Pharmacology Update
August 1, 1999 5 minutes read
Pharmacology Update
Orlistat Capsules (XenicalRoche Laboratories)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The fda has approved the highly anticipated lipase inhibitor, orlistat (Xenical-Roche) for the management of obesity. The drug is an inhibitor of pancreatic and gastric lipases in the lumen of the gastrointestinal (GI) tract. Inhibition of these enzymes results in a reduction of the amount of dietary fat absorbed and associated caloric intake. Roche has already marketed orlistat in 17 countries, where it has been used in more than 1 million patients.
Indications
Orlistat is indicated for obesity management (weight loss and weight maintenance) when used in conjunction with a reduced-calorie diet. It is indicated for obese patients with an initial body mass of 30 kg/m2 or greater and in patients with an initial weight of 27 kg/m2 or greater in the presence of other risk factors such as hypertension, diabetes, or dyslipidemia.1
Dosage
The recommended dose of orlistat is 120 mg three times a day with fat-containing meals. It may be taken during or up to one hour after meals.1 Gastrointestinal side effects may be reduced by consuming a high-fiber diet and reducing the amount of dietary fat.8
Patients should be advised to take a multivitamin supplement containing fat-soluble vitamins. These should be taken two hours before or after orlistat (e.g., bedtime). Orlistat is available as 120 mg capsules.
Potential Advantages
Orlistat acts within the gastrointestinal tract with negligible systemic exposure or systemic effects.2-4 In clinical trials, orlistat was reported to improve lipid profiles (total cholesterol and low-density lipoprotein cholesterol) and fasting serum insulin.5 Some studies report an improvement in triglyceride levels as well.6,7 Improved glycemic control has been reported in type 2 diabetic patients as reflected in glycosylated hemoglobin and reduced sulfonyurea dose compared to placebo.6
Potential Disadvantages
The most common side effects of orlistat are gastrointestinal and include flatus with discharge (40.1%), oily spotting (32.7%), fecal urgency (29.7%), fatty/oily stool (19.8%), fecal incontinence (11.8%), and increase in defecation (11.1%).5 Diets high in fat may increase GI side effects. Most GI events last less than one week and generally no more than four weeks. In some individuals, however, GI side effects may continue for more than six months.1 The absorption of fat-soluble vitamins may be reduced by orlistat, particularly vitamins D, E, and beta carotene. Patients should be advised to take multivitamin supplements containing fat-soluble vitamins while on the drug.1 Vitamin K absorption may also be decreased. Patients on concomitant warfarin therapy should be monitored carefully.1 Orlistat should be used in caution with patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis as increased levels of urinary oxalate may result.1 It is also possible that orlistat may increase gallstone formation since cholecystokinin release is inhibited by the drug, decreasing gallbladder contraction.11 Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis.1
Comments
Orlistat is a reverse inhibitor of gastric and pancreatic lipases. Inhibited lipases fail to hydrolyze dietary triglycerides into absorbable free fatty acids and monoglycerides, preventing absorption. Effects are seen as soon as 24-48 hours after dosing. After discontinuation of the drug, fecal fat content returns to pretreatment levels within 48-72 hours.1 About 30% of ingested fat is lost in the feces during orlistat therapy. Increasing the dose or increasing the amount of dietary fat does not significantly affect the percent of fecal fat lost.2 In two large trials (n = 892, 688) using intent-to-treat analysis and last observation carried forward technique, orlistat-treated patients lost 8.76 kg-10.3 kg vs. 5.81-6.1 kg for placebo-treated patients at one year when used in conjunction with a hypocaloric diet.5,9 When subjects were switched to a eucaloric (maintenance) diet after one year of therapy, orlistat-treated patients regained less of their weight lost (35.2%), compared to 63.4% for placebo-treated patients.5 Over two years, 34.1% of orlistat-treated patients lost 10% of initial body weight and 57.7% lost 5%, compared to 17.5% and 37.4% for placebo. Weight loss from initial body weight was 7.6% vs. 4.5%. The two-year completion rate ranged from 45% to 63% for these studies. In a one-year study involving obese patients with type 2 diabetes, orlistat reduced total cholesterol, LDL-cholesterol, triglycerides, and improved glycemic control as indicated by decrease in glycosylated hemoglobin (mean, -0.28% vs +0.18%) and significant reduction in the dose of sulfonylurea medication (23% vs 9%).6 The improvement in the lipid profile appears to be independent of weight lost.5 Obese patients on orlistat were reported to be less likely to progress from normal glucose tolerance to diabetic or impaired glucose tolerance.1 The cost of orlistat is about $1.10 per capsule or $3.30 per day.
Clinical Implications
Clinically significant obesity is classified as BMI of 30 kg/m2 or greater. The recent National Health and Nutritional Examination Survey III (NHANES III) estimated the prevalence of obesity in the U.S. population to be 22.5%.10 Current treatment modalities include diet and behavior modification, exercise, pharmacologic intervention, and surgery. Pharmacologic interventions include anorexiants such as phentermine and subutramine. Orlistat offers an antiobesity drug that is different from anorexiants in that it has a nonsystemic mechanism of action. However, the long-term effects of reducing free fatty acids and increasing triglycerides in the GI tract are not known. Weight losses produced by orlistat are quite modest. The weight loss differential between orlistat and placebo is only 3-4% of body weight after one year. The improvements in the lipid profile are also modest (e.g., approximately an 8% reduction in LDL-C), and these changes were only achieved in conjunction with a hypocaloric diet and behavior modification in a controlled study setting. The results may be further clouded by a high dropout rate and potential bias using the last observation carried forward technique for data analysis.12 It is unclear how the drug will perform in the "real world" setting where diet and lifestyle are less likely to be controlled.
References
1. Xenical Product Information. Roche Laboratories. April 1999.
2. McNeely W, et al. Drugs 1998;56(2):241-249.
3. Guerciolini R. Int J Obes Relat Metab Disord 1997; 21(suppl 3):S12-23.
4. Zhi J, et al. J Clin Pharmacol 1999;39(1):41-46.
5. Davidson MH, et al. JAMA 1999;281:235-242.
6. Hollander PA, et al. Diabetes Care 1998;21(8): 1288-1294.
7. Zavoral JH. J Hypertens 1998;16(12 Pt 2):2013-2017.
8. Van Gaal LF, et al. Eur J Pharmacol 1994;54:125-132.
9. Sjostrom L, et al. Lancet 1998;352(9123):167-172.
10. Flegal KM, et al. Int J Obes 1998;22:39-47.
11. Froehich F, et al. Dig Dis Sci 1996;41(12):2404-2408.
12. Williamson DF. JAMA 1999;281:278-280.
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