Smiter said:
The Core Problem: Patients are rarely on the same medication level twice during standard titration because these drugs have long half-lives and accumulate in the system (21:20-23:16). This often pushes patients above their therapeutic window , resulting in side effects without added weight loss benefits (24:50-26:30).
The concept of therapeutic window with GLP drugs is actually unusual. Most drugs act on receptor systems at between 0-100% of naturally occurring levels. GLP drugs are still doing the same at the receptors, but are at hundreds or thousands of times the effect of naturally occurring GLP-1, which never gets close to fully activating receptors and has a half life of minutes.
The therapeutic window of GLP drugs is not really based on the underlying pharmacology, it is determined by the clinical trials, where effects and rates of side effects were observed and decisions were made about what doses did a reasonable job at causing weight loss or blood sugar improvements at lowish rates of side effects. And for semaglutide it was decided on 2.4mg as the max dose for weight loss and either 1-2 mg for diabetes. They then did further studies at higher doses of 7.2mg and 16mg where there was a bit of extra weight loss but not a lot and much higher rates of side effects.They dropped plans for a 16mg dose, and kept 7.2mg as an option for poor responders.
So increasing doses of GLP drugs gets to a point where higher doses stop causing any extra weight loss, and side effects are increased by increasing doses. Because there seems to be a lot of variability in effects and side effects of GLP drugs between people individualised dosing is sensible, but is often not done for practical reasons. Having variable dose pens makes it more likely people will make errors, so the pens are designed to only give certain doses to prevent dose errors ( this can be gotten around by counting clicks ). Adjusting doses of these drugs based on effects and side effects is just what is normally done in clinical practice, adjusting doses precisely is hard for practical reasons ( with non grey GLP's ), but dropping doses for side effects is just everyday as is increasing doses to cause more weight loss.
But the results of the studies generally showed that with the dose ranges tested up to 2.4mg , higher doses caused more weight loss, and more side effects. Were there some people who could not tolerate 2.4mg, yes about 10% or so stopped, and in normal practice the dose should have been reduced rather than stopped. But his basic idea that a lot of patients are above the dose that causes maximum weight loss for them, and having side effects that are unnecessary, is not what was seen in the studies, and in the real world the answer to this problem is a lower dose.
Are there patients who cannot achieve adequate weight loss because doses are limited by side effects? Yes, it is extremely common, especially in severe obesity, and is an argument in favour of split dosing not against it, as a higher total weekly dose is likely to be better tolerated split into multiple doses than a single large dose that causes higher peak drug levels. And is exactly what I experienced with ozempic.
That the drugs accumulate in the system is not abnormal, all drugs do this, and the long half life allows weekly dosing and steady state levels are reached in about 4 half lives or 4 weeks for sema. He is implying that this accumulation is somehow a bad thing and causes problems, when it is how basically all drugs work, nearly all drugs aim to achieve stable blood levels, so that the effect of the drug is consistent over time, in this case you do not want to be hungry one day and not the next, and if side effects occur at peak drug levels like they do for GLP drugs then you want to minimise the peaks as much as possible.
I find those few sentences in the quote to be very irritating, it is using correct pharmacological terminology, but displaying a quite large degree of not really understanding the fundamentals of the concepts he is using, especially as applied to GLP drugs. It suggests he has not studied pharmacology at tertiary level, which is fine , so long as you then do not claim expertise. These fundamental misunderstandings of what is occurring at a molecular level allows him to reach conclusions that fly in the face of obvious evidence and the basic science from the GLP studies, and the idea that split dosing is less effective with more side effects is just plain wrong in every way, and just does not make sense scientifically. The idea that many on these drugs could lose as much weight at much lower doses is not supported by the studies. Patients are not kept on doses with intolerable side effects, unless their managing doctor lacks competence or is occurring as part of a clinical trial, and even the drug companies doing the trials have worked this out now.
