Orlistat (Xenical)

Orlistat in Brief
  • Generic name : Orlistat
  • Brand names: Xenical®, Alli® (OTC)
  • Therapeutic class: Antiobesity
  • Pharmacologic class: Lipase Inhibitor
  • FDA Approved: April 23, 1999
  • Pregnancy Category: X (contraindicated)
  • Habit forming? No
  • Originally discovered: 1983, Hoffmann-La Roche & Co., Switzerland Switzerland
Introduction

Orlistat is an inhibitor of pancreatic lipase, the enzyme which plays a key role in dietary fat absorption. It is used to support the weight loss process, to maintain weight at a certain level and to prevent weight regain. Orlistat does not influence energy expenditure.

Unlike other popular weight loss medications such as phentermine, that stimulate the central nervous system and suppress appetite, Orlistat works locally -- it blocks absorption of a considerable amount (about 30%) of ingested fat.

History

Orlistat was originally developed as an inhibitor of pancreatic lipase. Orlistat is the name for tetrahydrolipstatin (THL), which is a saturated derivative of lipstatin.

Lipstatin is a natural product, and was first isolated from the Actinobacterium Streptomyces toxytricini7 by Swiss researchers from Hoffmann-La Roche & Co., Ltd.

In 1998 Xenical® was launched in EU, and later in April 1999 was approved in United States. Alli® (marketed by GlaxoSmithKline), a lower dose formulation of orlistat, was approved for over-the-counter (OTC) use in 2007.

FDA approved uses
  • Managing obesity in adults and adolescents 12 years and older in conjunction with a reduced-calorie diet.
  • Reduction of the risk for weight regain after previous weight loss.

Orlistat is indicated for people who are considerably overweight (have a body mass index of 30 or greater). Orlistat is also for people who are overweight (have a body mass index of 27 or greater) and also have other risk factors such as high blood pressure, high cholesterol, heart disease or diabetes.

Off-label & Investigational uses
  • Polycystic ovarian syndrome (PCOS)
    In women with PCOS orlistat promotes weight loss and a reduction in testosterone concentration. In a randomized, open-labeled study the improvement seen after treatment with orlistat was additionally similar to that seen with metformin, reaffirming the potential for orlistat to be a useful adjunct in the treatment of PCOS4.
  • Obese teenagers (children younger 12 years)1
  • Chronic idiopathic constipation
Orlistat "pros" and "cons"

Orlistat mechanism of action provides unique benefits.

Advantages and benefits:

  • Effective - significant and consistent weight loss. Orlistat promotes gradual, noticeable weight loss. It is an effective therapy that not only helps people lose weight, but also helps them maintain achieved weight loss4. Orlistat reduces body weight by an average of 5-10%. The greatest rate of weight loss occurs within the first six months of treatment.
  • Helps to prevent the development of type 2 diabetes. FDA approved labeling shows that weight loss with Xenical delayed the onset of type 2 diabetes in obese patients with impaired glucose tolerance2.
  • Extra health benefits. Orlistat can lower the level of total cholesterol and triglycerides in the blood, produce positive effect on levels of blood sugar and insulin. May improve endothelial function 10.
  • Orlistat modestly reduces blood pressure 8.
  • Works locally in the digestive system. Orlistat acts only in the digestive tract. Due to its negligible absorption orlistat does not have negative impact on cardiovascular system or other body systems. Virtually 97% of orlistat is excreted in the faeces, and about 83% as an unchanged drug.
  • Non-addictive. No potential for misuse.
  • Safest diet pill on the market and safe for long-term use. Not even 1% of orlistat is absorbed by the bloodstream, which makes it by far the safest weight loss drug on the market. Safety and efficacy were investigated in 4-years clinical study 2.
  • Few drug interactions. Orlistat has low potential for interactions, does not interfere with centrally acting medications.
  • Overall good tolerability. Side effects are predictable and manageable.
  • May improve microvascular endothelial function6.

Disadvantages:

  • Pregnancy Category X. In 2012 the US FDA has changed orlistat pregnancy category from "B" to "X".
  • High rate of unpleasant gastrointestinal side effects, such as flatus with discharge, oily spotting, fecal urgency, oily stool, increased defecation and fecal incontinence. The incidence of these increases the The diet High-fat diet content of the diet. This bowel discomfort is a natural effect of fat-blocking action, and indicates that Xenical is working.
  • Increased appetite sensations and food consumption13. Orlistat alters the secretion of appetite regulating gastrointestinal hormones and can cause an increased appetite and food consumption.
  • Vitamin starvation - need for vitamin supplementation. Along with dietary fat, orlistat decreases the absorption of some fat-soluble vitamins and beta-carotene. It is recommended to take a multivitamin supplement containing vitamins A, D, E, and K to ensure good nutrition.
  • Kidney stones. Orlistat increases the likelihood of kidney stones14. Orlistat has potential to increase intestinal absorption of dietary oxalate, contributing to urinary oxalate excretion and increased risk of stone formation5.
  • Orlistat alters gastric and gallbladder emptying and causes changes in gastrointestinal hormone concentrations. This may raise appetite sensations and increase food consumption3.
  • Concern regarding possible increase in bone turnover7.
  • Frequent dosage regimen - 3 times daily dosage schedule.

Effectiveness

Onset of action: Weight loss begins within 2 weeks and continues for 6 to 12 months.

Mean weight loss is about 3-7 kg after 1 year11,12.

The proportion of patients achieving at least 5% weight loss is about 35-73%9.

Mode of action

Orlistat is a potent long-acting gastrointestinal lipase inhibitor. It exerts its therapeutic activity in the stomach.

Dietary fats are large molecules that need to be broken down before they can be absorbed into the body. They are broken down by enzymes called lipases. When taken with a meal, Orlistat interferes with the activity of these enzymes and allows about 30% of the fat eaten in the meal to pass through the gut undigested. Therefore, your body cannot store these excess calories as fatty tissue or use them as a source of energy.

This helps you to reduce your weight by burning up fat that you are already carrying, maintain your weight loss and minimise any weight regain.

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Time to clear out of the system

The half-life of the absorbed orlistat ranges from 1 to 2 hours.

Further reading
References
  • 1. Weibel EK, Hadvary P, Hochuli E, Kupfer E, Lengsfeld H. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J Antibiot (Tokyo). 1987 Aug;40(8):1081-5. PubMed
  • 2. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004 Jan;27(1):155-61. Erratum in: Diabetes Care. 2004 Mar;27(3):856. Full PDF
  • 3. Ellrichmann M, Kapelle M, Ritter PR, Holst JJ, Herzig KH, Schmidt WE, Schmitz F, Meier JJ. Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations. J Clin Endocrinol Metab. 2008 Oct;93(10):3995-8 PubMed
  • 4. Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL. Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome. Journal of Clinical Endocrinology & Metabolism 2005 Feb;90(2):729-33. PubMed
  • 5. Sarica K, Akarsu E, Erturhan S, Yagci F, Aktaran S, Altay B. Evaluation of urinary oxalate levels in patients receiving gastrointestinal lipase inhibitor. Obesity (Silver Spring). 2008 Jul;16(7):1579-84. PubMed
  • 6. Al-Tahami BA, Ismail AA, Bee YT, Awang SA, Salha Wan Abdul Rani WR, Sanip Z, Rasool AH. The effects of anti-obesity intervention with orlistat on microvascular endothelial function. Clin Hemorheol Microcirc. 2013 Sep 3. PubMed
  • 7. Gotfredsen A, Westergren Hendel H, Andersen T. Influence of orlistat on bone turnover and body composition. Int J Obes Relat Metab Disord. 2001 Aug;25(8):1154-60. PubMed
  • 8. Siebenhofer A, Jeitler K, Horvath K, Berghold A, Siering U, Semlitsch T. Long-term effects of weight-reducing drugs in hypertensive patients. Cochrane Database Syst Rev. 2013 Mar 28. PubMed
  • 9. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014 Jan 1;311(1):74-86. PubMed
  • 10. Yu CC, Li AM, Chan KO, Chook P, Kam JT, Au CT, So RC, Sung RY, McManus AM. Orlistat improves endothelial function in obese adolescents: a randomised trial. J Paediatr Child Health. 2013 Nov;49(11):969-75 PubMed
  • 11. Rowe R, Cowx M, Poole C, McEwan P, Morgan C, Walker M. The effects of orlistat in patients with diabetes: improvement in glycaemic control and weight loss. Curr Med Res Opin. 2005 Nov;21(11):1885-90
  • 12. Li Z, Maglione M, Tu W, Mojica W, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med. 2005 Apr 5;142(7):532-46. PubMed
  • 13. Ellrichmann M, Kapelle M, Ritter PR, Holst JJ, Herzig KH, Schmidt WE, Schmitz F, Meier JJ. Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations. J Clin Endocrinol Metab. 2008 Oct;93(10):3995-8. PubMed
  • 14. Buysschaert B, Aydin S, Morelle J, et al. Weight loss at a high cost: Orlistat-induced late-onset severe kidney disease. Diabetes Metab. 2016 Feb;42(1):62-4. PubMed

Published: December 12, 2008
Last updated: January 27, 2017

Interesting facts
Orlistat molecule
  • Alli is the first and only over-the-counter weight loss pill approved by the FDA.
  • Orlistat is the only weight loss medication that has no cardiovascular side effects.
  • Unlike appetite suppressants, orlistat alters fat metabolism and aids for weight loss by acting peripherally at the gastrointestinal tract.
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