Does tirz really have an effectiveness window and should I try to dose up?

[Sarsippius]

Yeah, I just picked up a T30 kit. I'm not sure what to do with it yet. Do I add Tirz to the stack, or replace Tirz for Cargri or Reta, or just go to straight Tirz? I should probably start a thread about it.

 

[spanky2026]

The original Surmount trials showed the weight loss peaked over 72 weeks, and yes that is spoken of as the "runway". They also showed the higher doses (10 and up) are where the most significant weight loss occured. The pace of loss tends to slow at the one year mark (though not stop), which is why particularly for people with a lot to lose they do not advise abiding by the social media popular "low and slow" method.

 

[woundcarping]

Yeah, I just picked up a T30 kit. I'm not sure what to do with it yet. Do I add Tirz to the stack, or replace Tirz for Cargri or Reta, or just go to straight Tirz? I should probably start a thread about it.

I went from Tirz to Reta, rather cold turkey but used a bump of Tirz twice along the way… no big deal. I used frequent small doses to get through the loading phase of Reta quickly, with the target to get to 6-8mg levels as quickly as sides allowed.

I have a theory of transitioning from Reta back to Tirz for maintenance but I’ve still got several months to develop that theory.

Adapting your story to mine, I’d have increased my Reta dose before adding Cagri. Since you’re transitioning to appetite control only I’d drop to only Tirz and use Cagri prn to support the transition. I'd take frequent small doses based on appetite suppression and "feels" working my way to a presumptively therapeutic level then translate that level to less frequent (weekly or 2x weekly) maintenance dosing for the cruise.

 

[lessthanhalf]

You're going to have about a year before you buildup a tolerance and your appetite returns. Plan accordingly.

When this happens, after you have lost 125 lbs, it is a good example of where it looks like the medication is no longer working as well, or tolerance has developed.

Yes at this much weight loss hunger increases, but it is caused by your body's response to weight loss, not tolerance to the drug. And energy expenditure drops due to having less body mass lean and fat consuming energy plus a fair degree of metabolic adaptation to long term lower calorie intake. In combination these effects stop you from losing any more weight despite staying on the GLP. But importantly, if you stay on it you will not regain the weight, so it is just working to maintain a new lower normal weight and will keep on doing that if you stay on it.

Ideally you would like to be at your goal weight when this happens. If you are 6ft4in and want to get to a BMI of 25 for example that would be 90kg or 198 lbs, or 27lbs less than now. Obviously this depends on build / muscle mass. And if you started at 350 and are now 225 then you have already lost 35.7% of your starting weight. Which is a better result than anything ever produced in any GLP study, but reta and cagri have not been studied together.

You are already at max doses of reta and cagri, so there is no totally obvious way to get more weight loss. One solution is to try to be happy with what you have achieved, given it is about as good as bariatric surgery without the surgery part, and is enough to most get rid of the health risks from being obese, and in the long term maintaining that loss is much more important than losing more in terms of long term consequences. The reta/cagri combo is in theory about the best one that exists. Options at that point are either adding more reta or cagri or adding in tirz for a bit extra GIP agonism. Swapping to tirz is not really likely to help, options at this point probably depend on what side effects you currently have. Unfortunately pushing doses from where you are is starting to get into diminishing returns territory where higher doses or adding in tirz might cause more side effects without much extra weight loss.

 

[woundcarping]

You are already at max doses of reta and cagri, so there is no totally obvious way to get more weight loss...

The obvious choice for me was to increase the dose.

You're bang on about being well into the area diminishing returns. If the data isn't problematic (sides, blood work, RHR, HRV, sleep quality, etc), it's hard for me to argue against increasing the dose... especially split dosing to keep the peaks more subdued with the same area under the curve.

My take was to increase the dose sooner rather than later, under the premise that time isn't particularly on my side. It's not a race, but it's certainly not a lazy river.

On the high side outcome my equilibrium point is below my target weight, I titrated down to match my equilibrium point with my goal with no ill effects, and live my life as a high responder to Reta.

On the low side I'm irreparably damaging my receptors and my maintenance dose will have to be higher than it otherwise could have been, maybe.

On the abysmal side, elevated doses are later shown to radically shorten quality or duration of life and I've boned myself. Seems unlikely.

 

[lessthanhalf]

The obvious choice for me was to increase the dose.

You're bang on about being well into the area diminishing returns. If the data isn't problematic (sides, blood work, RHR, HRV, sleep quality, etc), it's hard for me to argue against increasing the dose... especially split dosing to keep the peaks more subdued with the same area under the curve.

My take was to increase the dose sooner rather than later, under the premise that time isn't particularly on my side. It's not a race, but it's certainly not a lazy river.

On the high side outcome my equilibrium point is below my target weight, I titrated down to match my equilibrium point with my goal with no ill effects, and live my life as a high responder to Reta.

On the low side I'm irreparably damaging my receptors and my maintenance dose will have to be higher than it otherwise could have been, maybe.

On the abysmal side, elevated doses are later shown to radically shorten quality or duration of life and I've boned myself. Seems unlikely.

Unless long term studies of reta show negative effects from glucagon agonism, then it is pretty unlikely. There is a lot of research on tirz , so new unexpected adverse effects are not very likely. And there was the 7.2mg and 16 mg studies on semaglutide, which unsurprisingly showed pretty high rates of nausea and vomiting, and not as much extra weight loss as they might have liked, but it did not show any new unexpected adverse effects, just higher rates of the usual well known ones. So for GLP-1 agonism , there is really very good evidence of no long term problems, even at doses that make me want to puke looking at them. Pretty good for GIP with tirz , and much earlier stage research for reta and cagri.

The only bit of research I have seen so far to suggest it might be possible to damage your receptors is the one there is a post about currently about stopping and restarting in mice causing problems, and less weight loss. There really are no other indications of long term problems, and weight loss was maintained for 5 years on a consistent dose with no trending up of weight over time at all, and if there was long term tolerance to the weight loss effects that graph would show increases in weight eventually.

 

[woundcarping]

Unless long term studies of reta show negative effects from glucagon agonism, then it is pretty unlikely. There is a lot of research on tirz , so new unexpected adverse effects are not very likely. And there was the 7.2mg and 16 mg studies on semaglutide, which unsurprisingly showed pretty high rates of nausea and vomiting, and not as much extra weight loss as they might have liked, but it did not show any new unexpected adverse effects, just higher rates of the usual well known ones. So for GLP-1 agonism , there is really very good evidence of no long term problems, even at doses that make me want to puke looking at them. Pretty good for GIP with tirz , and much earlier stage research for reta and cagri.

The only bit of research I have seen so far to suggest it might be possible to damage your receptors is the one there is a post about currently about stopping and restarting in mice causing problems, and less weight loss. There really are no other indications of long term problems, and weight loss was maintained for 5 years on a consistent dose with no trending up of weight over time at all, and if there was long term tolerance to the weight loss effects that graph would show increases in weight eventually.

That’s my take on it.

My “advanced” dose of Reta and titrating based on my observable data is calculated move, presumptively favorably tipping the odds of me losing 32-35% of my starting weight with minimal to no downsides.

 

[bellanoise]

So I have been doing 6 of tirz for 5 months now, down 35 lbs and would like to take off another 45 to get to goal-ish. I thought slow and steady was good because I lose at a consistent rate even if not a TON and I have almost no side effects. But then I saw somewhere that tirz weight loss tapers off after 72 weeks or so. If I’ve already eaten up a third of that window should I dose up to try to accelerate the weight loss? Add Reta if I can ever figure out how to order from China? I would hate to stall out…

I found my weight loss started to slow with tirz around the 1 year mark and then by 18 months I was losing at all, I was maintaining. I came off it completely for 3 months to get it fully out of my system then started a low dose of reta 3 months ago, I added in cagrilintide a month ago just to help with the food noise aspect a bit more (it's not as strong on ret as it is on tirz) and the weight is dropping again at around 2lb a week which is what I averaged on tirz I think giving my system a break and letting it reset fully before jumping back on a GLP1 was the key for me

 

[Jfrick11]

So I have been doing 6 of tirz for 5 months now, down 35 lbs and would like to take off another 45 to get to goal-ish. I thought slow and steady was good because I lose at a consistent rate even if not a TON and I have almost no side effects. But then I saw somewhere that tirz weight loss tapers off after 72 weeks or so. If I’ve already eaten up a third of that window should I dose up to try to accelerate the weight loss? Add Reta if I can ever figure out how to order from China? I would hate to stall out…

I think you've actually been approaching this in a more sustainable way than the " just keep titrating it up" crowd. One thing that helped me reframe this: that the 72 week number people quote (from trials like Surmount 1 trial) doesn’t mean the medication suddenly stops working. It just shows that weight loss naturally slows and plateaus over time, mostly because the body adapts, not because you’ve “used it up.”

Also, those studies titrate people up every 4 weeks for standardization, not because that’s the best approach for real humans. In real life, it makes more sense to match dose to response , not a schedule.

With something like tirzepatide, the goal isn’t to eat as little as possible, it’s to reduce hunger enough that you can create a sustainable deficit, and make better food choices. If you push the dose too high too fast, a few things can backfire:

You end up under eating protein = lose more muscle

Energy drops = you move less without realizing

Fat loss slows and it feels like the med stopped working

So instead of trying to outrun a plateau, a more effective strategy is:

Use the lowest effective dose that keeps hunger manageable

Prioritize protein and resistance training to protect lean mass

Keep daily movement up (NEAT matters more than people think)

Reassess intake periodically as your body weight changes

Tracking can absolutely help, but don't kill yourself being overly obsessive.... It isn’t really realistic, and being consistent and directionally accurate is enough.

Also, you don’t have to treat this as one long sprint. Building in periods of maintenance can actually help reduce that body defending effect over time and make the whole process more sustainable.

Bottom line: you’re not burning through a limited window. You’re building a foundation. Going slower with good habits in place often gives better long term results than pushing dose aggressively and dealing with side effects or muscle loss later.

 

[Wecandothis]

So I have been doing 6 of tirz for 5 months now, down 35 lbs and would like to take off another 45 to get to goal-ish. I thought slow and steady was good because I lose at a consistent rate even if not a TON and I have almost no side effects. But then I saw somewhere that tirz weight loss tapers off after 72 weeks or so. If I’ve already eaten up a third of that window should I dose up to try to accelerate the weight loss? Add Reta if I can ever figure out how to order from China? I would hate to stall out…

This was me a while ago, I felt the tirz wasn’t working anymore so I added a little Reta, and as I increased the Reta I decreased the tirz. I am below goal now, Reta helped me get there.

 

[Grogu]

The 72 weeks is just the longest follow up that has been done so far, and shows that the weight loss is maintained for that time if the person stays on the drug at the dose they used to lose the weight.

72 weeks really isn't the longest followup for patients on tirzepatide. The research followed individuals for 193 weeks in SURMOUNT. And if we look at the weight loss curves there is still a decline up to week 72, albeit a very modest one from week 60. It's difficult to tell, but it looks like on the 15mg curve that there is still some weight loss to week 85. Then all three curves flatline.

I've been thinking lately that given how close the 10mg and 15mg lines are in this chart that there is diminishing returns on higher doses. I'm not sure if a higher dose is really the solution to a stall as people approach week 72.

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I'm literally on week 70 (and not at goal) so I have a slightly vested interest in what happens next. My gut is that alternative pathways, more protein, and resistance training are likely to break the stall than more tirzepatide.

 

[lessthanhalf]

You are right , I must have been thinking months not weeks as I knew it was 4 or 5 years. And 193 weeks is just under 4 years.

It is a pity the high dose tirz study is not available yet. The difference in weight loss from 10mg to 15 is fairly small for tirz on that graph, which does suggest it is close to the diminishing returns dose.

Reta might be better, but despite seeing quite a few people on this forum on doses of tirz greater than 15mg , I have seen hardly anyone on more than 12mg of reta.

This paper attempted to make mathematical models of predicted weight loss at different doses.

"Comparative efficacy and safety of GLP-1 receptor agonists for weight

reduction: A model-based meta-analysis of placebo-controlled trials"

And it suggests there might be further weight loss from higher doses of reta, though it was written before the most recent reta results, though my maths is too rusty to be that useful in interpreting it properly. I got chatgpt to estimate possible max weight loss from reta at higher doses from the formulas in the paper and it was high 30% range at 20mg of reta or so.

 

[woundcarping]

…I have seen hardly anyone on more than 12mg of reta…

 

[Grogu]

You are right , I must have been thinking months not weeks as I knew it was 4 or 5 years. And 193 weeks is just under 4 years.

It is a pity the high dose tirz study is not available yet. The difference in weight loss from 10mg to 15 is fairly small for tirz on that graph, which does suggest it is close to the diminishing returns dose.

Reta might be better, but despite seeing quite a few people on this forum on doses of tirz greater than 15mg , I have seen hardly anyone on more than 12mg of reta.

This paper attempted to make mathematical models of predicted weight loss at different doses.

"Comparative efficacy and safety of GLP-1 receptor agonists for weight

reduction: A model-based meta-analysis of placebo-controlled trials"

And it suggests there might be further weight loss from higher doses of reta, though it was written before the most recent reta results, though my maths is too rusty to be that useful in interpreting it properly. I got chatgpt to estimate possible max weight loss from reta at higher doses from the formulas in the paper and it was high 30% range at 20mg of reta or so.

Thanks for the study! I'll definitely take a look. The big takeaway for me (so far with a quick glance) is the age analysis. Gives me an excuse why I might have not reach my own weight loss targets being in my mid-50s . A lot of times in online forums and other venues when people don't reach goal a portion of that could be age and the things related to aging that might affect the effectiveness of these medications. Thanks again!

 

[DidntMakeBrownies]

This was me a while ago, I felt the tirz wasn’t working anymore so I added a little Reta, and as I increased the Reta I decreased the tirz. I am below goal now, Reta helped me get there.

Can I ask how you introduced Reta? Did your heart rate jack up? What dose did you do?

 

[Wecandothis]

Can I ask how you introduced Reta? Did your heart rate jack up? What dose did you do?

Yes it skipped beats, at the beginning, and my resting heart rate was higher, when exercising and at rest, I started with .5 and added the other .5 four days later, I stayed on tirz, and as I moved up in Reta, I decreased in tirz. Current about 2 tirz with 6-8 Reta. I still need the tirz for anti inflammatory effects.

 

[Wecandothis]

Thanks for the study! I'll definitely take a look. The big takeaway for me (so far with a quick glance) is the age analysis. Gives me an excuse why I might have not reach my own weight loss targets being in my mid-50s . A lot of times in online forums and other venues when people don't reach goal a portion of that could be age and the things related to aging that might affect the effectiveness of these medications. Thanks again!

Don’t go by this, I am much older then you and I am two pounds under my goal, which is skinnier then I have ever been in my life. Just eat right and exercise and the weight will come off.

 

[DidntMakeBrownies]

Yes it skipped beats, at the beginning, and my resting heart rate was higher, when exercising and at rest, I started with .5 and added the other .5 four days later, I stayed on tirz, and as I moved up in Reta, I decreased in tirz. Current about 2 tirz with 6-8 Reta. I still need the tirz for anti inflammatory effects.

I had a cardiac ablation for a heart arythmia so I am kind of afraid of this.

 

[Grogu]

I had a cardiac ablation for a heart arythmia so I am kind of afraid of this.

Yeah, good reason to be cautious. Not sure if preexisting heart conditions will end up in the black box notice when full prescribing materials are released, but until then I personally wouldn’t mess with Reta if I was in your shoes.

 

[Wecandothis]

I had a cardiac ablation for a heart arythmia so I am kind of afraid of this.

I have known pvcs. My hubbie had an ablation years ago and and he uses Reta successfully. But maybe your doctor should give you advice on this. My cardiologist knows I take it.