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Drug Linked to Lower Dementia Risk for Type 2 Diabetics

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People with Type 2 diabetes are around twice as likely to develop dementia as non-diabetics. Now, a new study has found that the diabetes drug pioglitazone is associated with a reduced risk of dementia in newly diagnosed Type 2 diabetes patients. The research is published in Neurology.

Diabetes and dementia

Over 37 million US Americans have diabetes, with Type 2  accounting for around 90–95% of cases. Type 2 diabetes is caused by insulin resistance, where cells no longer respond to insulin, the hormone that regulates blood sugar. The pancreas ramps up insulin production in response to resistance, but it cannot keep up and, without treatment, blood sugar can rise to dangerous levels.

Unfortunately, with Type 2 diabetes also comes an increased risk of developing other conditions such as cardiovascular disease and nerve damage, as well as double the risk of dementia, including Alzheimer’s disease (AD).

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Previous studies have suggested that the diabetes drug pioglitazone may have neuroprotective effects against AD in mice, as well as reduce the risk of strokes – another key risk factor for the onset of dementia.

“Pioglitazone is a potent insulin-sensitizing anti-diabetic drug working as a peroxisome proliferation-activated receptor gamma (PPARγ) agonist,” explains Eosu Kim, senior author of the study and professor in the Department of Psychiatry at Yonsei University. “Stimulating PPARγ is known to be related to various beneficial effects in terms of cellular metabolism. As metabolism of the brain is pathologically associated with AD, this PPARγ agonist was expected to have anti-dementia effects as well.”

However, the effects of pioglitazone on dementia in human studies have been mixed, as the drug has not provided significant protection for those with, or at risk of, dementia or cognitive decline who did not also have diabetes. Kim elaborates on one possible explanation for these observations: “As painkillers would show no apparent effect on people with no pain, this anti-diabetes drug could have little effects on the brain in AD patients without diabetes. This speculation leads to another suggestion that the anti-dementia action of pioglitazone might be diabetes context-dependent,” he explains.

Actualizing personalized medicine?

In their study, Kim and colleagues investigated whether pioglitazone was linked to a reduced risk of dementia in Type 2 diabetics and if there were other patient characteristics – such as a history of stroke – that could influence its effects.

The researchers used data from the Korean National Health Insurance Service gathered between 2002 and 2017. Data from over 91,000 individuals newly diagnosed with diabetes with no history of dementia were analyzed – 3,467 of these were pioglitazone users, while the remainder were non-users.

The participants were followed up for an average of 10 years, with 8.3% of pioglitazone users developing dementia compared to 10% of non-users. After accounting for other possible risk factors for dementia like high blood pressure and smoking, Kim and colleagues found pioglitazone users had a 16% lower risk compared to non-users.

This effect increased with the length of pioglitazone use – those taking the drug for 1–2 years were 22% less likely to develop dementia, while 4 years of use led to a 37% lower risk.

History of ischemic heart disease or stroke were also key factors for reducing dementia risk among pioglitazone users, with reduced risks of 54% and 43%, respectively. “This is intriguing because this kind of finding implies that we may actualize personalized medicine: physicians would know better which one among many available diabetes medications is more effective to prevent dementia in which population,” says Kim.

Promising protective effects

While the study does not prove that pioglitazone lowers the risk of dementia among Type 2 diabetics, it does show an association. “Pioglitazone use is associated with a lower risk of dementia in newly diagnosed diabetes patients upon approximately 10 years-observation. Particularly, such protective effect of the drug is more prominent in those with a history of stroke or ischemic heart disease,” Kim summarizes.

The authors elaborated on some of the limitations of the study, including the drawbacks of sourcing data from insurance claims, as patients may not have taken the drug exactly as prescribed. “It is not a clinical trial showing pioglitazone’s preventive effects compared to placebo,” Kim says. “We only found an association between pioglitazone use and a lower incidence of dementia. In addition, insurance claim-based data is liable to misclassification error due to code-based diagnosis.”

Kim and colleagues now plan further analyses to investigate the link between anti-diabetic drugs and dementia risk. “We are conducting studies to find out which anti-diabetic drugs show similar effects like pioglitazone in terms of dementia suppression, and animal studies to elucidate molecular mechanisms underlying their anti-AD actions,” he adds.

Reference: Ha J, Choi DW, Kim, Kim KY, Nam CM, Kim E. Pioglitazone use and reduced risk of dementia in patients with diabetes mellitus with a history of ischemic stroke. Neurology. 2023. doi: 10.1212/WNL.0000000000207069

Prof. Eosu Kim was speaking to Dr. Sarah Whelan, Science Writer for Technology