You Can Get There From Here

Back in The Real Bathroom Scales, we learned that obesity has less to do with excess consumption than with insufficient energy expenditure, and that energy expenditure is very tightly regulated by our bodies, such that we cannot fool our fat-making machinery with simple changes to diet and exercise. Then, in my most recent post, Through Thick and Thin, we looked at a couple of major physiological determinants of that regulatory process—specifically, the degree of alpha and beta adrenergic stimulation and the amount of insulin our bodies produce. In this post, we’ll continue that discussion by examining a study of several drugs in the so-called “appetite suppressant” class, and look at how they really get the job done. “Back to the Future” Weight Loss TabletsUnless you’ve been living under a rock or aren’t yet 12 years old, you’ve no doubt heard of the infamous “fen-phen” diet drug combination. Fen-phen was short for Fenfluramine and Phentermine, two drugs classified as appetite suppressants, which were at one time heralded as the answer to obesity when used together. Unfortunately, the propensity of Fenfluramine to increase the risk of primary pulmonary hypertension resulted in that drug being removed from the marketplace, but fortunately, Phentermine is still available, and contrary to the mythology of the day, works just as well, if not better, by itself, than in combination with Fen. Some less well-known drugs in this class are Diethylproprion, Mazindol, Sibutramine, and more recently, Bupropion (Wellbutrin), originally intended as a smoking-cessation aid.  All of these drugs have a broadly similar mechanism—they alter the ebb and flow of neurotransmitters in the brain in such a way that thermogenesis is increased, either through direct stimulation of the beta adrenergic receptors or by inhibition of insulin release via the alpha adrenergic receptors. I’ll get further into the mechanics of these actions in another post, but for those of you who are looking for answers now, let’s get down to the brass tacks of what we can expect from drugs in this class. “Back to School” I’d like to review a study that compared the four most common diet drugs of its day (1981). In this study, researchers gave Phentermine, Mazindol, Fenfluramine, and Diethylpropion to four groups of mice, allowing them to eat freely as their respective appetites directed, for a period of 28 days. A group of unmedicated, ad libitum fed mice served as controls, while one other group, also unmedicated, were fed a restricted calorie diet for comparison. Although it is a mouse study and not a human study, I chose this one because of its excellent design, which eliminates the common confounding variables found in most diet drug studies, namely, caloric restriction and added exercise.  Due to the pervasive mythology about the cause of obesity, the vast majority of diet medications are tested in conjunction with a reduced calorie regimen and/or exercise program, which completely obscures the actual effects of the drugs. Since we know that reducing calories and increasing exercise causes both a temporary period of weight loss and a gradual metabolic slowdown, adding these variables into a medication trial is clearly…well, stupid! It makes a fair evaluation of the drug’s effects impossible to tease out. By allowing the subjects in this study to eat and exercise at will, the researchers were able to give a useful assessment of the drugs themselves. Weight Loss Tablets Okay, back to the study. As you can see in these graphs, all of the study treatments resulted in voluntarily reduced intake and some weight loss, but what’s important to note here is the relationship between the reduction in food intake and the amount of weight lost. Notice the bar lengths do not track—the highest intakes, relative to the control group, resulted in the lowest amount of body fat. Phentermine and Mazindol clearly offer a greater bang for the buck than Fenfluramine, Diethylpropion, and the standard caloric restriction. Here are the numbers as percentage reductions from control:
TreatmentIntakeFat WeightRatio
Low Calorie22.3%12.4%0.56
What this is telling us is that for the 22% reduction in calories experienced by the Low-Calorie mice, there was only a 12% drop in fat mass, relative to the controls, while for the lucky mice on Phentermine, there was a mere 6.6% decrease in intake, yet a whopping 15.9% decline in bodyfat, 2.4 times the change in intake.  Looking at the numbers this way, Phentermine and Mazindol are again the clear winners. “Get Your Back into It!” So where do these differences in results come from?  At the risk of charting you to death, let’s look at another interesting and critical statistic from this study:  energy expenditure. Weight Loss Tablets I keep saying that it is innate EE and not intake that ultimately determines our bodily fat content; well, here is more proof of that concept.  If you compare the body fat mass graph (above) with this EE graph, you will see that these bars do track–the drugs which induced the greatest energy expenditure (as measured during the six hours post-medication at four time points) resulted in the least fat mass.  Among these four drugs, again, Phentermine is the obvious star, raising EE by 43% over control. Before I leave this informative study, I would like to point out one more set of measurements the researchers made—body water and lean mass.  At this point, it shouldn’t surprise you to learn that only Phentermine and Mazindol increased both body water and lean mass by a statistically significant amount compared to control.  Good luck getting that result with any old low-calorie diet regimen! If the underlying cause of obesity is actually low energy expenditure and not high calorie intake, then isn’t the obvious solution something that increases EE rather than decreases intake?  From the results of this study, it should seem clear that a good diet medication will be a poor appetite suppressant and a powerful energy enhancer.