GLP-1 Receptor Agonists as Multisystem Therapeutics: Mechanistic Basis, Translational Evidence, and Emerging Clinical Applications Beyond Metabolic Disease

Q: What is the clinical evidence from this study?

Study design: Review. Population: Multisystem metabolic and non-metabolic diseases (including atherosclerotic cardiovascular disease, HFpEF, chronic kidney disease, MASLD/MASH, and neurological and musculoskeletal disorders). Intervention: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and multi-incretin therapies.

Preeti Sah Sah; Zahid Husain Husain; Kashish Verma Verma; Anurag Kumar Sharma Sharma; Nadeem Ahmed Farooqui; Gouri Barasker Barasker; Nimita Manocha Manocha

doi:10.64062/jpgmb.vol2.issue5.3

October 23, 2026Journal of Pharmacology Genetics and Molecular BiologyOpen Access

GLP-1 Receptor Agonists as Multisystem Therapeutics: Mechanistic Basis, Translational Evidence, and Emerging Clinical Applications Beyond Metabolic Disease

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Key result

GLP-1 receptor agonists provide multisystem cardio-renal-hepatic protection, but evidence remains variable in emerging indications.

Why the study?

Growing evidence suggests GLP-1 receptor agonists offer benefits across multiple organ systems beyond glycaemic control and weight management, requiring examination of their molecular mechanisms and clinical evidence to distinguish established benefits from emerging hypotheses.

Key Points

To review the intracellular signalling pathways, translational evidence, and clinical applications of GLP-1 receptor agonists across cardiovascular, renal, hepatic, and other organ systems beyond metabolic disease.
Narrative review examining molecular signalling mechanisms including cAMP–PKA–EPAC, PI3K–AKT, AMPK, and MAPK pathways.
Synthesized translational, preclinical, and randomized clinical trial evidence across cardiovascular, renal, hepatic, neurological, respiratory, musculoskeletal, and oncological domains.
In the LEADER trial, liraglutide reduced major adverse cardiovascular events (MACE) by 13% compared with placebo (HR 0.87; 95% CI 0.78–0.97), and semaglutide reduced MACE by 20% in the SELECT trial (HR 0.80; 95% CI 0.72–0.90).
In the FLOW trial, semaglutide reduced the primary composite kidney and cardiovascular-death outcome by 24% in patients with type 2 diabetes and chronic kidney disease (HR 0.76; 95% CI 0.66–0.88).
A 2025 meta-analysis of 21 randomized trials involving 99,599 participants reported a 13% reduction in MACE with GLP-1 receptor agonists.

Structured PICO

P

Population

Patients with metabolic and non-metabolic multisystem conditions, including type 2 diabetes mellitus, overweight/obesity, atherosclerotic cardiovascular disease (ASCVD), obesity-related heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH), neurodegenerative and psychiatric disorders, and musculoskeletal/inflammatory disorders

I

Intervention

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs; e.g., exenatide, liraglutide, semaglutide) and multi-incretin receptor agonists (e.g., tirzepatide, survodutide)

This narrative review synthesizes the molecular mechanisms and clinical trial evidence supporting GLP-1 receptor agonists as multisystem therapeutics with established benefits in cardiovascular, renal, and hepatic diseases and emerging potential in neurological and musculoskeletal conditions.

Limitations

Evidence for direct receptor-mediated effects in several peripheral organs remains limited or debated, as some systemic benefits may occur indirectly through weight loss and improved metabolic control.
Clinical translation in neurological and psychiatric disorders is constrained by small sample sizes, heterogeneous patient populations, short follow-up periods, and differences in drug selection and outcome measures.
Important knowledge gaps remain regarding optimal duration of treatment, blood-brain barrier penetration, long-term safety, rare adverse effects, and reliable biomarkers for identifying patient subgroups most likely to benefit.
Evidence for direct GLP-1 receptor-mediated effects in several peripheral organs remains limited or debated, and some systemic benefits may occur indirectly through weight loss and improved metabolic control
Clinical evidence for neurological and psychiatric disorders is constrained by small sample sizes, heterogeneous patient populations, short follow-up periods, and differences in drug selection and outcome measures
Knowledge gaps remain regarding optimal treatment duration, blood-brain barrier penetration, rare adverse effects, and reliable biomarkers for identifying responders

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Implication

Reinforces established cardio-renal benefits of GLP-1 receptor agonists; leaves open efficacy in emerging non-metabolic indications.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained popularity as important therapeutic agents extending beyond glycaemic control and weight management. Growing evidence suggests their potential benefits across multiple organ systems through metabolic regulation, intracellular signalling, anti-inflammatory activity, and effects on cellular energy homeostasis. This review examines the molecular basis of GLP-1 receptor signalling, including cAMP–PKA–EPAC, PI3K–AKT, AMPK, and MAPK pathways, and their possible contributions to multisystem protection. Particular emphasis is placed on cardiovascular and renal outcomes, including atherosclerotic cardiovascular disease, obesity-related heart failure with preserved ejection fraction, and chronic kidney disease. Hepatic applications are explored through the effects of GLP-1 RAs on metabolic dysfunction-associated steatosis liver disease and steatohepatitis, with consideration of histological outcomes and emerging multi-incretin therapies. The review further evaluates potential applications in neurological and neuropsychiatric disorders, musculoskeletal and inflammatory conditions, respiratory diseases, sleep-related disorders, and oncology. Evidence from clinical trials is considered alongside preclinical findings to distinguish established therapeutic benefits from emerging hypotheses. Safety considerations, including gastrointestinal and hepatobiliary adverse effects, long-term treatment, discontinuation, affordability, and equitable access, are also discussed. Finally, developments in oral and long-acting formulations, combination therapies, biomarker-guided treatment selection, and artificial intelligence-assisted drug discovery are examined as potential directions for precision incretin pharmacotherapy. Overall, GLP-1-based therapies represent a promising platform for addressing interconnected metabolic and non-metabolic diseases. However, the strength of evidence varies substantially across indications, highlighting the need for well-designed clinical trials, long-term safety evaluation, and clearer identification of patients most likely to benefit from these therapies.

Discussion

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Cite This Study

Sah et al. (2026) conducted a review in Multisystem metabolic and non-metabolic diseases (including atherosclerotic cardiovascular disease, HFpEF, chronic kidney disease, MASLD/MASH, and neurological and musculoskeletal disorders). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and multi-incretin therapies was evaluated. GLP-1 receptor agonists demonstrate multisystem protection across cardiovascular, renal, and hepatic disorders, though clinical evidence varies substantially across emerging non-metabolic indications.

synapsesocial.com/papers/6aebc8ba3e63ca1b6c315df5 https://doi.org/10.64062/jpgmb.vol2.issue5.3

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GLP-1 Receptor Agonists as Multisystem Therapeutics: Mechanistic Basis, Translational Evidence, and Emerging Clinical Applications Beyond Metabolic Disease

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

GLP-1 Receptor Agonists as Multisystem Therapeutics: Mechanistic Basis, Translational Evidence, and Emerging Clinical Applications Beyond Metabolic Disease

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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