Should healthy people take metformin? (benefits vs. negative exercise effects) | Rhonda Patrick

So the real interesting question, as you mentioned, you knew people that don't have type 2 diabetes that are taking metformin, right? So the real question is, well, what about people that don't have type 2 diabetes? Like, we want to get a tighter control on our blood glucose levels and our insulin sensitivity. And probably one of the studies that sort of sparked that interest was a large study, prospective study, Yeah. That showed— it was like 78,000 individuals. Some of these people took metformin. There were type 2 people with type 2 diabetes that took metformin, and some were people with type 2 diabetes that did not take metformin. And there was also some that took another type of drug. I forgot the name of it.

But the interesting thing was that the people with type 2 diabetes taking metformin lived on average— I should also mention there were age-matched controls that did not have type 2 diabetes. Right. The people with type 2 diabetes that were taking metformin lived on average around 15% longer than the age-matched controls without type 2 diabetes. Like, that's what got my interest. That's what I was like— that's the, that's the study where that really piqued my interest, where I was like, okay, what's going on, right? Yeah, it's like, do I have to— now can I be a healthy individual and take metformin, or do I have to go get type 2 diabetes first? Right. Or do you— are— okay, so you said healthy individual and take, and take metformin, or Or are you a healthy individual and you exercise?

So there was a large randomized controlled trial done by the U.S. Diabetes Prevention Program. I don't remember when this was published, a few years ago. They showed that a hundred and fifty—this is a randomized controlled trial, okay?—hundred and fifty minutes of moderate intensity exercise per week prevented the progression of prediabetes to type two diabetes by about almost sixty percent. So people with prediabetes that were assigned to this exercise group to do 150 minutes of moderate intensity per— exercise per week. Which is a good amount of exercise. It is. It is. But— and that's— but that's pretty robust, 60— about 60%, you know, preventing the progression, right? Yeah. Now the other group was also people with prediabetes. They were given metformin.

And metformin prevented the progression into type 2 diabetes by 31%. So exercise that— moderate-intensity exercise, 150 minutes a week, was about twice as good, right? Right. Now, the real question is, what if you were a healthy individual that exercises like you, me, and probably most of your friends in Silicon Valley are and you took metformin? Is there a synergistic effect, right? Is there an additive effect? Right. Like that's the real question. And, I'll tell you, Multiple, multiple randomized controlled trials now—not just one, not just two, not just three, not just four—more than that have shown that the opposite seems to be true, where taking metformin in the context of either aerobic exercise or strength training exercises seems to blunt many of the positive effects of exercise.

So let me get a little more specific there. There was a randomized controlled trial. Published, I believe it was a year ago or something, that was done because there had been multiple ones done in people with type 2 diabetes or prediabetes showing that metformin could blunt some of the positive effects of exercise on insulin sensitivity and things like that. But this is like one of the first real randomized controlled trials done in healthy individuals that were at risk for type 2 diabetes but didn't have type 2 diabetes, okay? They were Basically, given increasing doses of metformin starting from 500 milligrams and then increasing up to 2,000 milligrams depending on their body weight. This was a 4-week trial, so it was about a month long.

And they were doing 45 minutes of aerobic exercise on elliptical 3 times a week. Metformin prevented the exercise-induced improvements in cardiorespiratory fitness by 50%. Other randomized controlled trials have shown this to be true in people with type 2 diabetes, and also there's one other study in health of active adults. So, that's really concerning. Cardiorespiratory fitness is one of the biggest predictors of disease and mortality. So, that is really not good that metformin prevented it by 50%. Wow. It also inhibited improvements in mitochondrial respiration. And, that may be something linked to some of— I didn't talk about all the mechanisms of metformin.

One of the molecular One of the mechanisms that's thought to play a role in improving all this glucose regulation and insulin sensitivity is the activation of an important pathway called AMP kinase. That pathway is activated by energy stress. And, energy stress can be caused by things like exercise, can be caused by fasting or caloric restriction or metformin. Another thing that metformin does, and it's actually even thought by some people that this is how AMP kinase is activated is by basically disrupting a certain part of the mitochondria that generates energy called complex I. You've got 5 complexes inside your mitochondria. They're basically just passing electrons around and this is how you can make energy in the form of ATP.

Well, metformin disrupts one of those complexes, mildly disrupts it, complex I. For the longest time, I wasn't a huge— I wasn't hugely convinced by that because the majority of data was in vitro, meaning you dump metformin on cells in culture and this happened. And it's like, well, that could be a really big dose-dependent thing. Most in vitro studies, you can show one thing and completely show an opposite thing if you were talking about what's called in vivo or at the level of the whole organism. Uh-huh. But there was a study published a few years, like 2014 or '15 or something like that, showing giving— if you fed rats Actually, they were rats that had type 2 diabetes and they were fed various doses of metformin, 30 milligrams per kilogram body weight, 100, or 300 milligrams, right?

Showed that at higher doses, 100 or 300 milligrams per kilogram body weight, metformin could decrease the mitochondrial oxidative capacity specifically linked to complex I activity if they isolated muscle from these rats that were orally given these doses. So, I was like, okay, that's evidence that it is obviously doing something that's physiologically relevant. So, that could be why it's preventing cardiorespiratory fitness, which has been linked to mitochondrial function. It could be why it's— metformin's inhibiting adaptations with mitochondria. Metformin also diminished whole-body insulin sensitivity after aerobic exercise. But, it wasn't like everything was bad.

So, metformin didn't diminish other improvements from exercise like the decrease in HbA1c, which is a long-term marker of blood sugar. Okay. glucose levels. It didn't affect fasting insulin or blood glucose or fat mass or skeletal muscle telomere length, which increased with exercise. So that's good. But it is concerning that it had all those negative effects, right? And these are in healthy people. Do you think this is something where eventually, you know, we— because we do want this activation of AMPK, right? That's a positive thing. So here's the thing. So activation of AMPK— Can we pulse it? So the activation of— so here's the thing. That's the question, right? Well, what if you time your metformin, right?

There's things to consider other than the half-life of metformin or, you know, the important thing is— so for example, exercise activates AMP kinase. The activation is relatively transient but the effects of exercise last about 48 hours. Metformin activates AMP kinase and the effects of metformin last about 36 hours after the last dose. So is it the AMP kinase activation that's responsible for these effects? We don't even know. Like that's not even— it's not even known or how long is the complex PPAR-alpha inhibition lasting after you take your last dose? Is that also 36 hours after? We don't know. They're open questions, right? Right.

Not to mention that there was just, I don't know, a couple of months ago, another randomized double-blind controlled trial showing metformin— this was also in healthy adults that were doing resistance training, and they were older adults. Both of these studies were older adults, 65, you know, age 65 years and older. But this study also showed after 14 weeks of taking about 1,700 milligrams of metformin, which is quite high, that it— and this gets back to your friend's anecdote— the participants that took the placebo gained more lean muscle— lean body mass and also thigh muscle mass compared to those who took metformin. So metformin blunted some of the gains in muscle mass. Right. It also diminished the strength, but those results were not significant, statistically significant.

So it's trending towards Your friend's anecdote, what he— what he found with his power and output and stuff. What about brain health? What do we know that metformin does there? Well, because it— you know, glucose levels like glucose dysregulation is, you know, heavily tied to, you know, disrupting brain health. It makes sense that improving— and improving blood glucose levels and glucose— blood glucose regulation improves brain health. So there have been some clinical studies showing that metformin in people with type 2 diabetes taking metformin can improve cognitive function and things like that. Which is almost certainly linked to the improvements in, you know, gluco-regulatory improvements.

I say my thoughts, my concluding thoughts on this is that I think exercise is better than metformin for preventing type 2 diabetes. That's been shown treating type 2 diabetes, but also I think it's better than metformin in delaying aging. I think that you're better off doing exercise than taking a metformin pill. Yeah. Now, I don't think the effects are gonna be synergistic. So, you know, is there a place for metformin? Absolutely. I mean, there are tons of people that will never exercise, right? So you sit down, you tell someone you have to exercise 150 minutes a week or you can take this pill, they're gonna be like, give me the pill, you know? Right.

But that doesn't mean that, you know, we don't know all the other side effects of metformin or for people like you and I that it's not just about laziness. It's about wanting the best, right? I want the best. So, currently, my thoughts on the field are the best is exercise. And, I am not convinced that taking metformin in addition to exercise is good. In fact, I think it's actually not beneficial for people that are exercising. And, you can do this whole argument, I'll take it on days I don't exercise, but we don't know how long the effects, you know, of this metformin. Like I said, 36 hours after the last dose of metformin, you still have AMP kinase activation. AMP kinase activation, by the way, inhibits mTOR downstream.

And part of the— the blunting of the muscle hypertrophy effects of resistance training, it's thought, at least the authors of that randomized controlled trial think, has to do with the fact that mTOR was not being activated enough in the muscle because the metformin was kind of dampening it too much. Hmm. You know, again, it's not just about, well, how long does metformin stay in my system? then I'll exercise on a day when it's not in my system. Right. This comes down to you can look at anything. You can look at things like, you know, using the sauna activating heat shock proteins which we can talk about. But, you know, like those effects last for 48 hours after you get out of the sauna. There's lasting effects on these molecular pathways that it's perturbing, right? So, that's what you really need to consider, not just the bioavailability, the half-life of the compound that you're ingesting.