Emerging incretin- and multi-agonist-based treatments – the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond

Jan 21, 2026Metabolism: clinical and experimental

New incretin and multi-target treatments expanding options for heart, kidney, liver, and metabolic diseases

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Abstract

Innovative incretin- and multi-agonist-based therapies may deliver an increasing double-digit percent weight loss.

Molecular pathways associated with GLP-1, GIP, amylin, glucagon, and peptide YY are linked to improved outcomes in obesity and related disorders.
Research is ongoing into single, dual, and triple drug combinations in various phases of clinical trials.
The development of unimolecular multi-receptor activating drugs is facilitated by similarities in peptide sequences.
Clinical trials and real-world evidence support the potential effectiveness of incretin and multi-agonist therapies.
Early initiation of incretin-based therapy may improve body weight and cardiovascular risk management across various disorders.

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While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.

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Emerging incretin- and multi-agonist-based treatments – the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond

Abstract

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