Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus

Study Questions:

What is the safety and efficacy of saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, with respect to cardiovascular outcomes in patients with type 2 diabetes mellitus (DM2) who are at risk for cardiovascular events?

Methods:

The SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) investigators randomly assigned 16,492 patients with DM2 who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo, and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or ischemic stroke.

Results:

A primary endpoint event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan–Meier estimates; hazard ratio [HR] with saxagliptin, 1.00; 95% confidence interval [CI], 0.89-1.12; p = 0.99 for superiority; p < 0.001 for noninferiority); the results were similar in the “on-treatment” analysis (HR, 1.03; 95% CI, 0.91-1.17). The major secondary endpoint of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1,059 patients in the saxagliptin group and in 1,034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan–Meier estimates; HR, 1.02; 95% CI, 0.94-1.11; p = 0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; HR, 1.27; 95% CI, 1.07-1.51; p = 0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).

Conclusions:

The authors concluded that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased.

Perspective:

This trial reported that the DPP-4 inhibitor saxagliptin neither reduced nor increased the risk of the primary composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke, when added to the standard of care in patients at high risk for cardiovascular events. Saxagliptin was associated with significantly improved glycemic control and reduced the development and progression of microalbuminuria; however, it increased the risk of hospitalization for heart failure and the risk of hypoglycemic events. This trial thus establishes the cardiovascular safety profile of saxagliptin for use in patients with DM2. As has been true for almost all diabetes medications, lowering glycated hemoglobin was not associated with improved cardiovascular outcomes (macrovascular outcomes) in the short-term. For now, clinicians need to continue to focus on other modifiable risk factors for cardiovascular risk reduction among individuals with DM2, such as hypertension and dyslipidemia, in addition to glycemic control.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Myocardial Infarction, Stroke, Kaplan-Meier Estimate, Pancreatitis, Heart Failure, Hypoglycemic Agents, Hospitalization, Dipeptidyl-Peptidase IV Inhibitors, Diabetes Mellitus


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