lessthanhalf said:
Ahmyrlynd said:
As the title says, stacking — is it a good thing or a bad thing?
Clearly people do it, but what are the potential downsides? The reason it happens is that one GLP isn't doing the job for them, whether for appetite suppression or for keeping the weight coming off, so they add a second one and hope that does it — I've seen this across every GLP. I asked somebody on another platform why they'd add another GLP rather than adding, or at least trying, Cagrilintide first? No logical answer came back.
I'm not aware of any studies (I'd love to read them if they exist) covering anything but Mono-GLP use? Short term — and this is opinion only — there would seem to be benefits IF the side effects stay tolerable. Those side effects would probably persist, and likely worsen. Longer term it would likely??? come out worse overall, once you've hit your goal and are trying to hold the weight steady ie;(insulin resistance/metabolic function etc). No personal experience & I haven't tried it, these are nothing more than thoughts & or opinions.
Any thoughts, feedback or personal experience would be very welcome.
Many thanks
Truth is, stacking multiple GLP's has zero science behind it. What exists so far is the high dose sema studies at 7.2 and 16mg: no new unexpected adverse effects, not much extra weight loss, considerably more GI side effects and skin sensitivity, and 7.2mg sema got approved.
On stacking GLP's with amylin agonists, the cagrisema studies were broadly disappointing — less effective than plain tirz with far more side effects — while the tirz and elora results are very preliminary but sound amazing.
The one advantage stacking GLP drugs — reta/tirz/sema — offers is fiddling with how much each receptor gets hit, in pursuit of a slightly different profile from the drug alone. You might, for instance, tolerate a marginally higher total GLP dose by adding tirz to 12mg of reta instead of pushing reta past 12mg, since reta carries slightly worse GI effects and more skin sensitivity, and tirz has the stronger GIP agonism that may take the edge off reta's GI effects.
Plenty of people do it purely to experiment with no obvious rationale at all, particularly at lower doses, though it can still help maximise the effects-to-side-effects ratio. Everyone seems to believe tirz is better for food noise, so it must be true, and that often gets used to justify combining reta with tirz.
Following a year of side effects on low dose sema, tirz at 15mg surprised me with how few side effects it brought — and having lost 70kg a couple of years earlier I was still hungry, so instead of swapping over I added reta 5mg in, which looked like the lower risk of stuffing things up. Another 13kg or so came off during the following year. Neither reta nor tirz can go up any further without my skin sensitivity getting much worse, so I tried a bit of cagri to see whether it curbed hunger, 0.5mg/w, maybe? A year of reta/tirz has produced no bad effects so far, holding at 55% weight loss, Hb1ac down from 5 to 4.5 (not diabetic, but fasting sugars used to be on the high side), lipids improved, though with statins ezetimibe in play the glp effect isn't visible.
All else being equal, going above standard doses of tirz or reta, or combining the two, probably doesn't make a big difference — the exception being when one of them generates more or fewer side effects, in which case swapping or combining makes better sense. Low dose sema added in might be sensible, but seeing as overall it buys a lot less effectiveness for a lot more side effects, adding more reta or tirz is usually the smarter move.
Overall, adding elora to tirz actually has been studied, so even with the results far too early it looks very promising, and by analogy the same applies to reta plus elora, or cagri where availability or cost is the obstacle. Bringing in a drug that works on an entirely separate receptor system makes more sense for sidestepping the diminishing returns problem. Cagri plus sema did not deliver much more weight loss than sema alone, 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. My strong suspicion is that reta/elora and tirz/elora will become the state of the art treatment for severe obesity, ( may even replace most bariatric surgery ) and perhaps for less severe obesity too, since lower total doses of each might give better results with fewer side effects than higher doses of a single drug. Studies will be needed, though, and cost may prove the biggest problem for anyone not using grey sources.
As of now the safety of high doses of reta or tirz, or their combinations, isn't known; given how well understood their pharmacology is, and the high dose sema studies, extra unexpected side effects from higher doses or combos look unlikely — but the risk isn't zero. My usual reasoning here is that high doses or combos are really only needed in severe obesity where max doses failed to produce adequate weight loss, and the risks of that residual obesity are probably greater than the risks of the drugs treating it. These drugs lower mortality in high risk groups and ease many specific medical problems, and that benefit very likely dwarfs the possible downside of high doses or combos. So far the evidence says maximum doses beat lower doses at preventing diabetes or heart disease, with nothing on higher doses — mildly reassuring, and it's possible higher doses cut mortality and cardiovascular disease further still, though information on that is very unlikely to appear anytime soon.
The clear downside of higher doses, or of combining reta and tirz, is the diminishing returns problem. Beyond a certain point more drug simply brings more side effects and no further weight loss. The high dose sema studies make that plain, though equivalent data for reta or tirz doesn't exist yet apart from one paper I found modelling projected effects from higher doses of the various GLP's. The lack of evidence notwithstanding, there is zero doubt the effect is real — what isn't known is the dose at which it becomes obvious, and it quite likely depends on individual response, with those suffering relatively fewer side effects or less weight loss at standard maximum doses tolerating higher ceilings.
