Number of CV events prevented in 200 T2DM patients over a period of 5 years in whom HbA1c was lowered by 0.9%, LDL cholesterol by 1 mmol/L, and systolic blood pressure by 4 mmHg and who were given 45 mg pioglitazone (Pio) or empagliflozin (EMPA) (10 or 25 mg per day) (1,11,17).
Kaplan-Meier plot of the effect of various interventions on CV outcome. A: Effect of pravastatin on CV events in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study (29). B: Effect of lowering blood pressure on mortality in the ACCORD study (4). C: Effect of empagliflozin on CV events in the EMPA-REG OUTCOME study (1). D: Effect of spironolactone on mortality in patients with CHF (40).
Schematic representation of the possible metabolic and hemodynamic mechanisms via which empagliflozin reduced mortality and hospitalization for heart failure in the EMPA-REG OUTCOME study. Because of the rapidity of onset of these beneficial effects and the known CV benefits of blood pressure and volume reduction from previous trials with antihypertensive agents and diuretics, it is likely that the hemodynamic and volume-depleting actions play a pivotal role in the cardioprotective effects of empagliflozin. It seems less likely that the metabolic/hormonal effects (shift from glucose to fat/ketone oxidation, reduced plasma uric acid concentration, weight loss, increased glucagon secretion, increased angiotensin [Ang] 1-7, and AT2 receptor activation) of empagliflozin therapy could play a role in the drug’s cardioprotective effects (see text for a more detailed explanation). ECFV, extracellular fluid volume.