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Controlled studies have shown that sibutramine produces dose-related weight loss when given in the range 5-30 mg per day, with optimal doses of 10 and 15 mg per day. Weight loss with sibutramine is 3-5 kg better than placebo at 24 weeks, and weight loss is maintained to 52 weeks at doses of 10 and 15 mg. By six months, 69% of patients treated with sibutramine 15 mg achieve a 5% or greater reduction in their baseline weight. The weight loss achieved with sibutramine was similar to that achieved with dexfenfluramine over 12 weeks (4.5 kg compared with 3.2 kg). Sibutramine-induced weight loss has been found to be accompanied by a significant reduction in waist/hip ratio, and decreases in plasma triglycerides, total cholesterol and low density lipoprotein (LDL) cholesterol. There were also increases in high density lipoprotein (HDL) cholesterol. In patients with type II diabetes, sibutramine-induced weight loss was accompanied by a shift towards improved glycaemic control. In controlled studies, 84% of sibutramine-treated patients reported adverse events, compared with 71% of patients receiving placebo. The most frequently reported adverse events are related to pharmacological actions of sibutramine, and include dry mouth, decreased appetite, constipation and insomnia.
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PMID:Sibutramine--a review of clinical efficacy. 913 39

Visceral adiposity has a strong and independent association with obesity and its related co-morbidities, particularly metabolic complications such as cardiovascular disease and type II diabetes. Waist circumference and waist-to-hip ratio (WHR) are both secondary indicators of visceral obesity. This paper examines the effect of sibutramine, a new serotonin and noradrenaline re-uptake inhibitor, on weight reduction and changes in fat distribution. A meta-analysis of four long-term, placebo-controlled, double-blind studies showed significantly greater mean decreases in waist circumference in sibutramine-treated subjects compared with placebo (P < 0.001). Similar results were seen for WHR, with 15 mg sibutramine daily producing a significant reduction of 0.02 compared with placebo (P < 0.02). Changes in fat distribution have been examined using computerised tomography (CT) scans as part of the Sibutramine Trial of Obesity Reduction and Maintenance (STORM). Preliminary results showed a mean weight loss from baseline of 11.2 +/- 6.3 kg after 6 months of 10 mg sibutramine treatment. Decreases in total abdominal fat (18%), total subcutaneous fat (17%) and total visceral fat (22%) were observed, and there was a significant increase in the subcutaneous-to-visceral fat ratio (P = 0.04). These changes in fat levels and distribution were associated with improvements in related risk factors such as fasting blood glucose and insulin levels, and blood pressure. In conclusion, sibutramine produces statistically and clinically significant decreases in waist circumference and WHR, and preferentially reduces visceral fat levels.
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PMID:Sibutramine and fat distribution: is there a role for pharmacotherapy in abdominal/visceral fat reduction? 975 42

Sibutramine is a serotonin and noradrenaline re-uptake inhibitor (SNRI) which induces weight loss via a dual mode of action: enhancing both satiety and energy expenditure. Sibutramine exerts its in vivo effects predominantly via its secondary and primary amine metabolites. Following oral ingestion, sibutramine is well absorbed and undergoes extensive first pass metabolism. Sibutramine produces statistically and clinically significant, dose-related weight loss over the range 5-30 mg once daily; active weight loss occurs for 6 months. Long-term studies of up to 1 year have found that weight loss is maintained with continued sibutramine therapy. Sibutramine-induced weight loss is associated with beneficial changes in obesity-related risk factors, such as serum lipids, uric acid levels, and glycaemic control (in patients with type 2 diabetes). Subcutaneous/visceral fat ratio was found to increase significantly under sibutramine treatment, indicating that relatively more visceral fat than subcutaneous fat is lost. Sibutramine is well tolerated; side-effects are generally mild, non-treatment limiting, and consistent with the known mechanism of action of the drug. Overall, studies have found sibutramine to be an effective weight loss agent with a good safety profile.
Exp Clin Endocrinol Diabetes 1998
PMID:Anti-obesity drugs: what does sibutramine offer? An analysis of its potential contribution to obesity treatment. 979 80

Sibutramine is an orally administered centrally acting weight management agent apparently devoid of amphetamine-like abuse potential. Its primary (M2; BTS 54,505) and secondary (M1; BTS 54,354) amine metabolites are pharmacologically active and are thought to induce the natural processes leading to enhancement of satiety and thermogenesis by inhibiting serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) reuptake. In clinical trials, once-daily sibutramine was administered at dosages of < or = 30 mg for < or = 24 weeks and 10 or 15 mg for 1 year in conjunction with reduced calorie intake, increased daily exercise and advice on eating behaviour. Dose-related bodyweight loss was greater with sibutramine than with placebo. Clinical effects were most commonly apparent at dosages > or = 10 mg/day. Weight loss of > 1% within the first month of treatment appears indicative of good long term response with sibutramine. Weight loss was maintained during therapy for 1 year; longer term data are lacking. Weight regain occurred after treatment cessation in studies of < or = 24 weeks' duration; data from longer trials are unavailable. Up to 15% of patients in < or = 6-month studies did not respond to treatment irrespective of dose. Obese patients with type 2 (non-insulin-dependent) diabetes or hypertension lost significantly more mean bodyweight with sibutramine than with placebo, although weight loss was less than that in obese patients without comorbidities. The effect of sibutramine on mean fasting blood glucose levels and plasma lipid levels was unclear. Sibutramine, compared with placebo, statistically significantly increased blood pressure and heart rate in obese patients with or without hypertension when given for up to 12 months. However, after 12 weeks' treatment in hypertensive obese patients, diastolic blood pressure was reduced by similar amounts with sibutramine or placebo. Concerns over potential pressor effects with sibutramine are reflected in the manufacturer's dosage and administration recommendations.
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PMID:Sibutramine. A review of its contribution to the management of obesity. 987 96

Obesity is a well-known risk factor for the development of Type 2 diabetes mellitus. The management of the obese diabetic patient remains a challenge for the clinician but, in any case, weight reduction should be considered as a key objective. In this respect, several antiobesity drugs have demonstrated potential. However, while fenfluramine and dexfenfluramine have been shown to promote weight loss and to directly improve insulin sensitivity, being two mechanisms contributing to better blood glucose control in obese Type 2 diabetic patients, they were recently withdrawn due to safety problems. Sibutramine, a new selective norepinephrine and serotonin reuptake inhibitor, promotes weight loss by decreasing food intake, an effect which leads to a mild improvement (significant in patients losing > or =5% of initial body weight) of blood glucose control in obese diabetic patients. Similarly, orlistat, a selective gastrointestinal lipase inhibitor which increases faecal fat losses, enhances diet-induced weight reduction and improves both blood glucose control and vascular risk profile, especially dyslipidaemia, in obese Type 2 diabetic patients. Further studies are required to better identify good responders to pharmacotherapy and specify the role of antiobesity agents in the overall long-term management of obese subjects with Type 2 diabetes. Other novel pharmacological approaches deserve further consideration, for instance beta-3 agonists aiming to increase energy expenditure, drugs interfering with tumor necrosis factor-alpha (TNF-alpha) or free fatty acid release by the adipose tissue or agents that slow gastric emptying. However, until now, results regarding efficacy and/or safety have been disappointing or preliminary in humans.
Diabetes Metab Res Rev
PMID:Antiobesity pharmacotherapy in the management of type 2 diabetes. 1075 51

Obesity is one of the most common medical problems in the United States and a risk factor for illnesses such as hypertension, diabetes, degenerative arthritis and myocardial infarction. It is a cause of significant morbidity and mortality and generates great social and financial costs. Obesity is defined as a body mass index greater than 30. Many patients accomplish weight loss with diet, exercise and lifestyle modification. Others require more aggressive therapy. Weight loss medications may be appropriate for use in selected patients who meet the definition of obesity or who are overweight with comorbid conditions. Medications are formulated to reduce energy intake, increase energy output or decrease the absorption of nutrients. Drugs cannot replace diet, exercise and lifestyle modification, which remain the cornerstones of obesity treatment. Two new agents, sibutramine and orlistat, exhibit novel mechanisms of action and avoid some of the side effects that occurred with earlier drugs. Sibutramine acts to block uptake of serotonin, norepinephrine and dopamine, while orlistat decreases fat absorption in the intestines.
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PMID:Medical management of obesity. 1092 4

Obesity is a chronic disease and requires ongoing treatment. Type 2 diabetes is associated with obesity and improves with weight loss. Diets of 800 kcal/d induce twice the weight loss induced by weight loss medications. The strength of weight loss medication, which should be used with diet and a lifestyle change program, is the maintenance of weight loss. Sibutramine and orlistat are the only two medications approved for the long-term treatment of obesity. Orlistat gives a reduction of low-density lipoprotein (LDL) cholesterol in excess of that expected with weight loss, and the drop in blood pressure expected with weight loss is not seen with sibutramine. Except in newly diagnosed patients with diabetes subjects, patients with diabetes lose half the weight of subjects who do not have diabetes when treated with weight loss medications. Metformin and, to a lesser extent, acarbose cause weight loss, making them attractive choices for the treatment of obese type 2 diabetic subjects. Repaglinide appears to be weight-neutral, but other medications for patients with diabetes can be associated with weight gain. Many new medications are in development for the treatment of obesity. These new medications act through a variety of mechanisms and will surely play an increasingly important role in the treatment of obese patients with type 2 diabetes.
Diabetes Technol Ther 1999
PMID:Obesity medications and the treatment of type 2 diabetes. 1147 74

Sibutramine (Reductil, Abbott-Knoll, 10 mg and 15 mg) is a new appetite regulator recommended in the treatment of obesity. It is a noradrenaline and 5-hydroxytryptamine reuptake inhibitor which exerts its effects in vivo predominantly via its secondary and primary amine metabolites. Sibutramine is indicated as an adjunctive therapy within a weight management programme in patients with obesity (BMI > or = 30 kg/m2) or in overweight subjects (BMI > or = 27 kg/m2) if other eight-related risk factors are present (dyslipidaemias, diabetes mellitus). In those patients with an inadequate response on initial dose of 10 mg per day (suggested as less than 2 kg weight loss in four weeks), the dose may be increased to 15 mg once daily, providing that sibutramine is well tolerated. Several large-scale randomized clinical trials demonstrated the efficacy of long-term (at least one year) treatment with sibutramine in obese subjects with or without type 2 diabetes. Sibutramine was also shown to help in maintaining long-term weight reduction. Most frequent side-effects are dry mouth and constipation, as well as mild increase in heart rate and arterial blood pressure. The impact of sibutramine on cardiovascular morbidity and mortality of obese nondiabetic and diabetic patients will be studied soon in a large international prospective clinical trial.
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PMID:[Pharma-clinics. Medication of the month. Sibutramine (Reductil)]. 1170 9

The growing recognition of the health risks of obesity coupled with the difficulties in treating it successfully by lifestyle modification predicates a need for effective drug treatment. The history of drug treatment in the second half of the 20th century is, however, one of disappointment and concern over drug toxicity. However, the advances in our understanding of the mechanism of weight control, together with improved ways of evaluating anti-obesity drugs, has resulted in two effective compounds, sibutramine and orlistat, becoming available for clinical use. Sibutramine has actions on both energy intake and expenditure and had been shown to enhance weight loss and weight maintenance achieved by diet, in simple obesity as well as when accompanied by complications of diabetes or hypertension. About 50-80% of patients can achieve a >5% loss, significantly more than if patients receive the same lifestyle intervention with placebo. Orlistat, which acts peripherally to block the absorption of dietary fat, has had similar results in clinical trials; a recent study (XENDOS) has just reported results which show that the enhanced, albeit modest, weight loss achieved with orlistat delays the development of diabetes over a 4-year period. A number of other compounds are expected to complete or enter clinical trials over the next decade. There is considerable optimism that we will soon have the pharmacological tools needed to make the treatment of obesity feasible.
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PMID:Pharmacotherapy of obesity. 1246 17

In the normal population, the prevalence of obesity is almost 20%. It is a condition influenced by genetic factors, so that individual behavior cannot be regarded as its sole cause. The amount of food is essentially determined by the hormone leptin, the feedback regulation of which can be disturbed by a modification of the molecule or a mutation of the receptor. A further important determinant is energy consumption, which is subject to large individual variations, which partly result from thermogenesis. With regard to the fat distribution, it is concentrated on the trunk in the android form as compared to the hips in the gynecoid form. The android form is subject to a higher incidence of cardiovascular morbidity and mortality. The indirect determination of body fat by measuring the body mass index (weight [kg]/body weight [m(2)]) is hence less reliable than measuring the waist (women > 80 cm, men > 94 cm). The effects of generalized obesity on cardiovascular function are chiefly an increase of blood volume and an eccentric left ventricular hypertrophy. This first of all results in diastolic dysfunction, which can give rise to a disturbance of systolic function in left ventricular dilatation. Concentric hypertrophy develops in the presence of arterial hypertension. This is twice as frequent in obese patients than in the normal population, which is due to increased activity of the sympathetic nervous system and stimulation of the renin-angiotensin system. A disturbance of lipid metabolism is observed four to six times more frequently. The qualitative change in LDL fraction with a raised concentration of low density LDL particles appears to be of crucial importance. With increasing fat mass, the sensitivity to insulin is lowered, so that in obesity the risk of developing diabetes mellitus type 2 is tripled. Since there has been a dramatic increase in the numbers of overweight children and adolescents (from 10.5% to 15.5% within the past five years), prevention programs should be started in good time. A reduction in calorie intake and an altered dietary composition (55% complex carbohydrates, 30% fat and 15% to 20% protein) on the one hand, and increased physical activity on the other hand continue to be the central components. The latter is especially effective when it regularly gives rise to an increased turnover of fatty acids as a result of an increased energy metabolism at moderate intensity. This leads to adaptation, i. e. an increase in the activity of lipoprotein lipase. If prevention programs and/or changes in lifestyle do not give rise to the desired weight reduction, medication is indicated in some adults. Sibutramine (Reductil and orlistate (Xenical) lead to an additional weight loss of up to 10%. However, consistent treatment of any cardiovascular risk factors present is more important. Treatment of arterial hypertension is of greatest prognostic significance, especially in concomitant diabetes mellitus. In individual cases and after thorough discussion of indication surgical options should be considered.
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PMID:[Obesity and cardiovascular diseases-theoretical background and therapeutic consequences]. 1524 61


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