Buyers' Guide Quick Facts News Articles Links Xenical FAQ's Should You Take It? Weight Loss Info Dietary Advice BMI Calculator Health Professionals Data Sheet
Xenical is indicated for:
The most commonly observed adverse events (incidence of ³5% and twice that of placebo) were oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence. Because Xenical has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin supplement containing fat-soluble vitamins once a day at least 2 hours before or after the administration of Xenical, such as at bedtime. Contraindicated in patients with chronic malabsorption syndrome or cholestasis (impaired bile flow). Organic causes of obesity, such as hypothyroidism, should be excluded before prescribing Xenical."
Obesity is increasingly being recognised as a serious, chronic disease associated with significant morbidity and mortality. Indeed, the rapidly escalating prevalence of obesity represents one of the largest challenges facing public health in the new millennium. In Europe, the prevalence of obesity ranges from 10% to 40%, rates being particularly high in some Eastern and Mediterranean European countries. A similar situation exists in the United States, where 20% of adult men and 25% of women have a body mass index, or BMI, in excess of 30 kg/m2.
The rising prevalence of obesity is placing a growing burden on public health provision in many countries. The obese patient is at increased risk of a wide range of obesity-related co-morbidities. These include cardiovascular disease, type 2 diabetes, hypertension, dyslipidaemia, sleep apnoea, osteoarthritis and certain cancers.
Epidemiological studies have shown that obesity is a major risk factor for cardiovascular disease. Data from the Framingham Heart Study has indicated that the incidence of cardiovascular disease increases with body weight in both men and women, independently of age, smoking and other risk factors. Also, a study of over 6500 middle-aged Swedish men found that, after controlling for age, smoking and physical activity, those with a BMI of &Mac179;30 kg/m2 were more than twice as likely to die from coronary heart disease as those with a BMI of between 20 and 22.5 kg/m2. Similarly, the Nurses Health Study found that women with a BMI of 32 kg/m2 or higher were four times as likely to die of cardiovascular disease as women with a BMI of <19 kg/m2 As a result of these, and other studies, the American Heart Association has stated that obesity should rank alongside smoking, high serum cholesterol, hypertension and a sedentary lifestyle as major modifiable factors that cause coronary heart disease.
Obesity has also been identified as the most important modifiable risk factor for the development of type 2 diabetes. In the Nurses Health Study, BMI was the main predictor of risk for type 2 diabetes. Indeed, women with a BMI of &Mac179;35 kg/m2 had a massive 93.2% greater risk of developing type 2 diabetes than women with a BMI of <22 kg/m2. Similarly, the Health Professionals Study found that men with a BMI of &Mac179;35 kg/m2 had a 42 times higher relative risk for type 2 diabetes compared with men with a BMI of <23 kg/m2.
There is increasing evidence that moderate and sustained weight loss of 5-10% is sufficient to achieve clinically meaningful improvements in obesity-related co-morbidities and cardiovascular risk factors. Studies have shown that weight loss is associated with a reduced risk of cardiovascular disease and type 2 diabetes. Moderate weight loss is also associated with improvements in obesity-related co-morbidities including serum cholesterol, blood pressure and glucose tolerance.
As a consequence, clinical guidelines for the treatment of obesity today focus on moderate weight loss of 5% to 10% of initial body weight rather than a non-realistic return to a supposedly ideal body weight. However, it is widely recognised that obese patients experience difficulty in achieving and maintaining clinically meaningful weight loss through conventional dietary and behavioural modification alone. This is primarily a result of declining long-term compliance with necessary lifestyle changes together with physiological processes which oppose the maintenance of a lower body weight following weight loss. Thus, there is increasing recognition of the need for a well-tolerated pharmacological agent as part of a comprehensive weight management programme.
The aetiology of obesity is multifactorial and involves the complex interaction of many environmental, social and genetic factors. However, excess dietary fat consumption has been identified as a significant causative factor in weight gain. Fat is energy-dense, providing 9 kcal/g compared to 4 kcal/g from carbohydrate and protein. Moreover, unlike either carbohydrate or protein balance, fat balance is not tightly regulated, fat oxidaetion not being correlated with fat intake. Thus, excess dietary fat is readily stored in the body’s adipose tissue depots. High fat foods may also encourage over-consumption since they are palatable, require less chewing and produce a lower sense of satiety than carbohydrates. As such, targeting the absorption of dietary fat is a logical approach for obesity pharmacotherapy.
Gastrointestinal lipase is the key enzyme involved in the digestion of dietary fat, predominantly in the form of triglyceride. Lipase hydrolyses fat to monoglyceride and free fatty acids which are absorbed through the intestinal wall. In 1981, a compound with high pancreatic lipase inhibitory activity was identified during screening of soil samples from the Spanish island of Mallorca. This compound, produced by Streptomyces toxytricini and named lipstatin, was isolated and purified. Xenical, a more stable hydrogenated analogue of lipstatin, was ultimately synthesised.
Xenical blocks the activity of gastrointestinal lipase by binding to the enzyme’s active site. As a result approximately 30% of dietary triglyceride remains undigested and passes through the gastrointestinal tract. Because it is highly selective, Xenical does not effect the hydrolysis and absorption of carbohydrates, proteins or phospholipids.
The absorption of Xenical from the gastrointestinal tract is minimal, with plasma concentrations accounting for less than 1% of the total dose. Thus Xenical has no effect on systemic lipoprotein or hepatic lipase. The non-systemic mode of action of Xenical also means that central nervous system adverse events commonly observed with other anti-obesity drugs are avoided.
Using faecal fat excretion as a marker of pharmacological effect, Xenical has been shown to prevent the absorption of up to 30% of ingested dietary fat. The pharmacological activity of Xenical is dose-dependent, with the optimal therapeutic dose being 360 mg/day. Since Xenical must be administered with food to exert its therapeutic effect the recommended dosage regimen is 120 mg three times a day with main meals.
Over 4000 obese patients have participated in long-term phase III clinical studies with Xenical, making it the most comprehensively studied anti-obesity drug. These studies have included the two largest ever double-blind, randomised, placebo-controlled trials of adjunctive drug therapy for obesity.
In a US-based 2-year study involving over 1100 obese patients with a BMI of between 30-43 kg/m2, those treated with Xenical 120 mg three times daily in combination with a mildly hypocaloric diet achieved significantly greater weight loss after one year than patients receiving dietary intervention alone. Similar weight loss was achieved after one year in a 2-year European study of over 700 obese patients. In both studies, significantly more Xenical-treated patients than placebo recipients achieved weight loss of >5% or >10% after 1 year. Xenical also effectively reduced the long-term regain of lost body weight. Placebo recipients regained twice as much of their lost weight as patients treated with Xenical.
Treatment with Xenical is also associated with significant improvements in several cardiovascular risk factors. Both serum total cholesterol and serum LDL-cholesterol were reduced to a significantly greater extent with Xenical plus diet than with diet alone. Indeed, Xenical has a beneficial effect on total and LDL-cholesterol that is independent of weight loss. Xenical is also associated with significant improvements in systolic and diastolic blood pressure, serum fasting insulin, serum fasting glucose and waist circumference.
Xenical may also be a useful adjunct in the treatment of obese patients with type 2 diabetes. Weight loss is a primary goal of therapy among these patients. However, many find clinically meaningful weight loss difficult to achieve, especially since insulin, sulphonylureas and other diabetic medications can all promote weight gain. However, in a study of over 300 obese patients with type 2 diabetes controlled with oral sulphonylureas, Xenical promoted significantly greater weight loss than diet alone. Patients treated with Xenical also had significant improvements in glucose tolerance, reflected by reductions in serum fasting glucose and glycosylated haemoglobin. In addition, Xenical-treated patients had a 25% reduction in the need for oral hypoglycaemic medication, compared with just a 9% reduction among patients treated with diet.
Xenical may also play a role in preventing or delaying the development of type 2 diabetes. In an analysis of patients on whom oral glucose tolerance tests were performed before and after treatment, half as many Xenical-treated patients as placebo-recipients who had normal glucose tolerance before treatment developed impaired glucose tolerance after 2 years. Furthermore, a significantly larger proportion of Xenical-treated patients with impaired glucose tolerance before treatment had normal glucose tolerance after 2 years.
Treatment with Xenical is well tolerated by the majority of obese patients, very few of whom withdraw from treatment as a result of the predictable gastrointestinal side effects associated with the partial inhibition of dietary fat absorption. These gastrointestinal effects occur soon after the start of treatment and are generally mild, transient, and limited to 1 or 2 events per patient. The gastrointestinal effects associated with Xenical can even help improve compliance with a reduced fat diet, patients quickly learning that they can control these adverse events by adjusting their fat intake.
In summary, adjunctive pharmacotherapy with Xenical promotes clinically meaningful weight loss, reduces weight regain and is associated with improvements in several obesity-related disease risk factors. As such, treatment with Xenical, as part of a comprehensive weight control programme involving dietary and behavioural change, offers a new option in the long-term management of obesity.
Back
drug information
