Obesity drug therapy.

Obesity is a chronic disease, and it requires chronic therapy. Hypertension, dyslipidemia, diabetes and cardiovascular diseases are leading causes of mortality in the modern world. All of them are strongly linked to obesity. While treating obesity, those conditions are also managed. Obese patients should always be treated through lifestyle interventions, though the results of such interventions are modest. Pharmacotherapy is a second step in the treatment of obesity, approved only when weight loss targets were not reached through lifestyle intervention. During the history of antiobesity drugs, many of them were withdrawn because of their side effects. Various guidelines recommend prescribing drug therapy for obesity through consideration of the potential benefits and limitations. Orlistat deactivates intestinal lipase and inhibits intestinal fat lipolysis. It is actually the only drug on the European market approved for the treatment of obesity. Orlistat therapy reduces weight to a modest extent, but it reduces the incidence of diabetes beyond the result achieved with lifestyle changes. Recently, some effective antiobesity drugs like sibutramine and rimonabant have been removed from the market due to their side effects. The new combination of topimarate and fentermine is approved in the US but not in Europe. The cost effectiveness of long-term pharmacotherapy of obesity is still an unresolved question.

Assessment of maximum weight change and duration of therapeutic effect for non-surgical treatment of obesity using an exponential model.

Efficacy of weight loss and maintenance therapies in obesity is difficult to quantify due to continuous weight changes over time. We assessed a single exponential model of weight changes during selected non-surgical therapies of non-diabetic obese subjects. We analyzed published mean weight data from 6 studies of ≥12 weeks duration, with comparable treatment groups, and ≥4 weight measurements during very low carbohydrate or fat diets, or treatment with Lorcaserin, Sibutramine or Orlistat. We fit data to a single exponential model to estimate maximum predicted weight loss or regain and duration of weight loss or regain for each therapy. A single exponential is the appropriate model as determined by Kolmogorov-Smirnov, constant variance, and Durbin-Watson tests. Validity of parameter estimates was indicated by coefficients of variation <25%. Sensitivity analysis showed that weight regain at the end of the weight loss phase affected parameter estimates in some instances, with variations of weight loss of 0.2-0.7% of basal. Estimated weight loss and regain were similar to observed weight changes in all studies. The model could also be used to assess dose-response relationships. Estimates from the model were used to compare concurrent obesity regimens using 95% confidence intervals, taking into account pre-determined minimal clinically important differences. This exponential model may provide accurate estimates of maximum achievable weight loss or regain and optimal duration of efficacy for a variety of non-surgical weight loss and maintenance regimens from published mean weight data and may be useful to more accurately evaluate weight loss and maintenance regimens.

What is the clinical effectiveness and cost-effectiveness of using drugs in treating obese patients in primary care? A systematic review.

BACKGROUND: Obesity [defined as a body mass index (BMI) ≥ 30 kg/m(2)] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients. DATA SOURCES: Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature. REVIEW METHODS: A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin. RESULTS: Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > £2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of £20,000 per QALY. LIMITATIONS: The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses. CONCLUSION: The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of £20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Adherence to weight loss medications; post-marketing study from HMO pharmacy data of one million individuals.

INTRODUCTION: Post-marketing data on weight-loss medications in free living population are a necessary adjunct to data from clinical trials. MATERIALS AND METHODS: We conducted a population-based analysis of first-time medication users based on HMO pharmacy purchasing data serving > one million adults. RESULTS: During 5 years, usage of orlistat and sibutramine more than doubled and rates were higher during the months May-Aug. As compared to non-users (n = 1,038,828), annual weight-loss drug users (n = 7175) had higher women proportion, body-mass-index (BMI), bariatric surgery history, and usage of diabetes, depression, and cardiovascular medications (p < 0.001 for all). Among users, men had higher BMI (34.4 kg/m(2) vs. 32.5 kg/m(2)), prevalence of diabetes (25.4% vs. 10.7%) and heart disease (14.2% vs. 3.5%) than women. Mean duration of purchasing weight-loss medications was 2.1 months for orlistat and 2.9 months for sibutramine. Fewer than 2% completed 12 months of weight-loss medication therapy. Among the 25% who continued to purchase at least 4 months, BMI (sub-group analysis) reduced from 33.02 kg/m(2) to 32.04 kg/m(2) (p < 0.001). In a multivariate model, long-term adherence (≥ 4 months) to weight-loss medications was associated with use of sibutramine vs. orlistat (OR = 2.08; 95%CI: 1.76-2.45), and prevalence of diabetes (OR = 1.20; 95%CI: 1.01-1.25). Age, gender, and baseline BMI were not associated with long-term adherence. CONCLUSIONS: Usage of weight-loss drugs is higher among diabetes patients. However, the poor adherence to therapy is substantially below levels reported in clinical trials.

Fatal and non-fatal cardiovascular events in a general population prescribed sibutramine in New Zealand: a prospective cohort study.

BACKGROUND: The cardiovascular safety of sibutramine is currently under review by medicines regulatory authorities worldwide after the SCOUT (Sibutramine Cardiovascular Outcome Trial) showed an increased risk of cardiovascular events in patients taking sibutramine. Further data regarding the cardiovascular safety of sibutramine in a general population are now required. OBJECTIVE: To quantify the risk of fatal and non-fatal cardiovascular adverse events in a general population prescribed sibutramine in postmarketing use. STUDY DESIGN: Observational prospective cohort study of patients dispensed sibutramine during a 3-year period (2001-4) and followed up for at least 1 year after their last prescription. The study included record-linkage to national mortality datasets to identify fatal events. SETTING: Postmarketing 'real-life' use of sibutramine in a general population in New Zealand. PATIENTS: All New Zealand patients dispensed a prescription for sibutramine in a 3-year period (for whom a National Health Identification number could be validated). 15 686 patients were included in the record linkage study for fatal events. A subgroup of 9471 patients was followed up by intensive methods for non-fatal events. MAIN OUTCOME MEASURES: (i) Rate of death from all causes and from cardiovascular events; and (ii) rates of non-fatal cardiovascular adverse events. RESULTS: Total exposure to sibutramine for 15 686 patients in the validated cohort was 5431 treatment-years. The rate of death from all causes in this cohort was 0.13 (95% CI 0.05, 0.27) per 100 treatment-years exposure. The rate of death from a cardiovascular event was 0.07 (95% CI 0.02, 0.19) per 100 treatment-years exposure. The most frequent non-fatal cardiovascular events in the intensively followed up cohort were hypertension, palpitations, hypotensive events and tachycardia. CONCLUSIONS: Risk of death from a cardiovascular event in this general population of patients prescribed sibutramine was lower than has been reported in other overweight/obese populations. The results of this study suggest that further evaluation of the benefit-risk profile of sibutramine is now required.

Assessment of the application of the intragastric balloon together with sibutramine: a prospective clinical study.

BACKGROUND: The aim of this study is the prospective evaluation of the results of Bioenterics intragastric balloon (BIB) with sibutramine and BIB placement alone in the treatment of obesity. METHODS: The patients evaluated between March 2006 and January 2007 and enrolled in this study were assessed in two groups as group A (BIB + sibutramine) and group B (BIB). After the follow-up of the patients for 6 months, body mass index (BMI), weight loss, excess weight loss (EWL%), and excess body mass index loss (EBMIL%) values of the patients in both groups were compared. RESULTS: According to the comparison of the weights of the patients in groups A and B at 6 months with the beginning weights of the patients in both groups, there was statistically significant weight loss (p < 0.01). The total weight loss at 6 months in group A was statistically significantly higher than that in group B (p < 0.05). The patients in group A had a mean BMI 34.53 +/- 6.63 kg/m(2), EWL% 38.77 +/- 11.88%, EBMIL% 49.93 +/- 21.52% after 6 months; the patients in group B had a mean BMI 35.29 +/- 6.36 kg/m(2), EWL% 29.06 +/- 17.82%, EBMIL% 36.51 +/- 23.69% after 6 months. There was no statistically significant difference between group A and group B according to the BMI, EWL%, and EBMIL% values (p > 0.05). CONCLUSION: In the management of obesity, using BIB together with sibutramine before the treatment in the patient group who are planned to have surgery, compared with using only BIB, provides more effective weight loss.

Rise in antiobesity drug prescribing for children and adolescents in the UK: a population-based study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The antiobesity drugs sibutramine and orlistat are not licensed for use in children and adolescents in the UK or USA. * Clinical trials suggest antiobesity drugs are effective and well-tolerated in obese adolescents. WHAT THIS STUDY ADDS: * Prescribing of unlicensed antiobesity drugs in children and adolescents has increased significantly in the past 8 years. * Most prescribed antiobesity drugs in children and adolescents are rapidly discontinued before patients can see clinical benefit, suggesting they are poorly tolerated or poorly efficacious. AIMS: The international childhood obesity epidemic has driven increased use of unlicensed antiobesity drugs, whose efficacy and safety are poorly studied in children and adolescents. We investigated the use of unlicensed antiobesity drugs (orlistat, sibutramine and rimonabant) in children and adolescents (0-18 years) in the UK. METHODS: Population-based prescribing data from the UK General Practice Research Database between 1 January 1999 and 31 December 2006. RESULTS: A total of 452 subjects received 1334 prescriptions during the study period. The annual prevalence of antiobesity drug prescriptions rose significantly from 0.006 per 1000 [95% confidence interval (CI) 0.0007, 0.0113] in 1999 to 0.091 per 1000 (95% CI 0.07, 0.11) in 2006, a 15-fold increase, with similar increases seen in both genders. The majority of prescriptions were made to those >or=14 years old, although 25 prescriptions were made for children <12 years old. Orlistat accounted for 78.4% of all prescriptions; only one patient was prescribed rimonabant. However, approximately 45% of the patients ceased orlistat and 25% ceased sibutramine after only 1 month. The estimated mean treatment durations for orlistat and sibutramine were 3 and 4 months, respectively. CONCLUSIONS: Prescribing of unlicensed antiobesity drugs in children and adolescents has dramatically increased in the past 8 years. The majority are rapidly discontinued before patients can see weight benefit, suggesting they are poorly tolerated or poorly efficacious when used in the general population. Further research into the effectiveness and safety of antiobesity drugs in clinical populations of children and adolescents is needed.

Cost-effectiveness of pharmacological anti-obesity treatments: a systematic review.

AIM: To review economic evaluations of weight loss drugs and compare reported incremental cost-effectiveness ratios (ICERs). METHODS: A literature search was conducted for cost-effectiveness (CEAs) and cost-utility analyses (CUAs) of sibutramine, orlistat and rimonabant. RESULTS: Fourteen unique articles were identified (11 CUAs and 3 CEAs; 9 orlistat, 4 sibutramine and 1 rimonabant). All used diet and exercise as comparator, whereas none included indirect costs. Time horizons varied from treatment period only (1-4 years) to 80 years (median 7.5 years). Longer studies modeled effects on diabetes, micro- and macrovascular complications, coronary heart disease and death. Of the CUAs, the median ICER was 16,000 euro(2007)/QALY (quality-adjusted life-year; range 10,000-88,000), with the worst cost-effectiveness when recommended stop rules for non-responding patients were not applied. All studies but three were funded by the manufacturing company, and the median ICER was considerably higher for independent than for sponsored analyses (62,000 euro vs 15,000 euro/QALY). However, two of the three independent CUAs did not use recommended stop rules, as compared with one of eight manufacturer-sponsored analyses. The results were most sensitive to assumptions regarding weight loss sustainability and utility per kilogram lost. Side effects and dropout because of reasons other than lack of efficacy were generally not incorporated. CONCLUSION: Published economic evaluations indicate that orlistat, sibutramine and rimonabant are within the range of what is generally regarded as cost-effective. Uncertainty remains about weight loss sustainability, utility gain associated with weight loss and extrapolations from transient weight loss to long-term health benefits. Modeling of head-to-head comparisons and attrition is needed, as are analyses conducted independently of manufacturing companies.

Can sibutramine alter systemic blood pressure in obese patients?: systematic review and meta-analysis / A sibutramina pode alterar a pressão sangüínea sistêmica em pacientes obesos?: revisão sistemática e metanálise

CONTEXT: Systemic arterial hypertension is part of the metabolic syndrome resulting from obesity. OBJECTIVE: To evaluate the effect of sibutramine on overweight and obese patients' blood pressure through a systematic review. METHODS: All the studies included needed to be randomized controlled trials. The methodological quality of the selected trials was assessed using the criteria described in the Cochrane Handbook. The participants were overweight and obese patients; the intervention was sibutramine compared with placebo. The primary outcome measurement was systolic and diastolic blood pressure and the secondary measurement was blood pressure. Studies were identified by searching the following sources: Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), Medline, Cochrane reviews, manual searches, personal communication and contact with the pharmaceutical industry. There were no language, date or other restrictions. Data collection and extraction was performed by two reviewers, who independently obtained the full articles of all eligible papers. RESULTS: Three meta-analyses were produced: 1) systolic blood pressure outcome (eight studies) did not show statistical significance between sibutramine and placebo: weighted mean difference (WMD) 1.57, confidence interval (CI) -0.03 to 3.18; 2) diastolic blood pressure outcome (ten studies) did not show statistical significance between sibutramine and placebo: WMD 1.13, CI -0.49 to 2.76; 3) blood pressure outcome (two studies) also did not show statistical significance between the groups: relative risk (RR) 0.69, CI 0.07 to 7.01. CONCLUSIONS: The meta-analyses presented in this systematic review show that sibutramine does not have a statistically significant effect on blood pressure, compared with placebo.

CONTEXTO: Hipertensão arterial sistêmica é parte da síndrome metabólica relacionada à obesidade. OBJETIVO: Avaliar o efeito da sibutramina na pressão arterial sistêmica de pacientes com sobrepeso e obesos através de uma revisão sistemática. MÉTODOS: Tipos de estudos: todos os estudos devem ser controlados e aleatórios. A qualidade metodológica dos estudos selecionados foi acessada usando os critérios descritos no Cochrane Handbook; participantes: pacientes com sobrepeso e obesos; intervenção: sibutramina comparada com placebo. Desfechos primários: pressão arterial sistólica e diastólica; secundário: pressão arterial. Estratégia de busca: os estudos foram identificados das seguintes fontes: Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), Medline (Medical Literature Analysis and Retrieval System Online), Cochrane reviews (fontes eletrônicas), manuais, comunicação pessoal e contato com indústria farmacêutica, sem limites. Coleta de dados: dois revisores independentemente obtiveram os artigos completos de todas as publicações elegíveis. RESULTADOS: Três metanálises foram realizadas: no desfecho pressão arterial sistólica, com oito estudos, não houve significância estatística para a diferença entre a sibutramina e o placebo, WMD (weighted mean difference) 1.57, intervalo de confiança (IC) de -0,03 a 3,18; no desfecho pressão arterial diastólica, com 10 estudos, também não houve significância estatística na diferença entre a sibutramina e o placebo, WMD 1.13, IC de -0,49 a 2,76) e no desfecho pressão sangüínea com somente dois estudos, também não foi demonstrada diferença estatisticamente significante entre os grupos experimental e controle, risco relativo de 0,69, IC de 0,07 a 7,01. CONCLUSÃO: O resultado das metanálises apresentadas nesta revisão mostra que a sibutramina utilizada em pacientes obesos, quando comparada ao placebo, não tem efeito estatisticamente significante na pressão arterial.

[Pharmacological therapy of obesity]. / La terapia farmacologica dell'obesità.

Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and uric acid as well and it increases HDL cholesterol; in diabetics it improves glycated hemoglobin. Sibutramine has conflicting effects on blood pressure: in some studies there was a minimal decrease, in some others a modest increase. In all the studies this drug increased pulse rate. Sibutramine is not recommended in patients with uncontrolled hypertension, or in case of history of cardio- and cerebrovascular disease. Orlistat is a pancreatic lipase inhibitor that reduces fat absorption by partially blocking the hydrolysis of dietary triglycerides. A recent meta-analysis evaluated 22 studies lasting for at least 12 months, in obese patients with a mean body mass index of 36.7 kg/m2, where orlistat was associated with hypocaloric diet or behavioral interventions: the net average weight loss was 2.89 kg (confidence interval 2.27-3.51 kg). Considering the principal studies, attrition rate ranged from 33 to 57%. Orlistat significantly decreases waist circumference, blood pressure, total and LDL cholesterol, but has no effect on HDL and triglycerides. This drug significantly reduced the incidence of diabetes only in subjects with impaired glucose tolerance. The major adverse effects with orlistat are mainly gastrointestinal (fatty and oily stool, fecal urgency, oily spotting, fecal incontinence) and attenuate over time. Orlistat should be avoided in patients with chronic malabsorption and cholestasis. Rimonabant is a selective antagonist of cannabinoid type 1 receptor. This drug, by inhibiting the overactivation of the endocannabinoid system, produces anorectic stimuli at the central nervous level, but also has effects on the peripheral systems involved in metabolism control, such as liver, adipose tissue, skeletal muscles, endocrine pancreas, and gastrointestinal apparatus, influencing many processes partially unknown. An ample experimental program named RIO (Rimonabant In Obesity) involved about 6600 obese or overweight patients to identify the effects of rimonabant in weight loss and associated cardiometabolic abnormalities, over and beyond a caloric restriction of 600 kcal in the treatment and placebo arms. In the four double-blind RIO trials published (Rio-North America, RIO-Europe, RIO-Lipids, RIO-Diabetes), rimonabant 20 mg significantly (p <0.001) reduced weight by 6.3-6.9 kg in the non-diabetic groups vs placebo (-1.5-1.8 kg), whereas in the diabetic subjects enrolled in RIO-Diabetes, weight loss was 5.3 vs 1.4 kg in the placebo group. Attrition rate at 1 year ranged between 40 and 50%, similar to the studies with sibutramine or orlistat. Similarly to weight loss, also waist circumference was significantly reduced by rimonabant. As for cardiometabolic parameters, rimonabant induced a significant increase in HDL cholesterol and a significant decrease in triglycerides. Even if no significant LDL reduction was achieved, the RIO-Lipids study showed a significant decrease in small dense LDL particles, more atherogenic, in rimonabant-treated subjects. Non-diabetic treated patients improved basal insulin and indirect indexes of insulin resistance, while in the RIO-Diabetes study, the only one including diabetics, glycated hemoglobin improved by 0.7% in the active treatment arm vs placebo. The effects on HDL cholesterol and glycated hemoglobin seem in a large percentage unrelated to weight loss. These effects have been confirmed by another trial, named SERENADE, evaluating the treatment in naive diabetic patients. Rimonabant is not recommended in patients with a history of depressive disorders or suicidal ideation and with uncontrolled psychiatric illness, and is contraindicated in patients with ongoing major depression or ongoing antidepressive treatment. In conclusion, despite an enormous advancement in basic research to understand the pathogenetic mechanisms at the base of obesity, the pharmacological research did not reach the therapeutic opportunities available for other chronic conditions, like hypertension and dyslipidemia. However, the few molecules available for clinical practice (sibutramine, orlistat, rimonabant) have shown, when properly used, to contribute to reduce body weight and undoubtedly improve cardiometabolic risk factors. With this preamble, according to current guidelines and pharmacoeconomic studies, patients who might benefit from antiobesity treatment are those with a body mass index > or =30 or 27-29.9 kg/m2 with major obesity-related comorbidities such as hypertension, diabetes, dyslipidemia, obstructive sleep apnea, and metabolic syndrome.

National trends in the use and costs of anti-obesity medications in England 1998-2005.

BACKGROUND: To report the trends in the use and costs of anti-obesity medications in England from 1998 to 2005. METHODS: We analysed data on all community anti-obesity drug prescriptions in England collated by the prescription cost analysis system. RESULTS: Between 1998 and 2005, Orlistat prescriptions rose 36-fold from 17,880 to 646,700 and total cost increased by over 35-fold. Sibutramine prescriptions rose from 2001 to 2005 from 53,393 to 227,000, a 4-fold increase. Although prescriptions of Orlistat and Sibutramine have increased substantially since they were first introduced, the rate of growth decreased substantially in recent years until 2005, when a significant increase in the number and cost of prescriptions for orlistat occurred yet again. CONCLUSIONS: We found a large increase in the use and costs of anti-obesity prescriptions, consistent with the increased awareness of obesity amongst health care professionals and the public. Despite this large increase, there are still no head-to-head studies at a national level that directly compare all anti-obesity medication in use in the UK.

The effect of sibutramine on energy expenditure and body composition in obese adolescents.

CONTEXT: Childhood obesity is now considered to be an epidemic. Drug therapy in this age group remains a topic of research. OBJECTIVE: The objective of this study was to examine the effect of treatment with sibutramine (10 mg) on body composition and energy expenditure in obese adolescents. DESIGN: The study was conducted as a randomized, double-blind, placebo-controlled trial. SETTING: The study was set in an obesity research center. PATIENTS: The patients were 24 obese adolescents (age 12-17 yr, 11 boys); four patients withdrew. INTERVENTION: Intervention was sibutramine (Meridia) or placebo in combination with an energy-restricted diet and exercise plan for 12 wk, followed by an identical, but medication-free, treatment period (follow-up). MAIN OUTCOME MEASURE: Change in body mass index (BMI) sd score (BMI-SDS) was the principal measure of efficacy. Body composition and total energy expenditure were measured by stable isotopes and further calculated according to the four-component model, using underwater weighing and dual x-ray absorptiometry. Basal metabolic rate (BMR) was measured by ventilated hood and adjusted for sex and body composition (BMRadj). RESULTS: After intervention, the decrease in BMI-SDS was comparable in both groups. During follow-up, BMI further decreased in the placebo group but stabilized in the sibutramine group. Changes in the percentage of fat mass were not different between both groups. BMRadj decreased in the placebo group and remained constant in the sibutramine group. During follow-up, BMRadj decreased in the sibutramine group and increased in the placebo group. Changes in total energy expenditure were not significantly different. CONCLUSION: The effect of sibutramine on BMI-SDS was not significant. Sibutramine may diminish the decrease in BMRadj associated with energy restriction in obese adolescents.

Assessment of clinical and economic benefits of weight management with sibutramine in general practice in Germany.

Obesity is associated with major health risks and a high economic burden impacting on health care systems. This study utilises the latest evidence from randomised clinical trials (RCTs) to explore and to assess the cost effectiveness of sibutramine in combination with diet and lifestyle advice compared to diet and lifestyle advice alone for the treatment of obese subjects without comorbidities at baseline in Germany. New evidence from recently published RCTs and post-marketing surveillance studies, including health economic data as well as quality of life (QoL) data, were used to model the long-term outcomes of weight management with sibutramine in German practice. German healthcare costs and new data from over 8,000 patients were analysed based on a recently published model. These new RCT data were used to model weight losses, proportion of responders to treatment, utilities by weight loss and variability in weight regain post-treatment. Costs and QoL benefits associated with weight loss (using SF-36 data from sibutramine trials), reduced incidence of coronary heart disease (using Framingham equations) and diabetes were used to estimate the cost per quality adjusted life year of sibutramine treatment. For 1,000 patients treated with sibutramine for 1 year, extrapolating outcomes over 4 further years, sibutramine is estimated to save 4.18 CHD events, 2.58 diabetes incident cases and give 51.5 more quality-adjusted life years (QALYs). The cost-utility analysis (CUA) estimates 13,706 euro per QALY gained. Results are sensitive to changes in weight loss, rate of weight regain and discounting rate. Although the non-pharmacological weight management programme in the comparator arm yielded higher weight losses than generally observed in clinical practice, these results demonstrate that additional sibutramine treatment is a cost effective therapy for an obese population without comorbidities in Germany. The CUA results are within the range generally accepted as cost effective and should be viewed as conservative when generalizing to settings offering standard non-pharmacological treatment.

Assessment and management of the obese adult female: a clinical update for providers.

Obesity is epidemic in the United States, affecting 61% of adults and 14% of children. Today's health care providers should recognize obesity as a chronic disease and offer up-to-date information and management. Treatment options currently available are diet and behavior modification, medications, and surgical procedures. Implications for clinical practice include recognition of the problems associated with obesity, education of current patients as well as young women who may become patients, and appropriate diagnosis and management or referral.

Central nervous system biogenic amine targets for control of appetite and energy expenditure.

Central biogenic amine systems have long been studied for their effects on feeding behavior, energy balance, and maintenance of body weight. Those monoaminergic systems that use dopamine (DA), norepinephrine (NE), and serotonin (5-hydroxytryptamine, 5-HT) as neurotransmitters have been the main targets of study. A number of antiobesity medications that affect monoaminergic activity have appeared on the market and/or in clinical trials. Early examples of such agents are the so-called CNS stimulants, e.g., the amphetamines, phentermine, ephedrine, etc. These agents release monoamines from neuronal stores, and their antiobesity activity seems to be tied most closely to their ability to release NE. Inhibitors of neuronal reuptake of NE or 5-HT have been shown to reduce feeding and weight gain both preclinically and clinically. However, the magnitude and sustainability of such effects in clinical trials has generally not been great enough to register or label these agents for the treatment of obesity. Sibutramine, however, is an exception. This compound is metabolized in vivo to produce metabolites that have varying degrees of inhibition of NE, 5-HT, and/or DA uptake. Sibutramine is the only drug affecting monoaminergic systems currently approved for the long-term control of obesity. Research continues on serotonergic and histaminergic systems to determine if targets such as the 5-HT2C and H3 receptors may be suitable for developing antiobesity agents. Because the clinical antiobesity effects of monoaminergic drugs have been modest, future directions include looking at combinations of different monoaminergic mechanisms and/or combinations of monoaminergic drugs with non-monoaminergic mechanisms.

Pharmacotherapy for obesity.

The current obesity pandemic imposes a major global disease burden. However, sustained weight loss of between 5 and 10% in the obese confers marked health benefits. Currently available pharmacotherapies, orlistat and sibutramine, can induce weight loss of between 5 and 10% over 2 years or more. However, in these trials, drug induced weight loss tends to be only 2-4 kg greater than that produced by placebo control. Despite this, in the XENDOS trial, the modest placebo-subtract weight loss produced by orlistat (2.8 kg) reduced the incidence of diabetes by over a third. Recent data on the potential anti-obesity drug rimonabant are also reviewed.

Cost-effectiveness of sibutramine in the LOSE Weight Study: evaluating the role of pharmacologic weight-loss therapy within a weight management program.

UNLABELLED: the cost-effectiveness of drug therapy when used in conjunction with a weight management program (WMP) for treatment of obesity. The objective was to compare the cost-effectiveness of sibutramine (Meridia) plus a structured WMP versus only a structured WMP in both overweight and obese individuals. The core WMP was a physician-supervised, multidisciplinary program for which each enrollee paid $100 out of pocket. METHODS: A cost-effectiveness analysis was performed based upon the results of a previously published randomized controlled trial conducted within a managed care organization. The target population for this study was obese or overweight persons. The perspective of the study was that of a managed care organization. The intervention consisted of subjects receiving a WMP with or without sibutramine. The primary outcomes of this study were (a) absolute change in body weight and percentage change in body weight over 12 months, (b) change in obesity-related and total medical costs from 12 months prior to enrollment through 12 months after enrollment, and (c) cost-effectiveness in terms of cost per pound of weight loss. All costs were adjusted to 2004 dollars using the respective components of the consumer price index for each medical service or medication. RESULTS: A total of 501 evaluable subjects were enrolled in the study, with 281 receiving sibutramine plus a structured WMP and 220 receiving only the structured WMP. The meanSD weight loss was significantly greater in the sibutramine (13.715.5 pounds, 4.8%) group than in the nondrug group (513.2 pounds, 2.2%) (P < 0.001). The change in obesity-related total cost was a median increase of $408 for the sibutramine group compared with $31 for the nondrug group (P < 0.001). The change in total health care cost was a median $1,279 increase in the sibutramine group compared with $271 for the nondrug group (P < 0.001). Adding sibutramine to the WMP increased the total cost by $44 per additional pound of weight loss (95% confidence interval, 42-46). Sensitivity analyses found that the results were sensitive to the price of sibutramine, whereas varying the cost of clinic visits did not substantially change the results. CONCLUSION: Patients enrolled in a WMP receiving sibutramine had greater weight loss and decrease in body mass index at greater cost than did patients enrolled in the same program who did not receive sibutramine. There were no observed savings in total health care resource utilization or cost in the sibutramine group compared with the nondrug group.

Does prior authorization of sibutramine improve medication compliance or weight loss?

OBJECTIVE: This study was designed to examine whether prior authorization for insurer reimbursement of weight loss medication affects compliance with taking sibutramine or adherence to a medical weight control program. The underlying hypothesis is that physician advocacy through prior authorization increases patient compliance and treatment outcomes. RESEARCH METHODS AND PROCEDURES: A retrospective review was conducted of 22 subjects who had received a prescription for sibutramine that was reimbursed through their health insurer by prior authorization (PAR) and compared them with 47 randomly selected subjects who were also prescribed sibutramine but did not receive reimbursement (non-PAR). Outcome measures included the percentage weight lost, visits to the clinic, and number of prescriptions received at 3, 6, 9, and 12 months. RESULTS: The proportion of subjects remaining in the clinic program, the number of clinic visits made, the number of prescriptions received, and the amount of weight lost were all significantly greater among PAR subjects than among non-PAR subjects. PAR subjects used the medication 37% longer by month 6 (2.43 vs. 1.52 prescriptions; p<0.02), visited the clinic 44% more often (72.5 vs. 40.5 visits in 12 months; p<0.0006), and achieved 38% better maximal weight loss (16% vs. 9.9% at 6 months; p<0.49) than non-PAR subjects. DISCUSSION: This study suggests that, when those medications are not included on a health insurer's formulary, the use of the prior authorization process may improve both medication and behavioral compliance.

The Long-term Outcomes of Sibutramine Effectiveness on Weight (LOSE Weight) study: evaluating the role of drug therapy within a weight management program in a group-model health maintenance organization.

OBJECTIVE: To assess the benefit of sibutramine hydrochloride monohydrate within a weight management program. STUDY DESIGN: Prospective randomized controlled trial in a health maintenance organization. PATIENTS AND METHODS: Obese patients (n = 588) starting a weight management program were enrolled. Patients were randomly assigned to participate in the program alone or to participate in the program and receive sibutramine for 12 months. Outcome measures were change in weight, body mass index (BMI), percentage body fat, serum lipids, serum glucose, and blood pressure. RESULTS: At baseline, there was a younger age and higher weight, BMI, and waist circumference in the drug group. There was more degenerative joint disease in the nondrug group. The mean weight loss at 6 months was 6.8 kg (95% confidence interval [CI], -7.4 to -6.1 kg) in the drug group vs 3.1 kg (95% CI, -3.8 to -2.4 kg) (P < .001) in the nondrug group. Weight loss was maintained at 12 months. Significant reductions in BMI, body fat, and waist circumference occurred in the drug group. There were no significant changes in laboratory values or blood pressure. Patients taking sibutramine experienced a significant increase in heart rate (1.7 beats/min [95% CI, 0.5-2.9 beats/min] vs -0.4 beats/min [95% CI, -1.5 to 0.8 beats/min]; P <.004). CONCLUSION: In this managed care setting, the effectiveness and safety of sibutramine were similar to those observed in randomized, double-blind clinical efficacy trials.