What were the characteristics, results, and criticisms of the EMPA-REG OUTCOME (Empagliflozin) trial in patients with type 2 diabetes mellitus (T2DM)?

EMPA-REG OUTCOME Trial: Characteristics, Results, and Criticisms

The EMPA-REG OUTCOME trial demonstrated that empagliflozin significantly reduced cardiovascular mortality by 38% in patients with type 2 diabetes and established cardiovascular disease, making it a landmark study that changed diabetes management guidelines. 1, 2

Trial Characteristics

• EMPA-REG OUTCOME was a randomized, double-blind trial that assessed the effect of empagliflozin versus placebo on cardiovascular outcomes in 7,020 patients with type 2 diabetes and existing cardiovascular disease 1
• Study participants had a mean age of 63 years, 57% had diabetes for more than 10 years, and 99% had established cardiovascular disease 1, 3
• At baseline, patients were treated with one (30%) or more (70%) antidiabetic medications including metformin (74%), insulin (48%), and sulfonylurea (43%) 3
• All patients had established atherosclerotic cardiovascular disease at baseline including coronary artery disease (76%), stroke (23%), or peripheral artery disease (21%) 3
• Patients were randomized to receive empagliflozin 10 mg, 25 mg, or placebo once daily in addition to standard of care and followed for a median of 3.1 years 1, 3
• The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE) 3

Key Results

• Empagliflozin reduced the composite primary outcome of MI, stroke, and cardiovascular death by 14% (HR 0.86 [95% CI 0.74–0.99]; P = 0.04 for superiority) 1, 3
• The most striking finding was a 38% reduction in cardiovascular death (absolute rate 3.7% vs. 5.9%, HR 0.62 [95% CI 0.49–0.77]; P < 0.001) 1, 3
• Empagliflozin reduced hospitalization for heart failure by 35% (HR 0.65 [95% CI 0.50–0.85]) 1, 4
• The medication also showed significant renal benefits, reducing incident or worsening nephropathy by 39% 5
• The benefits of empagliflozin were consistent across the spectrum of cardiovascular risk categories, including patients with and without prior myocardial infarction or stroke 6
• Total (first plus recurrent) cardiovascular events were reduced by 22% (RR 0.78 [95% CI 0.67 to 0.91]), indicating benefits beyond just first events 7

Strengths of the Trial

• EMPA-REG OUTCOME was the first cardiovascular outcomes trial of an SGLT2 inhibitor to demonstrate cardiovascular benefits in patients with type 2 diabetes 1
• The trial had high completion rates with vital status obtained for 99.2% of subjects 3
• Results were consistent across both empagliflozin doses (10 mg and 25 mg) 3
• Benefits were observed early in the trial and maintained throughout the follow-up period 1, 7
• The trial demonstrated benefits across multiple important clinical outcomes including cardiovascular death, heart failure hospitalization, and renal outcomes 8, 5

Criticisms and Limitations

• The trial enrolled only patients with established cardiovascular disease, limiting generalizability to primary prevention populations 1
• The mechanism behind the rapid cardiovascular benefits remains incompletely understood, as the modest improvements in glycemic control, blood pressure, and weight cannot fully explain the magnitude of benefit 2, 9
• There was an unexpected increase in stroke events (HR 1.24 [95% CI 0.92-1.67]), although this did not reach statistical significance 3
• The trial was not powered to assess differences in individual components of the primary outcome, particularly non-fatal MI and stroke 3
• The study population was predominantly white (72.4%) and male (71.5%), raising questions about generalizability to other demographic groups 1
• The rapid separation of survival curves (within months) suggests mechanisms beyond atherosclerotic risk modification 7, 4

Impact on Clinical Practice

• EMPA-REG OUTCOME led to updates in diabetes management guidelines, with the American Diabetes Association now recommending SGLT2 inhibitors for patients with type 2 diabetes and established cardiovascular disease 1
• The trial established empagliflozin as having a class I recommendation for reducing cardiovascular mortality in patients with type 2 diabetes and established cardiovascular disease 2
• The results shifted the paradigm of diabetes management from focusing solely on glycemic control to considering cardiovascular risk reduction as a primary goal 2, 9
• The findings led to FDA approval of empagliflozin for reducing cardiovascular death in adults with type 2 diabetes and established cardiovascular disease 3
• The trial helped establish the cardiorenal protective effects of SGLT2 inhibitors, leading to further studies in heart failure and chronic kidney disease populations regardless of diabetes status 8, 5