Pioglitazone Safe but Not Effective for Alzheimer's Disease

Deborah Brauser

September 15, 2010

September 15, 2010 — Pioglitazone, a medication designed to treat diabetes, is not effective in treating patients with Alzheimer's Disease (AD), a randomized pilot study suggests.

Although it was generally well tolerated, with no serious or unanticipated adverse events, "no significant treatment effect was observed on exploratory analysis of clinical efficacy," write the researchers.

"This was an exploratory study designed to determine whether patients with Alzheimer's could take an antidiabetic drug over the long term; and our safety results came out favorably," David S. Geldmacher, MD, Harrison distinguished teaching associate professor of neurology at the University of Virginia Health System at Charlottesville, told Medscape Medical News.

He said that their second goal was to determine whether an effect from the medication on cognitive or functional outcomes could be discerned for patients with AD. "And if so, how many people would be required to come up with a definitive study?"

Overall, Dr. Geldmacher said that the study results "don't support the long-term development" of pioglitazone for symptomatic AD. "If we were to move forward with this type of drug, we probably would want to do so in an earlier stage of the disease."

"I think the number 1 takeaway is that we did not establish, nor would we expect to, a therapeutic role for pioglitazone treatment for AD. But other related drugs or other related populations still look favorable for ongoing testing of this conceptual approach," he added. "The conceptual approach is not undermined by our absence of definitive findings in this study."

The study was published online September 13 in the Archives of Neurology.

Exploring AD's Neuropathology

AD research has been especially focused lately on agents that might alter the disease's pathological expression or progression, write the study authors. However, "the failure of several recent treatment trials directed at the β-amyloid peptide, a key pathological correlate of AD, suggests a need to explore alternative approaches."

One of these alternatives is to target peroxisome proliferators-activated receptor gamma (PPARy), which regulates both glucose and lipid metabolism — 2 measures that are abnormal in patients with AD.

Pioglitazone and rosiglitazone, both part of the thiazolidinedione class, are PPARy agonists developed to decrease insulin resistance in type 2 diabetes mellitus.

Although recent trials have shown "limited efficacy" for rosiglitazone as an AD treatment, possibly because of its "poor bioavailability to the central nervous system," pioglitazone has demonstrated blood–brain barrier penetration and activity on AD-related pathophysiology in laboratory mouse models.

For this study, 29 nondiabetic patients with probable AD were enrolled at 2 outpatient clinics between 2001 and 2004 and randomly assigned to receive for 18 months either pioglitazone tablets titrated to 45 mg daily (n = 14; 64% women; mean age, 74.9 years) or matching placebo (n = 15; 60% women; mean age, 67 years).

All patients also received 200 international units of vitamin E capsules once daily and were prescribed cholinesterase inhibitors to maintain treatment. Based on subject demand, they were also allowed to start memantine therapy, if prescribed.

The primary outcome measure was safety and tolerability of the drug's long-term use, measured by the frequency of adverse effects (AEs). Secondary outcomes included cognition, activities of daily living, neuropsychiatric symptoms, and global function.

The researchers also sought "to explore treatment effect sizes to guide design of future clinical trials." They note that this pilot study "was not designed to demonstrate statistically significant effects on these outcomes. Given the small sample size, efficacy analyses were intended to be exploratory."

Safety was assessed by physical and neurological exams, routine blood tests, and electrocardiograms performed at baseline and at study conclusion. In addition, physical and neurological exams were conducted and complete blood cell count, blood glucose level, hemoglobin A1c level, and hepatic function markers were collected.

Efficacy measures included the Clinical Dementia Rating sum of boxes, the Alzheimer's Disease Assessment Scale Cognitive Score, the Neuropsychiatric Inventory, the Alzheimer's Disease Functional Assessment and Change Score, the Nurses' Observation Scale for Geriatric Patients, and the Clinician's Interview-Based Impression-Plus.

Safety but Not Efficacy

Results showed no pattern of effect for the patients on any of the safety measures.

Although no serious AEs were reported by the group taking pioglitazone, peripheral edema was the most common AE reported compared with those taking placebo (28.6% vs 0%).

"This is consistent with the known AE profile of pioglitazone," investigators write.

Other common AEs reported by the pioglitazone-treated patients included cold symptoms (9 vs 11 of the placebo-treated patients), muscle/skeletal pain (4 vs 4, respectively), and nausea/vomiting (4 vs 3, respectively). All were reported to have mild to moderate severity.

A total of 4 of the enrolled patients (2 from each group) did not complete the study, but this was not attributed to any AEs.

In addition, no significant effect of treatment was observed on any clinical outcome measure, suggesting that "mild to moderate AD is not likely to be an appropriate population for further study of thiazolidinediones," the researchers write.

However, they note that disease severity may be 1 reason why the PPARy agonists showed efficacy in AD models but not in this study. Therefore, further exploratory studies of this drug class may be warranted in patients in earlier disease stages.

In addition, these new trials should be "augmented by biomarkers, such as nuclear imaging techniques to measure changes in microglial activation," they add.

"Although our study did not suggest opening up further treatment options for this patient population with pioglitazone, it is informative and helps to steer us toward other potentially effective routes of therapy," said Dr. Geldmacher.

He noted that although both pioglitazone and rosiglitazone are pure PPARy agonists, there are currently other medications in early development that influence other receptors, such as the PPAR-alpha receptor. "These could possibly have a more favorable efficacy vs toxicity profile in the populations we looked at in our study."

This study was supported by a grant from the National Institute on Aging. Dr. Geldmacher and another study author reported receiving consulting fees from Takeda Pharmaceuticals North America (the maker of pioglitazone) and research support from GlaxoSmithKline (maker of rosiglitazone). Case Western Reserve University, in Cleveland, Ohio, where some of the study authors are from, has been issued a patent for the use of pioglitazone in the treatment of central nervous system disorders.

Arch Neurol. Published online September 13.

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