Anyone found a solution to high heart rate on Tirzepatide?

[Hardtimes]

I have searched the forum and seen others have been getting high resting heart rate from tirz but didn’t see anyone finding a solution. I’m currently using around 3 mg weekly and mg resting heart rate has gone from 60 to 80 is there anything I can do to help apart from stop the Tirzepatide? Is an increase like that a cause for concern with no other health issues? I know lots of people have a rhr of 80 and my fitness watch tells me my heart rate is average to good for my age group but I’m used to being a lot lower so it’s bothering me.

 

[roofer22]

GLP isn't an appetite suppressant. It's a naturally produced hormone that's central to the energy homeostasis (weight regulation) system.

Neuroendocrine Control of Body Energy Homeostasis - Endotext - NCBI Bookshelf

Tolerance doesn't develop to insulin, or testosterone, requiring ever increasing doses.

All the evidence shows at a fixed dose, weight drops to a certain level, and stays there, with some minor variation, until the dose is titrated up, then weight drops more, and stays there until it's titrated up again.

Once treatment is stoped, in the overwhelming majority of cases, weight gradually returns.

If tolerance developed, then weight wouldn't stabilize for years at the same dose, but gradually return as tolerance builds. A "maintainance dose" wouldn't be possible, yet it clearly exists.

https://investor.lilly.com/news-releases/news-release-details/treatment-tirzepatide-adults-pre-diabetes-and-obesity-or#:~:text=%22Individuals%20treated%20with%20tirzepatide%20lost,of%20developing%20type%202%20diabetes.

When people get bariatric surgery, weight loss and improved glucose control aren't because their stomachs are reduced in size, but because food moves into the intestines quickly, stretching them more than usual. Intestinal hypertrophy releases GLP-1, and this increased level of GLP has all the same effects as a shot of the exogenous GLP.

Basically, this is the *hard way* of compensating for a GLP hormone deficit vs injecting it.

The Role of GLP-1 in the Metabolic Success of Bariatric Surgery - PMC

Two of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered metabolic surgeries because they are thought to affect metabolism in a weight loss–independent manner. In ...

pmc.ncbi.nlm.nih.gov

If someone stays on the same dose of exogenous GLPs, and weight starts to return, that's a sign of immunogenicity, with antibodies developing to neutralize the drug. Immunogenicity didn't rise to a clinically significant level in the pharma trials of Sema and Tirz (it has with other pharma GLPs), but we're not dealing with carefully manufactured pharma products designed to minimize that reaction. It's entirely possible haphazard use of UGL versions are gradually making people immune to Sema and Tirz, reducing or completely eliminating their effectiveness.

I should have been more specific. Lets not call it tolerance. But the ability to eat food and want to eat food comes back. When I first started sema I could barely eat on .25mg. Now I'm on a bulk taking 2.5mg eating fine. That's what I mean by tolerance. That doesn't come and go with weight fluctuation. At least not with me.

 

[Ghoul]

Friendly warning that this doesnt seem to work for some people. I tried it for about a month and it was an abject failure to split the dose up and inject more frequently.

I went from 10mg weekly, to 2mg daily for 30 days and it didnt work even though my dosage went up to 14mg. I had zero reaction to the 2mg daily shot. After that I did 12mg in a single weekly shot and it started working again.

I think I know why it doesnt work. You would need much higher dosage. So when I sat down to run the numbers using daily 2mg I got

effective range of 12.48 - 14.48mg with an average of 13.48mg over 14 days

This sounds good except for one thing... when you do weekly of 14mg, you get this:

effective range of 8.48 - 22.48mg with an average of 15.48mg over 14 days

See the difference? The average isnt far off but look at the spike. Its that spike at day 7 that might be making the difference for me. On that day, you still have most of your dose from the previous week and you inject another dose on day 7 which spikes your dose for a few days post. This gets higher until we reach the total elimination of the 1st dose which takes almost a month. So that spike, keeps getting higher for almost the entire time!

So I have a feeling that its not about the average dosage but rather the spikes and how your body reacts to said spike.

Again all anecdotal but that seems to be the case for me.

The other reason to avoid more frequent injections is that frequency of administration is a major factor in triggering stronger immunogenicity. Several small doses typically increase antibody levels much more than a single larger dose. In other words. the likelihood of immunogenicity going from "clinically insignificant", ie, not enough to have a measurable impact on the drug, to "clinically significant" leading to reduced effectiveness is higher.

"Typically, repeated administration is more immunogenic than a single dose, and immunogenicity increases with more frequent dosing and longer-term treatment "

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins - PMC

The subcutaneous route of administration has provided convenient and non-inferior delivery of therapeutic proteins compared to intravenous infusion, but there is potential for enhanced immunogenicity toward subcutaneously administered proteins in a ...

pmc.ncbi.nlm.nih.gov

 

[Ghoul]

I should have been more specific. Lets not call it tolerance. But the ability to eat food and want to eat food comes back. When I first started sema I could barely eat on .25mg. Now I'm on a bulk taking 2.5mg eating fine. That's what I mean by tolerance. That doesn't come and go with weight fluctuation. At least not with me.

If you've been going off and on, something I did years ago, the effectiveness when returning to Sema is often much lower. So much so I thought the batch for my second cycle was bunk. Then someone else with no prior use tried the same batch, and had as strong effect as I did the first time. A long time after that observation, others I spoke to had a similar experience, and more recently I've read anecdotal reports from clinicians who's observed the same in their patients. They needed much higher doses to get the same effect as before.

Obviously, it's still early days, research wise, with these compounds and even peptides in general, but re-exposure is a known risk factor with protein drugs. Meaning a break, vs continuous use, carries the risk of high immunogenicity when resuming treatment with the same peptide.

"Intermittent treatment or re-exposure after a long treatment free interval may be associated with an increase in immunogenicity. Previous exposure to similar proteins can lead to pre-sensitisation and cause an immune response."

https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-immunogenicity-assessment-biotechnology-derived-therapeutic-proteins-first-version_en.pdf

 

[glpfun]

The other reason to avoid more frequent injections is that frequency of administration is a major factor in triggering stronger immunogenicity. Several small doses typically increase antibody levels much more than a single larger dose. In other words. the likelihood of immunogenicity going from "clinically insignificant", ie, not enough to have a measurable impact on the drug, to "clinically significant" leading to reduced effectiveness is higher.

"Typically, repeated administration is more immunogenic than a single dose, and immunogenicity increases with more frequent dosing and longer-term treatment "

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins - PMC

The subcutaneous route of administration has provided convenient and non-inferior delivery of therapeutic proteins compared to intravenous infusion, but there is potential for enhanced immunogenicity toward subcutaneously administered proteins in a ...

pmc.ncbi.nlm.nih.gov

I never suggested splitting up the dose, I said just increase the frequency, 15 mg every 5 days instead of 7

 

[Ghoul]

I never suggested splitting up the dose, I said just increase the frequency, 15 mg every 5 days instead of 7

That's still increased frequency. 15mg every 5 days is the equivalent of spitting up a 21mg once a week dose.

In other words, that's 7 injections every 35 days vs 5. Not nearly as significant as micro dosing of course. It's just that minimizing the risk of immunogenicity involves a bunch of factors, cumulatively adding up to a potential problem.

It's a really complex issue, and since no one is having antibody levels tested it's all feels based, so we're blind.

(HGH users can easily get tested for growth hormone antibodies, since that's a regular part of GH treatment most walk in test centers offer it).

Pharma prescribing guidelines for Sema and Tirz call for termination of treatment if the patient can't titrate up to a certain dose within 6 months. I thought that was weird, and wondered why staying at a low dose indefinitely could possibly be an issue.

It turns out that low levels of a protein drug tend to develop a stronger immune response than higher levels, so they want you to reach a minimum level for long term use.

 

[Sampei]

That's still increased frequency. 15mg every 5 days is the equivalent of spitting up a 21mg once a week dose.

In other words, that's 7 injections every 35 days vs 5. Not nearly as significant as micro dosing of course. It's just that minimizing the risk of immunogenicity involves a bunch of factors, cumulatively adding up to a potential problem.

It's a really complex issue, and since no one is having antibody levels tested it's all feels based, so we're blind.

(HGH users can easily get tested for growth hormone antibodies, since that's a regular part of GH treatment most walk in test centers offer it).

Pharma prescribing guidelines for Sema and Tirz call for termination of treatment if the patient can't titrate up to a certain dose within 6 months. I thought that was weird, and wondered why staying at a low dose indefinitely could possibly be an issue.

It turns out that low levels of a protein drug tend to develop a stronger immune response than higher levels, so they want you to reach a minimum level for long term use.

If one has developed GH antibodies, is there anyway to reduce the level of antibodies and have the GH work again? Or one is just fucked for life?

 

[Ghoul]

If one has developed GH antibodies, is there anyway to reduce the level of antibodies and have the GH work again? Or one is just fucked for life?

Likely not for life, but it has happened.

There's a chart below to illustrate. Bear in mind all peptides are subject to similar dynamics.

When a patient under HGH treatment isn't responding as expected, they're given an antibody test (RIA #). If it's high, they can either increase the dose (immunogenicity doesn't always go up with dose) to overcome the immune system neutralizing the drug, take a break and retry if and when the antibody levels go down, or switch brand of HGH in the hopes it won't trigger the same reactions

Here, the 3 patients with the strongest immunogenic reactions stopped growing completely. Two of them, 10 and 11, switched brands, showed no improvement, and treatment stopped. 15 took a 3 month break. antibody levels dropped, brand was switched, and treatment continued successfully. Another needed a 2 year break before treatment could continue.

Inhibition shows how much of the HGH was being neutralized, effectively lessening how well the HGH worked. So often HGH is still effective, even with high antibodies, but less than it would be normally.

With GLP users that develop this problem, it usually manifests as a loss of glucose control.

So it's not an "all or nothing" problem. Notice it can take a LONG time for immunogenicity to build. Often, antibodies build up quickly, then stabilize, in which case it's no problem (other than some degree of effectiveness may be reduced). But change brand, batch, or use a cheap vial that has some particulates in it, or one of the many immunogenic inducing factors, and it could rise again and become a serious issue.

 

[HB_22]

In addition, from extensive experience with. both, UGL tirz is not as strong as the equivalent dose of pharma. If I had to guess, it's at least a 25% difference in potency, if not a little more.

Just so people know there is no evidence at all to back up this claim other than just a few anecdotal reports from users who claim it to be weaker.

 

[SubparMarioBro]

When people get bariatric surgery, weight loss and improved glucose control aren't because their stomachs are reduced in size, but because food moves into the intestines quickly, stretching them more than usual. Intestinal hypertrophy releases GLP-1, and this increased level of GLP has all the same effects as a shot of the exogenous GLP.

Sorry to derail this but given evidence that GLP-1 is involved in addiction pathways (with widespread anecdotal reports of reduction in alcohol consumption) and given that bariatric surgery also works along a GLP-1 pathway, is there a link here between bariatric surgery’s effects on GLP-1 and the high incidence of alcoholism in bariatric surgery patients?

For example could the increased endogenous production in the intestines of a hormone with a 2-minute half life be leading to deficiencies elsewhere that are creating a vulnerability to substance use disorders (whereas the longer half lifes of semaglutide and co provide systemic effects that create the opposite effect)?

 

[Ghoul]

Sorry to derail this but given evidence that GLP-1 is involved in addiction pathways (with widespread anecdotal reports of reduction in alcohol consumption) and given that bariatric surgery also works along a GLP-1 pathway, is there a link here between bariatric surgery’s effects on GLP-1 and the high incidence of alcoholism in bariatric surgery patients?

For example could the increased endogenous production in the intestines of a hormone with a 2-minute half life be leading to deficiencies elsewhere that are creating a vulnerability to substance use disorders (whereas the longer half lifes of semaglutide and co provide systemic effects that create the opposite effect)?

That's basically it.

Endogenous GLP has a very short half life, and its production is directly linked to food intake, so levels vary greatly throughout the day vs the incretin drugs that provide a stable, consistant level.

Bariatric patients sometimes experience "addiction transfer", and get hooked on things other than food.. There's some logic to that. because the intake of food is followed by a GLP boost, making that "addiction", which is essentially what appetite is, a necessary addiction, self regulating.

While taking a drink or getting high isn't followed by an increase in GLP.

Bariatric surgery is becoming increasingly rare, since it's pretty obvious it's a less effective way of addressing insufficient GLP production (or sensitivity).

 

[SubparMarioBro]

That's basically it.

Endogenous GLP has a very short half life, and its production is directly linked to food intake, so levels vary greatly throughout the day vs the incretin drugs that provide a stable, consistant level.

Bariatric patients sometimes experience "addiction transfer", and get hooked on things other than food.. There's some logic to that. because the intake of food is followed by a GLP boost, making that "addiction", which is essentially what appetite is, a necessary addiction, self regulating.

While taking a drink or getting high isn't followed by an increase in GLP.

Bariatric surgery is becoming increasingly rare, since it's pretty obvious it's a less effective way of addressing insufficient GLP production (or sensitivity).

And another unrelated question for you. You’ve talked a lot about immunogenicity concerns with grey and compounded GLP-1s. Would something like Orforglipron potentially be safer in this regard?

 

[Ghoul]

And another unrelated question for you. You’ve talked a lot about immunogenicity concerns with grey and compounded GLP-1s. Would something like Orforglipron potentially be safer in this regard?

Probably.

SubQ administration is essentially the worst route of administration in terms of immunogenicity. Defenses against infection are strongest in subcutaneous tissue.

Repeatedly ingesting proteins causes a tolerance to develop, actively suppressing an immune response to them.

The problem is getting them to survive the gut intact.

This has been proposed as a method to prevent or overcome immunogenic responses to peptides. especially in patients that developed immunity to critical lifesaving protein therapeutics.

https://www.sciencedirect.com/science/article/abs/pii/S0008874922001666

 

[SubparMarioBro]

Probably.

SubQ administration is essentially the worst route of administration in terms of immunogenicity. Defenses against infection are strongest in subcutaneous tissue.

Repeatedly ingesting proteins causes a tolerance to develop, actively suppressing an immune response to them.

The problem is getting them to survive the gut intact.

This has been proposed as a method to prevent or overcome immunogenic responses to peptides. especially in patients that developed immunity to critical lifesaving protein therapeutics.

https://www.sciencedirect.com/science/article/abs/pii/S0008874922001666

If I’m understanding this correctly Orforglipron is a small molecule GLP-1 agonist (neither a peptide nor a protein) so wouldn’t it avoid a lot of these issues with immunogenic response?

Orforglipron got better results in phase 2 than Sema’s phase 2 obesity trial did (at the same time frame).

 

[MyNameIsJeff]

Probably.

SubQ administration is essentially the worst route of administration in terms of immunogenicity. Defenses against infection are strongest in subcutaneous tissue.

https://www.sciencedirect.com/science/article/abs/pii/S0008874922001666

Very important information, thanks! In that case I will inject my HMG intramuscularly. LH and FSH is the last thing I want to develop antibodies against.

 

[MyNameIsJeff]

GPT o1:

• Subcutaneous (SC) Injection:
  
  • Local APC-Rich Environment: SC tissue typically contains a relatively high density of dendritic cells and other APCs. These cells can capture and process peptide aggregates, increasing the likelihood of initiating an adaptive immune response.
  • Prolonged Residence Time: Peptides injected subcutaneously often have slower absorption into the bloodstream, prolonging local tissue exposure. This extended presence can give immune cells more time to interact with the peptide, potentially increasing immunogenicity when aggregates or impurities are present.
• Intramuscular (IM) Injection:
  
  • More Rapid Absorption (Generally): Muscle tissue is well-vascularized, which can lead to quicker systemic uptake. Faster dispersion may reduce the peptide’s local concentration and time spent in contact with immune cells at the injection site.
  • Fewer Resident APCs than SC Tissue: While muscle tissue does have immune cells, it typically has fewer surface-resident dendritic cells compared to the subcutaneous space. This can potentially lower the initial risk of encountering APCs capable of processing the peptide into an antigenic form.

General Trend: SC administration may pose a higher relative risk of immunogenicity compared to IM due to greater APC presence and longer local exposure times.

 

[Ghoul]

Very important information, thanks! In that case I will inject my HMG intramuscularly. LH and FSH is the last thing I want to develop antibodies against.

Pharma FSH has a low potential for immunogenicity, but in this study looking specifically at it:

"Based on existing literature on immunogenicity of FSH (including r-hFSH), the anticipated incidence of ADA to r-hFSH was very low. The results reported here confirm the low immunogenic potential of the tested preparation of r-hFSH and provide further evidence for the efficacy and safety of this preparation.

Although not routinely investigated in clinical practice, an immune response could be responsible for unexpected clinical outcomes. The clinical manifestations may include loss of efficacy, neutralization of the natural counterpart, and immune effects such as allergy, anaphylaxis, or serum sickness.[2,10,11] The development of such antibodies is usually exposure dependent, and the risk increases in line with several factors, such as time on treatment, changes in the drug formulation, alterations to the protein structure, and the manufacturing process, variations between batches of the drug, the route of administration, the dose level, and the frequency of dosing.[6]"

A Multicenter Phase IV Study to Investigate the Immunogenicity of Recombinant Human Follicle-Stimulating Hormone and Its Impact on Clinical Outcomes in Females Undergoing Controlled Ovarian Stimulation - PMC

Therapeutic proteins can cause immune responses, which may have clinical implications. The aim of the study was to assess the immunogenicity of recombinant human follicle-stimulating hormone (r-hFSH), when used for controlled ovarian stimulation ...

pmc.ncbi.nlm.nih.gov

So assuming UGL is gong to elicit a stronger immunogenic response, which is very likely, IM will lesson the risk.

 

[Ghoul]

If I’m understanding this correctly Orforglipron is a small molecule GLP-1 agonist (neither a peptide nor a protein) so wouldn’t it avoid a lot of these issues with immunogenic response?

Orforglipron got better results in phase 2 than Sema’s phase 2 obesity trial did (at the same time frame).

I assumed it was similar to oral semaglutide and not a small molecule ligand. Immunogenicity is extremely rare with small molecules and a non issue for all practical purposes.

 

[SubparMarioBro]

I assumed it was similar to oral semaglutide and not a small molecule ligand. Immunogenicity is extremely rare with small molecules and a non issue for all practical purposes.

Would something like Orforglipron potentially be effective even if a venturous researcher had developed a significant immune response to GLP-1 peptides, or even endogenous GLP-1? Or would a small molecule be vulnerable to cross-reactivity?

 

[songsofpyramids]

so they want you to reach a minimum level for long term use.

Do we know what that dose is sema and tirz? Great thread

 

[Ghoul]

Would something like Orforglipron potentially be effective even if a venturous researcher had developed a significant immune response to GLP-1 peptides, or even endogenous GLP-1? Or would a small molecule be vulnerable to cross-reactivity?

Since the target receptor is the same for both, the development of adhesion-inhibitory antibodies induced by some trash UGL GLP could, in theory, interfere with the function of a non-peptide ligand like Orforglipron.