Heart failure in <scp>SAVOR‐TIMI</scp> 53: The hindsight of diabetic retinopathySAVOR‐TIMI 53研究中的心脏衰竭：糖尿病视网膜病变的后尘
摘要
The SAVOR-TIMI 53 Trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus conducted by the Thrombolysis in Myocardial Infarction Group) was designed to evaluate cardiovascular safety and efficacy in patients with diabetes who, by virtue of a history of established cardiovascular disease or multiple risk factors for it, were at high risk of cardiovascular events. Although the primary and secondary composite endpoints were similar in placebo and saxagliptin groups, subjects assigned to receive saxagliptin experienced an unanticipated 27% relative increase (0.7% absolute risk over 2 years) in hospitalization for heart failure.1 Although conceivably a play of chance, several factors suggest that this may not necessarily be the case. Heart failure in SAVOR-TIMI 53 was centrally and blindly adjudicated with statistical adjustment for multiple comparisons. Furthermore, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes and Acute Coronary Syndrome) Trial, which compared another dipeptidyl peptidase (DPP)-4 inhibitor, namely alogliptin, with placebo also noted a similar numerical trend,2 so that when the findings of SAVOR and EXAMINE were combined, a significant odds ratio (OR) for heart failure hospitalization was apparent (OR 1.24; 95% confidence interval [CI] 1.07–1.44; P = 0.004).3 Probing the trial database, the TIMI Group has identified several factors most strongly associated with hospitalization for heart failure, regardless of treatment. These include prior heart failure, estimated glomerular filtration rate ≤60 mL/min per 1.73 m2, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP).4 Importantly, the Group also conducted landmark analyses demonstrating that most of the increased risk of heart failure hospitalization with saxagliptin occurred early, with a 6 month rate of 1.1% compared with 0.6% in the placebo group (hazard ratio [HR] 1.80;