The contemporary role of sodium-glucose co-transporter 2 inhibitor (SGLT2i) and angiotensin receptor-neprilysin inhibitor (ARNI) in the management of heart failure: State-of-the-art review

Abstract

Novel therapies for heart failure with reduced ejection fraction (HFrEF) are angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose co-transporter 2 inhibitor (SGLT2i), etc. The purpose of this review is to determine the effects of ARNI and SGLT2i in heart failure (HF), compare the impact of SGLT2i with ARNI, and finally evaluate the current data regarding the combination of these two drugs in HF. Various trials on the respective medications have shown some significant reduction in all-cause mortality and cardiovascular (CV) death. The combination of these drugs has shown more CV benefits than monotherapy. There is emerging data about these two drugs in patients with heart failure with preserved ejection fraction (HFpEF). At present, there are less head-to-head comparison trials of these two drugs. This review provides insights on the current evidence, comparative efficacy, and combination therapy of ARNI and SGLT2i in managing HF, focussing on HFrEF and HFpEF.

1. Introduction

Heart failure with reduced ejection fraction (HFrEF), which signifies that left ventricular ejection fraction (LVEF) less than or equal to 40 %, is associated with reduced cardiac contractility.¹ In HFrEF, pathological left ventricular (LV) remodelling and progressive dilatation are typical hallmarks resulting in adverse clinical outcomes. Medications such as sodium-glucose co-transporter 2 inhibitor (SGLT2i), angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker (BB) and mineralocorticoid receptor antagonist (MRA) are the foundational pillars of drug therapy for HFrEF.¹ Among these, SGLT2i and ARNI are novel drugs that are considered the game changers of HF.

ARNI is a combination of sacubitril and valsartan.² Sacubitril is an inhibitor of neprilysin, which degrades natriuretic peptides, bradykinin, adrenomedullin and other vasoactive peptides. On the other hand, Valsartan is an angiotensin receptor blocker (ARB); it acts by selectively blocking the AT1 receptor, which decreases vasoconstriction, sodium and water retention and myocardial hypertrophy. The combination of these two drugs (ARNI) increases circulating A-type natriuretic peptide (ANP), B-type natriuretic peptide (BNP), diuresis, natriuresis, myocardial relaxation and anti-remodelling. The PARADIGM-HF trial compared ARNI with angiotensin converting enzyme inhibitor (ACEi) and demonstrated that sacubitril/valsartan (97/103 mg b.i.d.) was superior to enalapril (10 mg b.i.d.) in improving outcomes such as reduction in hospitalizations for worsening HF, cardiovascular (CV) mortality and overall mortality in patients with symptomatic HFrEF with LVEF ≤40 %.²

The 2016 European Society of Cardiology (ESC) guidelines for Heart Failure (HF) incorporated ARNI as a mainstay in treatment for HFrEF.³ It was suggested that ACEi should be withheld for at least 36 h before initiating ARNI to minimize the risk of angioedema, but this delay is not required when switching from ARB to ARNI. The combination of an ARNI with ACEi/ARB for treating HFrEF is contraindicated.⁴ The 2017 American College of Cardiology (ACC) HF guidelines recommended that patients with chronic symptomatic HFrEF with New York Heart Association (NYHA) class II or III could be treated with an ARNI to further reduce morbidity and mortality.⁵ In 2021, ESC Heart Failure Guidelines recommended ARNI as a replacement for ACEi or ARB and issued a class I recommendation for treating HFrEF patients.⁶ A 2023 Practical Recommendations from Indian Cardiologists stated that the use of ARNI in Heart Failure is supported by clinical trials and guidelines, with ARNI being one of the four medications recommended for treating HFrEF and that ARNI can improve diastolic and left ventricular function, quality of life, and reduce the risk of ventricular arrhythmias.⁷

SGLT2 inhibitors are a new class of anti-diabetic medications that showed significant benefit in patients with HFrEF.¹ In 2021, ESC issued a class I recommendation to SGLT2i for treating HFrEF patients with or without diabetes mellitus (DM).⁶ At present, SGLT2i is recommended in patients with diabetes at high risk of CV disease to prevent HF hospitalization and CV death and improve cardiac morbidity.⁶ The Current 2022 guidelines by ACC, AHA (American Heart Association) and HFSA (Heart Failure Society of America) recommend both ARNI and SGLT2i for the management of HFrEF. However, the safety of the combination of SGLT2i and ARNI in various sub-categories of HF has not been studied extensively.⁸

Patients with heart failure with preserved ejection fraction (HFpEF) have normal LV systolic function (LVEF ≥50 %), but diastolic dysfunction and elevated natriuretic peptide levels are commonly diagnosed in older populations with comorbidities like obesity and diabetes. HFpEF is a multifaceted syndrome with complex diagnosis and management, reflecting its intricate pathophysiology and shifting diagnostic and therapeutic strategies. Data on the usage of ARNI and SGLT2i in HFpEF are emerging.

Besides HFrEF and HFpEF, newer concepts, such as heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with improved ejection fraction (HFimpEF) have been recognized to address gaps in the traditional classification of chronic heart failure, helping to better describe the spectrum of the disease.^3,9 Patients with HFmrEF have an LVEF of 41–49 %, while patients with HFimpEF are defined as those who previously had HFrEF with LVEF of 40 % or less but now have LVEF over 40 %.⁸ These sub-categories of HF are not as well documented as other types of HF and their management is currently being actively researched.

This review aims to determine the current evidence of SGLT2i and ARNI in HF, compare the efficacy of SGLT2i with ARNI in HF, and finally evaluate the potential benefits and outcomes of combination therapy of SGLT2i and ARNI in HF.

2. SGLT2i in HFrEF

There are two sodium-glucose co-transporters (SGLT) responsible for renal glucose reabsorption.¹⁰ Reabsorption of 80–90 % of filtered glucose is due to the SGLT2, which is located in the early part of the proximal renal tubule. SGLT1 accounts for the reabsorption of the remaining 10–20 % of filtered glucose and is located in the more distal part of the proximal renal tubule. SGLT2i reduces both preload and afterload, relieves wall stress, improves left ventricular diastolic function, improves cardiac work performance, diminishes tissue fibrosis, regresses LV mass and improves LV remodelling and ejection fraction.^11,12 SGLT2i facilitates the shift in metabolic fuel of the myocardium by increasing the oxidation of fatty acids and ketogenesis and simultaneously reducing the heart's use of carbohydrates as energy substrates.¹¹ SGLT2i causes natriuresis and glucosuria and decreases pulmonary congestion and systemic oedema.¹² These effects may help to reduce the recurrent hospitalizations for HF. SGLT2i can lower blood pressure by 3–5 mmHg without an increase in heart rate and may also decrease the sympathetic nervous system overdrive of HF.¹² At present, several SGLT2i are commercially available for treating patients with established HF, such as Dapagliflozin, Empagliflozin, and Sotogliflozin.

The DAPA-HF trial was the first study to evaluate the efficacy of dapagliflozin on patients with HFrEF, regardless of diabetic status. 4744 participants with NYHA class II-IV were randomized to either dapagliflozin or placebo alongside standard care.¹³ The primary endpoint was the occurrence of worsening HF (requiring hospitalization or urgent intravenous therapy) or CV death. Over a median follow-up of 18.2 months, dapagliflozin significantly reduced the risk of the primary outcome compared to the placebo group (16.3 % vs. 21.2 %), with consistent benefits across patients irrespective of diabetes status. Dapagliflozin also improved all-cause mortality and reduced HF symptoms. There were no significant differences between groups in adverse events related to volume depletion, renal dysfunction, or hypoglycemia.¹³

The EMPEROR-Reduced Trial examined whether the diuretic effects of empagliflozin contributed to its benefits in HFrEF patients.¹⁴ This trial involved 3730 participants, 40 % of whom had recent volume overload, and assessed empagliflozin's impact on heart failure symptoms, health, and major outcomes. Despite volume overload in some patients, empagliflozin consistently improved CV outcomes and health status and reduced HHF, regardless of the recent volume overload status.¹⁴ The findings suggest that diuresis is not the main mechanism by which SGLT2 inhibitors confer clinical benefits in HFrEF.

In the DECLARE-TIMI 58 trial, dapagliflozin was safe for patients with type 2 diabetes mellitus (T2DM), reducing HHF and renal issues without increasing major CV events.¹⁵ The VERTIS CV trial assessed ertugliflozin, an SGLT2i, in T2DM patients with atherosclerotic CV disease.¹⁶ Results showed no significant reduction in first HHF combined with CV death, but a notable decrease in first HHF events. The benefits were especially significant in patients with reduced EF (≤45 %). Ertugliflozin also reduced total HHF events and the combined total of HHF and CV deaths, indicating its potential for preventing heart failure in this patient population.¹⁶

The meta-analysis of the two large-scale trials with 8474 patients (Table 1), namely DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials, assessed the effects of SGLT2i on CV outcomes in patients with HFrEF with or without diabetes.¹⁷ This meta-analysis showed a 13 % reduction in all-cause mortality and 14 % in CV death. Moreover, a significant 26 % decrease in CV death or HHF and a 25 % reduction in recurrent HHF or CV death were observed. The treatment also led to a notable reduction in renal complications. These results were consistent across both trials, highlighting the benefits of SGLT2i in improving heart and renal outcomes in HFrEF patients, irrespective of diabetes status.

Table 1.

Meta-analysis studies of SGLT2i in HFrEF.

Study	Number of studies included in meta-analysis	Number of patients	Treatment groups	Outcomes
Zannad F, et al10	2 trials DAPA-HF and EMPEROR-Reduced	8474 patients	prespecified meta-analysis of the two large-scale trials assessing the effects of SGLT2i on CV outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin).	13 % reduction in all-cause death
				14 % reduction in CV death
				26 % relative reduction in the combined risk of CV death or first HHF
				25 % decrease in the composite of recurrent HHF or CV death
				The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF.
Yan Y et al12	6 trials	19,150 participants	Embase, Medline, and Cochrane Central Registry of Controlled Trials of randomized controlled trials evaluating SGLT2i or ARNI in HFrEF.	SGLT2i could safely reduce cardiovascular death or hospitalization for heart failure in HFrEF regardless of diabetes mellitus status. SGLT2i and ARNI demonstrate similar effects, while combination of SGLT2i and ARNI results in a better cardiovascular protective effect.
Lu Y, et al13	8 trials	16,460 patients	SGLT2i	Use of SGLT2i was associated with a statistically significant 32 % reduction in HHF
				15 % reduction in CV death
				16 % reduction in all-cause mortality
				SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with or without Type2 DM, and displayed a strong trend to be effective in HFpEF.

Note:- SGLT2i: sodium-glucose cotransporter-2 inhibitor; HFrEF: heart failure with reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; CV: cardiovascular; HHF: hospitalisation for heart failure; DM: Diabetes mellitus.

In the meta-analysis of six trials of 19,150 participants by Yan Y et al, treatment with SGLT2i was associated with a 27 % decrease in CV mortality and a 31 % decrease in hospitalization for HFrEF.¹⁸ There was also a 16 % reduction in both CV and all-cause mortality. SGLT2 inhibitors were effective in both diabetic and non-diabetic individuals for these primary outcomes, suggesting their broad utility in reducing cardiovascular death and heart failure hospitalizations, regardless of diabetic status.¹⁸ In another meta-analysis of 8 trials, including 16,460 patients by Lu Y et al, SGLT2i use was associated with a 15 % reduction in CV death and a 16 % reduction in all-cause mortality. The benefits of SGLT2i were seen regardless of the presence or absence of diabetes.¹⁹

The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) have recommended SGLT2i for patients at high risk of HF or with index HF.¹⁹ However, the dilemma of whether SGLT2i or metformin should be considered as the first-line drug therapy for diabetics continues. At present, ADA/EASD continues to recommend metformin as the drug of first choice, whereas SGLT2i are recommended as add-on drugs for diabetic patients with HF or chronic kidney disease irrespective of HbA_1c.20, 21, 22

When incorporating SGLT2 inhibitors into clinical treatment, it's important to be vigilant about the risks of euglycemic ketoacidosis, infections of the genitalia and urinary tract, and reduction of diuretic therapy to avert potential volume depletion.⁸

3. ARNI in HFrEF

In patients with HF, a higher risk of renal events has been observed as compared to patients without chronic kidney disease. In the PARADIGM-HF trial, it was noted that ARNI decreases CV morbidity and mortality as compared to ACEi (enalapril) in patients with HFrEF.23, 24, 25, 26 It was also observed that ARNI reduced CV death and HHF throughout the LVEF spectrum (in both reduced and preserved HF).²³ The benefit of ARNI compared to an ACEi was consistent irrespective of background therapy and previous coronary revascularization or β-blocker dose.²⁴ Circulating levels of BNP could rise after initiation of treatment with ARNI. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is not a substrate of neprilysin inhibition, and could cause less clinical confusion when measured within 8–10 weeks of drug initiation. However, during treatment, either biomarker predicted the risk of major adverse outcomes in patients treated with ARNI.^25,26 In the study by Carnicelli AP et al, 897 patients hospitalized for HFrEF were prescribed ARNI at discharge.²⁷ Patients who had a high adherence to ARNI within 90 days after discharge had significantly lower rates of rehospitalization and death.

In the meta-analysis by Nielsen EE et al, 48 trials (19,086 patients) were included (Table 2).²⁸ ARNI was observed to reduce the risk of death by 15 % and hospitalization by 15 % compared to the control group. Comparative results were observed in reducing myocardial infarction. The prevalence of angioedema was also comparable between the two treatment groups.²⁸ Xie W et al conducted a meta-analysis of 21 studies (69,229 patients) where ACEi, ARB and ARNI were used. ARNI was the most effective drug, followed by combination therapy (ARB plus ACEi).²⁹ Tromp et al analysed 75 relevant trials with HFrEF, including 95,444 patients, and showed that a combination of ARNI, BB, MRA and SGLT2i was the most effective in reducing all-cause death (HR: 0.39; 95 % CI: 0.31–0.49).³⁰ Wang et al analysed twenty studies enrolling 10,175 patients and showed that ARNI improved functional capacity in patients with HFrEF increasing NYHA functional class.³¹

Table 2.

Meta-analysis studies of ARNI in HFrEF.

Study	Number of studies included in meta-analysis	Number of patients	Treatment groups	Outcomes
Nielsen EE, et al23	48 trials	19,086 patients	ARNI	ARNI reduced the risk of death by 15 % and hospitalization by 15 % as compared to the control group.
				No difference was observed between ARNI and control in reducing myocardial infarction.
				No evidence of a difference between ARNI compared with control on angioedema.
Xie W, et al24	21 trials	69,229 patients	ACEI ARB ARNI	The most efficacious therapy for preventing HHF was ARNI, followed by combination therapy with an ARB plus an ACEI
Tromp J, et al25	75 relevant trials	95,444 patients	ACEI, ARB, BB, MRA, digoxin, hydralazine-isosorbide dinitrate, ivabradine, ARNI, SGLT2i, vericiguat, and omecamtiv-mecarbil	A combination of ARNI, BB, MRA, and SGLT2i was the most effective in reducing all-cause death
Wang Y, et al26	20 studies	10,175 patients	ARNI vs ACEI ARNI vs ARB	ARNI improved functional capacity in patients with HFrEF increasing NYHA functional class and 6-min walking distance.
				In patients of HFpEF treatment with ARNI there were no significant improvements in various indices except left ventricular mass index.
				There were improvements in cardiac reverse remodelling indices at 3 months and were also noted with longer follow-up to 12 months.

Note:- ARNI: angiotensin receptor-neprilysin inhibitor, ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta blocker, MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose cotransporter-2 inhibitor; HFrEF: heart failure with reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; CV: cardiovascular; HHF: hospitalisation for heart failure; NYHA: New York Heart Association.

The innovator recommended that the starting dose of ARNI be 100 mg twice daily. Indian doctors, based on clinical experience, prefer to initiate at a lower starting dose of 50 mg twice daily for their patients.⁷ The gradual up-titration over 3 weeks for the 100 mg twice daily starting dose and 6 weeks for the 50 mg twice daily starting dose is reported to be well-tolerated and effective in reaching the target dose of 200 mg twice daily. The TITRATION trial compared two methods of initiating and escalating ARNI doses in HFrEF who had a systolic blood pressure of at least 100 mmHg.³² Patients were sorted into groups according to their initial SBP: 100–110, 111–120, 121–139, and 140 mmHg or higher. In these groups, the majority reached their ARNI target dose without needing to pause or lower the dose, with success rates ranging from 72.7 % to 82.9 %. Those with SBPs on the lower end (100–110 mmHg) fared better with a six-week gradual increase as opposed to a three-week faster approach. The study concluded that a lower SBP doesn't significantly affect the ability to reach the target dose, implying that lower SBP shouldn't hinder the commencement of ARNI therapy.³²

The PARADISE–MI trial compared the effects of ARNI versus ramipril in 5661 patients with acute myocardial infarction and signs of reduced LVEF (≤40 %) or pulmonary congestion over 22 months.³³ Those treated with ARNI did not show a statistically significant improvement in reducing CV death or HF incidents compared to those treated with ramipril.

These results suggest that while ARNI has proven benefits in the management of chronic HF, its advantages over ramipril in the acute post-myocardial infarction setting are not conclusively better.

4. Comparison of SGLT2i vs ARNI in HFrEF

ARNI and SGLT2i, in addition to BB and MRA, have been established as cornerstone drugs in the treatment of HFrEF. Various trials done on both these classes of drugs have confirmed them as significant entities in HF management. In the meta-analysis by Yan Y, an indirect treatment comparison demonstrated that SGLT2i and ARNI had comparable effects on primary outcome (hazard ratio [HR] 0.93, 95 % confidence interval [CI] 0.82–1.06).¹⁸ The combination of SGLT2i and ARNI improved prognosis (HR 0.68, 95 % CI 0.53–0.89) compared to monotherapy with ARNI. A metanalysis by Luo L et al, involving 17 randomized controlled trials with 38,088 patients compared SGLT2i, ARNI and Vericiguat, a soluble guanylate cyclase stimulators (sGCs) with the traditional golden triangle standard-of-care therapy (ACEi/ARB, BB and MRA).³⁴ Results of this meta-analysis have indicated that SGLT2i, ARNI and sGCs can improve the prognosis of heart failure. ARNI may have the best efficacy in improving all-cause and CV mortality. SGLT2i and ARNI have similar efficacy in improving CV death or HHF rate. SGLT2i may be the most effective in improving quality of life and reducing NT-proBNP level.³⁴

5. Combination of SGLT2i and ARNI in HFrEF

An observational, retrospective, multicentre study from Spain, enrolled 144 patients with HFrEF treated with ARNI and SGLT2i.³⁵ The results indicated that concomitant administration of SGLT2i and ARNI in routine care for patients with HFrEF caused a slight reduction in eGFR at 6 months follow-up. This decrease was particularly significant in elderly patients and those who initiated both drugs simultaneously (Table 3). In the study by Hsiao FC et al (2312 patients), treatment with a combination of SGLT2i and ARNI in diabetic patients with HFrEF was associated with lower risk of HHF and was well tolerated.³⁶

Table 3.

Studies of Combination therapy of ARNI and SGLT2i in HF.

Study	Number of studies included	Number of patients	Treatment groups	Outcomes
Jiménez-Blanco Bravo M, et al28	consecutive, observational, retrospective, multicentre study conducted in 3 Heart Failure Units	144 patients with HFrEF	Safety and efficacy of combination of ARNI and SGLT2i in HFrEF	Co-administration of SGLT2i and ARNI in routine care of HFrEF patients produced a slight decrease in eGFR at 6 months follow up. The decrease was significant in elderly patients.
Hsiao FC, et al29	Multicenter study: During 2016 to 2018, patients with HFrEF and Type2 DM were identified from Chang Gung Research Database; a database deriving from the original electronic medical records of 7 hospitals in Taiwan.	2312 patients between 2016 and 2018 of HFrEF and DM	4 groups – SGLT2i + ARNI; SGLT2i; ARNI; No SGLT2i and no ARNI	Treatment with the combination of SGLT2 inhibitors and ARNI was well tolerated in diabetic patients with HFrEF and associated with lower risk of HHF.
Jariwala P, et al30	Single centre retrospective analysis of 104 symptomatic patients of HFrEF despite of optimal medical management with ARNI between January–June 2020.	104 symptomatic patients of HFrEF		SGLT2 inhibitors should be used in symptomatic refractory HFrEF patients despite use of ARNI.
De Marzo V, et al31	69 trials metanalysis	91,741 patients	step-wise introduction of ARNI, SGLT2i, IVA and/or Vericiguat to the disease-modifying neurohormonal inhibitors (ACEI/ARB, BB and MRA) were compared with placebo	the combination SGLT2i + ARNI + BB + MRA was associated with the lowest hazard ratio.
Xiang B, et al32	48 trials metanalysis	68,074 patients	Monotherapies or combinations of ACEI, ARB, ARNI, BB, MRA, SGLT2i, IVA, and placebo	ARNI + BB + MRA, SGLT2i + ACEI + BB + MRA, and IVA + ACEI + BB + MRA were associated with significant reductions in the risk of all-cause death, CV mortality and HHF.

Note:- ARNI: angiotensin receptor-neprilysin inhibitor, ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta blocker, MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose cotransporter-2 inhibitor; HFrEF: heart failure with reduced ejection fraction; CV: cardiovascular; HHF: hospitalisation for heart failure: eGFR: estimated glomerular filtration rate: IVA: ivabradine; DM: Diabetes mellitus.

In a retrospective analysis by Jariwala et al, 104 patients with HFrEF who remained symptomatic despite receiving optimal medical management with ARNI were studied after the addition of the SGLT2i (dapagliflozin).³⁷ At 6-month follow-up, there was a significant change in LVEF 9.00 ± 0.62 (p < 0.001). An improvement in NYHA class was also observed (92.6 % of patients were in NYHA class I and 7.4 % were in NYHA class II). The subgroup of diabetic patients reached the HbA1C goal of <7 %. The authors concluded that dapagliflozin should be used in symptomatic, refractory HFrEF patients who have not responded to the use of an ARNI. The combination of ARNI and SGLT2i was well tolerated, but the results must be corroborated in large, randomized trials.³⁷

In the meta-analysis by De Marzo V et al, 91,741 patients from 69 trials were included.³⁸ The effects of step-wise introduction of new drugs such as ARNI, SGLT2i, Ivabradine (IVA) and/or Vericiguat to the disease-modifying neurohormonal inhibitors (ACEi/ARB, BB and MRA) were compared with placebo in this meta-analysis. The combination regimen of SGLT2i + ARNI + BB + MRA was associated with the lowest hazard ratio compared to the combination of SGLT2i + ACEi + BB + MRA (HR 0.28, 95 % CI 0.16–0.45 vs HR 0.40, 95 % CI 0.24–0.60).³⁸ Xiang B et al, conducted a meta-analysis of 48 trials with 68,074 patients and analysed 13 different types of interventions, including monotherapies or combinations of ACEi, ARB, ARNI, BB, MRA, SGLT2i, IVA and placebo.³⁹ Patients treated with ARNI + BB + MRA, SGLT2i + ACEi + BB + MRA and IVA + ACEi + BB + MRA had significant reductions in the risk of all-cause death, CV mortality and HHF.³⁹ Based on the results of this meta-analysis, it can be speculated that SGLT2i + ARNI + BB + MRA is the optimal therapy for HFrEF. The combined therapy of SGLT2i and ARNI contributed to more CV benefits than ARNI monotherapy.¹⁸

6. Heart failure with preserved ejection fraction (HFpEF)

The global incidence of HFpEF among the population of HF patients is almost 50 %.⁴⁰ As per the data from the Trivandrum Heart Failure Registry, the proportion of HFpEF is lower (20 %) in India, with the mean age at diagnosis being about 59 years.^40,41 Hypertension is the most common comorbidity, and 50 % of HFpEF patients are women in the ASIAN-HF registry.⁴² In HFpEF, the cardiac output is maintained at the cost of abnormally elevated filling pressure. The diagnosis of HFpEF poses a challenge and is diagnosed by a combination of clinical presentation, biomarkers (BNP/NT-proBNP), preserved LVEF (≥50 %) with diastolic dysfunction on echocardiogram. In addition to lifestyle modification and control of risk factors, the management of HFpEF includes spironolactone, ARNI and SGLT2i in some cohorts of patients.⁴⁰ SGLT2i reduces hospitalizations in both diabetic and nondiabetic patients with HFpEF.⁴⁰

In the double-blinded PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction), 4822 symptomatic HFpEF patients (age≥50 years, LVEF ≥45 %, NYHA class II-IV) were randomized to receive ARNI or valsartan.⁴³ ARNI was not effective at reducing the primary outcome of CV death or HHF rate compared with valsartan in HFpEF patients. Subgroup analysis showed that ARNI was beneficial with a reduction of the primary outcome in women than men when initiated in close proximity to index hospitalization and in those with the lower range of LVEF (<57 %). There was a more remarkable improvement in NYHA class and quality of life, and there was a lesser decline in renal function with ARNI than with valsartan.^44,45

In the double-blind EMPEROR-Preserved Trial, 5988 HF patients (NYHA class II-IV, LVEF >40 %) were randomly assigned to receive either empagliflozin 10 mg once daily or a placebo added to usual therapy.⁴⁵ Over a median duration of 26.2 months, those treated with empagliflozin experienced fewer CV deaths or HHF (13.8 %) compared to the placebo group (17.1 %), demonstrating a significant reduction in risk (hazard ratio, 0.79). This benefit was primarily due to fewer HHF and was consistent among patients with or without diabetes. The benefit on total HHF rate was similar in patients with LVEF of >40 % to <50 % and 50 % to <60 %, but was reduced at higher EF.⁴⁶

In the DELIVER trial, a total of 6263 patients with HF and LVEF greater than 40 % were randomized to receive either SGLT2i (dapagliflozin at a dose of 10 mg once daily) or matching placebo in addition to the standard therapy.⁴⁷ The primary outcome, a composite of worsening HF and CV death, was significantly lower in the dapagliflozin group compared to the placebo group (16.4 % vs. 19.5 %, HR 0.82, 95 % CI 0.73–0.92, p < 0.001).⁴⁷ The incidence of CV death and hospitalization for heart failure were also lower in the dapagliflozin group. The effect of dapagliflozin on the primary composite endpoint, such as time to the first occurrence of hospital admission for worsening heart failure or death from CV causes, was also studied. Dapagliflozin reduced the risk of this outcome by 22 % (HR 0.78, 95 % CI 0.72–0.86, p < 0.001), and the benefit appeared consistent across all EF categories.⁴⁸ The DELIVER trial also demonstrated that starting dapagliflozin during or shortly after HHF in patients with mildly reduced or preserved ejection fraction appears safe and effective.⁴⁹ Treatment with dapagliflozin is expected to extend event-free survival by up to 2–2.5 years in middle-aged and older individuals with HF, regardless of ejection fraction status.⁵⁰

The recently published PARAGLIDE-HF trial assessed ARNI vs valsartan in patients HFmrEF or HFpEF following a recent worsening of HF.⁵¹ Among HF patients with LVEF >40 % (particularly those with LVEF <60 %) stabilized after worsening of HF, ARNI led to a greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone. Improvements in clinical outcomes like CV death and HHF were not statistically significant. Additionally, ARNI was associated with higher rates of symptomatic hypotension, but fewer renal complications compared to valsartan. A pre-specified pooled analysis of PARAGLIDE-HF and PARAGON-HF revealed that ARNI reduced cardiovascular and renal events among patients with HFmrEF or HFpEF compared with valsartan.⁵²

A meta-analysis of 5 trials on patients with mildly reduced or preserved EF (DELIVER and EMPEROR-Preserved), reduced EF (DAPA-HF and EMPEROR-Reduced), and those hospitalised with worsening HF irrespective of EF (SOLOIST-WHF), showed that SGLT2 inhibitors reduced the risk of CV death and HHF in a broad range of patients with HF, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting.⁵³

The FDA recently approved Sotogliflozin, the first dual SGLT2i and SGLT1i (acts in the gut) for treating both HFrEF and HFpEF. The multicenter, randomized, double-blinded SOLOIST-WHF trial assessed the efficacy of sotagliflozin compared to placebo over 9 months in 1222 patients with T2DM recently hospitalized for worsening HF.⁵⁴ Despite early termination of this trial due to funding loss, results indicated that sotagliflozin significantly reduced the total number of CV deaths, hospitalizations, and urgent HF visits compared to placebo. The findings of this trial support the initiation of sotagliflozin either before or soon after hospital discharge in this patient group. The post hoc analysis of the SOLOIST-WHF trial found that sotagliflozin reduces CV deaths and HF-related events by 33 %, and these benefits are observable within 27 days after treatment initiation regardless of LVEF.⁵⁵ The treatment also consistently decreased hospitalizations and urgent visits for HF. Early initiation of sotagliflozin is critical for effectively managing CV risks in these patients. Hence Sotagliflozin may be a new arsenal in treating HF in diabetic patients.

7. Heart failure with mildly reduced ejection fraction (HFmrEF)

Patients with HFmrEF have LVEF of 41–49 %, and this classification was introduced in the 2016 ESC guidelines when it was referred to as HF with mid-range EF.^3,8,56,57 It represents an intermediary state of shifting HF status bridging HFrEF and HFpEF. HFmrEF is present in 18 % of patients with HF in the Trivandrum HF registry.⁴¹ HFmrEF is a distinct clinical entity with specific diagnostic criteria and varied patient characteristics, pathophysiology, and prognosis due to diverse risk factors, comorbidities, and disease stages.⁵⁸ While HFmrEF shares some features with other types of HF, its mechanisms and treatments are not fully understood.⁵⁸ Diagnosing HFmrEF is challenging due to the subtle reduction in EF, necessitating precise diagnostics and discernment of symptoms that could mimic normal aging or other illnesses.

Post hoc analyses of several HF trials indicate that standard HF treatments are also beneficial for HFmrEF.⁵⁷ Recent trials EMPEROR-Preserved and DELIVER show SGLT2 inhibitors empagliflozin and dapagliflozin benefit HF with LVEF 41–49 %, impacting HF guidelines for HFmrEF.^45,47 Empagliflozin reduced hospitalizations for HF without affecting CV death, regardless of diabetes status, while dapagliflozin lowered CV death or worsening HF risks and improved symptoms across various LVEF levels. A meta-analysis combining data from these trials confirmed a 20 % reduction in the composite endpoint of CV death or first HHF, with a specific 26 % reduction in HF hospitalizations alone.⁵³ These findings underscore the efficacy of SGLT2 inhibitors across a broad range of LVEF, prompting new clinical guidelines. The trials collectively demonstrate that while SGLT2is significantly reduce HF hospitalizations, they do not significantly affect CV death rates.⁵⁷ These findings have led to updated HFmrEF treatment recommendations without specific NT-proBNP thresholds. According to the 2023 focussed update on 2021 ESC guidelines, SGLT2i (dapagliflozin or empagliflozin) is recommended to reduce the risk of HHF or CV death in HFmrEF with Class IA recommendations, while it is still Class IIa recommendations as per 2022 ACC/AHA guidelines (Table 4).^8,57

Table 4.

Guideline recommendations for SGLT2i and ARNI for the Treatment of Heart Failure.

HF category	SGLT2i		ARNI
	Recommendations of ACC/AHA guidelinesa	Recommendation of ESC guidelinesb	Recommendations of ACC/AHA guidelinesa	Recommendation of ESC guidelinesb
HFrEF (LVEF ≤40 %)	1	1	1	1
HFmrEF (LVEF 41–49 %)	2a	1	2b	2b
HFpEF (LVEF≥50 %)	2a	1	2b	Currently no recommendations
HFimpEF (previously LVEF ≤40 % now EF>40 %)	1 (Continue and optimize GDMT)	Currently no recommendations	1 (Continue and optimize GDMT)	Currently no recommendations

Note:- HF: heart failure; HFrEF: Heart failure with reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; HFmrEF: heart failure with mildly reduced ejection fraction; HFimpEF: heart failure with improved ejection fraction; SGLT2i: sodium-glucose co-transporter 2 inhibitor, ARNI: angiotensin receptor-neprilysin inhibitor, GDMT: guideline-directed medical therapy.

^a2022 AHA (American Heart Association)/ACC (American College of Cardiology)/HFSA (Heart Failure Society of America) Guideline for the Management of Heart Failure.

^b2023 Focused Update of the 2021 ESC (European Society of Cardiology) Guidelines for the diagnosis and treatment of acute and chronic heart failure.

As per the recent guidelines, ARNI, ACEi, ARB, BB and MRA can be used in HFmrEF with Class IIb recommendations for reducing HHF and death.^8,56,57 A subgroup with LVEF 45 %–57 % in PARAGON-HF trial showed that ARNI was more effective than valsartan alone in reducing HF-related events.⁴³ The PARAGLIDE-HF trial showed that ARNI led to a greater reduction in NT-proBNP levels compared to valsartan alone in HFmrEF subgroup.⁵¹ A network meta-analysis evaluated treatments for HFmrEF, analyzing over 7966 patients showed that SGLT2i significantly reduced CV events by 19 %, while ARNI also decreased hospitalizations.⁶⁵ No single treatment was superior, indicating that therapies such as SGLT2i, ARNI, MRA, and BB effective in HFrEF are also beneficial for HFmrEF.⁵⁹ A Systematic Review and Network Meta-Analysis of 13 studies with a total of 29,875 patients with HF and LVEF over 40 % showed that a combination of ARNI, BB, MRA, and SGLT2i significantly lowers the risk of CV death and HHF and this effect mainly driven by the triple combination of ARNI, MRA, and SGLT2i, especially in HFmrEF patients.⁶⁰ These findings suggest that treatments conventionally used for HFrEF can be effective for patients in the HFmrEF category.

HFmrEF group tends to share more characteristics and comorbid conditions with HFpEF than with HFrEF.⁶¹ Notably, many HFmrEF patients experienced changes in their EF classification, with nearly 27 % deteriorating to an EF below 40 % and about 45 % improving to an EF above 50 %.⁶¹

8. Heart failure with improved ejection fraction (HFimpEF)

Improvements in LV function, or reverse LV remodelling, correlate with better outcomes in HFrEF patients. However, many such patients experience recurrent LV dysfunction and HF episodes, even after achieving normal EF.⁶² This issue has heightened interest in managing HF with recovered EF, a condition lacking a clear definition and established management guidelines. HFimpEF refers to patients who previously had HFrEF with LVEF ≤40 % and now have an improved LVEF >40 % following guideline-directed medical therapy (GDMT).⁸ Discontinuation of GDMT increases the risk of mortality and HHF in HFrEF patients. Current evidence shows continuing GDMT in HFimpEF, even in patients who may become asymptomatic unless there is a clear reversible cause, as discontinuing it leads to relapse of HF and LV dysfunction.⁸ They also require frequent clinical monitoring due to a substantial risk of HF recurrences. Device therapy should be continued indefinitely in these patients.⁶² The decision of whether to maintain GDMT or decrease/stop it in patients who have fully recovered LVEF is practically challenging for clinicians. The TRED-HF trial, a randomized open-label pilot study, assessed the risk associated with discontinuing HF medications in patients with dilated cardiomyopathy who showed recovery and had no symptoms.⁶³ Participants were split into two groups: one underwent a gradual cessation of medication, and the other maintained their treatment regimen. The study primarily looked at the re-emergence of dilated cardiomyopathy within a six-month period. The findings revealed a 44 % relapse rate in the group that stopped medication, while none who continued treatment relapsed. Following six months, 96 % of patients in the ongoing treatment group tried stopping medications, leading to relapse in nine patients. These outcomes indicate that persistent treatment with GDMT may reduce the likelihood of cardiomyopathy relapse in patients who have recovered LVEF.⁶³

In the DELIVER trial, a subgroup of 1151 (18 %) patients with HFimpEF showed a significantly reduced risk of CV death or worsening HF events to a similar degree as in patients with consistently higher EF.⁶⁴ The drug dapagliflozin significantly reduced CV death, especially sudden deaths and worsening HF events in these patients, suggesting the benefits of incorporating this medication into the treatment regimen for HFimpEF.^64,65 ARNI is to be continued as a part of GDMT in patients with HFimpEF.⁷

A study analyzed 7948 HF patients, comparing those with HFimpEF to those with heart failure persistently reduced EF (pHFrEF).⁶⁶ HFimpEF patients demonstrated milder HF severity, better renal function, and higher exercise capacity. They also had significantly lower cardiovascular mortality (26.6 vs. 46.9 per 1000 person-years) and a better long-term prognosis compared to those with pHFrEF. HFimpEF patients still face considerable risks despite their improvements, but they exhibit distinct clinical profiles indicative of partial systolic function recovery.

A meta-analysis covering 9 studies and 9491 HF patients found that during an average follow-up of 3.8 years, 22.64 % of patients with HFrEF improved to HFimpEF, resulting in a 56 % reduction in their risk of mortality.⁶⁷ HFimpEF patients have a significantly lower risk of mortality and cardiac hospitalization compared to those with HFrEF, and moderately lower risks when compared to those with HFpEF. This indicates that HFimpEF patients generally fare better than both HFrEF and HFpEF patients in terms of survival and hospitalization rates, and improving EF in HF patients could lead to better outcomes.

9. SGLT2i and ARNI in HF with renal dysfunction

SGLT2i restores the tubuloglomerular feedback, leading to vasoconstriction of afferent arterioles. This lowers the intraglomerular pressure, and there will be a minor reduction of eGFR in the range of 3–5 mL/min/1.73 m² over the first few weeks of SGLT2i initiation, followed by stabilisation of eGFR.¹¹ Thus, SGLT2i reduces hyperfiltration and delays the progression of chronic kidney disease (CKD). DAPA-CKD and EMPA-KIDNEY were randomized controlled trials that specifically evaluated the effect of SGLT2i on a primary kidney endpoint.^68,69 Both trials revealed an impressive benefit of SGLT2i on renal endpoints in patients with CKD with albuminuria regardless of diabetic status. Dapagliflozin and empagliflozin are used across the spectrum of HF with all LVEF at a standard dose of 10 mg once daily without needing up-titration. For the treatment of HF or CKD, dosage adjustment is not recommended for dapagliflozin until eGFR is less than 25 mL/min/1.73 m² and for empagliflozin until eGFR less than 20 mL/min/1.73 m².68, 69, 70 Although initiation of these drugs is not recommended below these respective eGFR values, they may be continued to reduce the risk of decline in eGFR, progression of CKD to end-stage renal disease (ESRD), CV death, and HHF. Currently, the usage of SGLT2i is contraindicated in hemodialysis patients. The DAPA-HD trial (NCT05179668) is an ongoing phase II trial evaluating the cardiovascular effects of dapagliflozin vs. placebo in hemodialysis patients, focusing on the change in left ventricular mass over six months.⁷¹

In the SCORED trial, 10,584 patients with T2DM and an estimated glomerular filtration rate (eGFR) of 25–60 mL/min/1.73 m² with or without albuminuria were enrolled.⁷² The primary endpoints, such as CV death, HHF, and urgent HF visits, were reduced by 26 % with sotagliflozin compared to placebo in this trial. The CANVAS trial showed that canagliflozin reduced major CV events in T2DM patients with high CV risk but increased the risk of amputation, especially at the toe or metatarsal level.⁷³ Although renal outcomes did not reach statistical significance, there was a potential benefit in reducing the progression of albuminuria and serious renal outcomes in this trial. CREDENCE trial involving T2DM patients with CKD, canagliflozin significantly reduced risks associated with kidney failure and CV events compared to placebo.⁷⁴ This trial was stopped prematurely due to these positive results, highlighting canagliflozin's efficacy in lowering the rates of ESKD, doubling of creatinine levels, and CV complications like heart attacks and strokes. There were no increased risks of amputation or fractures. A meta-analysis including trials such as DAPA-CKD, EMPA-KIDNEY, CREDENCE, and SCORED examined the effects of SGLT2i in patients with and without T2DM.⁷⁵ The results indicated a consistent reduction in HHF and CV death across all these patients, including HF and CKD trials. However, the benefit was not significant in patients without diabetes when only CKD trials were considered. SGLT2i are therefore recommended for patients with CKD and T2DM, particularly those with an eGFR >20–25 mL/min/1.73 m², to lower the risk of HHF or CV death.

ARNI can be prescribed to non-dialysis patients with CKD and HF.⁷ The usage of ARNI in such patients reduces CV risk and improves eGFR. The PARADIGM-HF study analysis of CKD patients with eGFR of 30–60 mL/min/1.73 m² demonstrated that using ARNI resulted in a decreased risk of CV events compared to ACEi treatment.⁷⁶ This included 24 % reduction in the risk of CV death, a 21 % decrease in the risk of HHF, and 36 % decrease in the risk of composite kidney events. It was observed in this study that ARNI treatment led to a slight increase in urine albumin creatinine ratio, which could be attributed to improved renal perfusion resulting from enhanced cardiac function. Real-world studies conducted in Taiwan and Italy also supported the findings of reduced risk of CV death and hospitalization, along with improved eGFR, in patients treated with ARNI.^77,78 In the PARAGON-HF study of patients with HFpEF, an analysis of the CKD subgroup revealed a 50 % reduction in the risk of the renal composite endpoint when comparing ARNI to ARB.⁴³ A retrospective cohort study indicated that patients with CKD and HFpEF treated with ARNI had higher eGFR than those treated with valsartan. Furthermore, a meta-analysis demonstrated that ARNI improved eGFR and reduced NT-proBNP levels compared to ACEi/ARB.⁷⁹ No dosage adjustment is recommended for ARNI until eGFR is less than 30 mL/min/1.73 m² when the dose is halved.⁷⁶ Studies have shown that ARNI could improve LV systolic and diastolic function in patients with HFrEF and ESRD on dialysis.^80,81 Some nephrologists use ARNI with concomitant potassium-lowering agents in dialysis patients with HF. A few studies endorse the use of ARNI for HF patients with CKD on maintenance dialysis to improve myocardial remodelling and heart function, alleviate HF symptoms, protect residual kidney function, and reduce the risk of CV events.^7,82,83 Although ARNI treatment significantly lowered all-cause mortality in dialysis patients with HF, it did not significantly reduce CV mortality, indicating a need for further research on its long-term benefits in this group.⁸³ However, there is currently no American or European guideline recommendation for using ARNI in ESRD patients undergoing dialysis. These findings re-emphasize that ARNI is useful in patients with CKD not only for improving HF but also for improving renal functions. Thus, CKD per se should not be an absolute contraindication for not initiating or discontinuing ARNI.

10. Acute heart failure (AHF)

The two main objectives in treating AHF during hospitalization are to achieve complete decongestion of the patient and to optimize GDMT to improve outcomes. The EMPULSE trial investigated empagliflozin's impact on AHF management, demonstrating the clinical advantages of administering this SGLT2 inhibitor early during hospital stays.⁸⁴ The drug notably improved mortality rates, heart failure events, and patient-reported symptoms. Moreover, empagliflozin significantly decreased weight and other congestion indicators over three months. Outcomes by the 90th day suggested that empagliflozin offers a promising strategy for early and continued relief from fluid build-up, enhancing overall patient health in AHF cases. The DICTATE-AHF trial evaluated the effect of dapagliflozin on diuretic efficiency in patients with AHF requiring intravenous loop diuretics.⁸⁵ It hinted at improved diuretic response with dapagliflozin in acute HF, echoing findings from EMPULSE with empagliflozin, but didn't significantly reduce 30-day readmissions. Starting SGLT2 inhibitor therapy during hospitalization for AHF seems safe and potentially advantageous, prompting consideration for more extensive trials to solidify these early findings.

The PIONEER-HF trial indicated that starting ARNI therapy in patients hospitalized for acute decompensated heart failure reduces NT-proBNP levels without raising the risk of adverse events compared to enalapril.⁸⁶ Further analysis suggested potential reductions in all-cause mortality and HHF, although these findings were exploratory and inconclusive. Additionally, initiating ARNI treatment during hospitalization was more beneficial than starting it after discharge. The TRANSITION study found that initiating ARNI in patients stabilized after AHF is feasible either pre- or post-discharge, with half achieving the target dose by 10 weeks and a tolerable safety profile.⁸⁷ Thus, ARNI is recommended as de novo treatment in hospitalized patients with acute HF before discharge.

The COACH trial enrolled 5452 patients with AHF and examined whether a decision-support strategy and rapid outpatient follow-up could improve outcomes in these patients.⁸⁸ It is a complex intervention strategy (stepped-wedge, cluster-randomized) trial consisting of a one-way crossover from the control phase (usual care) to the intervention phase. The Emergency Heart Failure Mortality Risk Grade 30 Day Mortality-ST Depression (EHMRG30-ST) score was used to risk stratify and categorize patients in the intervention phase into low, intermediate, or high risk of death within 7 or 30 days. The protocol suggested early discharge (within ≤3 days) and standardized outpatient care for low-risk patients up to 30 days while recommending hospital admission for intermediate and high-risk patients. Despite similar early discharge rates in both phases (57 % in intervention vs. 58 % in control), the hospital-based strategy led to a 12 % reduction in the rate of all-cause death or hospitalization for CV reasons (HR 0.88, 95 % CI 0.78–0.99), indicating a beneficial impact of post-discharge care within 30 days compared to usual care.

Patients tolerated rapid up-titration and optimisation of intensive treatment of GDMT with close follow-up after AHF admission. The STRONG-HF trial investigated an aggressive treatment approach in hospitalized AHF patients.⁸⁹ This multinational, open-label, randomised study with 1078 participants compared the usual local care to a high-intensity treatment strategy with rapid up-titration of medications to full recommended levels within two weeks post-discharge and close follow-up that included four follow-up outpatient visits over two months with detailed health monitoring. The study concluded prematurely when notable benefits emerged early in the high-intensity treatment group. By the 90th day, more patients in this group met their medication targets, reported fewer symptoms, and enjoyed a better quality of life. Furthermore, at 180 days, they had a lower rate of death or HHF, despite experiencing more side effects.⁸⁹ An intensive approach involving the initiation and rapid increase of evidence-based treatments before discharge, along with frequent and thorough follow-up visits in the first 6 weeks after HHF, is recommended to lower the risk of rehospitalization or death from HF.⁵⁷

11. Sequencing of medications in HF

Physicians conventionally initiated drug therapies for HFrEF in a sequential order and up-titrated each drug to the target dose used in clinical trials before adding another therapy. Thus, 6 months or more is required to prescribe all the recommended drugs for HFrEF, but this delay is unacceptable because each of the foundational drugs has been shown to reduce morbidity and mortality within 30 days of initiating treatment. Prespecified secondary analysis of the DAPA-HF trial and the DELIVER trial showed that a rapid statistically sustained significant reduction in the risk of CV death or worsening HF was observed after treatment initiation by 28 days in HFrEF patients and by 13 days in HFmrEF or HFpEF patients.^90,91 Hence, in 2021, McMurray JJV et al proposed a “new sequence” algorithm to initiate HF patients decongested with diuretics.⁹² This accelerated three-step approach consisted of simultaneous initiation of BB and SGLT2i as the first step, the addition of ARNI within 1–2 weeks as the second step, and the addition of an MRA within the next 1–2 weeks as the third step. The order of the latter two steps can be adjusted based on the patient's individual circumstances. According to the 2022 AHA/ACC/HFSA Guidelines for HF, the foundational medications such as ARNI in NYHA class II-III (ACEi/ARB in NYHA II-IV), SGLT2i, BB and MRA, which constitute the pillars of GDMT for HFrEF may be initiated as the first line medications, either multiple drugs simultaneously at low doses or sequentially without any specific order.⁸ The order of titration and optimization of GDMT is usually individualized according to the patient's symptoms, hemodynamics, functional status, tolerance, renal function, electrolytes, comorbidities, the specific cause of HF, and the ability of follow-up. Medication doses should be increased to target as tolerated without delay, and there is no need to achieve target dosing before initiating the next medication. Thus, it is essential to follow the recommendations of HF guidelines to simultaneously or sequentially initiate multiple GDMTs as early as possible, up-titrate their dosages rapidly and continue them to reduce risks of mortality and rehospitalization.

12. Usage of GDMT

Despite the knowledge about the benefits of GDMT in HF patients, the usage of these medications is not up to the mark. An observational study of GDMT for HF involving 266,589 patients showed that, compared to more traditional therapies, novel GDMT like SGLT2i (dapagliflozin) and ARNI were initiated significantly later following hospital discharge.⁹³ Almost one out of four patients prematurely discontinued GDMT within the first year of treatment initiation, with MRA and ACEi having the highest discontinuation rates. Dapagliflozin showed higher persistence rates compared to other drugs studied. Only a small proportion of patients reached the target dosages recommended by guidelines within the first year of treatment.

Although there's strong evidence supporting the use of ARNI in HF treatment, real-world application and appropriate dosage up-titration are still not at expected levels.⁶ According to the National Heart Failure Registry, only one of two (47.5 %) patients with HFrEF in India are currently receiving GDMT, and the data also states that ARNI is underutilised with only 4.8 % of HFrEF patients receiving it.⁹⁴ Trivandrum Heart Failure Registry showed that lack of GDMT was associated with higher 5-year mortality in Indian HFrEF patients.⁴¹

The following are the various factors involved in the low usage and the failure to up-titrate GDMT in HF patients:^6,93

• •Side effects and tolerability: Concerns about the common side effects of ARNI, such as hypotension, hyperkalemia and worsening renal function, can affect the initiation/titration of its dosage. However, with appropriate patient education and regular monitoring, these can be managed, and dosages can be safely adjusted over time. Hypotension is a significant initial side effect when starting ARNI therapy, particularly in patients with HFrEF. This often prevents reaching the optimal dosage due to concerns about low blood pressure. However, blood pressure usually recovers as cardiac function improves, allowing for continued treatment. Renal function must be monitored when patients are on ARNI. Elevated creatinine and reduced clearance, along with hyperkalemia, might necessitate stopping the medication. Hyperkalemia is especially critical and warrants close observation, adjusting or halting ARNI if potassium levels exceed safe limits. Treatment should be tailored to individual needs based on specific health indicators and body weight, avoiding a one-size-fits-all approach. The usage of SGLT2i is at times limited due to urinary infection and genital fungal infections (vaginal yeast infection, balanitis, balanoposthitis etc), but this can be overcome by maintaining genital hygiene.
• •Clinical inertia: Physicians must overcome clinical inertia and actively manage and adjust the dosing of GDMT, aiming to achieve the best possible therapeutic outcome for each patient. Healthcare providers may hesitate to adopt new treatment guidelines due to unfamiliarity or concerns about the safety and efficacy of new therapies.
• •Guideline Implementation: The guidelines may not be widely disseminated and adopted in practice settings, and there might also be a lack of clear protocols for transitioning patients from older therapies to newer options.
• •Patient-Specific Factors: Variabilities in patient demographics and comorbidities, such as age, gender, diabetes, and kidney disease, can affect drug tolerability and safety, reducing the likelihood of dose increases.
• •Healthcare System Differences: Variations in healthcare infrastructure and patient management strategies can affect the adoption speed of new therapies
• •Regulatory and Access Issues: Depending on the country, newer medications may be approved with delays, pricing negotiations, or insurance coverage issues can impede medication availability.

There is a noticeable reluctance in not only initiating and up-titrating GDMT in HF but also in the continuation of these medications in these patients. LVEF deteriorates significantly, end-diastolic volume returns to the baseline (increased dimension), and NYHA class worsens on discontinuation of ARNI in HFrEF patients and shifting to ACEi or ARB.⁹⁵ The reasons for high discontinuation rates of GDMT in HF patients are adverse effects of these medications, interactions from multiple comorbidities that can reduce efficacy or increase side effects, insufficient awareness about the benefits of continuous medication use results in poor adherence, financial issues and lack of insurance coverage can prevent ongoing treatment and clinical inertia of healthcare providers with lack of timely medication adjustments to meet changing health needs can cause patients to stop treatment.⁹³

13. Summary

Dapagliflozin, empagliflozin, and sotagliflozin are the SGLT2i recommended in patients with HFrEF, regardless of their diabetes status, to reduce CV death and HHF. In addition to these, SGLT2i, canagliflozin and ertugliflozin are recommended in patients with T2DM at risk of CV events to reduce HHF, major CV events, ESRD, and CV death.

13.1. When is SGLT2i to be considered as the first choice?

• •SGLT2i has emerged as an ideal drug in intensive care because it has no immediate drastic hemodynamic effect on heart rate, blood pressure, or LV end-diastolic pressure. Hence, it is preferred when borderline hemodynamics work against the initiation of BB and ARNI.
• •Considering that the net benefit of SGLT2i starts appearing as early as 12 days after therapy is initiated, it scores when speed matters in clinical practice.
• •In the setting of acute kidney injury or, more importantly, cardiorenal syndrome scenarios where we are sceptical about starting ARNI, SGLT2i is the first choice. It is even more relevant in established ESRD, where the risk of hypoglycemia is also non-existent.
• •With manifest HF but near normal LVEF, the benefits of SGLT2i outweigh the ARNI, as the summary of DELIVER and PARAGON HF would vouch. Simply put, the higher the LVEF, the more effective SGLT 2 is than ARNI.
• •Although such direct comparisons are inappropriate and not tangible in the research world, all HF and CKD trials with SGLT2i have a net clinical benefit in mortality and HHF reductions in the range of 30–37 %, while with ARNI, the number never crosses 20 %.

13.2. When is ARNI to be considered as the first choice?

• •Hypertensive Heart Failure with difficult to treat hypertension will respond well to ARNI initiation and up-titration as compared to SGLT2i.
• •In the context of an intensive care setting and poorly controlled glycaemic status, ARNI would be a better choice to avoid precipitating a metabolic crisis with SGLT2i initiation.
• •A documented episode of pyelonephritis is an absolute contraindication to starting SGLT2i, more so in the female population, and ARNI would obviously be the first choice in such a scenario.

14. Conclusion

In conclusion, the management of HF has been greatly advanced by the introduction of ARNI and SGLT2i. These therapies have significantly impacted treatment guidelines, improving cardiovascular outcomes and reducing hospitalizations. Current guidelines have provided significant roles to both ARNI and SGLT2i in the management algorithm of HFrEF. On the other hand, SGLT2i has steadily and strongly gained its position in treating HFpEF, while ARNI is still not firmly established to treat HFpEF. The potential for combining these therapies suggests a synergistic benefit that could enhance patient outcomes, although further research is needed to fully understand the effects of such combinations. Moving forward, the application of ARNI and SGLT2i must be tailored to individual patient needs and continuously refined by new research and clinical practice updates. This represents a significant stride in reducing the burden of HF and improving the quality of life for patients, signalling a hopeful future in HF management.

Funding/grants

No funding/grant was obtained for this study.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.