Megan Brooks

July 24, 2014

COPENHAGEN, Denmark — Long-term use of the diabetes drug pioglitazone (Actos, Takeda Pharmaceuticals) may protect against dementia, an observational study suggests.

The study was presented here at the Alzheimer's Association International Conference (AAIC) 2014.

Pioglitazone is a peroxisome proliferator activated receptor-γ (PPAR-γ) agonist used to treat type 2 diabetes.

In murine models of Alzheimer's disease, PPAR-γ activation improves behavioral deficits and neuropathologic changes by suppressing neuroinflammation, increasing β-amyloid clearance, and modulating β-secretase-1 promotor activity.

On the basis of preclinical data, Gabriele Doblhammer, PhD, and colleagues from the German Center for Neurodegenerative Diseases, Bonn, Germany, hypothesized that long-term use with pioglitazone would reduce the risk for dementia.

Using prescription data from a German database, they studied the association of pioglitazone and dementia incidence in a prospective cohort study of 145,717 adults age 60 years and older who were free of dementia at baseline in 2004 and followed until 2010. The information on prescriptions of pioglitazone on a quarterly basis was expressed as a linear variable covering the time-dependent number of quarters of prescriptions, which ranged between 0 and 28 quarters.

In a Cox proportional hazard model, they calculated the relative risk for dementia with use of pioglitazone, adjusted for sex; age; and use of nonsteroidal anti-inflammatory drugs, rosiglitazone, and metformin; and cardiovascular comorbidities, including diabetes, cerebrovascular disease, hypertension, ischemic heart disease, atrial fibrillation, and hypercholesterolemia.

During follow-up, 13,841 participants developed dementia. With each additional quarter of pioglitazone prescription, the relative risk for dementia fell by 6% (hazard ratio [HR], 0.94; P = .004).

"Intriguing" Data

"It is important to note that this is not a clinical trial, so the data, while intriguing, are not so relevant to the clinic at this point," Keith Fargo, PhD, a director of medical and scientific relations at the Alzheimer's Association, told Medscape Medical News.

"That said, the results of this study support the idea that pioglitazone may be useful in preventing or delaying the onset of dementia, and those investigations seem to be worth pursuing," he added. "If this turns out to be a safe and effective intervention, it could have a major impact on public health, as would any effective new Alzheimer's treatment."

He noted that a large clinical trial testing whether pioglitazone can delay the onset of mild cognitive impairment due to Alzheimer's disease is underway. It's called the TOMMORROW study and "is expected to provide important data in this line of research," Dr. Fargo said.

Several major Alzheimer's prevention studies are underway or are starting soon, with significant funding from the Alzheimer's Association, he added.

For example, the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is now recruiting patients. It will assess the safety, tolerability, and biomarker efficacy of the experimental antiamyloid drugs gantenerumab (Roche) and solanezumab (Eli Lilly) in people with a genetic mutation for autosomal-dominant Alzheimer's disease.

As reported by Medscape Medical News in March, the Alzheimer's Association announced its largest ever research grant — $8 million over 4 years — to support the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.

The first of its kind, LEARN will be a companion study to the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is investigating whether antiamyloid treatments block build-up of amyloid and slow or prevent Alzheimer's in asymptomatic individuals with no known genetic risk mutations but with some amyloid in their brain.

One objective of LEARN is to determine causes of cognitive decline besides buildup of amyloid-β in the brain, the Alzheimer's Association says.

The Alzheimer's Association is also a cosponsor of the Collaboration for Alzheimer's Prevention (CAP). "CAP brings together the principal investigators of the Alzheimer's disease prevention trials to maintain a regular dialogue as they plan and implement their studies," Dr. Fargo noted.

"One key goal of this collaboration is for the researchers to make the data from the separate trials more comparable. We believe this will increase the amount that scientists can learn both from each individual trial and from comparing results across the trials," he said.

Alzheimer's Association International Conference (AAIC) 2014. Abstract #P2-295 Presented July 14, 2014.

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