SVT810E said:
I’m awfully skeptical of his claim that split dosing leads to receptor downregulation and a loss of clinical effect. It’s extremely speculative and not supported by actual trial data.
You know we had a split dosing study done for semaglutide, with daily dosing of all things. If split dosing lead to receptor downregulation and a loss of clinical effect we’d expect to see worse results than we do in weekly dose studies, but we don’t. They got the same sort of results you’d expect to see with semaglutide weekly. Check it out yourself: https://gwern.net/doc/longevity/glp/semaglutide/2018-oneil.pdf
Thanks for that link . I was not aware this study had been done so I will be reading it.
This relates to the comments by Ironbull.
Unfortunately the fact that someone has a medical degree, does not automatically mean that their views are supported by scientific evidence. The louder, more controversial or even more popular they are the more likely they are to be talking BS. This seems to be especially the case in the US where celebrity / influencers often have strong financial motives to support particular products or simply to provide controversy to increase engagement with their posts/videos, and there seem to rarely be any professional consequences for Doctors using these systems to promote unscientific viewpoints. I personally am grateful that this is less of an issue in Australia, where doctors can face professional consequences for supporting unproven or potentially dangerous therapies for personal gain or otherwise.
There is nothing in the pharmacology of these receptors or drugs that indicates that peaks and dips are needed for effects, it just does not make sense on a mechanistic level. Yes weekly dosing was chosen partly for convenience, but this makes sense, making it easier for patients to remember their dose is a good idea , it increases compliance by requiring less frequent injections and without complex reminder systems to remember 5th or 6th daily dosing which I know from experience is much easier to mess up. And increased compliance makes the drugs work better in real life, which is the point, rather than being aimed at maximising compliance for maximising profit.
Most drugs for long term administration have more stable blood levels than weekly glp's, usually being dosed more often than the half life, as generally most drugs benefit by having consistent levels and consistent effects. For me I prefer more frequent use than weekly to reduce side effects for a given weekly dose. I was able to tolerate 0.8mg of semaglutide a week by second daily dosing of 0.22mg , but was unable to tolerate a weekly dose of 0.55mg, any higher than either of these doses caused very unpleasant nausea, and 0.2mg/2days provided improved hunger control than 0.5mg/week.
Given the research was done , it make sense to follow their guidelines, as there is information about what to expect. If there are no problems and it works there are no sensible reasons to change it. More frequent smaller doses are entirely aimed at reducing peak blood level side effects for a given dose, you could use it if effects wore off after 5 or 6 days or you could just increase the weekly dose in that case. The vast majority of experience from frequent smaller doses is online and not in studies, it is unfortunately not very reliable evidence , but nothing I have seen suggests there is any difference in the effects on weight if it is used weekly or more often for a given weekly dose.
