May 29, 2023

Metformin is a molecule that I personally took because of initial encouraging data. However, a massive 2021, randomized, placebo-controlled trial was published showing that for non-diabetic people, there was no benefit from taking metformin.

Metformin which is a medication that i prescribe to my type 2 diabetics had great promise as a way to extend lifespan and it’s a molecule that i personally took we had my starter published in 2008 showing a 37.8 percent increase in lifespan and in 2014 we had observational human data showing that diabetics who were taking metformin appeared to live 15 percent

Longer compared with matched individuals without diabetes since that initial promise though data has steadily trickled through suggesting that metformin for non-diabetic patients probably won’t extend lifespan and towards the end of 2021 we had a high quality long-term human trial that convinced me to stop taking metformin so let’s go through the initial data

That generated the excitement around metformin then the steady trickle of disappointing data and then we’ll finish up by having a deep look into this long-term human trial let’s get into it let’s start by taking a closer look at the 2008 paper showing that metformin slows down aging and extends the lifespan of shr mice now i’m a medical doctor so i’ve had to

Educate myself about how pre-clinical trials work particularly the different types of mice that are used in these trials so when we’re talking about shr mice what does that actually mean so shr mice are spontaneously hypertensive rats so first of all they’re inbred rats and they’ve got a particular set of genes that causes them to have high blood pressure so yes

In these mice metformin will extend lifespan but that doesn’t really correlate to human data we are not inbred and most of us don’t have particular genes that causes us to have high blood pressure so we need to tread carefully when interpreting this data which brings me on to the interventions testing program this is a program that uses genetically heterogeneous

Genius mice so the mice are not inbred and they’re genetically diverse so it more closely resembles the general human population they also test each molecule at three separate sites so this is to make sure that the results that they get are reproducible that we’re not just seeing a quirk from a particular lab and in 2016 the interventions testing program they turned

Their attention to metformin and they found that metformin did not significantly extend lifespan so this is the creme de la creme of pre-clinical work and it suggests that metformin it won’t extend lifespan so that’s the pre-clinical work what does the human data show well starting with a study published in 2005 from the british medical journal it suggests that any

Exposure to metformin it reduced cancer rates by around 21 in 2014 we had an observational human trial that suggests that people who didn’t not take metformin they had a 15 lower survival rate compared to diabetic people who did take metformin one of the crucial things that i need to highlight about this paper is that it’s an observational paper so it’s looking

In the rear view mirror and the trouble with that is that we can have a lot of different factors that can influence the data and we’ll dive a bit deeper into that later on in the video but still from 2014 the human data is looking extremely promising for metformin so how does metformin actually work well one of the mechanisms is that it activates an enzyme called

Ampk now ampk is heavily involved in the responses to exercise so that led some researchers to think would metformin interfere with exercise benefits and in 2019 a troubling paper was published so this paper wanted to look at the combination of metformin and exercise the trouble is though metformin it seemed to stop the benefits of exercise so so the participants

Undertook 12 weeks of exercise training and metformin it seemed to blunt the positive effects on vo2 max by around 50 percent so this just means that people who weren’t taking metformin were receiving the full benefit but those taking metformin only received about half of the benefit metformin also seemed to blunt the positive effects on strength training so after

Looking at this data i made the decision to only take metformin on rest days i didn’t want metformin to be getting in the way of my exercise training now ideally i’d want to be exercising around five to six times a week so that means that i’m only taking metformin once to twice a week so a significant reduction from what i used to do so the pre-clinical work isn’t

Looking too promising and we’ve got good human data suggesting that metformin should not be taken on exercise days and that leads us on to this 2021 paper that i only just became a whereabout in the past couple of weeks and it’s a long-term paper that started in 1996 and it involved over 3 000 adults at high risk for type 2 diabetes this is important because if we’re

Going to see a positive effect for already healthy people when they take metformin we should see even greater benefits if we take metformin for high-risk individuals the participants were divided into three separate groups one with intensive lifestyle intervention the other one with metformin or the other one placebo overall they were followed up for 21 years so

Again this is a long-term human trial and here’s what they found although metformin it prevented diabetes it did not reduce all cause cancer or cardiovascular death rates this is a crucial finding so we’re going to spend a lot of time diving into the details about this paper metformin does have evidence for lifespan and health span extension in animal models but

Like we’ve gone through that evidence is shaky in addition there’s numerous observational studies that suggest that metformin may reduce the risk of all cause cardiovascular and cancer death rates among people with type 2 diabetes and we’ve gone through that data already a recent trial from the uk shows that adults with newly diagnosed diabetes it does demonstrate

Positive effects of metformin in lowering the death rates so this is why for my type 2 diabetic patients i still prescribe metformin it’s the number one choice however no trial has evaluated the effect of metformin on all cause death rates in a population of adults at high risk for developing type 2 diabetes because diabetes increases the risk of all cause cancer

And cardiovascular death rates we hypothesized that metformin it should lower the risk for all cause cancer and cardiovascular death rates so the authors started this trial with the idea that metformin would lower the death rates for high risk individuals so let’s go through the trial from 1996 over 3 000 adults aged over 25 years old were enrolled in this trial

Involving 27 different clinical sites to be included in this trial they had to be either overweight or have high fasting blood sugar levels one group took metformin 850 milligrams twice a day with the standard diet and exercise recommendations or a placebo twice daily again with the standard diet and exercise recommendations from 1996 to 2001 the trial it was

Stopped because the primary outcome of figuring out would metformin lower the rates of newly diagnosed diabetes it was successful so in my pre-diabetic patients i do prescribe them metformin because i want to reduce the chances that they will develop full-blown type 2 diabetes but here’s the interesting thing about this trial those people who did not develop type 2

Diabetes the group that were already on metformin were continued on metformin and those who weren’t taking metformin they didn’t receive it and they wanted to see would those taking metformin who did not develop type 2 diabetes would they have lower rates of death we had over 2 500 people continue this trial and they were offered quarterly lifestyle sessions those

People originally randomized to metformin they continued taking the metformin and over the 21-year period that the trial ran we had 453 deaths from the trial population and here’s what they found there was no difference between metformin and placebo groups and the risk of all cause cardiovascular and cancer death rates this is a crucial finding and i do want to

Repeat it so for people who are at high risk of developing type 2 diabetes the all-cause death rate it did not differ between metformin and placebo although metformin it was associated with reductions and several risk factors for heart disease those interventions did not actually lower the death rates from heart disease cancer was the leading cause of death in the

Study population but metformin it did not reduce the risk of cancer death rates compared to placebo this trial is unique in its ability to examine the effect of metformin on all cause and cause specific death rates in a study population at high risk for developing type 2 diabetes and again this is so important because if we’re going to see a benefit for otherwise

Healthy people when they use metformin we should see an even greater benefit for high-risk people but from this long-term human data again that’s forward-looking we don’t see any benefit by taking metformin so why is there a difference between this forward-looking trial and the observational data where we’re looking in the rear view mirror well let’s go through

Some of the reasons past observational findings they may differ from our results due to potential confounding because some pay patients who were on metformin they’re probably healthier compared to the comparison groups being treated with other anti-diabetic medications although the observational studies attempted to account for these different factors there still

Could be residual confounding factors by diabetes duration severity and complications overall i want to try and sum things up for my pre-diabetic or early diabetic patients i still prescribe them metformin and for my type 2 diabetic patients i definitely prescribe metformin it’s still the first line but here we can see from this long-term trial that people who

Are at high risk for developing diabetes so they’re not yet early diabetic patients there was no benefit seen so there doesn’t appear to be a strong reason to take metformin so the pre-clinical work from the interventions testing program it doesn’t support taking metformin and this long-term human data doesn’t support taking metformin either and the problem with

Metformin is that it does appear to to interfere with exercise benefits there is a trial called the tame trial so it’s the targeted aging with metformin trial so what they’re trying to figure out is wood giving metformin to otherwise healthy people give lifespan benefits but coming back to this 2021 paper we’ve already got the data we’ve got high risk individuals

Who were taking metformin compared to placebo and there wasn’t any benefit truth be told i’m a bit gutted about this because i was holding metformin in high hope the observational data supported it and the initial pre-clinical work in mice also supported taking metformin so it’s disappointing to see that metformin hasn’t panned out yes we can always wait for more

Data to come through but for me the pre-clinical work it doesn’t support taking metformin and this 2021 trial is a long-term trial forward-looking and it’s placebo-controlled we didn’t see any benefit so i’ve made the decision to stop taking metformin and that’s all we we can do we can only react to the latest high quality data so please let me know in the comments

Section what you thought of this video and what you’re going to do about metformin are you going to continue taking metformin on rest days or are you going to stop metformin like i have and a massive thank you to all of the patrons who support the channel and please make sure to check out my clinicaltrial fundraiser for rapamycin and until next time thanks very much

Transcribed from video
Metformin – New Longevity Research is Game Changing! By Dr Brad Stanfield