Cardiovascular Outcome Reduction with Empagliflozin in Type 2 Diabetes: EMPA-REG OUTCOME Results
Empagliflozin reduces the composite outcome of myocardial infarction, stroke, and cardiovascular death by 14% (HR 0.86,95% CI 0.74-0.99) and cardiovascular death alone by 38% (HR 0.62,95% CI 0.49-0.77) in patients with type 2 diabetes and established cardiovascular disease. 1
Primary Cardiovascular Outcomes
The EMPA-REG OUTCOME trial enrolled 7,020 patients with type 2 diabetes and established atherosclerotic cardiovascular disease, with a mean age of 63 years and 99% having documented cardiovascular disease at baseline 2. Over a median follow-up of 3.1 years, empagliflozin demonstrated the following effects:
Major Adverse Cardiovascular Events (MACE)
- 3-point MACE composite (cardiovascular death, non-fatal MI, non-fatal stroke): 14% relative risk reduction (absolute rate 10.5% vs 12.1% placebo; HR 0.86,95% CI 0.74-0.99; p=0.04 for superiority) 1
- Cardiovascular death: 38% relative risk reduction (absolute rate 3.7% vs 5.9% placebo; HR 0.62,95% CI 0.49-0.77; p<0.001) 1
- Non-fatal myocardial infarction: No significant reduction (HR 0.87,95% CI 0.70-1.09) 1
- Non-fatal stroke: No significant reduction (HR 1.24,95% CI 0.92-1.67) 1
Heart Failure and Hospitalization Outcomes
- Hospitalization for heart failure: 35-39% relative risk reduction (HR 0.61,95% CI 0.42-0.87) 3, 4
- All-cause hospitalization: 19% relative risk reduction (HR 0.81,95% CI 0.72-0.92) 4
- All-cause mortality: 24-32% relative risk reduction (HR 0.68-0.76) 1, 4
Key Clinical Insights
The cardiovascular mortality benefit appears rapidly (within months) and is likely mediated through mechanisms beyond glucose lowering, particularly prevention of heart failure rather than prevention of atherothrombotic events. 5 This is evidenced by the lack of effect on MI or stroke, combined with the substantial reduction in heart failure hospitalizations and the rapid onset of mortality benefit 5.
Total Event Burden
When analyzing total (first plus recurrent) events rather than just first events, empagliflozin demonstrated even greater benefit 6:
- Total MACE events: 22% relative risk reduction (RR 0.78,95% CI 0.67-0.91; p=0.0020), preventing 12.88 events per 1000 patient-years 6
- Total heart failure hospitalizations: 42% relative risk reduction (RR 0.58,95% CI 0.42-0.81; p=0.0012), preventing 9.67 events per 1000 patient-years 6
Renal Protection Benefits
Empagliflozin reduces incident or worsening nephropathy by 39% (HR 0.61,95% CI 0.53-0.70) and slows progression of kidney disease. 7 Specific renal outcomes include:
- Doubling of serum creatinine: 44% relative risk reduction (1.5% vs 2.6% placebo) 7
- Initiation of renal replacement therapy: 55% relative risk reduction (0.3% vs 0.6% placebo) 7
- Composite worsening nephropathy: 39-47% relative risk reduction across KDIGO risk categories 1, 3
Consistency Across Subgroups
The cardiovascular and renal benefits of empagliflozin are consistent across all baseline kidney function categories, including patients with eGFR 30-60 mL/min/1.73 m². 3, 4 In patients with prevalent chronic kidney disease at baseline (eGFR <60 mL/min/1.73 m² and/or urine albumin-creatinine ratio >300 mg/g), empagliflozin maintained similar risk reductions for cardiovascular death (HR 0.71,95% CI 0.52-0.98) and heart failure hospitalization (HR 0.61,95% CI 0.42-0.87) 4.
FDA Indication and Clinical Application
The FDA has approved empagliflozin specifically to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease. 1, 2 This represents a unique indication among glucose-lowering medications, reflecting the robust mortality benefit demonstrated in EMPA-REG OUTCOME 1, 8.
Patient Selection Criteria from EMPA-REG OUTCOME
The trial enrolled patients with 2:
- Type 2 diabetes with HbA1c ≥7% (mean 8.1%)
- Established atherosclerotic cardiovascular disease (100% of patients)
- eGFR ≥30 mL/min/1.73 m² at screening
- Mean age 63 years, 57% with diabetes duration >10 years
- 76% with documented coronary artery disease, 23% with prior stroke, 21% with peripheral artery disease
Safety Considerations
The adverse event profile in EMPA-REG OUTCOME was generally favorable, with the notable exception of increased genital infections 3. The safety profile remained consistent even in patients with impaired kidney function (eGFR <60 mL/min/1.73 m²) 7, 4. Clinicians should monitor for volume depletion when combining empagliflozin with other diuretics or antihypertensive agents, given its diuretic mechanism 5.
Mechanism of Cardiovascular Benefit
The cardiovascular benefit appears independent of glucose-lowering effects and likely relates to the diuretic action of empagliflozin, with particular efficacy in preventing heart failure rather than atherothrombotic events. 9, 5 The rapid onset of mortality benefit (within months), combined with no effect on MI or stroke but substantial reduction in heart failure, supports a hemodynamic mechanism rather than prevention of diabetic vascular complications 5.