Orlistat (Xenical / alli)

What orlistat is

Orlistat is a lipase inhibitor taken as a capsule with meals. In the EU it is available as Xenical at 120 mg, prescription-only and approved since 1998, and as alli at 60 mg, available without a prescription since 2007. There are also products from other manufacturers.

What is rated is the state of knowledge. Orlistat is well studied: randomized trials lasting up to four years, meta-analyses with more than 10,000 participants and a review of liver injury by the European Medicines Agency. Compared with the newer weight-loss injections such as semaglutide and tirzepatide, the effect is small.

How it works

Orlistat inhibits the fat-splitting enzymes, the lipases, in the stomach and intestine. As a result, about 30 percent of the fat in a meal is not digested and is excreted unchanged. The drug is barely absorbed into the blood.

Orlistat therefore acts in the digestive tract, not on appetite. GLP-1 receptor agonists such as semaglutide and liraglutide, by contrast, act via satiety and gastric emptying. The typical side effects follow from the mechanism of action, fatty stools and urgent bowel movements, as does a possibly reduced absorption of the fat-soluble vitamins A, D, E and K.

What the studies show

XENDOS: four years of diabetes prevention

Torgerson 2004 (Diabetes Care) randomized 3,305 people with a BMI of 30 or more to lifestyle changes plus orlistat 120 mg three times daily or plus placebo, over four years and double-blind. New cases of type 2 diabetes occurred in 6.2 versus 9.0 percent, a relative reduction of 37.3 percent; according to further analyses, the effect was attributable to the 21 percent of participants with impaired glucose tolerance. Body weight fell by 5.8 versus 3.0 kg. Only 52 percent on orlistat and 34 percent on placebo completed the four years; if the baseline weight of those who dropped out is carried forward, the difference shrinks to 3.6 versus 1.4 kg.

Meta-analysis of the long-term trials

Rucker 2007 (BMJ) pooled double-blind trials lasting at least one year, including 16 with orlistat and 10,631 participants. Orlistat lowered body weight by 2.9 kg more than placebo. On average, 30 to 40 percent of participants dropped out of the trials early. Gastrointestinal side effects were more common on orlistat.

Five weight-loss drugs compared

Khera 2016 (JAMA) compared five weight-loss drugs approved in the US over one year in a network meta-analysis of 28 randomized trials with 29,018 participants. Compared with placebo, those treated lost 2.6 kg more with orlistat, 5.3 kg with liraglutide and 8.8 kg with phentermine-topiramate. At least 5 percent weight loss was achieved by 44 percent on orlistat, 63 percent on liraglutide and 23 percent on placebo. In the ranking, orlistat came last.

The over-the-counter dose

Anderson 2006 (Ann Pharmacother) studied orlistat 60 mg three times daily in 391 mildly to moderately overweight people over 16 weeks, combined with a reduced-calorie diet. Body weight fell by 3.05 versus 1.90 kg. Total cholesterol fell by 4.4 versus 0.0 percent, LDL cholesterol by 7.2 versus 0.6 percent. Gastrointestinal complaints were more common on orlistat.

Where the data stop

• Hard endpoints. A trial measuring heart attacks, strokes or mortality on orlistat is not among the sources reviewed here. Diabetes prevention was shown only in impaired glucose tolerance.
• Adherence. In the long-term trials, 30 to 40 percent of participants dropped out; in XENDOS, just under half of the orlistat group did not complete the four years. The results apply to those who stayed in, and only to a limited extent to everyone.
• The gap to newer drugs. There is no head-to-head comparison with semaglutide or tirzepatide in the sources reviewed here. In the network comparison, even liraglutide, at 5.3 kg, was clearly ahead of orlistat.
• The time afterwards. The over-the-counter dose is limited to six months; the longest trials run for four years. What happens to body weight after stopping is not answered by the studies reviewed here.

Status, approval and legal

Xenical at 120 mg has been approved in the EU since July 29, 1998, and is prescription-only. Indication: adults with a BMI of 30 or more, or over 28 with risk factors, together with a mildly reduced-calorie diet. The approved dose is 120 mg with each main meal. According to the summary of product characteristics, anyone who has not lost at least 5 percent after 12 weeks should stop treatment.

alli at 60 mg has been approved without a prescription since July 22, 2007, for adults with a BMI of 28 or more, together with a mildly reduced-calorie, lower-fat diet. The approved dose is 60 mg three times daily, no more than three capsules in 24 hours and for no more than six months. In Germany, orlistat is prescription-only, with the exception of products containing no more than 60 mg per unit and no more than 180 mg per day.

Statutory health insurance does not pay for weight loss: § 34 of the German Social Code Book V (SGB V) excludes medicines for weight reduction and for regulating body weight.

Safety

The most common side effects concern the bowel: oily discharge, abdominal discomfort, urgent bowel movements, fatty stools and flatulence, mostly at the start of treatment. The absorption of the fat-soluble vitamins A, D, E and K can decrease; the alli summary of product characteristics therefore provides for a multivitamin product at bedtime.

Contraindications include concomitant treatment with ciclosporin or with warfarin and other oral anticoagulants, chronic malabsorption, cholestasis, pregnancy and breastfeeding. With levothyroxine, antiepileptics and amiodarone, medical advice is needed; with severe diarrhea, the contraceptive pill may become less reliable.

On liver injury, the EMA reviewed 21 reports of severe liver injury with Xenical and 9 of liver failure with alli in 2012. It found no good evidence of a causal relationship; the number was below that expected in this population. Since then, the product information has mentioned very rare liver side effects.

Sources

• Torgerson JS et al., Diabetes Care 2004 – XENDOS, orlistat for diabetes prevention, RCT with 3,305 participants over 4 years
• Rucker D et al., BMJ 2007 – meta-analysis of long-term pharmacotherapy for obesity, 16 orlistat trials with 10,631 participants
• Khera R et al., JAMA 2016 – network meta-analysis of five weight-loss drugs, 28 RCTs with 29,018 participants
• Anderson JW et al., Ann Pharmacother 2006 – orlistat 60 mg, RCT in 391 overweight adults over 16 weeks
• EMA – Xenical, European public assessment report (EPAR)
• EMA – alli, European public assessment report (EPAR)
• EMA – alli, product information (summary of product characteristics)
• EMA, 2012-02-16 – positive benefit-risk balance of orlistat-containing medicines confirmed after review of liver injury
• German Ordinance on Prescription-Only Medicines (AMVV), Annex 1 (prescription-only substances)
• German Social Code Book V, § 34 – medicines excluded from statutory health insurance coverage