The results of cardiovascular endpoint studies showing that dapagliflozin and empagliflozin significantly improve outcomes in HFpEF and HFmrEF have prompted the European Society of Cardiology (ESC) to adapt its recommendations. The use of SGLT-2 inhibitors is therefore currently recommended for patients with heart failure across the entire spectrum of left ventricular ejection fraction (LVEF).
The 2023 update of the 2021 ESC guideline on the diagnosis and treatment of heart failure is based on the latest scientific findings from randomized controlled clinical trials and meta-analyses [1]. “SGLT-2 inhibitors are now recommended by the international guidelines of the European Society of Cardiology for heart failure regardless of LVEF – that means we can use them and we should use them for HFrEF, HFmrEF and HFpEF,” summarized Prof. Christine Meyer-Zürn, MD, University Hospital Basel [2]. This is a significant extension of the indication. In contrast to HFrEF, the treatment options for HFmrEF and HFpEF were very limited until recently; apart from diuretics, there was no prognosis-improving drug therapy.
A meta-analysis that included data from all large studies on SGLT-i in heart failure – including DAPA-HF, DELIVER, EMPEROR-Reduced and EMPEROR-Preserved – was published in the Lancet in 2022 (Tab. 1) [3]. Across the 21,947 study participants, SGLT-2-i reduced the risk of cardiovascular death or heart failure-related hospitalization in patients with HFrEF, HFmrEF or HFpEF, as well as the risk of a first hospitalization for heart failure and all-cause mortality. In summary, these data show that SGLT-2-i reduces morbidity and mortality in heart failure across the spectrum of left ventricular ejection fraction (LVEF), with both non-diabetic and diabetic patients benefiting from these effects [3].
Proven benefit for HFmrEF and HFpEF patients
DELIVER and EMPEROR-PRESERVED were the first studies to show that the use of empagliflozin and dapagliflozin (each 10 mg once daily) can also improve prognosis in heart failure patients** with moderate or preserved ejection fraction (HFmrEF or HFpEF). In the DELIVER study (n=6263), dapagliflozin significantly reduced the primary endpoint of cardiovascular death or worsening heart failure (HF-related hospitalization or HF emergency consultation) in HF patients with LVEF >40% (HR 0.82; 95% CI 0.73-0.92; p<0.001), although heart failure patients without type 2 diabetes also benefited and the efficacy of dapagliflozin was consistent even in those patients who remained symptomatic despite improved LVEF [4]. And in the EMPEROR-Preserved study (n=5988), empagliflozin also significantly reduced the primary endpoint (HR 0.79; 95% CI 0.69-0.90; p<0.001). This effect occurred in patients with and without type 2 diabetes and was mainly due to a reduction in HF hospitalizations in the empagliflozin arm [5–7].
** NYHA Class II-I
HFrEF is to be used as part of the “Fantastic Four”
In HFrEF, SGLT-2-i is one of the four pillars of HF drug therapy: ARNI, SGLT-2 inhibitor, beta blocker and mineralocorticoid receptor antagonist (MRA). The prognosis-improving effects of SGLT-2-i in HFrEF are essentially based on the DAPA-HF and EMPEROR-Reduced studies, in which it was shown in the same group of heart failure patients that SGLT-2-i significantly reduces the combined endpoint of death and heart failure-related hospitalizations, according to Prof. Meyer-Zürn [2,8,9]. The patient population comprised heart failure patients with HFrEF$, NYHA& II-IV and an LVEF ≤40% [8]. In the DAPA-HF study, a significant risk reduction was achieved in the dapagliflozin arm for a primary endpoint of heart failure worsening (hospitalization or intravenous therapy) or cardiovascular mortality compared to placebo (HR: 0.74; 95% CI: 0.65-0.85; p<0.001). And the EMPEROR Reduced study also demonstrated a significant risk reduction for empagliflozin with regard to the primary endpoint of cardiovascular mortality and heart failure-related hospitalization (HR: 0.75; 95% CI: 0.65-0.86; p<0.001) [9].
$ HFrEF = Heart failure with reduced ejection fraction
& NYHA = New York Heart Association
The order of initiation and the dosage of the four-drug combination of ARNI, SGLT-2 inhibitor, beta-blocker and MRA should be based on the spectrum of side effects, the respective comorbidities and individual tolerability and should be carried out according to the following principles: Initiation one after the other if possible, not >2 substances at the same time, titration at 2- to 4-week intervals if possible up to the target dose or the highest individually tolerated dose, close monitoring. The guideline does not make a specific recommendation as to the order in which the combination of four should be used, but advises that it should be initiated and dosed quickly, if possible during an inpatient stay, according to the speaker [1,2].
Congress: SGAIM Fall Congress
Literature:
- McDonagh TA, et al.; ESC Scientific Document Group. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023; 44(37): 3627–3639.
- «Focus Heart: SGLT-2-Inhibitors», Prof. Dr. Christine Meyer-Zürn, SGAIM Annual Meeting, 21.–22.9.2023.
- Vaduganathan M, et al.: SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet 2022; 400(10354): 757–767.
- Solomon SD, et al.: Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. The New England Journal of Medicine 2022; 387: 1089–1098.
- Anker SD, et al.: Empagliflozin in heart failure with a preserved ejection fraction. The New England Journal of Medicine 2021; 385: 1451–1461.
- Vardeny O, et al.: Dapagliflozin in heart failure with improved ejection fraction: a prespecified analysis of the DELIVER trial. Nat Med 2022; 28: 2504–2511.
- Anker SD, et al.: Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial. Eur J Heart Fail 2020; 22: 2383–2392.
- McMurray JJV, et al.: Dapagliflozin in patients with heart failure and reduced ejection fraction. The New England Journal of Medicine 2019; 381(21): 1995–2008.
- Packer M, et al.: Cardiovascular and renal outcomes with empagliflozin in heart failure. The New England Journal of Medicine 2020; 383: 1413–1424.
HAUSARZT PRAXIS 2023; 18(12): 26–27
