11th Dec 2021, Dr Chee L Khoo
By now, most of you would be familiar with the significant cardiovascular benefits with all the SGLT2 inhibitors (SGLT2i). This is particularly stark in the reduction in hospitalisation for heart failure (Hhf). Of course, patients with heart failure is not a homogeneous group. There is heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection (HFrEF). While the original cardiovascular outcome trials (CVOTs) did not really separate out the different types of heart failures, subsequent dedicated heart failure trials have demonstrated significant benefits in patients with HFrEF (DAPA-HF and EMPA-REDUCED), a more recent HF trial have demonstrated similar benefits in patients with HFpEF (EMPA-PRESERVED). We now have a landmark trial that look at both HFpEF as well HFrEF.
When EMPA-REQ first reported its CVOT results in Stockholm back in 2015, it was a jaw dropping but pleasantly surprising result. In patients with type 2 diabetes (T2D) at high risk for cardiovascular events, empagliflozin reduce death from cardiovascular causes. In particular, hospitalization for heart failure was reduced by 35% (1). EMPA-REQ was very quickly followed by CVOTs of the other SGLT2i. Dapagliflozin reduced hospitalisation for heart failure by 27% in patients who either had CV disease or at risk of one (2). Canagliflozin and Ertugliflozin both demonstrated similar reduction in CANVAS and VERTIS-CV trials (3,4).
The only problem with the above CVOTs is that the reduction in Hhf was part of the composite major cardiovascular events (MACE) or part of a secondary outcome. We needed those signals to be confirmed in dedicated heart failure trials. Indeed, these were confirmed in later trials.
The first of these was DAPA-HF (5). In patients with ejection fraction ≤ 40% and moderate NYHA Class ≥2, dapagliflozin resulted in a significant 26% relative risk reduction in worsening heart failure (5). This was followed by EMPA-REDUCED (6). In patients with similar characteristics of heart failure, empagliflozin significantly reduced Hhf by 25% regardless of whether patients had diabetes or not.
Both DAPA-HF and EMPA-REDUCED demonstrated benefits in patients with HFpEF. What about those patients with HFrEF? Do SGLT2i work for them too? Well, we looked at EMPA-PRESERVED recently. We saw that in patients with or without diabetes but with NYHA ≥2 and ejection fraction >40%, empagliflozin also significantly reduced Hhf by 27%.
EMPA-PRESERVED seems to suggest that SGLT2i may have benefits for patients with heart failure whether it is HFpEF or HFrHF although dapagliflozin is due to report on patients with preserved ejection fraction in PRESERVED-HF. But wait, the canagliflozin people have just announced the results of CHIEF-HF at the American Heart Association’s Scientific Sessions, which took place virtually in November 2021.
448 adults with HFrEF or HFpEF were randomised to either canagliflozin 100mg or placebo. The primary outcome of the trial was change in KCCQ Total Symptom Score (KCCQ-TSS) at 12 weeks. The KCCQ measures symptoms, physical and social limitations, and quality of life in patients with heart failure. Patients’ median age was 65 years, 45% were female, 59% had HFpEF, 28% had type 2 diabetes, and 14% were black. Baseline KCCQ-TSS was 58.0 in the placebo group and 57.4 in the canagliflozin group.
Treatment with canagliflozin significantly improved KCCQ-TSS at 12 weeks, with a difference, compared with placebo, of 4.3 points (95% confidence interval 0.80–7.80, P = .016). Separation between the two groups was evident as early as 2 weeks and remained consistent across the key prespecified subgroups, including participants with HFrEF or HFpEF and in those with and without type 2 diabetes. The number needed to treat (NNT) to avoid large deterioration was 15, and the NNT to obtain large improvement was 27.
We don’t have all the data on all the SGLT2i in their effect on patients with HFpEF but it would seem that SGLT2i significantly reduce worsening of heart failure in patients with either HFrEF or HFpEF. We anxiously await PRESERVED-HF with dapagliflozin to complete the picture.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925.
- Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020 Oct 8;383(15):1425-1435. doi: 10.1056/NEJMoa2004967.
- Martinez FA, Serenelli M, Nicolau JC, et al. Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to Age: Insights From DAPA-HF. Circulation. 2020 Jan 14;141(2):100-111. doi: 10.1161/CIRCULATIONAHA.119.044133.
- Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28. PMID: 32865377.