Tirzepatide: Beyond Appetite Control

[pizzathehutt]

...and really all the other GLP-1 and multi-receptor agonists. For simplicity, I'm focusing on what I have personal experience with, Tirzepatide.

Many get hung up on the appetite suppression benefits of these agonists -- for good and bad.

I believe the narrative needs a shift. In my mind, Tirzepatide’s (and the others) weight loss effects extend beyond simple appetite suppression.

From my understand, these agonists improves insulin sensitivity, increases energy expenditure, enhances lipid metabolism, positively alters gut hormone levels, reduces fat accumulation, possesses anti-inflammatory properties, and improves glycemic control.

All of these combined mechanisms contribute to its overall effectiveness in promoting weight loss and improving metabolic health.

Yes, appetite suppression and caloric deficits is the main player but there's so much more.

Next, I'd like to tie together current public research alongside the wealth of reports across various places to really hone in a solid, data backed, message.

Why? I have friends and colleagues that reject these peptides. Smart folks that have unfortunately accepted narratives that have made even considering usage socially taboo. Folks that could really benefit from them. I'd like them to be around.

 

[egruberman]

I know many here have moved beyond their initial dismissal of GLP class peptides, but the evidence of non-weight loss benefits have been long standing, going back over 30 years. Most of the GLP receptors throughout the body have nothing to do with weight loss:

I’d like to do a deep dive on the available literature and see what we can tease out that is definitively distinct from a reduction in body mass. If you have anything specific that is handy, I’d love to see it. Otherwise m, I’ll dig in a bit later.

 

[Ghoul]

I’d like to do a deep dive on the available literature and see what we can tease out that is definitively distinct from a reduction in body mass. If you have anything specific that is handy, I’d love to see it. Otherwise m, I’ll dig in a bit later.

It's going to largely depend on your standard of evidence.

Research bandwidth is saturated, and those issues with the most profit potential as an FDA approved "on label" use, which compels insurance companies to pay for the drugs, are going to get the most attention and expensive human involved studies first.

Longevity improvements will be the last to get funding, as it's not a category of healthcare covered by the payers, generally.

So the highest quality studies thus far have involved diabetics, then the obese, and more recently heart failure patients. Alcoholics were next.

On the other hand, there's a huge amount of in vitro and animal research going back decades, showing a myriad of positive effects on every organ, like nerves, for instance (an area of particular interest to me, for the potential to preserve senses and cognition), and directly exerting an anti-inflammatory effect on blood vessels.

There's certainly benefits unrelated to weight loss, the most well substantiate have been the ones on addictive behavior, which manifest so quickly weight loss hasn't had time to take place to any great degree, but, yet again, the majority of data was tangentially gathered from studies focused on other issues with diabetics and the obese as subjects.

 

[Ghoul]

I just checked for an "update" search for "GLP-1 Neuroprotection"

No less than 500 distinct research projects, going back 25 years, all pointing the molecule exhibiting positive effects on nerves in general, and the brain.

GLP-1 is a growth factor that strengthens the blood brain barrier. Who knew? You can't walk 2 feet into GLP research land without falling over another promising candidate for a full investigation. And most of this was before a long lasting GLP became viable with Sema and Tirz.

https://www.semanticscholar.org/paper/Alleviation-of-Depression-by-Glucagon-Like-Peptide-Kim-Kim/39dd2ee3f26a6dbd46a5a29b9930f514b04d6c0d

 

[egruberman]

It's going to largely depend on your standard of evidence.

I don’t mean to imply that an absence of evidence means that there aren’t benefits, but I am curious what already exists in the literature. Obviously, we’d like multiple RCTs, but your point is well taken about the areas of focus presently. I’d be satisfied with quality mechanism of action data.

 

[Ghoul]

I don’t mean to imply that an absence of evidence means that there aren’t benefits, but I am curious what already exists in the literature. Obviously, we’d like multiple RCTs, but your point is well taken about the areas of focus presently. I’d be satisfied with quality mechanism of action data.

Hopefully this won't sound like a cop out, but as I started to gather links I realized I'm so spoiled for choice you'd be better off searching for "GLP neurogenesis mechanism", "GLP endothelial anti-inflammatory", and you'll find countless papers describing the multiple mechanisms of action involved in GLP receptor activated cardiovascular and neuro protection.

The hardest thing when talking about this drug, is that there's SO much amazing shit going on here, you can easily start sounding like a nut to those who aren't into the science. I have to read a few more well substantiated papers to remind myself I'm not dreaming here lol.

 

[OldGHGuy]

Great discourse Meso! So what is the current "consensus" protocol for Tirz (assuming, for the sake of argument and simplification, at least TRT) for gradual fat loss AND minimal muscle loss over the course of say 6-12 months with minimal sides? First hand experience preferred.

 

[MrTexas2]

Women react more strongly due to a lower density of GLP receptors vs males, and effect strength appears correlated with total receptor saturation.

Side effects are mostly associated with "eating beyond your hunger", and out of habit. Because there's a delay between eating and the sides, it takes some time to "learn" that lesson.

Small portions, then wait to see how it goes before eating again, and a glass of metamucil go a long way towards alleviating sides.

The kid (young doc) who prescribed it for me was pretty sharp (MD/PhD).

He warned of a 30% loss in muscle mass, which I am finding hard to believe. Smart people make errors all the time.

Having said that, are you aware of any loss in muscle associated with Tirz. I am on HRT only but thinking of adding Primo to offset any loss in size.

 

[Ghoul]

Great discourse Meso! So what is the current "consensus" protocol for Tirz (assuming, for the sake of argument and simplification, at least TRT) for gradual fat loss AND minimal muscle loss over the course of say 6-12 months with minimal sides? First hand experience preferred.

Follow the pharma protocol, once weekly, 4 weeks each at 2.5, 5, 7.5, 10, 12.5, 15.

You can remain at any dose level as long as you like. It does take 4 weeks to achieve maximum blood concentration for each dose, and therefore experience its full potential.

Once you hit goal weight, if you're still losing, drop one dosage level for maintenance. At maintainance you'll feel nothing.

Each dose should be .5ml, ideally to maintain proper pharmacokinetics.

In studies involving thousands of subjects, this slow and steady protocol has been demonstrated to be effective for 98%+, with no loss of efficacy or weight gain after 3 years of use.

Obviously you don't need the speech about protein and exersize.

 

[Ghoul]

The kid (young doc) who prescribed it for me was pretty sharp (MD/PhD).

He warned of a 30% loss in muscle mass, which I am finding hard to believe. Smart people make errors all the time.

Having said that, are you aware of any loss in muscle associated with Tirz. I am on HRT only but thinking of adding Primo to offset any loss in size.

Significant loss of muscle mass is entirely down to reduced protein intake and lack of exercise.

Insurance requires nutrition counseling and an exercise program for GLP coverage, and I think 99% of docs are lying about it. I actually took the opportunity to teleconference with a Nurse Practitioner nutritionist, and she had some useful tips.

The volume of food is so much smaller, most people just eat less of what they had been already, leading to all sorts of nutritional deficiencies, hair problems, weakend nails, etc.

Meanwhile, the Veterans Administration medical system, who are loath to pay for GLPs, enforces the "exercise" requirement by requiring in person physical training, lol.



.

 

[AlexDavis43]

Any downside to 24/7 GIP/GCGR agonism in the long term?

Once weekly dosing usually provides 1-2 day relief and recovery. You get a little hunger and then hit 'em again. This might be part of the mechanism of why these drugs work so well consistently long-term.

I know people are accustomed to 24/7 dosing with TRT but all therapeutic modalities may not have the same mechanism of action.

 

[egruberman]

First hand experience preferred.

Escalate dosage as shown above to the point where you're losing ~.5-1% body weight per week and then hold it there. Get 1g/lb of body weight protein. Likely you'll struggle with that because it's goddamn hard to eat a pile of meat when you appetite is suppressed, so use whey protein if you can tolerate it.

Do resistance training as normal, helps to have a hefty TRT+ dosage and some GH as well. I was cruising all through last year on ~300mg/wk some primo on top, around 5iu of GH, and 9mg of tirz weekly. I went from 25% to 7% body fat and lost no muscle tissue, both verified by dexa.

 

[DeeX]

Sounds like your Vagus nerve is hypersensitive to GLP.

Perhaps one of the rare downsides to GLP class meds, is that they reduce Heart Rate Variability by activating GLP receptors in the Vagus nerve. This is why heart rate often rises after a large meal, though paradoxically, in some it slows heart rate by the same mechanism.

Believe it or not, for children who have "panic attacks", they advise trying standing on their heads, or apply abdominal pressure, simulating a large meal, to slow heart rate .

A very tiny dose of Atropine counteracts this effect within about an hour. It's found in this anti-diarrhea drug, and can be safely taken at a low dose indefinitely.

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Rarely, some people take large doses to get an opioid like high, and become dependent on it, but obviously if you're not popping handfuls at a time this won't happen, since it takes a huge dose to feel anything like that. It's used as a cheap heroin" in poor countries, just so you're aware.

Anyway, might solve your problem if
you feel like giving it a try.

Took 5 months for HRV and RHR to normalize on them, now it's better than before.

 

[Sampei]

Took 5 months for HRV and RHR to normalize on them, now it's better than before.

On what compounds?

 

[DeeX]

On what compounds?

Tirz.

When switching to Reta, similar effect but it only lasted 6 weeks.

 

[Sampei]

Tirz.

When switching to Reta, similar effect but it only lasted 6 weeks.

Interesting. I had crazy HR increase on tirzepatide but I didn't run it for many months. Only few weeks.

 

[IronMetal_2]

My HRV is also down from baseline on Tirzepatide. Nothing major but it's significantly enough for my Garmin to be like: "Your HRV is off!!".

@Ghoul What nutritional deficiencies should one be cautious with long term use of these drugs? I take a multi mineral, b complex and some heme iron.

Also electrolytes?

I'm currently maintaining on 5 mg and want to stay on this stuff long term because it had such a profound impact on other areas in my life, beside the weight loss which is obviously great.

Thanks!

 

[Ghoul]

My HRV is also down from baseline on Tirzepatide. Nothing major but it's significantly enough for my Garmin to be like: "Your HRV is off!!".

@Ghoul What nutritional deficiencies should one be cautious with long term use of these drugs? I take a multi mineral, b complex and some heme iron.

Also electrolytes?

Thanks!

There is no evidence inherent nutrient deficiency caused by this class of meds (despite some theories regarding iron), it's just the result of eating less.

I'm no expert on nutrition, but the first time I went on Sema years ago, weight, and muscle loss was rapid, and fatigue was severe.

All because VOLUME of food you can handle is drastically reduced, and the "can't eat another bite" limit hits so quickly it takes you by surprise, before you've eaten enough of the essential stuff.

Not only muscle loss, but even hair loss.

I leaned to focus on protein, and nutritionally dense foods. For vegetables, I made changes like avoiding salads and raw broccoli for steamed vegetables which occupy far less room (thank you nutritionist for that tip). A good multivitamin is a must.

Forget 3 meals and eat when you feel physical hunger. This is the key to avoiding sides as well. Few of us get genuinely hungry, rather we eat on a schedule. Learn to listen to the signals in the early stages of GLP use, and stop as soon as you feel full. I think I was eating 6-8 small amounts a day.

Sides are delayed, so if you eat "beyond your hunger" you'll be "punished" up to an hour later. I think this delay doesn't register in the minds of some people, so they keep eating themselves into a situation where they get sick later. So again, I emphasize, STOP EATING when hunger stops.

"MyFitnessPal" app gave me significant insight into nutrients I was lagging in,

Protein shakes help.

Stay hydrated, thirst diminishes along with hunger.

Keep in mind this is really an issue of most concern for the first couple of months, like hitting the brakes from 100mph. As your weight comes down, the restraints on food volume ease. Once you get to maintenance, eating is pretty much "thin person normal", and you don't have to obsess quite so much over nutrients.

 

[MrTexas2]

Significant loss of muscle mass is entirely down to reduced protein intake and lack of exercise.

Insurance requires nutrition counseling and an exercise program for GLP coverage, and I think 99% of docs are lying about it. I actually took the opportunity to teleconference with a Nurse Practitioner nutritionist, and she had some useful tips.

The volume of food is so much smaller, most people just eat less of what they had been already, leading to all sorts of nutritional deficiencies, hair problems, weakend nails, etc.

Meanwhile, the Veterans Administration medical system, who are loath to pay for GLPs, enforces the "exercise" requirement by requiring in person physical training, lol.



.

Nice work, Ghoul,

I have been involved in anabolic for more than 32 years...if fact going all the way back to Dan Duchain and I worked with some of the pros out of LA back in the early 90's. For example we pioneered the use of SERMS and AI's.

I am known locally as "the steroid guru" (but only among a very small handful of people I work with). With all due modesty I am pretty much a walking textbook in regards to steroids.

However, now that I am (much) older I do not learn things nearly so easily (like technology) so I am dependent upon you young bucks for my information.

So this is a long way of saying thank you very much, I consider you my "go to guy" when it comes to GLP-1.

My plan with the Tirz is to titrate up a bit from my 2.5 mgs. I feel absolutely nothing from it so far...no sides whatsoever and only minimum appetite loss.

Based upon your protocol I will go up to 5 then 7.5 mgs/week. I will consider 10 once I have been at 7.5 for a while.

But again, thanks!

 

[Clover 0080]

It's going to largely depend on your standard of evidence.

Research bandwidth is saturated, and those issues with the most profit potential as an FDA approved "on label" use, which compels insurance companies to pay for the drugs, are going to get the most attention and expensive human involved studies first.

Longevity improvements will be the last to get funding, as it's not a category of healthcare covered by the payers, generally.

So the highest quality studies thus far have involved diabetics, then the obese, and more recently heart failure patients. Alcoholics were next.

On the other hand, there's a huge amount of in vitro and animal research going back decades, showing a myriad of positive effects on every organ, like nerves, for instance (an area of particular interest to me, for the potential to preserve senses and cognition), and directly exerting an anti-inflammatory effect on blood vessels.

There's certainly benefits unrelated to weight loss, the most well substantiate have been the ones on addictive behavior, which manifest so quickly weight loss hasn't had time to take place to any great degree, but, yet again, the majority of data was tangentially gathered from studies focused on other issues with diabetics and the obese as subjects.

I can personally say this is definitely true. I am now an 8 year recovering alcoholic. I started tirz in April while I was slamming 2.5 boxes of red wine a week. Today I drink nothing as the want is not even there anymore. I originally thought it was because I was feeling too full from everything even drinking but now I know it's just because I don't WANT to drink every night.
Imaginehow many times I've tried to quit alcohol in my life just to start a "weight loss" shot and completely give it up within 2 months

 

[Ghoul]

I can personally say this is definitely true. I am now an 8 year recovering alcoholic. I started tirz in April while I was slamming 2.5 boxes of red wine a week. Today I drink nothing as the want is not even there anymore. I originally thought it was because I was feeling too full from everything even drinking but now I know it's just because I don't WANT to drink every night.
Imaginehow many times I've tried to quit alcohol in my life just to start a "weight loss" shot and completely give it up within 2 months

I've seen this happen numerous times in the last few years as I've helped people around me start using GLPs. Alcohol, cigarettes, pot, and of course excess food, diminished or gone entirely. It's opened room in their lives that most often gets filled with a focus on health, physical, psychological and social. Freed from something that had a powerful grasp in them. Silence and your own thoughts replacing the endless mental "noise" you try to perpetually resist, and, eventually, exhausted, capitulate.

The "Don't do it, use all your WILLPOWER before resorting to those terrible drugs!" crowd will be seen as unwitting villains in a more enlightened near future.

If this were the dawn of insulin, they'd be shaming diabetics over their choice to inject a hormone instead of expending a massive effort to carefully use diet to manage their blood sugar manually.

With any luck the expensive tests that are clearly identifying folks with GLP deficiency and/or resistance will become more widely available. The genetic tests that detect those with GLP problems correlate very closely with the presence of metabolic disorders and even the likelihood of having substance abuse disorder.