The SGLT-2 inhibitors were initially developed for diabetes but eventually noted to have significant effects on outcomes in patients with heart failure in addition to diabetes. The DAPA-HF trial established the usefulness of dapagliflozin in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. After that the EMPEROR-Reduced trial was announced to evaluate the efficacy of empagliflozin in similar population.
The EMPEROR Reduced trial evaluated the safety and efficacy of a empagliflozin in patients with HFrEF (<40%) with or without diabetes.
Similar to the results of the DAPA HF trial, empagliflozin group had a lower risk of CV death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.
Randomized, double-blind, parallel-group, placebo-controlled, event-driven trial
In total, 3730 patients were included and were randomized to empagliflozin (N=1863) or placebo (N=1867)
- Adults (≥18 years of age) who had chronic heart failure (functional class II, III, or IV) with a LVEF of 40% or less.
- All the patients were receiving appropriate treatments for heart failure, including diuretics, RAAS and neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and, if indicated, cardiac devices.
- HF hospitalization within 12 months
- N-terminal pro–B-type natriuretic peptide (NT-proBNP ≥600 pg/ml if EF ≤30%; ≥1000 pg/ml if EF 31-35%; ≥2500 pg/ml if EF >35%.
- Composite outcome of death from cardiovascular causes or hospitalization for heart failure %
19.4% patients in the empagliflozin had primary endpoint event compared to 24.7% in the placebo group.
HR 0.75; 95% CI, 0.65 to 0.86; P<0.001, NNT = 19
The primary endpoint was mainly driven by decrease in heart failure hospitalizations. The cardiovascular mortality did not reach statistical significance in empagliflozin favor.
Empaglizflozin vs placebo:
- Cardiovascular mortality: 10% vs. 10.8% (HR 0.92, 95% CI 0.75-1.12)
- Heart failure hospitalization: 13.2% vs. 18.3% (HR 0.69, 95% CI 0.59-0.81)
Key Secondary Outcomes:
Results are listed as empagliflozin vs placebo.
1. Hospitalizations for heart failure (no. of events)
388 (empagliflozin) vs 553 (placebo) hospitalizations.
HR 0.70; 95% CI, 0.58 to 0.85; P<0.001
2. Composite renal outcome (chronic hemodialysis, renal transplantation, profound sustained reduction in eGFR)
1.6% vs. 3.1
HR 0.50, 95% CI 0.32-0.77, P<0.01
3. All-cause mortality:
An important finding of the trial was no difference in overall all-cause mortality among the two groups.
13.4% vs. 14.2%
HR 0.92, 95% CI 0.77-1.10, P value NS
4. Rate of the decline in the estimated GFR
–0.55 ml/min/per year (empagliflozin) vs. –2.28 (placebo)
Difference 1.73 (95% CI, 1.10 to 2.37; P<0.001)
5. Composite renal outcome (chronic hemodialysis, renal transplantation, profound sustained reduction in eGFR)
1.6% vs. 3.1% (HR 0.50, 95% CI 0.32-0.77, p < 0.01)
Take Home Point:
Empagliflozin was initially tested in EMPA-REG OUTCOME trial which highlighted its usefulness in reducing CV mortality. The DAPA-HF and EMPEROR-Reduced trials have now established the efficacy of SGLT2 inhibitors in HF without DM. FDA has already approved dapagliflozin for HF treatment and empagliflozin will likely going to follow suit. The EMPEROR-Preserved trial is the next trial to look forward to which is evaluating empagliflozin in patients with HF and preserved EF.
Important Lessons from the EMPEROR-Reduced Trial
- The SGLT-2 inhibitors primarily empagliflozin and dapagliflozin are the next generation of heart failure meds that have not only shown a profound effect on cardiovascular outcomes but are also safe without any side effects. This is contrary to other agents like angiotensin/neprilysin inhibitors which can cause hypotension, renal damage, and even angioedema at times.
- The renal outcomes have shown that empagliflozin reduces adverse renal effects by over 50%. Additionally, they are equally effective in patients with baseline kidney dysfunction thus enabling them to be used in patients with concomitant HF and CKD.
- Diabetes is no longer a limiting factor. With EMPEROR-Reduced trial results, we can now use empagliflozin in patients with heart failure even if they don’t have diabetes.
- Many patients in this trial were not on optimized goal-directed medical therapy for heart failure and this did not affect the outcomes. Therefore, it would be safe to say that these agents can be utilized even in patients who are unable to tolerate other drugs. It’s ideal to have patients on maximum GDMT but it’s not necessary before starting SGLT2 inhibitors.
Results from the meta-analysis of the EMPEROR-Reduced and DAPA-HF trials
A recent meta-analysis published in the LANCET journal highlighted the importance of these drugs in reducing CV death in heart failure.
- Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (HR 0·87, 95% CI 0·77–0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76–0·98; p=0·027).
- There was 26% relative reduction in the combined risk of cardiovascular death or first hospitalization for heart failure (0·74, 0·68–0·82; p<0·0001), and a 25% decrease in the composite of recurrent hospitalizations for heart failure or cardiovascular death (0·75, 0·68–0·84; p<0·0001).
- The risk of the composite renal endpoint also showed a significant reduction (0·62, 0·43–0·90; p=0·013).