Ahmyrlynd said:
As the title says stacking, is it positive or negative?
Obviously people do this, but are there potential draw backs to doing it? It's being done because X(GLP) isn't working for them either appetite curbing or continuation of weight loss etc, so they add another hoping that does it and I've seen it with all the GLPs. I asked a person on another platform why they chose to add an additional GLP instead of adding or at least trying Cagrilintide first? I didn't get a logical answer.
I haven't seen any studies(if there are I'd love to read them) other than Mono-GLP use? Just in opinion only- it would seem that it would have benefits short terms IF side effects are tolerable. Those side effects possibly would continue and likely get worse. Lastly in the longer term, it would likely??? be more negative overall once your goal had been achieved and you now want to maintain weight ie;(insulin resistance/metabolic function etc). I don't know anyone personally & I have not done this, these are simply thoughts & or opinions.
Any thoughts, feedback or person experience is highly appreciated.
Thanks much
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When it comes to combining several GLP's, there is no scientific evidence at all. The only data available comes from high dose sema trials at 7.2 and 16mg. Those trials found no novel unexpected adverse events, only modest additional weight reduction, and a marked increase in GI side effects plus skin sensitivity. On that basis, 7.2mg sema received approval.
As for pairing GLP's with amylin agonists, the cagrisema trials were largely underwhelming — less effective than tirz alone while producing far more side effects — whereas very early data on tirz plus elora looks extremely encouraging.
The sole benefit of stacking GLP drugs (reta/tirz/sema) lies in tweaking the relative balance of receptor effects, in hopes of getting a slightly different profile than any single drug gives. For instance, you might tolerate a somewhat larger total GLP dose by adding tirz to 12mg of reta instead of pushing reta above 12mg, since reta tends to cause worse GI issues and more skin sensitivity, while tirz has stronger GIP agonism that could lessen the GI problems from reta.
Many people simply experiment with no clear rationale, particularly at lower doses, yet it can still help optimize the effects-to-side-effects ratio. There is a widespread belief that tirz handles food noise better — so it must be true — and this frequently gets 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 else being equal, I doubt there is much difference between escalating tirz or reta beyond standard doses versus combining them — unless one produces more or fewer side effects, in which case switching to it or using a combo makes more sense. Perhaps adding low dose sema is reasonable, but since it is overall far less effective with far more side effects, adding more reta or tirz is usually the better choice.
On the whole, adding elora to tirz has actually been studied, so even though the findings are far too preliminary, it does look very promising, and by extension this likely holds for reta plus elora, or cagri if availability or cost is a problem. Introducing a drug that acts on a completely different receptor system makes more sense for avoiding 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.
Right now, the safety of high dose reta or tirz or their combos is unknown. Given how thoroughly their pharmacology is understood, and the high dose sema trials, extra unexpected side effects from higher doses or combinations seem unlikely, but the risk is not zero. My usual reasoning here is that high doses or combos are truly needed only in severe obesity where max doses failed to deliver adequate weight loss, and the dangers of that residual obesity are probably greater than the dangers of the drugs used to treat it. These drugs lower mortality in high risk groups and help many specific medical conditions, and this benefit very likely far outweighs any possible harm from 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 clear drawback of higher doses or of combining reta and tirz is the diminishing returns problem — past some threshold, more drug merely brings more side effects without additional weight loss. This is plain from the high dose sema trials, though such data does not yet exist for reta or tirz apart from one paper I found modelling projected effects of higher doses of various GLP's. Despite the evidence gap, there is zero doubt the effect is real; what remains unknown is the dose at which it becomes obvious, and it very likely depends on individual responses, with maximum tolerated doses being higher in those who get relatively fewer side effects or less weight loss at standard maximum doses.
