Will the GLP-1 drugs promote longevity and healthspan?

[Neo]

Functional and multi-omic aging rejuvenation with GLP-1R agonism

Importantly, the beneficial effects are specific to aged mice, not young adults, and are achieved with a low dosage of GLP-1RA which has a negligible impact on food consumption and body weight. The molecular rejuvenation effects exhibit organ-specific characteristics, which are generally heavily dependent on hypothalamic GLP-1R. We benchmarked the GLP-1RA age-counteracting effects against those of mTOR inhibition, a well-established anti-aging intervention, observing a strong resemblance across the two strategies.

Functional and multi-omic aging rejuvenation with GLP-1R agonism

[Neo]

@DrFraser @adssx @AlexKChen you might find this study interesting

[AlexKChen]

"negligible impact on food consumption "? Hm interesting
I just injected myself with 1mg tirzepatide for the first time! it feels smoother though idk if this is enough for significant appetite suppression

“Glucagon-like peptide-1 receptor - Wikipedia” => and they INCREASE insulin. If they increase insulin while having a negligible impact on food consumption…

[adssx]

Can’t wait for the phase 3 trial results of exenatide for PD. I’m willing to bet it reverses Parkinson’s (and therefore neuro ageing?).

[DrFraser]

So @AlexKChen 1 mg will be homeopathic for most individuals — 2.5 to 3.75 mg weekly is a bit more likely to have a clinical effect. I’m still really torn in regard to neurocognitive decline whether GLPs/GIPs that cross the BBB are necessary. On a practical level, the compounders are not making the ones that cross the BBB as they aren’t that effective for weight loss - and this is where the $$$ are at.

My costs on Tirzepatide with Empower are ~$330 for 34 mg or $575 for 68 mg. However, this is in a vial at 17 mg/mL so really easy to titrate.

Tirzepatide is significantly GIP and weaker GLP-1 - and there is evidence that GIP is neuroprotective. I however think Semaglutide is probably the most potent on GLP-1 alone - but also doesn’t cross the BBB.

If you look at effects on the brain with GLP1’s- indirect effects through the vagus nerve seem very powerful, so the issue becomes do you need an actual brain level of the drug? If so, then Trulicity (Dulaglutide) is likely drug of choice, but then we have more expense with that.

I’ll address this issue in an upcoming blog on neurocognitive decline- I just went through the SGLT2-i on this series, but this is a particularly interesting area.

Do we go for lower GLP-1 potency, and a level in the brain, or do we go for a more potent GLP/GIP and think the effect is through vagus nerve signaling? There is a cost effect of this, which is $1100-1200/month vs. $100/month as I have no compounders doing dulaglutide.

My approach has been to go with the cost effective GLP, BUT not have all my “eggs in one basket” and make sure we have additional strategies in play.

The other complicating factor can be patients who really can’t afford to lose weight (yes this is a real factor in some patients — a rarity - but common in my patients) - so there we need to go with a less potent GLP and then look at Rx of Trulicity, but then dose splitting to keep costs down, and still give a decent brain level.

I suspect it will be some time before we get a trial with semaglutide or Tirzepatide to really understand whether a direct brain level is needed.

I’d love others thoughts on this, as it continues to be an area that I would love better certainty on.

@Neo - thanks for this study. Interestingly, TruDiagnostic even 18 months ago had indicated the GLP-1 drugs were tracking very well as compared to almost everything else on being predictive of a lower epigentic age vs. chronology. So this study isn’t surprising. I have a lot of patients on GLP-1’s for longevity and neurocognitive decline risk. With all the bad media reports on these agents, it is important to understand they generally have an excellent safety profile, and the main issue is cost. Most people have some weight to lose, and it helps optimize this also. There are individuals who have a “guilt” around taking a drug to lose weight, as they consider this a personal failure. I find it therapeutic as physician to completely dismiss this, and let them know these a amazing longevity drugs, and that I’m thrilled to be able to Rx it, as it would be a problem if they had no weight to lose. The same issue comes up with Telmisartan - I love it when my patient has a bit of hypertension - as this gives me the opportunity to Rx a drug with great data for longevity, whereas my patients who are ideal body weight and have a SBP of 105 — I can’t recommend these therapies.

[Joseph_Lavelle]

“ We benchmarked the GLP-1RA age-counteracting effects against those of mTOR inhibition, a well-established anti-aging intervention, observing a strong resemblance across the two strategies. ”

Would we assume these strategies stack (add up) or are alternatives (can only fire the bullet once)? If I use rapa would a low dose GLP1 add more benefit?

[Neo]

@Joseph_Lavelle

Would we assume these strategies stack (add up) or are alternatives (can only fire the bullet once)? If I use rapa would a low dose GLP1 add more benefit?

Seems jury it out, but the answer is that they both overlap and are distinct, see these parts from page 7 and 8 of the paper.

Also unclear even where similar effects since they arrive there from different starting pathways it might be still valuable to complement for max impact, use both but at lower dosages or just do one.

Similarities

Differences

Other analysis showing similarities

And differences

And from conclusions section:

Full paper with figures here:

https://www.biorxiv.org/content/10.1101/2024.05.06.592653v1.full.pdf

[Neo]

Did you ask ITP if they were going to test some GLP-1 things?

[adssx]

I think they don’t want to test injectable drugs. So oral semaglutide is the only option for now. And they rejected it because they think it’s too big a molecule. We’ll see how it performs on worms…

[Neo]

Time:

A New Genetic Test Could Determine Which Weight Loss Drug Will Actually Work For You

Weight loss drugs like Ozempic and Wegovy don’t work the same for all people. A new genetic test could tell you in advance which will for you.

A New Genetic Test Could Determine Which Weight Loss Drug Will Actually Work...

A New Test Predicts Who Will Benefit Most from Weight-Loss Drugs

MyPhenome could help identify patients for whom the drugs are worth the cost and potential side effects.

A New Test Predicts Who Will Benefit Most from Weight-Loss Drugs — TIME

[Bicep]

This is something I didn’t know about semiglutide:

We wouldn't have Ozempic without Gila monsters — their hunger-regulating...

It comes from the venom of the Gila Monster? Interesting back story, useless but interesting.

[adssx]

@Bicep

It comes from the venom of the Gila Monster?

Exenatide comes from Gila Monster’s venom, not semaglutide. Here’s a good podcast of the story behind GLP1RAs: Novo Nordisk (Ozempic): The Complete History and Strategy

[AgentSmith]

This MyPhenome test strikes me as unnecessary and another opportunistic money grab based on the false premise that the only option is to pay $1200 a month out of pocket for name brand drugs.

It’s $349 for a very limited scope genetic test that he says will indicate that about half of the population is expected to respond to a GLP.

The price is in this version of the article:

A New Genetic Test Could Help Doctors Prescribe Weight Loss Drugs

Yet a 50% response rate seems really low based on groups I’ve been on for over a year. Judging from the forums, there are very few non-responders. Odds are good that you won’t waste your money by simply trying the drug.

So instead of paying $349 for a test to tell you that you have “hungry gut” or “hungry brain”, which you will already know if you’re obese (because it’s obvious - believe me), how about spending the money on a 1-2 month supply of compounded tirzepatide? Or buy domestic gray market peptide versions, 1 vial each of semaglutide, tirzepatide, and retatrutide and just try them out… You’ll get about 3 months worth at starting doses.

Better yet, buy several months worth from an international vendor because prices are now as low as $1.10/mg for tirzepatide and retatrutide.

[Davin8r]

@DrFraser

With all the bad media reports on these agents, it is important to understand they generally have an excellent safety profile

Dr. Fraser, have you had any issues with semaglutide significantly cutting heart rate variability in your patients? My HRV took a big hit (down) with even oral semaglutide (Rybelsus 7mg) to the point I felt tired all the time and needed daytime naps, which gradually reversed after stopping the Rybelsus. I’m wondering if I should have just “hung in there” and that maybe it would have reversed over time(?), in case you have any real-world experience with this in patients. @AgentSmith, anything you can add?

[AgentSmith]

I have Oura Ring data and a log of each injection going back a year, but I started the tirzepatide 6 weeks before I got the Oura ring so I don’t have a good baseline. I’d also have to do a careful analysis and look for confounders - and there are many potentials.

I will say there are a lot of anecdotal reports about initial insomnia and elevated heart rate (presumably lowered HRV) on the forums, and I did experience that when starting tirzepatide and when trying retatrutide, but the insomnia and heart rate issues seemed transient. I’m going from memory here, not my data, so I might revise that statement later.

Fatigue is commonly reported, but I have assumed it was due to caloric restriction. Maybe due to lower glucose also.

I’ll report back if I have a chance to look at my records and see if there’s anything obvious.

[DrFraser]

Yes I’ve seen some literature on that. Overall, longevity and neurocognitive wise, I’d say great drugs.

It depends on why you are taking the drug. If for neurocognitive decline, then go with dulaglutide or exenatide as they cross the BBB. If you are taking it for weight loss and secondarily for neurocognitive decline, then Tirzepatide as this agent is primarily GIP and only mild on GLP-1 and better weight loss.

Hopefully that helps a bit. I think the evidence is regardless of impact on HRV, these drugs are beneficial on a longevity basis - but if having side effects, adjust things and go to another drug.

[DrFraser]

Also - my favorite compounding pharmacist Henry – at midtownexpresspharmacy in Nashville has a sublingual semaglutide that is daily under the tongue that seems as effective as injectable. Pretty cool stuff. I’ve not had enough experience with it yet, but he claims 4400 patients on it with similar results, and more tolerable.

[KarlT]

@AgentSmith

So instead of paying $349 for a test to tell you that you have “hungry gut” or “hungry brain”, which you will already know if you’re obese (because it’s obvious - believe me), how about spending the money on a 1-2 month supply of compounded tirzepatide?

Agree. Most people know within days if the medication is going to work, and it will work in most people.

As to health span and life span, I’d think it very likely helps. Decreased weight, calorie intake and blood sugar will be beneficial. Just a question of yet to be determined adverse side effects.

[SNK]

Thought this to be interesting.

Eli Lilly awaits head-to-head study on GLP-1s after new report reaffirms superiority (yahoo.com)

Now the question is; does Indian Pharma makes a generic of Mounjaro?

[Thorin]

One can buy Tirzepatide (the active ingredient in Mounjaro) from peptide suppliers. I believe the actual producers are all located in China, but there are US-based companies packaging it up and reselling it. It is readily available.

The price from US-based companies tends to be around $100 for 10 mg, or $10/mg. A typical weekly dose is ~ 10 mg (one starts at 2.5 mg, ramps up slowly, with the top dose being 15 mg per week). So this is not cheap.

I imagine if you buy in bulk directly from China you can pay much less. If anyone knows of a reputable supplier, I’d like to know.

You can also sign up for Telehealth services that will provide compounded Tirzepatide for around $400 per month. This makes more sense than buying from Peptide providers, in my opinion. I tried this using a place called Eden and it worked fine. But there are many such places, and I can’t say if Eden is the best one. A little work using Google will identify plenty of places, so if anyone is interested, I recommend doing that.

Recently I decided to try a different drug called Retatrutide. This is an Eli Lilly drug that has been through phase 2 trials but has not yet gone through phase 3 and is not on the market yet. So obviously one cannot get a prescription for this, but it is available through peptide suppliers, supposedly for research purposes.

Getting back to the question posed by this post (will the GLP-1 drugs promote longevity and healthspan?) the partial answer is obvious: Yes, in certain populations. Everything we see says that heart disease risk is reduced, kidney disease risk is reduced, sleep apnea is reduced, etc., etc. So if your BMI is 40, most likely these drugs will add years to your life. Not for everyone, but statistically speaking, on average, for that population, there is a major benefit.

Much less clear at this time is whether that benefit would accrue to those for whom these drugs are not currently indicated. That population (say, BMI < 27.5) has not been studied much yet. BMI is a coarse measure of metabolic health, but that is what has been used so far.

Anyway, I suspect that if you were a perfectly metabolically healthy person, the drugs would have the risk of side effects but little to no benefit - you generally can’t fix what isn’t broken. But over time we may get some data in this group and we should change our opinions if the data suggests otherwise.