CONCOMITANT USE OF SULFONYLUREAS AND BETA-BLOCKERS AND THE RISK OF SEVERE HYPOGLYCEMIA: POPULATION-BASED COHORT STUDY

Abstract

Objective: Evidence suggests that beta-blockers increase the risk of hypoglycemia. However, their effects among users of sulfonylureas, drugs that also cause hypoglycemia, are not well understood. Thus, our study assessed the potential association between concomitant use of sulfonylureas and beta-blockers and the risk of severe hypoglycemia. Design and method: This retrospective cohort study used the United Kingdom Clinical Practice Research Datalink linked to hospitalization and vital statistics data. It included patients with type 2 diabetes initiating sulfonylurea treatment between 1998 and 2020. Patients with use of beta-blockers in the 6 months prior to cohort entry were excluded. Time-dependent Cox proportional hazards models estimated confounder-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycemia associated with concomitant use of sulfonylureas and beta-blockers compared to sulfonylurea use alone. To account for residual confounding, we also performed an analysis using an active comparator, where the reference category was current concomitant use of sulfonylureas and thiazide diuretics. To explore the role of cardioselectivity in the hypoglycemic risk of beta-blockers, we further compared head-to-head current concomitant use of sulfonylureas and non-cardioselective beta-blockers (i.e., propranolol, carvedilol, sotalol, labetalol) versus current concomitant use of sulfonylureas and cardioselective beta-blockers (i.e., acebutolol, atenolol, bisoprolol, metoprolol, nebivolol, esmolol). Results: Our cohort included 252,869 patients initiating sulfonylureas. During a mean (standard deviation) follow-up of 8.6 (5.7) years, there were 16,857 events of severe hypoglycemia (crude incidence rate, 7.8 [95% CI, 7.6–7.9] per 1000 person-years). Compared to sulfonylurea use alone, concomitant use of sulfonylureas and beta-blockers was associated with a 53% increased risk of severe hypoglycemia (adjusted HR, 1.53; 95% CI, 1.42–1.65). The use of an active comparator led to consistent findings (adjusted HR, 1.69; 95% CI, 1.42–2.01). When comparing concomitant use of sulfonylureas and non-cardioselective beta-blockers to concomitant use of sulfonylureas and cardioselective beta-blockers, we were not able to detect an increased risk of severe hypoglycemia (adjusted HR, 0.95; 95% CI, 0.74–1.24). Conclusions: Our population-based study showed an increased risk of severe hypoglycemia associated with concomitant use of sulfonylureas and beta-blockers. Cardioselectivity of beta-blockers did not seem to play a major role in this regard.