Diabetes Drug Tied to Lower Dementia Risk

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

Dr Eosu Kim

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” co-investigator Eosu Kim, MD, PhD, Yonsei University, Seoul, Republic of Korea, told Medscape Medical News.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers note.

The results were published online February 15 in Neurology.

Dose-Response Relationship

Risk for dementia is doubled in adults with T2DM, the investigators write. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio [aHR], 0.84; 95% CI, 0.75 – 0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55 – 0.94).

Several Limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44 – 0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24 – 0.90) or stroke (aHR, 0.57; 95% CI, 0.38 – 0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66 – 1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he told Medscape Medical News.

The researchers caution that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they note.

More Data Needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo School of Pharmacy, Ontario, Canada, and colleagues write that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines ― and their use has significantly declined since the mid to late 2000s, the editorialists note.

They agree that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also note that sodium-glucose cotransporter-2 (SGLT-2) inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Maxwell and colleagues write.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they conclude.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

Neurology. Published February 15, 2023. Abstract, Editorial

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