In 1999, a new prescription weight-loss drug entered the U.S. market.¹ Contrary to the fanfare and excitement surrounding other recent introductions into the field of weight-loss drugs, this one was met with ridicule as much as anticipation. The timing should have been perfect, as the overweight and obese were clamoring for an effective alternative to replace the recently withdrawn drugs fenfluramine (Pondimin) and dexfenfluramine (Redux) which were found to cause serious health effects in some users.² Further, the furor surrounding the supplement ephedra was reaching a crest as certain consumer groups and industry lobbyists were pushing for it to be removed from the shelf due to safety concerns.³ Ephedrine HCl, the chemical responsible for most of ephedra’s weight-loss effects had already been severely limited due to its use in methamphetamine production (ephedrine and pseudoephedrine can be used as chemical precursors in manufacturing methamphetamine, thus the need to show identification when purchasing certain cough, cold and allergy products). Of course, there was also the growing awareness of an obesity epidemic plaguing the United States. The market for any new weight-loss product was ripe in 1999 and Xenical (orlistat) entered the market with high expectations from consumers and investors alike.

Xenical is interesting in that it employs a novel method of reducing weight; rather than suppressing the appetite or increasing calorie burning, Xenical reduces calorie intake by blocking the digestion and absorption of fat. On the face of things, this sounds like a very effective means of helping with weight loss, as fat is the most calorie dense of the three macronutrient groups (carbohydrates, protein and fat) and composes a significant proportion of the total calories consumed in the standard American diet (viva la cheeseburger!).

Clinical studies seemed to support the concept, as numerous trials demonstrated that Xenical increased weight loss in subjects on a hypocaloric diet by 50 percent to 100 percent.^4-6 In other words, whereas subjects trying to lose weight without Xenical might lose 5 to 10 pounds in six months, those given the drug were losing 7 to 20 pounds. Additionally, several health benefits are associated with the Xenical-associated weight loss, including loss of visceral fat (the metabolically dangerous fat inside your abdominal cavity), reduction of waist circumference, reduced triglycerides and improved cholesterol values, lower blood pressure, etc.⁷ While the amount of weight lost sounds modest, the benefits certainly appear to be significant.

Yet, even with the demonstrated weight-loss effects and health benefits, Xenical sales never reached the levels anticipated and public acceptance of the drug was limited.^8,9 Every drug has side effects, some are serious as demonstrated with Pondimin and Redux and others are less so, such as the slight increase in blood pressure and pulse seen with sibutramine (Meridia).⁶ With an effective drug, it is the emergence of side effects that limits its use clinically, as physicians might advise some patients to avoid certain drugs (e.g., not prescribing Meridia for people with high blood pressure). In other cases, patients will complain, asking to be switched to a different drug or stop taking their medication. If a medication is not taken as directed, the benefits are greatly reduced or disappear. Of course, when patients stop taking a drug, the sales of that drug go down, forcing pharmaceutical companies to respond to investor concerns.

Xenical is a good example of a drug that may succeed in clinical trials but fails in the real world, often through no fault of its own. Certain circumstances played against Xenical, including: patient expectations for a “don’t-have-to-think-about-it” lifestyle as provided by the Fen Phen combos that really drove down appetite and increased weight loss without much effort from the patient, consumer fear of another Pondimin and Redux health scare, media focus on low-carb diets (Atkins, South Beach, etc.), national attention on global terrorism following 9/11, etc.

It is important to consider the impact the Atkins diet (and similar plans) made on Xenical’s acceptance. Despite being contested by agencies such as the American Heart Association and many nutritionist groups, low-carb diets revitalized the national interest in losing weight through dieting, rather than depending upon pharmaceutical aids or even exercising.¹⁰ Pharmaceutical aids and supplements lost much of their appeal after the FDA clamped down on Pondimin, Redux, ephedrine, ephedra, phenylpropanolamine (Dexatrim) and others. Exercise has rarely been taken up by the overweight and obese, despite best intentions. Many gyms are filled with new members during the month of January, only to become fitness ghost towns a few weeks later as people lose interest in exercising or find it boring, too much work or overly inconvenient.

Hail To The Bacon!

So, millions of people began embracing bacon, steak and eggs as an interesting, tasty and fun way to lose weight. Traditional weight-loss centers gasped, but later clinical studies showed low-carb diets to be at least as effective as low-fat diets, faster and possibly even healthier. It was inevitable that many people experienced enough weight loss because of their commitment and renewed interest in dieting, brought on by Dr. Atkins and others. It was something to talk about and the quicker results were noticed and commented upon by co-workers and friends who might remark how wonderful that the loss was happening without drugs!

Of course, many people still asked their personal physician if a weight-loss drug might help accelerate their weight loss, and inevitably, some of those were likely following a low-carb diet, high in dietary fat. Herein lies the problem.

Xenical works by blocking lipase enzymes, which are chemicals released during a meal that digest fats so they can be absorbed. When lipase enzymes are blocked, much of the fat doesn’t get absorbed (reducing the absorption of fat calories by 30 percent) but travels down the intestines and eventually needs to be excreted in the usual fashion. Unfortunately, having a lot of undigested fat in the bowels leads to a condition known as steatorrhea. Some people develop steatorrhea as a consequence of certain diseases that affect the pancreas (the organ that produces most lipase enzymes) or the absorptive ability of the intestines— Crohn’s disease for example. When steatorrhea develops, it becomes quickly apparent as the stools (feces, bowel movement) become light-colored, bulky and float, making them difficult to flush. The odor changes for the worse as well, and many people notice oil droplets in the toilet water. Flatulence (gas) is very common, again, with a noxious change in the smell. Compounding the problem further is the likelihood of an “oily discharge” accompanying any gas-passing, resulting in stained and soiled undergarments.^4,6,11

In addition to the social challenges associated with steatorrhea, there is an increased risk of certain vitamin deficiencies, as some vitamins are fat-soluble (meaning they are absorbed into fat). By decreasing the amount of absorbable fat, it is possible that vitamin absorption could also be reduced, even to the point of causing health problems.^4,11 In clinical malabsorption syndromes that include steatorrhea symptoms, people can be present with deficiencies of vitamins A, D, E and/or K. If a vitamin deficiency persists, serious health conditions can arise (bleeding, bone loss, etc.). Some concern over orlistat’s effect on drug absorption has been raised, such as oral contraceptive pills, but research suggests these effects are not clinically significant.¹²

Returning to the interplay of the low-carb diets and Xenical— when a diet high in dietary fat is consumed and a lipase-inhibitor (Xenical) is consumed, a large volume of undigested and unabsorbed fat passes through the intestines into the colon, practically guaranteeing the onset of steatorrhea.¹³ Unquestionably, those who were having success with low-carb diets who attempted to add Xenical to their weight-loss effort were greeted with distasteful consequences, forcing them to make a choice between Atkins and Xenical. Considering that the steatorrhea-effect of Xenical can occur even with “normal” eating, it is easy to see why Americans failed to embrace Xenical with enthusiasm.

Marketing The Drug

Seeing the disappointing sales results of prescription Xenical, the pharmaceutical company Roche sought some way to reinvigorate the product. Another company, GlaxoSmithKline, purchased the rights to market orlistat in the United States in 2005.¹⁴ Their solution to the flagging prescription sales in this case was to put the product out as an over-the-counter (OTC) product. OTC drugs are familiar to everyone, including cough syrups, pain relievers, anti-fungal treatments and hair-loss products. In order to be considered acceptable as an OTC product, a drug must be proven to be safe and effective when used outside of a physician-patient relationship. People will now be able to grab orlistat without talking to their doctor first or being checked regularly for progress or the onset of adverse effects. Despite some controversy regarding the decision, the FDA approved orlistat to be sold as an OTC. GlaxoSmithKline is premarketing the product under the brand name Alli, at one-half the strength of Xenical and has committed $150 million to its market launch, according to one news story.¹⁴

Advocates for Alli (pronounced the same as ally— a friend or helper) state the drug is completely safe as it is not absorbed and that it is effective at increasing weight loss by 50 percent during a low-fat, hypocaloric diet.¹⁵ Further, GlaxoSmithKline is taking the tactic of stating that Alli is not for everyone and won’t work unless you do. To aid people in making the effort, GlaxoSmithKline has developed an interactive support website (www.myalli.com) which will include inspirational stories, diet and exercise advice and guidelines tailored to the individual. GlaxoSmithKline makes the grandiose implication that it is fairly unique to the weight loss world in providing the level of support it plans to make available though similar programs are common to most commercial weight-loss programs (www.jennycraig.com) and even products like Slim-Fast (www.slim-fast.com). Though many are praising the approach, some psychologists may be concerned at the focus on the individual as the key to weight-loss success or failure. The slogan associated with Alli, “If you have the will, we have the power” and comments such as stated in their promotional book: “Are you losing it? The most important element of successful weight loss: you,” may exacerbate feelings of self-loathing and despair among those who do not achieve weight-loss success. According to the clinical studies, this number could be significant, as approximately half failed to reach a 5 percent weight-loss goal in six months (9 pounds for a 180-pound person).

Of course, orlistat had its critics during the approval process for OTC sales. Public Citizen, a consumer advocacy group, petitioned against orlistat approval, challenging that animal studies had revealed a link between orlistat use and the development of pre-cancerous changes in the colon (large intestine), as well as an increased rate of breast cancer.^16,17 The possibility of inducing vitamin deficiencies was also raised as an issue. GlaxoSmithKline recommends a multivitamin taken at night to lessen the risk of deficiency in its support material. Lastly, Public Citizen cited the failure of orlistat to control appetite, meaning that overeating would continue unabated (unless the www.myalli.com program is successful in modifying behavior) and weight regain would occur once the drug is stopped.

Other comments have been made that Alli would be available indiscriminately to all, meaning the nonoverweight could use it as well. Individuals with eating disorders or image disorders (bulimia or anorexia nervosa) may flock to the drug, as well as athletes trying to lose weight and normal-weight executives trying to keep trim as they climb the corporate ladder. The use of any drug for other than its stated purpose is, by definition, misuse or even abuse. The potential for this with Alli, or any other weight-loss product, is very high.¹⁵ Further, no age restrictions are being placed on the drug, meaning adolescents could use this drug without supervision or even the knowledge of the parent. Remember, the only difference between prescription-strength Xenical and Alli is the dosage (120mg versus 60mg). While it may be of little practical consequence, as abuse of orlistat would be readily apparent to anyone walking behind or downwind, the concern is still present.

Orlistat is being touted as the first FDA-approved OTC weight-loss drug and the $150 million marketing campaign that will accompany its launch ensures that most Americans will hear about it on television, radio, in the papers or on the web. Despite having a scientifically reasonable approach to weight loss— reducing calorie intake by blocking fat absorption— orlistat has not proven itself to be very effective clinically.¹⁵ Patients are intolerant of the side effects, despite the attempts by GlaxoSmithKline executives to downplay “oily discharge” as “OOPS” moments. Also, the dietary restrictions that must be met in order for Alli to be effective at providing additional weight loss to a successful dieter are not well followed by the majority of dieters. Many people fail to follow a hypocaloric diet as they get hungry and Alli does nothing to control the appetite. The amount of fat that can be eaten without risking an “OOPS” moment is minimal (15 grams per meal), less than contained in 3 ounces of lean steak and half of the amount in a single fast-food cheeseburger.¹⁸ Those who are happy with low-carb diets will be absolutely dismayed, as they will be forced to choose Alli or Atkins unless they want to live a life of solitude.

The timing for this approval caused one colleague to raise a conspiracy theory regarding Big Pharma and the current administration (disclaimer: I voted for President Bush in 2000 and 2004). The rapid withdrawal of all effective OTC weight-loss products and supplements (PPA and ephedrine primarily) created a marketing opportunity of immense proportions for pharmaceutical companies. When Xenical failed to gain significant market share as a prescription drug, GlaxoSmithKline saw an opportunity in marketing orlistat OTC, but only if it could get on the market prior to the introduction of rimonabant, a very promising, appetite-suppressing drug that provides several health benefits (smoking cessation, improving cholesterol, etc.) in addition to weight loss.^5,19 The FDA has delayed the approval of rimonabant, though it is being sold throughout Europe following approval by their regulatory agencies. Ironically, the FDA is next scheduled to review rimonabant on June 13, 2007— two days before the OTC introduction of Alli.²⁰ The stated reasons for the delay in approving rimonabant relate to reports of increased rates of depression and anxiety in users, to which my colleague replied: “And how many people with OOPS moments* will have depression and increased anxiety?” *[Note: I censored his original term for oily discharge to avoid offending any readers.]

Orlistat is a drug that saw limited success in clinical weight-loss practices with greater supervision and in a higher dosage form. It is unlikely the drug will be any more effective within the informal structure of an interactive website rallying OTC consumers. Though there is little risk of negative health consequences, when properly used (including the use of multivitamin), unless the consumer is disciplined about following a hypocaloric, low-fat diet, the possibility of social consequences is not to be taken lightly. Some people believe the consequence of an OOPS moment will reinforce adherence to a low-fat diet, assuming people respond to that type of lesson.¹⁵ In fact, it seems more likely that people would view that as a reason to stop use of the drug. After all, how many places sell half-cheeseburgers and who really wants to limit olive oil on their salads and pasta? It is unlikely the world will be telling Rachael Ray, “Sorry, no can do on the EVOO” or asking Emeril Lagasse, “Can you turn it down a notch?”

Xenical was not a miracle prescription drug and Alli will not be a miracle OTC drug. Those who achieve success with Alli are people who would have experienced weight-loss success without the drug, with Alli providing a meager difference of 2 or 3 pounds over the course of six months. At a cost of approximately $2 per day, purchasing a treadmill or gym membership may be a better investment. This summer will be a make-or-break opportunity for the marketers of Alli, as once rimonabant is approved in the United States for weight loss and its effectiveness in suppressing the appetite and promoting weight loss is demonstrated, orlistat will be rarely considered.

References:

1. Stolberg SG. FDA approves diet drug that blocks fat absorption but experts caution it’s not a magic bullet. San Francisco Chronicle, 1999 April 27:A-1.

2. Boodman SG. Goodbye Redux and fen/phen, hello…? The Washington Post, 1997 September 20:E-1.

3. Lueck S, Mathews AW. FDA plans to ban ephedra, citing supplement’s risks. The Wall Street Journal, 2003 December 30.

4. Harp JB. Orlistat for the long-term treatment of obesity. Drugs Today, (Barc) 1999;35:139-45.

5. Bray GA, Ryan DH. Drug treatment of the overweight patient. Gastroenterology, 2007;132:2239-52.

6. Padwal R, Li SK, et al. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev, 2004;3:CD004094.

7.   Diego BG. Orlistat reduces anthropometric parameters in a different way according to sex. Int J Obes, 2007;31 Suppl 1:S169.

8.   Moore SD. Roche expects to see slimmer growth in sales of antiobesity drug Xenical. The Wall Street Journal, 2000 June 23.

9.   Brouneus F, Dahlin A, et al. Press coverage and sales of Xenical in Sweden, 1998-2000. Eur J Clin Pharmacol, 2005;61:285-9.

10.  Stein J. The low-carb diet craze. Time, 1999 Nov 1. Available at http://www.time.com/time/printout/0,8816,992401,00.html accessed May 20, 2007.

11.  Ballinger A. Orlistat in the treatment of obesity. Expert Opin Pharmacol, 2000;1:841-7.

12.  Hartmann D, Guzelhan C, et al. Lack of interaction between orlistat and oral contraceptives. Eur J Clin Pharmacol, 1996;50:421-4.

13.  Fox M, Schwizer W, et al. The physical properties of rectal contents have effects on anorectal continence: insights from a study into the cause of fecal spotting on orlistat. Dis Colon Rectum, 2004;47:2147-56.

14.  Elliot S. Telling dieters a pill works only if they work, too. The New York Times, 2007 May 9.

15.  Saul S. Over-the-counter weight-loss drug is approved. The New York Times, 2007 February 8.

16.  Rubin R. Petition seeks to stop Xenical from going OTC. USA Today, 2006 Apr 11:9D.

17.  Barbehann E, Wolfe S, et al. Petition to the FDA to immediately remove the diet drug orlistat (XENICAL) from the market (HRG Publication #1764). Available online at http://www.citizen.org/publications/release.cfm?ID=7423 accessed May 21, 2006.

18.  Squires S. Losing it: what to know about “new” drug Alli. Newsday, 2007 February 27:B12.

19.  Patel PN, Pathak R. Rimonabant: a novel selective cannabinoid-1 receptor antagonist for treatment of obesity. Am J Health Syst Pharm, 2007;64:481-9.

20.  Food and Drug Administration. Endocrinologic and metabolic drugs advisory committee: notice of meeting. Federal Register, 2007 March 27;72(58).