An Old-School Diabetes Drug Might Help Prevent Dementia

New research has shown that an older class of type 2 diabetes drugs may protect against dementia. A study of over 500,000 older adults with diabetes found that those who were prescribed glitazones – also known as thiazolidinediones, or TZDs – were 22 percent less likely to develop dementia.

If the link is confirmed in further study, it’s possible that TZDs, which are now only rarely used by people with diabetes, could eventually be prescribed for dementia prevention.

The analysis also found that another type of diabetes drug, sulfonylureas, may increase the risk of dementia.

The study (PDF) was published by BMJ Open Diabetes Research & Care, an open-access imprint of the prestigious British Medical Journal.

Experts have long known that there are physiological connections between diabetes and cognitive decline. Alzheimer’s disease, for example, appears to be at least partly caused by the insulin resistance that is a root cause of type 2 diabetes, and has even been called “type 3 diabetes.” Our researchers, therefore, decided to investigate whether or not diabetes drugs might also be able to prevent or treat dementia.

Most previous studies of the issue were smaller, and often had conflicting results. But the scope of the new BMJ study may convince experts that there’s something to it, and could spur the design of more robust experimentation to confirm the beneficial effect of TZDs.

TZDs have been described as “the forgotten diabetes medication.” They are uniquely effective at treating insulin resistance, a root cause of type 2 diabetes, protect the pancreatic Beta cells, and also reduce the amount of glucose released by the liver. Their use was once widespread, but today doctors are much less likely to recommend the drug to new patients. In the present study, only about 2.5 percent of patients were using a TZD, and it is likely that an even lower proportion of younger patients use the drug.

Why did TZDs fall out of favor? Some data has suggested that they may have unsafe side effects such as heart failure and increased risk of fractures. They are also associated with weight gain, a factor that has come under increasing scrutiny. Additionally, diabetes authorities have been wowed by the new generation of diabetes drugs, especially SGLT-2 inhibitors and GLP-1 receptor agonists, which are believed to have extra benefits beyond enhanced glycemic control, including weight loss and reduced risk of kidney disease. The latest treatment guidelines from the American Diabetes Association (ADA) greatly minimize the use of TZDs; in previous editions, TZDs were listed most prominently as options for patients without comorbidities for whom “cost is a major issue.”

While TZDs may or may not be one of our best options for diabetes treatment, the new study suggests that they may be extremely useful for dementia prevention. Use of a TZD (without metformin) resulted in an 11 percent lower risk of Alzheimer’s disease and a remarkable 57 percent lower risk of vascular dementia, for an overall reduction of 22 percent. When TZDs were taken alongside metformin, the positive effects were somewhat muted: an 11 percent reduction of dementia risk.

Sulfonylureas, meanwhile, increased the risk of dementia by 12 percent. The result could help push this other older class of drugs further out of favor. Sulfonylureas remain popular – about 45 percent of the population studied used the drug, either with or without other medications – partially because they are widely available as an inexpensive generic. Nevertheless, diabetes authorities have pivoted away from recommending sulfonylureas, for some of the reasons that TZDs have been minimized. While sulfonylureas can have a powerful glucose-lowering effect, they are also associated with both weight gain and the risk of hypoglycemia, and are seen to be less beneficial than newer options.

The new BMJ study, to be clear, is only a big first step. It was an observational study, not a randomized controlled trial, and as such its conclusions still need to be confirmed. Nevertheless, the results may begin to shift the way that experts look at these older and inexpensive diabetes drugs. Ideally, the finding will lead to more effective prevention and treatment of dementia, a scourge of older people both with and without diabetes.

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