I don’t think that analogy works because after you lose weight your endocrine system has shifted to make you gain the weight back. You don’t have that problem with smoking or getting married. With weight loss, you have to spend the rest of your life trying to stay one step ahead of your biology. When you get married you don’t have to deal with people constantly trying to break up your marriage.
Plus a good % of people (I’ve heard up to 40%) end up fatter than they were when they started after a weight loss attempt. If doctors had a treatment for smoking and after 5 years almost none had stopped and about 40% were even heavier smokers than before that treatment would be banned. But using willpower for weight loss is still considered good advice. If statistically you are more likely to end up fatter than keep the weight off, is it really a good idea with today’s medical technology?
If medicine really wants to make a dent in the obesity epidemic they have to start separating obesity treatment into two phases; weight loss and weight maintenance.
Weight loss is (reasonably) easy. Expend more calories than you take in. There are thousands of studies showing we know how to get people to lose weight, and lots of people have done it on their own. Most people can lose most of their excess weight in 6 months or less with lifestyle changes. They just can’t keep it off.
Weight maintenance on the other hand, aside from obesity surgery I don’t know if there are any studies showing we know how to achieve this. As you lose weight your body changes to make you gain it back. Leptin goes down. Ghrelin goes up. CCK goes down. The enzymes that synthesize bodyfat are transcribed more. T3 goes down. The end result is appetite goes up, it takes more food to get full, you recover from being full faster, you have a lower resting metabolism and you have less energy for activity.
Leptin could be the real key to weight maintenance, but we will see. Measure someone’s leptin at baseline, then have them lose weight over 6 months, then give them leptin plus a leptin sensitizing agent to get their levels back up to what they were before the weight loss. There is some preliminary research showing that this works to reverse the appetite and metabolic changes that come with weight loss.
But sadly, it probably won’t happen anytime soon. We have the technology to both sensitize leptin receptors and provide leptin injections, but I don’t know if anyone is working on it as a large scale obesity treatment.
We do? First I have heard of a leptin sensitizer (other than exercise and prolong hypocaloric diet). A reference would be appreciated.
Don’t forget the most important long term impact item: preventing obesity in the first place. And frankly that’s where we are making the most progress.
Also recognizing that the enemy is not the obesity but the health consequences of obesity. Nice to prevent obesity and to reverse it before it has become entrenched, but also important to remember that the lon time obese adult does not need to become normal weight to achieve major health impacts. (Yeah I know, broken record.)
Interesting about TUDCA and 4-PBA. Symlin I could find something re leptin resistance on with some digging. (I can’t find anything on Byetta impacting leptin resistance directly though. It is a GLP-1 like drug which impacts insulin and glucagon release and gastric emptying as its touted main mechanisms of action. There are brain GLP-1 receptors but those seem to be independent of the leptin ones.)
Not so sure. The statistics for quitting smoking are also fairly dismal, although I don’t think people end up smoking even more if they fail to quit.
Also, 40% gain additional weight… but how much would they have weighed if they never went on the weight loss regime? Could be even more.
Actually this seems to me the perfect case of 100 grams of prevention being worth a kilo of cure. Then again, we know people have a hard time listening to health care providers when there are relatively immediate, serious consequences. Telling people to stop overeating before they’re even fat could well be entirely futile.
Well, looks like I have a lot of fun to look forward to. I’ll report back in five years whether I’ve been able to beat the odds.
You’re wrong about bariatric surgery, though: those patients also tend to regain a good amount, although less than people who lost weight without surgery.
You’re probably a bit optimistic about the losing phase, plenty of people fail there, too. But it would be great if we got a hunger suppression drug that could help maintaing weight loss, make doing it in the first place a bit easier and even work prophylactically. (Wow, can’t believe I spelled that correctly the first try!)
I don’t think it’s just the hunger, though, that makes people regain. Lots of people have really screwed up eating habits, and eating 1200 kcal/day for six months does nothing to repair that. So even if they’re not all that hungry they may not know any better than to either undereat or overeat.
Yeah, because a drug that you have to take to lose weight and then the rest of your life to maintaing that weight loss, there’s no money in that. Or maybe evil big food is killing the research.
People fail at the losing phase, but it can be done for a lot of people. You just expend more calories than you need (either a ton so you lose 3-5 lbs a week like in a vlcd or a little so you lose 1-2 a week). If the lifestyle changes aren’t enough you take a diet drug to help with weight loss (phentermine, topamax, xenical, etc). if that isn’t enough you can get a temporary surgery like a gastric balloon or endoluminal sleeve. As you lose more weight and get further from your set point your endocrine system fights back and further weight loss is obviously harder. On the show extreme weight loss people who weigh 400+ pounds might lose 100 lbs in the first 3 months. Then 60-70 the next 3. Then maybe 40 in the next three. Then maybe 20-30 the next three. But it can be done.
The problem is again, people have trouble keeping it off. There are likely thousands of studies and hundreds of millions of individual examples of people losing large amounts of weight. But the maintenance phase is going to require a better understanding of how to trick the endocrine system into readjusting at the lower weight. Outside of surgery, and maybe a single study on 42 month usage of cimetidine, I don’t think I’ve ever seen a successful study on weight maintenance (and I don’t consider the national weight control registry a successful example because those people self select).
I don’t know why leptin is not being pursued as a weight maintenance drug. As far as I can tell it is only being looked into as an orphan drug for rare conditions. The market for leptin could make the market for insulin seem like chump change.
Well the stopper was leptin resistance. Rasing leptin levels tends to cause more of it so it ends up being a red queens race. Obesity is associated with high leptin but higher leptin resistance. More leptin results in more resistance.
That’s the big deal with your supplied references. It might need to be a two drug hit but decrease leptin resistance, even just prevent it worsening in response to more leptin being around, and then a leptin analogue might be a viable product.
Cost-wise and performance/safety-wise it has to at least compete with bariatric surgery surgery … not a given.
Are you talking about leptin for weight loss or weight maintenance? For weight loss it may not work alone, but since serious weight loss can result in leptin levels dropping 50-90%, using an injection to replace what your body stops making could put your metabolism back where it was before the weight loss and reverse most of the changes that lead to weight regain. I don’t know if leptin after a major weight loss to bring levels back to pre weight loss baseline causes the resistance issue, I have no idea. Leptin plus a sensitizer may be necessary to lose weight, but it seems leptin alone could be a maintenance drug. The only studies on sensitizers I can find are on mice.
Seeing how only about 1% of people who are eligible for bariatric surgery get it I think there would be a market for a less invasive obesity procedure. Daily injections are arguably less invasive than having your digestive system operated on.
Phentermine & an SSRI or Phentermine & Topamax can work to improve weight loss, I don’t think they are any drugs for weight maintenance. Weight maintenance seems to be the problem. If people only had to lose weight once then obesity wouldn’t be a problem.
This is the only study I’ve seen on a drug working for weight maintenance (42 months). Results weren’t bad, 15% of bodyweight was lost and kept off and 42 months is a reasonable window.
The paper itself seems to be behind a paywall, but I believe cimetidine works by increasing cholecystokinin production.
Heh. While sometimes a cigar is just a cigar (and t is next to r on the keyboard) it is pretty funny.
That is one of the oddest studies I have ever seen. Subjects self selected to be in a non-intervention or intervention group (dependent on motivation). The motivated intervention group had continued diet restriction, regular exercise, and intermmittent use of cimetidine; The less motivated non-intervention group … none of the above. Shockingly the less motivated people who did not continue with diet restriciton, who did not exercise (and who did not take a drug) gained weight back. This tells us what about cimetidine? This got published why?
Phentermine/Topamax extended release (Qsymia) has been studied in follow up use out for 108 weeks. Figure 2 is the part we want to look at. Weight loss, which was mostly achieved as much as it would go by 40 weeks out, was maintained at 108 weeks out continuing on the drug. Yes it would have been nice to have an arm comparing switch to placebo for the second year to demonstrate that without the med a large number regain the weight lost, but I think we can accept the historic precedence as likely.
From the article:
Does the effect of the med diminish with longer time of use? Unknown.
42 months of weight maintenance is pretty impressive. My impression is drugs don’t really work for weight maintenance, they just make you regain it slower. Over a long enough timeline you end up where you started, it may just take longer. The fact that people kept their weight stable at the lower weight evidenced by the loss of an additional 1-2kg over 3.5 years is pretty rare.
What that article tells us is that cimetidine could be a weight maintenance drug. A group motivated to keep the weight off who gets behavioral interventions is not going to have the level of success the cimetidine group did.
This is only partly true. The key is not complicated and people do it all the time, even if it’s a minority of people who lose weight:
They don’t lose weight by starving themselves, where the body tries to retain fat, which does indeed lower the metabolism because an increasing proportion of weight lost over time is lean mass (muscle) instead of fat - thus making it easier to regain weight when one resumes eating normally. This pattern is called yo-yo dieting. They lose weight by maintaining their metabolism to lose fat, and keep muscle (lean mass). By exercising while eating only a little less than maintenance calories.
I know this because I have done this myself - back in 2006, and lost 45 pounds in 7 months. I went from 242 lbs. to 194. Almost 8 years later I’ve gained back to 212 at one point last year, after basically losing the exercising habit after a prolonged injury and illness, but am now back down to under 200.
Select for the most motivated subpopulation, keep them on a calorie restricted diet coupled with exercise and a pill, and compare them to the less motivated group without any support back to regular diet? That tells you … that highly motivated people with ongoing calorie restriction and exercise can maintain weight loss. If they wanted to say anything about cimetidine they’d have divided them into cimetidine treatment and placebo both groups equally matched for motivation level and both getting the diet exercise support. Really really really odd.
Interestingly cimetidine for weight loss came up before, in 1993, and is used as a case study for the sort of work that should raise suspicion for scientific misconduct. Never proven. This one just is how to do a study wrong.
Then go find some studies where a motivated subpopulation can maintain a 15% weight loss for 42 months. Virtually all studies on weight maintenance are failures.
Sorry but it really is pretty basic: the point of an experiment is to have two groups as identical as possible and to try to vary only one factor, preferably with the groups blinded. Varying everything is useless.
Now sometimes you can take something suggestive away from a report without a control arm if it does much better than historic norms … like a case report of a patient cured from Ebola soon after administration of a medicine.
This is not that.
There just are not studies that have taken the group that has succeeded in losing weight and then selected for the most highly autonomously (self) motivated subpopulation and kept them on a prolonged hypocaloric diet and exercise program to compare to as even historic norms. We do know that autonomous motivation ishighly predictive of who succeeds in keeping it off though.
Honestly I have little doubt that we could, out of a group of individuals who have successfully lost weight, select for a subgroup that is the most highly self-motivated and keep them on a monitored prolonged diet/exercise plan and keep the weight off, with or without giving them a pill that they believed would help. If only everyone was above average for self-motivation, eh?
Weirder yet about this … study - 55 total subjects. 22 in the initial placebo group and opting for future non-intervention. 16 treated with the med and opted for additional active intervention, out of 22 who opted to be in the active intervention. 11 not accounted for. Maybe did not lose weight. Of course not all of that 16 were successful long term losers but more than half were … maybe 10? 12? 10 to 12 out of 55 total subjects lost weight and kept it off … pretty much in keeping with typical numbers.
What caught my eye here in the abstract (didn’t read the whole thing) is a very low calorie diet. Common sense has always been that losing the weight quickly makes maintaining harder (see below), but strangely, a bunch of papers tell the opposite.
I remember a lecture on Youtube that went along the following lines: people lose weight for about six months and then start regaining until they reach a stable weight. The curve starting at six months is basically the same for everyone, so the ones who lost the most initially end up with the most weight lost at the end of the process.
However, I have a very hard time believing that losing weight quickly is really a better idea than doing it slowly. Unless I’m severely misinformed, losing the weight quickly means losing more muscle, which means a lower base metabolic rate = you have to eat less to keep losing / maintain your weight. Also, a very low calorie diet doesn’t prepare you for eating like a normal weight person once you reach the goal weight. (There’s also the issues of fat soluble toxins being released quickly with fast weight loss and skin probably has a harder time “snapping back”.)
The only reason I can think of that explains faster loss = better maintenance that studies show is that everyone in the study tries to lose the weight quickly, and the people who are successful during that stage are also successful during maintenance, while the ones who try to lose weight fast but don’t quite succeed and thus lose it slowly, are the ones who also half-ass maintenance.
Or are there studies that compare maintenance between people who intend to lose quickly and are successful at that and people who intend to lose slowly and are successful at that?
Disclosure: I’m on team slow-and-steady, and so far (18 months) it’s working for me, although I still have at least 6 and probably 12 months to go before I switch to maintenance.
I do not know of studies like that and I think you have a very good point. Achieving your goal, be it rapid weight loss or more gradual loss, may be a marker for the self-motivation and discipline needed to achieve maintenance as well.
Meanwhile this, including this figure 2, might interest some. These were all people who lost over 10% of body weight. The average loss at the start of the maintenance phase was roughly 18% (and roughly 19 kg) down from peak before weight loss and even the control group stayed over 14% down at the end of 18 months. One finding was that ongoing face to face contact as an intervention resulted in a both a greater mean loss and more who did not gain 2.3 kg or more of their mean 19 kg losses back. Specifically the face to face intervention group was still on average almost 18% down from peak weight at the end of the 18 months and 43.8% of them gained back less than 2.3 kg. Another finding is that daily weighing was associated with better results. Personally my take is that this is a result of the same bit that you just brought up: those who are more self-motivated will be weighing themsleves more often, i.e. it is a marker of the motivation feature rather than a behavior that leads to the result. But who knows?
What’s really interesting about this study is that although the average amount of weight regained was pretty much the same for the internet based and no intervention groups, while the face-to-face group did much better, the number of people who regained was actually pretty close between the internet and face to face groups. So internet support is equally good at keeping people on track, but face-to-face does better limiting the amount regained for those who regain more than a token amount.
And apparently you really should weigh yourself every day (which I do) even though it can be hard to hang on to your sanity when confronted with significant daily fluctuations.
It seems to say that people who were formerly obese but lost weight are actually almost four times as likely to die within a given period than people who still are obese.
So what is killing all these people? Not their diabetes or heart disease, these get better when losing weight.
Annoyingly the writer of this post (I assume also involved in the research) talks a lot about reverse causalities, but fails to catch them here: are people dying because weight loss makes them sick, or are they losing weight as they die, from a disease that may or may not be weight-related?
Or maybe evil big food is killing the research.