Background: Pharmacokinetic studies suggest that adiposity may modify antidiabetic (AD) medication efficacy and safety via altered drug distribution. While sulfonylureas (SU) have been linked to a higher cardiovascular (CV) risk, with inconsistent results, the role of obesity remains unclear. We evaluated the effect of obesity on CV risk with SU as first-line therapies for type 2 diabetes in a clinical practice. Methods: Using the UK’s Clinical Practice Research Datalink, we conducted a cohort study of patients initiating AD treatment. Initiators of SU monotherapy were matched with initiators of metformin (MET) monotherapy on a high-dimensional propensity score. Patients were censored at the time of discontinuation or addition of another AD drug. We used Cox proportional hazards models within body mass index (BMI) categories (< 25 kg/m2 (normal weight; 26%), 25-30 kg/m2 (overweight; 42%), ≥ 30 kg/m2 obese; 32%)) to estimate hazard ratios (HR) of major adverse cardiovascular events (MACE), individual components of MACE, and all-cause mortality, comparing SU with MET.

Results: A total of 94,750 patients with type 2 diabetes initiated SU or MET. We matched 13,999 initiators of SU with 13,999 MET initiators. The overall HR of MACE comparing SU with MET was 1.23 (95% CI: 1.08-1.39); the HR was 1.33 (95% CI: 1.02-1.74) among obese patients, 1.27 (95% CI: 1.04-1.55) for overweight patients, and 0.99 (95% CI: 0.77-1.28) among normal weight patients. Similarly, the risk of all-cause mortality, CV death and ischemic stroke with SU was highest in obese individuals, with evidence of interactions for all-cause mortality and stroke.

Conclusion: Sulfonylureas as a first-line monotherapy for type 2 diabetes is associated with a higher risk of MACE compared with MET. Our data suggest that this effect might be strongest in obese patients, with no increased risk in normal weight patients. To ensure the best response to treatment, BMI level may be considered when choosing MET over SU for first-line treatment.


K. Suissa: None. A. Douros: None. L. Azoulay: Consultant; Self; Janssen Pharmaceuticals, Inc., Pfizer Inc. K.B. Filion: None. S. Schneeweiss: None.

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