This trial was designed to evaluate the long-term cardiovascular efficacy and safety of saxagliptin in 16,492 patients with type 2 diabetes at risk for cardiovascular events. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or ischaemic stroke. Hospitalisation for heart failure was a predefined component of the secondary endpoint. Subjects at greatest risk for hospitalisation for heart failure were found to have elevated levels of natriuretic peptides, prior heart failure, or chronic kidney disease.
The possible mechanism(s) for increased heart failure with DPP-4 inhibitors are not entirely clear. The decision to choose one antihyperglycaemic agent over another needs to take into account the potential benefit in reducing microvascular complications through improved glycaemic control together with potential adverse events such as hypoglycaemia and heart failure. The potential benefits of these diabetes medications may become evident with longer term follow-up, whilst the risk of heart failure appears to emerge very early. An editorial calls for more well-powered RCTs of diabetes medications with sufficient length of follow-up and that more fully integrate all relevant events, including heart failure, into the primary cardiovascular composite endpoint to more effectively address the crucial questions of net clinical outcomes and the comparative balance of benefit and risk.