Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic
drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma
glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control
without promoting hypoglycemia in the absence of exogenously administered insulin.
Methods: The present narrative review addresses the putative associations between SGLT2i and several cardiovascular
(CV) and microvascular risk factors, as well as their effects on cardiac and renal function.
Results: SGLT2i improve several CV risk factors, including fasting and postprandial plasma glucose levels, lipids,
blood pressure, body weight, serum uric acid and arterial stiffness. These drugs may also favorably modulate
cardiac and renal function via their effects on inflammation, oxidative stress, diuresis, fluid and sodium retention,
myocardial function, vascular resistance and ‘fuel’ metabolism. In the EMPA-REG OUTCOME study, the first
published large CV outcome SGLT2i trial, empagliflozin significantly reduced the primary composite outcome
(i.e. CV death, nonfatal myocardial infarction or stroke) and all-cause death as well as hospitalization for heart
failure. In addition, empagliflozin was associated with a slower progression of kidney disease and lower rates of
clinically relevant renal events than was placebo when added to standard care in patients at high CV risk.
Conclusion: Multiple metabolic benefits may account for the positive clinical outcomes in the EMPA-REG
OUTCOME study. Ongoing CV outcome trials involving other SGLT2i will help establish whether the reported
CV and microvascular risk benefits are compound-specific or drug class effects.