Effect of lorcaserin on weight reduction in persons with obstructive sleep apnea (OSA): a combined subgroup analysis from three randomized, controlled clinical trials.

STUDY OBJECTIVES: To evaluate weight loss with lorcaserin in persons with obstructive sleep apnea (OSA). METHODS: This retrospective analysis evaluated weight loss of lorcaserin (10 mg twice daily) versus placebo in persons with obesity or overweight persons with OSA from a pooled database of three randomized, controlled trials. Primary end points were reductions in the baseline body weight of ≥5% and ≥10% at year 1 and overall weight change at year 1. Changes in heart rate and blood pressure were also evaluated. RESULTS: A total of 336 persons with OSA were identified in the overall pooled population (N = 6,636). At year 1, more patients receiving lorcaserin lost ≥5% (47.2% lorcaserin vs. 25.6% placebo; p < 0.0001) and 10% (22.2% lorcaserin vs. 13.1% placebo; p < 0.0354) of their baseline body weight. Weight loss at year 1 was 6.4 kg versus 3.5 kg in the lorcaserin and placebo groups, respectively (p < 0.0001). Similar results were observed for change in blood pressure and heart rate, with responders having larger benefits. Weight loss was similar between persons with and without OSA. CONCLUSIONS: In this retrospective analysis, persons with OSA showed significant and meaningful weight loss, blood pressure and heart rate reductions in patients treated with lorcaserin versus placebo. Persons with OSA lost just as much weight as those without OSA. Health care providers can expect persons with OSA to lose weight by diet, exercise and the weight loss medication lorcaserin comparable with persons without OSA. Further prospective research is warranted to evaluate impact of weight loss on OSA and overall outcomes for patients.

Effect of lorcaserin in different age groups: a post hoc analysis of patients from the BLOOM, BLOSSOM and BLOOM-DM studies.

INTRODUCTION: The elderly population is projected to be the fastest growing group of individuals with obesity group in the United States. As such, there is merit in examining factors that contribute to healthy aging and weight management. The effects of newer weight loss medications approved after 2013 have been studied but are not often assessed specifically in older persons. METHODS: This post hoc analysis evaluated the magnitude of weight loss in adults across age quartiles with lorcaserin, a serotonin (5-HT) 2C receptor agonist indicated as an adjunct to a reduced-caloric diet and increased physical activity for chronic weight management. Data from three lorcaserin pivotal phase 3 studies were used in this analysis. Data for patients with overweight/obesity without type 2 diabetes (T2D; BLOOM/BLOSSOM; body mass index [BMI] 27.0-29.9 kg/m2 and ≥1 comorbidity or BMI 30.0-45.0 kg/m2) and patients with overweight/obesity with T2D (BLOOM-DM; BMI 27.0-45.0 kg/m2) were used. Patients were randomized to receive lorcaserin 10 mg twice daily or placebo in addition to diet and exercise for 52 weeks. Age quartiles between the studies differed as the T2D population was on average, 9 years older. RESULTS: This analysis shows that lorcaserin was associated with improved weight loss relative to placebo regardless of age. Importantly, these results were consistent for patients with and without T2D. Interestingly, the magnitude of weight loss for lorcaserin appeared to increase with increasing age. In patients without T2D, odds of achieving ≥5% and ≥10% reduction in body weight at 52 weeks were significantly higher for patients >36 years. Lorcaserin was well tolerated in all patients across all quartiles including the oldest quartile. CONCLUSIONS: In summary, this post hoc analysis demonstrates that lorcaserin treatment in patients with and without T2D was safe and effective at reducing weight across all age groups analysed. Weight loss appeared to be greater for older patients; additional analyses are warranted to confirm these findings and to better understand the factors for improved weight loss.

Quality of life, binge eating and sexual function in participants treated for obesity with sustained release naltrexone/bupropion.

Objective: This multicenter, randomized, controlled, open-label trial examined weight-related quality of life, control over eating behaviour and sexual function after 26 weeks of treatment with either 32 mg naltrexone sustained release (SR)/360 mg bupropion SR plus a comprehensive lifestyle intervention program (NB + CLI, N = 153) or usual care (UC, N = 89), which included minimal lifestyle intervention. Methods: Impact of Weight on Quality of Life-Lite, Binge Eating Scale and Arizona Sexual Experiences Scale were assessed at baseline (BL) and weeks 16 and 26. Results: NB + CLI and UC participants lost 9.46 and 0.94% respectively of initial body weight at week 26 (P < 0.0001). NB + CLI participants had greater improvements in Impact of Weight on Quality of Life-Lite total score than UC participants (P < 0.0001). In participants with moderate/severe Binge Eating Scale scores at BL, 91% of NB + CLI and 18% of UC participants experienced categorical improvements. In participants with Arizona Sexual Experiences Scale-defined sexual dysfunction at BL, 58% of NB + CLI and 19% of UC participants no longer met dysfunction criteria at week 26. The most frequent adverse events leading to discontinuation before week 26 in NB + CLI included nausea (10.5%); anxiety (3.3%); and headache, hypertension, insomnia and palpitations (1.3% each). Conclusion: Compared with UC, participants treated with NB + CLI experienced greater improvements in weight-related quality of life, control over eating behaviour, and sexual function.

Improvements in health-related quality of life over 3 years with liraglutide 3.0 mg compared with placebo in participants with overweight or obesity.

Previously in the SCALE Obesity and Prediabetes trial, at 1 year, participants with obesity (or overweight with comorbidities) and prediabetes receiving liraglutide 3.0 mg experienced greater improvements in health-related quality of life (HRQoL) than those receiving placebo. The current study extends these findings by examining 3-year changes in HRQoL. HRQoL was assessed using the obesity-specific Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, as well as the Short-Form 36 v2 (SF-36) health survey. At 3 years, mean change (±standard deviation) in IWQOL-Lite total score from baseline for liraglutide (n = 1472) was 11.0 ± 14.2, vs. 8.1 ± 14.7 for placebo (n = 738) (estimated treatment difference [ETD] 3.4 [95% confidence interval (CI): 2.0, 4.7], P < 0.0001). Mean change in SF-36 physical component summary (PCS) score from baseline for liraglutide was 3.1 ± 7.3, vs. 2.6 ± 7.6 for placebo (ETD 0.87 [95% CI: 0.17, 1.6], P = 0.0156). Mean change in SF-36 mental component summary score did not significantly differ between groups. Both IWQOL-Lite total score and PCS score demonstrated an association between greater HRQoL improvement with higher weight loss. Liraglutide 3.0 mg was also associated with improved health utility (Short-Form-6D and EuroQol-5D, mapped from IWQOL-Lite and/or SF-36) vs. placebo. Liraglutide 3.0 mg, plus diet and exercise, is associated with long-term improvements in HRQoL with obesity or overweight with comorbidity vs. placebo.

Mechanism of increased microbial autofluorescence by heat treatment.

The total direct count (TDC) microbial enumeration method is rapid and suitable for analysing environmental samples containing numerous un-culturable micro-organisms. Conventional TDC methods require the addition of a fluorescent stain and are thus unsuitable for automatic monitoring. We unexpectedly found that heated micro-organisms emit strong autofluorescence. This study was conducted to determine how heating enhances the autofluorescence of bacteria and fungi and to evaluate whether the phenomenon could be exploited to develop a new TDC method. Bacterial autofluorescence was augmented by heating cells at 200°C. ELISA results indicated that levels of advanced glycation end products (AGEs) increased in heated microbes. Catechin, an inhibitor of the Maillard reaction, disrupted the intensification of autofluorescence. These results suggest that the enhanced autofluorescence is associated with the formation of AGEs and that the reaction could be utilized as alternative probe in TDC methods. SIGNIFICANCE AND IMPACT OF THE STUDY: Autofluorescence of bacteria and fungi was prominently intensified by heat treatment at 200°C. This phenomenon was associated with advanced glycation end products formed in micro-organisms via the Maillard reaction. The fluorescence signal was strong enough to be utilized as an alternative probe for fluorescent dye in the total direct count method. This phenomenon could be incorporated in an automatic apparatus for microbial enumeration, as it does not require staining.

The relationship between early weight loss and weight loss at 1 year with naltrexone ER/bupropion ER combination therapy.

BACKGROUND/OBJECTIVES: Weight management medications increase the likelihood that patients will achieve clinically meaningful improvements in cardiovascular, metabolic and other weight-related measures of health. However, the weight loss achieved with any weight management intervention can vary widely among individuals, and patients who do not respond to pharmacotherapy by achieving clinically meaningful weight loss should discontinue therapy. We characterized 1-year weight loss in the phase 3 clinical trial program of the weight management medication, naltrexone/bupropion 32/360 mg (NB), as well as the relationship between early weight loss and long-term weight loss, particularly with respect to participants who achieved the clinically recommended threshold of ⩾5% weight loss by Week 16. PARTICIPANTS/METHODS: Data from participants from each of the four phase 3, randomized, placebo-controlled, 56-week clinical trials with NB were pooled (modified intent-to-treat population; NB N=2043, Placebo N=1319). This exploratory analysis examined the relationship between participant achievement of various weight loss thresholds early in treatment (at Week 8, 12 or 16) and the associated weight loss at Week 56 (Completers population; NB N=1310, Placebo N=763). RESULTS: In the NB participants who completed 1 year of treatment, weight loss of at least 5% at Week 16 (n=873) was associated with least-squares mean weight loss of 11.7% at Week 56 and 85% of these participants had Week 56 weight loss of ⩾5%. Eighty percent (95% confidence interval: 78-82%) of the participants who would, and would not, achieve ⩾5% weight loss at Week 56 were correctly identified using the clinically recommended threshold of ⩾5% at Week 16. Safety and tolerability of NB was similar to previously published reports. CONCLUSIONS: Participants who meet the Week 16 threshold of ⩾5% weight loss are likely to maintain clinically significant weight loss after 1 year of treatment. Further evaluations are required to evaluate improvements in measures of cardiovascular and metabolic risk.

Improvements in health-related quality of life with liraglutide 3.0 mg compared with placebo in weight management.

Obesity has a negative impact on health-related quality of life (HRQoL). The SCALE Obesity and Prediabetes study investigated the effect of liraglutide 3.0 mg, as adjunct to diet and exercise, on HRQoL in patients with obesity [body mass index (BMI) ≥ 30 kg m(-2) ] or overweight (BMI ≥ 27 kg m(-2) ) with comorbidity. Participants were advised on a 500 kcal d(-1) deficit diet and a 150-min week(-1) exercise programme and were randomised 2:1 to once-daily subcutaneous liraglutide 3.0 mg or placebo. HRQoL was assessed using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) and Short-Form 36 (SF-36) v2 health questionnaires. Individuals on liraglutide 3.0 mg (n = 2046) had significantly greater improvements in IWQOL-Lite total score (10.6 ± 13.3) vs. placebo (n = 1020) (7.7 ± 12.8) and SF-36 physical (PCS) and mental (MCS) component summary scores (PCS, 3.6 ± 6.8; MCS, 0.2 ± 8.1) vs. placebo (PCS, 2.2 ± 7.7; MCS, -0.9 ± 9.1). The estimated treatment differences were IWQOL-Lite total score 3.1 (95% CI: 2.2; 4.0), P < 0.0001; SF-36 PCS 1.7 (95% CI: 1.2; 2.2), P < 0.0001 and MCS 0.9 (95% CI: 0.3; 1.5), P = 0.003. All subscales of the IWQOL-Lite and SF-36 were significantly improved with liraglutide 3.0 mg vs. placebo. More patients on liraglutide 3.0 mg experienced meaningful improvement on the IWQOL-Lite total (P < 0.0001) and the SF-36 PCS (P < 0.0001) scores.

Evolution of pharmacological obesity treatments: focus on adverse side-effect profiles.

Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine-induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non-fatal cardiovascular events (sibutramine), and neuro-psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti-obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk-benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight-reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post-marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post-marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti-obesity pharmacotherapy and consider how the history of high-profile toxicity issues has shaped the current regulatory landscape for new and future weight-reducing drugs.

What weight loss treatment options do geriatric patients with overweight and obesity want to consider?

INTRODUCTION: Since the 1990s, a number of weight loss medications have been removed from the USA and or European market because of adverse events associated with these medications. These medications include fenfluramine (heart valve thickening), sibutramine (cardiovascular risk) and rimonabant (depression). This history may affect a patient's desire to consider weight loss medications as an option for weight management. OBJECTIVE: This descriptive study was designed to observe what treatment options the geriatric patient (age 65 or higher) seeking weight loss would like to consider, as well as the reasons they felt they struggled with overweight or obesity. METHODS: A questionnaire was given to 102 geriatric patients with overweight or obesity before starting a weight loss programme at a weight management centre. The questionnaire asked the patient why they felt they were overweight or obese and what treatment options they wished to consider. The geriatric patients were matched with younger patients in body mass index and sex. RESULTS: The three most common perceptions that geriatric patients felt were causes of their increased weight were 'lack of exercise' (76.2%), 'poor food choices' (59.4%) and 'cravings' (47.5%). When geriatric patients were asked what treatment options they would like to discuss, the four most common options requested were 'diet and healthy eating' (67.3%), weight loss medications (57.4%), a request for a 'metabolic work up' (55.4%) and 'exercise' (53.5%). These responses were no different from their younger cohorts. When geriatric patients with a body mass index of 35 or higher were given bariatric surgery as a treatment option, 21.9% marked it as a treatment option they would like to consider. CONCLUSIONS: Over half of geriatric patients desired to discuss weight loss medications as a treatment option. Diet and exercise were also of strong interest, which is in line with current weight management guidelines.

Current and emerging medications for overweight or obesity in people with comorbidities.

Recently, the recognition of obesity as a complex disease that requires chronic management has become more widespread. There has also been a movement away from a focus on body mass index alone, and toward the management of obesity-related comorbidities as well as excess weight. This article examines the current and emerging pharmacological options for weight management in people with overweight or obesity who have, or are at a high risk of, weight-related comorbidities. In the USA, the current options for pharmacological weight management are phentermine (indicated for short-term use only), orlistat, combined phentermine/topiramate extended release, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg. Currently, orlistat, naltrexone/bupropion and liraglutide 3.0 mg are approved in Europe. All of the above-mentioned medications have shown weight-loss efficacy versus placebo. Those approved for long-term weight management have also been associated with improvements in weight-related comorbidities, such as hypertension, prediabetes, diabetes or dyslipidaemia, or related biomarkers. As with all drugs, the safety and tolerability profiles of medications for weight management should be considered alongside their efficacy to ensure correct use. Additional medications for weight management that are in clinical development include bupropion/zonisamide and beloranib. The field of obesity treatment is advancing with a number of medications being recently approved, and with other pharmacological options emerging.

Ion-induced gamma-ray detection of fast ions escaping from fusion plasmas.

A 12 × 12 pixel detector has been developed and used in a laboratory experiment for lost fast-ion diagnostics. With gamma rays in the MeV range originating from nuclear reactions (9)Be(α, nγ)(12)C, (9)Be(d, nγ)(12)C, and (12)C(d, pγ)(13)C, a high purity germanium (HPGe) detector measured a fine-energy-resolved spectrum of gamma rays. The HPGe detector enables the survey of background-gamma rays and Doppler-shifted photo peak shapes. In the experiments, the pixel detector produces a gamma-ray image reconstructed from the energy spectrum obtained from total photon counts of irradiation passing through the detector's lead collimator. From gamma-ray image, diagnostics are able to produce an analysis of the fast ion loss onto the first wall in principle.

N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction.

OBJECTIVE: To compare serum N-terminal pro-brain natriuretic peptide levels at birth between monochorionic diamniotic twins with and without selective intrauterine growth restriction. STUDY DESIGN: Blood samples were collected from 73 monochorionic diamniotic twins without twin-to-twin transfusion syndrome. Two groups were studied on the basis of fetal ultrasonographic findings: 16 twins with and 57 twins without selective intrauterine growth restriction. Selective intrauterine growth restriction was defined as an estimated fetal weight below the 10th percentile in one twin at 18 to 26 weeks of gestation. Serum N-terminal pro-brain natriuretic peptide levels were measured. RESULT: Serum N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction were significantly higher than in those without selective intrauterine growth restriction. Selective intrauterine growth restriction was independently associated with increased N-terminal pro-brain natriuretic peptide levels. CONCLUSION: N-terminal pro-brain natriuretic peptide levels at birth are elevated in monochorionic diamniotic twins with selective intrauterine growth restriction.

Combination therapy with naltrexone and bupropion for obesity reduces total and visceral adiposity.

The effects of combination naltrexone/bupropion therapy on body composition and visceral adipose tissue (VAT) mass were examined in a subset (n = 107) of obese subjects from a Phase 2 trial that compared the efficacy and safety of placebo, naltrexone monotherapy, bupropion monotherapy or one of three naltrexone/bupropion dose combinations for 24 weeks. Body composition data were obtained using dual-energy X-ray absorptiometry and computed tomography. Eighty subjects completed the substudy. Naltrexone/bupropion resulted in weight loss and a greater reduction in body fat (-14.0 ± 1.3%) than placebo (-4.0 ± 2.0%), naltrexone monotherapy (-3.2 ± 2.5%) and bupropion monotherapy (-4.1 ± 2.9%; all p < 0.01). Reduction in VAT mass was also greater with naltrexone/bupropion (-15.0 ± 1.8%) than placebo (-4.6 ± 2.7%), naltrexone monotherapy (-0.1 ± 3.5%) and bupropion monotherapy (-2.3 ± 4.2%; all p < 0.01). Reductions in body fat and VAT mass with naltrexone/bupropion were proportional with weight loss. Weight loss with naltrexone/bupropion was not associated with a greater relative reduction in lean mass than placebo or the monotherapies.

Renin is activated in monochorionic diamniotic twins with birthweight discordance who do not have twin-to-twin transfusion syndrome.

OBJECTIVE: To assess renin, aldosterone, human atrial natriuretic peptide (hANP) and brain natriuretic peptide (BNP) levels in cord blood from monochorionic diamniotic (MD) twins with a birthweight (BW) discordance that do not satisfy the criteria of twin-to-twin transfusion syndrome (TTTS). STUDY DESIGN: Cord blood samples were obtained from 28 MD twins without TTTS. They were divided into two groups on the basis of BW discordance as follows: large (>7.5%) and small (7.5%). Cord blood renin, aldosterone, hANP and BNP levels were measured. RESULT: Renin levels in MD twins with a large BW discordance were significantly higher than those in MD twins with a small BW discordance, with no significant differences in aldosterone, hANP and BNP levels. A significant correlation was found between renin levels and BW discordance. CONCLUSION: Renin is activated in MD twins with a BW discordance of >7.5%, even in non-TTTS.

Impact of severe coronary disease associated or not associated with diabetes mellitus on outcome of interventional treatment using stents: results from HERZ (Heart Research Group of Kanazawa) analyses.

Percutaneous coronary intervention (PCI) using a drug-eluting stent (DES) leads to less re-stenosis than PCI using a bare metal stent (BMS), however there is still controversy whether use of a DES for severe coronary disease leads to an acceptable outcome in patients with diabetes mellitus (DM). In this study 8159 lesions were treated in 6739 patients (mean age 68.9 years) with coronary artery disease. Use of a DES significantly decreased the re-stenosis rate compared with BMS in both DM (9.6% versus 21.3%) and non-DM (9.5% versus 17.1%) patients. The re-stenosis rate was significantly higher in DM than in non-DM patients in the BMS group but not in the DES group. There was no statistically significant difference in event-free survival after stenting of patients with left main coronary artery (LMCA) disease between the BMS and DES groups. It was concluded that, compared with BMS, DES reduced re-stenosis in patients with DM, however, we advise careful treatment after using DES for severe coronary disease, including LMCA lesions, in patients with DM.

Dietary prescriptions for the overweight patient: the potential benefits of low-carbohydrate diets in insulin resistance.

Obesity in the USA continues to be a medical problem of epidemic proportions, affecting one-third of American adults. This increase in body weight and body mass index (BMI) is a risk factor for insulin resistance; individuals with insulin resistance are at increased risk for the development of type 2 diabetes and cardiovascular disease. The identification of effective dietary treatments (e.g. low-carbohydrate diet, low-fat diet) for patient populations with insulin resistance remains controversial. While a variety of dietary approaches will result in weight and cardiac risk factor reduction, individuals who have been identified as insulin-resistant may derive additional short-term weight loss results from a low-carbohydrate diet compared to a low-fat diet.

Development and irradiation test of lost alpha detection system for ITER.

We developed a lost alpha detection system to use in burning plasma experiments. The scintillators of Ag:ZnS and polycrystalline Ce:YAG were designed for a high-temperature environment, and the optical transmission line was designed to transmit from the scintillator to the port plug. The required optical components of lenses and mirrors were irradiated using the fission reactor with the initial result that there was no clear change after the irradiation with a neutron flux of 9.6×10(17) nm(-2) s(-1) for 48 h. We propose a diagnostic of alpha particle loss, so-called alpha particle induced gamma ray spectroscopy. The initial laboratory test has been carried out by the use of the Ce doped Lu(2)SiO(5) scintillator detector and an Am-Be source to detect the 4.44 MeV high energy gamma ray due to the (9)Be(α,nγ)(12)C reaction.

A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes.

AIM: To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM). METHODS: This was a multicenter, double-blind, randomized, placebo-controlled study in overweight and obese patients with T2DM (ages > or = 18 and < or = 75 years) with a BMI > or = 27 kg/m(2) and < or = 43 kg/m(2) and HbA1c > or =7.0 and < or = 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (> or = 1500 mg/day). After a 2-week placebo run-in, patients were randomized to placebo (N = 156) or taranabant 0.5-mg (N = 155), 1-mg (N = 157), or 2-mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints. RESULTS: In the all-patients-treated population, using a last-observation-carried-forward analysis, reductions in BW were -2.5, -3.7, -4.5 and -5.1 kg at Week 36 and -2.4, -4.0, -4.6 and -5.3 kg at Week 52 in the placebo, 0.5-, 1- and 2-mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost > or = 5 and > or = 10% of their baseline BW was significantly greater in the 1- and 2-mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were -0.40, -0.47, -0.68 and -0.71% at Week 36 and -0.30, -0.43, -0.65 and -0.64% at Week 52, in the placebo, 0.5-, 1- and 2-mg groups, respectively (1- and 2-mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system-related (dizziness, sensory-related), and psychiatric (irritability, depression-related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group. CONCLUSIONS: After 36 and 52 weeks, treatment with taranabant at the 1- and 2-mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose-related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity.

Potent and selective agonism of the melanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects: energy intake predicts lack of weight loss efficacy.

MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24-h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK-0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed-dose study and also after 18 weeks of stepped-titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.