Results from Human Clinical Trials Do Not Support Metformin as a Longevity Drug

The SENS Research Foundation staff have carried out the public service of extensively discussing and dismantling the evidence commonly cited in support of metformin as a way to modestly slow aging, showing that said evidence is problematic, to say the least. Metformin might make life modestly better for diabetics, but it doesn't slow aging. This view of the human data matches the poor quality of the animal model data, in which metformin makes a poor showing in comparison to the robust data for a modest slowing of aging that is produced by the use of, say, mTOR inhibitors, or the practice of calorie restriction.

Regardless of what you, I, the SENS Research Foundation staff, or just about anyone else thinks of the merits of metformin and the problems with human studies of metformin, the TAME trial to assess the use of metformin to treat aging will forge ahead. Regardless of whether it succeeds or (as I expect) fails, the point of the TAME trial is to pave the way, to have browbeaten the FDA into accepting a trial design in which the target is aging, not any specific disease of aging. That has essentially taken place. The next well-funded group will try that same trial design with mTOR inhibitors, or plasma dilution, or senolytics, or small molecule reprogramming agents. Sooner or later, it will become commonplace to run trials that target aging, rather than development programs sidetracking into the treatment of specific age-related disease while hoping for off-label use to take off.

More Studies on Metformin and Survival

In an earlier five-part series, I laid out the reasons to be skeptical that metformin would pan out as a longevity therapeutic. The centerpiece of the second post in the metformin series was a 2014 observational study, which is the one study that is most often cited as evidence that metformin slows aging in humans. A press release that accompanied the Bannister paper wrongly stated that it showed that "Type 2 diabetics can live longer than people without the disease" if they take metformin.

But as other scientists had pointed out before me, the study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients whose blood sugar was harder to get under control (those on second-line diabetes medications) as well as to a random assortment of the nondiabetic population. Their study design then unwittingly but systematically pushed subjects who were taking metformin "off the books" as soon as their diabetes got worse. This methodological artifact created the illusion that metformin users lived longer lives than nondiabetics, because it meant that the study would only count metformin users as metformin users if they managed to stay healthy.

In the months since I wrote the original blog post explaining this, I've become aware of two other studies asking the same core question but using different methods - and they both find that, as you would expect, people on metformin for diabetes are shorter-lived than people without diabetes. Because these studies address this question more directly than any of the studies discussed in that blog post, we'll review them here. In summary, the metformin users were clearly dying more often than the nondiabetic population. The long-term effect on metformin was better than going untreated as a diabetic, but its benefits were clearly not even enough to get them back on the miserable course of "normal" aging, let alone to have a real anti-aging effect.

We shouldn't stop looking for hidden benefits in common medications - and if we find good evidence that such a drug might slow something as terrible as degenerative aging, it may be worth it to follow that signal up with clinical trials. But with metformin, a story that emerged in cell culture and some poorly-designed animal and human observational studies have led many smart people astray. And even if metformin had turned out to be as effective as it seemed to be in some of the early studies of metformin in abnormally short-lived animals, the implied potential benefits for aging humans would have been pretty modest. It would garner an aging humanity a far greater gain if the media, many advocates, and scientists would redirect the resources and attention that have gone into metformin into developing therapies that directly repair the damage in aging tissues.