Drug Therapy For Obesity Research Articles

Head‐to‐head studies evaluating efficacy of pharmaco‐therapy for obesity: a systematic review and meta‐analysis

Randomized controlled trials (RCTs) directly comparing weight loss drugs approved in the European Union were reviewed and the results analysed by meta-analysis. Eight RCTs including 885 patients were found comparing weight loss of orlistat and sibutramine, while no study including rimonabant was found. The median study duration was 7 months (range 3-12). Four of the seven studies comparing sibutramine and orlistat mono-therapy showed that sibutramine was significantly more efficacious for weight loss, while the remaining three showed equivalence. The weighted mean difference in weight loss was 2.2 kg (95% CI 0.5-3.9) favouring sibutramine. Three studies investigated orlistat and sibutramine as combination therapy, and two found it to be significantly better than orlistat alone, but not better than sibutramine alone. Based on these head-to-head RCT data, sibutramine appears to be significantly more efficacious for achieving weight loss than orlistat. This is concordant with indirect evidence from previous meta-analyses, where the respective compounds were compared with placebo. Only four studies reported attrition, and the pooled risk ratio was 0.6 (0.3-1.4) indicating lower dropout for sibutramine. This information together with an understanding of the clinical properties of each drug should help to guide the prescribing physician in the selection of adequate drug therapy for obesity.

Antiobesity drug therapy: a call for more rigorous end-point evaluation

Over 1.1 billion people worldwide are overweight or obese and at risk for the numerous potential complications of excess body fat [1]. Prevalence estimates for adult obesity, which continue to rise in both developed and developing nations, are over 20% in many countries and have reached 32% in the USA [2,101]. Consequently, in the coming decades, marked increases in premature mortality, healthcare utilization and the incidence of chronic conditions, such as cancer and cardiovascular disease, are expected to result. Individual lifestyle modification, idyllically viewed as the solution to the obesity epidemic, clearly has had limited effectiveness [3]. Obesity is a complex disorder that requires a sophisticated, multifaceted treatment approach at both the individual and societal levels. Pharmacotherapy is indicated in patients with medically complicated obesity and body mass index (BMI) levels of 27 kg/m2 or greater, or in patients with BMI levels of 30 kg/m2 or greater [3]. Drug therapy for obesity has traditionally languished on the fringes of mainstream medical science. To some extent, cynicism towards antiobesity drugs has been unjustifiably fueled by negative stereotypes of obesity as a condition borne from a ‘lack of willpower’ [4]. In addition, highly publicized cases of serious adverse events associated with past antiobesity drugs have cast a cloud over the entire therapeutic class. Obesity drug development is a legitimate and essential enterprise. Already, the efforts to identify new drug targets have resulted in major advances in our understanding of the intricate pathways involved in body weight regulation [5]. However, caution is indeed warranted and a systematic and comprehensive approach to the evaluation of new and existing antiobesity drugs is an absolute necessity. Historical pitfalls of obesity pharmacotherapy Although thermogenic agents, such as thyroid hormone, have been used to induce weight loss since the 1800s [6], the first agents officially approved for the treatment of obesity were the amphetamines and related congeners (Table 1). The anorectic agent desoxyephedrine was the first of this class approved by the US FDA in 1947 [7]. Amphetamines and related compounds have primarily only been studied in short-term clinical trials and result in average placebo-subtracted weight reductions of less than 4 kg in follow-up periods of less than 1 year [8]. They are not commonly prescribed for obesity because of their addictive potential and unfavorable adverse-effect profile (Table 1). In addition, aminorex, a sympathomimetic compound structurally related to amphetamines, released in Europe in 1965, was removed from the market 7 years later after published reports associated the drug with a 1000-fold increase in the odds of developing pulmonary hypertension [9].

EDITORIAL [Hot Topic: Novel Approaches to the Drug Therapy of Obesity (Guest Editor: Prof. Paolo Magni)

EDITORIAL [Hot Topic: Novel Approaches to the Drug Therapy of Obesity (Guest Editor: Prof. Paolo Magni)

Neuropeptide Y receptors as targets of obesity treatment

The prevalence of obesity continues to increase throughout the world and the burden of obesity and related co-morbidities is large. However, existing drug therapies for obesity are limited, and agents with high efficacy, safety and tolerability are expected to better meet patient needs and lead to more substantial commercial success. Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Multiple receptor subtypes mediate the effects of NPY on energy homeostasis and many pharmacological studies indicate the involvement of Y1 and Y5 receptor subtypes in NPY-induced feeding and obesity. In addition, recent observations with gut-derived peptides suggest a role for Y2 and Y4 receptor subtypes as catabolic receptors. This article highlights and reviews recent observations and patents regarding NPY receptor ligands for drug discovery as antiobesity agents.

Current and novel approaches to the drug therapy of obesity

Obesity has been described as the greatest current threat to human health. Although diet and lifestyle changes remain the cornerstones of therapy for obesity, weight losses are often small, and long-term success is disappointing. When these lifestyle-modifying attempts fail, the use of anti-obesity drugs is warranted. Drug treatment is often indicated, but is somewhat limited by the minimal number of well-tolerated drugs that have proven to have long-term efficacy in maintaining body weight loss. The currently available drugs, sibutramine and orlistat, appear modestly effective in promoting weight loss. However, pharmacological therapy for obesity is in transition; expanding knowledge of the physiological mechanisms of body weight regulation has revealed new molecular targets, and more than 150 novel agents are under active development. Because weight regulation is complex, and redundant systems protect against perceived starvation, optimal treatment of obesity will likely require combinations of therapies. In addition, a better comprehension of the problem prior to its treatment would be preferable before targeting homeostatic pathways which could be irrelevant.

Emerging aspects of pharmacotherapy for obesity and metabolic syndrome

Obesity is a multifactorial, chronic disorder that has reached epidemic proportions in most industrialized countries and is threatening to become a global epidemic. Obese patients are at higher risk from coronary artery disease, hypertension, hyperlipidemia, diabetes mellitus, cancers, cerebrovascular accidents, osteoarthritis, restrictive pulmonary disease, and sleep apnoea. In particular, visceral fat accumulation is usually accompanied by insulin resistance or type 2 diabetes mellitus, hypertension, hypertriglyceridemia, high uremic acid levels, low high density lipoprotein (HDL) cholesterol to define a variously named syndrome or metabolic syndrome. Metabolic syndrome is now considered a major cardiovascular risk factor in a large percentage of population in worldwide. Both obesity and metabolic syndrome are particularly challenging clinical conditions to treat because of their complex pathophysiological basis. Indeed, body weight represents the integration of many biological and environmental components and relationships among fat and glucose tolerance or blood pressure are not completely understood. Efforts to develop innovative anti-obesity drugs, with benefits for metabolic syndrome, have been recently intensified. In general two distinct strategies can be adopted: first, to reduce energy intake; second, to increase energy expenditure. Here we review some among the most promising avenues in these two fields of drug therapy of obesity and, consequently, of metabolic syndrome.

Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease.

DATA ON SURROGATE END POINTS SUCH AS BLOOD pressure or body weight have often been used to support the approval of new pharmacologic treatments for cardiovascular risk factors. In small, short-term studies, a new drug reduces the level of a risk factor, and the changes in risk factor levels are interpreted as if the health benefits expected on the basis of those changes will necessarily follow. An editorial on the pharmacotherapy of obesity illustrates the argument: in the context of discussing the association between appetite suppressant drugs and primary pulmonary hypertension, the editorialists used observational evidence on the association of body mass index with mortality and translated data on weight loss in a small, short-term trial of dexfenfluramine into an estimate of lives that could be saved by long-term drug therapy for obesity. The US Food and Drug Administration (FDA) approved dexfenfluramine on the basis of this same surrogate end point argument: “the potential health benefits of anorectic drugs outweigh their risk when considered against the health hazards of obesity.” When, after the drug was approved, the adverse effects were found to be greater than estimated on the basis of preapproval trials, the drug was withdrawn. Is this an example of the drug-approval process working well, or does it point to a fundamental flaw in the way drugs are approved? Surrogate end points sometimes fail to serve as valid predictors of important health outcomes. One remedy would be to require, prior to approving new drug therapies for cardiovascular risk factors, large, long-term clinical trials to assess the drug’s effects on major disease end points. The historical precedent of having accepted surrogate end points and the current interest in minimizing the time to drug approval may make this approach impracticable. Alternatively, a regular requirement for phase 4 trials would perhaps be a practical and achievable strategy for drug approval, one that improves incrementally upon the current approach, which usually requires no other evaluation than the use of surrogate end points.

Drug Therapy of Obesity

Drug Therapy of Obesity

Drug Therapy for Obesity—A Therapeutic Option?

Drug Therapy for Obesity—A Therapeutic Option?

Drug therapy for obesity in the elderly.

The prevalence of obesity is increasing rapidly in the US and other developed countries. Even though the percentage of older individuals is increasing worldwide, obesity has only recently become a recognised problem in this population. Obesity occurs when energy intake chronically exceeds energy expenditure. Moreover, advancing age is associated with an inability to couple energy intake with energy expenditure. Obesity contributes to many adverse health outcomes, including non-insulin-dependent (type II) diabetes mellitus, as well as to an increase in both cardiovascular and all-cause mortality. Only recently has the medical community begun to accept obesity as a disease with a multifactorial pathogenesis that requires systematic lifestyle changes and pharmacological treatment. Several groups of drugs are available for the pharmacotherapy of obesity; anorectic medications (e.g. fenfluramine, dexfenfluramine); substances affecting energy expenditure and body composition [e.g. chromium (chromium picolinate), ephedrine, anabolic steroids, beta 3-adrenoceptor agonists]; and drugs affecting the absorption of nutrients (e.g. orlistat). To date, few drugs have produced and sustained a significant bodyweight loss. However, some drugs induce a significant short term reduction in bodyweight compared with placebo. Moreover, there is a paucity of information regarding the effectiveness of these drugs in the treatment of obesity in the elderly. Furthermore, it is even debated whether obesity should be treated with drug intervention in the elderly. Clinicians prescribing medications for obesity treatment in the elderly need to carefully consider the benefit: risk ratio, given the high prevalence of polypharmacy in elderly patients. Furthermore, physiological changes that occur with aging may affect the pharmacokinetics of administered drugs and need to be taken into consideration.

Emotional problems during weight reduction: Advantages of a combined behavior therapy and antidepressive drug therapy for obesity

Depressive symptoms may increase in a subgroup of obese individuals shortly after beginning a weight-reducing diet. Therefore an additional antidepressive medication should have a positive effect on the course and results of therapy. This hypothesis was tested in three different institutional settings, with identical therapeutic programs. In this study there were 23 obese women. Therapeutic strategies were concerned with an increase of self-control over eating behavior, the improvement of social skills, and the establishment of new problem- solving abilities. Doxepin was used as the anti-depressant in a double blind procedure. Our results seem to support the hypothesis of this study: depressive symptoms markedly increased soon after the beginning of weight-reduction: additional antidepressive medication helped to improve the symptoms and in the long term had a positive effect on the rate of weight loss.