Orlistat -Our New OTC Friend for Weight Loss by Sitesh Patel

We all know that in the wonderful world of dietary supplements, there are many ingredients and products which boast the end-all claim – fat blocking. Most of these products are quite similar, they contain fiber-derived products which claim to either bind to the fat or contain lipophilic properties which allow fat to be dissolved and then excreted. The problem is that some of these products have been shown in trials not to be as effective as we would have hoped, and many companies use illegitimate extracts or sources to produce products which have very few beneficial effects to begin with. Rather then wasting money, and even worse, time, it seems as if most bodybuilders and fitness enthusiasts have derailed this idea of using a ‘fat-blocker’ and have stuck to the tried and proven supplements.

Luckily the good folks at Roche Pharmaceuticals have developed a product to treat obesity called Xenical®. Xenical® (orlistat) is a prescription weight loss medication which has shown in studies to be quite effective when it comes to blocking fat out of the diet. The new gets better, the FDA has just recently approved for orlistat to be sold over the counter by GlaskoSmithKline under the trade name Alli™. Alli™ should be available in stores nation wide summer 2007 as part of a weight loss package. This is good news for us! We now have a pharmaceutical grade FDA approved fat blocker in which we don’t need to go through the shady little bald guy in the corner of the gym to get for us. In this article I am going to discuss the pharmacology, dosing and side effects of orlistat, so you can make up your own mind if you want to use this product or not in your weight loss needs.


In order to properly understand the mechanism behind orlistat, we need to understand how the enzyme lipase works and its effects on fat absorption. Lipase is an enzyme which is secreted from the pancreas and is necessary for the absorption and digestion of fatty acids which are ingested from the diet. While different forms of lipase do exist, i.e. hepatic lipase and pharyngeal lipase, orlistat’s mechanism of action focuses solely on pancreatic lipase. Triglycerides which are taken in through the diet cannot be directly absorbed in the intestinal mucosa. Instead, when inside the lumen the triglyceride chains are coated with bile salts which allows for them to be broken down more easily. Sufficient amounts of pancreatic lipase are then released into the lumen in the form of pancreatic juice, allowing the hydrolysis of the triglycerides. The net result leaves us with monomers in the form of 2-monogylceride and free fatty acids which are then moved into the small intestine and absorbed through the lymphatic system via the lacteal vessel.

xenicalNinety-percent of dietary fat comes in the form of triglycerides. Of this 90%, 95% of the fat is actually broken down and absorbed in the small intestine after being broken down by lipase. Orlistat works as a reversible inhibitor of lipase. It forms a covalent bond with the lipase enzyme occupying the same site which triglycerides normally would. Due to the fact that orlistat possesses a structural similarity to triglycerides, it can keep the lipase enzyme bound for a significant amount of time allowing 30% of the fat which was taken in from the diet to pass through the intestine without being absorbed.

xenicalThe above diagram gives us an easy to follow outline of how orlistat’s mechanism takes place inside the intestinal tract. On the left hand side we can see what normally happens when triglycerides are taken in through the diet. They interact with bile acids and the lipase enzyme to systematically breakdown and cleave the fatty acid into its counter parts. The fatty acids and the monoglycerides are then taken up through the mucosal cell. On the right side of the diagram, we can see how Xenical® binds to the lipase enzyme thereby occupying the enzyme’s activity allowing the triglycerides to pass through the intestine unchanged.

Orlistat is currently available in two strengths:

– Prescription Only: Xenical® Orlistat 120mg Capsule
– Over-The-Counter: Alli™Orlistat 60mg Capsule

As we can see the OTC version of Xenical is half the strength, so we would obviously have to take two for equivalence. During use of the medication, we would expect fecal fat loss to rise and then to return to normal upon discontinuing. Fecal fat loss was shown in studies to reach a plateau at doses of 400mg-600mg per day, meaning optimal dosing would be seen at 120mg with each meal, 3 to 5 times a day. The typical ‘more is better’ thinking would serve to be useless in this case, as additional dosing may not have any beneficial effect and would be quite heavy on the wallet.

Orlistat should be taken directly with the meal or up to one hour after, and the meal should contain approximately 30% of its calories from fat. Systemic absorption is at most minimal and a study showed in male rats dosed at 1000mg/kg/day absorbed only 0.59% of the medication. Orlistat is 99% bound to plasma protein and majority of the metabolism occurs in the intestine and is excreted through the feces.

Side Effects

The most common side effects with orlistat are usually gastrointestinal related. Since orlistat promotes the excretion of unmetabolized fats through the feces, roughly a quarter of the users report oily stools or oily spotting. Also flatulence is a common side effect that is reported by many users. The majority of the gastrointestinal side effects occurring during the first week of use. By the second week, over 50% of the patients using the medication had reported that these effects had subsided, and by the 4-week period majority reported no side effects.

Adverse Event

Year 1

Year 2

% of Patients

% of Patients

% of Patients

% of Patients (N=524)

Oily Spotting





Flatus with Discharge





Fecal Urgency





Fatty/Oily Stool





Oily Evacuation





Increased Defecation





Fecal Incontinence





*Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
**Table taken from Xenical Package Insert Roche Pharmaceuticals

As noted above, meals that are taken with orlistat should contain approximately 30% of its calories from fat. Meals which are very high in fat have been reported to cause a higher incidence of gastrointestinal effects, especially oily spotting and oily stools. So unfortunately, the discomfort level may be too high for orlistat to be called the ‘magic pill’ that will keep you lean while eating double-bacon cheeseburgers.

Other adverse events included abdominal pain, nausea, upper respiratory infection, and musculoskeltal pain. However, the percentage of all of these were similar to those on placebo, so it is safe to say that the ADR’s are very low with this drug due to its low systemic absorption.

It is also recommended to those using orlistat to be taking a good multivitamin containing the fat-soluble vitamins A, D, E, and Beta-carotene. Being a lipase inhibitor, orlistat has been reported in patients to decrease the absorption of these fat-soluble vitamins leading to a deficiency in those using the drug who are already somewhat malnourished to begin with. If you are baseline with your nutritional values and are supplementing with a multivitamin, this may not be as much of a concern for you as the levels which we see being dropped are not that significant to begin with. Just be sure to space out your multivitamin from your orlistat dose by 2 hours. Although the data isn’t significant, you would want to space out your fatty acid oil supplementation as well (i.e. fish oil, flax seed oil, CLA) to ensure proper absorption.

Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values – First and Second Year)

Placebo* Xenical*
Vitamin A 1.0% 2.2%
Vitamin D 6.6% 12.0%
Vitamin E 1.0% 5.8%
Beta-Carotene 1.7% 6.1%

* Treatment designates placebo plus diet or Xenical plus diet


As we can see, prescription or over-the-counter orlistat can be a safe and effective way to increase weight loss. With proper diet and exercise, orlistat has been shown in trials to be statistically and clinically significant in reducing body weight. At the end of a four year clinical trial, 28% of patients receiving placebo and 45% of patients receiving orlistat lost ?5% of there baseline body weight and 10% of placebo patients and 21% of orlistat patients had lost more ?10% of there bodyweight. Working as a fat-blocker, orlistat will allow you throw that cheese onto your chicken and not have to worry about wearing the fat.

But if you can handle it, you can probably get the same effects just by cutting out 30% of the fat from your diet and not have to worry about any GI distress or it being costly on your wallet. With time, more companies will release more effective lipase inhibitors, which will hopefully surpass the 30% block and reduce GI effects. But for now orlistat is the way to go if your looking for a FDA approved pharmaceutical weight loss agent. On another note, it would be interesting to see what kind of effect orlistat would have when taken with pseudoephedrine (240mg/day) for both appetite suppression and a fat blockade. Good luck with your goals and if you have any questions email me at [email protected].


1. Zhi J, Melia AT, Guerciolini R, et al. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther. 1994 Jul;56(1):82-5.

2. Lookene A, Skottova N, Olivecrona G. Interactions of lipoprotein lipase with the active-site inhibitor tetrahydrolipstatin (Orlistat). Eur J Biochem. 1994 Jun 1;222(2):395-403.

3. Jianguo Zhi, Angela T. Melia, Christoph Funk, et al. Metabolic Profiles of Minimally Absorbed Orlistat in Obese/Overweight Volunteers. J. Clin. Pharmacol. 1996 Nov;36:1006-1011.

4. Zhi J, Melia AT, Eggers H, et al. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol. 1995 Nov;35(11):1103-8. Review.

5. Xenical® [package insert]. Nutley, NJ: Roche Laboratories, Inc.; December 2003.

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