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The pharmacological treatment of obesity should be considered when cannot be achieved a 10% weight loss with diet therapy and physical activity. The drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake, inhibition of fat absorption, increase of thermogenesis and stimulation of adipocyte apoptosis. At present, we only have two marketed drugs for obesity treatment. Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis. Sibutramine administration for a year can induce a weight loss of 4-7%. Its main side effects are hypertension, headache, insomnia and constipation. Orlistat is an inhibitor of pancreatic lipase which is able to block the absorption of 30% of ingested fat. Its administration induces weight loss and reduction of ulterior weight regain. Also, this drug improves hypertension dyslipdaemia and helps to prevent diabetes in 52% of cases when administered over four years. The increase in frequency of stools and interference with vitamin absorption are its main side effects. Glucagon-like peptide 1, which increases insulin sensitivity and satiety, adiponectin and PPAR-gamma agonists which reduce insulin resistance and modulates adipocyte generation are the basis for future therapeutic approaches of obesity. Phosphatase inhibitors induce PPAR-gamma phosphorylation and UCP-1 expression leading to an increase in thermogenesis and reduction in appetite.
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PMID:[Pharmacological treatment of obesity]. 1538 15

The aim of this study was to evaluate the effects of sibutramine on body composition and fat distribution, insulin resistance, and serum adiponectin levels in obese women. A total of 28 obese, premenopausal women (mean age, 34.5 +/- 13.7 years; BMI, 31.00 +/- 4.10 kg/m2) was studied before and after 12-week-course of sibutramine (10mg/day). Sibutramine treatment reduced body mass index (P < 0.05) and total body fat (P < 0.05). Abdominal subcutaneous and visceral fat areas (ASFA and AVFA) and mid-thigh low density muscle areas (LDMA) measured by computed-tomography decreased significantly (all, P < 0.05). Insulin resistance (IR) calculated from the homeostasis model assessment (HOMA) method decreased (P < 0.05) and serum adiponectin levels increased significantly (P < 0.05). In our sequential data, the changes of fasting serum insulin levels and the HOMA-IR scores, serum free fatty acids and triglyceride levels, serum adiponectin levels and the mid-thigh LDMA preceded significant changes of body weight, total body fat, and abdominal fat distribution, suggesting sibutramine might improve insulin sensitivity directly by alterations of fatty acid metabolism or secondarily by increasing serum adiponectin levels. Conclusively, sibutramine improved fat distribution and insulin resistance, and increased serum adiponectin levels in Korean obese nondiabetic premenopausal women.
Diabetes Res Clin Pract 2004 Dec
PMID:Sibutramine improves fat distribution and insulin resistance, and increases serum adiponectin levels in Korean obese nondiabetic premenopausal women. 1556 65

Obesity is a chronic disease with a marked impact on health and the prevalence of obesity in Croatia is rapidly rising. Since obesity plays a significant role in the etiology of cardiovascular diseases, diabetes mellitus type 2 and of some cancers, it is an obvious target of public health activities. Weight-reducing drugs, like sibutramine, in combination with diet, exercise and behavioral changes have a role in the management of obesity. Sibutramine acts centrally as a serotonergic and noradrenergic reuptake inhibitor. It reduces body weight by enhancing satiety and stimulating thermogenesis. The aim of this multicenter prospective study was to evaluate the efficacy, tolerability and safety profile of sibutramine in the treatment of overweight patients in Croatia. Patients received 10 mg of sibutramine daily for 12 weeks. The main outcome measures were changes in body weight, BMI, waist and hip circumferences, laboratory assessments (serum triglicerida, cholesterol, glucose, HbA1c), blood pressure and heart rate profile. Of 461 patients included (mean BMI = 35.81+/-6.48 kg/m2, mean age = 43.65+/-10.90 years), 392 completed the study. Three months of sibutramine treatment lead to a significant reduction in body weight, BMI, waist and hip circumferences and improvement in metabolic parameters. Loss of over 5% of their initial body weight was found in 359 patients (91.58%), while 179 patients (45.66%) achieved weight loss over 10%. A decrease of both systolic (-3.39%) and diastolic (-3.75%) blood pressure was noted, while the pulse rate rose slightly (+0.13%). Adverse events were reported by 124 (26.90%) patients, but they precipitated only 17 (3.69%) withdrawals. Results of our study confirmed that sibutramine is an effective and safe weight-reducing drug.
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PMID:Croatian experience with sibutramine in the treatment of obesity--multicenter prospective study. 1563 78

Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing >or=5% and >or=10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus. Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (<or=1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to sibutramine (2 years) and orlistat (4 years). These are the only drugs currently approved for the long-term management of obesity in adults. Sibutramine recipients randomised following 6 months' treatment to either sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p<0.001), with >or=10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2 kg greater than those on placebo at 4 years (p<0.001), with significantly more patients achieving >or=10% loss of initial bodyweight (26.2% and 15.6%, respectively; p<0.001). Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16-26 weeks' treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss. Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.
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PMID:Pharmacotherapy for obesity. 1597 70

The global obesity epidemic is causing much concern among health professionals due to the major health risks associated with obesity. Excess weight, particularly abdominal obesity, elevates multiple cardiovascular and metabolic risk factors, including Type 2 diabetes, hypertension, dyslipidaemia and cardiovascular disease. Thus obesity management goals should encompass health improvement and cardiometabolic risk reduction as well as weight loss. While lifestyle and diet modification form the basis of all effective strategies for weight reduction, some individuals may need additional intervention. About one in four people with BMI >27 kg/m(2) (those who have weight-related morbidity and who have been unsuccessful losing weight in standard ways) may require adjunctive therapy such as pharmacotherapy, very low energy diets/meal replacements, or bariatric surgery. This review focuses on appropriate use of pharmacotherapy for obesity and cardiometabolic risk. Sibutramine and orlistat are currently available for use in Australia. Rimonabant has been approved for use in the European Union, and is being considered for regulatory approval in the USA and Australia. The efficacy and safety of these three agents are examined. In addition, several novel pharmacotherapy agents in development are discussed.
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PMID:Emerging pharmacotherapy for treating obesity and associated cardiometabolic risk. 1692 62

Antiobesity treatment is recommended for selected patients in whom lifestyle modification is unsuccessful. Two antiobesity drugs are currently licensed for long-term use. Orlistat, a gastrointestinal lipase inhibitor, reduces weight by around 3 kg on average and decreases progression to diabetes in high-risk patients; adverse gastrointestinal effects are common. Sibutramine, a monoamine-reuptake inhibitor, results in mean weight losses of 4-5 kg, but is associated with increases in blood pressure and pulse rate. Rimonabant, the first of the endocannabinoid receptor antagonists, reduces weight by 4-5 kg on average and improves waist circumference and concentrations of HDL cholesterol and triglyceride; however, an increased incidence of mood-related disorders has been reported. To date, all antiobesity drug trials have been limited by their high attrition rates and lack of long-term morbidity and mortality data. Other promising antiobesity drugs, including those acting within the central melanocortin pathway, are in development, but are years away from clinical use. In light of the lack of successful weight-loss treatments and the public-health implications of the obesity pandemic, the development of safe and effective drugs should be a priority. However, as new drugs are developed we suggest that the assessment processes should include both surrogate endpoints (ie, weight loss) and clinical outcomes (ie, major obesity-related morbidity and mortality). Only then can patients and their physicians be confident that the putative benefits of such drugs outweigh their risks and costs.
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PMID:Drug treatments for obesity: orlistat, sibutramine, and rimonabant. 1741 51

Cardiovascular disease is a major killer in women yet is frequently considered a male-dominated disease. The risk of cardiovascular disease in women is frequently underestimated and there is also considerable evidence of a treatment bias against women. Women are generally underrepresented in cardiovascular clinical trials yet there is evidence of gender-specific differences in the responses to pharmacotherapy. The Sibutramine Cardiovascular Outcomes (SCOUT) trial has been designed to determine whether weight management with sibutramine together with a diet- and exercise-based lifestyle intervention can prevent cardiovascular morbidity and mortality in high-risk overweight and obese patients. The SCOUT population includes a large number of older women, at high risk for cardiovascular disease. Data from the trial's lead-in phase indicate that treatment with sibutramine and lifestyle management for 6 weeks result in clinically important weight loss and reduction in waist circumference. Despite an initial lower body weight, older women with cardiovascular disease and diabetes mellitus appear to lose as much weight as men. In the overall SCOUT population, treatment with sibutramine is associated with small median decreases in systolic and diastolic blood pressure and small median increases in pulse rate. The side-effect profile of sibutramine in this older, 'at-risk' population was similar to that previously observed in younger patients.
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PMID:The obese older female patient: CV risk and the SCOUT study. 1796 34

Obesity is becoming one of the most common health problems in the world. Many other disorders, such as hypertension and diabetes are considered as the consequences of obesity. Since effective remedies are rare (only two drugs, Orlistat and Sibutramine, were officially approved by the US Food and Drug Administration for long-term obesity treatment so far), researchers are trying to discover new therapies for obesity, and acupuncture is among the most popular alternative approaches. To facilitate weight reduction, one can use manual acupuncture, electroacupuncture (EA) or transcutaneous electrical acupoint stimulation (TEAS). As the parameters of the EA or TEAS can be precisely characterized and the results are more or less reproducible, this review will focus on EA as a treatment modality for obesity. Results obtained in this laboratory in recent five years will be summarized in some detail.
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PMID:Electroacupuncture in the treatment of obesity. 1871 95

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.
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PMID:[Pharmacological therapy of obesity]. 1877 55

Obesity is considered as a major health problem, as its prevalence continuously rises worldwide. One of the common health consequences of obesity is type 2 diabetes mellitus. Therefore, antiobesity management is a prerequisite in treating diabetic patients. Lifestyle modifications combined with pharmacological agents appear to be an effective approach. Sibutramine is a serotonin-noradrenaline reuptake inhibitor, which acts centrally by promoting the feeling of satiety and decreasing caloric intake, thus resulting in weight loss. A potential association with cardiovascular side effects has been noted. Orlistat, a gastric and pancreatic lipase inhibitor, also achieves significant weight loss and improves glycaemic status, but it has gastrointestinal side effects. Rimonabant, the first endocannabinoid CB1 antagonist, is associated with weight reduction and it improves diabetic parameters; nevertheless, it is associated with psychiatric disorders; indeed, a recently conducted safety review led to the temporal suspension of its commercialization. The above-mentioned medications seem to be currently useful agents for treating obesity in patients with type 2 diabetes mellitus. Other medications used for diabetes management, such as exenatide, liraglutide and pramlintide, have also shown body weight reduction. Ongoing research is needed to scrutinize the precise impact of these agents in the daily clinical practice of management of obesity in patients with type 2 diabetes mellitus.
Diabetes Obes Metab 2009 Jul
PMID:Effect of antiobesity medications in patients with type 2 diabetes mellitus. 1923 42


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