Rev Endocr Metab Disord. 2001 Oct;2(4):403-18.
Drug treatment of obesity.
Bray GA.
Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA.
At present only two drugs are approved for long-term treatment of obesity. Sibutramine inhibits the reuptake of serotonin and norepinephrine. In clinical trials it produces a dose-dependent 5-10% decrease in body weight. Its side effects include dry mouth, insomnia, asthenia, and constipation. In addition, sibutramine produces a small increase in blood pressure and pulse that is a contraindication to the use of this drug in some individuals with heart disease. Xenical is the other drug approved for long-term use in the treatment of obesity. It works by blocking lipase and thus increasing the fecal loss of triglyceride. One valuable consequence of this mechanism of action is the reduction of serum cholesterol that averages about 5% more than can be accounted for by weight loss alone. In clinical trials it produces a 5-10% loss of weight. Its side effects are entirely due to undigested fat in the intestine that can lead to increased frequency and change in the character of stools. It can also lower fat-soluble vitamins. The ingestion of a vitamin supplement before bedtime is a reasonable treatment strategy. The effect on weight loss during long-term trials with these two drugs is shown in Figs 7 and 8 above. Also in this figure is data on phentermine used in trials of six months or more. Although there were differences in mean weight losses with these drugs, when the placebo effect was taken into account they all had a surprisingly similar magnitude of weight loss.
PMID: 11725727 [PubMed - indexed for MEDLINE]
Control Clin Trials. 2001 Oct;22(5):515-25.
Principles for enhanced recruitment of subjects in a large clinical trial. the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study experience.
Torgerson JS, Arlinger K, Käppi M, Sjöström L.
Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden.
In most clinical trials it is problematic to recruit enough patients within a reasonable time period. Prolonged or inefficient recruitment or both can have negative scientific and economic consequences. The XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study is an ongoing randomized, double-blind, placebo-controlled, prospective, multicenter trial investigating whether orlistat combined with hypocaloric diet and moderate physical exercise can reduce the incidence of diabetes in obese subjects. To implement the XENDOS protocol and recruit the study patients, we designed a system for centralized patient recruitment and centralized scheduling of patients and staff at the 22 collaborating centers. The recruitment and inclusion phase was divided into a series of different consecutive examinations of increasing complexity. Relatively simple initial examinations enabling a large throughput of patients were followed by more detailed examinations of fewer subjects, by then known to fulfil some of the study-specific requirements. With the aid of object-oriented techniques, the software was modularized to enable concurrent engineering. We also selected a structure where plug-in modules handling specific tasks could be added to the system as needed. The design was supported by a flow-oriented view of the progress of the patients through the study. With this overall solution we managed to include 3305 subjects (98.8% of the requested number) within less than 4 months. The sex distribution (44.8% men) and the number of patients with impaired glucose tolerance (IGT), (21.1%) were in close accordance with, or far better than, the requirements of the protocol (45% men, at least 10% IGT patients). The basic design of the XENDOS information system can be adapted to fulfil the requirements of other study protocols within the fields of obesity, diabetes, hypertension, coronary heart disease, etc. Shortening the recruitment and inclusion phase of large clinical trials is of great value both to be medical society and the pharmaceutical industry.
Pol Arch Med Wewn. 2004 Dec;112(6):1415-23.
[Effect of orlistat therapy on carbohydrate, lipid, vitamin and hormone plasma levels in obese subjects]
[Article in Polish]
Czerwienska B, Kokot F, Franek E, Irzyniec T, Wiecek A.
Katedra i Klinika Nefrologii, Endokrynologii i Chorób Przemiany Materii Sl. AM w Katowicach.
Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY. CONCLUSIONS: (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.
PMID: 15962606 [PubMed - indexed for MEDLINE]
Therapie. 2005 Jan-Feb;60(1):17-24.
[Results from the observational study EPIGRAM: management of excess weight in general practice and follow-up of patients treated with orlistat]
[Article in French]
Vray M, Joubert JM, Eschwège E, Liard F, Fagnani F, Montestruc F, Fages S, Bégaud B.
Institut Pasteur, Bâtiment Laveran, Paris, France. vray@pasteur.fr
The EPIGRAM pharmacoepidemiological study was conducted in general practitioners (GPs) prescribing orlistat (Xenical) in order to describe, under real clinical conditions, the management of obese or overweight patients, as well as a 1-year follow-up of a patient cohort treated with orlistat. A total of 714 GPs participated in this study and recruited a total of 6801 patients. Forty percent were treated with orlistat, 76% were women and 63% presented with a comorbidity. With a mean body mass index of 33.1+/-5.1 kg/m2, 85% of the patients treated with orlistat were in agreement with the indications of this drug. Comparison of patients treated and not treated with orlistat did not allow identification of any key factor able to predict prescription of the treatment. Patients treated with orlistat on inclusion and reviewed at least once by their doctor were followed up for an average of 11 months and a maximum of 23 months. Between 64% and 77% of patients stopped treatment with orlistat during the follow-up period. The treatment cost was the main reason for definitive treatment discontinuation for more than 50% of the patients. The average weight loss was 5% and 9% after 3 and 12 months of treatment, respectively.
Drug Ther Bull. 2009 Nov;47(11):125-7.
Over-the-counter weight loss with orlistat?
[No authors listed]
Orlistat first became available (as 120 mg capsules [Xenical]) around 10 years ago as a prescription-only treatment for obesity. Earlier this year, orlistat 60 mg capsules (alli - GlaxoSmithKline Consumer Healthcare) became available for sale without a prescription to the public in the European Union. Orlistat 60 mg is available in the UK as a Pharmacy (P) medicine and so can be purchased over-the-counter (OTC) from pharmacies. OTC orlistat is promoted as a new weight loss aid, "boosting weight loss by 50%" when added to a reduced calorie, lower-fat diet. Here we review the place of OTC orlistat in tackling obesity.
PMID: 19887686 [PubMed - in process]
Obesity (Silver Spring). 2010 Jan;18(1):108-15. Epub 2009 May 21.
Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical).
Kopelman P, Groot Gde H, Rissanen A, Rossner S, Toubro S, Palmer R, Hallam R, Bryson A, Hickling RI.
St Georges, University of London, London, UK.
The objective of this multicenter, randomized, double-blind study was to determine the efficacy and safety of cetilistat and orlistat relative to placebo in obese patients with type 2 diabetes, on metformin. Following a 2-week run-in, patients were randomized to placebo, cetilistat (40, 80, or 120 mg three times daily), or orlistat 120 mg t.i.d., for 12 weeks. The primary endpoint was absolute change in body weight from baseline. Secondary endpoints included other measures of obesity and glycemic control. Similar reductions in body weight were observed in patients receiving cetilistat 80 or 120 mg t.i.d. or 120 mg t.i.d. orlistat; these reductions were significant vs. placebo (3.85 kg, P = 0.01; 4.32 kg, P = 0.0002; 3.78 kg, P = 0.008). In the 40 mg t.i.d. and placebo groups, reductions were 2.94 kg, P = 0.958 and 2.86 kg, respectively. Statistically significant reductions in glycosylated hemoglobin (HbA(1c)) were noted. Cetilistat was well tolerated, and showed fewer discontinuations due to adverse events (AEs) than in the placebo and orlistat groups. Discontinuation in the orlistat group was significantly worse than in the 120 mg cetilistat and placebo groups and was entirely due to gastrointestinal (GI) AEs. Treatment with cetilistat 80 or 120 mg t.i.d., or with orlistat 120 mg t.i.d., significantly reduced body weight and improved glycemic control relative to placebo in obese diabetic patients. Cetilistat was well tolerated with the number of discontinuations due to AEs being similar to placebo.
Prescription weight-loss drugs such as Xenical can improve your health, if used in combination with a healthy diet and regular exercise. Find out if you could benefit from taking these medications.
Weight-loss drugs may sound like a dieter's dream. But they aren't a good choice for everyone who's overweight. In fact, many doctors reserve them for people with weight-related health problems.
The best way to lose weight is through a healthy diet and regular exercise. But if you're among those who struggle to lose weight and the excess weight has produced medical problems, weight-loss drugs may be able to help you.
OBJECTIVE: To examine the effect of orlistat ( Xenical) treatment on body composition and resting energy expenditure (REE) during a 2 y weight-reduction programme in obese Finns. SUBJECTS: Of initially 96 obese subjects who participated in the weight-reduction programme, those 72 subjects (13 men, 59 women, body mass index (BMI) 35.9 +/- 3.9 kg/m2, age 43.4 +/- 6.0 y, mean +/- s.d.) with the complete set of data for 2 y were included in the study. DESIGN: After a 4-week lead-in period, subjects were randomized with either orlistat 120 mg t.i.d. or placebo t.i.d. in conjunction with a mildly hypoenergetic balanced diet for 1 y. This was followed by 1 y double-blind period with the subjects within each treatment group re-assigned to receive orlistat 120 mg t.i.d. or placebo t.i.d. in conjunction with a weight maintenance diet. MEASUREMENTS: Body composition and REE were measured after an overnight fast by a bioelectrical impedance method and indirect calorimeter, respectively. The measurements were performed at the beginning and at 3, 6, 12 and 24 months. RESULTS: During the first year, the orlistat-treated group had greater reduction of body weight and fat mass but not of fat-free mass or REE as compared to placebo. During the second year, orlistat treatment was associated with smaller regain of body weight and fat mass with no significant differences in the changes of fat-free mass or REE as compared to placebo. CONCLUSION: In addition to better weight loss and maintenance of reduced weight, orlistat treatment is associated with beneficial changes in body composition but with no excess decrease in resting energy expenditure as compared to that achieved during placebo with a dietary therapy alone.
Objective: Glucagon-like peptide-1 is an insulin secretion-stimulating gut hormone that is produced in response to food intake. Orlistat ( Xenical, F. Hoffman-La Roche, Basel, Switzerland), which decreases fat absorption and increases intestinal fat content, may therefore affect the secretion of glucagon-like peptide-1. In this study we examined the immediate effects of orlistat on postprandial serum glucose, insulin and glucagon-like peptide-1 levels prior to a change in body weight. Design: Randomized, clinical study. Patients: Sixteen nondiabetic obese patients (body mass index 35.7+or-3.8 kg/m2, range 32.5-43.1) were enrolled in this study. The patients were randomly assigned to either the group treated with orlistat (120 mg, single dose) or the control group. There were eight patients in each of the two groups. Orlistat was given before a standard 600-kcal mixed meal containing 60% carbohydrates, 25% lipids and 15% protein. Blood samples were collected at baseline and at 30-min intervals for 180 min after the test meal. Graphical tendencies, peak value, time to reach the peak value, and area under the curve in the two groups were compared. Measurements: Blood samples were obtained for the measurement of GLP-1, glucose, insulin, high density lipoprotein, total cholesterol and triglycerides. Results: We found no difference in sex distribution, mean age, anthropometric measurements, or baseline glucose, insulin and glucagon-like peptide-1 levels between the orlistat and placebo groups. The peak insulin and glucagon-like peptide-1 levels were determined at 60 min in the control group. Hourly changes in serum glucose and insulin levels were similar between the groups, although the peak insulin and glucagon-like peptide-1 levels were reached at 120 min in the orlistat group. There were no statistically significant differences between the groups. Conclusions: A single dose of 120-mg orlistat caused no change in postprandial serum glucose, insulin or glucagon-like peptide-1 levels in nondiabetic obese patients. Although glucagon-like peptide-1 increases were delayed in the orlistat group, these changes were nonsignificant.
Research has yet to determine the long-term health effects of weight-loss drugs. To date, the longest study is a 4-year investigation of orlistat (aka Xenical or alli ). Most other studies have lasted 6 to 12 months or less. In addition, research has not examined rare side effects (those occurring in less than 1 per 1,000 patients), and the optimal duration of treatment is unknown.
When considering long-term weight-loss drugs to treat obesity, you should consider the following areas of concern and potential risks.
Potential for abuse or dependence. Currently, all prescription medications to treat obesity except orlistat are controlled substances, meaning doctors need to follow certain restrictions when prescribing them. Although abuse and dependence are not common with nonamphetamine appetite-suppressant medications, doctors should be cautious when they prescribe these medications for patients with a history of alcohol or other drug abuse.
Development of tolerance. Most studies of weight-loss drugs show that a patient’s weight tends to level off after 6 months while still on medication. Although some patients and doctors may be concerned that this shows tolerance to the medications, the leveling off may mean that the medication is no longer effective. Based on the currently available studies, it is not clear if weight gain with continuing treatment is due to drug tolerance. A recent study found that orlistat aids in weight maintenance over a 3-year period, but more research is needed to confirm these findings and investigate other drugs.
Reluctance to make behavioral changes while using prescription medications. Patients who are overweight or obese should be able to seek medical treatment to prevent health risks that can cause serious illness and death. Weight-loss drugs, however, are not “magic bullets” or a one-shot fix for this chronic disease. They should always be combined with a healthy eating plan and increased physical activity.
Side effects. Because weight-loss drugs are used to treat a condition that affects millions of people, many of whom are basically healthy, the possibility that side effects may outweigh benefits is of great concern. Most side effects of these medications are mild and usually improve with continued treatment. Rarely, serious and even fatal outcomes have been reported. Some of the common side effects of medications are explained below.
Consumer Reports recently reviewed several thousand adverse event reports from the Food and Drug Administration that show side effects associated with the drug Orlistat—the active ingredient in the over-the-counter (OTC) weight-loss drug Alli and the prescription drug Xenical.
The worrying findings have further strengthened our earlier advice: Avoid both versions of this drug.
Xenical (orlistat) is a lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.
Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Its empirical formula is C29H53NO5, and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm.
Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no pK a within the physiological pH range.
Xenical is available for oral administration in dark-blue, hard-gelatin capsules, with light-blue imprinting. Each capsule contains 120 mg of the active ingredient, orlistat. The capsules also contain the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. Each capsule shell contains gelatin, titanium dioxide, and FD&C Blue No.1, with printing of pharmaceutical glaze NF, titanium dioxide, and FD&C Blue No.1 aluminum lake.