Retatrutide平台期/对Retatrutide的适应或耐药性

[bluefootedboobie]

有没有人成功突破过瑞他曲肽（retatrutide）的平台期，即使增加剂量也无法突破？

我服用瑞他曲肽的前三个月减掉了大约30磅脂肪，剂量逐渐增加到每周6毫克。我一直以来都有食物依赖/食物成瘾的问题，但瑞他曲肽最终治愈了我的问题，让我的大脑意识到“嘿，我对暴饮暴食没兴趣了”。瑞他曲肽还帮助我减少了酒精摄入。我以前是个酗酒者，但服用后发现自己的饮酒量大大减少了。

然而，三个月后，我的大脑就像撞上了一堵墙，瑞他曲肽的心理作用完全消失了。我对食物的渴望又回来了，我又开始毫不费力地一天摄入7000到8000卡路里。最终，我对酒精的渴望也回来了。

胃动力似乎也受到了影响。在瑞他曲肽起作用的那三个月里，我感觉我的胃一直很饱，以至于我的食道“堵塞”了，我根本无法把食物塞进喉咙。我觉得我的肠道蠕动速度比服用瑞他莫昔芬之前慢了一些，但与之前完全清澈的状态不同，我现在进食完全没问题。

为了突破瓶颈期，我逐渐将瑞他莫昔芬的剂量增加到每周12毫克，但没有任何效果。简而言之，几个月以来，我感觉瑞他莫昔芬似乎已经失效了。

顺便一提，可能有些人还没听说过——这种瓶颈期似乎因人而异。有些人会经历，而很多人则不会。

问题是：

有什么解决办法吗？

有没有人曾经服用瑞他莫昔芬一段时间后效果不佳，然后又恢复了效果？

如果有，你们是怎么做到的？或许是停药一段时间？如果是，停药多久？

或者尝试服用卡格里林汀？或者替索芬辛？

任何建议都将不胜感激。

 

[Calm Logic]

Most popular options seem to be sema or cagri for stacking with reta at that dose.

Cagri more as like a cycle eventually since it tends to poop out.

The teso seems like a decent idea to me as an additional add-on, and it's also sold in oral liquid form at Umbrella Labs (and even more expensive elsewhere). The liquid dosing helps with lower dosing, since the long half-life causes issues for people.

Another option would be EOD dosing (every other day) with the teso capsules. I haven't tried it myself, but I have tried other stimulants like modafinil. GLPs are way better though than such stimulants. I haven't seen any glowing success stories using stimulants long-term.

 

[CNCCurrency]

Most popular options seem to be sema or cagri for stacking with reta at that dose.

Cagri more as like a cycle eventually since it tends to poop out.

The teso seems like a decent idea to me as an additional add-on, and it's also sold in oral liquid form at Umbrella Labs (and even more expensive elsewhere). The liquid dosing helps with lower dosing, since the long half-life causes issues for people. I haven't tried it myself, but I have tried other stimulants like modafinil. GLPs are way better though than such stimulants.

Agreed, I take tirz along with reta

 

[Calm Logic]

I've since titrated up to 12 mg of reta per week in an attempt to overcome the plateau, but it hasn't had any affect whatsoever. For several months now, in short, it simply feels like reta no longer works.

Is your weight going up (overall) or staying the same (overall)?

If it is staying the same, then it's still working to some degree at least. Though taking a lower dose may be just as effective/ineffective.

How much more weight are you trying to lose?

 

[bluefootedboobie]

Is your weight going up (overall) or staying the same (overall)?

If it is staying the same, then it's still working to some degree at least. Though taking a lower dose may be just as effective/ineffective.

How much more weight are you trying to lose?

It's had a slow rebound trending up, but I feel at least a little more in control of my eating than I did pre-reta. I do feel it's working to at least some degree (just not close to what it was the first few months).

From the reta low, I'd like to lose another ~18 lbs (which is 30 lbs from current). 170 would be an "ideal" weight, but 180 is probably a fairer target where I'd be considered a good, muscular lean and would fit well in my many unworn size medium shirts.

 

[Calm Logic]

Have you tried splitting the reta dose to prevent rebound hunger? I don't take any GLPs weekly anymore.

 

[bluefootedboobie]

I'm currently splitting the 12 mg to 6 mg taken twice per week, but EOD or even daily would be easily doable. I'll give that a try, the only downside is the hassle of extra pinning but that's not all that bothersome to me. Thank you for the idea, I appreciate it!

I have cagri and teso on the way, hopefully arriving today. Those might be my first attempts (introduced one at a time of course, and in a very small dose to start (.125 mg), I'm aware that cagrilintide in particular can really mess some people up).

 

[Calm Logic]

Of course, another add-on people try are the GH secretagogues, like tesamorelin (tesa) for visceral fat loss. I haven't taken them long enough to notice any fat loss, but I like them for recovery. Though there can be more risk with them, Dr. Seeds is a fan. I fast for doing those (before and after) and take twice a day, so that routine helps with me doing some intermittent fasting.

More controversially, @DwightTheDelight once reminded me that the focus on protein in the peptide community can lead to weight gain (at least with fatty protein sources) since starches, beans, and lentils generally have a higher satiety per calorie than animal protein:

While some ultra-lean dairy might be lower in calories by volume, beans and starches offer higher satiety per calorie because their fiber content physically keeps the stomach full and promotes better insulin sensitivity compared to the high insulin response triggered by dairy proteins.

Dairy products have a low Glycemic Index (low blood sugar rise) but a high Insulin Index . Amino acids "mimic" a sugar spike to the pancreas. High insulin index foods are notorious for causing "rebound hunger," even if they are low in calories.

Food Type Insulin Response Brain Fuel (Glucose) Fiber/Bulk Resulting Hunger Beans/Lentils Low & Steady Yes (Slow release) High Low (Full for hours) Boiled Potato Moderate Yes Moderate Lowest (Top satiety score) Lean Dairy/Whey High No Zero High (The "1-hour" hunger)

High-Dose Tirz Weight Loss

I just hit overweight on the BMI scale and figured it would be a good time to post an update, since I'm not sure how many other people are above the 15mg/week threshold and it might be useful info to some. My doctor recently told me I need to start wrapping this up and slowing down. High dose...

glp1forum.com

 

[Calm Logic]

I have cagri and teso on the way, hopefully arriving today. Those might be my first attempts (introduced one at a time of course, and in a very small dose to start (.125 mg), I'm aware that cagrilintide in particular can really mess some people up).

"Low and slow" for teso too since you are already on 12 mg of reta. The 9-day half life of teso is something else. It takes a long time to reach steady state (making it tempting to raise the dose), and longer to clear, which is a problem if your HR spikes (which is more likely being on both reta and teso). Heart rate and BP should be checked often/daily:

Because it takes so long to build up, you won't feel the full effect of a specific dose for several weeks. Many people think it’s not working at week 2, raise the dose, and then get hit with severe insomnia or heart rate spikes at week 6 when the "steady state" finally hits.

Dose Frequency Daily Avg. Time to Steady State Key Characteristic 0.25 mg Daily 0.25 mg 6–9 Weeks Standard low-dose entry point. 0.50 mg Daily 0.50 mg 6–9 Weeks Clinical weight loss dose. 0.50 mg EOD 0.25 mg 6–10 Weeks Smoother levels; reduces jitters/insomnia. 1.00 mg Daily 1.00 mg 6–9 Weeks High risk of HR/BP spikes. 1.00 mg EOD 0.50 mg 6–10 Weeks Alternative to 0.5mg Daily; long half-life allows this.

https://4everyoungantiaging.com/anti-aging-tips/tesofensine-explained-a-new-approach-to-weight-loss-and-metabolism/

On the standard 0.5 mg dose, resting heart rate rose by about 7–8 beats per minute on average, which is a fat-burning supplement-like effect of its stimulant properties. Blood pressure did not significantly increase at that dose in trials – changes in systolic/diastolic blood pressure were minimal.

This cardiovascular data is encouraging, since some past appetite suppressant pills were notorious for causing dangerous blood pressure spikes or heart valve issues. Tesofensine’s impact on pulse and blood pressure appears comparatively mild, but it will still require careful monitoring, especially in individuals who have pre-existing hypertension or heart conditions.

Portico

access.portico.org

Tesofensine has been found relatively safe and the most common adverse events

observed are nausea, dry mouth, constipation, hard stool, diarrhea and insomnia.

Elevations in blood pressure and heart rate have been reported with clinically used doses.

To overcome the cardiac adverse effects, its combination with metoprolol is under investigation in clinical trials.

 

[Main75]

Has anyone here successfully overcome a retatrutide plateau, that couldn't be overcome by increasing the dose?

I dropped approximately 30 lbs of fat in my first three months taking reta, titrating up to 6 mg per week. I'd had food noise / food addiction all my life, but reta was finally the cure that got my brain to say hey, I'm just not interested in overeating. The reta also manifested with lower alcohol. I was a problem drinker, but found myself drinking a LOT less.

After those three months though, it was like my brain hit a wall and the mental effects of reta completely stopped working. Cravings returned and I again started having no trouble putting down 7 to 8000 calories in a day. The desire to drink returned eventually as well.

Gastric motility appears to have been impacted as well. For those three months when reta was working, it felt like my stomach was constantly full, to the point that my esophagus was "backed up" and I couldn't physically cram food down my throat. I believe my motility remains a bit slower than it was prior to reta, but unlike before when it was 1000% crystal clear, I now have no trouble always fitting food in.

I've since titrated up to 12 mg of reta per week in an attempt to overcome the plateau, but it hasn't had any affect whatsoever. For several months now, in short, it simply feels like reta no longer works.

For what it's worth, and for those who haven't heard -- this plateau-ing seems to be very individualized. Some folks experience it, and many don't.

The question:

What is the solution for this?

Has anyone had success with reta for a period, had it lose its effectiveness, then regained it?

If so, how did you do it? Perhaps by taking a sustained break? If so, for how long?

Or perhaps the introduction of cagrilintine? Or tesofensine?

Any and all advice would be greatly appreciated.

Yep drinking is down not gone but light and few and far between…man does beer and wine make you feel like s*^t the that night and next day. Gin was ok.

Sounds like very similar first three months weight and dose and same increased dose too.

Hunger and gastric mobility (nice term) seem like pre Reta start. Luckily I started with with a little base so while hungry I am still keeping calories in check….but has been no weight lock for 7 weeks

I started mid August 314 area with a 5 day water ,minerals , vitamins fast which’s sets a mental stage for “yes I can” mentality and followed will good sleep focus and two meals and few drinks, 8 pounds in 6 weeks of this… this gets me feeling that I am taking it seriously. Added Reta as an agent of change after I was on The right track. Worked like charm , definitely focused more on hydration, vitamins and minerals and higher protein .

Ohh really liked the addition of NAC and glycine (for sleep quality

2 1/2 months great progress.. thought I would spice it up focusing muscle maintenance and bell fat so I turned to add Tessa/ipa… I am not thinking that that addition may have fully stopped weight loss and may be associated with hunger returning even though Reta dose was being increased. Felt like food noice was back in full effect and no scale losses for the past 7 weeks. Only Reta side effect has been cold feet (literal cold feet)

Stopped ipa and Tessa Feb 17 ( 5 days ago) because it may have been effecting Reta positives and that’s not cool , it’s simply not worth it to me. Weight target is my primary goal . Pandemic game me bad habits which bumped me from previous high about 280 into 305-320 for past 5 years.. that’s just too much and start to snore and feel slow. Headed back to mid 250’s which good fighting weight …feel quick and not sluggish and better sleep..

Sleep is soo important.. never thought like that before.

Focused getting 140-170 grams of protein daily, hydration and good sleep.

I was thinking of adding another hunger thing…but I will not at least for the next month as I and going to see if Tessa/ipa was THE factor in my weight loss stall.

If this does not reboot some progress in the next month then maybe another fast is in the cards .. good for the mind too..first two days suck then it smooth sailing

 

[lessthanhalf]

What you are describing does sound a lot like some genuine loss of effect of reta. Normally when people say this, it is just that they have lost weight, their metabolic rate goes down, hunger goes up, so it feels like it is not working but if your weight is not going up then it is working fine. I think some of that is happening here as you are still 20 pounds or so down.

The simplest add on is low and slow cagrilintide, but if you are not getting nausea from reta, semaglutide as an add on might also be an option instead.

As you describe eating many thousands of calories per day when you would clearly prefer not to be eating that much, that does sound suspiciously like binge eating disorder. GLP medications are probably the most effective medical treatment for it but this is not yet scientifically proven. My personal solution was to treat high calorie, highly rewarding foods as dangerous addictive drugs and avoid them totally and hopefully forever, but this is a fairly drastic way to deal with it although in my case it has been extremely effective. But a more limited version of this might be worth considering. I am not sure I can say the other treatment options for binge eating disorder are all that great, cognitive behavioural therapy and lisdexamphetamine are the only standard treatments but neither is really all that great.

 

[Main75]

What you are describing does sound a lot like some genuine loss of effect of reta. Normally when people say this, it is just that they have lost weight, their metabolic rate goes down, hunger goes up, so it feels like it is not working but if your weight is not going up then it is working fine. I think some of that is happening here as you are still 20 pounds or so down.

The simplest add on is low and slow cagrilintide, but if you are not getting nausea from reta, semaglutide as an add on might also be an option instead.

As you describe eating many thousands of calories per day when you would clearly prefer not to be eating that much, that does sound suspiciously like binge eating disorder. GLP medications are probably the most effective medical treatment for it but this is not yet scientifically proven. My personal solution was to treat high calorie, highly rewarding foods as dangerous addictive drugs and avoid them totally and hopefully forever, but this is a fairly drastic way to deal with it although in my case it has been extremely effective. But a more limited version of this might be worth considering. I am not sure I can say the other treatment options for binge eating disorder are all that great, cognitive behavioural therapy and lisdexamphetamine are the only standard treatments but neither is really all that great.

Just got a different order in, so maybe the last is simply weaker (degraded) . lol that would be funny if somehow even though I was shooting 12mg is was acting as far less….even though I’ve been careful with storage

Almost forgot today is the day ….

 

[lessthanhalf]

I tried cagrilintide 0.25 mg for a couple of weeks. Chatgpt convinced me it might reduce abdominal pain from ulcerative colitis/ibs-d, so I though it was worth trying and anything that would make keeping off 54% of my weight easier is nice. Already on tirz 16mg and reta 5mg . I am fairly sure it made gut symptoms worse, given there is variation day to day and from what I eat it is hard to be sure. I will probably try again at some stage when my gut is extra stable. I am asking the tirz and reta to do way more than they showed in any of the trials.

 

[Gr33dyOctopus]

Agreed, I take tirz along with reta

Me too, I stack that shit

 

[Gr33dyOctopus]

Just got a different order in, so maybe the last is simply weaker (degraded) . lol that would be funny if somehow even though I was shooting 12mg is was acting as far less….even though I’ve been careful with storage

Almost forgot today is the day ….

Fuck yea! Keep us in the loop Brutha, wouldn't it be super cool if thats the case? I shoot tirz on friday and reta on monday, burn blend.

 

[Calm Logic]

I am not sure I can say the other treatment options for binge eating disorder are all that great, cognitive behavioural therapy and lisdexamphetamine are the only standard treatments but neither is really all that great

So I don't see any advantage in differentiating the two usually, except there are always lessons to be learned in psychology, at least to distract us until the meds kick in. Like the hack with smaller plate size and trying to get dopamine elsewhere.

To complicate things further:

Eating disorders and obesity: bridging clinical, neurobiological, and therapeutic perspectives

Obesity may act as (a) a previous condition or (b) a consequent condition for the development of eating disorders. However, they can also interact simultaneously, with obesity being (c) the primary or (d) the secondary disorder.

 

[dndgeek]

So what's the thought process on stacking Reta with Tirz vs Sema? I was thinking Sema would be better because its supplementing only the GLP1 side of Reta which is weaker. Stacking Tirz in my thinking would add more GIP into the equation but Reta already highly favors GIP above all else. I have and still do add Cagri but I really dont think it does anything for me.

 

[Calm Logic]

One line of thinking: Maximize reta first. Then if that is not enough, consider switching (back) to tirz. No stacking necessary, except as a bridge for switching.

But as far as stacking reta with tirz or sema, you can argue either way, as you are saying.

 

[lessthanhalf]

So what's the thought process on stacking Reta with Tirz vs Sema? I was thinking Sema would be better because its supplementing only the GLP1 side of Reta which is weaker. Stacking Tirz in my thinking would add more GIP into the equation but Reta already highly favors GIP above all else. I have and still do add Cagri but I really dont think it does anything for me.

This is based more on theory or animal research than proven effects in human studies. I have explained this before in other posts but a lot of the information there is about the relative effects of different GLP drugs on the different receptors is wrong. Standard AI responses are not correct. And it is complex. The simple Ki or binding affinity numbers are not close to the whole story. 99% of the drugs are bound to albumin to start with , and then when they bind to receptors there can be different or even deliberately biased intracellular responses to those drugs. It is the secondary intracellular response that determines what effects they have in the end. Tirzepatide for example is biased towards cAMP signalling over beta-arrestin signalling at the GLP-1 receptor, so it can have a stronger total effect on glp-1 than semaglutide, and less adverse effects, despite much lower binding affinity. And there is less receptor internalisation and inactivation due to the lower beta-arrestin signalling.

My understanding is: Tirzepatide strongest GIP, fairly strong GLP-1, 15mg tirz is possibly stronger than semaglutide 2.4mg on glp-1

Retatrutide weaker GIP than tirz, stronger but not biased glp-1 agonism plus glucagon agonism.

Tirzepatide has probably the least side effects due to the biased agonism on GLP-1, plus the strong GIP agonism counteracts the nausea and malaise response in the brain caused by glp agonism

Reta causes a bit more gi side effects due to the non biased signalling at glp-1 and the weaker GIP agonism, having less of a counteracting effect on glp nausea, but better weight loss due to the added glucagon agonism.

I spent quite a bit of time reading papers and arguing with chatgpt ( with extensive promting ) over whether adding in extra semaglutide to tirzepatide would increase overall glp-1 agonism, and really did not reach a definite conclusion. I thought chatgpt's pharmacology is really very good, though I think promting it to not agree with you without evidence is essential.

I had horrible nausea and malaise from low dose semaglutide so for me it was not really an option.

The most logical add on is almost certainly cagrilintide to retatrutide or tirzepatide. Cagrilintide is not low on side effects so doses need to be very low and slowly increased if already at full doses of reta or tirz. It is a pity the research on combining cagri is with semaglutide, for ownership reasons , combining it with reta is probably state of the art at this stage.

Or switching from tirzepatide to retatrutide for a few extra percent weight loss, but maybe a bit more side effects.

In my case I was pleasantly surprised by how few side effects I got from 15mg of tirzepatide compared to 0.8mg semaglutide, and rather than mess that up added in reta for it's glucagon agonism rather than switched, in theory the extra gip agonism of tirz should cause less nausea even when combined with reta than just reta alone.

 

[dndgeek]

This is based more on theory or animal research than proven effects in human studies. I have explained this before in other posts but a lot of the information there is about the relative effects of different GLP drugs on the different receptors is wrong. Standard AI responses are not correct. And it is complex. The simple Ki or binding affinity numbers are not close to the whole story. 99% of the drugs are bound to albumin to start with , and then when they bind to receptors there can be different or even deliberately biased intracellular responses to those drugs. It is the secondary intracellular response that determines what effects they have in the end. Tirzepatide for example is biased towards cAMP signalling over beta-arrestin signalling at the GLP-1 receptor, so it can have a stronger total effect on glp-1 than semaglutide, and less adverse effects, despite much lower binding affinity. And there is less receptor internalisation and inactivation due to the lower beta-arrestin signalling.

My understanding is: Tirzepatide strongest GIP, fairly strong GLP-1, 15mg tirz is possibly stronger than semaglutide 2.4mg on glp-1

Retatrutide weaker GIP than tirz, stronger but not biased glp-1 agonism plus glucagon agonism.

Tirzepatide has probably the least side effects due to the biased agonism on GLP-1, plus the strong GIP agonism counteracts the nausea and malaise response in the brain caused by glp agonism

Reta causes a bit more gi side effects due to the non biased signalling at glp-1 and the weaker GIP agonism, having less of a counteracting effect on glp nausea, but better weight loss due to the added glucagon agonism.

I spent quite a bit of time reading papers and arguing with chatgpt ( with extensive promting ) over whether adding in extra semaglutide to tirzepatide would increase overall glp-1 agonism, and really did not reach a definite conclusion. I thought chatgpt's pharmacology is really very good, though I think promting it to not agree with you without evidence is essential.

I had horrible nausea and malaise from low dose semaglutide so for me it was not really an option.

The most logical add on is almost certainly cagrilintide to retatrutide or tirzepatide. Cagrilintide is not low on side effects so doses need to be very low and slowly increased if already at full doses of reta or tirz. It is a pity the research on combining cagri is with semaglutide, for ownership reasons , combining it with reta is probably state of the art at this stage.

Or switching from tirzepatide to retatrutide for a few extra percent weight loss, but maybe a bit more side effects.

In my case I was pleasantly surprised by how few side effects I got from 15mg of tirzepatide compared to 0.8mg semaglutide, and rather than mess that up added in reta for it's glucagon agonism rather than switched, in theory the extra gip agonism of tirz should cause less nausea even when combined with reta than just reta alone.

Thank you for your response!