Cardioprotective Benefit of DPP-4 Inhibitor Unclear

Although the selective dipeptidyl peptidase 4 (DPP-4) inhibitor saxagliptin significantly improved glycemic control in patients with type 2 diabetes, the risk of hospitalization for heart failure increased, as did the risk of hypoglycemic events, according to results from the SAVOR-TIMI 53 trial [N Engl J Med. 2013;doi:10.1056/NEJMoa1307684].

The purpose of the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus—Thrombolysis in Myocardial Infarction) 53 trial was to evaluate the safety and efficacy of saxagliptin from a cardiovascular perspective in patients with type 2 diabetes at risk for cardiovascular events. SAVOR-TIMI 53 was a multicenter, randomized, double-blind, placebo-controlled, phase 4 trial consisting of 16,492 patients and was conducted in 26 countries.

To be eligible for study inclusion, patients with type 2 diabetes had to have a glycated hemoglobin level of 6.5% to 12% and either a history of established cardiovascular disease (CVD) or be at risk for CVD. Between May 2010 and December 2011, patients were randomized to either saxagliptin at a dose of 5 mg daily (2.5 mg in those with an estimated glomerular filtration rate of ≤50 mL/min) or matching placebo, and were stratified according to their disease state or risk factors and renal function.

The primary efficacy and safety end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke. The secondary efficacy end point included the primary composite end point as well as hospitalization for heart failure, coronary revascularization, or unstable angina. The researchers analyzed all data according to the intention-to-treat principle with the use of a Cox proportional hazards model. The median follow-up was 2.1 years and the maximum follow-up time was 2.9 years.

Results showed significantly lower fasting plasma glucose levels for those in the saxagliptin group compared with placebo at 2 years and at the end of the treatment period (P<.001 for both). Glycated hemoglobin levels were significantly lower in the saxagliptin group compared with the placebo group at 1 year (7.6% vs 7.9%), at 2 years (7.5% vs 7.8%), and at the end of the treatment period (7.7% vs 7.9%; P<.001 for all).

A significantly greater proportion of patients taking saxagliptin had glycated hemoglobin levels <7% by the end of the treatment period (36.2% vs 27.9%; P<.001). There were also fewer patients in the saxagliptin group that required a dose increase compared with those taking placebo (23.7% vs 29.3%; hazard ratio [HR] with saxagliptin, 0.77; 95% confidence interval [CI], 0.73-0.82; P<.001), and fewer patients that required the initiation of insulin for more than 3 months (5.5% vs 7.8%; HR, 0.70; 95% CI, 0.62-0.79; P<.001).

The researchers found the primary composite end point occurred in 613 patients taking saxagliptin compared with 609 patients taking placebo (7.3% vs 7.2%; HR, 1.00; 95% CI, 0.89-1.12; P=.99 for superiority and P<.001 for noninferiority). They also found the major secondary end point occurred in 1059 patients in the saxagliptin group versus 1034 in the placebo group (12.8% vs 12.4%; HR, 1.02; 95% CI, 0.94-1.11; P=.66). A greater number of patients who took saxagliptin were hospitalized for heart failure compared with the placebo group (3.5% vs 2.8%; HR, 1.27; 95% CI, 1.07-1.51; P=.007).

Results also showed significantly more patients taking saxagliptin reported at least 1 hypoglycemic event (15.3% vs 13.4%; P<.001), with major hypoglycemic events occurring in 2.1% versus 1.7% (P=.047). Hypoglycemic events classified as minor occurred in 14.2% of patients in the saxagliptin group compared with 12.5% in the placebo group (P=.002). Hospitalizations related to hypoglycemia were infrequent and occurred in similar rates for both groups (0.6% and 0.5%, respectively).

Despite the improved glycemic control of the patients who took saxagliptin, the researchers concluded there was no evidence of cardioprotective benefit, for which there may be several possible explanations. One may be the relatively short length of time study participants were exposed to the drug.