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HFrEF or HFpEF indicate that patients with a LVEF between 40–50% benefitted from similar therapies to those with LVEF ≤40%.445 However, to date, no definitive RCT has evaluated therapies exclusively in patients with HFmrEF. The best evidence so far derives from SGLT2-inhibitor studies. The EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure With Preserved Ejection Fraction) trial included patients with NYHA class II–IV, an LVEF >40%, and an elevated NT-proBNP (>300 pg/mL in sinus rhythm; >900 pg/mL in AF).530 Patients with an eGFR <20 mL/ min/1.73 m2 were excluded. Compared with placebo, empagliflozin reduced the risk of the primary outcome, a composite of CV death or hospitalization for HF, by 21%, which was mainly related to a 29% lower risk of hospitalization for HF.530 This effect was independent of diabetes status, and baseline HbA1c did not modify the effects on the primary outcome.531 The DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial included 6263 patients with NYHA class II–IV, an LVEF >40%, an elevated NT-proBNP (>300 pg/mL in sinus rhythm; >600 pg/mL in AF), and an eGFR ≥25 mL/min/1.73 m2. Compared with placebo, dapagliflozin reduced the primary outcome, a composite of worsening HF or CV death, by 18%, which was mainly driven by a reduction in hospitalization for HF. This effect was independent of diabetes status.532 A meta-analysis including 12 251 participants from DELIVER and EMPEROR-Preserved showed that SGLT2 inhibitors, compared with placebo, reduced a composite of CV death and first hospitalization for HF (HR 0.80; 95% CI, 0.73–0.87), with consistent reductions in both components: CV death (HR 0.88; 95% CI, 0.77–1.00) and first hospitalization for HF (HR 0.74; 95% CI, 0.67–0.83).533 There is no specific trial evaluating ARNI in patients with HFmrEF. The PARAGON-HF trial, which included patients with EF ≥45%, although missing its primary endpoint overall, showed significant EF-by-treatment interaction. Sacubitril/valsartan, compared with valsartan, reduced the likelihood of the primary composite outcome of CV death and total HF hospitalization by 22% in those with an LVEF below or equal to the median of 57%.534

7.4.3 Treatment of heart failure with preserved

ejection fraction Over the past decade, several large RCTs failed to achieve statistical significance with regard to effects on the primary outcomes in patients with HFpEF including: PEP-CHF (perindopril), CHARM-Preserved (candesartan), I-PRESERVE (irbesartan), TOPCAT (spironolactone), DIG Ancillary Trial (digoxin), and PARAGON-HF (sacubitril/valsartan).477,534–538 As presented above in section 7.4.2, the SGLT2 inhibitors empagliflozin and dapagliflozin both reduced the RR of the primary composite outcome, CV death or hospitalization for HF, by 21% and 18%, respectively.530,532 The treatment effect on the incidence of the primary outcome did not differ between LVEF sub-groups nor between patients with and without diabetes.531–533 The combined SGLT1 and -2 inhibitor sotagliflozin was investigated in patients with T2DM who were recently hospitalized for worsening HF, irrespective of their LVEF (SOLOIST-WHF trial); 20.9% of the patients had an LVEF ≥50%. Sotagliflozin reduced the risk of the primary composite outcome of CV death, HF hospitalization, and urgent visit for HF by 33%, with a consistent effect across the spectrum of baseline LVEF. However, the number of events in the HFpEF group was too small to draw any firm conclusion.189 Diuretic therapy should be used to reduce symptoms of congestion.520 Loop diuretics are preferred, but low-dose thiazide diuretics might be useful for managing hypertension. For treating comorbidities alongside HFpEF, refer to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.445

7.5 Safety profile of glucose-lowering

agents in patients with heart failure and diabetes For glycaemic targets in patients with diabetes, please refer to Section 5.2.

7.5.1 Sodium–glucose co-transporter-2 inhibitors

Sodium–glucose co-transporter-2 inhibitors (see also Section 7.4.1.1) have been investigated in different populations with diabetes, ranging from patients with ASCVD or multiple ASCVD risk factors to patients recently hospitalized for worsening HF, with increasing ARR for HF-related outcomes according to higher patient risk (Figure 15; Supplementary data online, Table S15). As outlined above, in dedicated HF trials, dapagliflozin and empagliflozin reduced CV death and HF hospitalization in patients with HFrEF with or without diabetes, and sotagliflozin reduced CV death and HF hospitalization in patients with T2DM and recent hospitalization for HF of any aetiology.189,491,494 Moreover, empagliflozin and dapagliflozin reduced the risk of CV death or HF hospitalization in patients with HFmrEF or HFpEF.530,532 While the EMPA-REG OUTCOME (empagliflozin) and VERTIS CV (ertugliflozin) trials investigated patients with T2DM and established ASCVD risk, the CANVAS Programme (canagliflozin) and DECLARE-TIMI 58 trial (dapagliflozin) included patients with established ASCVD or multiple ASCVD risk factors. In all of these placebo-controlled CVOTs of SGLT2 inhibitors, only a small proportion of patients had a baseline history of HF. Empagliflozin reduced the risk of HF hospitalization by 35% in patients with and without previous HF.71 Canagliflozin also significantly reduced the risk of HF hospitalization by 33%.151 Dapagliflozin significantly reduced the combined endpoint of CV death or HF hospitalization, a result driven mainly by lower rates of HF hospitalization.152 This effect was independent of pre-existing HF.540 Ertugliflozin did not reduce the combined endpoint of CV death or HF hospitalization, although there was a significant reduction in HF hospitalization and repeated hospitalizations.154,541

Recommendation Table 21 — Recommendations for heart failure treatments in patients with diabetes and left ventricular ejection fraction over 40%

Recommendations Classa Levelb

Empagliflozin or dapagliflozin are recommended in patients with T2DM and LVEF >40% (HFmrEF and HFpEF) to reduce the risk of HF hospitalization or CV death.530–533 I A Diuretics are recommended in patients with HFpEF or HFmrEF and diabetes with signs and/or symptoms of fluid congestion to improve symptoms, exercise capacity, and HF hospitalization.520 I C © ESC 2023

CV, cardiovascular disease; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; T2DM, type 2 diabetes mellitus. aClass of recommendation. bLevel of evidence.

ESC Guidelines                                                                                                                                                                                          4091

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