Metformin - Based on latest 2022 info, Any health / lifespan benefit for Non-Diabetics?

I don’t look at patients on GLP-1 agents as often clinical experience-wise, but it seems when discontinued, there is a close to original weight rebound and positive cardiometabolic effects are largely gone.

I’m not sure it’s a “cure” (depending on your definition) that reverses metabolic syndrome entirely as much as a tradeoff since there are some potentially serious side effects and one appears to have to be on it continually. Not to mention, lifestyle factors are still part of combined treatment. Don’t get me wrong - I agree it’s closer to a “miracle” diabetes drug than metformin is assuming carefully titrating and all. I just have reservations regarding expression of the GLP-1 receptors in tissues where it may not be favorable (ie long term use and pancreatic hyperplasia) hence I caution those who are borderline overweight but no risk factors when they are considering an adjunct.

Would be interesting to hear your clinical experience

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My team has treated several thousand patients over 2 years with the GLP’s. I am , of course, using the term cure as a layman would, since really we only actually cure infections, everything else is chronically controlled.
Naturally, when you remove the the control, the disease recurs, but this is no different from removing the antihypertensive agent and seeing the hypertension return, or stopping statins and the lipids go back up. This doesn’t stop us from controlling the disease to the best of our abilities.

As far as side effects, it’s almost entirely GI related and with careful titration, mostly mild. Nausea is easily controlled with zofran when necessary. The most serious possibility is medullary thyroid cancer and it wasn’t clear at all if this was a serious concern from the study on mice. It’s a contraindication if there’s a FH of such.

Tirzepatide seems stronger and possibly with less GI issues.

There’s many more in the pipeline.

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Yeah

Rapamycin + anything.

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Yeah, agreed - I’m not super convinced about the mice studies for the thyroid side, since it probably is only relevant to a minor degree to humans at best.

However, there is an association between pancreatitis and subclinical pancreatic inflammation though. I suspect it is more relevant considering GLP-1 expression on human exocrine duct and beta cells. Cholangiocytes are another potential issue long term.

Not the type to inadvertently risk rare pancreatic cancer which as you know is pretty deadly. I personally think right around the top 10 cancer-related deaths (adjusted for “healthy” non-smoking/non-obese men personally) are worth being slightly more cautious especially if early stage is asymptomatic, even if rapa may help.

I was bullish on dual agonist tirzepatide as you mentioned (and made a small but sweet sum on a small position on Eli Lilly stock so perhaps I’m biased), but we shall see in longer-term use. I’m not ready to try shooting these agents at even a low dose when exercise, diet, sleep, and acarbose (100 mg tid)/recent intermittent canaglifozin (100 mg, I have FHx of gout & HTN - wanted to keep serum uric down to <5.8) seem to do well for HOMA-IR for me personally to modulate GLP-1 instead of going to DPP-4i or GLP-1 agonists. Would rather see more longer-term data particularly with tirzepatide.

Btw, on an slight tangent - had a tiny possibly unusual observation that may be of a curiosity to you as it appears to be potentially related to rapa - with a washout - my fasting insulin (14 hrs fasting) went lower than “normal” to 0.8 mIU/mL and fasting glucose 88 (I have naturally higher glucose levels near 100 before cana/acarbose, despite “perfect” diet, low-normal BMI and 12% body fat via DEXA so I wonder if it’s a low beta cell/adiponectin issue), but A1c discordant and went up to 6% (resolved intermittent anemia related perhaps? Reticulocytes still at the very low end of normal, perhaps still from temporarily discontinued rapa?).

Gonna keep checking to see with a crossover soon (doing unblinded for this one). Wondering if you had any recommended endo specialist buds preferably with some research experience/prior or current attending at an academic hospital I can consult directly for a second opinion that might be familiar and interested to check this one out without chewing me out for using rapa? Always looking for a few more brains to make sure I’m not missing something. Not particularly concerned with expense and I’m probably gonna test fructosamine anyways at this point even though there’s not enough evidence to warrant it and merely on theoretical basis.

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You’re right, we have seen someone with pancreatitis. Probably from semaglutide.

I also am prone to having my FBS at 100. Must be genetic. Are you pretty sold on acarbose. Might have to try it. Side effects?

If your retic count is slowly normalizing, then I suspect rapamycin and its influence on cell proliferation.

I’ll keep an eye out for endocrinologists, but in my experience they view rapamycin as a dangerous drug except for transplant medicine. Very smart, but narrow view. Mainly, they don’t take, or have, the time to look into it.

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Acarbose side effects for me have been only increased flatulence (not odorous for me personally, but a general suggestion would be activated carbon underwear if odor is an issue and perhaps exploring very low dose lactitol) with titration - as you know the main reason most do not prescribe acarbose is the usual GI toxicities and low adherence - not any serious long term side effects. In terms of A1c lowering, it may be non-inferior to metformin as shown in a large Chinese MARCH2 trial. It’s first-line over metformin in mainland China - perhaps it’s “working better” due to higher carb/rice intake?

But I’m not sure flatulence is necessarily a bad thing and it may be a good “side effect” - may be an indicator that the fermentation in the gut is working - somewhat analogous to increased fiber intake.

The main issue as I’ve frequently alluded to is the potential for “acarbose resistance” by the microbiota in the long term, but that could potentially be avoided by using multiple potential natural inhibitory agents from diet alone - similar to how we avoid antibiotic resistance but without the side effects associated with antibiotics. Acarbose was originally discovered from the fermentation of Actinoplanes utahensis and resistance for these agents are sort of a product of microbial warfare - my current hypothesis is one would want to side with the SCFA producing communities slightly more so. Acarbose and the inhibitory agents I’m referring to are 98-99% not systemically absorbed. Other pharmalogical agents in the same class have higher rates of systemic absorption, hence I do not use those out of an abundance of caution. I’ll also add the ITP PI Richard Miller MD PhD is taking acarbose personally (for starchy meals), but doesn’t publicly endorse it of course. So perhaps he’s also seen something I haven’t mentioned to warrant taking it.

An issue of note is a rare potential for increased hepatic enzymes on LFTs for some people, but it’s currently attributed to SCFAs most likely, which is indirectly produced from acarbose. I had no increased LFTs and they are low-normal.

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Thanks tong. You’re a font of information and I’m sold.

To your point on flatulence Men fart more when eating a plant-based diet due to good gut bacteria | New Scientist

My main hesitancy with acarbose is that we rarely prescribe it here, so I figured that there’s a good reason for that, but it’s certainly just the side effect issue. No big deal.

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Haha thank you for the compliment and happy to oblige anytime.

I understand the general hesitation with less clinical use here in the US - I’ve gotten that before with some docs asking why I’m on this “not-a-first-line-med”. I have a few MBBS buds from HKU that were familiar with these larger-scale Chinese studies and clinical use (as mentioned, MARCH2 on Lancet may be of interest), so I asked them - just partly relaying their experience and literature review, I can’t take credit as the originator for most of the things I’ve mentioned on acarbose. However, I did do my own review independently to consider the pros and cons of the intervention and I suggest any doc to do the same.

I’ll also mention I specifically use the branded Precose which is not generally recommended - I’m just a stickler about avoiding long-term generics use personally when possible, despite increased costs out of an abundance of caution. Generics destined for developed countries (particularly “authorized generic”) are highly, highly likely to be equivalent with better cost-effectiveness and may be at best a tiny chance of a marginal difference in terms of QC/QA.

BTW, another interesting observation I forgot to mention is a better lipid profile on acarbose, particularly lower TG, compared to metformin - in the trial I mentioned, as well as empirical in the clinic. And another update on my previous NMR Lipoprofile result I mentioned in case you’re interested - I learned from a lipidologist consult who reviewed my labs and claimed low HDL-P but “optimal” HDL-C is not an issue, when in the context of my low TG personally.

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It only makes sense since hepatic production of triglycerides is glucose and insulin dependent, so the lack of glucose and less insulin is inhibiting hepatic lipogenesis.

On the other hand, there’s some evidence that triglycerides are a marker of inflammation,in which case just inhibiting their production wouldn’t be telling the whole story but merely limiting the usefulness of a biomarker.

On the other hand, it could be that triglycerides actually cause inflammation.

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You suggested: activated carbon underwear if odor is an issue.

They really make those? My gas is pretty odorless too… but hmmm… might check it out on Amazon.

Also, yes… flatulence - gas ican indicate a healthy group of microbes at work in the gut.

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I am assuming that was a very good joke… Though not an unreasonable product opportunity given my early experience with acarbose and my children’s reaction to the increased gas…

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Not so fast RapAdmim. Tootles… Check this out! https://a.co/d/3JQ6Uzo

Mens fart filtering underwear… let them rip!! LOL.
I wonder if the final air can be scented… pine forest or sandlewood? My next skunk works! Kidding.

Visit the Stitches Medical Store

The answer to Acarbose gas. I was being serious…Amazon has everything… with the right description terms. Hahaha.

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Yes, they do make those. Wasn’t kidding. I won’t be naming any brands for now.

Although now that I think of it - I did want to ask if everyone feels it alright - @RapAdmin and y’all - I may soon experiment with getting a few of my personal assistants to help me work on a website with a list of what I use or recommend for my patients with only Amazon or equivalent retailer affiliate links, not supplement maker websites, to avoid incentives to rely on sponsorship by any particular brand. I won’t be selling any supplements either. It’ll also have the pros and cons with detailed literature references and preventative medicine and occasional “precision medicine” content in a more layman-friendly format.

A bit of a long story so TLDR: I’ve been down the road of a few copywriting gig before med school and I believe there is some value in avoiding brand sponsorships to avoid the appearance of impropriety. I quickly realized affiliate marketing is not my cup of tea in the long run, but unfortunately, I can only put so much of my own money into clinical trials - so I’ve been mostly relying on extending the life of older shelter dogs and metabolic kennels - they often don’t come with associated adoption costs. It’s been hard to convince foundations for funding and no investors want to go for generics, so 100% of the proceeds minus minor operational costs of the website and staff (almost all of them in the Philippines with one US staff member) would go to help financially support a proposed human clinical trial that I’ve been trying to get funded on regarding preventative once weekly rapamycin, acarbose, and “polypill” for 3 years for those with early signs of mild cognitive impairment and elevated stroke risk with “typical” risk factors (ie prehypertension, smoking, overweight, physical inactivity or inadequate diet), but exclusion of those with chronic diseases or hyperlipidemia. It would be a great step into proof of concept and human safety to combine the winners in the ITP and an existing life-extending “polypill” in a combination therapy approach rather than monotherapy. I believe that will likely move the biogerontology field and combination therapies forward the most - if it is successful.

It’s not for my personal benefit besides my interest in the results of the trial and would be under an audited 501c3 - if the trial doesn’t get funded enough in 5 years - it’ll just be donated to a separate human rapa trial decided by popular vote.

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Yes, that is from a joke tweet by Dr.Blagosklonny, but it doesn’t make it true and it’s not science.

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To be clear, it’s not a joke and that’s what I suggested with a few patients with gas problems in their personal context - although I caution these underwear products are not clinically validated, probably due to lack of interest. It does have some valid anecdotes I’m aware of and makes sense in theory, hence I mentioned it as a possible inexpensive trial use.

SCFA production can be odorous, but usually, it’s more on the sulfur and ammonia end (as well as indoles, skatoles or volatile amines) when it comes to odor.

If anyone has odorous gas and desires to reduce it, I’d also consider checking diet - cutting down on cysteine/sulfur-containing compound intake ie eggs may help - although the jury is still out on potential positive health effects of some H2S gas production. However, I’d also beware of alarm features in flatulence, particularly in older adults and/or unknown cause, and one should consider talking to a physician for ie malabsorption or obstruction (a possible sign of colon cancer). I should also mention there are certain contraindications for drugs such as acarbose or FODMAP foods that increase flatulence ie IBS, intestinal obstruction, etc. I forgot to mention for acarbose hence I always suggest looking to your doctor before adding anything. Don’t rely on anything I say for any hint of medical advice.

As for very low dose lactitol, it may cut down on ammonia gas and increase transit time slightly to also reduce odorous flatulence. It is used in Japan at around 2g and seems to have better documented clinical evidence.

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Sorry, I was not texting about acarbose. I was responding to rapamycin + metformin.

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I find that meditation helps to increase my HRV. This might be worth considering if you don’t already do this……

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I am a bit baffled about all the negative comments here on Metformin. There is numerous studies that shows that it has positive effects for men. Blunts prostate cancer, lower PSA, Helps with BPH and so on.
I take 750mg extended release every night before I go to bed, and I can feel that my swollen prostate is a lot less irritated when I use Metformin.
Yes it lowers testosterone, but that is exactly my problem. Unfortunately I have to much of it.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641083/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758272/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405102/

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Great idea. You provide great quality information so i think it would help people.

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This has been a lively back-and-forth debate. Personally, I took metformin for many decades and I am a big believer in the overwhelming evidence, IMO, that metformin is beneficial for life extension. Some of these studies suggest a diminishing return for the elderly and that is the only reason I stopped taking it. Even that is problematic.

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