Research in context
Evidence before this study
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been studied in large cardiovascular outcome trials in patients with type 2 diabetes and were shown to reduce the risk of cardiovascular events. Both patients with established atherosclerotic cardiovascular disease and those with multiple risk factors but without the disease were studied in these trials. Within individual trials, the magnitude of benefit appeared to be greater on major adverse cardiovascular events in subgroups with established atherosclerotic cardiovascular disease, although formal heterogeneity was not shown. Based on these findings, American and European guidelines recommend use of SGLT2i for patients with type 2 diabetes and atherosclerotic cardiovascular disease, independent of glucose control considerations. However, no single trial has been adequately powered to test for such heterogeneity because the number of patients and events in those patients with multiple risk factors alone have been low. We prospectively planned to meta-analyse cardiovascular outcome results from the dedicated cardiovascular outcome trials stratified by presence or absence of established atherosclerotic cardiovascular disease, once data from the DECLARE-TIMI 58 trial of dapagliflozin versus placebo became available. We searched PubMed and Embase using the Medical Subject Heading terms “diabetes mellitus, type 2”, “sodium-glucose-co transporter 2 inhibitor”, and “clinical trial” for trials published up to Sept 24, 2018, to find all randomised cardiovascular outcome trials for SGLT2i.
Added value of this study
Incorporating data from the trials EMPA-REG OUTCOME, the CANVAS Program, and DECLARE-TIMI 58, the present meta-analysis of SGLT2i cardiovascular outcome trials showed that the clinical benefit of SGLT2i in reducing the risk of myocardial infarction, stroke, or cardiovascular death was present only in patients with established atherosclerotic cardiovascular disease and not in those with multiple risk factors. Conversely, the reductions in risk of hospitalisation for heart failure or progression of renal disease were robust regardless of the presence of atherosclerotic cardiovascular disease or heart failure at baseline.
Implications of all the available evidence
These data suggest that SGLT2i should be considered in patients with type 2 diabetes regardless of presence of atherosclerotic cardiovascular disease or history of heart failure, given that SGLT2i safely reduce HbA1c and reduce the risk of hospitalisation for heart failure and progression of renal disease across a broad spectrum of patients with type 2 diabetes. Reductions in major adverse cardiovascular events can also be expected in patients with established atherosclerotic cardiovascular disease.