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Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

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Anti-Obesity Therapy: from Rainbow Pills to Polyagonists 1521-0081/70/4/712–746$35.00 https://doi.org/10.1124/pr.117.014803 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:712–746, October 2018 Copyright © 2018 The Author(s). This is an open access article distributed under the CC BY Attribution 4.0 International license. ASSOCIATE EDITOR: BIRGITTE HOLST Anti-Obesity Therapy: from Rainbow Pills to Polyagonists T. D. Müller, C. Clemmensen, B. Finan, R. D. DiMarchi, and M. H. Tschöp Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (T.D.M., C.C., M.H.T.); German Center for Diabetes Research, Neuherberg, Germany (T.D.M., C.C., M.H.T.); Department of Chemistry, Indiana University, Bloomington, Indiana (B.F., R.D.D.); and Division of Metabolic Diseases, Technische Universität München, Munich, Germany (M.H.T.) Abstract ....................................................................................713 I. Introduction . ..............................................................................713 II. Bariatric Surgery: A Benchmark for Efficacy ................................................714 III. The Chronology of Modern Weight-Loss Pharmacology . .....................................715 A. Thyroid Hormones ......................................................................716 B. 2,4-Dinitrophenol .......................................................................716 C. Amphetamines. ........................................................................717 Downloaded from 1. Methamphetamine ..................................................................717 2. Amphetamine Congeners ............................................................718 a. Phenmetrazine . ..................................................................718 b. Phendimetrazine .................................................................718 c. Diethylpropion . ..................................................................718 by guest on September 29, 2021 d. Phentermine . ..................................................................719 D. The Rainbow Pills ......................................................................719 E. Serotonergics . ........................................................................719 1. Fenfluramine........................................................................719 2. Phentermine-Fenfluramine ..........................................................720 3. Dexfenfluramine. ..................................................................720 4. Sibutramine . ........................................................................720 F. Phentermine and Topiramate (Qsymia). ................................................721 G. Orlistat. ..............................................................................721 H. Lorcaserin ..............................................................................721 I. Rimonabant ............................................................................722 J. Leptin..................................................................................722 IV. From Glucagon-Like Peptide 1 Monoagonism to Multimode Incretin-Based Pharmacology . 723 A. Optimized Glucagon-Like Peptide 1 Monoagonists.. .....................................723 B. Coadministration of Single Hormones . ................................................725 V. Unimolecular Multiagonism: Closing the Gap to Bariatric Surgery. .........................726 A. Glucagon-Like Peptide 1/Glucagon Coagonism . ..........................................726 B. Glucagon-Like Peptide 1/Amylin Coagonism . ..........................................729 Address correspondence to: T. D. Müller, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Parkring 13, 85748 Garching, Germany. E-mail: [email protected]; or M. H. Tschöp, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Parkring 13, 85748 Garching, Germany. E-mail: matthias.tschoep@helmholtz- muenchen.de This work was supported in part by Alexander von Humboldt Foundation, Helmholtz Alliance ICEMED and Helmholtz Initiative on Personalized Medicine iMed by Helmholtz Association, and Helmholtz cross-program topic “Metabolic Dysfunction” (to M.H.T.). This work was further supported by German Research Foundation Grants DFG-TS226/1-1 and DFG-TS226/3-1, European Research Council ERC AdG HypoFlam 695054, and German Center for Diabetes Research (DZD e.V.). T.D.M. and C.C. have nothing to disclose. B.F. and R.D.D. are current employees of Novo Nordisk. R.D.D. is a cofounder of Marcadia, a company that pioneered the discovery of glucagon mixed agonists. It was acquired by Roche and later Novo Nordisk. M.H.T. is a scientific advisor for Novo Nordisk and Erx Biotech. https://doi.org/10.1124/pr.117.014803. 712 Anti-Obesity Pharmacotherapies 713 C. Glucagon-Like Peptide 1/Glucose-Dependent Insulinotropic Polypeptide Coagonism ......729 D. Glucagon-Like Peptide 1/Glucagon/Glucose-Dependent Insulinotropic Polypeptide Triagonism .............................................................................731 VI. Peptide-Mediated Delivery of Nuclear Hormones . ..........................................732 A. Glucagon-Like Peptide 1–Mediated Delivery of Estrogen . ...............................734 B. Glucagon-Mediated Delivery of Thyroid Hormone Tri-iodothyronine . ...................735 C. Glucagon-Like Peptide 1–Mediated Delivery of Dexamethasone . .........................736 VII. Outlook ....................................................................................737 Acknowledgments . ........................................................................737 References..................................................................................737 Abstract——With their ever-growing prevalence, when used as a single hormone therapy, most of these obesity and diabetes represent major health threats of drugs are underwhelming in their efficacy or safety, and our society. Based on estimations by the World Health placebo-subtracted weight loss attributed to such therapy Organization, approximately 300 million people will be is typically not more than 10%. In 2009, the generation of a obese in 2035. In 2015 alone there were more than 1.6 single molecule with agonism at the receptors for glucagon million fatalities attributable to hyperglycemia and and the glucagon-like peptide 1 broke new ground in diabetes. In addition, treatment of these diseases places obesity pharmacology. This molecule combined the an enormous burden on our health care system. As a result, beneficial anorectic and glycemic effects of glucagon-like the development of pharmacotherapies to tackle this life- peptide 1 with the thermogenic effect of glucagon into a threatening pandemic is of utmost importance. Since the single molecule with enhanced potency and sustained beginning of the 19th century, a variety of drugs have action. Several other unimolecular dual agonists have been evaluated for their ability to decrease body subsequently been developed, and, based on their weight and/or to improve deranged glycemic control. preclinical success, these molecules illuminate the path The list of evaluated drugs includes, among many others, to a new and more fruitful era in obesity pharmacology. In sheep-derived thyroid extracts, mitochondrial uncouplers, this review, we focus on the historical pharmacological amphetamines, serotonergics, lipase inhibitors, and a approaches to treat obesity and glucose intolerance and variety of hormones produced and secreted by the describe how the knowledge obtained by these studies led gastrointestinal tract or adipose tissue. Unfortunately, to the discovery of unimolecular polypharmacology. I. Introduction impair systems metabolism through local tissue inflam- mation and induction of ER stress (Unger, 2002; Virtue The escalating prevalence of diabetes and obesity and Vidal-Puig, 2008; Symons and Abel, 2013; represents an incessant and escalating burden to Contreras et al., 2014). modern societies. Obesity is characterized by an excess Of the numerous comorbidities linked to obesity, the of body fat resulting from a chronic surplus in energy most common are T2D; a variety of cardiovascular intake over energy expenditure. In the progression of complications such as hypertension, coronary artery obesity, the lipid deposition in adipose tissue can exceed disease, and stroke; and certain types of cancer (Guo the storage capacity of adipocytes, resulting in elevated and Garvey, 2016). Notably, obesity and T2D represent circulating concentrations and inappropriate accumu- top preventable causes of premature death and disabil- lation in multiple tissues, most notably liver and ity (Mathers and Loncar, 2006; Bauer et al., 2014), and skeletal muscle. Fat deposits in such ectopic tissues the World Health Organization estimates that annually are unhealthy and can initiate tissue inflammation, approximately 1.5 million deaths are directly attribut- endoplasmic reticulum (ER) stress, and endothelial able to diabetes (WHO, 2016). In the United States dysfunction, accelerating the development of obesity- alone, about a quarter of a million adults prematurely associated pathologies, such as insulin resistance and die every year due to the consequences of excess body type 2 diabetes (T2D) (Hotamisligil et al., 1993, 1996; weight (Allison et al., 1999). The global burden that Ozcan et al., 2004). In line with this
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