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Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study

BMJ 2018; 362 doi: (Published 18 July 2018) Cite this as: BMJ 2018;362:k2693
  1. Antonios Douros, postdoctoral fellow123,
  2. Sophie Dell’Aniello, statistician1,
  3. Oriana Hoi Yun Yu, endocrinologist14,
  4. Kristian B Filion, assistant professor125,
  5. Laurent Azoulay, associate professor126,
  6. Samy Suissa, professor125
  1. 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste-Catherine, H-461 Montréal, QC H3T 1E2, Canada
  2. 2Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montréal, QC, Canada
  3. 3Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
  4. 4Division of Endocrinology, Jewish General Hospital, Montréal, QC, Canada
  5. 5Division of Clinical Epidemiology, Department of Medicine, McGill University, Montréal, QC, Canada
  6. 6Gerald Bronfman Department of Oncology, McGill University, Montréal, QC, Canada
  1. Correspondence to: S Suissa samy.suissa{at}
  • Accepted 11 June 2018


Objective To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes.

Design Population based cohort study.

Setting General practices contributing data to the UK Clinical Practice Research Datalink.

Participants Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013.

Main outcome measures Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes.

Results Among 77 138 metformin initiators, 25 699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 v 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 v 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 v 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 v 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 v 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia.

Conclusions Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.


  • Contributors: AD, SD, OHYY, KBF, LA, and SS contributed to the study concept and design, analysed and interpreted the data, and critically revised the manuscript. AD drafted the manuscript. AD, SD, and SS conducted the statistical analysis. SS acquired the data, obtained funding, and supervised the study. SS is the guarantor.

  • Funding: AD is the recipient of a Research Fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft). KBF holds a Chercheur Boursier award from the Fonds de recherche du Québec-Santé (FRQS). LA holds a Chercheur Boursier award from the FRQS and is the recipient of a William Dawson Scholar award. SS is the recipient of the James McGill Professorship award.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: this research was funded in part by grants from the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and Boehringer Ingelheim. Boehringer Ingelheim were provided with the opportunity to comment on the manuscript, but they were not directly involved in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. SS has received research grants and has participated in advisory board meetings or as a speaker at conferences for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Merck, and Novartis. No other potential conflicts of interest relevant to this article were reported.

  • Ethical approval: The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD (protocol 14_019AMn) and by the Research Ethics Board of the Jewish General Hospital, Montréal, Canada.

  • Data sharing: No additional data are available.

  • Transparency: The manuscripts guarantor (SS) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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