SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study

Abstract

Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium-glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin's metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients.

Figure 1

Number of CV events prevented in 200 T2DM patients over a period of 5 years in whom HbA_1c 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).

Figure 2

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).

Figure 3

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.