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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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January 14, 2010

Gaining and Losing and Discovering and Selling

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Posted by Derek

Obesity has been one of those therapeutic areas that drug companies can't quite stay away from. A glance at the potential patient ranks, expanding in every sense of the word, is enough to explain why. But as I've detailed here in the past, finding an effective obesity drug is not easy, for many good reasons.

One response has been that such a drug wouldn't have to work spectacularly well to be effective, since calories add up so alarmingly. The "one cookie a day" model of weight gain is often referenced. But just how useful is it? According to this paper in JAMA (PDF), not so much (emphasis added):

How much weight would an individual gain by eating an extra chocolate chip cookie every day for life? One approach to answering this question, frequently used in textbooks and scientific articles, is based on the assumption that a pound (454 g) of fat tissue has about 3500 kilocalories (kcal). Thus, a daily 60-kcal cookie would be expected to produce 0.2 kg (0.5 lb) weight gain in a month, 2.7 kg (6 lb) in a year, 27 kg (60 lb) in a decade, and many hundreds of pounds in a lifetime. This of course does not happen. . .

So what does happen? If a person takes in a steady excess of calories, they most certainly will gain weight. But some of those extra calories then go into maintaining (and carrying around) that new weight. The result is a slow climb up to a new equilibrium weight. The 60-calorie cookie example above would be expected to lead to about 6 lbs of total weight gain over a period of years. Most of that will be put on early, with an asymptotic rise to the final value.

Now, if you're trying to avoid gaining weight, this is probably good news. The effects of having some extra food now and then aren't quite as catastrophic as the usual calculations would make you think (although there is that faster-weight-gain-at-first effect, so you have to separate the short-term and long-term consequences a bit). For someone that's significantly overweight and wants to lose it, the implications are mixed. One way to look at it is that the maintenance costs of extra body mass are substantial, meaning that a person doesn't have to suddenly go on a 1400-calorie-a-day diet to see results. Another thing this paper tells us that significantly overweight people have gotten to that point only by having significant calorie imbalances. A cookie a day is not going to do it. A lot of people are taking in a lot more excess calories than that:

These calculations suggest that small changes in lifestyle would have a minor effect on obesity prevention. Walking an extra mile a day expends, roughly, an additional 60 kcal compared with resting—equal to the energy in a small cookie. Physiological considerations suggest that the apparent energy imbalance for much of the US population is 5- to 10- fold greater, far beyond the ability of most individuals to address on a personal level. . .

The authors go on to call from greater regulation of the food supply, greater public health efforts, and so on, but I have to say that I'm skeptical of the ability of these to do the trick (or, given my political leanings, of the amount of coercion that might be needed to make them really work). It's clear that many people would like to be less overweight than they are, but (revealed preference time), it's also clear that they have enjoyed running up their caloric imbalances even more. So while the authors may be right that significant weight loss may be beyond most people's ability to address on a personal level, it's hard for me to see any other level that's really going to work.

So what would help? Would an anti-obesity drug? On the one hand, a good one might alter the physiological underpinnings of weight gain (and weight loss) in such a way to help people escape the squirrel-cage aspects of dieting and rebound weight gain. But that's asking a lot, and I remain uncertain about whether a really good weight-loss drug is even possible. The other difficulty is that any such treatment still has to be coupled with all those things that patients don't want to hear about: less food, more exercise. The time course needed is also a hard sell, particularly when you consider all the scam ads that bombard everyone. It seems clear that any sustainable weight loss probably should take about as much time as the initial weight gain did, which is not what many people are wanting to hear, particularly when someone else is promising umpteen pounds a week of magic weight loss.

Then there's the commercial consideration: that a new approved obesity drug, regardless of whether it works very well in the real world or not, would nonetheless sell like crazy. And if it doesn't work quite as well as the rigorously controlled clinical trials indicated it would, well, you can always blame the patients themselves (and for that matter, in many cases you'd be right). It's enough to make me think that the whole therapeutic area is a moral hazard.

Comments (32) + TrackBacks (0) | Category: Diabetes and Obesity


1. Tok on January 14, 2010 10:06 AM writes...

One step in the right direction would be shifting corn subsidies to fruit/vegetable subsidies. All those high fructose corn syrup empty calories would be priced where they should be, and fruits and vegetables would come down in price. No extra regulations, no extra taxes, just doing the same thing to something different.

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2. Hap on January 14, 2010 10:09 AM writes...

When I switched to diet soda from regular soda, I didn't lose any weight - I don't think I exercised less (difficult), so more likely I simply ate more and so didn't consume fewer calories. (also, see: seat belts). It's possible that any long-term obesity drug that works would simply enable people to eat what they want with fewer consequences, which would not be completely constructive. It's also been noted (in Better) that any useful obesity drug would probably increase the social sanctions on obesity - while that in itself might reduce obesity, it would more likely give society (yet) another way to destroy itself and cause more grief than it would remove.

An obesity drug that works would be useful for really overweight people, but would almost certainly be oversold to lots of people in whom the risk-reward balance is not beneficial. It doesn't seem reasonable either to ignore the people who could truly (medically) benefit or to ignore their potential for nonproductive use. Counting on pharma (or its customers) to restrain themselves is probably silly, and I don't think lots of people trust the gov't to do so. The anti-obesity field looks like an awful minefield.

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3. retread on January 14, 2010 10:16 AM writes...

As someone who weighed 40 pounds more in medical school, there are a few extra points worth mentioning. As you note, the 60 or so kiloCalories burnt off by walking a mile are trivial (but do realize that the heavier you are, the more calories you will burn). But in some way for most people (not my wife), exercise itself seems to be mildly anorexic, which probably accounts for a lot (if not all) of the weight loss it seems to promote. Not always, Syracuse NY had an annual short fat guys run for some charity or other. I think to get in, the waistline had to equal the inseam on the pants.

For people with hypertension, diabetes, hyperlipidemia etc. weight loss is nearly guaranteed to improve matters. I've seen this happen many times. People like being in control, particularly when ill, and I would tell them that they could do more for themselves with significant weight loss then docs could do for them with pills. Any (relatively safe) weight loss drug would be worthwhile medically. Keep on Pharmin'

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4. Stewie Griffin on January 14, 2010 10:43 AM writes...

I agree with Tok. I highly recommend reading "The Omnivore's Dilemma" as it is related to the topic of obesity. Why do I have to pay more for broccoli and spinach (high nutrients, low calories) than others have to pay for a cheeseburger (low nutrients, high calories)? It's because we subsidize corn. Although the cheeseburger is cheaper for the individual, the cost to society is greater (not only the weight gain, but also problems associated with fertilizing all the corn, taking care of the animal wastes, pumping cows full of antibiotics, etc). As a chemist I think an obesity drug would certainly be worthwhile. But as a citizen I just can't understand why we don't focus more on preventative measures...something as simple as making the healthy food the cheap alternative rather than making the unhealthy food the cheap food.

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5. Wavefunction on January 14, 2010 10:49 AM writes...

I never get a good feeling about these obesity drugs. While there would certainly be a market for them and they would be helpful under certain circumstances, as you hinted, it would just be another excuse for people to stay off healthy (and less) food and exercise. At some point we all need to realize that diet and exercise (and especially diet) are really the best way to go. An 80-year old uncle who has maintained the same waist dimensions and weight since he was 25 said he followed only two simple rules throughout his life; don't eat too much, and eat mostly vegetables (something along the line of Michael Pollan). No elevator there, we need to take the stairs.

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6. Hap on January 14, 2010 11:02 AM writes...

There are probably some people for who "eat less and exercise" isn't going to work, or isn't appropriate treatment for the problems they have. An obesity treatment would be helpful for them - it's the likelihood that it will be used on people who could lose weight by other means that might be a problem.

Lots of the evil people do would be best remedied by, well, not doing that, and yet we continue - hoping people will be better is not usually an effective method for changing much of anything. Removing the economic incentives to eating badly (the subsidies that decrease the cost of food that isn't good for us) would be helpful, but telling people that they should do what they already know they should do (but don't) doesn't seem like an effective strategy to reduce obesity.

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7. PharmaHeretic on January 14, 2010 11:07 AM writes...

The reality of weight gain is much more complex and involves muscle mass, levels of basal activity, source of calories etc.. but people like simple sound bites like calories.

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8. PJ Hansen on January 14, 2010 11:10 AM writes...

I have had concerns about how an anti-obesity drug would work in practice. The first concern is that the drug would be chronically dosed so very high safety margins would be necessary. Controlling appetite usually means a CNS active drug as well. If caloric intake is not reduced, the only approaches are to limit absorption, increase excretion, or boost energy consumption. The first two seem to offer unpleasant side effects. Boosting energy consumption would seem make patients either jumpy by using the energy or hot through uncoupling. I've always imagined the MTD of a successful anti-obesity drug in the lab to be the point at which the brown fat-pad begins to smoke.

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9. opsomath on January 14, 2010 11:24 AM writes...

I think you got it in one with the "moral hazard" line. That is an elegant and concise statement of the dangers of meddling with an issue so fraught with moral judgment in the public eye as weight loss. It's not like the pharma industry can really afford many more hits to their public image in this era of siccing the federal government on companies (justifiably or no) which arouse the anger of John Q. Public.

Also, add me to the list of people who think that we could make great public-health leaps by killing corn subsidies. I am a starving grad student trying to take care of a wife, a baby, and a mortgage on a PhD stipend - often I eat unhealthy 'cause eating healthy costs more.

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10. Anon on January 14, 2010 11:26 AM writes...

I remind the amphetamines were very effective at causing people to lose weight. Conscientious people were able to use them without getting addicted. It was only the exploitation by those attracted to drug abuse that caused this class to be pulled from the market.

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11. Little Miss Process on January 14, 2010 11:32 AM writes...

*personal opinion disclaimer*

Of course it's a moral minefield... How can it ever be remotely ethical to create and market a drug that allows the "haves", the 1/10ths* or so of the world's population, to stuff themselves even more silly with food, when the remaining 9/10ths, the "have nots", are starving?

I'm just so very glad I've never been asked to work on such a compound. I'd have real issues doing so.

* - I may have the figures slightly wrong, but you get my drift...

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12. claud on January 14, 2010 12:09 PM writes...

It is overly simplistic and misleading to the American population to think of weight gain as resulting simply from an over supply of calories and lack of activity. Modulating body mass for optimal health is much more complicated than simply eliminating fat and sugar and hitting the eliptical three days a week.

The body is a complex system and "fixing" one aspect without investigating another (like stress, disease, lack of sleep etc...) can only lead to temporary solutions.

For the morbidly obese, a drug to get them statred, in combination with excersize, good (complete!) nutrition and emotional therapy is probably not too bad.

For those of us who are just a little too saggy 'round the middle, obesity drugs would just be a crutch.

The real question is why is the US so fat? Is it our food? our stress? our amazing television programming that keeps us from going for a walk?

When i talk my collegues in Holland, they are amazed that I only get 2 weeks vacation. "How do you relax?" they ask....

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13. Little Miss Process on January 14, 2010 1:03 PM writes...

Obesity rates in the UK are approaching those in the US despite 4-5 weeks annual leave...

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14. milkshake on January 14, 2010 1:26 PM writes...

the drugs that turn on the thermogenic properties of brown fat could be effective. There were some promising results recently.

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15. Morten G on January 14, 2010 2:13 PM writes...

Not less food, more food! More food, less candy (sweets, white "bread", chips+fries, soda - all the things where we can't control ourselves once we start eating them and that we buy despite ourselves because we are hungry when we go shopping).
Exercise if we want strong, beautiful, useful bodies.

All of it personal opinion of course =)

How about botox or something along those lines in the tongue? Disabling the sweet sensation receptor for 3-6 months?

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16. Panch0 on January 14, 2010 3:34 PM writes...

Romania is introducing a new tax on unhealthy food. Migt be a good approach - will wait and see...

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17. milkshake on January 14, 2010 4:10 PM writes...

If the ATF agents want my French fries, they will have to prey them out from my cold dead hands.

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18. retread on January 14, 2010 6:13 PM writes...

One more time, forget the morality of letting the self-indulgent have such a drug, there are sick people out there who really need such a drug. It's not just diabetics, hypertensives, and hyperlipidemics, its the zillions of overweight people with bad backs, arthritic hips and knees, the overweight chronic lungers, the overweight wheelchair confined for whatever reason etc. etc.

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19. Kent G. Budge on January 14, 2010 8:00 PM writes...

I have lost at least sixty pounds in the last year. I lost the last thirty by strictly controlling total calorie intake and exercising for at least 50 minutes six days a week. My dachshunds were never so indulged in walks before. I guarantee it will work if you will do it.

Now for the rest of the story.

I lost the first thirty through diabetic ketosis, a kind of Atkins' diet via severe metabolic disturbance. It was the weight loss -- at a time when I was eating like a hog and moving like a sloth -- that forced me to take seriously the fact that I was peeing a lot, see a doctor, and get diagnosed with Type 2 diabetes. My blood glucose had been averaging 350 mg/dL up until then, based on my initial HgA1c. It's better now, though it will never be all better.

Motivation is everything.

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20. researchfella on January 14, 2010 10:13 PM writes...

PharmaHeretic (#7) is right -- body weight gain and loss, metabolism, and caloric storage are complex issues. A very interesting paper was just published showing different body weight gain in rats fed the same number of calories, but different fat vs carbohydrate ratio. Guess what? Those high fat foods ain't so bad. Rats fed with a high carbohydrate/fat ratio diet gained about 20% less weight than rats that were fed the same number of calories, but on a high fat/carbohydrate ratio diet. And this finding held true for two different calorie-load diets. And, the high carbohydrate/fat ratio diet resulted in a higher % fat mass body composition. So, back off the carbs and eat the fats! (At least, if you're a rat.) See Shankar et al., Endocrinology 151: 153-164, 2010. It would be nice to see more studies re: simple vs complex carbohydrate diets, measures of energy expenditure, etc.

I also agree with some of the other comments... the high-fructose corn syrup added to almost everything we eat could be a major factor in the obesity epidemic. But you need to fight the corn subsidies and lobbyists. We need some studies comparing weight gain for diets with complex carbs vs glucose vs sucrose vs fructose, at the same caloric level...

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21. Aspirin on January 14, 2010 11:38 PM writes...

While the actual relationship is undoubtedly quite complex, I doubt there's major disagreement that *generally speaking*, exercising regularly and watching carbs leads to healthier, slimmer lives with a low prevalence of diabetes and heart disease.