Higher Risk of Hypoglycemia with Glimepiride Versus Vildagliptin in Patients with Type 2 Diabetes is not Driven by High Doses of Glimepiride: Divergent Patient Susceptibilities?

Abstract

Introduction: In a previously published study, vildagliptin showed a reduced risk of hypoglycemia versus glimepiride as add-on therapy to metformin at similar efficacy. Glimepiride was titrated from a starting dose of 2 mg/day to a maximum dose of 6 mg/day. It is usually assumed that the increased hypoglycemia with glimepiride was driven by the 6 mg/day dose; it was therefore of interest to assess whether the risk of hypoglycemia is also different between vildagliptin and a low (2 mg/day) dose of glimepiride.

Methods: Data (n = 3,059) were from the aforementioned randomized, double-blind study. Comparisons between vildagliptin (50 mg twice daily) and glimepiride (subgroups of patients on 2 mg/day, 6 mg/day, and 'other', and overall glimepiride group) were done by modeling hypoglycemia risk as a function of time and last-measured glycated hemoglobin (HbA1c) using discrete event time modeling, with treatment, age, gender as additional covariates.

Results: The hypoglycemia risk was significantly lower in patients receiving vildagliptin versus patients remaining on glimepiride 2 mg/day throughout the study, with similar results unadjusted or adjusted for last HbA1c [adjusted hazard ratio (HR) = 0.06 (95% CI 0.03, 0.11)]. The risk of hypoglycemia was very low with vildagliptin over the full HbA1c range, while the risk with glimepiride 2 mg/day increased with lower HbA1c. The increase for lower levels of HbA1c was more pronounced in the glimepiride 2 mg/day than 6 mg/day subgroup, with the 6 mg/day subgroup showing the lowest hypoglycemia risk among the glimepiride groups [adjusted HR vildagliptin vs. 6 mg/day glimepiride = 0.21 (95% CI 0.11, 0.40)].

Conclusion: The data show a substantially lower risk of confirmed hypoglycemia with vildagliptin compared to low-dose (2 mg/day) glimepiride. The analysis indicates that the previously reported results are not driven by high doses of glimepiride and points to interesting differences among patients regarding the susceptibility to hypoglycemia with sulfonylureas.

Fig. 1

Risk of confirmed hypoglycemia as a function of the most recently measured glycated hemoglobin (HbA_1c) in patients with type 2 diabetes mellitus after treatment with vildagliptin 50 mg bid + metformin (solid line; n = 1,539), glimepiride ‘overall’ + metformin (dashed line; n = 1,520) or glimepiride 2 mg/day + metformin (dotted line; n = 417). Risks are shown for week 24 [intent-to-treat (ITT) population]

Fig. 2

Risk of confirmed hypoglycemia as a function of the most recently measured glycated hemoglobin (HbA_1c) in patients with type 2 diabetes mellitus after treatment with glimepiride 6 mg/day + metformin (open diamond; n = 589), glimepiride “other” + metformin (dash dotted line; n = 514) or glimepiride 2 mg/day + metformin (dotted line; n = 417). Risks are shown for week 24 [intent-to-treat (ITT) population]