Nutrient-Stimulated Hormone Therapies in Heart Failure: Targeting Cardiometabolic Burden Beyond Weight Reduction

Abstract

The intersection of obesity and heart failure (HF) represents a growing epidemic characterized by a distinct cardiometabolic phenotype. Historically, management has been hamstrung by a significant therapeutic gap: lifestyle interventions often fail to overcome metabolic inertia, yielding negligible weight reduction, while bariatric surgery remains limited by invasiveness. The emergence of Nutrient-Stimulated Hormone (NuSH) therapies, including glucagon-like peptide-1 receptor agonists, has revolutionized this landscape. This review delineates the paradigm shift driven by these agents, which act as a “medical bypass” offering surgical-magnitude weight loss and broad pleiotropic cardioprotection. We analyze pivotal evidence from the STEP-HFpEF and SUMMIT trials, demonstrating that NuSH therapies have established a new standard of care in heart failure with preserved ejection fraction (HFpEF) by not only restoring functional capacity but also significantly reducing hard clinical endpoints. Conversely, we navigate the uncertainty surrounding heart failure with reduced ejection fraction (HFrEF), where historical safety signals regarding chronotropic effects and arrhythmias necessitate a cautious, precision-based approach. Finally, we discuss critical future frontiers, emphasizing the “muscle imperative” to mitigate sarcopenic obesity and the need for biomarker-guided protocols. NuSH therapies have evolved from metabolic tools into essential disease-modifying pillars, necessitating a fundamental recalibration of clinical practice to target the metabolic root of HF.

Graphical Abstract

INTRODUCTION

Obesity has long been established as a major independent risk factor for the development of heart failure (HF).¹⁾ The pathophysiology of obesity-related HF is driven by the mechanical load of excess adiposity, which increases hemodynamic stress, alongside metabolic derangements caused by dysfunctional adipose tissue.²⁾ Adipocytes secrete pro-inflammatory adipokines that induce systemic inflammation, promote insulin resistance, and impair myocardial energetic efficiency.³,⁴⁾ Notably, the obesity-related phenotype represents the archetype of cardiometabolic heart failure with preserved ejection fraction (HFpEF), a condition characterized by a distinct pathophysiology and poor clinical prognosis.⁵⁾ Pragmatically, this phenotype is defined by a body mass index (BMI) ≥30 kg/m² (or ≥25 kg/m² in Asian populations), severe exercise intolerance, and a high burden of co-clustering metabolic derangements such as type 2 diabetes and systemic inflammation (e.g., elevated high-sensitivity C-reactive protein [CRP]).²⁾ A critical diagnostic caveat in this population is that natriuretic peptide levels are often disproportionately lower relative to their actual hemodynamic stress.⁶⁾ Therefore, a comprehensive strategy to manage the substantial cardiometabolic burden in these patients is clinically imperative.

Historically, the management of obesity in HF has been challenging. While lifestyle modifications such as diet and increased physical activity are the cornerstone of therapy, they often fail to achieve sustained weight loss.⁷,⁸⁾ This failure is largely attributed to the body’s compensatory neurohormonal mechanisms that defend a metabolic “set point,” thereby resisting deviations from established homeostasis.⁹⁾ Consequently, for decades, bariatric surgery remained the only intervention capable of delivering substantial weight reduction and improving cardiac outcomes.¹⁰⁾ However, a significant therapeutic gap existed between conservative lifestyle modifications and invasive surgical procedures.

The emergence of Nutrient-Stimulated Hormone (NuSH) therapies—including glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) and dual/triple agonists—has bridged this chasm.¹¹⁾ These agents have demonstrated the capacity to reset metabolic homeostasis, offering surgical-magnitude weight loss. Furthermore, landmark trials have revealed that NuSH therapies provide benefits beyond weight reduction, exhibiting pleiotropic effects that stabilize atherosclerotic plaques, reduce inflammation, and improve renal function.¹²⁾ Building on this foundation, recent evidence confirms that NuSH can significantly improve clinical outcomes in patients with HF, particularly those with the obesity-related HFpEF phenotype.¹³,¹⁴,¹⁵⁾ Thus, NuSH has emerged as a fundamental therapeutic pillar, specifically targeting and managing the underlying cardiometabolic burden in HF.

This review synthesizes the evolving role of NuSH in HF, exploring the transition from weight management to cardiovascular protection, and discusses the remaining challenges and future perspectives in this rapidly advancing field.

THE REMARKABLE EFFICACY OF NuSH: A NEW ERA OF WEIGHT MANAGEMENT

The landscape of obesity management has undergone a paradigm shift with the evolution of NuSH therapies. Historically, pharmacological options were limited by modest efficacy and safety concerns, leaving bariatric surgery as the sole intervention capable of achieving substantial, double-digit weight loss.⁷,¹⁰⁾ However, recent innovations in molecular engineering have bridged this gap, ushering in an era where pharmacotherapy rivals surgical outcomes.

The first major leap in this field was the transition to weekly semaglutide. Semaglutide was developed to overcome the pharmacokinetic limitations of daily GLP-1 RAs. By substituting Alanine with α-aminoisobutyric acid at position 8 to confer resistance against dipeptidyl peptidase-4 degradation, and attaching a C-18 fatty di-acid chain to facilitate strong albumin binding, semaglutide significantly reduced renal clearance (Figure 1). This structural optimization extended the half-life to approximately 165 hours, allowing for once-weekly administration and stable drug concentrations. The clinical impact of this innovation was established in the STEP-1 trial, where semaglutide 2.4 mg set a new benchmark with a mean weight loss of 14.9% over 68 weeks (Table 1).¹⁶⁾

Figure 1. Structural evolution of GLP-1 receptor agonists and synergistic mechanisms of dual GIP/GLP-1 agonism. (A) Molecular engineering for half-life extension: comparison of native GLP-1, liraglutide, and semaglutide. Semaglutide incorporates the substitution of alanine with α-aminoisobutyric acid at position 8 to prevent DPP-4 degradation and the attachment of a C-18 fatty di-acid chain to enhance albumin binding, extending the half-life to approximately 165 hours. (B) Synergistic mechanisms of dual GIP/GLP-1 agonism: the dual agonist (e.g., tirzepatide) leverages complementary pathways. GLP-1 receptor activation primarily mediates weight loss through appetite suppression in the central nervous system and delayed gastric emptying. Uniquely, GIP receptor activation targets white adipose tissue to enhance lipid buffering capacity, improve insulin sensitivity, and reduce inflammation. These distinct mechanisms synergize in the pancreas to potentiate glucose-dependent insulin secretion, resulting in superior metabolic efficacy compared to GLP-1 mono-agonism.

GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic polypeptide; DPP-4 = dipeptidyl peptidase-4.

Table 1. Nutrient-Stimulated Hormone landmark trials for obesity management.

Drug class	Trial (treatment duration)	Agent vs. Comparison	Weight loss	Key clinical implication
GLP-1 RA	STEP-116) (68 weeks)	Semaglutide 2.4 mg vs. Placebo	−14.9%	Setting the benchmark: established the standard for modern pharmacological obesity treatment.
Dual agonist (GLP-1/GIP)	SURMOUNT-117) (72 weeks)	Tirzepatide 15 mg vs. Placebo	−20.9%	Breaking the 20% barrier: demonstrated efficacy approaching that of bariatric surgery for the first time.
Head-to-head	SURMOUNT-518) (72 weeks)	Tirzepatide 15 mg vs. Semaglutide 2.4 mg	−20.2% vs. −13.7%	Superiority confirmed: direct comparison proved dual agonist is superior to mono-agonist (approximately 1.5× more potent).
High-dose GLP-1 RA	STEP-UP19) (72 weeks)	Semaglutide 7.2 mg vs. Placebo	−18.7%	Dose matters: achieving dual-agonist level weight loss (−18.7%) with a mono-agonist through high-dose escalation.
Triple agonist (GLP-1/GIP/Gcg)	Phase 220) (48 weeks)	Retatrutide 12 mg vs. Placebo	−24.2%	Triple synergy: current highest efficacy among published data.
Amylin combo (GLP-1 + Amylin)	REDEFINE 121) (68 weeks)	Semaglutide 2.4 mg + Cagrilintide 2.4 mg vs. Placebo	−20.4%	New pathway validation: confirmed that combining amylin with GLP-1 induces massive weight loss, distinct from incretin-only approaches.

GLP-1 RA = glucagon-like peptide-1 receptor agonist; GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic polypeptide; Gcg = glucagon.

Building on this success, the therapeutic focus shifted from single receptor agonism to multi-receptor synergies. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, leverages the complementary effects of GIP to further enhance metabolic regulation. In the SURMOUNT-1 trial, tirzepatide 15 mg broke the “20% barrier,” achieving a 20.9% weight reduction.¹⁷⁾ Furthermore, the head-to-head SURMOUNT-5 trial confirmed the superiority of this dual mechanism, demonstrating significantly greater weight loss compared to semaglutide 2.4 mg (−20.2% vs. −13.7%).¹⁸⁾

Current research is now exploring the upper limits of efficacy through dose escalation and novel combinations. The STEP-UP trial revealed that increasing the dose of semaglutide to 7.2 mg could yield a weight loss of 18.7%, approaching the efficacy of dual agonists, albeit with increased adverse events.¹⁹⁾ Simultaneously, the REDEFINE 1 trial validated a non-incretin pathway, showing that CagriSema—a fixed-dose combination of semaglutide and the amylin analogue cagrilintide—achieved a 20.4% reduction in body weight.²⁰⁾ Finally, the “next-generation” triple agonist Retatrutide (GLP-1/GIP/Glucagon) has demonstrated unprecedented efficacy in phase 2 trials, with weight loss exceeding 24%, challenging the “gold standard” of bariatric surgery.²¹⁾

These advancements suggest that the physiological “set point” of body weight can now be effectively reset pharmacologically, offering a potent, non-invasive alternative to surgery for high-risk patients with HF.

BEYOND WEIGHT LOSS: CARDIOVASCULAR OUTCOME TRIALS (CVOTs) AND PLEIOTROPIC EFFECTS

While obesity has long been recognized as a pivotal independent risk factor for cardiovascular disease, demonstrating that weight reduction directly improves cardiovascular outcomes has historically been elusive. It is generally accepted that a weight loss threshold of at least 10% is necessary to derive meaningful prognostic cardiovascular benefits.²²⁾ However, previous large-scale lifestyle intervention trials yielded disappointing results. For instance, the Look AHEAD trial, which evaluated intensive lifestyle intervention in patients with type 2 diabetes, achieved a modest mean weight loss of approximately 6% and failed to reduce the primary composite cardiovascular endpoint.²³⁾ Yet, a crucial post hoc analysis provided a compelling ray of hope, revealing that patients who successfully achieved a weight loss of greater than 10% did indeed experience a significant reduction in cardiovascular events.²⁴⁾ This underscored the concept that a substantial magnitude of weight reduction is requisite to modify cardiovascular risk. Prior to the advent of potent NuSH therapies, older anti-obesity agents lacked robust CVOT data. Even liraglutide, despite its success in the LEADER trial, was primarily studied in the context of diabetes management rather than non-diabetic obesity.²⁵⁾ Consequently, for decades, bariatric surgery remained the only intervention proven to improve hard cardiovascular outcomes.

Improvement of CVOTs

The SELECT trial marked a monumental paradigm shift, bridging the gap between medical and surgical efficacy. In this landmark study involving non-diabetic patients with overweight or obesity, semaglutide 2.4 mg reduced the risk of major adverse cardiovascular events (MACE) by 20%.²⁶⁾ Although post hoc analyses suggested that approximately 33% of this benefit was mediated through reductions in waist circumference, a significant portion of the cardioprotective effect was independent of baseline adiposity and the magnitude of weight loss.²⁷⁾ This finding implies that the cardiovascular protection provided by NuSH is not solely driven by weight reduction but is mediated by direct pleiotropic effects, including plaque stabilization and systemic anti-inflammatory actions. Furthermore, the SURPASS-CVOT reinforced the cardiovascular safety and efficacy of dual agonism; while tirzepatide did not demonstrate superiority over dulaglutide, establishing non-inferiority against an active comparator with proven cardiovascular benefits confirms its robust protective role.²⁸⁾

Solidifying this evidence base, a recent comprehensive systematic review and meta-analysis encompassing 99,599 patients across 21 randomized controlled trials (RCTs) provided conclusive, high-certainty evidence of the class-wide cardioprotective profile. GLP-1 RAs significantly reduced the risk of MACE (incidence rate ratio 0.87; number needed to treat=66) compared with controls.²⁹⁾ Beyond this robust cardiovascular protection, the analysis highlighted broad organ-protective effects, including reductions in myocardial infarction (−15%), HF (−15%), and acute kidney failure (−9%). While these benefits were associated with known side effects such as increased gastrointestinal (+63%) and gallbladder (+26%) disorders, the overall reduction in serious adverse events (−9%) confirms a highly favorable net clinical benefit.

Pleiotropic effects of NuSH therapies

These pleiotropic benefits extend beyond the vasculature to multiple organ systems, offering comprehensive protection for the “cardiometabolic HF phenotype,” as demonstrated in Figure 2 and Table 2. Beyond simple weight loss, NuSH therapies have demonstrated profound disease-modifying effects across the cardiorenal, respiratory, and hepatic axes. The FLOW trial highlighted the critical importance of the cardiorenal axis, demonstrating that semaglutide significantly reduced the risk of primary kidney disease events and renal death by 24% compared to placebo.³⁰⁾ Secondary outcomes further favored semaglutide, with the mean annual estimated glomerular filtration rate slope being less steep—indicating a slower decline in kidney function—by 1.16 mL/min/1.73 m² (p<0.001). Given the bidirectional relationship between heart and kidney failure, this nephroprotection is a key component of comprehensive HF management.

Figure 2. Pleiotropic disease-modifying effects of NuSH therapies and potential to target cardiometabolic burden in heart failure. This figure illustrates how NuSH therapies exert comprehensive protective effects across multiple organ systems, converging to mitigate cardiometabolic risk in heart failure. (A) Vascular axis: semaglutide stabilizes atherosclerotic plaques and reduces systemic inflammation, translating to a 20% reduction in MACE (SELECT trial), independent of baseline weight. (B) Cardiorenal axis: through mechanisms of natriuresis and reduced glomerular hyperfiltration, semaglutide lowers the risk of major kidney disease events by 24% and slows eGFR decline (FLOW trial), preserving the cardiorenal axis essential for HF management. (C) Respiratory axis: tirzepatide significantly alleviates the mechanical load on the upper airway and reduces right ventricular strain, resulting in a reduction in the AHI by 20.0–23.8 events/h (SURMOUNT-OSA). (D) Hepatic axis: NuSH therapies resolve MASH in approximately 62% of patients (ESSENCE, SYNERGY-NASH), thereby decreasing the systemic inflammatory burden driven by lipotoxicity. (E) Adipose tissue axis: NuSH therapies reduce adipose tissue volume and improve dysfunctional fat. These mechanisms attenuate pro-inflammatory cytokines (TNF-α, IL-6) and decrease mechanical fat load, including epicardial fat, which collectively contribute to the improvement of heart failure outcomes (SUMMIT CMR study, STEP-HFpEF).

NuSH = Nutrient-Stimulated Hormone; MACE = major adverse cardiovascular events; eGFR = estimated glomerular filtration rate; HF = heart failure; AHI = apnea-hypopnea index; MASH = metabolic dysfunction-associated steatohepatitis; TNF-α = tumor necrosis factor-alpha; IL-6 = interleukin-6; HFpEF = heart failure with preserved ejection fraction; CV = cardiovascular; HHF = hospitalization for heart failure; RV = right ventricular.

Table 2. Nutrient-Stimulated Hormone landmark trials for CVOT and pleiotropic effects.

Domain	Trial (treatment duration)	Agent vs. Comparison	Key outcome (primary endpoint)		Clinical implication
CVOT	SELECT26) (mean 39.8 months)	Semaglutide 2.4 mg vs. Placebo	MACE reduced by 20% (CV death, MI, stroke)		Demonstrated CV protection beyond simple weight loss. Mediation analysis suggests only ~33% of the benefit is driven by waist circumference reduction.
CVOT	SURPASS-CVOT28) (median 48 months)	Tirzepatide vs. Dulaglutide	Non-inferiority confirmed (for MACE)		Established robust cardiovascular safety compared to a GLP-1 RA with proven CV benefits, rather than just placebo.
Renal	FLOW30) (median 40.8 months)	Semaglutide 1.0 mg vs. Placebo	Kidney events reduced by 24% (eGFR decline, ESKD, renal death); eGFR slope benefit: +1.16 mL/min/1.73 m2		Cardiorenal protection: confirmed nephroprotection, a critical component for managing the bidirectional heart-kidney failure axis.
Respiratory (OSA)	SURMOUNT-OSA31) (52 weeks)	Tirzepatide vs. Placebo	AHI reduced by 20.0–23.8 events/h (trial 1 & trial 2)		Relieving mechanical load: significant improvement in sleep apnea severity, potentially reducing hypoxia and right ventricular strain in HF patients.
Hepatic (MASH)	SYNERGY-NASH32) (52 weeks)	Tirzepatide 15 mg vs. Placebo	MASH resolution: 62% (vs. 10% placebo)		Resolving inflammation: demonstrated high rates of MASH resolution, reducing the systemic inflammatory burden associated with metabolic dysfunction.
Hepatic (MASH)	ESSENCE33) (72 weeks)	Semaglutide 2.4 mg vs. Placebo	MASH resolution: 62.9% (vs. 34.3% placebo)		Fibrosis improvement: confirmed efficacy in reversing steatohepatitis and improving fibrosis, targeting the root cause of cardiometabolic syndrome.
Vascular (peripheral artery disease)	STRIDE34) (52 weeks)	Semaglutide 1.0 mg vs. Placebo	Walking distance improved ratio to baseline: 1.13 (+13%)		Vascular function: improved functional capacity in patients with PAD and T2DM, addressing peripheral vascular limitations that contribute to exercise intolerance in HF.
Musculoskeletal (osteoarthritis)	STEP 935) (68 weeks)	Semaglutide 2.4 mg vs. Placebo	Pain & weight reduction		Enabling physical activity: significant pain relief and weight loss break the vicious cycle of immobility, facilitating exercise rehabilitation in obesity-related HF.
				- WOMAC pain score: −14.1 points
				- Body weight: −10.5%

CVOT = cardiovascular outcome trial; MACE = major adverse cardiovascular events; CV = cardiovascular; MI = myocardial infarction; GLP-1 RA = glucagon-like peptide-1 receptor agonist; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; OSA = obstructive sleep apnea; AHI = apnea-hypopnea index; HF = heart failure; MASH = metabolic dysfunction-associated steatohepatitis; PAD = peripheral artery disease; T2DM = type 2 diabetes mellitus; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

Additionally, the SURMOUNT-OSA trial demonstrated that tirzepatide significantly improved the apnea-hypopnea index in patients with obstructive sleep apnea, a major comorbidity that exacerbates right ventricular strain in HFpEF.³¹⁾ In Trial 1, which enrolled participants not receiving positive airway pressure (PAP) therapy, the estimated treatment difference was −20.0 events per hour, while in Trial 2, involving patients on PAP therapy, the difference was −23.8 events per hour. Finally, regarding hepatic health, trials such as ESSENCE and SYNERGY-NASH have proven that NuSH therapies can resolve metabolic dysfunction-associated steatohepatitis (MASH) and improve fibrosis, thereby reducing the systemic inflammatory burden that contributes to myocardial dysfunction. Biopsy-confirmed results from SYNERGY-NASH showed that 62% of participants in the 15-mg tirzepatide group achieved MASH resolution.³²⁾ Similarly, in the semaglutide group of the ESSENCE trial, resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of patients compared to 34.3% in the placebo group.³³⁾

Finally, recent evidence suggests that NuSH therapies also address physical limitations caused by peripheral and musculoskeletal comorbidities, which are crucial barriers to exercise in HF. The STRIDE trial demonstrated that semaglutide 1.0 mg significantly improved functional status in patients with peripheral artery disease (PAD) and type 2 diabetes, increasing the maximum walking distance by 13% compared to baseline.³⁴⁾ Furthermore, the STEP 9 trial showed that semaglutide 2.4 mg provided substantial relief in patients with knee osteoarthritis, significantly reducing the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score by 14.1 points while achieving a 10.5% weight loss.³⁵⁾ By alleviating the burden of PAD and osteoarthritis, NuSH therapies may break the vicious cycle of immobility, facilitating the physical rehabilitation essential for holistic HF management.

While lifestyle modification is fundamental to HF management, its ability to reverse the obesity-HF phenotype is limited. The landmark HF-ACTION trial demonstrated that while exercise training and home-based programs improved quality of life, they resulted in a negligible weight reduction of only 0.5 kg, particularly in obese patients.³⁶,³⁷⁾ Furthermore, usual care plus exercise training led to a modest improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score compared with usual care alone (mean difference 1.93; 5.21 vs. 3.28). This implies that lifestyle intervention alone is often insufficient to overcome the physiological inertia of obesity in HF. Conversely, bariatric surgery has provided proof-of-concept that substantial weight loss can fundamentally alter the disease trajectory. Aleassa et al.³⁸⁾ reported that in 2,810 patients with a principal discharge diagnosis of HF, a history of prior bariatric surgery was associated with an almost 50% reduction in in-hospital mortality and shorter length of stay. However, the invasiveness of surgery limits its widespread applicability, highlighting the need for a “medical bypass” capable of delivering similar metabolic benefits.

The SELECT trial provided the first robust evidence that NuSH therapies could bridge this therapeutic gap. In a population of 17,604 patients, 4,286 (24.3%) had a history of investigator-defined HF.³⁹⁾ Semaglutide improved clinical outcomes irrespective of HF status (p-interaction>0.19). Notably, treatment resulted in consistent benefits across HF phenotypes: reducing the risk of MACE in both heart failure with reduced ejection fraction (HFrEF, hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49–0.87) and HFpEF (HR, 0.69; 95% CI, 0.51–0.91). These findings strongly suggested that NuSH therapies possess a broad cardioprotective potential that extends across the entire spectrum of HF.

HFpEF

Historically, HFpEF treatment has been a landscape of failures, with traditional neurohormonal blockades struggling to show consistent benefits.⁴⁰⁾ While sodium-glucose cotransporter-2 (SGLT2) inhibitors have become the sole guideline-recommended pillar by targeting metabolic burden, their weight loss effect remains modest (~3 kg), and functional improvements are statistically significant but clinically modest.⁴¹,⁴²⁾ The emergence of NuSH therapies has redefined expectations in this field, demonstrating efficacy that is not merely additive but overwhelming when compared to historical benchmarks.

Landmark trials using NuSH therapies in HFpEF

The therapeutic potential of NuSH in HFpEF was illuminated by the “Twin” trials: STEP-HFpEF and STEP-HFpEF DM.¹³,¹⁴⁾ These trials investigated semaglutide 2.4 mg in the obesity-HFpEF phenotype. The results were striking: semaglutide produced substantial weight loss (−13.3% in obesity; −9.8% in diabetes mellitus [DM]) and massive improvements in the KCCQ Clinical Summary Score (KCCQ-CSS) of approximately 7.8 points in the obesity cohort and 7.3 points in the DM cohort compared to placebo. To put this into perspective, the magnitude of KCCQ improvement seen with SGLT2 inhibitors in landmark trials like EMPEROR-Preserved, DELIVER, and FINEARTS-HF was generally in the range of 1 to 2 points over placebo (Figure 3).⁴²,⁴³,⁴⁴,⁴⁵,⁴⁶⁾ The improvement observed with NuSH is several times greater, signifying a profound restoration of functional capacity. Alongside subjective relief, semaglutide demonstrated objective benefits, including a significant increase in 6-minute walk distance and a robust reduction in CRP, confirming that the agent effectively targets the systemic inflammatory underpinnings of the disease.⁴⁷⁾

Figure 3. Comparative efficacy of pharmacological therapies on functional status in HFpEF. This timeline illustrates the evolution of therapeutic efficacy in HFpEF, focusing on the improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score relative to placebo. Historical trials of neurohormonal modulators (TOPCAT, PARAGON, FINEARTS-HF) and sodium-glucose cotransporter-2 inhibitors (EMPEROR-Preserved, DELIVER) demonstrated modest improvements, typically ranging from +0.5 to +2.3 points (blue bars). In stark contrast, Nutrient-Stimulated Hormone therapies targeting the obesity-related HFpEF phenotype—Semaglutide in STEP-HFpEF and Tirzepatide in SUMMIT—achieved unprecedented improvements of +7.8 and +6.9 points, respectively (purple arrows). This represents a paradigm shift from marginal symptomatic relief to substantial restoration of functional capacity.

HFpEF = heart failure with preserved ejection fraction.

While the STEP trials confirmed symptomatic relief, the SUMMIT trial with tirzepatide provided the definitive evidence required to establish NuSH as a disease-modifying therapy.¹⁵⁾ This trial went beyond symptom control to demonstrate a reduction in hard clinical endpoints. The primary composite outcome of adjudicated cardiovascular death or a worsening heart-failure event was significantly reduced by tirzepatide (HR, 0.62; 95% CI, 0.41–0.95; p=0.026). This benefit was primarily driven by a remarkable reduction in worsening heart-failure events (HR, 0.54; 95% CI, 0.34–0.85). Furthermore, at 52 weeks, the mean change in KCCQ-CSS was 19.5 in the tirzepatide group vs. 12.7 in the placebo group (difference 6.9; p<0.001), reinforcing the functional benefits seen in the STEP program. Table 3 summarizes key results of the STEP-HFpEF and SUMMIT trials.

Table 3. NuSH landmark trials for HFpEF.

Feature	STEP-HFpEF program13,14)		SUMMIT15)
Agent	Semaglutide 2.4 mg (GLP-1 RA)		Tirzepatide up to 15 mg (dual GIP/GLP-1 RA)
Population	HFpEF (LVEF ≥45%), BMI ≥30 (non-DM cohort & DM cohort)		HFpEF (LVEF ≥50%), BMI ≥30 (includes both non-DM and DM)
Primary endpoint	Dual primary:		Dual primary:
		1. Change in KCCQ-CSS		1. Time to CV death or worsening HF event
		2. Change in body weight		2. Change in KCCQ-CSS
Functional restoration (placebo-adjusted difference)	KCCQ-CSS: +7.8 pts (obesity)/+7.3 pts (DM)		KCCQ-CSS: +6.9 pts
	6MWD: +20.3 m (obesity)/+14.3 m (DM)		6MWD: significant improvement (+18 m approximately)
Weight loss	−13.3% (obesity)/−9.8% (DM)		−13.9% (treatment regimen)
Clinical outcomes	Win ratio 1.65: benefit driven by weight/symptoms.		Hazard ratio 0.62 (38% risk reduction): Significantly reduced CV death or worsening HF events (driven by worsening HF).
Key implication	Established NuSH as a potent therapy for symptom control and physical recovery.		First trial to prove NuSH reduces hard clinical endpoints, establishing it as a disease-modifying pillar.

NuSH = Nutrient-Stimulated Hormone; HFpEF = heart failure with preserved ejection fraction; GLP-1 RA = glucagon-like peptide-1 receptor agonists; GIP = glucose-dependent insulinotropic polypeptide; LVEF = left ventricular ejection fraction; BMI = body mass index; DM = diabetes mellitus; KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; CV = cardiovascular; HF = heart failure; pts = points; 6MWD = 6-minute walk distance.

Clinical protocols using NuSH therapies in HFpEF

When viewed in the context of the broader HFpEF landscape, the performance of NuSH is overwhelming. Unlike SGLT2 inhibitors, which target metabolic burden but achieve limited weight reduction, NuSH therapies address the upstream root cause: adiposity-driven metabolic and inflammatory stress. The substantial weight loss (10–15%) acts as a “metabolic reset,” leading to improvements in symptoms and event rates that correlate directly with the magnitude of weight reduction. Regarding therapy sequencing, NuSH therapies should not be viewed merely as late-stage add-on metabolic interventions. Instead, for the obesity-driven HFpEF phenotype, they should be conceptualized as a foundational component of treatment alongside SGLT2 inhibitors.

Consequently, for the specific phenotype of obesity-related HFpEF, NuSH is rapidly emerging not just as an option, but as an essential pillar of care. To translate these trial findings into practice, NuSH therapies should be initiated early in patients with HFpEF and obesity who exhibit significant symptom burden (e.g., low KCCQ scores) and co-clustering conditions like obstructive sleep apnea, MASH, or chronic kidney disease. Intervening at this stage addresses the upstream root cause before metabolic inertia permanently limits functional recovery, establishing NuSH as a foundational treatment that rivals existing standards.

To ensure the safe and effective integration of NuSH therapies into routine care, clinicians should systematically monitor a pragmatic set of clinical endpoints. Weight trajectory and functional symptom response must be assessed regularly. Furthermore, continuous assessment of congestion status and renal function is necessary, particularly because gastrointestinal adverse effects, such as nausea and vomiting, can significantly affect oral hydration and nutrition. These gastrointestinal symptoms can mimic or exacerbate perceived HF symptoms and increase the risk of acute volume depletion, especially when patients are on background diuretic therapy.

HFrEF AND ADVANCED HEART FAILURE

While NuSH therapies have firmly established their role as a pillar of care in HFpEF, their application in HFrEF and advanced HF remains a subject of debate and caution.³⁷⁾ Unlike the consistent benefits observed in HFpEF, historical data in HFrEF have been mixed, raising concerns regarding safety, particularly related to chronotropic effects and the “obesity paradox.”

Early investigations using the first-generation GLP-1 RA in HFrEF

Early investigations using the first-generation GLP-1 RA, liraglutide, failed to demonstrate clinical benefits in HFrEF and raised safety signals. The FIGHT trial, which studied 300 patients with HFrEF who had been recently hospitalized found that liraglutide did not reduce the primary hierarchical endpoint of death or rehospitalization.⁴⁸⁾ Concerningly, there was a nonsignificant numerical increase in rehospitalization for HF and no benefit in mortality. Similarly, the LIVE trial, focused on stable chronic HFrEF patients, showed no improvement in left ventricular ejection fraction (LVEF) or functional class.⁴⁹⁾ More importantly, serious cardiac adverse events, including ventricular tachycardia and atrial fibrillation requiring cardioversion, were significantly more frequent in the liraglutide group compared to placebo (10% vs. 3%; p=0.04).

A consistent finding across these trials was a sustained increase in resting heart rate. In the LIVE trial, heart rate increased by 6–7 bpm, and Holter monitoring studies have reported increases as high as 13 bpm.⁴⁹,⁵⁰⁾ This chronotropic effect is likely mediated through direct stimulation of GLP-1 receptors in the sinoatrial node rather than reflex tachycardia from volume depletion.⁵⁰,⁵¹,⁵²,⁵³⁾ A recent study involving HFrEF patients with implantable cardiac devices found that GLP-1 RA initiation was associated with a significant increase in heart rate (+7 bpm) and a significant increase in non-sustained ventricular arrhythmias and total shock/antitachycardia pacing therapies.⁵⁴⁾ These findings highlight a potential pro-arrhythmic risk in patients with advanced structural heart disease. Given that elevated resting heart rate is a well-established independent predictor of adverse outcomes and mortality in HFrEF, this chronotropic effect warrants cautious consideration and close monitoring.⁵⁵⁾

Newer-generation NuSH therapies in HFrEF

Despite these historical concerns, recent data suggest that newer-generation NuSH therapies may yield different outcomes. In a prespecified analysis of the SELECT trial, semaglutide 2.4 mg consistently reduced MACE regardless of baseline HF status or phenotype, including those with HFrEF.³⁹⁾ However, this trial enrolled a relatively healthy population with 90% in New York Heart Association (NYHA) class I–II, limiting its generalizability to advanced HFrEF. Conversely, a recent propensity score-matched analysis from the Swedish Heart Failure Registry (SwedeHF) provided compelling real-world evidence. In this study, GLP-1 RA use was associated with a significant 47% reduction in cardiovascular mortality (HR, 0.53; p=0.012) in patients with LVEF ≤40%.⁵⁶⁾ Farkouh and Nunes⁵⁷⁾ suggest that this discrepancy reflects “drug evolution,” implying that newer agents like semaglutide and tirzepatide possess superior anti-inflammatory and metabolic potencies compared to liraglutide, potentially overcoming the hemodynamic risks associated with heart rate elevation.

Clinical protocols using NuSH therapies in HFrEF

Given the potential risks, Hussani et al.⁵⁸⁾ proposed a rigorous clinical protocol for using NuSH in HFrEF, emphasizing safety over aggressive titration. The protocol mandates strict patient selection, requiring that patients be clinically stable. In practice, this entails implementing a reasonable avoidance window after any recent HF decompensation and conducting a thorough baseline rhythm assessment. Because these agents have been associated with increases in heart rate, careful monitoring is necessary, and initiation should generally be deferred if the resting heart rate exceeds 100 beats per minute. The protocol excludes those with recent ventricular arrhythmias, while recommending an implantable cardioverter-defibrillator if indicated. Regarding initiation, routine reduction of diuretic dosing is not required, unlike with SGLT2 inhibitors. Furthermore, close monitoring for signs of HF exacerbation is essential, as differentiating between gastrointestinal side effects and congestion can be challenging.

Finally, the “obesity paradox”—where higher BMI is associated with better survival in advanced HF—remains a conceptual hurdle. Rapid weight loss carries the risk of sarcopenia (loss of muscle mass). In the STEP-1 trial, lean mass loss accounted for approximately 20–25% of total weight loss.¹⁶⁾ Therefore, NuSH therapy in HFrEF must be coupled with strategies to preserve lean mass, such as resistance exercise and adequate protein intake, ensuring that the “metabolic reset” does not come at the cost of functional reserve.

While HFrEF represents a frontier with greater uncertainty than HFpEF, the “drug evolution” from liraglutide to potent NuSH therapies offers renewed hope. Large-scale RCTs specifically targeting HFrEF are now imperative to confirm whether the pleiotropic benefits of these newer agents can safely translate into disease-modifying outcomes in this high-risk population.

REMAINING CHALLENGES AND FUTURE DIRECTIONS

Despite the paradigm-shifting potential of NuSH therapies in HF, several critical challenges must be addressed to optimize their integration into standard clinical practice. The most pressing concern regarding the widespread adoption of these agents is the quality of weight loss. Clinical trials indicate that a proportion of the weight reduced by GLP-1 RAs comprises lean muscle mass.¹⁶,¹⁷⁾ In older patients with HF, who are already predisposed to frailty and sarcopenia, the loss of skeletal muscle could potentially offset cardiovascular benefits by impairing physical function and increasing the risk of falls.⁵⁹⁾ Therefore, future therapeutic strategies must prioritize “high-quality weight loss” that specifically targets adipose tissue while preserving lean body mass. This may necessitate multimodal interventions, combining NuSH with structured resistance exercise programs or potentially co-administering novel anabolic agents to defend muscle integrity. In clinical practice, screening using body composition analysis and hand-grip strength can be utilized to monitor for sarcopenia. Furthermore, physicians should be prepared to slow titration, pause dose escalation, or reconsider therapy entirely if functional decline or excessive lean mass loss is detected.

Furthermore, the long-term sustainability of therapy poses a significant question. Evidence suggests that cessation of NuSH leads to a rapid “rebound” phenomenon, characterized by weight regain and the reversal of cardiometabolic improvements.⁶⁰⁾ This implies that obesity-related HF should be managed as a chronic, relapsing disease requiring indefinite maintenance therapy, raising substantial issues regarding cost-effectiveness and healthcare accessibility.⁶,⁷⁾ Additionally, identifying the optimal responder phenotype remains a priority. Not all patients with obesity and HF respond equally, partly because the magnitude of NuSH-induced weight loss varies substantially across individuals. However, emerging evidence suggests that meaningful cardiovascular benefits may still be achievable even in patients with minimal weight reduction. For instance, observations from the SELECT trial indicate that the reduction in cardiovascular risk is largely independent of the extent of weight loss, highlighting the direct pleiotropic and anti-inflammatory effects of these agents.²⁷⁾ Therefore, future research must leverage biomarkers and genetic profiling to better characterize these non-responders and predict which individuals will derive the greatest prognostic benefit from these potent therapies.

Figure 4 summarizes the evolutionary trajectory of NuSH in HF. In the past, therapeutic options were limited by the struggle against metabolic inertia, where lifestyle interventions alone yielded negligible weight reduction (~0.5 kg) and surgical options were restricted by high barriers. The present era is defined by the emergence of NuSH therapies, which act as a medical master key for a systemic metabolic reset. As evidenced by the STEP-HFpEF and SUMMIT trials, these therapies have solidified a dual-pillar standard of care in HFpEF by not only achieving profound functional recovery but also significantly reducing hard clinical events such as worsening HF. Looking toward the future, the focus must shift to precision medicine, specifically navigating the specific safety challenges in HFrEF such as arrhythmia risks, addressing the critical need to preserve muscle mass to prevent sarcopenic obesity, and establishing biomarker-guided protocols to optimize long-term maintenance.

Figure 4. The paradigm shift in targeting metabolic burden in heart failure: from lifestyle to precision medicine with NuSH. This central illustration depicts the evolution of therapeutic strategies for obesity-related heart failure. (Left) The past: historically, management relied on lifestyle interventions, which, despite improving exercise capacity, resulted in negligible weight reduction (~0.5 kg in HF-ACTION) and failed to overcome metabolic inertia. Bariatric surgery provided proof-of-concept for metabolic benefits but remained limited by its invasiveness. (Center) The present: the advent of NuSH therapies has revolutionized care, acting as a “medical bypass.” These agents deliver substantial weight loss (>10–15%) and broad cardioprotection (SELECT trial). In HFpEF, they have established a new standard of care by not only improving quality of life (STEP-HFpEF) but also significantly reducing hard clinical endpoints such as worsening heart failure events (SUMMIT). (Right) The future: the frontier now shifts to refining care for high-risk populations. Key priorities include establishing safety and efficacy in HFrEF (addressing arrhythmia concerns), developing strategies for muscle preservation to prevent sarcopenia, and identifying novel biomarkers to guide personalized phenotyping and long-term maintenance therapy.

NuSH = Nutrient-Stimulated Hormone; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HF = heart failure; GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic polypeptide; Gcg = glucagon; CV = cardiovascular; MACE = major adverse cardiovascular events; KCCQ = Kansas City Cardiomyopathy Questionnaire; pts = points.

CONCLUSION

The advent of NuSH therapies marks a pivotal turning point in cardiovascular medicine, fundamentally altering the management landscape of the obesity-HF phenotype. By delivering surgical-magnitude weight loss combined with pleiotropic cardioprotective effects, these agents have effectively bridged the longstanding therapeutic gap between conservative lifestyle measures and invasive bariatric surgery.

In the domain of HFpEF, NuSH therapies have transcended their initial role as metabolic interventions to become essential disease-modifying pillars. As evidenced by landmark trials, they uniquely offer a dual benefit: profound restoration of functional capacity and significant reduction in hard clinical endpoints. This shift from a “glucocentric” or “cosmetic” approach to a “cardioprotective” strategy underscores that targeting excess adiposity is targeting the root cause of the disease.

However, the journey is not yet complete. As we embrace this new era, clinical focus must now sharpen towards precision medicine. This entails rigorously defining safety profiles in HFrEF to mitigate arrhythmic risks, implementing strategies to preserve lean muscle mass against sarcopenia, and establishing personalized maintenance protocols. Ultimately, the integration of NuSH into standard care represents not just an addition to the pharmacopeia, but a necessary paradigm shift to comprehensively address the metabolic burden driving the modern HF epidemic.