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specific characteristics for patients with diabetes are presented in the following sections.

7.4.1.1 Sodium–glucose co-transporter-2 inhibitors

Two randomized placebo-controlled trials have investigated the effect of an SGLT2 inhibitor compared with placebo added to optimal medical therapy (OMT) in patients with HFrEF with and without diabetes. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial included patients if they were in New York Heart Association (NYHA) class II–IV, had an LVEF ≤40% despite OMT, and had elevated NT-proBNP (in sinus rhythm ≥600 pg/mL, in AF ≥900 mg/mL, or ≥400 pg/mL if they had been hospitalized for HF within the previous 12 months). Patients with T1DM or an eGFR <30 mL/min/ 1.73 m2 were excluded. Therapy with dapagliflozin 10 mg o.d. vs. placebo reduced the risk of the primary outcome, a composite of worsening HF (hospitalization or an urgent visit resulting in i.v. therapy for HF) or CV death, by 26% (HR 0.74; 95% CI, 0.65–0.85). In addition, dapagliflozin reduced all-cause mortality (HR 0.83; 95% CI, 0.71–0.97) and improved symptoms, physical function, and quality of life in patients with HFrEF.491,492 All of the clinical benefits observed were independent of baseline diabetes status and background glucose-lowering therapy, and consistent across the spectrum of HbA1c.491,493 The EMPEROR- Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction) trial evaluated empagliflozin vs. placebo and included patients with HFrEF with and without diabetes, with NYHA class II–IV, and LVEF ≤40% despite OMT, an eGFR ≥20 mL/min/1.73 m2, and an elevated NT-proBNP (EF ≤30% or EF ≤40% and HF hospitalization within 12 months: NT-proBNP ≥600 pg/ mL; EF 31–35%: NT-proBNP ≥1000 pg/mL; EF 36–40%: NT-proBNP ≥2500 pg/mL). Empagliflozin 10 mg o.d. reduced the risk of the primary outcome, a composite of CV death or HF hospitalization, by 25% vs. placebo (HR 0.75; 95% CI, 0.65–0.86).494 This effect was consistent across patients with and without diabetes at baseline.495 Treatment with empagliflozin improved quality of life.496 A meta-analysis of the DAPA-HF and EMPEROR-Reduced trials showed a consistent reduction in HF hospitalization or CV death, CV death, and all-cause mortality by SGLT2-inhibitor treatment without significant heterogeneity between trials.497 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 [Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure] trial). Patients with an eGFR <30 mL/min/ 1.73 m2 were excluded. Sotagliflozin significantly reduced the RR of the composite primary outcome (CV death, HF hospitalization, or urgent visit for HF) by 33% compared with placebo (HR 0.67; 95% CI, 0.52–0.85). The treatment effect was consistent across the spectrum of LVEF.189 Thus, the SGLT inhibitors dapagliflozin, empagliflozin, and sotagliflozin are recommended, in addition to OMT (with an ARNI/ACE-I, betablocker, and MRA), in patients with HFrEF and diabetes to reduce CV death and HF hospitalization. Three studies have investigated whether SGLT2 inhibitors can be safely started in patients hospitalized for acute HF. The EMPA-RESPONSE-AHF (Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure) trial randomized 80 patients with acute HF with (approximately one-third) and without diabetes to either empagliflozin or placebo for 30 days.498 Treatment with empagliflozin did not affect visual analogue scale dyspnoea, diuretic response, NT-proBNP levels, or duration of hospital stay, but was safe, increased urinary output, and reduced a combined endpoint of worsening HF, re-hospitalization for HF, or death at 60 days compared with placebo. In the SOLOIST-WHF trial mentioned above, 1222 patients with T2DM received sotagliflozin or placebo, with a median follow-up of 9 months (trial stopped prematurely).189 Sotagliflozin therapy, initiated before or shortly after discharge, resulted in significantly fewer deaths from CV causes and hospitalizations and urgent visits for HF than placebo, with no increase in acute kidney injury. The EMPULSE (A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure) trial randomized 530 hospitalized patients with and without diabetes with a primary diagnosis of acute de novo or decompensated HF, regardless of LVEF when clinically stable, to receive either empagliflozin or placebo. More patients treated with empagliflozin had clinical benefit (win ratio 1.36; 95% CI, 1.09–1.68) compared with placebo. This effect was consistent for acute de novo and decompensated chronic HF and was observed regardless of LVEF or the presence of diabetes.499 In these trials, very few cases of euglycaemic diabetic ketoacidosis were reported; still, physicians treating patients with diabetes with SGLT2 inhibitors in this setting should be aware of this rare but potentially serious complication. Of note, misinterpreting eGFR changes can lead to inappropriate discontinuation of disease-modifying agents and should be avoided.

7.4.1.2 Angiotensin receptor–neprilysin inhibitor and

angiotensin-converting enzyme inhibitors The ARNI sacubitril/valsartan has shown superior efficacy to enalapril in reducing CV death and HF hospitalization in patients with HFrEF, with or without diabetes.471 Patients were up-titrated to 200 mg b.i.d. sacubitril/valsartan within 2–4 weeks.471 The beneficial effect of sacubitril/ valsartan over enalapril was consistent for patients with and without diabetes and across the spectrum of baseline HbA1c. ACE-Is were the first class of drugs shown to reduce mortality and morbidity and improve symptoms in patients with HFrEF.500 There is no difference in efficacy in patients with and without diabetes.501–503 As RAS inhibitors increase the risk of hyperkalaemia and may acutely compromise kidney function, routine surveillance of serum creatinine and potassium levels is advised.504,505 However, misinterpreting eGFR changes often leads to inappropriate discontinuation of diseasemodifying agents and should be avoided.504–506

7.4.1.3 Mineralocorticoid receptor antagonists

The steroidal MRAs spironolactone or eplerenone reduce death and HF hospitalization in patients with HFrEF, with consistent results in patients with or without diabetes.507,508 Eplerenone is more specific for blocking aldosterone and, therefore, causes less gynaecomastia. Caution should be exercised when using MRAs in patients with impaired renal function and in those with serum potassium concentration >5.0 mmol/L. The non-steroidal MRA finerenone has not been investigated in patients with HFrEF (Section 9).

7.4.1.4 Beta-blockers

Beta-blockers are effective at reducing all-cause death and hospitalization for HF in patients with HFrEF, with or without diabetes.509–512 Treatment benefits strongly support using beta-blockers in patients with HFrEF and diabetes.

7.4.1.5 Angiotensin-II receptor blockers

The place of ARBs in managing HFrEF has changed over the last few years. They are now recommended for patients who cannot tolerate ARNI or ACE-Is because of serious side effects. ARBs have similar treatment effects in patients with HFrEF with or without diabetes.513–515

ESC Guidelines                                                                                                                                                                                          4089

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