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Emerging combinatorial hormone therapies for the treatment of obesity and T2DM

Nature Reviews Endocrinology volume 9, pages 425–433 (2013)Cite this article

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Abstract

Peptide hormones and proteins control body weight and glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of body weight and euglycaemia. The development of obesity, often in association with type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic, anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM. Here, we review advances in the science of co-agonist therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of glucagon-like peptide 1, glucagon, gastric inhibitory polypeptide, gastrin, islet amyloid polypeptide and leptin, which enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation.

Key Points

  • Multiple enteroendocrine and adipose-derived hormones convey satiety signals to the central nervous system

  • Many regulatory peptides exert glucoregulatory actions independent of their effects on appetite and body weight

  • Most organisms exhibit robust counter-regulatory responses to one anorectic agent acting through a single signalling pathway

  • Combining two or more hormones with complementary anorectic and glucoregulatory activities might be a promising approach for the treatment of obesity and diabetes mellitus

  • The safety of new co-agonists in the brain and cardiovascular system, and their potential for promoting cell proliferation, requires careful scrutiny

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Figure 1
Figure 2: Mechanisms for leptin and IAPP co-agonism in the control of body weight and glucose homeostasis.

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  1. Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue TCP5–1004, Toronto, M5G 1X5, ON, Canada

    Sharon A. Sadry & Daniel J. Drucker

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Correspondence to Daniel J. Drucker.

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S. A. Sadry declares no competing interests. D. J. Drucker has served as an advisor or consultant within the past 12 months to Arisaph Pharmaceuticals Inc., Diartis Pharmaceuticals., Eli Lilly Inc, Glaxo Smith Kline, Merck Research Laboratories, Novo Nordisk Inc., NPS Pharmaceuticals Inc., Sanofi, Takeda, and Transition Pharmaceuticals Inc. Neither Dr Drucker nor his family members hold stock directly or indirectly in any of these companies.

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Sadry, S., Drucker, D. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat Rev Endocrinol 9, 425–433 (2013). https://doi.org/10.1038/nrendo.2013.47

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