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. 2018 Jul 18:362:k2693.
doi: 10.1136/bmj.k2693.

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

Antonios Douros  1   2   3 , Sophie Dell'Aniello  1 , Oriana Hoi Yun Yu  1   4 , Kristian B Filion  1   2   5 , Laurent Azoulay  1   2   6 , Samy Suissa  1   2   5
Affiliations

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

Antonios Douros et al. BMJ. .

Abstract

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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf 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.

Figures

Fig 1
Fig 1
Flowchart showing the base and study cohorts. HES=Hospital Episode Statistics; ONS=Office for National Statistics; CPRD=Clinical Practice Research Datalink.
Fig 2
Fig 2
Forest plot summarising the primary analysis and all sensitivity analyses
See this image and copyright information in PMC

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