Perhaps vastly more people should be on FDA-approved weight loss medication

[-]ChristianKl4y140

The fact that there's a correlation between BMI and lifespan that coresponds to one point of BMI being linked to 0.7 years of lifespan doesn't mean that if you intervene and take a drug to reduce your weight you will gain 0.7 years of lifespan per point of BMI that you lower your BMI.

There's unhealthy behavior like eating sugar that does lead to weight-gain but it also messes up the insulin management.

It is, however, worth pointing out that the FDA is vigorous about pulling drugs that have been shown to have even small risks of causing life-threatening conditions

A drug can reduce your life span for by a few years if you take it over decades without "causing life-threatening conditions".

[-]25Hour4y40

Can you give any examples of that happening, where a drug reduces lifespan but not by causing any specific fatal effect?

[-]ChristianKl4y60

There's very little money into chosing causation in cases like this but sleeping pills would be one example.

In general many drugs cause the liver to have to do extra work and put stress on it.

[-]25Hour4y30

I suppose that's reasonable, though i will point out that this is a fully-general argument against taking any drugs long-term at all.

[-]ChristianKl4y30

Yes, you should generally minimize the amount of drugs you take long-term.

[-]25Hour4y80

I suppose. But it's also true that you should minimize the number of debilitating medical conditions you're suffering from long-term.

Which brings us back to the thing where we end up having to choose between a chronic condition which is heavily correlated with a whole bunch of secondary health problems and reduced life expectancy, and being on a drug from which we have not (yet) observed long-term ill effects.

The back-of-the-envelope life expectancy calculations were mostly just there to point out that under most plausible assumptions, the risk/benefit calculations seem lopsided to the point where it shouldn't be a terribly difficult decision.

[-]JenniferRM4y50

This conversation has basically recapitulated most of the ideas that lead to the antagonist pleiotropy hypothesis, except over "conscious lifelong health interventions" instead of over "blind mutations retained by natural selection".

Short term wins often have long term costs.

As clever hack piles on top of clever hacks, the combinatorial explosion of possible interactions goes up pretty fast.

Once wins of this sort pile up, your functional planning horizon shortens. At some point you just say "X will almost certainly get me before the bad parts of Y gets me" and you do Y anyway? But eventually the house of cards topples over.

If your lifelong health meta-strategy is aimed at still being able to ski when you're 85, you probably want to minimize pills in general? Find tiny repeatable actions with numerous positive effects that fit into a weekly routine in a way that adapts to a variety of contexts and have many positive effects and stick the adherence? Green veggies? Walk a mile every day? And so on?

If you're overweight and 51 and smoke and are pre-diabetic and walking gives you back pain and you'd still prefer to die in ~12 years of a new thing rather than in ~4 years from the thing your doctor recently mentioned... sure... try some pills maybe? Or maybe bariatric surgery? Lots of stuff works locally in the short run, and the long term, in general, often can't be touched without running into a morass of interlinked complexity.

[-]25Hour4y30

This is an interesting argument! I certainly acknowledge that if you can become non-obese via purely dietary means, that is best.

I wonder whether your analogy holds in the circumstance where dietary means have been attempted and failed, as often happens judging by the truly staggering number of posts online on this very topic-- whether becoming non-obese via medication constitutes a short-term win outweighed by long-term detriments, and whether the effects of the pills turn out to be more harmful than the original obesity it was meant to treat.

But it's not totally clear to me that you have attempted to make an affirmative case for this being true, as opposed to suggesting it as a pure hypothetical.

[-]gilch4y*120

the existence of effective anti-obesity medications is not particularly well-known

I had at least heard of the ECA stack (ephedrine, caffeine, and aspirin) before. It's available over-the-counter. The prescription meds were news to me though.

Is ECA effective? Yes. Bodybuilders are rumored to use it while cutting. Studies show you lose an extra two pounds per month. Is it safe? At reasonable dosage, yes, relatively. It's not going to kill you or cause psychosis, ~~depression~~["serious psychiatric events"], or seizures [EDIT: see comments below], but side effects can be unpleasant, including nausea, vomiting, and anxiety, so the ephedrine is kinda restricted. You have to sign for it, and in some places the amount you can get per month is limited. I'm not desperate enough to try it yet, since fasting is keeping my weight under control so far.

the amount of life-years you can expect to gain over the long term by losing that much weight.

Do these drugs actually reduce all-cause mortality? Or are we just guessing based on a proxy measure? Is it the extra weight per se that causes the poor health or is the weight just an obvious side effect of some other underlying metabolic problem that the drugs are doing nothing to address? Inflammation? Insulin resistance? Micronutrients? Toxins? Gut flora imbalance? Fatty liver? Something else? Diet might fix these, while drugs might not.

[-]lionhearted (Sebastian Marshall)4y100

There's a very thorough paper published in the American Journal of Epidemiology, "Use of a prescribed ephedrine/caffeine combination and the risk of serious cardiovascular events: a registry-based case-crossover study", DOI: 10.1093/aje/kwn191

Apparently, and this really surprised me,

"Use of prescribed ephedrine in Denmark — Letigen was a pharmaceutical product containing 20 mg of synthetic ephedrine and 200 mg of caffeine, available only by prescription. Its recommended dose was 1–3 tablets per day, depending on the user’s tolerance. It was approved for sale in Denmark in 1990. During the peak of its use in 1999, some 110,000 persons, corresponding to 2% of the Danish population, were treated. In 2002, the marketing license was suspended, after a number of reports had suggested a safety problem."

So there's a pretty big sample there.

Now note, I'm not a doctor and this just my opinion — it seems that some people should never take ephedrine under any circumstances (certain heart problems or family history of certain heart problems, etc) and anyone else ought to be really quite careful taking it if it's legal and approved in one's jurisdiction.

Ephedrine increases metabolic activity and thermogenesis — heat production — and it's more dangerous when it's hot outside, when you're doing any aerobic activity, or if you've had any other stressors on one's heart or get into other contraindication with stressors.

Speculatively, it seems possible that safety rates in Denmark might be higher than elsewhere since it doesn't get very hot there. If you compared someone using ephedrine/caffeine in Siberia in the winter to Dubai in the summer, the increased thermogenesis and physically radiating more heat might seem like a beneficial side effect in an arctic blizzard whereas both uncomfortable and dangerous under a desert sun.

[-]gilch4y20

The safety information I had came from here.

RAND reviewed adverse events reported in 52 published randomized controlled clinical trials. No serious adverse events (death, myocardial infarction, cerebrovascular/stroke events, seizure, or serious psychiatric events) were reported in the clinical trials. However, evidence from the trials was sufficient to support the conclusion that the use of ephedrine, ephedrine plus caffeine, or ephedra plus caffeine is associated with 2-3 times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations. The contribution of caffeine to these symptoms cannot be determined.

There seems to be a disagreement in the literature about the facts. This one had randomized controlled trials. Maybe the sample size was too small though? In that case, are the "suggestions" of a safety problem enough to be a concern? How strong were these suggestions? Obesity also increases risk of death. Perhaps ECA still wins on net cost-benefit. Maybe the risks are very small. Death is a very serious side effect, to be taken very seriously, unfortunately, many over-the-counter medications we use routinely carry this risk. Degrees of risks matter. Maybe the ephedrine was correlated but wasn't the cause. We'd need the numbers, and maybe more statistical know-how than I've got.

[-]25Hour4y20

Oh, I'm guessing based on purely correlational studies, with all the uncertainty and fuzziness that implies. Added a disclaimer to the relevant section to this effect, since it's worth calling out.

That said, I'd be shocked if the whole effect was due to confounders, since there are so many negative conditions comorbid with obesity, along with the existence of some animal studies also pointing in the direction of improved lifespan with caloric restriction.

Unfortunately, we don't have the ability to run controlled studies over a human lifespan, so we end up needing to do correlational studies and control for what we can. It seems like a bad idea to simply throw up our hands in complete epistemic helplessness and say that we don't know anything for sure; we need to act in the presence of incomplete information.

Also, re: the specific point of

Diet might fix these, while drugs might not.

Keep in mind that these drugs cause weight loss by way of causing dietary changes.

[-]gilch4y*20

Is that really how all of them work? In the case of ECA, I thought it was due to increased metabolism. But it might also have an effect on appetite.

And even when it is, is that good enough? It's possible for dietary changes to promote weight loss, but still be unhealthy. If you just eat junk food, and then the drugs reduce your appetite so you eat less food, but it's still junk food, then technically that's "dietary changes", but you're still not getting the micronutrients, fiber, prebiotics, and possibly bacteria that you would from fruits and vegetables. To the extent that the poor health is caused by excess Calories, it helps. But to the extent that poor health is caused by eating the wrong things, then simply eating less of them can only go so far.

Of course, I expect that using the prescription drugs as directed would be a last resort after dietary improvements prove insufficient, but doctors can only do so much to influence behavior.

[-]25Hour4y10

Whoops, sorry, I don't actually know anything about ECA. Possibly that's how it works, at least partially! I'm pretty sure it's true that stimulants are appetite suppressants, but it's also possible it has another mechanism of action having to do with non-exercise activity thermogenesis or similar.

Anyway: the way I was thinking about this is, obesity is caused by excess calories. That being the case, there's no particular reason to anticipate obese people wouldn't be getting appropriate amounts of fiber/micronutrients/etc; or at very least, I have not heard anyone make such a case.

So while it's definitely true that drugs wouldn't help with nutritional deficiencies, it's also not clear to me that this is necessarily relevant to the health impacts of obesity.

[-]ChristianKl4y10

It seems like a bad idea to simply throw up our hands in complete epistemic helplessness and say that we don't know anything for sure; we need to act in the presence of incomplete information.

Pretending you know something that you don't is not something you want to do in the presence of incomplete information.

In this case you would want to look for studies that actually look at the lifespan effects of successful weight loss. Estimating confidence intervals to be more explicit about one's uncertainty is also helpful.

[-]25Hour4y20

I feel my disclaimer in the post:

>[Note: as pointed out by comments below, extrapolation to life-years saved is very speculative, since all the studies on this in humans are going to be confounded all to hell by healthy user bias and socioeconomic correlations and the like. That said, it feels like a fairly reasonable extrapolation given the comorbidity of obesity to various extremely problematic medical conditions. Be warned!]

should be sufficient to exempt me from charges of "pretending to know things."

The confidence intervals thing is probably a good idea, but I have no idea where to start on that, really, since the confidence intervals would be mostly driven by "how confident am I feeling about using correlational studies on health outcomes to make causal claims about the effects of a treatment" more than any objective factor.

I'm not actually sure about whether a study looking at the effects of successful weight loss on mortality would be all that helpful for this conversation, since that would still end up being a totally correlational study with enormous error bars and confounders, and successful long-lasting weight loss isn't very common (itself which will introduce yet more confounders). Also I don't think such a study exists.

[+]ChristianKl4y-80

[-]Josh Jacobson4y60

I haven’t fully understood why weight loss drugs are so little used in the US given the health effects of being overweight/obese either. I think it’s good that you’ve shined a light on this and your overview is helpful guidance to someone getting oriented. Many aspects of this feel aligned with my research on the topics.

That said, Plenity (https://www.myplenity.com/) is a non-drug option that looks particularly promising and should potentially be at the top of the list here.

I haven’t looked into the longevity effects of weight loss yet myself, but the treatment here seems pretty unsophisticated and strikes me as likely incorrect. The cited study appears to be correlational rather than causal (only read the abstract, could be wrong). Additionally I would expect that age at which you lose weight has an impact, for example, and last I read a BMI that was borderline healthy/overweight is actually what maximizes longevity. I think there’s significantly more work to be done before the longevity conclusions would seem well-substantiated to me.

That said, I think putting numbers on it is totally fine and a good thing to do as directional information, I’d just prefer their (seemingly high) uncertainty was highlighted.

[-]Elizabeth4y*30

The mechanism for Plenity, a dry cellulose matrix that expands with water, seems extremely promising, but the experimental results don't seem that good even when selected by the manufacturer. The one study has weight loss of 6.4% of body weight with Plenity vs. 4.4% with placebo, over six months. Given the publication biases, that's nothing.

That said, I think the metrics used for most weight loss studies, including this one, are wrong. The control and treatment groups were on equally calorie-restricted diets, and my belief on hearing the mechanism was never that Plenity would accelerate calorie deficits (although it might smooth out sugar spikes), it's that it would make calorie restriction more bearable, which the study doesn't seem to have checked for (which is normal for weight loss studies).

A second argument I'd consider is that weight loss is held back by different things for different people, and Plenity is extremely good for a handful of people for which satiety is their main problem. I don't see anything in the paper that would suggest that, but it does seem possible.

[-]25Hour4y20

Also, good point about highlighting the uncertainty; I've added a disclaimer to that effect at the beginning of the section.

[-]25Hour4y20

All fair points! That said, I think extended lifespan is a very reasonable thing to expect, since IIRC from longevity research that caloric restriction extends lifespan (from animal studies); this seems like a very natural extrapolation from that.

[-]gilch4y20

I think metformin was supposed to have effects similar to caloric restriction, and does appear to reduce all-cause mortality, even though most users are diabetic.

[-]Josh Jacobson4y10

Surgical options may be useful for some as well. https://care.diabetesjournals.org/content/32/4/567.short

[-]romeostevensit4y*20

have there been any updates on the wellbutrin (edit: meant metformin) front? My understanding is that berberine has a similar mechanism of action and is OTC.

[-]25Hour4y20

Oh, Wellbutrin (bupropion) is totally a thing you can use for weight loss, and is even found in Contrave (one of the drugs I listed) for that reason. Lesser effect, though, since its weight loss effects are additive with naltrexone.

Berberine is one I hadn't heard of before; unfortunately I can't find any articles discussing its use in weight loss.

[-]romeostevensit4y20

whoops, meant metformin. Always confuse those two.

[-]25Hour4y10

Not a drug I've looked into! I ended up confining my research into FDA-approved weight loss medication, so I probably missed a number of non-FDA-approved medication that also works for weight loss.

[-]noggin-scratcher4y20

Is topiramate taken on its own expected have any noteworthy diet/appetite/weight-loss effects? I know someone who's on it to try and control their migraines.

[-]25Hour4y50

Yup! It's branded as "Topamax", but I've heard that some users refer to it as "Stupamax" because of the brain fog effect. It doesn't sound awesome.

Also, it sounded like it increases probability of getting a kidney stone by a lot, though I'd need to track down the reference. All told, feels like one of the worse options out there.

As far as I understand it, "combination" drugs don't really do anything together that each component doesn't do alone. For example, bupropion causes weight loss if you take it alone; it just causes more when you pair it with naltrexone, which also causes weight loss.

[-]noggin-scratcher4y10

God to know, thanks.

I could have imagined a case where the weight-loss effects were coming solely from the phentermine, with topiramate added to the combination for other reasons. But it having its own independent/added effect makes sense. For the person I know taking it, her appetite does seem quite reduced since switching from amitriptyline (I think that one increases appetite, so there will have been a double-effect from switching off that and onto something that suppresses it)

The brain fog is unfortunate, but also still less bad overall than the migraines were.

LESSWRONG
LW

LESSWRONG
LW

59

Perhaps vastly more people should be on FDA-approved weight loss medication

59

59

Introduction

Quantifying Life-Years Saved by Losing A Certain Amount Of Weight

Weight Loss Drug Studies

The Drugs (at least, the better ones)

Conclusion

FAQs

Giving a life-years-saved number for if someone takes a drug implies they'll be on it forever. But what about the unquantified risks of being on some drug for the rest of your life? Especially semaglutide, which hasn’t been around very long?

Isn't just eating less a much healthier and better-proven means of weight loss than pills?

Isn't this just a way of letting lazy people off the hook?

If these meds are so great, shouldn’t I have heard about them by now?

I had bad experiences on phentermine.

[Insert Certification Body Here] doesn't think [Insert Drug Here] passes a cost/benefit analysis, even though the FDA does.

Shouldn’t we just, as a society, just develop a healthier culture around food? Wouldn’t that be better than medicating ourselves?

Aren’t you, personally, just a lazy trash-person?

I found a factual error in this post.

Are you a doctor? You're a doctor, right? You’re probably a doctor, so I should take this as medical advice.