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Peer-reviewedCC BY-NC-ND 4.0Diabetes, Obesity & Metabolism

Incretin‐Based Therapies as Cardiometabolic Interventions: Outcome Hierarchy, Receptor‐Network Pharmacology and Phenotype‐Based Clinical Positioning

  • Ferenc Sztanek1
  • Hajnalka Lőrincz1
  • Mariann Harangi1,2,3
  • Attila Csaba Nagy4
4 affiliations
  1. 1Division of Metabolism, Department of Internal Medicine, Faculty of Medicine University of Debrecen Debrecen Hungary
  2. 2Institute of Health Studies, Faculty of Health Sciences University of Debrecen Debrecen Hungary
  3. 3HUN‐REN‐UD Vascular Pathophysiology Research Group University of Debrecen Debrecen Hungary
  4. 4Department of Epidemiology, Faculty of Health Sciences University of Debrecen Debrecen Hungary
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Abstract

Aims: Incretin‐based pharmacotherapy was initially developed to improve glucose‐dependent insulin secretion and glycaemic control in type 2 diabetes, but its clinical interpretation has expanded substantially with cardiovascular outcome trials, kidney outcome data, obesity studies and next‐generation polyagonist development. This narrative clinical review uses structured literature identification and outcome‐stratified synthesis to evaluate incretin‐based therapies as cardiometabolic interventions across diabetes, obesity, cardiovascular disease and chronic kidney disease.

Materials and Methods: The available evidence was interpreted according to therapeutic class, clinical domain, outcome maturity and safety boundaries, integrating clinical outcome evidence with receptor‐network pharmacology.

Results: Selected GLP‐1 receptor agonists are supported by hard cardiovascular and renal outcome data, whereas several dual, triple, amylin‐linked and oral small‐molecule strategies are currently supported mainly by glycaemic, weight‐loss, metabolic or early translational endpoints. This distinction is clinically important because treatment positioning should depend on patient phenotype, outcome maturity and safety boundaries rather than mechanistic plausibility alone. In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, GLP‐1 receptor agonists with proven cardiovascular outcome benefit should be prioritised when atherosclerotic risk reduction is a major treatment goal. In type 2 diabetes with chronic kidney disease, semaglutide has dedicated kidney outcome evidence. In obesity with cardiometabolic risk, high‐magnitude and sustained weight reduction has become a clinically relevant therapeutic target. Receptor‐network pharmacology, including GLP‐1, GIP, glucagon and amylin receptor signalling, provides a useful explanatory framework for heterogeneous efficacy, tolerability and tissue‐level effects.

Conclusions: However, clinical use remains bounded by gastrointestinal tolerability, lean‐mass preservation, treatment durability, discontinuation effects and long‐term safety. This review therefore proposes phenotype‐based clinical positioning rather than a prescriptive treatment algorithm.

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Cite

BibTeXRIS
BibTeX
@article{sztanek2026incretinbased,
  title = {{Incretin‐Based Therapies as Cardiometabolic Interventions: Outcome Hierarchy, Receptor‐Network Pharmacology and Phenotype‐Based Clinical Positioning}},
  author = {Ferenc Sztanek and Hajnalka Lőrincz and Mariann Harangi and Attila Csaba Nagy},
  journal = {Diabetes, Obesity \& Metabolism},
  year = {2026},
  month = sep,
  doi = {10.1111/dom.71277},
  url = {https://doi.org/10.1111/dom.71277},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Incretin‐Based Therapies as Cardiometabolic Interventions: Outcome Hierarchy, Receptor‐Network Pharmacology and Phenotype‐Based Clinical Positioning
AU  - Ferenc Sztanek
AU  - Hajnalka Lőrincz
AU  - Mariann Harangi
AU  - Attila Csaba Nagy
PY  - 2026
DA  - 2026/09/01
JO  - Diabetes, Obesity & Metabolism
DO  - 10.1111/dom.71277
UR  - https://doi.org/10.1111/dom.71277
AB  - Aims: Incretin‐based pharmacotherapy was initially developed to improve glucose‐dependent insulin secretion and glycaemic control in type 2 diabetes, but its clinical interpretation has expanded substantially with cardiovascular outcome trials, kidney outcome data, obesity studies and next‐generation polyagonist development. This narrative clinical review uses structured literature identification and outcome‐stratified synthesis to evaluate incretin‐based therapies as cardiometabolic interventions across diabetes, obesity, cardiovascular disease and chronic kidney disease.  Materials and Methods: The available evidence was interpreted according to therapeutic class, clinical domain, outcome maturity and safety boundaries, integrating clinical outcome evidence with receptor‐network pharmacology.  Results: Selected GLP‐1 receptor agonists are supported by hard cardiovascular and renal outcome data, whereas several dual, triple, amylin‐linked and oral small‐molecule strategies are currently supported mainly by glycaemic, weight‐loss, metabolic or early translational endpoints. This distinction is clinically important because treatment positioning should depend on patient phenotype, outcome maturity and safety boundaries rather than mechanistic plausibility alone. In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, GLP‐1 receptor agonists with proven cardiovascular outcome benefit should be prioritised when atherosclerotic risk reduction is a major treatment goal. In type 2 diabetes with chronic kidney disease, semaglutide has dedicated kidney outcome evidence. In obesity with cardiometabolic risk, high‐magnitude and sustained weight reduction has become a clinically relevant therapeutic target. Receptor‐network pharmacology, including GLP‐1, GIP, glucagon and amylin receptor signalling, provides a useful explanatory framework for heterogeneous efficacy, tolerability and tissue‐level effects.  Conclusions: However, clinical use remains bounded by gastrointestinal tolerability, lean‐mass preservation, treatment durability, discontinuation effects and long‐term safety. This review therefore proposes phenotype‐based clinical positioning rather than a prescriptive treatment algorithm.
SN  - 1462-8902
SN  - 1463-1326
ER  -