Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality.

AIMS: There are safety concerns related to sulphonylurea treatment. The objective of this nationwide study was to compare the risk of cardiovascular disease (CVD), all-cause mortality and severe hypoglycemia in patients with type 2 diabetes (T2D) starting second-line treatment with either metformin+sulphonylurea or metformin+dipeptidyl peptidase-4 inhibitor (DPP-4i).

METHODS: All patients with T2D in Sweden who initiated second-line treatment with metformin+sulphonylurea or metformin+DPP-4i during 2006-2013 (n=40,736 and 12,024, respectively) were identified in this nationwide study. The Swedish Prescribed Drug Register and the Cause of Death and National Patient Registers were used, and Cox survival models adjusted for age, sex, fragility, prior CVD, and CVD-preventing drugs were applied to estimate risks of events. Propensity score adjustments and matching methods were used to test the results.

RESULTS: Of 52,760 patients; 77% started metformin+SU and 23% metformin+DPP-4i. Crude incidences for severe hypoglycemia, CVD, and all-cause mortality in the SU cohort were 2.0, 19.6, and 24.6 per 1000 patient-years and in the DPP-4i cohort were 0.8, 7.6, and 14.9 per 1000 patient-years, respectively. Sulphonylurea compared with DPP4i was associated with higher risk of subsequent severe hypoglycemia, fatal and nonfatal CVD, and all-cause mortality; adjusted HR (95% CI): 2.07 (1.11-3.86); 1.17 (1.01-1.37); and 1.25 (1.02-1.54), respectively. Results were confirmed by additional propensity-adjusted and matched analyses. Among the SU drugs, glibenclamide had the highest risks.

CONCLUSIONS: Metformin+SU treatment was associated with an increased risk of subsequent severe hypoglycemia, cardiovascular events, and all-cause mortality compared with metformin+DPP4i. Results from randomized trials will be important to elucidate causal relationships.