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Evevident
Original paper
2015NEJMEndocrinology/Metabolism

EMPA-REG OUTCOME

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

RCTDiabetes / CV outcomes

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Overview

Empagliflozin reduced CV death, all-cause mortality, and HF hospitalization in T2DM with established cardiovascular disease.

Clinical takeaway

EMPA-REG OUTCOME transformed SGLT2 inhibitors into cardioprotective drugs for selected patients with T2DM and ASCVD.

Key result

Three-point MACE was reduced (HR 0.86; 95% CI 0.74-0.99).

Practice impact

SGLT2 inhibitors became preferred therapy for T2DM with ASCVD, HF, or CKD indications.

Evidence

Study design

Randomized, double-blind, placebo-controlled cardiovascular outcomes trial.

Enrollment

7,020

Follow-up

Median 3.1 years.

Geography

Multinational

Clinical question

Does empagliflozin improve cardiovascular outcomes in T2DM with established cardiovascular disease?

Population

  • Patients with type 2 diabetes and established cardiovascular disease.

Intervention

Empagliflozin 10 mg or 25 mg daily (pooled).

Comparator

Placebo, both added to standard care.

Primary outcome

Three-point MACE: CV death, nonfatal MI, or nonfatal stroke.

Empagliflozin reduced the primary composite cardiovascular outcome, driven mainly by lower cardiovascular death rather than fewer MIs or strokes.

Hazard ratio / 0.86 / CI 95.02% CI 0.74-0.99 / p=0.04

Key results

  • Primary MACE: 10.5% with empagliflozin vs 12.1% with placebo; HR 0.86; 95.02% CI 0.74-0.99; p=0.04 for superiority.
  • Cardiovascular death was reduced by 38% (3.7% vs 5.9%).
  • All-cause mortality was reduced by 32% (5.7% vs 8.3%).
  • Hospitalization for heart failure was reduced by 35% (2.7% vs 4.1%).
  • Rates of MI and stroke did not differ significantly between groups.

Harms

  • Genital mycotic infections were more common with empagliflozin.
  • SGLT2 inhibitors carry a class risk of euglycemic diabetic ketoacidosis and volume depletion.

Clinical Use

When to cite

  • When discussing cardiovascular outcome evidence for SGLT2 inhibitors in type 2 diabetes with established ASCVD.

Practice impact

  • SGLT2 inhibitors became preferred therapy for T2DM with ASCVD, HF, or CKD indications.

Applicability

  • Most applicable to patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

Limitations

  • Enrolled an established-CVD population, limiting generalization to lower-risk primary prevention.
  • Cannot separate the individual contributions of the 10 mg and 25 mg doses, which were pooled.
  • Genital infections and volume effects require monitoring.

Common misinterpretations

  • The MACE benefit was driven by lower cardiovascular death and heart-failure hospitalization, not by fewer MIs or strokes.
  • The rapid separation of event curves argues against a glucose-lowering or antiatherosclerotic mechanism.

Related evidence

LEADER - Same DiseaseCREDENCE - Same Drug ClassDAPA-HF - Same Drug Class

Citation

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720

Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.