Peptide hormones play a central role in maintaining metabolic homeostasis by integrating complex signaling pathways to coordinate interorgan crosstalk. Aberrant production and/or dysfunction of peptide hormones are important contributors to the pathophysiology of a cluster of interrelated chronic metabolic diseases (CMDs), including obesity, type 2 diabetes mellitus, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and cardiovascular diseases. These CMDs often co-occur, ranking among the top causes of death and disability in the rapidly aging population. Peptide hormone-based pharmacotherapies are the mainstay of treatment for these CMDs. Analogs and agonists of peptide hormones produced by classical endocrine cells, especially insulin and glucagon-like peptide-1, are cornerstones in managing diabetes and obesity. Furthermore, peptide hormones released from nonclassical endocrine organs, such as liver-secreted fibroblast growth factors 21 and growth differentiation factor 15, have emerged as highly promising therapeutic candidates for obesity-related metabolic comorbidities. These peptide hormones act synergistically and/or complementarily to exert pleiotropic metabolic benefits through their distinct receptors in different target organs/tissues. Combination pharmacotherapies with these peptide hormones are much more effective than monotherapy and hold promise to address the multimorbidity issue in patients with CMDs. This review summarizes recent advances in the pharmacoengineering and pharmacology of these peptide hormone-based long-acting analogs and coagonists and discusses their synergistic and antagonistic interactions in the treatment of CMDs. Furthermore, we highlight major challenges and future perspectives in the clinical development of multiple peptide hormone-based coagonists as safe and effective pharmacotherapy for the management of metabolic comorbidities. SIGNIFICANCE STATEMENT: This review highlights recent clinical advances in combination peptide hormone therapies for chronic metabolic diseases, emphasizing their superior efficacy over monotherapies in addressing metabolic multimorbidity. Summarizing the latest developments in long-acting analogs and coagonists of peptide hormones provides critical insights into their synergistic mechanisms, clinical potential, and future challenges, offering a comprehensive perspective for improving the management of complex metabolic disorders.
