Can Diabetics On Metformin Really Outlive Non-Diabetics? Revisiting An Old Longevity Mystery

Though many would disagree, metformin is often cited as a promising drug candidate for slowing human ageing. Metformin is a drug for the treatment of diabetes, but has been shown to extend lifespan and delay age-related diseases in various animal models. A lot of the excitement around metformin originates from a study comparing the people diabetics taking metformin to those on another major diabetes drug class (sulphonylureas) and to the general population.

The study found that not only did the people taking metformin live longer on average than those taking sulphonylurea, they also lived slightly longer than the non-diabetic controls. This remarkable result seemed to imply that metformin was so good at improving human lifespan, even diabetics taking it could outlive people without the disease.

Unfortunately, there are a few problems with this conclusion. Metformin is generally the first drug that a diabetic patient receives, and patients only receive other drugs if their diabetes progresses. Because the researchers wanted to isolate the effects of metformin, participants were removed from the metformin group as soon as they started taking other drugs – those whose diabetes got worse were increasingly excluded, leaving behind only those whose disease remained well controlled.

This meant that even though the researchers matched the diabetic groups to the control groups at the start of the study, the metformin group would have represented an increasingly healthy sample relative to the other groups, who underwent no such selection.

Compounding this problem was the relatively short duration of the study’s follow up. While diabetes increases the risk of most known age-related diseases, these diseases take time to develop, but follow up only lasted 5 years per person on average. Thus, the study probably ended before diabetes had taken its full toll on participants’ lifespans.

So, what happens when further studies attempt to address these problems? One such study was published this month: researchers examined anonymised medical records in Wales, identifying around 200 000 patients who were diagnosed with type II diabetes and taking either metformin or sulphonylureas. They matched these patients with non-diabetic controls and looked at how long they survived after being diagnosed, using various different follow-up periods of up to 20 years.

So, under these conditions, did the metformin recipients still outlive the non-diabetic controls? Here’s where things get interesting. By the end of the full 20 year followup, diabetics treated with metformin were, on average, surviving about 80% as long as their matched counterparts – diabetics on metformin did not outlive non-diabetics. However, when the followup period was truncated to just 3 years or less, metformin recipients did have a slight survival advantage over non-diabetic controls. Sulphonylurea recipients, on the other hand, had shorter survival times than either of the other groups, regardless of when the study was truncated.

What’s going on here? There are a few possible explanations. One is that confounding factors are involved – for example, maybe people make an effort to change their lifestyle in the years following their diagnosis, but lapse later on, resulting in a short lived dip in mortality during those initial years. This doesn’t explain why sulphonylurea recipients didn’t experience any reduction in mortality. However, as we already established, diabetics taking sulphonylurea are an inherently different group of people with more severe diabetes compared to those taking metformin. Whatever the case, we can’t rule this explanation out completely.

Another, simpler explanation, is that the longevity benefits of metformin just don’t last very long, which would obviously be bad news for what many people hope is an anti-ageing drug. The third explanation is that metformin reduces the risk of age related disease, but the accelerated ageing related to diabetes eventually outstrips any benefit gained from metformin therapy. Of course, a combination of all three explanations is also a possibility. Either way, giving yourself diabetes in order to get prescribed metformin seems like an increasingly bad idea…

When all is said and done, the only way we will know whether metformin works in healthy, ageing humans is by doing long-lasting clinical trials. The largest such trial currently underway is the Targeting Aging with Metformin (TAME) Trial, which includes 3000 65-79 year-olds and will last 6 years. Many are sceptical that much meaningful benefit will be found. Though small and short-lived, previous clinical trials in healthy humans generally find that metformin is less beneficial than a healthy lifestyle, and that the effects of metformin and healthy practices like exercise are not cumulative. Even animal studies using metformin are mixed. Most disappointingly, metformin failed to extend lifespan in the Interventions Testing Program, considered by many to be the gold standard assessment of whether a drug extends mouse lifespan.

On the other hand, metformin already has a very well established safety profile compared to drugs that many would consider to be more promising anti-ageing candidates. If the TAME trial is successful, we may expect to reap the benefits sooner, and it will pave the way for similar trials on potentially superior drugs.