Orlistat first became available (as 120mg capsules [Xenical]) around 10 years ago as a prescription-only treatment for obesity.1 Earlier this year, orlistat 60mg capsules (alli – GlaxoSmithKline Consumer Healthcare) became available for sale without a prescription to the public in the European Union. Orlistat 60mg is available in the UK as a Pharmacy (P) medicine and so can be purchased over-the-counter (OTC) from pharmacies. OTC orlistat is promoted as a new weight loss aid, “boosting weight loss by 50%” when added to a reduced calorie, lower-fat diet. Here we review the place of OTC orlistat in tackling obesity.
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Around a quarter of adults in England are obese (i.e. have a BMI of 30kg/m2 or more).2 Obesity reduces life expectancy3 and is associated with hypertension, dyslipidaemia, type 2 diabetes mellitus, gallbladder disease, coronary heart disease, osteoarthritis of the hip and knee, many cancers and adverse outcomes in pregnancy.4 5 6
The mainstay of managing people who are overweight involves modification of diet, physical activity levels and behaviour. For instance, a diet with a 600 calorie per day deficit may be expected to produce a weight loss of 5.3kg (95% CI 4.8kg to 5.9kg) over 1 year, with exercise and behavioural therapy providing additional weight loss of approximately 2.0kg (95% CI 0.7kg to 3.2kg) and 7.7kg (95% CI 3.4kg to 12.0kg), respectively.7 The National Institute for Health and Clinical Excellence (NICE) advises that lifestyle changes should form the mainstay of management in obesity and that drug treatment should be considered only after lifestyle changes, including behavioural approaches, have been started.8 NICE recommends bariatric surgery as a treatment option for people with a BMI of at least 40mg/m2 or with a BMI of 35–40kg/m2 plus other significant disease that could be improved with weight loss, if all appropriate non-surgical measures have been tried but have failed to achieve or maintain adequate, clinically beneficial weight loss for at least 6 months.8
What is orlistat?
Orlistat is an inhibitor of gastrointestinal lipase, an enzyme that catalyses hydrolysis of dietary fat. By inhibiting fat hydrolysis, orlistat reduces fat absorption and thereby reduces overall calorie intake. The drug is minimally absorbed; animal studies indicate that it is metabolised mainly in the intestinal wall.9
Orlistat 120mg is available as a prescription-only medicine (Xenical) for the treatment, for up to 2 years, of adults who are obese (i.e. their BMI is at least 30kg/m2) or who are overweight (BMI at least 28kg/m2) and also have associated risk factors.10 When used at the licensed dose of 120 mg three times daily, the drug reduces absorption of ingested fat by around 30%.11 The summary of product characteristics (SPC) recommends that treatment with orlistat 120mg should be discontinued after 12 weeks if less than 5% of initial body weight has been lost.10
Orlistat 120mg three times daily, when administered with a hypocaloric diet, has been shown to aid weight loss in patients who are obese.1 The average weight lost at 1 year with orlistat beyond that with placebo is around 2.9kg (95% CI 2.5kg to 3.2kg).12 Also, results from a 4-year double-blind randomised placebo-controlled trial involving 3,305 adults with obesity, showed that the addition of orlistat 120mg three times daily to lifestyle changes reduced the risk of progressing to type 2 diabetes from 9.0% to 6.2% (p = 0.0032).13 Whether these benefits are sustained in the long term or reduce mortality is unknown.
The licensed dose of OTC orlistat is 60mg three times daily for adults who are overweight or obese (i.e. BMI at least 28kg/m2). Orlistat 60mg reduces absorption of ingested fat by around 25%.9 The SPC states that a dose should be taken immediately before, during or up to 1 hour after, each main meal, and that if a meal is missed or contains no fat, the dose should be omitted.9 The SPC also states that a patient who has not lost weight after 12 weeks' treatment with the drug should consult a doctor or pharmacist, as it may be necessary to discontinue treatment. Orlistat 60mg is licensed for use for up to 6 months.9
How is OTC orlistat being sold?
Orlistat 60mg is advertised directly to the public and sold through pharmacies, including internet pharmacies and pharmacy phone-lines. The cost of 6 months' treatment with orlistat 60mg three times daily is around £325.
The Royal Pharmaceutical Society of Great Britain has issued practice guidance for pharmacists on the sale of orlistat 60mg.14 This recommends that they should be satisfied that the individual is aged 18 years or over and has a BMI of at least 28kg/m2, and that they should refuse sale to those who may be misusing the medicine.
The company marketing OTC orlistat has provided training programmes on selling OTC orlistat and weight management to UK pharmacists and their staff via online, distance learning and face-to-face workshops.
For customers, the company provides a “support programme”, consisting of booklets and a website including advice on calorie and fat intake targets, tips on healthier eating and exercise, a food diary and recipes, and an online discussion forum.
Of relevance, the Centre for Pharmacy Postgraduate Education (www.cppe.manchester.ac.uk) has produced a training pack for pharmacists entitled Weight management – understanding the causes, prevention, assessment and management of obesity. This covers various aspects of weight management including ways to give information and how to address individuals' weight management issues.
Efficacy of orlistat 60mg
One trial involved 796 adults who were obese (BMI of 30–44kg/m2).15 All the participants took part in a run-in phase during which they received (single blind) placebo for 4 weeks. Participants who completed this phase with at least 75% adherence to the regimen (80% of those who entered the trial), were randomised to orlistat (60mg or 120mg three times daily) or placebo, for 2 years. All participants were prescribed a reduced-energy diet for the first year, a weight-maintenance diet for the second year and were encouraged to walk briskly for 20–30 minutes three to five times each week throughout the study period. They did not receive formal counselling from dieticians or behavioural psychologists. After 1 year, mean weight loss in the 635 randomised patients, (from a mean weight of around 100kg at trial entry) was greater in those receiving orlistat 60mg (7.1kg, 7.1%) and orlistat 120 mg (7.9kg, 7.9%) than with placebo (4.1kg, 4.1%; p<0.01 for both comparisons). Roughly two-thirds of this weight loss was maintained at the end of the second year in those on orlistat 60mg (4.5kg, 4.4%) and orlistat 120mg (5.0kg, 5.0%), and the losses were still greater than with placebo (1.7kg, 1.6%; p = 0.001 for both comparisons). The percentage of participants achieving a weight loss of 5% or more with orlistat 60mg was 48.8% after 1 year and 33.8% after 2 years and greater than with placebo (30.7% [p<0.001] and 24.1% (p<0.03], respectively). This compares to 50.5% and 34.3%, respectively, for orlistat 120mg. Nearly half of people on orlistat withdrew early from the study (46% with either dose), although the number was fewer than with placebo (57%), mainly because of loss to follow-up; 11% on orlistat 120mg and 6.6% on orlistat 60mg withdrew because of unwanted effects (vs. 7.1% of those on placebo).
In a similar study, 729 adults who were overweight or obese (BMI 28–43kg/m2) were randomised (following a 4-week single-blind placebo run-in phase, after which 54 patients with poor adherence were withdrawn) to orlistat 60mg or 120mg three times daily or placebo, for 2 years.16 Participants had a reduced-calorie diet in the first year and a weight-maintenance diet in the second year. They received dietary advice from dieticians but no formal advice appears to have been given on physical exercise. After 1 year, mean weight loss was greater in those on orlistat 60mg (8.5kg, 8.6%) and orlistat 120mg (9.4kg, 9.7%) than with placebo (6.4kg, 6.6%; p<0.001 for both comparisons). Most of the weight loss was maintained at the end of the second year with orlistat 60mg (6.6kg, 6.8%; p = 0.005 ) and 120mg (7.4kg, 7.6%; p<0.001), and was greater than with placebo (4.3kg, 4.5%). During the first year of the trial, around 25% of people withdrew from orlistat therapy (vs. 35% of those on placebo). Withdrawal was due to unwanted effects in 6–7% of those on orlistat (vs. 1.6% of those on placebo).
Data from the above two trials were reanalysed and pooled to provide evidence for the European Medicines Agency on 6 months' treatment with orlistat 60mg (the licensed maximum treatment duration). This information is presented in the SPC for alli, which states that in both trials, most weight loss occurred within the first 6 months of treatment. At 6 months, people on orlistat 60mg had lost 4.4kg (vs. 2.1kg with placebo, p<0.001) from after the placebo run-in; the proportion who had lost at least 5% of weight was 46.7% (vs. 26.4% with placebo, p<0.001).9
Limitations of the data
It is important to remember that the trial results were from a select group of patients more likely to adhere to treatment. Whether they apply directly to the general population must therefore be in question. What happens after cessation of treatment with OTC orlistat is also not clear. This is of significance given the well-recognised phenomenon of rebound weight gain after weight loss interventions are stopped. For example, published data from one randomised controlled trial of orlistat 120mg suggest that much of the weight lost while on orlistat is regained by 1 year after stopping the drug.17
Unwanted effects with OTC orlistat
The most common unwanted effects with orlistat are gastrointestinal, in keeping with its mechanism of action. In clinical trials with orlistat 60mg, at least 10% of people reported experiencing one or more of the following: oily spotting, flatus with discharge, faecal urgency, fatty oily stool, oily evacuation, flatulence and soft stools; and 1–10% of patients reported abdominal pain, faecal incontinence, liquid stools and increased defecation.9 These effects are more likely if a meal or the diet is high in fat. Other unwanted effects include anxiety (in 1–10% of people); the SPC states that it is plausible that anxiety might occur in anticipation of, or secondary to, the gastrointestinal effects of orlistat.9
Cautions and contraindications
OTC orlistat is contraindicated in people with cholestasis or chronic malabsorption syndrome, and (because of a lack of data) in women who are pregnant or breastfeeding.9
Due to its action on fat absorption, orlistat has the potential to impair the absorption of fat-soluble vitamins (A, D, E and K). However, in most patients who took orlistat 120mg three times daily in trials for 4 years, vitamin concentrations stayed within the normal range.9 Even so, the SPC recommends that patients on OTC orlistat should take a multivitamin supplement at bedtime, which would need to be purchased separately so incurring additional cost to the customer. (For orlistat 120mg, the SPC says that a multivitamin supplement could be considered.)10
The SPC advises that the patient should consult a doctor or pharmacist before taking orlistat if they are on medication for diabetes, or while taking orlistat if they are on medication for hypertension or hypercholesterolaemia, as weight loss may be accompanied by improvement in these conditions.9
Concurrent use of OTC orlistat with ciclosporin is contraindicated because plasma concentrations of ciclosporin have been found to decrease under such circumstances. Concurrent use of OTC orlistat with warfarin and other oral anticoagulants is also contraindicated because coagulation times might be affected through reduced absorption of vitamin K.9 The SPC advises that orlistat may reduce plasma concentrations of amiodarone, which may require a change in the dose of amiodarone. Concurrent use of orlistat and acarbose (an antidiabetic drug that delays digestion and absorption of starch and sucrose) is not recommended in the SPC because of a lack of data.9
If orlistat causes diarrhoea, the bioavailability of the oral contraceptive pill may be reduced; the SPC therefore recommends that women who experience an episode of severe diarrhoea with orlistat should use an additional form of contraception.9
In theory, OTC orlistat may be used repeatedly or misused. We have found four case reports of misuse of the prescription-only version of orlistat by patients with a history of an eating disorder.18 19 20
An over-the-counter (OTC) version of the weight-loss drug orlistat (orlistat 60mg – alli) is available in the UK for purchase without a prescription from pharmacies, by adults who are overweight or obese (body mass index [BMI] 28kg/m2 or more) for up to 6 months' use. Published evidence indicates that, over a course of 6 months, people on orlistat together with a reduced calorie diet, shown likely to adhere well to the treatment, lost an average of 2.3kg in addition to the 2.1kg lost with lifestyle measures alone. It is not known how effective orlistat 60mg is in the general, non-selected, population. Also it is not clear what happens at the end of a 6-month course of treatment.
OTC orlistat provides a reasonable choice for motivated individuals who can afford the drug (around £55 per month plus the cost of multivitamins). People who want to buy it should receive full counselling about the unwanted gastrointestinal effects and how these relate to diet. Weight regain is likely to be a problem when the drug is stopped and individuals should be advised to discuss long-term weight management options with a healthcare professional at an early stage.