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Meta-Analysis of Trials of SGLT-2 Inhibitor Use in Heart Failure
Quick Takes
- SGLT-2 inhibitor use reduces the risk for CV death or first hospitalization for HF over a broad range of LVEFs.
- SGLT-2 inhibitor use has continued benefit in many subgroups, including LVEF ≥60% and with concurrent MRA or ARNI therapy.
Study Questions:
In a meta-analysis of five randomized controlled trials (RCTs) of sodium-glucose cotransporter-2 (SGLT-2) inhibitor use in patients with heart failure (HF), what is the effect on HF hospitalizations, mortality, and health status across various subgroups?
Methods:
This was a prespecified meta-analysis of the recent DELIVER and EMPEROR-Preserved trials examining SGLT-2 inhibitor use in patients with HF with mildly reduced (HFmrEF) and preserved ejection fraction (HfpEF). In addition, a post hoc analysis including patients with HF with reduced EF (HfrEF) from the DAPA-HF and EMPEROR-Reduced trials and those hospitalized with worsening HF with any left ventricular EF (LVEF) from the SOLOIST-WHF trial was conducted to assess SGLT-2 inhibitor use across LVEF categories and care settings. The primary endpoint for this study was a composite of time to cardiovascular (CV) death or first hospitalization for HF. Secondary endpoints included CV death, first hospitalization for HF, CV death or any worsening HF event, and death from any cause.
Changes from baseline to 8 months in health status and quality of life were determined using the Kansas City Cardiomyopathy Questionnaire (KCCQ). The treatment effects of SGLT-2 inhibitors were also assessed across 14 subgroups, which included LVEF, history of diabetes, age, sex, race, geographical region, KCCQ total symptom score, body mass index, estimated glomerular filtration rate (eGFR), history of atrial fibrillation or flutter, New York Heart Association (NYHA) functional class, hospitalization for HF within 12 months, N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration, baseline use of mineralocorticoid receptor antagonists (MRAs), and baseline use of angiotensin receptor neprilysin inhibitors (ARNIs).
Results:
Overall, the majority of the patients from the five trials had chronic ambulatory HF, with the exception of the SOLOIST-WHF study and a small subset of the DELIVER study participants. All trials included only patients with elevated concentrations of natriuretic peptides. Minimum eGFR for inclusion was 20 mL/min/1.73 m2 for the two empagliflozin trials and 30 mL/min/1.73 m2 for the dapagliflozin and sotagliflozin trials. Median follow-up time ranged from 9 months to 28.1 months.
In the combined analysis of the DELIVER and EMPEROR-Preserved trials enrolling patients with HFmrEF and HFpEF, a total of 12,251 participants were included. There was a significant reduction in the primary endpoint of time to CV death or first hospitalization for HF for patients receiving and SGLT-2 inhibitor compared to placebo (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.73-0.87). Treatment effects were consistent across all the subgroups assessed. In looking at the components of the primary endpoint, there was a significant reduction in time to first hospitalization for HF (HR, 0.74; 95% CI, 0.67-0.83) and borderline significant reduction in CV death (HR, 0.88; 95% CI, 0.77-1.00). No effect on death from any cause was found (HR, 0.97; 95% CI, 0.88-1.06). No serious adverse events were noted with SGLT-2 inhibitors when compared to placebo.
In a larger analysis of all five SGLT-2 inhibitor RCTs including patients with HFrEF and in the hospitalized setting, a total of 21,947 participants were studied. There was a significant reduction in the primary endpoint with SGLT-2 inhibitor use compared to placebo (HR, 0.77; 95% CI, 0.72-0.82). Reductions were also seen in the key secondary endpoints of CV death (HR, 0.87; 95% CI, 0.79-0.95), first hospitalization for HF (HR, 0.72; 95% CI, 0.67-0.78), and all-cause mortality (HR, 0.92; 95% CI, 0.86-0.99). SGLT-2 inhibitor use compared to placebo also was associated with more participants achieving clinically meaningful improvements and fewer having clinically meaningful deterioration in KCCQ scores. The treatment effect of SGLT-2 inhibitors on the primary endpoint was consistent in all subgroups, except for NYHA functional classification (attenuated effect with NYHA III or IV compared to NYHA class II patients [HR, 0.86; 95% CI, 0.77-0.95]). Notably, SGLT-2 inhibitor’s treatment effect was similar across KCCQ tertiles, LVEF groups (extending even to LVEF ≥60%), and background MRA and ARNI use.
Conclusions:
SGLT-2 inhibitor use compared to placebo reduces the risk for CV death or first hospitalization for HF in a pooled cohort of patients with a broad range of LVEF and in different care settings.
Perspective:
SGLT-2 inhibitors have already become a Class I indication for the care of patients with HFrEF. Weaker recommendations exist for its use in patients with HFmrEF and HFpEF given the evidence base is not as well established. This meta-analysis, which follows the results of the recently published data from the DELIVER trial, significantly adds to this evidence base. It is important to note that in the individual trials, the primary composite outcome of CV death or first HF hospitalization was primarily driven by HF hospitalization. In this pooled analysis, the signal for reduction in CV death became stronger and had borderline statistical significance. Also, the benefit from SGLT-2 inhibitors was consistent in the subgroup analysis and importantly extended to patients with LVEF on the higher end (>60%) and to patients already on background MRA or ARNI therapy. This will help inform clinical practice given prior concerns about diminishing benefits in these groups. Overall, this meta-analysis does an excellent job of highlighting the broad clinical benefit of SGLT-2 inhibitors in patients with HF across the LVEF spectrum and care settings.
Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Atrial Fibrillation, Body Mass Index, Cardiomyopathies, Diabetes Mellitus, Glomerular Filtration Rate, Heart Failure, Metabolic Syndrome, Mineralocorticoid Receptor Antagonists, Natriuretic Peptides, Neprilysin, Quality of Life, Receptors, Angiotensin, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume
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