryl Verhesen, Afshan Zahedi, Nashwah Taha, Marci Turner, Madalena Neculau, Cathy Robb, Krystyna Szwiega, Grace Lee, Evelyne Rey, Sophie Perreault, Jillian Coolen, Thomas Ransom, Raquel Dias, Janet Slaunwhite, Darlene Baxendale, Cora Fanning, Ilana Halperin, Veronica Gale, Tina Kader, Heidi Hirsimaki, Hélène Long, Julie Lambert, Annie Castonguay, Steve Chalifoux, Ruth McManus, Margaret Watson, Anne Marie Powell, Munira Sultana, Vinolia ArthurHayward, Mauricio Marin, Lorraine Cauchi, Leila MacBean, Erin Keely, Janine Malcolm, Heather Clark, Allan Karovitch, Heather Belanger, Josee Champagne, Kayla Schutt, Jennifer Sloan, Joyce Mitchell, Colette Favreau, Elaine O'Shea, Debbie McGuire, Melin Peng, Dynika St Omer, Julie Lee, Jennifer Klinke, Sharon Young, Agnieszka Barts, Francina Carr, Peter Subrt, David Miller, Karen Coles, Sarah Capes, Galina Smushkin, Richard Phillips, Carol Fergusson, Stacey Lacerte, Robyn Houlden, Adriana Breen, Bonnie Stone-Hope, Sarah Kwong, Heather Rylance, Rshmi Khurana, Tammy McNab, Shirley Beauchamp, S. John Weisnagel, Martin D'Amours, Christyne Allen, Marie Christine Dubé, Valérie Ève Julien, Camille Lambert, Marie Claude Bourbonniere, Louise Rheaume, Myriam Bouchard, George Carson, Suzanne Williams, Maria Wolfs, Howard Berger, Alice Cheng, Joel Ray, Amir Hanna, Leanne De Souza, Leslie Berndl, Sara Meltzer, Natasha Garfield, Amira El-Messidi, Louise Bastien, Shari Segal, David Thompson, Ken Lim, Jason Kong, Sharon Thompson, Christine Orr, Brenda Galway, Minnie Parsons, Krista Rideout, Bernadette Rowe, Joan Crane, Wayne Andrews, Carol Joyce, Jill Newstead-Angel, Judy Brandt, Simona Meier, Josephine Laurie, David McIntyre, Helen Liley, Jane Fox, Helen Barrett, Frances Maguire, Marnie Nerdal-Bussell, Wenjun Nie, Carolyn Bergan, Bekki Cavallaro, Anne Tremellen, Anne Cook, Rohit Rajagopal, Lisa Vizza, Maureen Mattick, Claudia Bishop, Jodie Nema, Renee Kludas, Mark McLean, Susan Hendon, Allison Sigmund, Vincent Wong, Prem Lata, Hamish Russell, Razita Singh, Jon Barrett, Kellie Murphy, Keitha McMurray, Paul Karanicolas, Helen Murphy, Johanna Sanchez, Gail Klein, Simon Tian, Kathryn Mangoff

Research output: Contribution to journalArticlepeer-review

162 Citations (Scopus)

Abstract

Background: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. Methods: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1–4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. Findings: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [–10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference −0·2 [–0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference −0·4 [95% CI −0·5 to −0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference −1·8 [–2·7 to −0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference −218 [–353 to −82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference −1·41 [–2·6 to −0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). Interpretation: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. Funding: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.

Original languageEnglish
Pages (from-to)834-844
Number of pages11
JournalThe Lancet Diabetes and Endocrinology
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 2020

Bibliographical note

Funding Information:
The trial was funded by the Canadian Institutes of Health Research, the Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada, and the Department of Medicine, University of Toronto, Toronto, ON, Canada. The study drugs, metformin and placebo, were provided by Apotex, Toronto, ON, Canada, and Bayer (Asencia) and Roche Diabetes Care provided the glucometers and strips. We thank all the women with type 2 diabetes who participated in the trial. We also acknowledge the invaluable support from the 29 diabetes research and clinical care teams and the Clinical Trials Services research team at Sunnybrook Research Institute, Toronto, ON, Canada. We thank the data safety monitoring board for overseeing the trial: Kevin Thorpe, Lelia Duley, and Michael Bracken. We would also like to acknowledge our steering committee member Arne Ohlsson for his very wise counsel and dedication to the trial. Arne Ohlsson unfortunately passed away before the writing of this manuscript. We are indebted to him for his important contributions and support for this trial.

Funding Information:
The trial was funded by the Canadian Institutes of Health Research, the Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada, and the Department of Medicine, University of Toronto, Toronto, ON, Canada. The study drugs, metformin and placebo, were provided by Apotex, Toronto, ON, Canada, and Bayer (Asencia) and Roche Diabetes Care provided the glucometers and strips. We thank all the women with type 2 diabetes who participated in the trial. We also acknowledge the invaluable support from the 29 diabetes research and clinical care teams and the Clinical Trials Services research team at Sunnybrook Research Institute, Toronto, ON, Canada. We thank the data safety monitoring board for overseeing the trial: Kevin Thorpe, Lelia Duley, and Michael Bracken. We would also like to acknowledge our steering committee member Arne Ohlsson for his very wise counsel and dedication to the trial. Arne Ohlsson unfortunately passed away before the writing of this manuscript. We are indebted to him for his important contributions and support for this trial.

Funding Information:
DSF reports grants from the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto Department of Medicine; non-financial support from Apotex, Bayer (Asencia), and Roche Diabetes Care; and personal fees from Medtronic and Novo Nordisk. IGF reports grants from the Canadian Institutes of Health Research. PJK reports grants from the Canadian Institutes of Health Research. JJS reports grants from the Canadian Institutes of Health Research. ST reports grants from the Canadian Institutes of Health Research. All other authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Ltd

ASJC Scopus Subject Areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial'. Together they form a unique fingerprint.

Cite this