SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control

SGLT2 inhibitors improve cardiovascular and renal outcomes even in patients without diabetes mellitus. In this Review, Cowie and Fisher describe the additional mechanisms of benefit of SGLT2 inhibitors, unrelated to improved glycaemic control. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic therapies in patients with type 2 diabetes mellitus and are associated with improved glycaemic control as well as with reductions in body mass and blood pressure. In large cardiovascular outcome trials in patients with diabetes, SGLT2 inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure, with this benefit extending to patients without diabetes who have heart failure with reduced ejection fraction. The possible mechanisms of benefit are being extensively investigated because they are unlikely to be related to improved glycaemic control. Early natriuresis with a reduction in plasma volume, a consequent rise in haematocrit, improved vascular function, a reduction in blood pressure and changes in tissue sodium handling are all likely to have a role. Additional mechanisms of SGLT2 inhibitors that might be beneficial include a reduction in adipose tissue-mediated inflammation and pro-inflammatory cytokine production, a shift towards ketone bodies as the metabolic substrate for the heart and kidneys, reduced oxidative stress, lowered serum uric acid level, reduced glomerular hyperfiltration and albuminuria, and suppression of advanced glycation end-product signalling. Further outcome trials and mechanistic studies, including in patients with heart failure with preserved ejection fraction or non-diabetic kidney disease, might identify other possible mechanisms of benefit of SGLT2-inhibitor therapy.