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No Heart Safety Issues Seen With Diabetes Drug Sitagliptin (Januvia)

Placebo-controlled study meets primary and secondary endpoints

Positive results have been reported from the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS), a placebo-controlled study of the cardiovascular (CV) safety of the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin (Januvia, Merck) added to usual care in more than 14,000 patients.

The study achieved its primary composite CV endpoint of noninferiority (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina) compared with usual care without sitagliptin. Overall, the primary endpoint occurred in 11.4% (n = 839) of sitagliptin-treated patients compared with 11.6% (n = 851) of placebo-treated patients in the intention-to-treat analysis (hazard ratio [HR], 0.98), and in 9.6% of patients (n = 695) in both the sitagliptin and placebo groups in the per-protocol analysis (HR, 0.98; P < 0.001 for noninferiority).

In addition, there was no increase in hospitalization for heart failure, and rates of all-cause mortality were similar in both treatment groups, which were two key secondary endpoints.

The data were presented June 8 at the 75th Scientific Sessions of the American Diabetes Association and were published in the New England Journal of Medicine.

Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus (T2DM). The drug should not be used in patients with type-1 diabetes or for the treatment of diabetic ketoacidosis.

TECOS was an event-driven study designed to assess the long-term CV safety of the addition of sitagliptin to usual care compared to usual care without sitagliptin in patients with T2DM and established CV disease. In addition to showing no increased risk for the primary composite CV endpoint, sitagliptin also met the secondary composite CV endpoint (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal MI, or nonfatal stroke), showing noninferiority compared with usual care without sitagliptin (HR, 0.99; P < 0.001 for noninferiority).

In additional secondary endpoints assessing the time to first confirmed event, hospitalization for heart failure was reported in 3.1% (n = 228) of sitagliptin-treated patients and in 3.1% (n = 229) of placebo-treated patients (HR, 1.00). All-cause mortality was similar in both treatment groups, occurring in 7.5% (n = 547) of patients in the sitagliptin group and in 7.3% (n = 537) of patients in the placebo group (HR, 1.01).

In additional secondary analyses of the composite of the time to first hospitalization for heart failure or CV death, the first confirmed hospitalization for heart failure or CV death occurred in 7.3% (n = 538) of patients in the sitagliptin group compared with 7.2% (n = 525) of patients in the placebo group (HR, 1.01). The proportions of patients with CV death were 5.2% (n = 380) in the sitagliptin group and 5.0% (n = 366) in the placebo group (HR, 1.03).

Patients enrolled in the TECOS trial had T2DM with established CV disease in the coronary, cerebral, or peripheral arteries. The patients were at least 50 years of age; had baseline hemoglobin A1c of between 6.5% and 8.0%; and were dose-stable for at least 3 months on either 1) monotherapy or dual combination therapy with metformin, pioglitazone, or a sulfonylurea; or 2) insulin as monotherapy or in combination with a stable dose of metformin. The patients were randomly assigned to treatment with sitagliptin 100 mg daily (50 mg daily if the baseline estimated glomerular filtration rate [eGFR] was greater than or equal to 30 and less than 50 mL/min/1.73 m2) or matching placebo.

Source: Merck; June 8, 2015.

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