iabetes mellitus (DM) adds incremental risk of the development and subsequent exacerbation of heart failure even after adjusting for common risk factors, such as ischemic heart disease and hypertension.1 Although incompletely understood, cardiac metabolic dysregulation of glycolysis and fatty acid oxidation observed in the heart of patients with Background-Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results-A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. Conclusions-In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01107886.

OBJECTIVEThe glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODSPatients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m 2 ; n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m 2 ; n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m 2 ; n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTSAfter a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ‡0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% .28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1. CONCLUSIONSSaxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.