Old Drug May Help Protect People With Diabetes Against Dementia

An older diabetes drug may help lower the risk for dementia in older people with new-onset type 2 diabetes, a Korean study suggested.

Among more than 91,000 newly-diagnosed diabetes patients ages 50 and older without a history of dementia, pioglitazone use was linked with a 16% lower risk for developing all-cause dementia compared with non-users (adjusted HR 0.84, 95% CI 0.75-0.95), Eosu Kim, MD, PhD, of Yonsei University in Seoul, Republic of Korea, and colleagues reported in Neurology.

This risk reduction appeared to be dose-dependent, with people in the highest quartile for cumulative pioglitazone dose seeing greater dementia protection (aHR 0.72, 95% 0.55-0.94). Dementia risk reduction was also most pronounced in patients who were taking pioglitazone for 4 years versus non-users (adjusted hazard ratio [aHR] 0.63, 95% CI 0.44-0.90).

The risk for dementia was slashed even more in those who had a history of ischemic heart disease or ischemic stroke prior to their diabetes onset (aHR 0.57, 95% CI 0.38-0.86; aHR 0.46, 95% CI 0.24-0.90, respectively). On top of that, stroke incidence trended lower with pioglitazone use in this population (aHR 0.81, 95% CI 0.66-1.00).

“Since dementia develops for years before diagnosis, there may be an opportunity for intervening before it progresses,” Kim explained in a statement. “These results may suggest that we could use a personalized approach to preventing dementia in people with diabetes in the case that they have a history of ischemic heart disease or stroke.”

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Kim added. “In some previous studies of people with dementia or at risk of cognitive decline who did not have diabetes, pioglitazone did not show any protection against dementia, so it’s likely that a critical factor affecting the effectiveness is the presence of diabetes.”

But additional research is needed to confirm these findings, he said.

Although patients who had a history of stroke prior to diabetes diagnosis saw some of the greatest protection against dementia, those who had a stroke after starting pioglitazone didn’t have this reduction in dementia risk (aHR 1.27, 95% CI 0.80-2.04).

On top of that, patients with a history of hemorrhagic stroke actually saw more than a three-fold higher risk for all-cause dementia with pioglitazone use (aHR 3.26, 95% CI 1.13-9.41).

There were no differences seen for other cardiovascular subgroups, including patients with a history of hypertension, atrial fibrillation, heart failure, or depression, the researchers said.

Despite these “promising findings,” however, the authors of an accompanying editorial said the clinical implications remain unclear, citing the many safety concerns with thiazolidinediones (TZDs) — the class of diabetes drug that pioglitazone belongs to.

Pioglitazone was first approved by the FDA in July 1999 under the brand name Actos, indicated for type 2 diabetes when paired with diet and exercise. In 2016, the FDA warned that the drug may be linked to an increased risk for bladder cancer based on findings from a 10-year epidemiologic study and added to the label that pioglitazone should not be used in patients with active bladder cancer. The label also has a boxed warning stating that pioglitazone may cause or worsen congestive heart failure for certain patient populations.

“Reflecting these risks, TZDs are not currently favored in diabetes management guidelines and their use has significantly declined since the mid-late 2000s,” Colleen Maxwell, PhD, of the University of Waterloo in Ontario, Canada, and co-authors pointed out in their editorial. They noted, however, that TZDs do have some specific benefits, including a lower risk for myocardial infarction, stroke, and cardiovascular death, and a reduced risk for hypoglycemia compared with other antidiabetic agents.

But until additional studies confirm the dementia risk reduction paired with all the lingering safety concerns, “pioglitazone should not be used to prevent dementia in patients with [type 2 diabetes],” Maxwell and co-authors warned.

The analysis took longitudinal data from the Korean National Health Insurance Service diabetes mellitus cohort between 2002 and 2017. The researchers followed 91,218 newly diagnosed diabetes patients without a history of dementia who were 50 and older. Dementia was defined as taking two or more prescriptions for any of the four anti-dementia drugs: donepezil (Aricept), rivastigmine, galantamine (Razadyne), and memantine (Namenda).

People were excluded if they weren’t using an antidiabetic medication, were using insulin for more than a month, had a history of dementia or anti-dementia medication use before diabetes diagnosis, had been diagnosed with dementia within 4 years after their diabetes diagnosis, or were prescribed with rosiglitazone during the study period.