SGLT2 inhibitors and heart failure

SGLT2 inhibitors in heart failure:

Two large clinical trials, the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death with Chronic Heart Failure (DAPA-HF) and the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced), have shown that SGLT2 inhibition in HFrEF patients with or without type 2 diabetes improves cardiovascular outcomes.

A study conducted a prespecified meta-analysis, to assess the effects and safety of SGLT2i treatment on CV death, HF hospitalization, renal outcomes and clinical effects on subgroups in HFrEF patients with or without T2DM. Published data from DAPA-HF and patient data from EMPEROR-Reduced were used (1).

DAPA-HF and EMPEROR-Reduced have shown a significant reduction in the combined primary endpoint of risk of CV death or hospitalization for HF(2,3). Neither of the trials was powered to adequately assess the treatment effects on secondary outcomes, such as CV death, all-cause mortality, or serious adverse renal events, or to characterize effects in clinically important subgroups.

Meta-analysis (1):

• 8474 Symptomatic HFrEF patients with LVEF <= 40%, with or without type 2 diabetes were included in the meta-analysis
• patients enrolled in the DAPA-HF trial had higher LVEF compared to patients in the EMPEROR-Reduced trial (31% vs. 27%, respectively), lower NT-proBNP concentration levels (1440 vs 1900 pg/mL, respectively), and higher eGFR levels ( 66 vs. 62 mL/min/1.73m², respectively). The median follow-up time in DAPA-HF was 18 months and 16 months in EMPEROR-Reduced was 16 months.
• the authors concluded (1):
  • meta-analysis of the DAPA-HF and EMPEROR-Reduced trials revealed that SGLT2 inhibition combined with standard HF care in HFrEF patients reduced all-cause mortality and CV death, HF hospitalization and serious adverse renal events, without any heterogeneity between the two trials. The risk reductions were independent of T2DM, sex, age, or ARNI treatment

Funding for meta-analysis: Boehringer Ingelheim

A further meta-analysis has been undertaken (4):

• a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF)
  • primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure.
• results
  • among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0.80 [95% CI 0.73-0.87]) with consistent reductions in both components:
    • cardiovascular death (0.88 [0.77-1.00])
    • first hospitalisation for heart failure (0.74 [0.67-0.83])
  • in the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0.77 [0.72-0.82]), cardiovascular death (0.87 [0.79-0.95]), first hospitalisation for heart failure (0.72 [0.67-0.78]), and all-cause mortality (0.92 [0.86-0.99])
    • treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials
    • treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction
• authors concluded (4):
  • SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting

Pooled analysis of DAPA-HF and DELIVER (5):

• pooled analysis (n=11,007) found dapagliflozin led to a 14% lower risk of CV death vs. placebo regardless of ejection fraction (HR 0.86; 95% CI 0.75-0.98; p=0.02), mainly due to lower rates of sudden (0.84; 95% CI, 0.70-1.01;p=0.02) & to a lesser extent to heart failure death

A review found significant CV benefits in terms of reduction in CV death or hospitalisation for heart failure (HHF) in patients without diabetes mellitus treated with SGLT2i vs placebo (OR 0.77,95% CI 0.68-0.87;p <0.0001), primarily because of decrease in HHF (6)

A review (15 trials; n=100,952) found that compared to placebo, SGLT2 inhibitors reduced risk of first hospitalisation for heart failure by 28-32% and reduced CVD death by 11-15% in those with heart failure, type 2 diabetes, atherosclerotic CVD and chronic kidney disease (7)

Reference:

1. Zannad F, Ferreiro JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials The Lancet 2020 Sep 19;396:819-829. doi: 10.1016/S0140-6736(20)31824-9.
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 DS, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. Engl J Med. 2020; 383:1413-1424.
4. Vaduganathan M, Docherty KF, Claggett BL, Jhund PS, de Boer RA, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, McMurray JJV, Solomon SD. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022 Aug 26:S0140-6736(22)01429-5.
5. Desai AS, Jhund PS, Claggett BL, et al. Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction: A Participant-Level Pooled Analysis of DAPA-HF and DELIVER. JAMA Cardiol. Published online October 03, 2022. doi:10.1001/jamacardio.2022.3736
6. Singh S et al. Cardiovascular Outcomes With Empagliflozin and Dapagliflozin in Patients Without Diabetes. American Journal of Cardiology February 29th 2024
7. Usman MS, Bhatt DL, Hameed I, Anker SD, Cheng AYY, Hernandez AF, Jones WS, Khan MS, Petrie MC, Udell JA, Friede T, Butler J. Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2024 May 17:S2213-8587(24)00102-5