My lukewarm take on GLP-1 agonists
!Disclaimer: Please consult your doctor about taking or stopping GLP-1s!
I have friends across the lazy-slob to pumped-jock spectrum.
I try (and fail) to not prompt my friends into taking risky substances.
But, if I did, I'd suggest the laziest and slobbiest of them take PEDs... nothing too crazy: take a bit of thyroid hormone, short periods of low doses of a safe SARM, or maybe a supplement that lowers SHBG and an AI.
Just try it for a bit, test your hormone levels throughout, and see how it makes you feel.
Anyhow, I don't have to give unpromoted suggestions about taking drugs to my friends, because they ask me. Guess where the people who ask me about creating or ramping up a PED regiment fall on the slob to pumped axis?
That's right, they are all, without exceptions, the fittest motherfuckers I know. Genetically lean and agile, enjoying daily hour-long intense workouts, watching their diet... the only thing that concerns me about them is that they don't chill enough.
!Disclaimer: Please consult your drug dealer or an angry-looking hoodie-wearing meathead that can bench twice his bodyweight about taking or stopping PEDs!
Conversely, GLP-1s seem to be great for people who are obese, diabetic, or both. Thus I've seen an increased interest in them coming from... friends who are fit, metabolically healthy, and probably have single-digit body fat percentages.
On Side Effects
Beyond a point, side effects are kinda silly, bodies are very adaptable, we ingest hundreds of toxins every day, and taking this or that drug once is often not a big deal. Unless you're IV-ing anthracyclines for fun you should be fine trying most things once.
But using a drug chronically for months or years is another story, and the risk of side effects should be weighed against the benefits.
For example, over a ~68-week period, 2% of users developed antibodies with affinity to endogenous GLP-1s. These were classified as "non-neutralizing". (different source for a 1-3% number)
So "there is a low chance you develop antibodies to GLP-1" and "there is some uncertainty about how long they'll be around and what their effects are but they seem mild"... what's the downside? Well, through the fog of uncertainty, there's like a 0.n% risk that you actually seriously fuck-up your metabolism... probably not, maybe it's impossible, if not, it's rare. But, would you take the risk?
A (maybe motivated) database study that mixes multiple GLP-1s (semaglutide and liraglutide, which likely has a worse side effect profile), compares these drugs with taking a Bupropion + Naltrexone combination for weight loss in subjects with no other server conditions. And finds large increases in e.g. pancreatitis (9x), biliary disease (1.5x), and gastroparesis (3.3x).
A broader look at studies finds a much lower increase in serious adverse events, all of which are very rare. And otherwise mild side effects, for example:
Gastrointestinal side effects in patients with overweight or obesity without diabetes mellitus treated with once-weekly semaglutide versus placebo: Nausea 4x, Vomiting 4x, Diarrhea 2x, Constipation 2x, Cholelithiasis 2x
And there are more worrying increases in various markers related to pancreas and thyroid health, the kind of stuff that medicine doesn't track as a "side effect" in the same way increasing ApoB (roughly meaning "cholesterol") wouldn't have been tracked as a "side effect" 30 years ago.
Ok, time for a bit of Q&A:
Are these side effects negligible compared to the risks from morbid obesity or diabetes?
Fuck yeah, not even close.
Are these side effects ok as long as these drugs reverse borderline obesity or prediabetes?
Very likely, be careful, maybe ask your doctor, but this is a solid choice to try.
Are these side effects ok as long as you are metabolically healthy and have reasonably healthy body fat (healthy as in < ~25% not as in < ~10%... let's not mix health and aesthetics)?
Ahm, it depends on what you want, but... idk, probably not. Also, have you considered that there's roughly 0 evidence around what effects these drugs have for your demographic? And that the people they are tested in have wildly different hormone profiles than you?
I think current evidence indicates there's enough risk I'd want a noticeable reward. I'll gladly keep my vitamin D within optimal levels via supplements because there are essentially no side effects from doing that. But this is not a D3 supplement... it's not a super freaky recombinant hormone, it's not poison, it's not an antibiotic... but it's not nothing.
My Own Experience
I'm told people love illustrative anecdotes, so here's an anecdote for you:
I was quitting nicotine (switched to an unpleasant administration method and gradual dose reduction), and I had put on 2-4 kgs of fat past what I'd consider optimal (but also, my 90% CI on optimal is like +/-6kg).
Given the reported ability to help with addictions and weight loss, I thought I'd be a nice double whammy. Make it easier to stay off nicotine, avoid weight gain, and maybe even lose that extra weight without having to diet for a few months.
My own experience with semaglutide was trying it at a small dose for about a month (~0.2mg IM ~1 week apart, dosed three times).
I certainly noticed some gastrointestinal effects, nothing major but I was slightly nauseated on a few mornings (I never get nausea), and I had mild abdominal pain a few times. I was also a tad bit more sluggish, but it could have been the summer heat.
What I didn't notice was a reduction in weight or a reduction in my desire to eat. I didn't try very hard to eat less, but I tried a little bit, and the stomach discomfort made it less appealing.
As an interesting note, I'm pretty sure I know how to decouple "hunger" from "need to chew on yummy stuff", and I'm pretty sure my "hunger" went down, but that's never the reason I eat anyway... I eat because I like chewing on yummy stuff.
I also didn't notice any ease in quitting nicotine, actually, the reverse, I seemed to peak in using my rather unpleasant nicotine supplement 2 to 4 days after taking an IM dose (roughly when I'd expect peak blood concentration to be reached).
Now, I was intentionally not trying to exert maximal willpower, but I was sorta trying. And nicotine addiction is odd, especially if you have it since your teens, and it takes a long time to fully break -- But compared to my "control" of low-dose naltrexone and gritting my teeth, semaglutide was noticeably worse, if I had to bet, I'd say it had the opposite effect.
Now, granted, this data is inconclusive and mixed up, but that's the nature of any self-experiment. You have to mix phenomenological self-assessment with relatively little data and draw tentative conclusions.
But, happily enough, I was not running an RCT, I just wanted a reasonably confident estimate about whether or not this GLP-1 helped me lose weight or alleviate addictions.
Rather boring, I know, no deadly side effects, nor miraculous cures, just a mildly negative pitter-patter.
I'm not saying:
I'm a reasonably healthy person who wanted to take these drugs for optimization reasons, I don't think they work, therefore nobody should take them for such.
I'm just pointing out the chain of reasoning that got me to stop my experiment, I felt some mild side effects, I saw no benefits, and I made the rational move.
How to take GLP-1s (and drugs in general)
And this is somewhat obvious but I feel like a lot of people get so pumped up about this or that drug or supplement that they will psych themselves up into finding effects that don't exist.
... which is fine for vitamin d3, at most, you get an increased risk of kidney stones
But less fine for the side effect profile I've just outlined.
My point here is not to po-po GLP-1s, I think they're probably great.
But no treatment is without side effects, and I'd urge people who want to take these drugs to:
- Note that there are side effects
- Note that there are unkown unkowns
- Note that, if they are in a demographic that is neither obese nor diabetic, they are in a demographic for which little data exists, and effects might differ quite a lot.
- Note that they are too lazy to do their own thorough literature review. And that studies can lie and twist the truth. And any analysis comes with biases, if not outright motivated reasoning. So any conclusion around risks and rewards should have error bars.
This shouldn't lead one to not take the drugs, but it should prompt a chain of thought that goes something like this:
- What is my goal with taking this drug?
- Is this a good goal if I put my reasonable hat on and think about it for 10 minutes?
- Can I quantify this goal exactly, put a number on what I want to achieve? What is my stopping condition? What risks and negative effects am I willing to tolerate to get there?
- Try the drug, in a small dose, figure out the negative effects (if any), and track your goal... is the drug helping you get closer to it?
It's probably good to rinse and repeat these steps every few weeks.
Published on: 2024-08-26
