THE BLOG

Weight Loss and Wonder Drugs: Something Is Fishy

07/21/2010 11:50 pm ET | Updated Nov 17, 2011

Having diabetes is not normal. Neither is having atherosclerosis, hepatitis, Parkinson's disease or malaria. Bringing the full force of modern medical advance to bear in efforts to prevent, treat and cure these conditions is fully justified.

Not so weight gain, however. Weight gain, alas, is normal. And there, folks, is the rub: you can't necessarily fix what ain't broken.

To be sure, obesity is a "problem" both personally, and at the level of public health -- and it can, indeed, seem as if something is broken. But what? Taking a surplus of calories and turning them into an energy reserve may not be it.

Throughout most of human history, calories were relatively scarce, and physical activity unavoidable. Survival required the work of muscles.

So to survive through all the ages that preceded the electronics revolution, the industrial revolution and the advent of agriculture, Homo sapiens were of necessity a pretty fuel-efficient lot. And in particular, our forebears needed the means to get through all-too-frequent rainy days. Like most animals dependent on an uncertain food supply, most prior generations of our own species experienced occasional feast, and periodic famine.

You can, in principle, store food from periods of abundance for periods of want. But nature tends not to reward those who take chances on such things as the vagaries of food preservation. Nature rewards survival strategies that are slam-dunk reliable. It rewards those strategies with survival -- and the chance to pass along the genes, and traits that fostered survival to the next generation.

Among these traits, clearly, was the ability to store food not outside the body -- but in it. That, in essence, is what body fat is all about. To be sure, we need some body fat for basic biological functions. But the fat reserves that come and go with calories are an energy storage system. Body fat is, in essence, the safest, surest, most reliable place to store today's surplus calories against the advent of a rainy day tomorrow.

So when calories in exceed calories out, it is, in a word, normal for a human body to turn that surplus energy into body fat. What isn't normal -- at least in the context of time-honored human experience -- is that the rainy day never comes. A surplus today is followed by a surplus tomorrow, and the next day.

It is in this context -- human bodies getting heavy not from behaving "badly" but from behaving as they always have, and in essence should -- that we best consider the most recent news about weight loss drugs.

There are currently three new weight loss drugs in the front of the queue for FDA consideration -- Qnexa, Contrave and lorcaserin -- and all of them made news this week.

Perhaps the lead news item is that an advisory panel to the FDA recommended against approval for Qnexa, a drug that combines phentermine (an amphetamine) and topiramate (an anti-convulsant). The drug produces weight loss, but at a cost in brain function -- impaired concentration and memory loss -- the advisory committee deemed too high. (I am tempted to consider that people taking the drug simply don't remember to eat, but that may take things too far.) The FDA is likely to follow the advice of its expert panel on this one.

Contrave is in the news at the moment only by association. This drug, a combination of the antidepressant bupropion and naltrexone, a drug used for treating addiction, comes up for its own FDA review later in the year. It appears to be slightly less effective than Qnexa, and perhaps slightly less encumbered by side effects, although nausea appears to be common enough to be rate-limiting.

The third drug, lorcaserin, which influences brain serotonin levels, was featured in a clinical trial just published in the New England Journal of Medicine. Most news reports seem to be putting a positive spin on the trial, which found the drug produced a 5 percent or greater weight loss when combined with a lifestyle intervention more often than the lifestyle intervention alone. But half of the study participants dropped out, and the rather modest weight loss achieved in those who remained lasted reliably only as long as they kept taking the drug. Half who stopped the drug gained back the weight, despite the lifestyle intervention. The drug company that sponsored the trial waxed optimistic, but honestly, I am much underwhelmed.

Anyone surprised by this most recent and potentially discouraging installment is either a perennial optimist, or hasn't been paying much attention. Because the history of weight loss drugs is a litany of disappointments, large and small. From the infamous demise of Fen-Phen, a combination antidepressant and stimulant that caused heart valve damage (due, most now concur, to the 'Fen,' or fenfluramine, not the 'Phen,'or phentermine which has reappeared in Qnexa), to the 2007 decision by the FDA to deny approval for rimonabant, the most promising weight loss drug to come down the pike in some time. FDA almost certainly got it right, however. The European Union approved rimonabant, then withdrew it from the market after noting a marked rise in the rate of depression and suicide among those taking it.

When one considers that the problem we are asking weight control drugs to fix -- a body turning surplus calories into an energy reserve -- is normal human physiology, the conclusion that they may prove to be elusive not just now, but forever, is hard to avoid. And if so, there may be much lost in waiting for them, namely opportunities to turn what we already know about the power of feet and forks over weight into policies, programs, practices and resources that can do what drugs may not.

None of this is to deny the important insights that will doubtless derive from the scrupulous pursuit of scientific details relating to weight control. Rather, it is to note we miss the forest- the fundamentals of human metabolism in native context -- for the densely clustered hormonal, neurochemical, and genetic trees- at our evident peril.

Stated differently, even as we analyze and attempt to compensate for the peculiarities of gills in a creature gasping at the air- we should not fail to see the fish. And just maybe devote our best efforts... to putting it back in the water.

Dr. David L. Katz; www.davidkatzmd.com