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Gemfibrozil Shows Promise in Predementia Alzheimer Disease Metabolic and CVD Outcomes

The agent, which is FDA-approved for hyperlipidemia, showed significant improvements in plasma glucose, lipid levels, and trends in cardiovascular imaging biomarkers.

Data from a phase 2 safety study (NCT02045056) presented at the 2021 Alzheimer’s Association International Conference, July 26-30, showed that gemfibrozil (Lopid; Pfizer), a lipid-lowering drug, had a robust impact on metabolic and cardiovascular disease (CVD) end points in patients with prodromal Alzheimer disease (AD).1

Lead author Gregory A. Jicha, MD, PhD, professor of neurology, Alzheimer’s Disease Research Center, University of Kentucky College of Medicine, and colleagues concluded that the overlap in disease mechanisms and possible therapeutics for prevention of dementia caused by AD and or CVD is “remarkable.”

The double-blind, placebo controlled, parallel-design study included 48 cognitively-intact subjects and 24 subjects with early cognitive decline (Clinical Dementia Rating score of 0.0-0.5). Individuals were randomly assigned to treatment with gemfibrozil 600 mg orally twice daily or placebo for 48 weeks and were evaluated on safety, microRNA-107 levels, and amyloid-beta (Aß) levels. The investigators observed metabolic parameters including plasma glucose, HgbA1c, cholesterol, triglyceride levels, and inflammatory plasma biomarker profiles, as well as MRI imaging biomarkers such as white matter hyperintensity (WMH) volumes, diffusion tensor imaging (DTI), and arterial spin labeling (ASL) measures.

Treatment with gemfibrozil resulted in significant improvements in plasma glucose (P <.001), lipid levels (P <.001), and trends in CVD imaging biomarkers including reductions in WMH volumes (P = .33), accompanied by ASL perfusion increases in the dorsolateral prefrontal cortex (P = .13), hippocampus (P = .10), and posterior cingulate cortex (P = .16). Following the conclusion of the 48-week treatment period, the authors hypothesized that the beneficial effects on cognitive outcome measures may be more related to metabolic and CVD influences than the direct effects influencing AD pathways that were the target of this clinical intervention.

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Participants in the treatment group experienced attenuation of reductions in the anti-inflammatory cytokine IL-13 (P <.05) and increases in proinflammatory tuberous necrosis factor alpha (P = .08). Previously reported data from the study indicated that gemfibrozil has an excellent safety profile, penetrates central nervous system (CNS), and trended toward reducing Aß levels (P = .063), hippocampal activity (P = .15), and decline on the Computer-Administered Neuropsychological Screen for Mild Cognitive Impairment cognitive battery (P <.01).

"Strong consideration of incorporating metabolic and CVD outcomes in AD trials may help us disentangle the conundrum of risks and treatments for both CVD and AD that are the leading causes of dementia worldwide today,” Jicha et al wrote.

Gemfibrozil is indicated as an adjunctive therapy to diet for adult patients with very high elevations of serum triglyceride levels (Types 4 and 5 hyperlipidemia) who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them.2 Additionally, the drug is also indicated to reduce the risk of developing coronary artery disease only in type 2b patients without history of or symptoms of existing coronary heart diease who have had an inadequate response to weight loss, dietary therapy, exercise, and other pharmacologic agents.

Previously published research in 2019 showed that gemfibrozil can lower the amyloid plaque burden in the hippocampus and cortex of the 5XFAD mouse model of AD. Additionally, gemfibrozil reduced microgliosis and astrogliosis associated with plaque in these mice. Administration of gemfibrozil also improved spatial learning and memory of the 5XFAD mice.3

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REFERENCES
1. Jicha GA, Kryscio RJ, Nelson PT. Metabolic and cerebrovascular effects of gemfibrozil treatment: a randomized, placebo-controlled, double-blind, phase 2 clinical trial for dementia prevention. Presented at 2021 AAIC Annual Meeting; June 26-29. Abstract 264
2. Lopid Indications and Usage. Pfizer. https://www.pfizermedicalinformation.com/en-us/lopid/indications-usage. Accessed July 26, 2021.
3. Chandra S, Pahan K. Gemfibrozil, a lipid-lowering drug, lowers amyloid plaque pathology and enhances memory in a mouse model of Alzheimer’s disease via peroxisome proliferator-activated receptor a. J Alzheimers Dis Rep. Published online May 18, 2019. doi: 10.3233/ADR-190104