Pharmacotherapy For Obesity Research Articles

Contemporary pharmacological obesity treatments

Abstract In the last few years, obesity has become a global epidemic. Consequently, worldwide costs associated with managing obesity and obesity-related comorbidities are huge. Numerous studies have focused on discerning the appropriate proper treatment of weight related problems such as overweight and obesity. Moreover, many clinical trials have been conducted for many years in order to introduce effective anti-obesity drugs. The aim of the present review is to provide an overview of current and future pharmacotherapy for obesity, and to provide the reader with a determination of the concentration and composition of long and short term anti-obesity drugs, doing so by placing emphasis on pharmacotherapy and up-to-day solutions. It should be noted that, currently, the worldwide pharmacotherapy is represented by phendimetrazine, benzphetamine and diethylpropion, as well as by orlistat, lorcaserin, phentermine/topiramate, naltrexone/bupropion and liraglutide. In our paper, individual cases of patients’ needs are thoroughly illustrated by way of examples. Medical prescriptions and contraindications are also described.

Pediatric obesity pharmacotherapy: current state of the field, review of the literature and clinical trial considerations.

Despite the increasing number of medications recently approved to treat obesity among adults, few agents have been formally evaluated in children or adolescents for this indication. Moreover, there is a paucity of guidance in the literature addressing best practices with regard to pediatric obesity pharmacotherapy clinical trial design, and only general recommendations have been offered by regulatory agencies on this topic. The purposes of this article are to (1) offer a background of the current state of the field of pediatric obesity medicine, (2) provide a brief review of the literature summarizing pediatric obesity pharmacotherapy clinical trials, and (3) highlight and discuss some of the unique aspects that should be considered when designing and conducting high-quality clinical trials evaluating the safety and efficacy of obesity medications in children and adolescents. Suggestions are offered in the areas of target population and eligibility criteria, clinical trial end-point selection, trial duration, implementation of lifestyle modification therapy and recruitment and retention of participants. Efforts should be made to design and conduct trials appropriately to ensure that high-quality evidence is generated on the safety and efficacy of various medications used to treat pediatric obesity.

GLP-1 and weight loss: unraveling the diverse neural circuitry.

Glucagon-like peptide-1 (GLP-1) is currently one of the most promising biological systems for the development of effective obesity pharmacotherapies. Long-acting GLP-1 analogs potently reduce food intake and body weight, and recent discoveries reveal that peripheral administration of these drugs reduces food intake largely through humoral pathways involving direct action on brain GLP-1 receptors (GLP-1R). Thus, it is of critical importance to understand the neural systems through which GLP-1 and long-acting GLP-1 analogs reduce food intake and body weight. In this review, we discuss several neural, physiological, cellular and molecular, as well as behavioral mechanisms through which peripheral and central GLP-1R signaling reduces feeding. Particular attention is devoted to discussion regarding the numerous neural substrates through which GLP-1 and GLP-1 analogs act to reduce food intake and body weight, including various hypothalamic nuclei (arcuate nucleus of the hypothalamus, periventricular hypothalamus, lateral hypothalamic area), hindbrain nuclei (parabrachial nucleus, medial nucleus tractus solitarius), hippocampus (ventral subregion; vHP), and nuclei embedded within the mesolimbic reward circuitry [ventral tegmental area (VTA) and nucleus accumbens (NAc)]. In some of these nuclei [VTA, NAc, and vHP], GLP-1R activation reduces food intake and body weight without concomitant nausea responses, suggesting that targeting these specific pathways may be of particular interest for future obesity pharmacotherapy. The widely distributed neural systems through which GLP-1 and GLP-1 analogs act to reduce body weight highlight the complexity of the neural systems regulating energy balance, as well as the challenges for developing effective obesity pharmacotherapies that reduce feeding without producing parallel negative side effects.

Current trends in the pharmacotherapy for obesity

Obesity represents a major global challenge from both healthcare and economic perspectives. Although lifestyle modifications aimed at reducing calorie intake and increasing energy expenditure remain the cornerstone of obesity management, pharmacotherapy can serve as a useful adjunct. Until recently, orlistat was the only medication registered for the treatment of obesity in the European Union (EU). A deeper understanding of the complexity of energy homeostasis has resulted in new pharmacological options for weight reduction. In 2015, two new antiobesity drugs were approved in the EU. These are a fixed combination of naltrexone/bupropion (Mysimba®) and liraglutide at a dose of 3.0 mg (Saxenda®). In addition, lorcaserin (Belviq®) and a fixed combination of phentermine/topiramate (Qsymia®) were introduced into the US market in 2012. However, the European Medicines Agency did not approve their use in the EU. The burden of previous weight loss agents that have been withdrawn due to safety concerns underlines the need for caution and close follow-up of patients undergoing pharmacological interventions for obesity treatment. This article provides an overview of the efficacy and safety of currently available weight loss pharmacotherapies.

The Current Role of Liraglutide in the Pharmacotherapy of Obesity

Liraglutide 3.0 mg daily dose is marketed under the brand name Saxenda and was recently approved by both the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) as adjunct to a comprehensive lifestyle intervention to achieve weight loss. Human studies using liraglutide 3.0 mg daily dose were selected through search based on PubMed listings and the Clinical trials.gov database using the term "liraglutide". During 56 weeks of treatment, liraglutide 3.0 mg treatment resulted in 5.9-8.0% weight reduction, while the placebo-subtracted weight loss was 3.9-6.0%. The proportion of treated patients with ≥ 5% weight loss was 50-76%, while the placebo-subtracted proportion was 29-46%. Liraglutide 3.0 mg treatment also induced a decrease in waist circumference, serum triglycerides, insulin resistance, blood pressure and an increase in high density lipoprotein-cholesterol (HDL-C). The most common side effects were nausea, hypoglycemia, diarrhea, constipation, vomiting and headache. In the majority of patients liraglutide 3.0 mg was well tolerated. Liraglutide 3.0 mg appears to be an effective adjunct to a comprehensive lifestyle intervention to achieve weight reduction and treat obesity-related comorbidities.

The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity.

There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity.

Current and Emerging Pharmacotherapies for Weight Management in Prediabetes and Diabetes.

Type 2 diabetes is a serious chronic disease that is associated with increased morbidity and premature mortality. It has become the tsunami of noncommunicable diseases, with more than 400 million people worldwide currently living with diabetes. The global diabetes epidemic is driven by rising obesity rates. Excess body fat increases the risk for insulin resistance and prediabetes; obese men and women, respectively, have a 7-fold and 12-fold higher risk for developing type 2 diabetes. Obesity also predisposes to the development of a myriad of medical complications leading to increased morbidity and mortality. Each increase in body mass index of 5 kg/m(2) or higher is, on average, associated with about a 30% higher overall mortality rate. Modest weight loss through health-behaviour modification can significantly prevent or delay the onset of type 2 diabetes in people at risk. Each kg of body weight loss is associated with a 16% relative reduction in diabetes risk. Intentional weight loss is also associated with a 15% reduction in all-cause mortality. Unfortunately, health-behaviour modification alone seldom sustains adequate weight loss to achieve the desired health outcomes, especially in people with diabetes who already have greater difficulty losing weight. Pharmacotherapy is a realistic treatment option as an adjunct to diet and exercise. In addition to orlistat, the glucagon-like peptide-1 receptor agonist liraglutide has recently been approved in Canada for the treatment of obesity in doses of up to 3.0 mg daily. This review is focused on current and emerging pharmacotherapies for obesity in people with prediabetes or diabetes.

Mimecan: A Newly Identified Adipokine and Regulator of Appetite

Originally adipose tissue was considered a site of energy storage, providing mechanical as well as heat insulation and playing a role in the regulation of thermogenesis. However, since the discovery of Leptin in 1994 adipose tissue is now also recognised as an endocrine organ that produces a multitude of substances referred to as “adipokines”. These include adipolin, adiponectin, interleukin-6 (IL-6), leptin, omentin, tumour necrosis factor alpha (TNFα) and visfatin which play important roles in the regulation of food intake and metabolism (Smitka and Maresova, 2015). Adipose tissue is currently considered the largest endocrine organ secreting a multitude of hormones and cytokines known to affect processes both within the peripheral and central nervous system. With respect to leptin and food regulation the adipose tissue acts as a ‘safety valve’ controlling the long term regulation of food intake. Leptin is released in proportion to the degree of adiposity and reduces food intake when energy reserves are sufficient. Unfortunately, in chronic high fat diet induced obesity the ‘safety valve’ malfunctions, with the occurrence of leptin resistance in the hypothalamus exacerbating the problem of obesity (Munzberg et al., 2004). Therefore, as a central target for the treatment of obesity, leptin and leptin analogues have proved disappointing as possible pharmacotherapies. The study by Cao et al. (2015) revealed that mimecan, first identified in the organic matrix of bovine bone, is also expressed in adipose tissue and is a potential target for the treatment of obesity. Cao et al. (2015) described mimecan as a satiety hormone with both intraperitoneal and intracerebroventricular injections suppressing food intake. Information on whether this is due to changes in meal size or meal frequency is unavailable but the cumulative effects of mimecan on food intake appear to be considerable. Cao et al. (2015) demonstrated that the anorexic effects of mimecan are independent from leptin and melanocortin signalling with data showing a reduction in food intake still observed in obese leptin receptor knockout mice (db/db mice) and Agouti mice (AY/a mice) respectively. Cao et al. (2015) suggest mimecan-induced anorexia, within the central nervous system, is probably mediated via interleukin 1β (IL-1 β) and IL-6. It is known that IL-6 production occurs selectively in microglia rather than astrocytes and primary hypothalamic neuronal cells and therefore the study by Cao et al. (2015) supports the emerging evidence for microglia mediated anorexic effects (Le Foll et al., 2015). Microglia and astrocytes may prove to be critical in appetite regulation within the central nervous system with the potential to be new novel targets for the treatment of obesity. There are still many questions to be answered before the importance of mimecan in food intake and appetite regulation can be determined. These include translation of findings in the mouse to the human and establishment of the effectiveness of mimecan on food intake in high fat diet induced obesity. For instance, leptin is effective at reducing food intake in leptin knockout mice (ob/ob mice) (Halaas et al., 1995) and also obese humans with defective leptin production (Paz-Filho et al., 2011). It is only in diet-induced obese conditions that leptin resistance is observed. It is therefore essential to establish the effectiveness of mimecan at reducing food intake in high fat diet induced obese mice. In addition, although the effect of mimecan on food intake is promising there appears to be desensitisation to mimecan over treatment days raising some doubts on the usefulness of mimecan as a pharmacotherapy for obesity. Cao et al. (2015) reason that, as lower concentrations of mimecan were required to elicit an anorexic effect via intracerebroventricular compared to intraperitoneal injections, mimecan is acting centrally. They discount any possible peripheral effect. It would be useful to know the circulating levels of mimecan after intraperitoneal injections in addition to the clearance rates. It is known that numerous adipokines are expressed in other peripheral regions associated with satiety signalling, such as the gastrointestinal tract. For example, leptin is not only expressed in adipose tissue but also the stomach where it modulates vagal afferent satiety signals (Kentish et al., 2013). Cao et al. (2015) demonstrated that mimecan is expressed in other organs and tissue such as the lungs but did not look at expression in the gastrointestinal tract where the short term regulation of food intake and meal size is initiated. It would be interesting to see if specific regions within the gastrointestinal tract express mimecan. In conclusion, mimecan is an adipokine hormone that induces anorexia centrally by increasing IL-1β and IL-6 in the hypothalamus. The role mimecan plays in the regulation of food intake in high fat diet induced obesity and the therapeutic potential of mimecan or analogues of mimecan in the treatment of obesity remains to be determined. The author declares no conflict of interest.

Current Perspectives on Long-term Obesity Pharmacotherapy.

Approximately 1 in 4 adult Canadians are obese and, thus, are at an elevated risk for developing type 2 diabetes, cardiovascular disease and other conditions. Current treatment guidelines recommend that obese individuals lose 5% to 10% of their starting weights to minimize the risk factors for cardiovascular disease and reduce the risk for developing type 2 diabetes or hypertension. All obesity-management strategies involve lifestyle management, but few patients will lose a significant amount of weight and manage to keep it off over the long term using just this strategy. Bariatric surgery is associated with significant long-term weight loss but is restricted to subjects with very high body mass indices, who often wait many years to undergo the procedure. Recent breakthroughs in understanding the mechanisms underlying the development and maintenance of elevated body fat have led to the arrival of new obesity pharmacotherapies. These novel antiobesity therapies, which work by reducing energy intake or through increasing satiety, decreasing hunger, or reducing absorption of calories, may be used indefinitely once patients have demonstrated significant responses (usually defined as ≥5% weight loss) over the first 12 weeks of treatment. To date, 2 long-term obesity pharmacotherapies have been approved and are available in Canada: liraglutide and orlistat. Here, I summarize the mechanisms and clinical features of medications for long-term obesity management that are available in Canada, as well as those available in other jurisdictions or are currently in development.

Horizons in the Pharmacotherapy of Obesity.

Obesity drugs have had a chequered history. In the recent past, only the low efficacy, pancreatic lipase inhibitor orlistat was available worldwide and it was little used. The 5HT2C agonist, lorcaserin, and two combinations of old drugs have been approved in the United States but not in Europe. The diabetes drug liraglutide has been approved in both the US and Europe and seems likely to be most widely accepted. In view of regulators' caution in approving obesity drugs, some (like beloranib) may initially be progressed for niche obesity markets. New drug targets have been identified in brown adipose tissue with the aim of not only activating thermogenesis but also increasing the capacity for thermogenesis in this tissue. Attempts are being made to match the efficacy of bariatric surgery by mimicking multiple gut hormones. Unapproved pharmacotherapies are tempting for some patients. Others remain optimistic about more conventional routes to pharmacotherapy.

Pharmacotherapy for the treatment of obesity

The recognition of the complex counter-regulatory hormonal, metabolic and neurochemical mechanisms that promote weight regain following weight loss and the conceptualisation of obesity as a chronic disease requiring long-term management has led to increasing focus on the role of adjunctive therapies for obesity, particularly pharmacotherapy.Currently available pharmacotherapy achieves a weight loss intermediate between that commonly attained by lifestyle intervention and bariatric surgery, however its accessibility, compared to bariatric surgery increases its appeal.Despite the poor history of obesity pharmacotherapy, novel agents that are in development appear to have several advantages over predecessors. They are generally more selective in their mechanism of action, thereby potentially minimising adverse sequelae and improving the risk-benefit ratio of pharmacotherapy. Another approach has been to use combined pharmacotherapy to better counteract the multiple counter-regulatory neuroendocrine mechanisms which promote weight regain, as well as allowing lower constituent doses of the combined monotherapy agents, which improves the safety and tolerability of these agents that are usually required long-term for chronic weight maintenance.This review will provide an overview of past, present and future pharmacotherapy for obesity. The efficacy and safety profile of currently available pharmacotherapy will be discussed in the setting of stringent regulatory review processes now in place given the fraught history of pharmacological interventions for obesity. Potential novel therapies that seek to better target the multiple complex counter-regulatory mechanisms promoting weight regain while improving the efficacy/safety profile, will also be examined.

Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy.

Obesity is a medical condition caused by accumulated excess body fat with negative impact on patients’ health, including decreased life expectancy. It has become a major health problem in most developed and developing countries, since the worldwide prevalence of obesity nearly doubled during the last 30 years. Consequently, novel treatments focusing on obesity are being investigated. Potential targets include several pathophysiological mechanisms involved in appetite control affecting multiple organ systems, like adipose tissue; some cell types in the stomach and gut; pancreas; thyroid gland; several hypothalamic areas; and centers located in the brainstem. One of the most important orexigenic neuropeptides is ghrelin, which is produced and secreted primarily by ghrelin cells located in the stomach and duodenum. In humans, plasma ghrelin levels rise when the stomach is empty and fall shortly after meal ingestion. In fat tissue, ghrelin increases fat storage. In the brain, it exerts its orexigenic action through activation of NPY/AgRP neurons in the arcuate nucleus. From the pharmacological point of view, it seems that opposing ghrelin activity could be used as a therapeutic principle in treating obesity. The principal idea of antiobesity drugs is to augment anorexigenic and lipolytic signaling, or to block orexigenic and lipogenic mediators. Recent studies have shown that therapeutic vaccines could be a new approach in the development of antiobesity medications. A vaccine should provoke an immune response to a specific causal factor for a particular disease. Several types of anti-ghrelin vaccines have been developed so far, with significant immune response in terms of rising anti-ghrelin antibodies. However, in the only clinical trial performed yet, the results were disappointing, showing no additional weight loss in the study group. Until now, several studies have demonstrated the “proof of concept”, but more studies are required to develop prophylactic and therapeutic vaccines to prevent and/or cure obesity.

The New Era of Drug Therapy for Obesity: The Evidence and the Expectations.

There is an urgent need for effective pharmacological therapies to help tackle the growing obesity epidemic and the healthcare crisis it poses. The past 3 years have seen approval of a number of novel anti-obesity drugs. The majority of these influence hypothalamic appetite pathways via dopaminergic or serotoninergic signalling. Some are combination therapies, allowing lower doses to minimize the potential for off-target effects. An alternative approach is to mimic endogenous satiety signals using long-lasting forms of peripheral appetite-suppressing hormones. There is also considerable interest in targeting thermogenesis by brown adipose tissue to increase resting energy expenditure. Obesity pharmacotherapy has seen several false dawns, but improved understanding of the pathways regulating energy balance, and better-designed trials, give many greater confidence that recently approved agents will be both efficacious and safe. Nevertheless, a number of issues from preclinical and clinical development continue to attract debate, and additional large-scale trials are still required to address areas of uncertainty.

Current and Emerging Pharmacotherapies for Obesity

Obesity is prevalent chronic condition associated with increased morbidity and mortality. Pharmacotherapy is indicated as adjuncts to health behavior modification when overweight or obese adults fail to achieve or maintain the desired weight loss to improve their health status. Orlistat, a lipase inhibitor that decreases fat absorption by 30%, is the only anti-obesity agent approved for long-term therapy in Canada. With the rapid advance in knowledge of the pathogenesis of obesity, the list of potential anti-obesity agents has increased considerably. Anti-obesity drugs lower body weight by 5-15% and fall into 3 major groups: centrally acting medications that inhibit appetite or promote satiety, or both; drugs that act peripherally to impair nutrient absorption; and drugs that increase energy expenditure. Phentermine and diethylpropion are adrenergic stimulants that inhibit appetite by increasing the release and reuptake of norepinephrine and dopamine in the brain. A low-dose combination of phentermine and extended-release topiramate, an antiepileptic drug, has recently been approved in the US. Lorcaserin decreases food consumption and promotes satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin (POMC) neurons located in the hypothalamus. Another FDA-approved combination pill - bupropion and naltrexone, increases dopamine activity in the brain, and increases in energy expenditure by increasing activity of POMC neurons. It regulates the dopamine reward system and control food cravings and overeating. The most recent FDA-approved drug is liraglutide, an incretin analogue that inhibits appetite and energy intake. The benefits and risks of current and emerging anti-obesity agent will be discussed in the presentation.

New medications and new ways to use them.

The field of obesity pharmacotherapy is in its infancy. While these drugs represent new tools to use to help patients in chronic obesity management, we need an educated and more experienced group of prescribers. Only then can we have a meaningful impact on the chronic disease risk driven by obesity. Understanding the basic principles of using obesity medication is the first step in that direction.

The Challenges and Opportunities Associated with Reimbursement for Obesity Pharmacotherapy in the USA.

Obesity has become a serious public health problem that has stimulated primordial and primary prevention efforts, and a triad of management options (lifestyle, pharmacotherapy, and surgical interventions). A growing body of evidence supports the need for a multi-pronged, clinic-based approach that leverages the synergy between pharmaceutical and lifestyle modification. Recent US policy changes—namely, the passage of the Patient Protection and Affordable Care Act coupled with recognition of obesity as a disease by the American Medical Association—suggest that financial incentives and attitudes towards obesity management are changing. This paradigm shift has implications for current and future obesity pharmacotherapy. However, barriers to pharmacotherapy utilization include patient and physician perceptions of modest efficacy, historical safety issues, regulatory obstacles, and lack of reimbursement. The shifting attitudes and challenges associated not only with a multi-payer system, but also the lack of clearly defined cross-payer reimbursement strategies, prompted a survey to determine coverage for obesity treatment. Participants indicated that federal/state mandates and growth of quality-driven healthcare initiatives will eventually drive wider pharmacotherapy reimbursement within 1–5 years. There are signs that federal/state programs are already moving towards reimbursement by improving quality measures to track obesity outcomes and reduce costs. Future research on clinical and economic outcomes of combination weight-management programs coupled with innovative approaches (e.g., eHealth) in the real-world setting that demonstrate value to patients, healthcare providers, payers, and employers will help reshape obesity management by reducing barriers and broadening reimbursement coverage for anti-obesity pharmacotherapy.

The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: II. Recent Topics on Care and Treatment of the Obesity Syndrome; 3. Pharmacotherapy of obesity

The Update of Obesity Syndrome: Molecular Mechanism, Pathophysiology and Therapies. Topics: II. Recent Topics on Care and Treatment of the Obesity Syndrome; 3. Pharmacotherapy of obesity

Orlistat improves release of gut hormones increasing satiety in obese women

Orlistat, which reduces fat absorption by inhibiting intestinal lipase is a registered drug for obesity pharmacotherapy. Meta-analyzes indicate various positive metabolic effects of orlistat, including improvements in glucose and lipid metabolism, lowering both systolic and diastolic blood pressure. It is assumed that orlistat can reduce postprandial satiety by inhibiting the release of intestinal hormones (incretins), especially glucagon-like peptide-1 (GLP-1). Impact analysis of the secretion of incretins, with prolonged use of orlistat was conducted. The aim of the study M.Olszanecka-Glinianowicz et al. was to evaluate the effect of 8 weeks of treatment with orlistat as part of a weight loss program for preprandialnye levels of peptide YY and GLP-1.

Quantitative Gastrointestinal and Psychological Traits Associated With Obesity and Response to Weight-Loss Therapy

Weight loss after pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy. In a prospective study, we measured gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety after an ad libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal-weight, overweight, or obese adults. We also analyzed data from 181 previously studied adults to assess associations betwecen a subset of traits with body mass index and waist circumference. Latent dimensions associated with overweight or obesity were appraised by principal component analyses. We performed a proof of concept, placebo-controlled trial of extended-release phentermine and topiramate in 24 patients to validate associations between quantitative traits and response to weight-loss therapy. In the prospective study, obesity was associated with fasting gastric volume (P= .03), accelerated gastric emptying (P < .001 for solids and P= .011 for liquids), lower postprandial levels of peptide tyrosine tyrosine (P=.003), and higher postprandial levels of glucagon-like peptide 1 (P < .001). In a combined analysis of data from all studies, obesity was associated with higher volume to fullness (n= 509; P= .038) and satiety with abnormal waist circumference (n= 271; P= .016). Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%), and gastric sensorimotor factors (11%). The combination of phentermine and topiramate caused significant weight loss, slowed gastric emptying, and decreased calorie intake; weight loss in response to phentermine and topiramate was significantly associated with calorie intake at the prior satiety test. Quantitative traits are associated with high body mass index; they can distinguish obesity phenotypes and, in a proof of concept clinical trial, predicted response to pharmacotherapy for obesity. ClinicalTrials.gov Number: NCT01834404.

Modern obesity pharmacotherapy: weighing cardiovascular risk and benefit.

Obesity is a major correlate of cardiovascular disease. Weight loss improves cardiovascular risk factors and has the potential to improve outcomes. Two drugs, phentermine plus topiramate and lorcaserin, have recently been approved by the US Food and Drug Administration for the indication of obesity; a third, bupropion plus naltrexone, is under consideration for approval. In clinical trials, these drugs cause weight loss and improve glucose tolerance, lipid profile, and, with the exception of bupropion plus naltrexone, blood pressure. However, their effect on cardiovascular outcomes is unknown. In defining appropriate roles for these drugs in preventive cardiology, it is important to remember the checkered history of drugs for obesity. New weight-loss drugs share the serotonergic and sympathomimetic mechanisms that proved harmful in the cases of Fen-Phen and sibutramine, respectively, albeit with significant differences. Given these risks, randomized cardiovascular outcomes trials are needed to establish the safety, and potential benefit, of these drugs. This review will discuss the history of pharmacotherapy for obesity, existing efficacy and safety data for the novel weight-loss drugs, and issues in the design of postapproval clinical trials.