Cardiovascular
Medicine
SGLT-2 Inhibition in Heart Failure with Mildly Reduced and Preserved Ejection Fraction
Further Education General Internal Medicine Cardiology Pharmaceutical Medicine
Heart Failure Treatment
Peer-review

SGLT-2 Inhibition in Heart Failure with Mildly Reduced and Preserved Ejection Fraction

Review Article
Further Education General Internal Medicine Cardiology Pharmaceutical Medicine
Philippe Meyer, Emmanuelle Massie, Nana Poku
Issue
2023/06
DOI:
https://doi.org/10.4414/cvm.2023.1243935382
Cardiovasc Med. 2023;26(06):186-188
Affiliations
Division of Cardiology, University Hospital of Geneva, Switzerland

Published on 22.11.2023

Abstract

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are now recommended in a wide spectrum of indications, including type 2 diabetes mellitus, heart failure (HF) and chronic kidney disease. Until 2021, data from randomized clinical trials (RCTs) were limited to patients with HF and reduced ejection fraction (EF). However, most HF patients have either a preserved or a mildly reduced EF, where the evidence for effective therapies is scarce. More recent RCTs with SGLT-2 inhibitors have been performed in these HF types. This review discusses the results of these studies and their implications for our clinical practice.
Keywords: SGLT2-inhibitors; heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction

Introduction

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are pharmacological agents that block the SGLT-2 located in the proximal tubule of the nephron, thereby provoking glycosuria, natriuresis and osmotic diuresis. Despite being originally developed for the treatment of type 2 diabetes mellitus (T2DM), SGLT-2 inhibitors have demonstrated a coincidental decrease in heart failure (HF) hospitalization consistent with all the different agents in the first large cardiovascular outcome trials performed in T2DM patients [1, 2]. These potential benefits were obviously only hypothesis-generating, because patients were not randomized according to the presence of HF and characterization of HF was not provided. The first dedicated HF randomized clinical trials were the DAPA-HF [3] and the EMPEROR-reduced [4] trials, that investigated dapagliflozin and empagliflozin in patients with HF and reduced (<40%) left ventricular ejection fraction (LVEF). In both studies, the primary outcome of cardiovascular mortality or HF hospitalization was significantly reduced in the treatment arms compared to placebo. Based on that evidence, SGLT-2 inhibitors have received a class IA indication in HF with reduced ejection fraction (HFrEF) in the latest European Society of Cardiology (ESC) guidelines [5], becoming part of the first-line therapeutic armamentarium for HFrEF, along with angiotensin converting enzyme inhibitors or angiotensin receptor neprilysin inhibitors, beta blockers and mineralocorticoid receptor antagonists.
However, HFrEF is only a part of the whole HF syndrome spectrum. Approximately 50% of the HF patients present with preserved ejection fraction (HFpEF) (≥50%) [6], and 10-25% with mildly reduced ejection fraction (HFmrEF) (41-49%) [7]. The evidence for effective therapies in these two HF types is scarce. The latest 2021 ESC HF guidelines stated, for the first time, that all the recommended therapies for HFrEF may also be considered for patients with HFmrEF (class IIb, level of evidence C) [5]. Since no substantial prospective randomized clinical trial had been performed in this population, these recommendations were mainly based on subgroup analyses of HFpEF trials that were overall negative. Regarding HFpEF, many trials have been performed in the last two or three decades, but no treatment has been shown to convincingly reduce mortality and morbidity even if some subgroups of HFpEF patients seemed to benefit from certain therapies. Therefore, in the 2021 ESC HF guidelines, only the treatment of comorbidities, such as coronary artery disease or hypertension and diuretic therapy in case of congestion, were recommended (class I, level of evidence C) [5].
Figure 1: General management of patients with heart failure (HF) and left ventricular ejection fraction (LVEF) > 40%.
CI: contraindications, GFR: glomerular filtration rate, LVEF: left ventricular ejection fraction, SBP: systolic blood pressure, T1DM: type 1 diabetes mellitus.
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Trials of SGLT-2 Inhibitors in HFmrEF and HFpEF

In August 2021, right after the presentation of the 2021 ESC HF guidelines, the EMPEROR-preserved trial was presented and concomitantly published in the New England Journal of Medicine [8]. This phase three randomized, double-blind, placebo-controlled trial aimed to investigate the efficacy and safety of empagliflozin in patients with HFmrEF and HFpEF. Adult patients with chronic symptomatic HF and a LVEF >40% were included, regardless of the presence or absence of T2DM. HF diagnosis was based on elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) levels (i.e., >300 ng/l and >900 ng/l in atrial fibrillation) and evidence of echocardiographic structural changes (i.e., increase in left atrial size or left ventricular mass) or a documented hospitalization for HF within the twelve months prior to randomization. Among the exclusion criteria were the presence of symptomatic hypotension and/or systolic blood pressure <100 mmHg and a glomerular filtration rate (GFR) <20 ml/min/1.73 m2. A total of 5988 patients were randomized to empagliflozin 10 mg once daily versus placebo, with a median follow-up of 26.2 months. The mean age of the patients was 72 years, they were mainly males (55%), non-diabetic (51%), in New York Heart Association (NYHA) class II (81%) with a mean LVEF of 54% and one third had HFmrEF (LVEF 41-49%). Median NT-proBNP was almost 1000 ng/l. The occurrence of the primary composite endpoint of cardiovascular mortality or HF hospitalization was significantly lower in the empagliflozin group compared to the placebo group (13.7% vs 17.1%, hazard ratio 0.79; 95% confidence interval [CI], 0.69 to 0.90; p <0.001). This effect was mainly driven by a reduction of HF hospitalizations since there was no effect on cardiovascular or total mortality alone. The prespecified subgroup analysis for the primary endpoint did not show significant interaction, but there was a trend toward fewer benefits in patients with LVEF ≥60% compared to patients in subgroups with lower LVEF. Serious adverse events were similar in patients treated by empagliflozin compared to placebo, but uncomplicated genital and urinary tract infections were more common (2.2% vs 0.7% and 9.9% vs 8.1%, respectively). The EMPEROR-preserved study was therefore the first positive randomized clinical trial in patients with HFpEF and HFmrEF.
A year later, the results of the DELIVER trial were published [9]. This was a similarly designed phase three randomized, double-blind, placebo-controlled trial that examined the efficacy and safety of dapagliflozin in patients with HFmrEF and HFpEF (including patients with previous HFrEF, i.e., HF with improved EF). Patients aged >40 years with chronic symptomatic HF and a LVEF >40% were included, regardless of diabetic status. HF diagnosis was based on elevated NT-proBNP levels (i.e., ≥300 ng/l and ≥600 ng/l in atrial fibrillation or flutter) and evidence of echocardiographic or cardiac magnetic resonance imaging structural changes (i.e., increase in left atrial size or left ventricular mass). Exclusion criteria included type 1 diabetes mellitus (T1DM), systolic blood pressure <95 mmHg and a GFR <25 ml/min/1.73 m2. A total of 6263 patients were randomized to dapagliflozin 10 mg once daily versus placebo, with a median follow-up of 2.3 years. The mean age of the patients was 72 years, they were mainly males (56%), non-diabetic (55%), three quarters were in NYHA class II with a mean LVEF of 54% and one third had HFmrEF. The occurrence of the primary composite endpoint of cardiovascular mortality or worsening HF (unplanned HF hospitalization or urgent HF visit) was significantly lower in the dapagliflozin group compared to the placebo group (16.4% vs 19.5%, hazard ratio 0.82; 95% CI, 0.73 to 0.92; p <0.001). There was no significant effect on cardiovascular or total mortality. The results were similar in all prespecified subgroups but, in contrast with the EMPEROR-preserved trial, there was a trend toward more benefits in patients with LVEF ≥60% compared to patients with lower LVEF. Adverse events occurred at a similar incidence in the dapagliflozin and the placebo group.
Figure 2: Practical use of SGLT-2 inhibitors in heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF).
ACEI: angiotensin-converting-enzyme inhibitor, ARBs: angiotensin receptor blockers, BB: beta blockers, GFR: glomerular filtration rate, HF: heart failure, LVEF: left ventricular ejection fraction, MRAs: mineralocorticoid receptor antagonists, SGLT-2: sodium-glucose cotransporter-2.
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Overall, the results of these two trials are very consistent, demonstrating benefits of a similar magnitude confirming a class effect of SGLT-2 inhibitors in the whole spectrum of HF with no particular safety issues. Several trialists have highlighted slight differences between the two trials in terms of inclusion and exclusion criteria and endpoint definitions, but patients’ baseline characteristics and results overall were very similar. Anker et al. performed an analysis of EMPEROR-preserved using DELIVER-like endpoint definitions, which resulted in similar results with regards to the primary endpoint [10]. A prespecified meta-analysis of DELIVER and EMPEROR-preserved has been performed recently using trial-level data with harmonized endpoint definitions [11]. The composite of cardiovascular death or first hospitalization for HF was reduced by SGLT-2 inhibitors (hazard ratio 0.80; 95% CI, 0.73 to 0.87) with consistent effects in both components of cardiovascular death (hazard ratio 0.88; 0.77 to 1.00) and first hospitalization for HF (hazard ratio 0.74; 0.67 to 0.83). Of note, no effects on renal endpoints have been observed in EMPEROR-preserved in contrast to the large benefits demonstrated with SGLT-2 inhibitors in HFrEF trials [12]. Regarding the intriguing difference between the two trials in the subgroup with an LVEF >60%, it is mostly likely attributable to chance. Another hypothesis is, that patients with an improved but previously reduced LVEF were also included in DELIVER and may have been part of the subgroup with an LVEF >60%, potentially increasing the drug's effect in this subgroup compared to the EMPEROR-preserved study, since SGLT2-inhibitors seem to have more benefits in HFrEF.
Another important, though smaller trial was published in 2022, investigating empagliflozin in patients with acute HF: the EMPULSE trial [13]. This randomized, double-blind, placebo-controlled trial investigated the effects of empagliflozin on survival, HF events and symptoms in patients hospitalized for acute HF regardless of LVEF. HF diagnosis was based on dyspnea, clinical HF signs, elevated BNP or NT-proBNP and treatment with 40 mg of furosemide or an equivalent diuretic before randomization that occurred 24 hours to five days after hospital admission. Patients were all stabilized with a systolic blood pressure ≥100 mmHg, no increase in intravenous (IV) diuretics or treatment with IV vasodilators or inotropes within six hours. Patients with T1DM and a GFR <20 ml/min/1.73 m2 were excluded. The primary endpoint was a hierarchical composite outcome including time to all-cause death, number of HF events, time to first HF event and a ≥5 point change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score. The primary outcome analysis was performed using a stratified win ratio. A total of 530 patients were randomized to empagliflozin 10 mg once daily versus placebo with a 90 day follow-up. The mean age of the patients was 70 years, three quarters were men, less than half had T2DM, one third had a LVEF >40% and one third had acute de novo HF. The win ratio of clinical benefit that included all the components of the primary outcome was 1.36 in favor of the empagliflozin group (95% CI, 1.09 to 1.68; p = 0.0054). Patients treated with empagliflozin also had a significantly higher diuretic response at 15 and 30 days. The results were consistent in all prespecified subgroups, including patients with a LVEF >40% and no difference were observed in adverse events between groups.

Conclusion

SGLT-2 inhibitors are the first medication class ever to have beneficial effects in patients with HFmrEF and HFpEF. The benefits are mainly driven by a decrease in HF hospitalizations. The absence of a significant effect on mortality could be related to the older age and the higher prevalence of comorbidities in theses HF patients, which may lead to a higher non-cardiovascular mortality not affected by SGLT-2 inhibition. The mechanisms of the benefits are still unclear and probably multifactorial. According to the 2023 ESC HF guidelines focused update [14], SGLT-2 inhibitors are recommended with a class IA indication in patients with chronic HFmrEF and HFpEF to reduce HF hospitalizations, whereas no specific recommendations have been provided for their use in the acute setting. In Switzerland, both empagliflozin and dapagliflozin are now approved by Swissmedics in patients with LVEF >40%. Even if no safety issues were observed during the clinical trials, clinicians should know how to prevent and treat euglycemic diabetic ketoacidosis that will probably occur more frequently considering the exponential rise of SGLT-2 inhibitor use. In this regard, SGLT-2 inhibitors should not be used in T1DM, should be withheld before surgery and in dehydrating illnesses.

Keypoints

  1. Two randomized controlled trials (EMPEROR-preserved and DELIVER) have demonstrated benefits of SGLT-2 inhibitors in chronic HFmrEF and HFpEF by reducing cardiovascular mortality and heart failure hospitalizations (mainly driven by reduction in the latter).
  2. Patients with heart failure and improved EF (from HFrEF) also benefit from this therapy (DELIVER).
  3. SGLT-2 inhibitors may also be initiated in the acute heart failure setting (EMPULSE), even if more data on safety are needed.
  4. Despite an excellent safety profile in randomized controlled trials, clinicians and patients should be educated about the risks of genital infections (local hygiene) and euglycemic diabetic ketoacidosis (sick day rules cards).
Philippe Meyer
Cardiology Service, Geneva University Hospitals
Rue Gabrielle Perret-Gentil 4
CH-1205 Geneva
philippe.meyer[at]hcuge.ch
1 Zinman B. The International Diabetes Federation World Diabetes Congress 2015. Eur Endocrinol. 2015 Aug;11(2):66.
2 Neal B, PErkovic V, Mahaffrey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug;377(7):644-57.
3 McMurray JJ, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov;381(21)1995-2008.
4 Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct;383(15):1413-24.
5 McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al.; ESC Scientific Dovument Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep;42(36):3599-726.
6 Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017 Oct;14(10):591-602.
7 Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol. 2022 Feb;19(2):100-16.
8 Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al.; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct;385(16):1451-61.
9 Solomon SD, McMurray JJ, Claggett B, de Boer RA, De Mets D, Hernandez AF, et al.; DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep;387(12):1089-98.
10 Anker SD, Siddiqi TJ, Filippatos G, Zannad F, Ferreira JP, Pocock SJ, et al. Outcomes with empagliflozin in heart failure with preserved ejection fraction using DELIVER-like endpoint definitions. Eur J Heart Fail. 2022 Aug;24(8):1400-5.
11 Vaduganathan M, Docherty KF, Claggett BL, Jhund PS, de Boer RA, Hernandez AF, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022 Sep;400(10354):757-67. Erratum in: Lancet. 2023 Jan;401(10371):104.
12 Packer M, Butler J, Zannad F, Pocock SJ, Filippatos G, Ferreira JP, et al. EMPEROR Study Group. Empagliflozin and Major Renal Outcomes in Heart Failure. N Engl J Med. 2021 Oct;385(16):1531-3.
13 Voors AA, Angermann CE, Teerlink JR, Collins SP, Kosiborod M, Biegus J, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022 Mar;28(3):568-74.
14 McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023 Aug 25:ehad195.
Conflict of Interest Statement
PM received grants from Novartis (30,000 CHF) and from AstraZeneca (10,000 CHF) in 2021. Vifor HFA arranged meetings in 2021 and 2022. He participated in advisory boards and seminars organized by AstraZeneca, Novartis, Abbot, Vifor, Bayer, Servier and Boehringer Ingelheim, with the honoraria being entirely paid to a private research foundation of the Cardiology Service of the University of Geneva (GEcor-foundation).
EM and NP have reported no financial support and no other potential conflict of interest.

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