Sema progress so far

ottozStrategy

ottozStrategy

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A few weeks into sema, I figured I'd write some of this down instead of only watching the number on the scale.

During the first 2 weeks, the main thing was feeling full a bit earlier, nothing else really stood out. Once week 3 came around, I realized I was passing on snacks almost automatically. My meals are still about the same, but that nagging pull to eat something in between meals has clearly eased up.

The scale is dropping gradually, and that's okay with me. For anyone who's been on sema for a longer stretch, did your appetite shift continue intensifying as time went on, or did things settle down once the first few weeks passed?
 
Welcome to the forum!! Sema worked really well for me. At last I could get some kind of handle on what I was eating. I'd done Keto for years with results that went back and forth, so having the food noise disappear was truly a relief. My one regret is that I raised my dose too quickly. I was impatient to drop all the weight right away!! Losing 2 or 3 lbs a week felt too slow, so I climbed to the max dose too soon. Once I'd been on the max dose for roughly 6 months, I stalled out. Had I only increased the dose when I stopped losing 2 to 3 lbs per week, I could have remained on it longer and shed even more weight with it. In the end I made the switch to tirzepatide and reached my goal weight and then some. I've just reduced my maintenance dose once more so I can put a little back on.
 
swimmer said:

Welcome to the forum!! Sema worked really well for me. At last I could get some kind of handle on what I was eating. I'd done Keto for years with results that went back and forth, so having the food noise disappear was truly a relief. My one regret is that I raised my dose too quickly. I was impatient to drop all the weight right away!! Losing 2 or 3 lbs a week felt too slow, so I climbed to the max dose too soon. Once I'd been on the max dose for roughly 6 months, I stalled out. Had I only increased the dose when I stopped losing 2 to 3 lbs per week, I could have remained on it longer and shed even more weight with it. In the end I made the switch to tirzepatide and reached my goal weight and then some. I've just reduced my maintenance dose once more so I can put a little back on.
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That genuinely helps a lot. It’s clear how tempting it would be to just keep raising the dose whenever the scale stalls more than you’d like. And the idea of leaving yourself room down the line really lands.
 
gooterp0t said:

Ties or Reta are the better drugs—make the switch.
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Jumping straight to Reta is overkill, like nuking one guy instead of just taking him out. There's no reason to hit all 3 receptors at once when starting with 1 delivers the same health perks and avoids the extra danger.
 
swimmer said:

gooterp0t said:

Ties or Reta are the better drugs—make the switch.
Click to expand...
Jumping straight to Reta is overkill, like nuking one guy instead of just taking him out. There's no reason to hit all 3 receptors at once when starting with 1 delivers the same health perks and avoids the extra danger.
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Just so you know, none of the big three have shown any signs of receptor burnout.
 
ladyj779 said:

swimmer said:

gooterp0t said:

Ties or Reta are the better drugs—make the switch.
Click to expand...
Jumping straight to Reta is overkill, like nuking one guy instead of just taking him out. There's no reason to hit all 3 receptors at once when starting with 1 delivers the same health perks and avoids the extra danger.
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Just so you know, none of the big three have shown any signs of receptor burnout.
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I suppose it comes down to how you define receptor burnout. A tolerance does build up, and to me that counts as a form of burnout. That tolerance is exactly why titration exists, and it's also why a plateau tends to show up eventually. It's well documented that once you stop a GLP1 medication and then start again, it isn't nearly as effective. I'd call that a kind of receptor burnout too.
 
gooterp0t said:

Ties or Reta are the better drugs—make the switch.
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Semaglutide works well and is a completely reasonable choice. Just because something is newer doesn't mean it's the better pick.

As for our OP: Sema treated me well until my coverage ended and I had a gap without it. After that, when I tried grey Sema, it didn't do anything for me, so I made a switch. I stuck with grey sema for 4 months with zero effect. I would have been perfectly happy staying on it.

The starting dose of 0.25mg exists so the body can get used to the medication. Even at 0.25mg, I felt some appetite suppression. Watch the official dosing guidelines closely. Research has gone beyond the original 2.4mg maximum. Whether it's been approved above that number, I can't remember.

Good luck!
 
ottozStrategy said:

gooterp0t said:

Ties or Reta are the better drugs—make the switch.
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Since I'm still at an early stage with sema, I'd prefer to first observe how my body reacts before I consider making a change.
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You aren't even settled on your starting dose yet.

Building up in your system takes 4 weeks, so before titration you should keep seeing solid results.

There are people who swear by sema and like it better.

Let's see if we can summon @chmuse in here to preach...
 
Skidude said:


You have not even leveled off with initial dose.

It takes 4 weeks to build in your system, so you should expect continued good results before titration.

Some people swear by sema and prefer it.

Let's try to get @chmuse in here to preach...

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Did I overlook anything?

Sema handles what it's supposed to, and it does that effectively — is that the right response?

Once I'm not rushing to pack for a flight, I'll give a proper reply. ilu
 
Way too soon to tell what's going to happen, and you haven't said what your goal is. Are you aiming to drop 100kg or 10? What about age, height, starting weight, goal weight, that sort of thing? Normally people bump the dose every 4 weeks. Honestly I think the standard sema schedule is pretty poorly put together and ought to move slower, so 0.25mg, 0.5mg, 0.75mg, 1mg every 4 weeks and so on, because a few of those dose jumps are too large, particularly since sema has the worst side effect profile. So if you stick with the standard schedule, appetite suppression ought to get better as you go up in dose, but you can always tweak it based on how much weight you're dropping, how hungry you feel, and what side effects show up. Check out Glp1plotter, it shows what the medication is doing inside your body, which makes figuring out what's happening a lot simpler, and the reason doses go up every 4 weeks is that's how long blood levels need to settle after a dose increase.

My view is that once you're on sema you may as well continue and see how well it works for you instead of trying to switch at this stage, and finding out will take months. The reason you'd switch would be bad side effects plus still being hungry or not losing, or you've plateaued at max dose or can't go higher because of side effects, yet you still have weight to lose.

There is zero evidence of tolerance to the weight loss effect of GLP drugs. There is some tolerance that builds very slowly to gastrointestinal side effects, so starting on the weakest GLP and then moving to tirz then reta is just nonsense. Same with saving room to increase doses later. If you're losing at a rate you're happy with, and hunger is controlled well enough that you don't feel like you're starving yourself to lose weight, then stay at that dose. But if you're hungry all the time then raise the dose until you aren't, so sticking to your diet long term is easy to tolerate.

If you are severely overweight, then tirz or reta might have been a better option to start with, if you want to lose 25% plus body weight, and you might need to swap later if you stop losing weight on sema, but since you started on sema why not find out if it agrees with you or not. Overall tirz has the lowest rates of side effects, then reta, then sema, but everyone has different responses to them. There is one study I saw that showed some people lose more weight on sema than tirz, depending on their initial blood levels of GLP-1 and GIP, but overall average weight loss at maximum doses at a year and a bit is around 15% for sema, 25% for tirz and 30% for reta.
 
lessthanhalf said:

Way too soon to tell what's going to happen, and you haven't said what your goal is. Are you aiming to drop 100kg or 10? What about age, height, starting weight, goal weight, that sort of thing? Normally people bump the dose every 4 weeks. Honestly I think the standard sema schedule is pretty poorly put together and ought to move slower, so 0.25mg, 0.5mg, 0.75mg, 1mg every 4 weeks and so on, because a few of those dose jumps are too large, particularly since sema has the worst side effect profile. So if you stick with the standard schedule, appetite suppression ought to get better as you go up in dose, but you can always tweak it based on how much weight you're dropping, how hungry you feel, and what side effects show up. Check out Glp1plotter, it shows what the medication is doing inside your body, which makes figuring out what's happening a lot simpler, and the reason doses go up every 4 weeks is that's how long blood levels need to settle after a dose increase.

My view is that once you're on sema you may as well continue and see how well it works for you instead of trying to switch at this stage, and finding out will take months. The reason you'd switch would be bad side effects plus still being hungry or not losing, or you've plateaued at max dose or can't go higher because of side effects, yet you still have weight to lose.

There is zero evidence of tolerance to the weight loss effect of GLP drugs. There is some tolerance that builds very slowly to gastrointestinal side effects, so starting on the weakest GLP and then moving to tirz then reta is just nonsense. Same with saving room to increase doses later. If you're losing at a rate you're happy with, and hunger is controlled well enough that you don't feel like you're starving yourself to lose weight, then stay at that dose. But if you're hungry all the time then raise the dose until you aren't, so sticking to your diet long term is easy to tolerate.

If you are severely overweight, then tirz or reta might have been a better option to start with, if you want to lose 25% plus body weight, and you might need to swap later if you stop losing weight on sema, but since you started on sema why not find out if it agrees with you or not. Overall tirz has the lowest rates of side effects, then reta, then sema, but everyone has different responses to them. There is one study I saw that showed some people lose more weight on sema than tirz, depending on their initial blood levels of GLP-1 and GIP, but overall average weight loss at maximum doses at a year and a bit is around 15% for sema, 25% for tirz and 30% for reta.
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There's some truth to what you're saying:

Desensitization does occur at GIP receptors, and glucagon receptors can behave similarly. That makes things more complicated than a straightforward GLP-1 picture.

GIP receptor

When GIP receptors are stimulated over the long term, clear functional desensitization shows up across multiple tissues:

In fat cells, sustained GIPR activation causes the receptor to desensitize in a way that functionally resembles GIPR blockade. This mechanism is well documented (backed by both in vitro and in vivo research) and helps account for why long-acting GIP agonists and GIP antagonists alike can both lower body weight in preclinical studies.

In pancreatic beta cells, newer findings indicate that prolonged exposure to GIPR agonists (tirzepatide included) triggers substantial homologous desensitization of the human GIPR. After that, the receptor responds less to further stimulation.

Based on certain trafficking and signaling studies, the human GIPR seems more susceptible to this than the mouse receptor.

So while it was earlier claimed that GLP-1 receptors exhibit minimal clinically relevant desensitization, GIP receptors genuinely do adapt at the receptor level when agonism continues. This adaptation varies by tissue and may even play a role in the therapeutic benefit seen in fat tissue.

Glucagon receptor

Agonist-induced internalization and β-arrestin recruitment also happen at glucagon receptors, which can lead to desensitization. With triple agonists like retatrutide, certain acute effects (such as slowed gastric emptying) diminish over time as tachyphylaxis develops. The energy-expenditure and hepatic actions of GCGR agonism are believed to last longer, though human data on receptor-level response loss over the long term is still scarce.

How this ties into the plateau discussion

Whether the agonist is dual (GIP/GLP-1) or triple (GIP/GLP-1/glucagon), the clinical weight-loss plateau that emerges after many months is still chiefly the result of the same homeostatic pressures covered earlier—lower energy expenditure, hormonal counter-regulation (leptin, ghrelin, etc.), and the body defending a new set point—not a broad, opioid-like progressive loss of receptor responsiveness. Receptor-level shifts do happen (particularly at GIPR), but they aren't the primary reason the scale stalls around month 12–18 at a steady high dose.

To put it briefly: chronic use does desensitize GIP receptors (and to a lesser degree glucagon receptors) in ways that pure GLP-1 receptors do not as noticeably. That is genuine pharmacodynamic adaptation. It remains mechanistically separate from classic opioid tolerance, and it doesn't completely explain the usual late weight-loss plateau.
 
I'm not trying to argue against the receptor data you've got — it's obviously more current than what I've read. But when it comes to practical or clinical reality, what I lean on for saying there's no meaningful tolerance to the weight loss effects of GLP drugs is the 5 year tirzepatide study, where people on a constant dose had an average weight that stayed flat across 4 years of follow up — SUMMIT, I believe.

The plateau in weight loss seems easy enough to account for. After a substantial amount of weight comes off, energy expenditure drops and hunger rises. So as you get closer to the new weight neutral point, a growing share of what the GLP drug is doing goes toward holding off regain against those shifts. Eventually there's no calorie deficit left to drive more loss — partly from lower energy expenditure, partly from eating more because weight loss has made you hungrier. If you're already at the maximum dose, then that's the most weight loss that drug can deliver without going past dose recommendations or adding other drugs. This is just the same issue viewed from the opposite side — not receptor physiology, but the practical, measurable effects on the person taking the drug.

The way these drugs behave is strange. With almost any other drug that acts on GPCR receptors, you can't simply flood them with levels far above physiological and count on useful effects — with many of them you'd more likely get overdose or death. Yet GLP drugs sit near maximal receptor saturation essentially all the time, acting at levels 10's to 100's of times those of the natural peptide agonists and for much longer. I'd have expected receptor systems to have evolved to respond optimally to the range of agonist levels seen physiologically, not to levels drastically higher than that.
 
Yeah, this is really interesting.

With continued agonism, GIP receptors do undergo desensitization through adaptation at the receptor level. In fat tissue, that adaptation may even play a part in the therapeutic effect.

According to preclinical studies, this desensitization on its own helps lower fat mass and body weight. That explains why, in animal models, long-acting GIP agonists and GIP antagonists can end up with comparable weight-loss outcomes. Wild!! This is nothing like the opiate tolerance I had in mind.
 
I recall coming across a paper showing that both GIP antagonists and agonists can lower body weight, and honestly I couldn't fully track the reasoning at the time and have lost most of the details since, yet it remains genuinely strange to me, since I can't think of another drug or receptor that behaves this way. On its own it doesn't accomplish much either, the earliest GIP agonist trials produced only minimal weight loss, so for years it was largely disregarded, but once combined with GLP-1 agonists the effect becomes quite different and synergistic. If my memory serves, the odd situation where either antagonists or agonists at GIP receptors produce results depends on GLP-1 receptors being active, since the two mostly sit on the same cells.

Also, glucagon antagonists had been explored before for lowering blood sugar in diabetes, which did work but brought side effects such as raised liver fat, whereas now, when paired with GLP-1 agonism, glucagon agonism performs very well as an antidiabetic agent that brings blood sugars down, which is roughly the reverse of what basic physiology would lead you to predict.
 
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