Basic Cardiovascular Benefits of the Oral Antidiabetic Medication Empagliflozin

Introduction

Empagliflozin is a selective competitive inhibitor of the sodium-glucose cotransporter 2 (SGLT2), which is mainly expressed in the kidneys. The primary function of SGLT2 is the reabsorption of glucose from the glomerular filtrate in the proximal tubule. By inhibiting SGLT2, empagliflozin induces therapeutic glycosuria, which leads not only to a reduction in blood glucose levels and glycosylated hemoglobin but also to a decrease in body weight, as the excreted glucose cannot be used as an energy substrate.

Other beneficial effects of empagliflozin include lowering blood pressure without a simultaneous increase in heart rate, positive effects on markers of arterial stiffness and vascular resistance, visceral adiposity, albuminuria, and plasma urates. Due to its comprehensive effects, empagliflozin has become a breakthrough antidiabetic medication in terms of its impact on CV morbidity and mortality, a positive effect confirmed by the key clinical study EMPA-REG OUTCOME.

Methods and Aims of the Study

The randomized, double-blind, placebo-controlled EMPA-REG OUTCOME study included patients with type 2 diabetes over 18 years old with high CV risk. They were randomly assigned to receive empagliflozin at doses of 10 or 25 mg once daily or a placebo.

The composite primary endpoint included death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. The main secondary endpoint was also composite and additionally included hospitalization for unstable angina pectoris.

Study Population

The primary analysis of the study included 7,020 patients with a median treatment duration of 2.6 years and a median follow-up of 3.1 years. CV disease was confirmed in more than 99% of participants, who were concurrently undergoing proper therapy to reduce CV risk, including lipid-lowering therapy and antihypertensives. Baseline demographic and clinical characteristics did not significantly differ between the groups.

Findings

The incidence of the primary endpoint was statistically significantly lower in the empagliflozin-treated group than in the placebo group, with a relative risk reduction of 14% (10.5% vs. 12.1%; hazard ratio [HR] 0.86; 95.02% confidence interval [CI] 0.74–0.99; for noninferiority p < 0.001, for superiority p = 0.04).

No statistically significant differences were observed between the therapeutic groups regarding the incidence of nonfatal myocardial infarction or nonfatal stroke. No difference was shown regarding the incidence of the main secondary endpoint either. However, significantly lower CV mortality (3.7% vs. 5.9%; HR 0.62; 95% CI 0.49–0.77; p < 0.001), incidence of hospitalizations for heart failure (2.7% vs. 4.1%; HR 0.65, 95% CI 0.50–0.85; p = 0.002), and overall mortality (5.7% vs. 8.3%; HR 0.68, 95% CI 0.57–0.82; p < 0.001) were observed in the empagliflozin group compared to the placebo.

The risk reductions were similar for both doses of empagliflozin.

Conclusion

The EMPA-REG OUTCOME study results showed that adding empagliflozin to standard therapy in patients with type 2 diabetes and high cardiovascular risk leads to a significant reduction in major CV events (death from CV causes, nonfatal myocardial infarction, nonfatal stroke) and also reduces overall mortality and the risk of hospitalization for heart failure. 

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Source: Zinman B., Wanner C., Lachin J. M. et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373 (22): 2117–2128, doi: 10.1056/NEJMoa1504720.