Orlistat (Xenical)

Orlistat is an inhibitor of fat digestion that does its whole job inside the gastrointestinal tract. It blocks gastric and pancreatic lipase, the enzymes that break dietary fat into fragments small enough to cross the gut wall. Fat that is not broken down cannot be absorbed and leaves the body unchanged in the stool.

That puts orlistat at odds with almost everything else in weight management. GLP-1 analogues, amylin analogues and the older appetite suppressants work through the brain and hormones. Orlistat touches no receptor in the body and changes neither hunger nor satiety. It simply removes part of the fat calories from a meal before they arrive.

The 120mg dose has been approved since the late 1990s. A 60mg half dose is sold over the counter in many countries. In the TPD range orlistat comes as a 120mg tablet, ten per blister.

This information is for research and educational purposes only. No medical advice.

Orlistat binds covalently to a serine residue in the active site of the lipases and shuts the enzyme down. Dietary triglycerides are no longer split into free fatty acids and monoglycerides and stay in the gut. At the therapeutic dose roughly 30 percent of ingested fat goes unabsorbed. On about 65g of fat a day that is some 20g, or just under 180 kcal, that never arrive. That is the whole effect.

The dose-response curve is well mapped. Zhi and colleagues (Clin Pharmacol Ther 1994) pooled eleven phase I studies with daily doses from 30 to 1200mg: on placebo about 5 percent of fat ended up in the stool, on orlistat a maximum of about 32 percent. Half the maximum effect was reached at just under 100mg per day. Above roughly 400mg per day the curve flattens. Three times 120mg therefore sits at the top of the range where more dose still buys more effect.

Almost nothing reaches the blood. In mass balance studies with labelled orlistat nearly the entire dose was recovered from the stool, plasma levels sat at the detection limit. The tiny absorbed fraction has a half-life of one to two hours. A practical rule follows: orlistat only acts on the fat eaten in the same meal. A tablet with a fat-free meal does nothing. A tablet taken long after the meal arrives too late.

The evidence is old, large and sobering. Sjöström and colleagues (Lancet 1998) enrolled 743 patients at 15 European centres, 688 of whom were randomised and treated for two years. On 120mg three times daily with a mildly reduced diet the orlistat group lost 10.2 percent of body weight in year one, the placebo group on the same diet 6.1 percent. In year two the orlistat patients regained only half as much. Total cholesterol, LDL, glucose and insulin fell further than on placebo.

XENDOS (Diabetes Care 2004) is the longest trial: 3,305 obese patients over four years. The weight advantage at the end was 5.8 versus 3.0kg. Diabetes incidence fell from 9.0 to 6.2 percent, a relative risk reduction of 37 percent that came entirely from the subgroup with impaired glucose tolerance at baseline. The dropout rate is telling: only 52 percent on orlistat and 34 percent on placebo lasted the four years.

The meta-analysis by Rucker and colleagues (BMJ 2007) pooled 16 orlistat trials with over 10,000 participants: on average 2.9kg more weight loss than placebo over one year or longer, plus fewer new cases of diabetes and better LDL and blood pressure, but slightly lower HDL and far more gastrointestinal complaints. That is the honest frame: a modest, well documented effect that is not available without changing the diet.

Orlistat acts on fat and nothing else. Anyone whose calorie surplus comes from sugar, refined flour or alcohol gets nothing from the substance except side effects. Anyone who already eats a fat-heavy diet and wants an agent that stays out of the central nervous system, the hormone system and heart rate has, in orlistat, a substance that does almost nothing systemically.

In a cutting context the WADA status matters: orlistat is not on the Prohibited List. At the same time it has to be clear that the effect, around three kilos over placebo, is small and that the bowel effects can genuinely interfere with daily life, training and travel. The substance rewards a disciplined, fat-aware diet and punishes everything else immediately and visibly.

There is very little data on combining orlistat with centrally acting agents. One small controlled trial that added orlistat to sibutramine found no further weight loss. What the research supports is orlistat plus a dietary change, nothing more.

• Gut: oily spotting, fatty stools, sudden urgency, flatulence with discharge and in the worst case faecal incontinence. This is not a side effect but the mechanism itself: fat that is not absorbed has to go somewhere. Intensity tracks the fat content of the meal directly. Usually worst in the first weeks, then milder as most people adjust what they eat.
• Fat-soluble vitamins: vitamin E absorption fell by around 60 percent in a study in healthy volunteers. Vitamin D, K and beta-carotene are affected too. A multivitamin taken at a distance is therefore mandatory, not optional.
• Interactions: ciclosporin levels drop, hypothyroidism has been reported on levothyroxine, seizures on antiepileptics and INR shifts on vitamin K antagonists. Amiodarone and some HIV drugs are also absorbed less well. Severe diarrhoea can make the contraceptive pill unreliable, so use additional contraception in that case.
• Liver: rare cases of severe liver injury are documented and have been in the product information since 2010. Jaundice, dark urine or itching are a reason to stop.
• Kidney: oxalate kidney stones and oxalate nephropathy are described, mainly with pre-existing kidney impairment. Drink plenty. With kidney problems, leave it alone.
• Other: rapid weight loss raises the risk of gallstones. In type 2 diabetes blood sugar can fall along with weight, so antidiabetic drugs may need adjusting. Not with chronic malabsorption syndrome, cholestasis, pregnancy or breastfeeding.

Store the tablets dry, at room temperature below 25 degrees and protected from light and moisture in the closed blister. Do not keep them in the bathroom, the humidity there degrades tablets. Keep out of reach of children.