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      Anti-obesity drug discovery: advances and challenges

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          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.

          Abstract

          The development of therapies that are capable of safely achieving sizeable and sustained body weight loss has proved tremendously challenging. Here, Müller et al. provide an overview of the history of anti-obesity drug development, focusing on lessons learned, ongoing challenges and recent advances in the field.

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          Most cited references357

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          Health Effects of Overweight and Obesity in 195 Countries over 25 Years.

          Background While the rising pandemic of obesity has received significant attention in many countries, the effect of this attention on trends and the disease burden of obesity remains uncertain. Methods We analyzed data from 67.8 million individuals to assess the trends in obesity and overweight prevalence among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body mass index (BMI), by age, sex, cause, and BMI level in 195 countries between 1990 and 2015. Results In 2015, obesity affected 107.7 million (98.7-118.4) children and 603.7 million (588.2- 619.8) adults worldwide. Obesity prevalence has doubled since 1980 in more than 70 countries and continuously increased in most other countries. Although the prevalence of obesity among children has been lower than adults, the rate of increase in childhood obesity in many countries was greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million (2.7- 5.3) deaths globally, nearly 40% of which occurred among non-obese. More than two-thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden of high BMI has increased since 1990; however, the rate of this increase has been attenuated due to decreases in underlying cardiovascular disease death rates. Conclusions The rapid increase in prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem.
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            Obesity: global epidemiology and pathogenesis

            The prevalence of obesity has increased worldwide in the past ~50 years, reaching pandemic levels. Obesity represents a major health challenge because it substantially increases the risk of diseases such as type 2 diabetes mellitus, fatty liver disease, hypertension, myocardial infarction, stroke, dementia, osteoarthritis, obstructive sleep apnoea and several cancers, thereby contributing to a decline in both quality of life and life expectancy. Obesity is also associated with unemployment, social disadvantages and reduced socio-economic productivity, thus increasingly creating an economic burden. Thus far, obesity prevention and treatment strategies - both at the individual and population level - have not been successful in the long term. Lifestyle and behavioural interventions aimed at reducing calorie intake and increasing energy expenditure have limited effectiveness because complex and persistent hormonal, metabolic and neurochemical adaptations defend against weight loss and promote weight regain. Reducing the obesity burden requires approaches that combine individual interventions with changes in the environment and society. Therefore, a better understanding of the remarkable regional differences in obesity prevalence and trends might help to identify societal causes of obesity and provide guidance on which are the most promising intervention strategies.
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              Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.

              Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.

                Author and article information

                Contributors
                timo.mueller@helmholtz-muenchen.de
                rdimarch@indiana.edu
                Journal
                Nat Rev Drug Discov
                Nat Rev Drug Discov
                Nature Reviews. Drug Discovery
                Nature Publishing Group UK (London )
                1474-1776
                1474-1784
                23 November 2021
                : 1-23
                Affiliations
                [1 ]GRID grid.4567.0, ISNI 0000 0004 0483 2525, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, , Helmholtz Zentrum München, ; Neuherberg, Germany
                [2 ]GRID grid.452622.5, German Center for Diabetes Research (DZD), ; Neuherberg, Germany
                [3 ]GRID grid.411339.d, ISNI 0000 0000 8517 9062, Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, ; Leipzig, Germany
                [4 ]GRID grid.4567.0, ISNI 0000 0004 0483 2525, Helmholtz Zentrum München, ; Neuherberg, Germany
                [5 ]GRID grid.6936.a, ISNI 0000000123222966, Division of Metabolic Diseases, Department of Medicine, , Technische Universität München, ; München, Germany
                [6 ]GRID grid.411377.7, ISNI 0000 0001 0790 959X, Department of Chemistry, , Indiana University, ; Bloomington, IN USA
                Author information
                http://orcid.org/0000-0002-0624-9339
                http://orcid.org/0000-0002-4744-371X
                http://orcid.org/0000-0003-0220-4085
                Article
                337
                10.1038/s41573-021-00337-8
                8609996
                34815532
                728cb022-1bc5-409c-9f9f-eba21adb80f9
                © Springer Nature Limited 2021

                This work was supported, in part, by funding from the Alexander von Humboldt Foundation, the European Research Council (ERC) AdG HypoFlam no. 695054 and the German Center for Diabetes Research (DZD e.V.). T.D.M. further received research funding from the German Research Foundation (TRR152 and TRR296). Figures were made using material provided by either Motifolio or Servier Medical Art (Servier), the latter under consideration of a Creative Commons Attribution 3.0 Unported License.

                History
                : 6 October 2021
                Categories
                Review Article

                obesity,diabetes
                obesity, diabetes

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