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Fewer Adverse Effects Observed When Adding Dipeptidyl Peptidase-4 Inhibitors to Metformin Therapy

Oct 30, 2015

Combination does not alter myocardial infarction, hospitalization risks.

The American Diabetes Association and the European Association for the Study of Diabetes recommend metformin as the first-line drug for type 2 diabetes (T2DM). Since T2DM is a progressive disease, usually another agent is added to improve glycemic control after a while. However, what agent is recommended as a second-line therapy is still unclear.


Several studies have shown that adding sulfonylureas to metformin may increase cardiovascular risks. Whereas several studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) with metformin “achieve similar glucose control with a lower risk of hypoglycemia than sulfonylureas plus metformin.” However, the recent SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53) study has raised some concerns due to their findings of an increased risk for heart failure in patients with T2DM when treating with DPP-4 inhibitors.

Previous studies that “compared the effects of DPP-4 inhibitors and sulfonylureas on major adverse cardiovascular events (MACE) components have been largely inconclusive.” Therefore, Shuo-Ming Ou, MD, Chia-Jen Shih, MD, and colleagues “performed a propensity score-matched study using Taiwan’s National Health Insurance Research Database (NHIRD) to compare all-cause mortality and the occurrence of MACE (including ischemic stroke and myocardial infarction), hospitalization for heart failure, and hypoglycemia among patients with T2DM treated with DPP-4 inhibitors or sulfonylureas as add-ons to metformin therapy.”

This was a population-based observational cohort study. The researchers looked at the exposures of DPP-4 inhibitors or sulfonylureas added to metformin therapy. The period of exposure extended from the day of prescription to the end of the last dispended drug supply.

During the mean follow-up of 3.3 years, a total of 563 (5.6%) DPP-4 inhibitors users and 4,425 (7.6%) sulfonylurea users died of any cause. Results showed that patients using DPP-4 inhibitors had lower risks for all-cause death, MACEs, risks for ischemic strokes, and hypoglycemia than sulfonylurea users. However, risks for hospitalization for heart failure and myocardial infarction were similar between the two groups.

The researchers concluded that “DPP-4 inhibitors reduced the risks for all-cause death and stroke but did not alter the risks for myocardial infarction and hospitalization for heart failure relative to sulfonylureas.” The information from this study can be helpful in the evaluation of cardiovascular risk in patients with T2DM treated with sulfonylureas versus DPP-4 inhibitors adding to metformin therapy.

Practice Pearls:

  • Metformin is recommended as first-line therapy for T2DM, but second-line therapy is unclear.
  • DPP-4 inhibitors adding to metformin therapy reduce risk for all-cause death and stroke when compared to adding sulfonylureas to metformin therapy.
  • No difference in risk of myocardial infarction and hospitalization for heart failure between groups of DPP-4 inhibitors and groups of sulfonylureas.

Ou SM, Shih CJ, Chao PW, et al. “Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus.” Annals of Internal Medicine. 2015;163(9). Web. 20 Oct 2015.