Major MACE Studies of Empagliflozin and Dapagliflozin
Empagliflozin: EMPA-REG OUTCOME Trial
EMPA-REG OUTCOME demonstrated that empagliflozin significantly reduces cardiovascular death by 38% and major adverse cardiovascular events by 14% in patients with type 2 diabetes and established cardiovascular disease. 1
Study Design and Population
- Randomized, double-blind trial enrolling 7,020 patients with type 2 diabetes and existing cardiovascular disease 1
- Mean age 63 years, 57% had diabetes for more than 10 years, and 99% had established cardiovascular disease at baseline 1
- Median follow-up of 3.1 years 1
- 77% on statin therapy, 74% on metformin at baseline 1
Primary Cardiovascular Outcomes
- 3-point MACE (cardiovascular death, MI, or stroke): HR 0.86 (95% CI 0.74-0.99) - representing a 14% relative risk reduction 1, 2
- Cardiovascular death: HR 0.62 (95% CI 0.49-0.77) - representing a 38% relative risk reduction, the most striking finding of the trial 1, 2
- Hospitalization for heart failure: HR 0.65 (95% CI 0.50-0.85) - representing a 35% relative risk reduction 1, 2
- All-cause mortality: HR 0.68 (95% CI 0.57-0.82) 1
Key Secondary Outcomes
- Myocardial infarction: HR 0.87 (95% CI 0.70-1.09) - not statistically significant 1
- Stroke: HR 1.18 (95% CI 0.89-1.56) - no benefit observed 1
- Worsening nephropathy: HR 0.61 (95% CI 0.53-0.70) 1
Risk Spectrum Analysis
The cardiovascular benefits of empagliflozin were consistent across the entire spectrum of baseline cardiovascular risk, from low to highest risk patients, with no significant interaction by prior myocardial infarction or stroke status 3
Dapagliflozin: DECLARE-TIMI 58 Trial
DECLARE-TIMI 58 showed that dapagliflozin significantly reduces hospitalization for heart failure by 27% and the composite of cardiovascular death or heart failure hospitalization by 17%, though it did not significantly reduce MACE in the overall population. 1, 4
Study Design and Population
- Randomized, double-blind trial enrolling 17,160 patients with type 2 diabetes and either established ASCVD (40.6%) or multiple risk factors (59.4%) 1, 4
- Mean age 64 years, mean diabetes duration 11.9 years 1, 4
- Median follow-up of 4.2 years (longer than EMPA-REG OUTCOME) 1, 4
- 10% had history of heart failure at baseline 4
- Mean eGFR 85.2 mL/min/1.73 m² 4
Primary Cardiovascular Outcomes
- 3-point MACE: HR 0.93 (95% CI 0.84-1.03) - met non-inferiority but not superiority versus placebo 1, 4
- Cardiovascular death or hospitalization for heart failure: HR 0.83 (95% CI 0.73-0.95) - statistically significant, representing a 17% relative risk reduction 4
- Hospitalization for heart failure: HR 0.73 (95% CI 0.61-0.88) - representing a 27% relative risk reduction, the primary driver of the composite endpoint 1, 4, 2
Key Secondary Outcomes
- Cardiovascular death: HR 0.98 (95% CI 0.82-1.17) - no significant reduction 1
- Myocardial infarction: HR 0.89 (95% CI 0.77-1.01) - not statistically significant 1
- Stroke: HR 1.01 (95% CI 0.84-1.21) - no benefit 1
- All-cause mortality: HR 0.93 (95% CI 0.82-1.04) - not statistically significant 1
Subgroup Analysis: Prior Myocardial Infarction
In the prespecified subgroup of 3,584 patients with previous MI, dapagliflozin demonstrated more robust MACE reduction: HR 0.84 (95% CI 0.72-0.99), representing a 16% relative risk reduction and 2.6% absolute risk reduction 5. The benefit appeared greater within 2 years after the last acute event 5.
VERTIS CV Trial: Ertugliflozin
VERTIS CV demonstrated non-inferiority but not superiority for MACE with ertugliflozin, though it did reduce hospitalization for heart failure by 30%. 1
Study Design and Population
- Randomized, double-blind trial enrolling 8,246 patients with type 2 diabetes and established ASCVD 1
- Mean age 64.4 years, mean diabetes duration 13 years 1
- Median follow-up of 3.0 years 1
Primary Cardiovascular Outcomes
- 3-point MACE: HR 0.97 (95% CI 0.85-1.11) - met non-inferiority but not superiority 1
- Hospitalization for heart failure: HR 0.70 (95% CI 0.54-0.90) - representing a 30% relative risk reduction 1
- Cardiovascular death: not significantly reduced 1
Direct Comparison and Clinical Implications
Cardiovascular Death Reduction
The most critical distinction is that empagliflozin demonstrated a 38% reduction in cardiovascular death, while dapagliflozin showed no significant effect on cardiovascular death in the overall DECLARE-TIMI 58 population. 1, 2 This represents the single most important difference in mortality outcomes between these agents.
MACE Outcomes
Both empagliflozin and dapagliflozin achieved similar 14% relative risk reductions in 3-point MACE, though empagliflozin reached statistical significance while dapagliflozin met non-inferiority but not superiority in the overall population 1, 2. However, in patients with prior MI, dapagliflozin demonstrated significant MACE reduction 5.
Heart Failure Hospitalization
Both agents consistently reduce heart failure hospitalization across all trials: empagliflozin by 35%, dapagliflozin by 27%, and ertugliflozin by 30% 1, 4, 2. This represents a robust class effect.
Population Differences
A critical caveat is that DECLARE-TIMI 58 enrolled a lower-risk population with only 40.6% having established ASCVD compared to 99% in EMPA-REG OUTCOME 1, 4. This may partially explain the differences in cardiovascular death reduction, though empagliflozin's benefits were consistent across the entire risk spectrum 3.
Cost-Effectiveness Analysis
A 2021 cost-effectiveness analysis found that empagliflozin dominated canagliflozin (more QALYs at lower cost) and was highly cost-effective compared to dapagliflozin with an incremental cost-effectiveness ratio of $3,054/QALY 2. The superior cost-effectiveness was driven primarily by empagliflozin's direct reduction in cardiovascular death 2.
Atrial Fibrillation
A 2024 network meta-analysis found that dapagliflozin demonstrated superior efficacy in preventing atrial fibrillation compared to empagliflozin, though both drugs showed comparable efficacy for MACE, cardiovascular mortality, heart failure hospitalization, and myocardial infarction 6.
Guideline Recommendations
Current ADA guidelines (2022-2025) recommend SGLT2 inhibitors with demonstrated cardiovascular benefit (empagliflozin, canagliflozin, and dapagliflozin) for patients with type 2 diabetes and established ASCVD or multiple risk factors to reduce major adverse cardiovascular events and heart failure hospitalization. 1 The guidelines note that ertugliflozin showed lesser cardiovascular benefits 1.