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.
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.
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.
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.
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.
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.
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.
>[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.
The confidence intervals thing is probably a good idea, but I have no idea where to start on that, really,
Basically you have no idea about which extrapolations are reasonable to make and do them anyway in spite of having no idea what’s reasonable to do.
If you don’t think you understand the subject well enough to give confidence intervals I don’t think you understand it well enough to give any extrapolations that have any usefulness.
The idea that an “objective” number that’s clearly wrong is better then a more subjective that factors in more knowledge is also flawed.
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.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.
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.
The safety information I had came from here.
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.
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
Keep in mind that these drugs cause weight loss by way of causing dietary changes.
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.
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.
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.
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.
Basically you have no idea about which extrapolations are reasonable to make and do them anyway in spite of having no idea what’s reasonable to do.
If you don’t think you understand the subject well enough to give confidence intervals I don’t think you understand it well enough to give any extrapolations that have any usefulness.
The idea that an “objective” number that’s clearly wrong is better then a more subjective that factors in more knowledge is also flawed.