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Review
. 2022 Mar;21(3):201-223.
doi: 10.1038/s41573-021-00337-8. Epub 2021 Nov 23.

Anti-obesity drug discovery: advances and challenges

Timo D Müller  1   2 , Matthias Blüher  3 , Matthias H Tschöp  4   5 , Richard D DiMarchi  6
Affiliations
Review

Anti-obesity drug discovery: advances and challenges

Timo D Müller et al. Nat Rev Drug Discov. 2022 Mar.

Abstract

Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut-brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.

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Conflict of interest statement

M.H.T. is a member of the scientific advisory board of ERX Pharmaceuticals, Cambridge, MA, USA; was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017 and 2019; attended a scientific advisory board meeting of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, in 2016; received funding for his research projects from Novo Nordisk (2016–2020) and Sanofi-Aventis (2012–2019); was a consultant for Bionorica SE (2013–2017), Menarini Ricerche S.p.A. (2016) and Bayer Pharma AG Berlin (2016); and, as former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum München (2011–2018), and, since 2018, as CEO of Helmholtz Zentrum München, has been responsible for collaborations with a multitude of companies and institutions worldwide — in this capacity, he discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industry and academia worldwide, including but not limited to pharmaceutical corporations such as Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BioSyngen and others; in this role, was/is further responsible for commercial technology transfer activities of his institute(s), including diabetes-related patent portfolios of Helmholtz Zentrum München as, for example, WO/2016/188932 A2 or WO/2017/194499 A1; and confirms that, to the best of his knowledge, none of the above funding sources were involved in the preparation of this paper. M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi. T.D.M. receives research funding from Novo Nordisk, but these funds are unrelated to the work here described, and further received speaking fees from Eli Lilly, Novo Nordisk, Mercodia, AstraZeneca, Berlin Chemie and Sanofi-Aventis. R.D.D. is a co-inventor on intellectual property owned by Indiana University and licensed to Novo Nordisk, and was recently employed by Novo Nordisk and, previously, Lilly Research Laboratories.

Figures

Fig. 1
Fig. 1. Obesity-associated metabolic disturbances.
Most prominent metabolic and psychological comorbidities associated with morbid obesity. ASVCD, atherosclerotic cardiovascular disease; COPD, chronic obstructive pulmonary disease; PCOS, polycystic ovary syndrome.
Fig. 2
Fig. 2. Gut–brain regulation of food intake.
Peripheral hormones integrate in central control of homeostatic and hedonic eating behaviour. α-MSH, α-melanocyte-stimulating hormone; AgRP, agouti-related peptide; AP, area postrema; ARC, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; CCK, cholescystokinin; CPu, caudate putamen; DMH, dorsomedial hypothalamus; DMV, dorsal motor nucleus of the vagus; FGF21, fibroblast growth factor 21; GIP, glucose-dependent insulinotropic polypeptide; GLP1, glucagon-like peptide 1; LH, lateral hypothalamus; MC4R, melanocortin 4 receptor; NAcc, nucleus accumbens; NPY, neuropeptide Y; NTS, nucleus tractus solitarius; OXM, oxyntomodulin; PFC, prefrontal cortex; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; PYY, peptide tyrosine tyrosine; VMH, ventromedial hypothalamus; VTA, ventral tegmental area; Y1R, neuropeptide Y receptor type 1.
Fig. 3
Fig. 3. Body weight loss by AOMs in humans and rodents.
Body weight loss achieved through lifestyle changes, currently approved anti-obesity medications (AOMs) and bariatric surgery (part a) and correlation of drug-induced body weight loss in rodents and humans (part b). Data in panel a refer to liraglutide 3 mg (ref.), orlistat, naltrexone/bupropion, phentermine/topiramate, semaglutide 1 mg (ref.), semaglutide 2.4 mg (ref.) and tirzepatide (5 and 15 mg). Data in panel b refer to naltrexone/bupropion,, orlistat,, lorcaserin,, sibutramine,, liraglutide,, phentermine,, semaglutide, and tirzepatide,.
Fig. 4
Fig. 4. Regulation of body weight and glucose metabolism by GLP1R agonism.
Glucagon-like peptide 1 receptor (GLP1R) agonism exerts both direct and indirect effects on energy and glucose metabolism in key peripheral organs as well as the brain.
See this image and copyright information in PMC

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