Pharmacologic Heterogeneity and Risk of Severe Hypoglycemia with Concomitant Use of Sulfonylureas and DPP-4 Inhibitors: Population-Based Cohort Study

Abstract

Dipeptidyl peptidase-4 inhibitors (DPP-4i) interact with sulfonylureas to increase their risk of hypoglycemia. Our population-based study assessed whether intraclass pharmacologic heterogeneity among sulfonylureas (long- vs. short-acting) and DPP-4i (peptidomimetic vs. non-peptidomimetic) modifies this interaction. We conducted a cohort study using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data. We assembled a cohort of patients initiating sulfonylureas (2007-2020). Using a time-varying exposure definition, we assessed the risk of severe hypoglycemia (hospitalization with or death due to hypoglycemia) associated with (i) concomitant use of long-acting sulfonylureas (glimepiride and glibenclamide) with DPP-4i compared with concomitant use of short-acting sulfonylureas (gliclazide and glipizide) with DPP-4i; and (ii) concomitant use of sulfonylureas with peptidomimetic DPP-4i (saxagliptin and vildagliptin) compared with concomitant use of sulfonylureas with non-peptidomimetic DPP-4i (sitagliptin, linagliptin, and alogliptin). Time-dependent Cox models estimated confounder-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Our cohort included 196,138 sulfonylurea initiators. During a median follow-up of 6 years, 8,576 events of severe hypoglycemia occurred. Compared with concomitant use of short-acting sulfonylureas with DPP-4i, concomitant use of long-acting sulfonylureas with DPP-4i was not associated with the risk of severe hypoglycemia (adjusted HR: 0.87, 95% CI: 0.65-1.16). Compared with concomitant use of sulfonylureas with non-peptidomimetic DPP-4i, concomitant use of sulfonylureas with peptidomimetic DPP-4i was also not associated with the risk of severe hypoglycemia (HR: 0.96, 95% CI: 0.76-1.22). Intra-class pharmacologic heterogeneity did not modify the association between concomitant use of sulfonylureas (short- vs. long-acting) and DPP-4i (peptidomimetic vs. non-peptidomimetic) and the risk of severe hypoglycemia.