James' World 2

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The type 2 diabetes drug metformin may reduce the risk of dementia. A randomised study that followed people for more than 20 years found that it seems to halve the risk of developing the condition.

This offers “the available best evidence, short of a long-term randomised clinical trial, that metformin may decrease the risk of dementia”, says José Luchsinger at Columbia University in New York. However, the finding isn’t conclusive, and the potential mechanism behind it is unclear.

Metformin, which helps control blood sugar levels, is a go-to drug for treating type 2 diabetes, with 150 million people taking it daily in 2022. “I’ve been very interested in the question of whether metformin increases or decreases the risk of dementia,” says Luchsinger. “There have been reports either way.”

Some studies suggest metformin increases dementia risk, possibly by causing a deficiency in vitamin B12 that has knock-on effects on cognition. On the other hand, a 2022 meta-analysis found that, on average, metformin was associated with a lower dementia risk.

To clarify the situation, Luchsinger and his colleagues have followed up with people who took part in a clinical trial of metformin in the 1990s called the Diabetes Prevention Program (DPP). The trial showed that metformin was effective at preventing type 2 diabetes in people at risk of the condition. Since 2002, the participants have been followed by the DPP Outcomes Study.

This involved comparing 1483 people who, in the 1990s, were given either metformin, a lifestyle intervention to reduce the risk of type 2 diabetes (which included a low-fat diet and regular exercise), or a placebo. The participants did multiple cognitive tests, beginning in 2009, then an intensive battery of such tests more than a decade later.

The team found that the people who had started taking metformin in the 1990s had a significantly lower chance of dementia later in life: just 1.9 per cent of those given metformin developed dementia, compared with 4.2 per cent of those given the lifestyle intervention and 3.5 per cent of those given a placebo. The metformin group also showed significantly better memory performance.

Luchsinger flags that the participants weren’t initially recruited with the aim of studying dementia, so some of them could have had early signs of the condition or cognitive impairment at the start of the trial. What’s more, only 48 people developed dementia in the entire study.

Nevertheless, it adds to the evidence that metformin has a protective effect, says Miia Kivipelto at the Karolinska Institute in Sweden. It is rare and valuable to have the chance to follow participants over so many decades, she says.

A 2023 study of more than 210,000 people with type 2 diabetes also suggests that the reduction in risk of dementia is more pronounced among those who stay on metformin for longer. “One trial can answer some questions, but then if you put together evidence from different studies, then we really start to see the pattern more clearly,” says Kivipelto.

It is unclear how metformin may reduce dementia risk because it affects many organs and systems in the body, including hormone-producing glands and the immune system. “Does metformin decrease vascular disease in the brain, for example, or does it decrease inflammation in the brain?” says Luchsinger. “Does metformin decrease the risk of amyloid [the protein implicated in Alzheimer’s disease] in the brain?”

While the protective effect is still unclear, both Luchsinger and Kivipelto point out that the study didn’t find any evidence of metformin increasing dementia risk. “Given that it’s such a widely used medication, if we can at least establish that it’s not harmful, with conviction, I think that that, in itself, would be of really great public health importance,” says Luchsinger.

He is now running a randomised controlled trial called Metformin in Alzheimer’s Dementia Prevention, which is following participants for 18 months to see if the drug reduces the risk of Alzheimer’s disease, the most common form of dementia. Luchsinger hopes to report the results by the end of the year.

Meanwhile, Kivipelto is leading a study called MET-FINGER to find out if lifestyle changes alone, or a combination of lifestyle changes and metformin, can reduce the risk of dementia. Results are expected in 2028.

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