by Dennis Tison, MD
The Food and Drug Administration (FDA) Endocrinology and Metabolic Drugs Advisory Committee recently approved the use of Orlistat, a novel weight loss medication that has been widely tested throughout Europe (see June 1997 OMR for story). Orlistat, manufactured by F. Hoffman-La Roche Ltd.1 of Switzerland, will bear the name of Xenical when it becomes available in the United States. Final approval was expected later this month, but Roche announced on August 28, that it withdrew its New Drug Application (NDA) with the FDA because of increased incidence of breast cancer in clinical trial participants. Roche said that it is convinced there is no link between orlistat and the breast cancer, and it plans to resubmit its application within the next few months.
Mode of action.
Xenical differs from previously available weight loss medications in that it works non-systemically acting locally in the gastrointestinal tract. It is a synthetic derivative of lipostatin, a naturally occurring lipase inhibitor ("fat blocker") which binds to gastric and pancreatic lipase, two digestive enzymes. Xenical also inhibits other digestive enzymes, including some found outside the gastrointestinal tract. When orlistat is taken with fat-containing foods, the fat passes through the gastrointestinal tract unchanged, and the calories are not absorbed. Pancreatic lipase reacts with the orlistat to reduce the absorption of about 30 percent of dietary fat, resulting in a reduction of approximately 200 calories per day. 1
Studies on orlistat.
Studies presented at the 8th European Congress on Obesity in Dublin, Ireland on June 19, 1997 compared one- and two-year trials of Xenical. The subjects ate a mildly reduced calorie diet with fat comprising about 30 percent of the total number of calories. The findings showed that the average patient in the study, weighing 220 pounds, lost 20 pounds, or about 10 percent of body weight, by taking Xenical. Additionally, most of the patients in the study maintained their weight loss. 2 Most importantly, life-risk factors were reduced such as LDL and total cholesterol, both systolic and diastolic blood pressure, and blood glucose levels. Improvement in insulin levels was also noted. The suggested dosage is 120 mg tid with meals. Commonly reported side effects include abdominal cramping and diarrhea, secondary to increased fat excretion in the feces. Since the decreased absorption of fat leads to concomitant malabsorption of the fat-soluble vitamins, A, D, E, & K, it is recommended that a multi-vitamin containing supplements of these vitamins be taken daily while undergoing Xenical administration. Also affected is the absorption of extremely lipophilic drugs.
Study highlights Absorption In short term treatment, there was a low degree of systemic absorption. In longer term studies, no system absorption was observed. Excretion After oral dosing, almost all the drug administered was recovered in feces. Drug-drug interactions Drug interaction studies have been conducted on digoxin, 3 dilantin, 4 warfarin, antihypertensives 5 (furosemide, captopril, atenolol and , nifedipine 6), glyburide7, and oral contraceptives 8. No significant interactions were seen. Adverse Effects Vitamin absorption In trials no patient developed clinical evidence of vitamin deficiency, but more orlistat treated subjects required vitamin supplementation for low vitamin levels. The mode of action predicts potential deficiencies in fat-soluble vitamins (A, D, E & K) 9 and beta-carotene. 10 Gastrointestinal symptoms 82 percent of orlistat-treated subjects, and 56 percent of controls had symptoms, mainly loose stools. Most were single episodes. Gallbladder disease None of the patients developed gallbladder disease, but several ultrasound scans showed dysfunction or gallstone formation in 7 percent of the orlistat group and 11 percent of the controls.
Two-Year Study Double- blind, randomized, parallel-group, placebo-controlled multicenter study with 783 subjects. Patients were recruited from 14 centers throughout Europe. To qualify subjects had to be 18 or older with a BMI of 28-43 kg/m 2, weight stable, no history of sever gastrointestinal or eating disorders. Patients with uncontrolled hypertension and drug treated diabetes mellitus were excluded. Diet First year: diet designed to cause a 600 calorie per day deficit, 30 percent of energy derived from fat. Second year: diet designed to maintain stable body weight. Dose Randomized placebo, orlistat 60 mg, or orlistat 120 mg. Premature Withdrawals 54 dropped out in first year, mostly because of failure to cooperate with protocol. Rate of withdrawal for adverse events was 1.7 percent for placebo, 6.7 percent for orlistat 60 mg, 5.4 percent for orlistat 120 mg in year one. In year two .8 percent, 3.0 percent and 2.5 percent respectively withdrew because of adverse events. Weight Loss 9.7 percent in the orlistat 120 mg group, 8.6 percent for orlistat 60 mg, 6.6 percent for placebo. 38.3 percent of subjects in the orlistat 120 mg group lost more than 10 percent of their initial body weight compared with 31.2 percent in the 60 mg group, and 18.8 percent of placebo recipients. Tolerability Gastrointestinal events occurred early in treatment, were moderate to severe, but resolved spontaneously, and were generally limited to one or two episodes per patient. Levels of fat soluble vitamins and beta-carotene in all three groups were in normal ranges for the two years. Vitamin supplementation was prescribed to one subject in the placebo group, 14 in the orlistat 60 mg group, and 12 in the orlistat 120 mg group.
By working in a non-systemic manner Xenical will aid those who in the past could not, or would not take weight loss medications that resulted in greater systemic side effects. This will undoubtedly help in reducing the number of deaths, over 300,000 in the U.S. last year, caused by obesity and obesity related diseases.
- Mode of action of orlistat . ( medline) Guerciolini, R. Int J Obes Relat Metab Disord 1997 Jun;21 Suppl 3:S12-S23.
- Weight control over two years: Clinical trial experience with Orlistat. Rossner, S. (Roche Obesity-Net).
A one-year trial to assess the value of orlistat in the management of obesity. ( medline) James WP. Int J Obes Relat Metab Disord 1997 Jun;21 Suppl 3:S24-S30.
- The influence of reduced dietary fat absorption induced by orlistat on the pharmacokinetics of digoxin in healthy volunteers. (medline) Melia, AT. J Clin Pharmacol 1995 Aug;35(8):840-843.
- The effect of orlistat on the pharmacokinetics of phenytoin in healthy volunteers. ( medline). Melia, AT. J Clin Pharmacol 1996 Jul;36(7):654-658.
- Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antihypertensive drugs in healthy volunteers. ( medline). Weber, C. Eur J Clin Pharmacol 1996;51(1):87-90.
- Lack of effect of orlistat on the bioavailability of a single dose of nifedipin extended-release tablets (Procardia XL) in healthy volunteers. ( medline). Melia, AT. J Clin Pharmacol 1996 Apr;36(4):352-355.
- The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. ( medline). Zhi, J. J Clin Pharmacol 1995 May;35(5):521-525.
- Lack of interaction between orlistat and oral contraceptives. ( medline). Hartmann, D. Eur J Clin Pharmacol 1996;50(5):421-424.
- The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. ( medline) Melia, AT. J Clin Pharmacol 1996 Jul;36(7):647-653.
- The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of beta-carotene in healthy volunteers. ( medline). Zhi, J. J Clin Pharmacol 1996 Feb;36(2):152-159.
Dr. Dennis Tison is a psychiatrist with bariatric medicine practices in Sacramento and Walnut Creek, CA. Dr. Tison holds a medical degree from Loma Linda University, Loma Linda, CA and a law degree from Hastings College of the Law, University of California, San Francisco, CA. He is an assistant clinical professor at University of California, Davis School of Medicine, and a member of the American Medical Association and the American Society of Bariatric Physicians. See http://www.ulink.net/~dtison/
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