Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases


Obesity and its comorbidities, such as type 2 diabetes mellitus and cardiovascular disease, constitute growing challenges for public health and economies globally. The available treatment options for these metabolic disorders cannot reverse the disease in most individuals and have not substantially reduced disease prevalence, which underscores the unmet need for more efficacious interventions. Neurobiological resilience to energy homeostatic perturbations, combined with the heterogeneous pathophysiology of human metabolic disorders, has limited the sustainability and efficacy of current pharmacological options. Emerging insights into the molecular origins of eating behaviour, energy expenditure, dyslipidaemia and insulin resistance suggest that coordinated targeting of multiple signalling pathways is probably necessary for sizeable improvements to reverse the progression of these diseases. Accordingly, a broad set of combinatorial approaches targeting feeding circuits, energy expenditure and glucose metabolism in concert are currently being explored and developed. Notably, several classes of peptide-based multi-agonists and peptide–small molecule conjugates with superior preclinical efficacy have emerged and are currently undergoing clinical evaluation. Here, we summarize advances over the past decade in combination pharmacotherapy for the management of obesity and type 2 diabetes mellitus, exclusively focusing on large-molecule formats (notably enteroendocrine peptides and proteins) and discuss the associated therapeutic opportunities and challenges.

Key points

  • The need for safe and efficacious treatment options to combat metabolic diseases such as obesity and type 2 diabetes mellitus is currently unmet.

  • Coordinated pharmacological targeting of multiple signalling pathways is probably required to obtain sizeable improvements in body weight and glucose metabolism.

  • Several classes of peptide-based multi-agonists and peptide–small molecule conjugates with robust preclinical efficacy are currently emerging.

  • Parallel to advancing interventions that modulate neurocircuits to drive weight loss, attention towards therapies designed to prevent weight rebound should be intensified.

  • Novel hormonal-based combination pharmacotherapies for metabolic diseases must undergo careful cardiovascular safety assessment.

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Fig. 1: Single-molecule peptide-based co-agonists.
Fig. 2: Peptide-governed tissue targeting.
Fig. 3: Potentiation of leptin pharmacology by GLP1–glucagon co-agonism.
Fig. 4: Pharmacological benefits of FGF19 and FGF21.
Fig. 5: Key targets for metabolic combination pharmacotherapy.


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The authors thank L. Albertsen for helping with the figure design. The authors acknowledge the support of Helmholtz Alliance ICEMED, the Helmholtz Initiative on Personalized Medicine iMed, the Helmholtz crossprogram topic “Metabolic Dysfunction”, the Alexander von Humboldt Foundation, the German Research Foundation (DFG) (SFB1123) and the European Research Council (AdG HypoFlam no. 695054). C.C. is supported by the Lundbeck Foundation (Fellowship: R238-2016-2859) and the Novo Nordisk Foundation (grant: NNF17OC0026114). Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark, and partially funded by an unconditional donation from the Novo Nordisk Foundation.

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C.C. and B.F. researched data for the article and wrote the article. C.C., B.F., T.D.M., R.D.D., M.H.T. and S.M.H. made substantial contributions to the discussion of the content and contributed to the writing, review and/or editing of the article.

Correspondence to Christoffer Clemmensen or Richard D. DiMarchi or Susanna M. Hofmann.

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C.C., T.D.M. and S.M.H. declare no competing interests. M.H.T has served as SAB member of ERX Pharmaceuticals. The Institute for Diabetes and Obesity cooperates with Novo Nordisk and Sanofi-Aventis. B.F. and R.D.D. are currently employees of Novo Nordisk.

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Clemmensen, C., Finan, B., Müller, T.D. et al. Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases. Nat Rev Endocrinol 15, 90–104 (2019). https://doi.org/10.1038/s41574-018-0118-x

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