Comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors: SGLT2 inhibitors in the real world

Abstract

Patients with type 2 diabetes (T2DM) are at high risk for the development of cardiovascular (CV) disease and premature death (1). Heart failure is a CV outcome whose association with diabetes is being increasingly recognised (2). Heart failure is not only a common complication of T2DM but is also associated with a very poor prognosis. The 5-year survival rate for people with T2DM that develop heart failure has been reported to be less than 25% (3). The results from two randomised clinical trials of glucose lowering medications belonging to the sodium-glucose co-transporter 2 (SGLT-2) inhibitor class which showed a reduction in CV events, especially those related to heart failure, in high risk vascular patients with T2DM have therefore been enthusiastically received (4,5). Evidence is now also available to suggest that SGLT-2 inhibitors may have similar effects outside of the clinical trial setting. Furthermore, this so called "real world" data infer a SGLT-2 inhibitor class effect for CV protection in patients with T2DM across a range of background CV disease risk.The SGLT-2 receptor mediates high-capacity glucose uptake in the early proximal tubule, and SGLT2 inhibitors, through their ability to promote glycosuria, have been developed as glucose lowering medications (6). As well as having a glucose lowering effect, SGLT-2 inhibitors also reduce blood pressure, promote weight loss and reduce uric acid levels. In the landmark CV safety trial of empagliflozin (EMPA-REG OUTCOME trial), 7,020 T2DM patients at high risk for CV events were randomised to receive empagliflozin versus placebo (4). The primary composite outcome of the trial, death from CV causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in 10.5% of empagliflozin and 12.1% of placebo treated patients when followed for 3.1 years (HR =0.86; 95% CI: 0.72-0.99, P=0.04). This reduction in the primary endpoint was mainly accounted for by lower rates of death from CV causes (HR =0.62; P<0.001). Other important benefit seen in empagliflozin treated patients included reductions in the rate for death from any cause (HR =0.68; 95% CI: 0.57-0.82; P<0.001).In a follow-up study that specifically focused on heart failure outcomes in EMPA-REG, empagliflozin versus placebo treated patients had a significantly lower risk of hospitalisation for heart failure (HR =0.65; 95% CI: 0.50-0.85; P=0.002) and the combined endpoint of hospitalisation for heart failure or CV death (HR =0.66; 95% CI: 0.55-0.79; P<0.001) (7). The risk in the primary CV endpoint and the heart failure outcomes in empagliflozin treated patients reported in EMPA-REG were consistently lower in subgroup analysis exploring the effects of age, renal function, blockers of the renin-angiotensin system, lipid