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Pharmacology & Therapeutics Feb 2017Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric... (Review)
Review
Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.
Topics: Animals; Anti-Obesity Agents; Drug Design; Eating; Homeostasis; Humans; Molecular Targeted Therapy; Obesity; Reward
PubMed: 27773782
DOI: 10.1016/j.pharmthera.2016.10.015 -
Expert Opinion on Pharmacotherapy Oct 2014A short overview of new drugs approved for the treatment of obesity (lorcaserin, phentermine/topiramate combination) as well as those with a perspective for approval as... (Review)
Review
A short overview of new drugs approved for the treatment of obesity (lorcaserin, phentermine/topiramate combination) as well as those with a perspective for approval as antiobesity drugs (cetilistat, naltrexone/bupropion combination, liraglutide) is presented. All these drugs produce significant weight loss accompanied by reductions in cardiometabolic health risks. Although the adverse events were rather rare and tended to decrease with the duration of treatment with most of these medications, the drug-specific safety concerns should be seriously considered. In order to ensure an appropriate, efficient and safe implementation of novel antiobesity drugs into the comprehensive treatment of obesity, it will be necessary to establish a network of physicians and other health-care providers well educated in obesity management.
Topics: Anti-Obesity Agents; Benzazepines; Benzoxazines; Bupropion; Drug Combinations; Fructose; Glucagon-Like Peptide 1; Humans; Liraglutide; Naltrexone; Obesity; Phentermine; Topiramate; Weight Loss
PubMed: 25100293
DOI: 10.1517/14656566.2014.946904 -
Journal of Cardiopulmonary... 2015Obesity is a major health priority in the United States, as well as globally. It is associated with multiple comorbidities and reduced life expectancy. Effective... (Review)
Review
Obesity is a major health priority in the United States, as well as globally. It is associated with multiple comorbidities and reduced life expectancy. Effective management of obesity involves producing an intervention plan tailored to the individual patient. Potential contributory factors to weight gain, including dietary habits, physical inactivity, associated medical conditions, and medications, should be identified and addressed. Lifestyle interventions comprising diet modification, physical activity, and behavior therapy are foundational to the management of obesity. Caloric restriction is the most important component in achieving weight loss through negative energy balance, whereas sustained physical activity is important in maintaining the weight loss. Adjunctive therapies in the form of pharmacotherapy and bariatric surgery are required in patients who do not achieve targeted weight loss and health goals with lifestyle interventions. Currently there are 3 drugs approved for long-term management of obesity, orlistat, phentermine/topiramate extended release, and lorcaserin, and there are 2 on the horizon, bupropion/naltrexone and liraglutide. Bariatric surgery is an effective strategy recognized to produce durable weight loss with amelioration of obesity-related comorbidities and should be considered a treatment option in eligible patients.
Topics: Anti-Obesity Agents; Bariatric Surgery; Benzazepines; Caloric Restriction; Drug Combinations; Exercise; Feeding Behavior; Fructose; Humans; Lactones; Obesity; Orlistat; Phentermine; Risk Reduction Behavior; Topiramate
PubMed: 25714749
DOI: 10.1097/HCR.0000000000000112 -
Trends in Pharmacological Sciences Jul 2016Five pharmaceutical strategies are currently approved by the US FDA for the treatment of obesity: orlistat, lorcaserin, liraglutide, phentermine/topiramate, and... (Review)
Review
Five pharmaceutical strategies are currently approved by the US FDA for the treatment of obesity: orlistat, lorcaserin, liraglutide, phentermine/topiramate, and bupropion/naltrexone. The most effective treatment seems to be the combined administration of phentermine/topiramate followed by lorcaserin and bupropion/naltrexone. In relation to the management of excessive weight, other aspects also need to be considered, including comorbidities accompanying obesity, drug interactions, and the risk of negative collateral effects, as well as individualized treatments based on the genetic make-up. This review aims to provide an overview of the approved anti-obesity drugs and newer molecules that could affect different targets in the central nervous system or peripheral tissues, the molecular mechanisms, emerging dietary treatments and phytogenic compounds, and pharmacogenetic/nutrigenetic approaches for personalized obesity management.
Topics: Anti-Obesity Agents; Energy Metabolism; Humans; Nutrigenomics; Obesity; Pharmacogenetics; Precision Medicine; Weight Loss
PubMed: 27236593
DOI: 10.1016/j.tips.2016.04.008 -
Seminars in Cancer Biology Jul 2023Obesity is a global pandemic that has been associated with the development of breast, endometrial, large intestine, renal, esophageal, and pancreatic cancer. Obesity is... (Review)
Review
Obesity is a global pandemic that has been associated with the development of breast, endometrial, large intestine, renal, esophageal, and pancreatic cancer. Obesity is also involved in the development of cardiovascular disease and type 2 diabetes mellitus. Recently, an increase in the incidence of obesity-related cancers has been reported. Multiple myeloma (MM) is the second most common hematological malignancy, after lymphoma. The aim of this review is to examine the epidemiological data on obesity and MM, assess the effect of obesity on MM outcomes, evaluate the possible mechanisms through which obesity might increase the incidence of MM and provide the effects of obesity management on MM. Current evidence indicates that obesity may have an impact on the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM and increase the prevalence of MM. However, data regarding the effect of obesity on MGUS incidence are controversial; further studies are needed to examine whether obesity affects the development of MGUS or the progression of MGUS to MM. In addition, obesity affects MM outcomes. Increased BMI is associated with decreased survival in patients with MM, while data regarding the effect of obesity on newly diagnosed MM subjects and autologous stem cell transplantation are limited. Interestingly, the obesity paradox may also apply to patients with relapsed/refractory MM who are overweight or obese, because they may have a survival advantage. The pathophysiological pathways linking obesity to MM are very complicated and include bone marrow adipose tissue; adipokines, such as adiponectin, leptin, resistin, and visfatin; inflammatory cytokines and growth factors, such as TNF-α and IL-6; hormones including insulin and the insulin-like growth factor system as well as sex hormones. In terms of the effect of pharmacological management of obesity, orlistat has been shown to alter the proliferation of MM cells, whereas no data exist on glucagon-like peptide-1 receptor agonists, naltrexone/bupropion, or phentermine/topiramate. Bariatric surgery may be associated with a reduction in the incidence of MM, however, further studies are needed.
Topics: Humans; Multiple Myeloma; Diabetes Mellitus, Type 2; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Obesity; Disease Progression
PubMed: 37030643
DOI: 10.1016/j.semcancer.2023.04.003 -
Clinica E Investigacion En... 2017Conventional treatment for obesity with diet, exercise and bariatric surgery has limitations; thus, it is necessary to have pharmacological tools. In the past, different... (Review)
Review
Conventional treatment for obesity with diet, exercise and bariatric surgery has limitations; thus, it is necessary to have pharmacological tools. In the past, different drugs were marketed that were withdrawn due to safety problems. There are currently 3 drugs approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for obesity therapy (orlistat, combination of bupropion and delayed-release naltrexone and liraglutide) and two more only authorized by FDA (lorcaserin and the combination of phentermine and extended release topiramate). It is recommended to use as a second therapeutic line and its choice should be individualized taking into account multiple aspects such as expected weight loss, route of administration, safety profile and cost. Currently there are several drugs under development that act on different therapeutic targets.
Topics: Anti-Obesity Agents; Drug Costs; Drug Design; Humans; Obesity; Weight Loss
PubMed: 28935287
DOI: 10.1016/j.arteri.2017.06.002 -
Mini Reviews in Medicinal Chemistry 2017Obesity is growing at an alarming rate with huge consequences on health and economy. The worldwide prevalence of obesity has nearly doubled in less than 35 years.... (Review)
Review
Obesity is growing at an alarming rate with huge consequences on health and economy. The worldwide prevalence of obesity has nearly doubled in less than 35 years. Obesity causes many physiological dysfunctions that affect nearly every organ producing multiple morbidities. Despite these facts, there is still no clear, well-defined solution. Notwithstanding the devastating prevalence and consequences of obesity, today only five medicines, orlistat, lorcaserin, phentermine-topiramate, bupropion-naltrexone and liraglutide, are approved by the FDA for long-term treatment of obesity. In this review, the current approaches to treat obesity such as the development of diacylglycerol Oacyltransferase- 1 inhibitors, growth hormone secretagogue receptor-1a antagonists/inverse agonists, melanocortin-3 receptors agonists and melanin concentrating hormone receptor-1 antagonists, will be discussed. The main focus will be on the molecules that were able to reach clinical trials. The last section is dedicated to the "browning" phenomenon of white adipose tissues and the potential of Aldh1a1 inhibitors to treat obesity.
Topics: Anti-Obesity Agents; Diacylglycerol O-Acyltransferase; Humans; Obesity; Receptor, Melanocortin, Type 3; Receptors, Ghrelin; Receptors, Somatostatin
PubMed: 27320641
DOI: 10.2174/1389557516666160617100328 -
The Cochrane Database of Systematic... Jan 2021This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect.
OBJECTIVES
Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction.
SEARCH METHODS
For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work.
SELECTION CRITERIA
Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity.
MAIN RESULTS
This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension.
AUTHORS' CONCLUSIONS
In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.
Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Bias; Blood Pressure; Body Weight; Bupropion; Diet, Reducing; Drug Combinations; Female; Fructose; Humans; Hypertension; Lactones; Male; Middle Aged; Naltrexone; Orlistat; Phentermine; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Safety-Based Drug Withdrawals; Time; Topiramate
PubMed: 33454957
DOI: 10.1002/14651858.CD007654.pub5 -
Adolescent Health, Medicine and... 2023The prevalence of pediatric obesity has increased exponentially over the past four decades. The American Academy of Pediatrics recently released updated clinical... (Review)
Review
The prevalence of pediatric obesity has increased exponentially over the past four decades. The American Academy of Pediatrics recently released updated clinical practice guidelines highlighting the importance of identifying pediatric obesity as a chronic disease. The guidelines support consideration of concurrent treatment with intensive lifestyle interventions, obesity pharmacotherapy, and bariatric surgery. The dramatic rise in pediatric obesity has spurred interest in utilizing obesity pharmacotherapy to support sustained weight reduction in pediatric cohorts, in the hopes of preventing the emergence of later-appearing, significant co-morbidities. Despite the enormous demand, the obstacles posed by performance of needed clinical trials in the pediatric population markedly limits available pharmacotherapy for the treatment of obesity in pediatrics. Currently, there are five medications approved by the Food and Drug Administration for use in youth with obesity. In 2022, the phentermine/topiramate (PHEN/TPM), once-daily, controlled-release, combination product received FDA approval, for the indication of chronic weight management, in youth with obesity, ages 12 years and older. The objectives of this narrative review are to: (1) Review the mechanism of action of phentermine and topiramate, (2) Summarize the safety and efficacy data of topiramate and phentermine use as both monotherapies and in combination, and (3) Discuss clinical practice guidelines and clinical implications, for the use of these agents in youths with obesity.
PubMed: 37641650
DOI: 10.2147/AHMT.S383454 -
Obesity Pillars Sep 2022Phentermine is a sympathomimetic amine, approved for "short-term"treatment of patients with obesity. Among phentermine contraindications include use in patients with...
BACKGROUND
Phentermine is a sympathomimetic amine, approved for "short-term"treatment of patients with obesity. Among phentermine contraindications include use in patients with cardiovascular disease or patients with uncontrolled hypertension.
METHODS
This roundtable discussion includes perspectives from 3 obesity specialists with experience in the clinical use of phentermine. The questions asked of the panelists were derived from publications regarding phentermine safety and efficacy.
RESULTS
While the panelists generally agreed upon core principles of phentermine use, each obesity specialist had their own priorities and style regarding the administration of phentermine. Among the variances in perceptions (based upon their individual "real world" clinical experiences) included the degree of efficacy and degree of clinical benefit of phentermine, degree of concern regarding phentermine use in patients with cardiovascular disease risk factors, the advisability of a screening electrocardiogram, and the role of telehealth in prescribing phentermine and monitoring for the efficacy and safety of phentermine.
CONCLUSIONS
Providing universal guidance regarding phentermine treatment for obesity is challenging because of the lack of long-term, prospective, randomized, placebo-controlled, health outcomes data. Such data is unlikely forthcoming any time soon. Also challenging are the substantial variances in governmental restrictions on phentermine use. Therefore, clinicians are left to rely on the best available evidence, their individual practical clinical experience, as well as the collective clinical experiences of others - as reflected by this roundtable.
PubMed: 37990729
DOI: 10.1016/j.obpill.2022.100024