Metformin versus sulphonylureas for new onset atrial fibrillation and stroke in type 2 diabetes mellitus: a population-based study

Aims: To gain insights on the cardiovascular effects of metformin and sulphonylurea, the present study compares the rates of incident atrial fibrillation, stroke, cardiovascular mortality and all-cause mortality between metformin and sulphonylurea users in type 2 diabetes mellitus.

Methods: This was a retrospective population-based cohort study of type 2 diabetes mellitus patients receiving either sulphonylurea or metformin monotherapy between January 1, 2000, and December 31, 2019. The primary outcome was new-onset AF or stroke. Secondary outcomes were cardiovascular, non-cardiovascular and all-cause mortality. Propensity score matching (1:2 ratio) between sulphonylurea and metformin users was performed, based on demographics, CHA-DS-VASc score, past comorbidities and medication use. Cox regression was used to identify significant risk factors. Competing risk analysis was conducted using cause-specific and subdistribution hazard models. Sensitivity analyses using propensity score stratification, high-dimensional propensity score and inverse probability of treatment weighting were conducted. Subgroup analyses were conducted for age and gender in the matched cohort.

Results: A total of 36,228 sulphonylurea users and 72,456 metformin users were included in the propensity score-matched cohort. Multivariable Cox regression showed that sulphonylurea users had higher risks of incident AF (hazard ratio [HR]: 2.89, 95% confidence interval [CI]: 2.75-3.77; P < 0.0001), stroke (HR: 3.23, 95% CI: 3.01-3.45; P < 0.0001), cardiovascular mortality (HR: 3.60, 95% CI: 2.62-4.81; P < 0.0001) and all-cause mortality (HR: 4.35, 95% CI: 3.16-4.75; P < 0.0001) compared to metformin users. Similarly, significant results were observed using cause-specific and subdistribution hazard models. Sensitivity analysis using techniques based on the propensity score also yielded similar results.

Conclusions: Sulphonylurea use was associated with higher risks of incident AF, stroke, cardiovascular mortality and all-cause mortality compared to metformin. Males and patients older than 65 years with sulphonylurea use were exposed to the highest risks.