A potential risk of liver toxicity was identified based on reports to the FDA Adverse Events Reporting System
Science has long been on the trail of a magic pill that will make the obesity crisis go away without any real effort on the part of the potential dieter or healthcare providers.
Enter orlistat - available over the counter (OTC) in the UK and elsewhere as Alli (pronounced ‘ally' - as in your best friend - and made by GlaxoSmithKline) and by prescription as Xenical (in the US, and made by Roche).
Orlistat was approved for OTC use by the US FDA in 2007 and Alli became the first weight loss product officially sanctioned by the US government for over-the-counter use. It comes in 60mg capsules - half the dose of prescription orlistat. Europeans have been able to buy Alli over the counter since January 21, 2009 and a month's supply - dieters take 3 capsules a day - costs around £45.
Orlistat is not a stimulant and does not affect the nervous system in the way that so many other weight loss drugs do. Instead it is what is known as a lipase-inhibitor - a drug that prevents the body from breaking down and absorbing fat. After taking it, approximately 30 per cent of the fat eaten in a meal passes unabsorbed through the intestines and is eliminated in the faeces.
Skimming the surface
At first glance Allil's statistics seem impressive. In several trials lasting up to 2 years, orlistat has been shown to be more effective than diet alone for weight reduction and maintenance of lost weight. Orlistat treatment also results in modest improvements in total cholesterol, low-density lipoprotein, blood pressure, and fasting glucose and insulin concentrations.
Analysis of data from five studies involving over 3000 people who were followed for a year or more showed that people taking orlistat - in combination with lifestyle modifications, such as a low fat diet and exercise - lose about 2-3 kilos (4.4-6.6 lb) more than those not taking the drug.
The promise of effortless weight loss is certainly appealing - until you read the fine print which says categorically that Alli must be taken with a low fat diet in order to work. It may be this little catch which is why Alli hasn't quite lived up to its predicted sales potential.
Not so rosy
When it was first released GlaxoSmithkline confidently predicted Alli to be one of the most successful drugs of all time but sales in the first year or so have been pretty underwhelming. Although the company predicted sales of $1.5 billion in the first year (and spent a whopping $150 million in advertising) figures show that sales only reached around $88 million in the first 9 months of 2008. Still a staggering amount of money but far below the blockbuster status predicted.
Apart from the "lazy fat people" stereotype, Alli also reinforces yet another unhelpful stereotype - that dietary fat is the enemy of all those who wish to be healthy. In fact we gain weight for a variety of reasons including exposure to certain pollutants in the environment (see the Big Fat Fix).
Also some dietary fat is necessary for health. The problem with the Western diet is that we get too much of the wrong kinds of fats - i.e. man-made trans fats, and certain unhealthy saturates - and not nearly enough of good fats - omega 3, 6 and 9 in good balance, and certain helpful saturates such as conjugated linoleic acid. Fats not only improve the taste and feel of food, they are essential for helping us absorb the essential fat-soluble vitamins A, D, E and K.
So the first question with any fat blocking type of drug would be does it affect the absorption of fat soluble vitamins. The answer is yes. Alli has been shown to interfere with the absorption of these, which is why in addition to taking it dieters are advised to take a second pill - a multivitamin supplement. With Alli the interference is greatest with vitamins D and E and beta-carotene.
Weight loss/Weight gain
The second problem with Alli is that it only works as long as you keep taking it - and then only moderately.
A 2007 editorial in the BMJ noted that that it is unlikely many users will see significant health benefits because the best results are obtained when dieters are well-motivated and supported by dedicated health professionals who reinforce lifestyle advice; without such support, it is not known how well Alli will perform.
In addition, it notes that while the benefits of orlistat are definite, clinical trials conducted over one year suggest that they are also modest. When the Orlistat was stopped, a significant number of people regained weight - in some cases up to 35 per cent of the weight they had lost. Had the participants been followed up for longer this figure would probably have been higher still.
Orlistat can produce results in those who are morbidly obese. Indeed it is really intended for those with a BMI of 25 or above and not the casual dieter who is looking to lose half a stone or so.
And then there are the adverse effects...
Even in the clinical trials, where dieters were supported, the adverse effects of orlistat - which include abdominal discomfort, liquid stools, soft stools, oily rectal spotting, flatulence and flatus with discharge, faecal urgency, fatty or oily stools, increased defecation, and faecal incontinence - meant that up to 40 per cent of subjects dropped out. Manufacturers, of course, are keen to point out that these symptoms decrease over time.
But the side-effects may extend beyond the physical. As the BMJ editorial notes: ‘Selling anti-obesity drugs over the counter will perpetuate the myth that obesity can be fixed simply by popping a pill and could further undermine the efforts to promote healthy living, which is the only long term escape from obesity. The only real beneficiary will be GSK. We will never know whether Alli is useful, as there will be no proper follow-up.'
In addition, while those taking orlistat in clinical trials were on highly calorie restricted diets, those taking it OTC may not be. It has been estimated that taking it without medical supervision may achieve an average daily energy deficit of only 100kcal - equivalent of leaving a few chips on your plate or eating an apple instead of ice cream.
The issue of proper follow-up isn't just about understanding whether or not Alli does the job it is supposed to do i.e. promote weight loss. Follow-up is also vital to monitoring any serious adverse effects that widespread, uncontrolled use of such a drug could provoke.
Safety concerns have been raised about the potential for the development of colon cancer: a 2006 animal study linked orlistat with what are known as aberrant crypt foci (ACF), lesions found in the colon which are believed to be one of the earliest precursors of colon cancer. Concerns have also been raised about the development of osteoporosis, kidney stones and impaired gallbladder function.
There has been one case report of a man taking orlistat who developed pancreatitis - a serious adverse effect in which the pancreas becomes inflamed - four days after starting the drug. Pancreatitis can lead to intermittent or constant pain and can lead to permanent damage of pancreatic tissues.
No other similar case reports on this have been published but 99 cases of orlistat-related pancreatitis have been reported to the Food and Drug Administration (FDA). On June 4, 2009, the US FDA released its quarterly list of drugs that are under investigation for potential safety issues. Orlistat was included in the list as having a ‘Potential Signal of Serious Risk' of liver toxicity meaning that a potential risk of liver toxicity was identified based on reports to the FDA Adverse Events Reporting System between October and December 2008.
Perhaps the final word should go to the UK's National Institute for Clinical Health and Excellence (NICE). In a recent review it suggested that further research needs to be done on long-term effects of orlistat, including the resulting weight loss influences, and adverse effects and also suggested that there was 'insufficient evidence on weight regain and long term safety.'
Pat Thomas is the former editor of the Ecologist.