Sodium–glucose cotransporter-2 (SGLT2) inhibitors are strongly recommended for heart failure (HF) patients with reduced left ventricular ejection fraction. Recently, the DELIVER and EMPEROR-Preserved trials showed that SGLT2 inhibitors are associated with reductions in the composite endpoint of cardiovascular death or heart failure events in patients with heart failure who have mildly reduced or preserved ejection fraction (>40%).
However, neither trial was designed to examine individual endpoints or determine what subpopulations benefit from SGLT2 inhibitors. Now, Scott D. Solomon, MD, director of the Clinical Trials Outcomes Center at Brigham and Women’s Hospital, and colleagues have concluded that SGLT2 inhibitors should be considered adjunctive therapy for all patients with heart failure, regardless of ejection fraction or care setting. Their recommendation is based on evidence from two meta-analyses published in The Lancet.
The researchers first conducted a prespecified meta-analysis of DELIVER (n=6,263, dapagliflozin) and EMPEROR-Preserved (n=5,988, empagliflozin). They then pooled the data from those trials with data from:
- Two trials that involved patients who had heart failure with reduced ejection fraction (DAPA-HF, n=4,744, dapagliflozin and EMPEROR-Reduced, n=3,730, empagliflozin)
- SOLOIST-WHF (n=1,222, sotagliflozin), which involved patients with diabetes who were hospitalized for worsening heart failure
Therefore, 21,947 participants were included across the five trials.
The primary endpoint of both meta-analyses was the composite of cardiovascular death or first hospitalization for heart failure. Treatment effects on health status and quality of life were assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), which patients completed at baseline and eight months after randomization.
In the meta-analysis of EMPEROR-Preserved and DELIVER, the estimates of the treatment effect of SGLT2 inhibitors compared with that of placebo were:
- Composite primary endpoint—HR, 0.80, with no heterogeneity by trial
- Cardiovascular death—HR, 0.88
- First hospitalization for heart failure—HR, 0.75
- All-cause mortality—HR, 0.97 (not statistically significant)
Treatment effects for the composite endpoint were consistent across 14 subgroups of interest: ejection fraction, history of diabetes, age, sex, race, geographic region, KCCQ total symptom score, body mass index, estimated glomerular filtration rate, history of atrial fibrillation or flutter, New York Heart Association (NYHA) functional class, hospitalization for heart failure within 12 months, N-terminal prohormone of B-type natriuretic peptide concentration, baseline use of mineralocorticoid receptor antagonists, and baseline use of angiotensin receptor neprilysin inhibitors.
Rates of selected adverse events (amputations, diabetic ketoacidosis, hypoglycemia, and renal events) could not be directly compared across trials. Still, rates were infrequent and well-balanced between groups in both trials.
For all five trials, the weighted mean follow-up was 23 months. The pooled estimates were:
- Composite primary endpoint—HR, 0.77; number needed to treat (NNT), 25
- Cardiovascular death—HR, 0.87; NNT, 88
- First hospitalization for heart failure—HR, 0.72; NNT, 28
- All-cause mortality—HR, 0.92; NNT, 92
There was no evidence of between-trial heterogeneity of treatment effect for any of these outcomes.
The effect of SGLT2 inhibitors on the composite endpoint was consistent across subgroups except for the attenuation of effect in patients in NYHA class III or IV compared with those in class II. Notably, SGLT2 inhibitors were beneficial across ejection fraction groups, including patients with ejection fraction ≥60%.
More patients in the SGLT2 inhibitor groups than in the placebo groups had clinically meaningful improvements in each of the three KCCQ summary scores within eight months, with no between-trial heterogeneity.
Guidance for Clinicians
Practice guidelines of the AHA/ACC/HFSA and the European Society of Cardiology currently offer no class I recommendation about any individual therapy other than diuretics for heart failure with mildly reduced or preserved ejection fraction.
The data from these new meta-analyses can inform those guidelines and individual clinician decision-making. They underscore that SGLT2 inhibitors significantly reduce the risk of mortality and worsening heart failure and improve symptoms and overall health status in both outpatients and hospitalized patients with heart failure when added to standard therapy.