I have greatly enjoyed reading Bill Roberts’ Anabolic Pharmacology Column and I applaud him for his help in bringing much needed common sense to the area of anabolic hormone research. Only recently with the HIV/AIDS epidemic and the AIDS wasting syndromes has research on the therapeutic use of anabolic steroids become respectable again. However, as clueless as the medical establishment has been on drugs that make you bigger, it is often even more misguided on the use of drugs that make you smaller. Unlike the minimal amount of research devoted to anabolic steroids which, millions and millions of dollars and hundreds and hundreds of studies have been done to develop and test the efficacy of diet drugs. The rapidly increasing plague of obesity in America has been well established, but nothing significant has been done to stop it despite the copious volumes of new research data and new diet drugs. This series is meant to expose the scandalous use of expensive and ineffective drugs, and show how cheaper and more effective drugs have been largely overlooked.
The Quest for the New “Phen-Fen”
For a brief moment, obesity had the appearance of being cured. Doctors were getting rich doling out a combination of Phentermine and Fenfluramine dubbed Phen-Fen. While these drugs were only indicated for seriously obese individuals, almost anyone looking to lose a few pounds had no trouble getting a prescription. Of course, both of these drugs had been around for years. The positive results of the long-term Weintraub obesity studies (1) with this combination drove the American obesity industry into a frenzy. The combination was more effective then either drug alone. As an added plus, the mildly sedating and satiating properties of Fenfluramine seemed to partially negate the stimulating effects of Phentermine. Thus the combination apparently had fewer side effects than either alone as well (or so we thought). However, phentermine is still on the market and new combinations are being concocted with it.
We all know now that Phen-Fen proved to be a fiasco. Needless to say, this “cure” for obesity and the millions doctors were making could not go on forever. The revelation that Fenfluramine can cause pulmonary disease and heart problems has lead the medical establishment to start over again in its quest to find a new “cure”, a new “Phen-Fen” that proves as effective (and profitable) as the original…
Attempt #1: Meridia (Sibutramine)
Meridia is an attempt to combine the properties of Fenfluramine and Phentermine in one pill. Phentermine is a stimulant, scientifically referred to as an adrenergic or catecholaminergic drug. A catecholanminergic drug increases brain levels of andrenaline and/or noradrenaline, your body’s most stimulating neurotransmitters. Phentermine makes you stimulated and energized, thus reducing appetite, delaying time for food intake and increasing your metabolic rate . Fenfluramine, on the other hand, stimulates serotonin release. Serotonin is one of your brain’s most sedating, satiating and relaxing neurotransmitters. Fenfluramine, by increasing serotonin levels, makes you feel less anxious, decreases carbohydrate cravings , and produces a feeling of rapid satiety – thus reducing food intake.
Meridia is a drug with both catecholaminergic and serotonergic properties. It works by blocking your brain’s reuptake of both serotonin and noradrenaline, thus prolonging and increasing the activity of these neurotransmitters (2). Theoretically at least, Meridia should be highly effective as it should help suppress appetite through two different pathways. So is Meridia theoretically should be the next Phen-Fen.
Early clinical trials do in fact did look impressive. Two separate year-long studies showed Meridia at recommended doses to produce much larger losses in weight than a placebo. At 10 mg per day, the Meridia group lost 4.8 kg over a year while the placebo group lost 1.8 kg. At 15 mg per day, the Meridia group lost even more weight – 6.1 kg while the placebo lost only 1.8 kg. (3)
However, Meridia is not exactly flying off the shelves like Phen-Fen. Very few of my patients have requested a prescription for Meridia, and many have told me that they have tried it and it didn’t do anything for them. None of my medical colleagues have reported much success with Meridia either. So why is Meridia so effective in studies (funded by the pharmaceutical company that makes it), and yet apparently ineffective in the real world? I believe the studies mentioned above are somewhat misleading since the drop out rates were exceptionally high – around 50% in both studies. A common reason people drop out of diet drug studies is because they feel the drug is ineffective. Obviously, the people losing the most weight are most motivated to stay in the study. Thus the results are likely biased.
A survey by the newsletter Obesity Meds and Research News showed that of 248 people who had used Meridia for longer than four weeks, 45% were deemed “non-responders” – i.e. failed to lose more than one pound per week (4). While this survey was not scientific, it does parallel with my own observations that Meridia is not especially effective.
Meridia’s apparent lack of efficacy may be due to its mode of action. Unlike Fenfluramine which stimulates the release of serotonin, Meridia is a serotonin reuptake inhibitor. Like Prozac and other anti-depressants, Meridia “recycles” your brain’s serotonin instead of increasing serotonin production. Meridia and Prozac are safer than Fenfluramine, as the excess serotonin from Fenfluramine is what led to heart problems in Phen-Fen users. However, serotonin reuptake inhibitors are simply not as effective as Fenfluramine. Prozac might have some use for short-term weight loss, but in trials lasting longer than six months it is a failure. Patients might even gain more weight than a placebo when using Prozac (3). Since Meridia has similar properties as Prozac, its lack of success as a new Phen-Fen does not surprise me.
ttempt #2: Xenical (Orlistat)
This is an especially silly drug. Yes, clinical trials do show that patients on Xenical lose more weight than a placebo, and even keeps weight off longer than Meridia does when the drugs were terminated. Perhaps it was simply Pavlovian conditioning with the fear that when you eat fat you may leak stool and get stinky.
In the real world, I predict Xenical will be even more of a flop than Meridia. Unlike studies on Meridia, the Xenical studies controlled for diet. Both the Xenical and the placebo groups were put on restricted calorie diets. Strictly speaking, Xenical is not a classic anorectic drug like Meridia, phentermine, or fenfluramine. Xenical does not effect appetite much but prevents your body from processing dietary fat by blocking the digestive enzyme lipase. As a result up to one third of your dietary fat is excreted in your feces when you are on Xenical. So if you have two group of people each with consuming the same amount of calories, and the same dietary composition the group taking Xenical will lose more weight since they will be absorbing less calories from their dietary fat.
But let’s look at real world conditions. Your average overweight person with a prescription for Xenical will not have his food intake monitored closely by a scientist. However, this patient will know that up to one-third of his fat calories will magically be gone. So do you think he will continue to eat as he was before, or might he be tempted to increase his fat intake by one-third? I’ll let you be the judge, but I’m quite sure what the outcome will be. Since Xenical does not suppress appetite or increase metabolism, I really doubt it will have any long term effects on weight loss. Xenical requires strict adherence to a low fat diet to have any effect, but its use will likely encourage people to eat more high-sugar, high fat junk food instead of less. Xenical will also cause a few unfortunate “bathroom-related” side effects. Anything that causes you to excrete more fat–leaky stool will inevitably make going to the bathroom a less pleasant experience, and compound the social problems that the obese all ready have. Side effects of Xenical include liquid stools, fecal urgency, fecal leaking, and fecal incontinence. The last side effect can be especially embarrassing – fecal incontinence is just a polite, scientific way of saying that Xenical can make you “crap in your pants”. Another problem is that the fat soluble vitamins–vitamin D, and the carotenes have been shown to be lowered in the Xenical studies. Researchers recommend daily multi-vitamin supplementation for those taking Xenical . Probably all fat soluble vitamin levels are ultimately affected—vitamin E, K etc.
I also don’t like Xenical because it promotes the fallacy that fat is evil and responsible for obesity. As I’m sure most Meso-Rx readers know, no macronutrient is “evil”. There are fats that can make you slimmer such as Omega-3 fatty acids, and those that can be fattening such as saturated fats and partially-hydrogenated fats. The key is to eat a diet balanced in proteins, fats, and carbohydrates with a good portion of the fat coming from Omega-3’s. Someone who is eating a good, balanced diet should not take Xenical as it would mean less absorption of beneficial fatty acids for optimum human health. I really believe that the only people who can benefit from Xenical are those with simply atrocious eating habits who simply cannot stay away from potato chips, ice cream, and other such high fat, high starch foods. However, these are the last people who I would prescribe diet drugs to.
Xenical or Meridia for Athletes and Bodybuilders?
Both Xenical and Meridia are indicated for obese individuals (BMI greater than 30). So would an already lean bodybuilder trying to reduce his bodyfat even further have any use for either of these drugs? I have not heard of any burgeoning black market in Venice Beach or West Hollywood for either of these drugs, nor have any of my bodybuilding patients asked me for a prescription. Xenical is a big no-no for any bodybuilder, as most bodybuilders already eat relatively healthy and balanced diets. All Xenical will do for them is increase their time in the bathroom and make them lose weight in their wallets.
Meridia may have some hope for bodybuilders, although not much. A couple of studies have shown Meridia to have some thermogenic activity (2). Thus it is possible that Meridia has some muscle sparing activity similar to other thermogenics such as ephedrine. However, the studies on Meridia measure only total weight loss, with no distinction between fat loss and muscle loss. It is possible that Meridia could be used as a mild thermogenic by those who are overly sensitive to ephedrine, but at $100 per month Meridia is probably not worth it for most. This brings me to my next issue:
Cost Effectiveness of Xenical and Meridia
This is probably the most absurd aspect of these new diet drugs. In general, insurance companies will not “foot” the bill for anti-obesity drugs. Unless you are morbidly obese, you have to pay for these drugs out of your own pocket. The cost for a months supply of either Xenical or Meridia is roughly $100 per month or more.
Let’s look at the economics of this. For Xenical, this is a ridiculous price. No trials have yet shown it to be effective in people whose diets are not closely monitored. My guess is that very few people will lose any weight at all from Xenical. So it is basically $100 down the toilet, quite literally considering some of the side effects of this drug.
Next, let’s look at Meridia. Let’s assume for a second that this drug is as effective as the studies say. Judging by two published studies mentioned above, taking 10-15 mg per day of Meridia for one year will produce anywhere from 6.6 to 9.46 lbs. greater weight loss than you would if you were given a placebo (3). Do the math yourself – at best you are paying $126.85 per pound of weight loss! To make matters worse, you don’t know how much of this weight loss is actually from fat and not muscle. And this is all assuming of course that the these studies are actually representative of how well Meridia really works.
Another way to evaluate the cost effectiveness of Meridia is to compare it to other diet drugs. A 1973 review study funded by the FDA did a meta-analysis of 105 studies on various diet drugs. The conclusion of this review study was that these diet drugs available in 1973 (mostly amphetamine-like stimulants) induced patients taking the drugs to lose a half a pound a week more than the placebo group (5). Most of the studies reviewed were short term, none lasting more than a few months. Since this review study was completed, a half a pound a week more than the placebo group has become the standard to evaluate the scientific effectiveness of a diet drug in short term trials.
Short term trials may be the better way to evaluate a diet drug, as After 3-6 months of use a drug may lose its effectiveness. Just about all weight loss drugs and other methods lose their effectiveness after 6 months of use from a combination of lowered resting energy rates and from a decreased energy expended with exercise.
So does Meridia live up to this standard of .5 lbs. per week? Let’s look at some of the shorter trials of Meridia to see how it compares to the classic stimulant drugs looked at in the 1973 review study. One of the largest short-term trials on Meridia on 1,047 total patients showed that this is not the case. At 10 mg per day, patients lost .32 pounds a week more than the placebo over 24 weeks. At 15 mg per day, this number moved up to .42 pounds a week more than the placebo – not quite up to par. Only at 30 mg per day did Meridia prove as effective as the “gold standard” of .5 pounds per week more than a placebo (2).
To be fair, some studies did show Meridia to induce a loss of more than .5 pounds a week more than the placebo, but these trials were very short term (12 weeks or less) and had lower sample sizes (1). However, the “kicker” in evaluating Meridia’s cost effectiveness is comparing it to far cheaper over the counter diet drugs.
Let’s look at phenylpropanolamine (PPA), commonly sold as Dexatrim or Accutrim. Short term trials have shown PPA to be about exactly as effective as Meridia – inducing anywhere from .3 to .5 pounds a week greater weight loss than a placebo (6). PPA cost just “pennies a day”, and has an excellent safety profile as well. PPA is not a miracle worker, but will do the trick just as well as Meridia for a tiny fraction of the price.
Another drug to look at is ephedrine. This is a similar drug to PPA (also called norephedrine) which has never been approved as a diet drug. It is sold strictly as a decongestant, but this has not stopped bodybuilders from using it as an energizer and fat burner. When combined with caffeine, ephedrine is at least as effective as Meridia and plenty of trials have showed it to induce .5 pounds more weight loss per week than a placebo (7). Like PPA, it is also just pennies a day to use. More trials need to be done to compare its safety and efficacy compared to PPA.
Redirecting the Quest for the New Phen-Fen
The pharmaceutical industry has basically failed at finding effective new drugs for treating obesity so far. With the prevalence of cheap and effective drugs such as PPA and ephedrine available, there is really no point in paying $100 per month on drugs that are potentially even less effective. I believe obesity research should refocus itself dramatically to get serious about finding effective treatments.
The Amgen studies so far on Leptin are not that exciting from a fat loss point of view. But they are helping to open the scientific window on the Leptin Resistance Syndrome that the obese seem to have. The story is similar to the insulin resistance picture seen in some types of obesity. But leptin clearly won’t live up to the media’s hype as the new cure for obesity.
One absurd aspect of the research on diet drugs is that 99% of the studies only measure weight loss instead of fat loss. The key to long-term weight loss is keeping the muscle, so only measuring total weight loss is quite useless. New studies should measure both fat loss and muscle loss using new advances in body composition measurement. I believe ephedrine and/or PPA–the Beta adrenergic drug category will prove superior to most diet drugs in this aspect, as thermogenic drugs have been shown to have a strong muscle-sparing effect during dieting. The diet drug industry needs to radically refocus itself from weight loss to fat loss, a concept easily understood by bodybuilders but still somewhat mysterious to diet drug researchers.
Another aspect of diet drug research should be on how to “cycle” diet drugs for optimum effect. The concept of “cycling” drugs is old hat for bodybuilders. The idea is that the human body will adapt to most drugs if taken for too long, so you will get more effect from drugs if you take them intermittently rather than continuously. One study on Phentermine lasting nine months showed that a group taking this drug intermittently in a one-month on, one month off pattern actually lost slightly more weight than a group taking phentermine continuously (7). Since few diet drugs have been shown to induce weight loss for longer than six months, perhaps intermittent “cycles” could prolong the effects of these drugs. Future research should emphasize this concept.
These are just a few ideas for finding an effective treatment for obesity. In Part II of this series, I will go into more detail about what the research says about diet drugs and outline my personal suggestions for fat loss drugs and supplements.
- Weintraub M, et al. “Long-term weight control study, I-VII”. Clin Pharmacol Ther. 1992 May;51(5):586-94
- Mcneely, Wendy, and Goa, Karen L. “Sibutramine: A Review of its Contribution to the Management of Obesity”, Drugs 1998 Dec 56(6) 1093-1124
- Scheen, AJ, and Lefebvre, PJ. “Pharmacological Treatment of Obesity: Present Status”, Int J Obes Relat Metab Disord. 1999 Feb;23 Suppl 1:47-53
- “OMR Meridia Survey Results” Obesity Meds and Research News, Volume 3, Issue 1 January/February 1999 Supplement,
- Scoville, BA. “Review of Amphetamine Like Drugs by the Federal Drug Administration: Clinical Data and Value Judgement”, In: George Bray, ed., Obesity in Perspective. Washington, DC US Government Printing Office, 1973
- Greenway, Frank L. “Clinical Studies with Phenylpropanolamine: A Metaanalysis”, Am J Clin Nutr, 1992;55:203S-5S
- Hobbs, Larry, “The New Diet Pills” Pragmatic Press, Irvine, CA, 1995