SGLT2 Inhibitors Benefit CV Outcomes Across Heart Failure, T2D, CKD Populations

Javed Butler, MD

Credit: Baim Institute for Clinical Research

Sodium-glucose cotransporter-2 (SLGT2) inhibitors were associated with a reduced risk of heart failure events in cohorts of patients with heart failure, type 2 diabetes (T2D), and chronic kidney disease (CKD), with a consistent benefit on cardiovascular (CV) death, according to new research.¹

The analysis of more than 90,000 patients showed SGLT2 inhibitors reduced the risk of first heart failure hospitalization and/or CV death by nearly 25% in the populations with heart failure, T2D, and CKD, as well as any combinations of these 3 diseases.

“These findings support a ‘call to action’ for the widespread adoption of the use of SGLT2 inhibitors across all 3 patient populations,” wrote the investigative team, led by Javed Butler, MD, from Baylor Scott and White Research Institute.

Clinical trial data, including from the DAPA-HF² and EMPEROR-Reduced³ trials, have shown improved heart failure outcomes in patients treated with SGLT2 inhibitors.As of now, the therapy class has been studied in 13 large-scale clinical outcome trials, representing a population of more than 90,000 patients. However, although T2D, CKD, and heart failure often coincide, the effect of SGLT2 inhibitors in patients with multimorbidity is unclear, as trials were underpowered to assess subpopulations.

Some suggest the benefit of SGLT2 inhibitors may be attenuated in the presence of multiple comorbidities, and the effects of the therapy class on CV death are unclear due to inconsistent findings across trials. The current systematic review and meta-analysis aimed to evaluate the effect of SGLT2 inhibitors on outcomes in subgroups of patients with varying combinations of CV, kidney, and metabolic comorbidity.

The investigative team searched the Medline, Scopus, and Cochrane Central databases from inception until the last week of November 2022. Trials were considered eligible for inclusion if they were either primary or secondary analyses of randomized controlled trials (RCTs), compared SGLT2 inhibitors with placebo, included patients with heart failure, T2D, CKD, or any combination, and reported the composite of first heart failure hospitalization or CV death, first heart failure hospitalization, or CV mortality. The analysis pooled data by means of a random-effects model to determine hazard ratios (HRs) and 95% confidence intervals (CIs).

From 5,366 initial results, investigators found 13 trials met the eligibility criteria. The 13 trials included 90,413 patients, including 48,485 who received SGLT2 inhibitors and 41,928 receiving placebo. The mean age of participants was 65 years, and 33% were women.

The analysis showed SGLT2 inhibitors, compared with placebo, reduced the risk of first heart failure hospitalization and/or CV death by 24% in heart failure (HR, 0.76; 95% CI, 0.72 - 0.81), 23% in T2D (HR, 0.77; 95% CI, 0.73 - 0.81), and 23% in CKD (HR, 0.77%; 95% CI, 0.72 - 0.82).

Investigators noted the benefit was consistent in heart failure with reduced or preserved ejection fraction, heart failure with or without T2D, and heart failure with or without CKD. Consistent benefits were also observed in T2D with or without CKD, T2D without heart failure, CKD without heart failure, and in those with all 3 comorbidities.

Analyses also revealed SGLT inhibitors significantly reduced CV death by 16% in heart failure, 15% in T2D, and 12% in CKD. Moreover, SGLT2 inhibitors were linked to a reduction in first heart failure hospitalization by 29% in heart failure, 29% in T2D, and 32% in CKD.

Investigators noted those with CKD without T2D did not experience a reduction in the first heart failure hospitalization and/or CV death with SGLT2 inhibition. However, the team indicated the data for these patients were reported by only 2 studies and may reflect a lack of power, rather than a lack of effect.

“The findings of the present analyses support the use of SGLT2 inhibitors to avert the risk of heart failure hospitalization and CV death in all patients with heart failure, regardless of ejection fraction, T2D status, and CKD,” they wrote.

References

1. Usman M, Siddiqi T, Anker S, et al. Effect of SGLT2 Inhibitors on Cardiovascular Outcomes Across Various Patient Populations. J Am Coll Cardiol. 2023 Jun, 81 (25) 2377–2387. https://doi.org/10.1016/j.jacc.2023.04.034
2. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381: 1995–2008.
3. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424.