Lower risk of hypoglycemia with sitagliptin compared to glipizide when either is added to metformin therapy: a pre-specified analysis adjusting for the most recently measured HbA_1c value

Abstract

Background:

In a previously-published study, adding sitagliptin or glipizide to ongoing metformin therapy provided similar HbA_1c improvement (both groups, −0.7%) after 52 weeks in patients with type 2 diabetes (T2DM). Significantly fewer patients experienced symptomatic hypoglycemia with sitagliptin (5% of 588 patients) compared to glipizide (32% of 584 patients). Glycemic efficacy and patient characteristics may influence hypoglycemic events. The present analysis evaluated the risk of hypoglycemia with sitagliptin or glipizide after adjusting for the most recently measured HbA_1c value.

Methods:

Data for this analysis were from the aforementioned 52-week, randomized, double-blind, active-controlled study. The primary endpoint was confirmed hypoglycemia (i.e., symptomatic hypoglycemia confirmed with a concurrent fingerstick glucose ≤70 mg/dL [3.9 mmol/L]); the secondary endpoint was severe hypoglycemia (requiring medical or non-medical assistance or symptoms of neuroglycopenia). Complementary log-log regression random effects models with terms for treatment, most recently measured HbA_1c value, time (i.e., days since randomization), gender, and age (< or ≥65 years) were used to assess adjusted subject-specific treatment effects.

Results:

Over the full range of HbA_1c levels and follow-up time, the risk of confirmed hypoglycemic events was lower with sitagliptin compared with glipizide (31 vs. 448 events; adjusted hazard ratio [HR] = 0.05 [95% CI: 0.03, 0.09], p < 0.001). The risk was also lower with sitagliptin in the younger (HR = 0.06 [95% CI: 0.03, 0.12], p < 0.001) and older (HR = 0.02 [0.01, 0.08], p < 0.001) age groups compared with glipizide. For severe hypoglycemia events (2 vs. 22), the risk was lower with sitagliptin (HR = 0.08 [95% CI: 0.01, 0.47]; p = 0.005).

Limitations:

The actual time between the HbA_1c measurement and the hypoglycemic event was variable and not controlled for in the analysis.

Conclusion:

In pre-specified analyses adjusting for the most recently measured HbA_1c value, there was a substantial reduction in risk for confirmed hypoglycemia with sitagliptin compared to glipizide when added to ongoing metformin therapy in patients with T2DM. The risk of confirmed hypoglycemia was very low in younger and older patients treated with sitagliptin.

Keywords::

• Dipeptidyl peptidase-4 inhibitors
• Hypoglycemia
• Relative risk
• Sulfonylureas
• Tolerability

Transparency

Declaration of funding

This analysis was funded by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA, the manufacturer of sitagliptin.

Declaration of financial/other relationships

K.J.K., S.A.F., M.J.D., T.S., G.E.M., D.W.H., K.D.K., and B.J.G. all declare that they are/were full-time employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA, at the time of the analysis and may potentially own stock and/or hold stock options in the company. Author contributions: G.E.M. and K.D.K. were involved in the concept and design of the study and data collection. K.J.K. designed the current analysis. S.A.F. performed the analyses. All authors were involved in interpretation of the results. M.J.D., K.J.K., and T.S. drafted the article and all authors were involved in the critical revision and approval of the article. CMRO peer reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgment

The authors wish to acknowledge Kristen Lewis (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA) for assistance in preparing this manuscript for publication.