lessthanhalf said:
The reality is there is zero science on stacking multiple GLP's. All there is so far is the high dose sema studies at 7.2 and 16mg, which showed no new unexpected adverse effects, not a lot of extra weight loss and a lot more GI side effects and skin sensitivity, and they approved 7.2mg sema.
In terms of stacking GLP's with amylin agonists there is the cagrisema studies that were generally disappointing , less effective than just tirz with a lot more side effects, and very preliminary results from tirz and elora that sound amazing.
The only advantage of stacking GLP drugs , reta/tirz/sema is to fiddle with the relative balance of the effects on the different receptors to try to achieve slightly different effects to the drug on its own, you might for example be able to tolerate a slightly higher total GLP drug dose by adding some tirz to 12mg of reta, rather than increasing the reta dose above 12mg for example, as reta has a bit worse GI side effects and more skin sensitivity, and the tirz has stronger GIP agonism that might reduce GI side effects from the reta.
A lot of people just do it to experiment without any really obvious rationale, especially at lower doses, but it can still be useful to maximise effects/side effect ratios. Everyone seems to believe tirz is better for food noise, so it must be true, so often this is used to justify combining reta with tirz.
After a year of side effects from low dose sema, I was pleasantly surprised by how few side effects I had with tirz at 15mg, and was still hungry after losing 70kg a couple of years before, so I added in reta 5mg rather than swapped to it as it seemed like a lower risk of stuffing things up approach. And dropped another 13kg or so in the next year. I cannot increase current doses of either reta or tirz without getting much worse skin sensitivity side effects, so I added in a bit of cagri to see if it made me less hungry, 0.5mg/w, maybe? No bad effects from a year of reta/tirz yet, maintaining at 55% weight loss, Hb1ac dropped from 5 to 4.5 ( not diabetic, but originally had highish fasting sugars ) , lipids improved, but on statins ezetimibe so not possible to see glp effect.
All things being equal I do not think there is a big difference in going to higher than standard doses of tirz or reta or combining them, with the exception being if one causes more or less side effects, then it makes more sense to swap to it or use a combination. Maybe low dose sema added in makes sense, but given overall it is a lot less effective for a lot more side effects, adding more reta or tirz makes more sense most of the time.
Overall, adding in elora to tirz is actually studied , so despite the results being way too early, it does seem very promising, and by analogy this applies to reta plus elora, or if availability or cost is an issue cagri. Adding in a drug working on an entirely different receptor system makes more sense to avoid the diminishing returns problem. Cagri plus sema did not show a lot more weight loss than just sema, but elora plus tirz showed an extra 11% over 32 weeks over just tirz - this is the only really solid evidence for substantial additive extra weight loss of any combination. I strongly suspect reta/elora and tirz/elora will be the state of the art treatment for severe obesity, ( may even replace most bariatric surgery ) and maybe even less severe obesity, as lower total doses of each might produce better results at lower rates of side effects , than higher doses of one drug. But it will need studies, and the cost might be the biggest problem, for those not using grey sources.
At this point the safety of high doses of reta or tirz or their combinations are not known, given how well the pharmacology of them is understood, and the high dose sema studies it is unlikely there will be extra unexpected side effects from higher doses or combos, but not zero risk. My usual logic on this is high doses or combos are really only needed in severe obesity where max doses did not produce adequate weight loss, and it is probable that the risks of this residual obesity are probably higher than the risks of the drugs to treat it. The drugs themselves reduce mortality in high risk groups and many specific medical problems, this positive effect is very likely to far outweigh the possible negative effects of high doses or combos. So far there is evidence that maximum doses are more effective than lower doses at preventing diabetes or heart disease, no evidence on higher doses, but this is a bit reassuring, and it is possible that higher doses reduce mortality and cardiovascular disease even more, but info on this is very unlikely to happen anytime soon.
The definite disadvantage of higher doses or combining reta and tirz is the diminishing returns problem. Where past a certain point more drug just causes more side effects but no extra weight loss. This is obvious from the high dose sema studies, but this data does not exist for reta or tirz yet other than one paper I found analysing projected effects from higher doses of different GLP's, but despite the lack of evidence there is zero doubt the effect is real, just at what doses it becomes obvious is not yet known, and quite likely it is dependent on individual responses, where maximum tolerated doses are higher in those with relatively less side effects or weight loss at standard maximum doses.
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