Glucose-Lowering Agents and the Risk of Hypoglycemia: a Real-world Study

Abstract

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) are increasingly recommended in type 2 diabetes. Hypoglycemia is a serious adverse effect of glucose-lowering agents. Real-world comparison of hypoglycemic risks among SGLT2i, GLP1RA, dipeptidyl peptidase-4 inhibitor (DPP4i), and sulfonylureas is limited.

Objective: Quantify the risk of hypoglycemia associated with SGLT2i, GLP1RA, DPP4i, and sulfonylureas (the primary reference group).

Design: Retrospective cohort study conducted using electronic health records from Geisinger Health, Pennsylvania (2015-2019).

Participants: A total of 10,713 patients with type 2 diabetes who newly received SGLT2i (n=1487), GLP1RA (n=1241), DPP4i (n=2938), or sulfonylureas (n=5047). Propensity score-based inverse probability of treatment weighting was used to balance patient characteristics across four treatment groups simultaneously.

Main measures: Hypoglycemia was defined as capillary blood glucose <70 mg/dL; severe hypoglycemia was defined as capillary blood glucose <54 mg/dL. A weighted Cox proportional hazards regression model was used to estimate the risk of outcomes for pairwise comparisons of SGTL2i, GLP1RA, DPP4i, and sulfonylureas.

Key results: Median follow-up was 21.3 months. Compared with sulfonylureas, the risk of hypoglycemia was lower with SGLT2i (hazard ratio 0.60 [95% confidence interval 0.48-0.75]), GLP1RA (0.49 [0.34-0.69]), and DPP4i (0.60 [0.48-0.78]). The risk of severe hypoglycemia was also lower with SGLT2i (0.43 [0.35-0.74]), GLP1RA (0.50 [0.28-0.87]), and DPP4i (0.64 [0.46-0.90]) compared to sulfonylureas. The risks of hypoglycemia and severe hypoglycemia were similar across the SGLT2i, GLP1RA, and DPP4i groups (SGLT2i vs. DPP4i: 0.95 [0.67-1.34]; GLP1RA vs. DPP4i: 0.81 [0.55-1.19]; SGLT2i vs. GLP1RA: 1.17 [0.76-1.82] for hypoglycemia).

Conclusion: SGLT2i and GLP1RA confer a lower risk of hypoglycemia compared with sulfonylureas and similar risk compared with DPP4i. Given the known cardiovascular benefits associated with SGLT2i and GL1PRA, our results suggesting the safety of SGLT2i and GL1PRA further support their use.