Liraglutide and cardiovascular outcomes in adults with overweight or obesity: A post hoc analysis from SCALE randomized controlled trials.

The cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist approved for weight management at a dose of 3.0 mg, was evaluated post hoc using data from 5908 participants in 5 randomized, double-blind, placebo-controlled clinical trials. Participants were randomized to liraglutide or a comparator group (placebo or orlistat). The objective was to evaluate whether cardiovascular risk was increased with liraglutide treatment. The primary composite outcome of this time-to-event analysis was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. These cardiovascular events were adjudicated prospectively for three of the trials and retrospectively for two trials by an event adjudication committee. The primary outcome was analyzed using a Cox proportional hazards model, stratified by trial. With liraglutide 3.0 mg, 8 participants had positively adjudicated cardiovascular events (1.54 events/1000 person-years) compared to 10 participants in the comparators group (3.65 events/1000 person-years). The hazard ratio for liraglutide 3.0 mg compared to comparators was 0.42 (95% confidence interval, 0.17-1.08). In this analysis, liraglutide 3.0 mg treatment was not associated with excess cardiovascular risk. However, the wide confidence intervals and retrospective adjudication of events in two of the trials are limitations of the analysis.

Metformin: an Old Therapy that Deserves a New Indication for the Treatment of Obesity.

Metformin is not currently used for weight loss or diabetes prevention because it lacks an FDA indication for obesity and/or pre-diabetes treatment. Based on the evidence, metformin has been shown to decrease the incidence of type 2 diabetes, and compares favorably to other weight-loss medications in terms of efficacy as well as safety. Thus, metformin should be considered for a treatment indication in patients with these conditions.

Pharmacological management of obesity: an Endocrine Society clinical practice guideline

OBJECTIVE: To formulate clinical practice guidelines for the pharmacological management of obesity. PARTICIPANTS: An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. This guideline was co-sponsored by the European Society of Endocrinology and The Obesity Society. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the European Society of Endocrinology, and The Obesity Society reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize some of the supporting evidence. CONCLUSIONS: Weight loss is a pathway to health improvement for patients with obesity-associated risk factors and comorbidities. Medications approved for chronic weight management can be useful adjuncts to lifestyle change for patients who have been unsuccessful with diet and exercise alone. Many medications commonly prescribed for diabetes, depression, and other chronic diseases have weight effects, either to promote weight gain or produce weight loss. Knowledgeable prescribing of medications, choosing whenever possible those with favorable weight profiles, can aid in the prevention and management of obesity and thus improve health.(AU)

New drug targets for the treatment of obesity.

There is a huge void in the current pharmacological treatment options for obesity. This gap is surprising given the high prevalence and associated costs of obesity. Many factors have prevented active drug development, including the poor safety and efficacy of earlier antiobesity drugs. However, there are now several compelling targets on the horizon. The new generation of antiobesity drugs offers hope for the management of obesity, but no single agent is likely to be a panacea. Rather, obesity will need to be managed like many other chronic diseases, with combination therapies and long-term treatment in order to achieve sustained success. New targets have arisen as more research has been performed to understand the complex circuitry that controls energy homeostasis. The goal of this review is to discuss the latest pharmacological agents and strategies that are under development and that may eventually be used for the treatment of obesity.

A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients. DESIGN: Double-blind, randomized, placebo-controlled study. SUBJECTS: Patients were >or=18 years old, with body mass index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks. MEASUREMENTS: Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points. RESULTS: On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo. CONCLUSION: Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.

Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial.

OBJECTIVE: To determine the magnitude and determinants of weight loss in humans exposed to betahistine, a centrally acting histamine-1 (H-1) agonist and partial histamine-3 (H-3) antagonist. DESIGN: A multicenter randomized, placebo-controlled dose-ranging weight loss trial with a 12-week treatment period. SUBJECTS: Two hundred and eighty-one obese but otherwise healthy participants. MEASUREMENTS: Weight and obesity-related comorbidities at baseline and at the end of the intervention. RESULTS: Betahistine, at the doses tested, did not induce significant weight loss. With the exception of headache, no difference in adverse effect profile was noted between placebo and treatment groups. Subgroup analysis revealed that age below 50 years, ethnicity (non-Hispanics) and gender (women) were the strongest predictors of weight loss in this population. When these three factors were combined together, the betahistine 48 mg group (n=23) lost -4.24+/-3.87 kg, whereas the placebo group (n=25) lost -1.65+/-2.96 kg during this time period (P=0.005). CONCLUSION: Betahistine, at the doses tested, induced significant weight loss with minimal adverse events only in women below 50 years.

PROCEED: Prospective Obesity Cohort of Economic Evaluation and Determinants: baseline health and healthcare utilization of the US sample.

AIM: To summarize baseline characteristics, health conditions, resource utilization and resource cost for the US population for the 90-day period preceding enrolment, stratified by body mass index (BMI) and the presence of abdominal obesity (AO). METHODS: PROCEED (Prospective Obesity Cohort of Economic Evaluation and Determinants) is a multinational, prospective cohort of control (BMI 20-24.0 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)) and obese (BMI >or= 30 kg/m(2)) subjects with AO and without AO [non-abdominal obesity (NAO)], defined by waist circumference (WC) >102 and 88 cm for males and females, respectively. Subjects were recruited from an Internet consumer panel. Outcomes were self-reported online. Self-reported anthropometric data were validated. Prevalence of conditions and utilization is presented by BMI class and AO within BMI class. Differences in prevalence and means were evaluated. RESULTS: A total of 1067 overweight [n = 474 (NAO: n = 254 and AO: n = 220)] and obese [n = 493 (NAO: n = 39 and AO: n = 454)] subjects and 100 controls were recruited. Self-reported weight (r = 0.92) and WC (r = 0.87) were correlated with measured assessments. Prevalence of symptoms was significantly higher in groups with higher BMI, as were hypertension (p < 0.0001), diabetes (p < 0.0001) and sleep apnoea (p < 0.0001). Metabolic risk factors increased with the BMI class. Among the overweight class, subjects with AO had significantly more reported respiratory, heart, nervous, skin and reproductive system symptoms. Overweight subjects with AO reported a significantly higher prevalence of diabetes (13%) compared with overweight subjects with NAO (7%, p = 0.04). Mean healthcare cost was significantly higher in the higher BMI classes [control ($456 +/- 937) vs. overweight ($1084 +/- 3531) and obese ($1186 +/- 2808) (p < 0.0001)]. CONCLUSION: An increasing gradient of symptoms, medical conditions, metabolic risk factors and healthcare utilization among those with a greater degree of obesity was observed. The independent effect of AO on health and healthcare utilization deserves further study with a larger sample size.

New targets for obesity pharmacotherapy.

An understanding of the mechanisms that regulate energy homeostasis is essential for understanding novel obesity therapies. The status of energy reserves is communicated to the brain by adiposity and satiety signals. These signals modify either anabolic or catabolic pathways and, consequently, alter food intake in line with signaled energy requirements. New antiobesity therapies are in development that target anabolic or catabolic regulatory networks to reduce food intake and/or increase energy expenditure to promote weight loss.

Putative contributors to the secular increase in obesity: exploring the roads less traveled.

OBJECTIVE: To investigate plausible contributors to the obesity epidemic beyond the two most commonly suggested factors, reduced physical activity and food marketing practices. DESIGN: A narrative review of data and published materials that provide evidence of the role of additional putative factors in contributing to the increasing prevalence of obesity. DATA: Information was drawn from ecological and epidemiological studies of humans, animal studies and studies addressing physiological mechanisms, when available. RESULTS: For at least 10 putative additional explanations for the increased prevalence of obesity over the recent decades, we found supportive (although not conclusive) evidence that in many cases is as compelling as the evidence for more commonly discussed putative explanations. CONCLUSION: Undue attention has been devoted to reduced physical activity and food marketing practices as postulated causes for increases in the prevalence of obesity, leading to neglect of other plausible mechanisms and well-intentioned, but potentially ill-founded proposals for reducing obesity rates.

Epidemiology, morbidity, and treatment of overweight and obesity.

Although still considered more of a cosmetic problem by both the general public and some areas of the medical community, overweight and obesity have reached epidemic proportions worldwide. Overweight and obesity have not only a significant psychological impact but also result in an increased risk for development of numerous chronic and sometimes fatal diseases. The morbidity from obesity-associated disorders increases with higher body mass index and begins within the normal weight range. The costs (direct and indirect) associated with treating obesity and its comorbid conditions are notable and increasing. Obesity rates in patients with schizophrenia are at least as high, if not higher, than in the general population. This article reviews the epidemiology and burden of obesity and its associated comorbid disorders. The guidelines from the National Heart, Lung, and Blood Institute of the National Institutes of Health for diagnosing and treating obesity are also discussed.

Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats.

Tachyphylaxis to the effects of anorexigenic agents, such as sibutramine (S), may be due, in part, to counterregulatory decreases in energy expenditure (EE) and increases in hunger that result from reduced circulating leptin (L) due to loss of body fat and lowered L production/adipocyte. The present study was conducted to test the hypothesis that L administered at low doses sufficient to restore ambient L to preweight loss concentrations would enhance the intercurrent efficacy of S by reducing the strength of physiologic counterregulation to weight loss. Forty male Sprague-Dawley rats were fed a high-fat (HF) diet (45% energy) to induce obesity. After 8 weeks, the obese rats (600 +/- 58 g) were weight-matched into 4 groups (N = 8/group) and implanted subcutaneously (SC) with 2 mL, 7-day Alzet mini-pumps that provided: vehicle (V, saline), L (0.5 mg/kg/d), S (3 mg/kg/d), or L+S. Food intake (FI) on the HF diet was measured daily. On day 7, 24-hour EE was measured by indirect calorimetry, and the animals then killed for body composition analysis. Compared with vehicle, treatment with S alone, but not L alone, produced significant weight loss (-23 +/- 26 v -6 +/- 16 g, P <.01). L alone, or with S, increased fat oxidation (decreased respiratory quotient [RQ]) compared with V (P <.05). The lack of decline in EE with S may be due to its documented effect to stimulate thermogenesis. Administration of L with S synergistically decreased FI and increased weight loss and fractional fat loss. A reduction in plasma L concentration may contribute to the "plateau phenomenon" observed in studies of weight loss therapies. Replacement doses of L during S administration increased weight loss and fractional fat loss by (1) decreasing food intake and (2) by increasing fat oxidation. Such drug combinations may be useful in the treatment of human obesity.

Treating obesity: a new target for prevention of coronary heart disease.

Recognition by the American Heart Association that obesity is a major modifiable risk factor for coronary heart disease has prompted health providers to take a more active role in obesity management. Obesity has long been known to accompany a host of chronic diseases, e.g., type II diabetes, hypertension, and dyslipidemia. We now recognize that obesity is itself a chronic disease with a complex etiology; like diabetes and hypertension, it is treatable with a similar chronic disease treatment model. Relatively modest weight loss confers disproportionate health benefits, improving a roster of risk factors. Diet, exercise, and behavior modification still compose the gold standard of treatment. If these measures fail, medication and surgery should be considered for appropriate patients. With current techniques, many patients can achieve realistic weight goals that can be maintained over the long term. Published management guidelines can now assist in integrating the practical applications of obesity-related research findings into everyday clinical practice.

The effects of drugs used to treat obesity on the autonomic nervous system.

OBJECTIVE: Body fatness is partly under hypothalamic control with effector limbs, which include the endocrine system and the autonomic nervous system (ANS). In previous studies we have shown, in both obese and never-obese subjects, that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the involvement of such ANS mechanisms in the action of anti-obesity drugs, independent of change in weight. RESEARCH METHODS AND PROCEDURES: Normal weight males (ages 22 to 38 years) were fed a solid food diet, carefully measured to maintain body weight, for at least 2 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single-blind, placebo/drug/placebo design, eight subjects received dexfenfluramine, seven phentermine (PHE), and seven sibutramine (SIB). ANS measures of parasympathetic and sympathetic activity included: determination of amount of parasympathetic control (PC) and sympathetic control (SC) of heart period (interbeat interval), using sequential pharmacological blockade by intravenous administration of atropine and esmolol. These autonomic controls of heart period are used to estimate the overall level of parasympathetic and sympathetic activities. Norepinephrine, dopamine, and epinephrine levels in 24-hour urine collections were measured and also resting metabolic rate (RMR). RESULTS: Sufficient food intake maintained constant body weight in all groups. PHE and SIB produced significant increases in SC but no change in PC or in RMR. In contrast, dexfenfluramine produced marked decreases in SC, PC, and RMR. For all three drugs, the effects on urine catecholamines directly paralleled changes in cardiac measures of SC. DISCUSSION: ANS responses to PHE and SIB were anticipated. The large, and unanticipated, response to dexfenfluramine suggests further study to determine whether there could be any relation of these ANS changes to the adverse cardiovascular effects of treatment with dexfenfluramine.

Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study.

BACKGROUND: Long-term maintenance of weight loss remains a therapeutic challenge in obesity treatment. OBJECTIVE: This multicenter, double-blind, placebo-controlled study was designed to test the hypothesis that orlistat, a gastrointestinal lipase inhibitor, is significantly more effective than a placebo in preventing weight regain. DESIGN: Obese subjects who lost > or = 8% of their initial body weight during a 6-mo lead-in of a prescribed hypoenergetic diet (4180-kJ/d deficit) with no adjunctive pharmacotherapy were randomly assigned to receive placebo, 30 mg orlistat, 60 mg orlistat, or 120 mg orlistat 3 times daily for 1 y in combination with a maintenance diet to help prevent weight regain. Of 1313 recruited subjects [body mass index (in kg/m2): 28-43], 729 subjects lost > or =8% of their initial body weight during the 6-mo weight-loss lead-in period and were enrolled in the double-blind phase. RESULTS: After 1 y, subjects treated with 120 mg orlistat 3 times daily regained less weight than did placebo-treated subjects (32.8 +/- 4.5% compared with 58.7 +/- 5.8% regain of lost weight; P < 0.001). Moreover, more subjects in the 120-mg orlistat group than in the placebo group regained < or = 25% of lost weight (47.5% of subjects compared with 29.9%). In addition, orlistat treatment (120 mg 3 times daily) was associated with significantly greater reductions in total and LDL-cholesterol concentrations than was placebo (P < 0.001). CONCLUSION: The use of orlistat during periods of attempted weight maintenance minimizes weight readjustment and facilitates long-term improvement in obesity-related disease risk factors.

Therapeutic controversy: Obesity--a modern-day epidemic.

While the hyperleptinemia of obesity is likely to be associated with the metabolic complications of obesity/hyperinsulinemia/insulin resistance, it is not associated with diabetes, with the relative hypercortisolism of upper body obesity, with hypertension in women, (it is in men), or with dyslipidemia. Overall, the correlations between leptin and the metabolic diseases associated with obesity are weak. The equivocal results of an association of leptin with components of the metabolic syndrome make it unlikely that leptin affects these directly. (On the other hand, these correlations, when found, preclude any causal relationship between leptin and metabolic diseases.) There are experimental data showing a definite role for insulin and glucocorticoids in the regulation of leptin, and of leptin in the regulation of insulin. More data are required on the effects of leptin, but it is likely that leptin will not be a major link between obesity and the metabolic syndrome. Certainly, however, when leptin is available for clinical use, its effect on different aspects of the metabolic syndrome will be worth studying.

Modern medical management of obesity: the role of pharmaceutical intervention.

The medical model of obesity treatment--combining diet, exercise, and behavior modification with antiobesity agents--suffered a setback when fenfluramine and dexfenfluramine were withdrawn from the market because of an association between these medications and valvular regurgitation. The Food and Drug Administration has recently approved sibutramine (Meridia), a norepinephrine and serotonin reuptake inhibitor that was originally developed as an antidepressant, but which has also been shown to reduce weight. In a 1-year placebo-controlled trial, 65% of patients receiving 15 mg sibutramine daily lost more than 5% of their body weight, compared with 29% of patients receiving a placebo; 39% of patients in the sibutramine group lost more than 10% of their body weight, compared with 8% of patients in the placebo group. Health benefits observed in patients receiving sibutramine include reductions in levels of triglycerides, uric acid, total cholesterol, and low-density lipoprotein (LDL) cholesterol and an increase in high-density lipoprotein (HDL) cholesterol levels. Another antiobesity drug currently under review by the Food and Drug Administration is orlistat (Xenical), a pancreatic lipase inhibitor that reduces the absorption of dietary fat by approximately 30%, thus reducing energy intake. In a 1-year placebo-controlled trial, 55% of patients receiving orlistat lost more than 5% of their body weight, and 25% lost more than 10% of their body weight, compared with 33% and 15%, respectively, of patients in the placebo group. In addition, orlistat slowed the rate of weight regain in the second year of treatment. Health benefits demonstrated in clinical trials of orlistat include reduced LDL cholesterol levels and increased levels of HDL cholesterol, reduced blood pressure and fasting insulin levels, improved oral glucose tolerance test outcomes, and improved glycemic control in obese patients with diabetes. The future of the pharmacologic treatment of obesity is promising. Many new antiobesity agents are in the early stages of development, and our understanding of the body's weight-regulating mechanisms is advancing steadily. Human trials of recombinant leptin are underway. Other promising compounds include those that block the Neuropeptide Y5 and Y1 (NY5, NY1) and Melanocortin-4 (MC4) receptors, stimulate uncoupling proteins, and unbind corticotrophin-releasing factor from its binding protein. As better medical treatments for obesity become available, the focus in dietary prescription may shift away from reducing energy intake toward healthier eating for disease prevention. At present, a comprehensive approach, which, in some patients, may include medical therapy as an adjunct, is necessary to treat obesity effectively.

Obesity.

Obesity is a chronic disease, which similar to diabetes and hypertension, requires long-term treatment. The patient must be willing to make major changes in eating habits, lifestyle, and physical activity to achieve long-lasting results.

The therapeutic efficacy of critical care units. Identifying subgroups of patients who benefit.

The majority of patients are admitted to critical care units for observation and to facilitate intervention if deterioration occurs or complications develop. We attempted to determine if a reduction in mortality in a subgroup of these patients admitted directly to the critical care units could be identified. A new method using the scientific principles of a randomized trial applied to the case-control design was employed. All 1905 patients admitted to the medical service over a three-month period were prospectively evaluated for illness severity and stability. Patients who would not have been eligible for a randomized clinical trial were excluded. Based on the prospective evaluations, four prognostically distinct subgroups of patients were formed. An odds ratio for each of the prognostic groups was calculated, a ratio of greater than 1 indicating a protective effect of direct critical care admission. Only one subgroup of patients, the unstable moderately ill, had an odds ratio greater than 1 (13.3). These results, in association with the results of our previous study, suggest that at the time of admission to the hospital, direct admission to the critical care unit reduced mortality among the unstable moderately ill subgroup of patients.