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Should you take metformin for longevity?

Recently, I’ve been doing a lot of reading on longevity and different areas of research related to the topic. One popular molecule that has been touted as a medical miracle is metformin. Metformin is most well known for it’s incredible benefits for diabetics in regulating their blood sugar, and no doubt it does do that. However, there has also been a ground swell in relation to its longevity effects, but why exactly? Is this some social media story or is there some scientific merit to the idea? Let’s find out.


So, I’ll go ahead and cut to the chase (I still don’t understand this expression, although plenty of people have written in and explained it to me… maybe I just don’t like the expression, yet here I am using it…) - there is a scientific basis for the claim of metformin extending lifespan. That scientific merit came about due to a single study [1]. This study compared people who did not have diabetes (healthy controls) against people who had diabetes and took metformin. Much to many’s surprise, the researchers showed data indicating the those with diabetes taking metformin experienced improved lifespan compared to the healthy controls - implicating metformin as a potentially potent longevity drug. From there, many people started pointing the finger at the many mechanisms that metformin acts through - I won’t detail them right now, but I will in the future. That is how the metformin story grew to be what it is today.


However, there are two major issues with this interpretation of the study. One, this was a retrospective, associative study - so, it couldn’t pin causation (aka, metformin causes longevity benefit). That said, I should quick point out that associative studies are still wonderful and can sometimes get us near a causative inference, so I don’t want you thinking we should just dismiss associative studies outright - that would be an incorrect way of going about the scientific literature. Anyway, the second, and much larger, issue is that the study made a critical error.


Essentially, the researcher had set their study criteria to only include people with diabetes that were only on metformin. Meaning, if they progressed to more advanced diabetes and were put on other drugs or therapies, they were excluded from the analysis. So, think about that: if you remove people whose condition worsens, how might that affect the mortality data? As you can likely guess - tremendously. So, the metformin data was artificially inflated (at fault of the researchers, but not purposefully). But, we don’t need to simply criticize the study - we can look at a followup analysis that accounted for this glaring issue.


A newer study looked over the same problem [2], but accounted for the removal of these worsening individuals and found the exact opposite: metformin did not offer a life extension effect compared to non-diabetic, non-metformin using controls. This certainly shows the importance of understanding study analysis, and not getting swept up in the headlines. That said, does that mean metformin does not offer a life extension effect?


Actually, no - metformin probably still offers benefit, but the effect is likely only present when comparing diabetics sans metformin versus diabetics taking metformin. As usual, the comparison is what makes the difference - as I’ve found with many of my analyses. Okay, but one standing question remains: does metformin benefit those without diabetes?


Honestly, the answer is: “we don’t know”, because no such studies have been performed. If we return to mechanisms, is metformin’s longevity effect present only when you lower blood sugar from a pathologic state or is there some other mechanism that provides the benefit that might also help those with normal blood sugar regulation? We don’t know.


Nic



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References [1] Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014;16(11):1165-1173. doi:10.1111/dom.12354 [2] Keys MT, Thinggaard M, Larsen LA, Pedersen DA, Hallas J, Christensen K. Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study. Int J Epidemiol. 2022;51(6):1886-1898. doi:10.1093/ije/dyac200




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