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

Figures

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  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.

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  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…

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  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.

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  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…