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SGLT2 Inhibitors in Patients With HFrEF
Quick Takes
- SGLT2 inhibition with empagliflozin or dapagliflozin on top of guideline-directed medical therapy reduced all-cause and cardiovascular death, HF hospitalizations, and serious adverse renal outcomes in HFrEF.
- This combination of benefits is unique among available drugs and suggests an important role for this class of drugs in treatment of HFrEF.
Study Questions:
What is the effect of sodium-glucose co-transporter-2 (SGLT2) inhibition on fatal and nonfatal heart failure (HF) events and renal outcomes in all randomly assigned patients with HF with reduced ejection fraction (HFrEF) and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials?
Methods:
The investigators conducted a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, they assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or HF hospitalization. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of HF hospitalization, estimated glomerular filtration rate (eGFR), body mass index, and region (post hoc). The authors used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model.
Results:
Among 8,474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR, 0.87; 95% confidence interval [CI], 0.77-0.98; p = 0.018) and 14% reduction in cardiovascular death (HR, 0.86; 95% CI, 0.76-0.98; p = 0.027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first HF hospitalization (HR, 0.74; 95% CI, 0.68-0.82; p < 0.0001), and by a 25% decrease in the composite of recurrent hospitalizations for HF or cardiovascular death (HR, 0.75; 95% CI, 0.68-0.84; p < 0.0001). The risk of the composite renal endpoint was also reduced (HR, 0.62; 95% CI, 0.43-0.90; p = 0.013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI, and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race.
Conclusions:
The authors concluded that the effects of empagliflozin and dapagliflozin on HF hospitalizations were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF.
Perspective:
This meta-analysis reports that in patients with a broad spectrum of severity of HFrEF, SGLT2 inhibition with empagliflozin or dapagliflozin on top of guideline-directed medical therapy reduced all-cause and cardiovascular death, HF hospitalizations, and serious adverse renal outcomes, without heterogeneity between the two trials. Furthermore, no important imbalances for adverse events of interest were raised in either the DAPA-HF or EMPEROR-Reduced trials, and the SGLT2 inhibitors were well tolerated in both studies. This combination of benefits is unique among available drugs and suggests an important role for this class of drugs in HFrEF.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure
Keywords: Body Mass Index, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Heart Failure, Metabolic Syndrome, Renal Insufficiency, Secondary Prevention, Sodium-Glucose Transport Proteins, Stroke Volume
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