Endocrinology · 2015
EMPA-REG OUTCOME
Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients
For decades, glucose-lowering trials in type 2 diabetes had been designed to show one thing: that a new drug did not kill people. The 2008 FDA guidance requiring cardiovascular safety data for all new diabetes agents grew directly from the rosiglitazone episode, in which a widely used drug appeared to increase myocardial infarction risk. Drug makers responded by running large cardiovascular outcome trials, most of which showed neutral results. The expectation, shared by investigators and regulators alike, was that empagliflozin would do the same.
EMPA-REG OUTCOME enrolled 7,020 adults with type 2 diabetes and established cardiovascular disease across 42 countries, randomizing them to empagliflozin (10 mg or 25 mg) or placebo added to standard care. The primary composite endpoint was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. When Bernard Zinman of Mount Sinai Hospital in Toronto presented the results at the European Association for the Study of Diabetes in Stockholm in September 2015, the audience was not prepared for a benefit. Empagliflozin cut the primary endpoint by 14%, cardiovascular mortality by 38%, and all-cause mortality by 32%; hospitalization for heart failure fell by 35%.
The magnitude of the mortality reduction surprised the field, partly because the HbA1c difference between groups was modest, roughly 0.5 percentage points at one year. That mismatch suggested the benefit was not primarily glycemic. Debate over mechanism centered on the drug's osmotic diuretic effect, reduction in arterial stiffness, ketone body metabolism, and direct cardiac and renal effects. The renal outcome data, showing a 39% slower progression of diabetic kidney disease, reinforced the view that SGLT2 inhibition was acting on hemodynamic and metabolic pathways beyond glucose disposal.
Silvio Inzucchi, one of the co-investigators who helped interpret the cardiorenal findings, noted that the benefit appeared within weeks of randomization, too fast to reflect atherosclerosis regression and more consistent with a volume or hemodynamic mechanism. Peer response ranged from enthusiasm to skepticism about whether the results could be generalized to lower-risk patients not yet carrying cardiovascular disease.
The clinical consequences arrived quickly. Within two years, SGLT2 inhibitors entered American Diabetes Association and European cardiology and nephrology guidelines as preferred agents for patients with heart failure, chronic kidney disease, or established cardiovascular disease, independent of glucose control. Subsequent trials, CREDENCE for canagliflozin and DAPA-HF and DAPA-CKD for dapagliflozin, confirmed organ protection across the class, extending indications to patients without diabetes entirely. The SGLT2 inhibitor class is now listed in heart failure guidelines at the same level of evidence as beta-blockers and renin-angiotensin system agents.
Key People
- Bernard Zinman — Principal investigator, led the EMPA-REG OUTCOME trial
- Silvio Inzucchi — Co-investigator, helped interpret cardiorenal outcomes
- Christoph Wanner — Led the renal outcomes substudy analysis
- Hans-Juergen Woerle — Boehringer Ingelheim sponsor representative; oversaw trial design
N Engl J Med. 2015;373(22):2117-2128.
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