CHICAGO—Atorvastatin offered no significant additional protection from decline in cognition and global functioning when used as an add-on therapy with donepezil, according to research presented by Howard H. Feldman, MD, at the 60th Annual Meeting of the American Academy of Neurology. However, findings from an early subanalysis showed that a protective response might exist for men.
Dr. Feldman, Professor and Head of the Division of Neurology at the University of British Columbia, Vancouver, and his coinvestigators screened more than 1,000 subjects with probable mild to moderate Alzheimer’s disease to participate in the Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study; 640 participants ages 50 to 90 were included. The largest single reason for exclusion from the study was that a subject’s LDL cholesterol level fell outside of the required range of 95 to 195 mg/dL, said Dr. Feldman. He also noted that the study population was “a bit older” than many studies of patients with Alzheimer’s disease, with a mean age of 74; that the mean Mini-Mental State Examination score of 21.8 was higher than that in many prior studies; and that the LDL cholesterol values (mean, 140 mg/dL) were somewhat lower than those in cardiovascular studies that have been performed.
Efficacy of Atorvastatin
All of the study participants received 10 mg/day of donepezil for at least three months prior to randomization to either the atorvastatin (80 mg/day) or placebo arms, which they continued for the 72-week study. LDL cholesterol levels were reduced significantly in the atorvastatin-treated arm, as were total cholesterol and triglyceride levels, reported Dr. Feldman. “And as anticipated, there was no effect seen on the HDL cholesterol,” he said. In addition, the values returned to baseline during the eight-week withdrawal period, suggesting that there was a high compliance to the study protocol.
Although there was “a numerical superiority of atorvastatin throughout the trial period” as measured by change on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), it did not achieve statistical significance at any time point. Similarly, no significant differences were observed on the ADAS–Clinical Global Impression of Change. Alternative statistical analyses using a last observation carried forward approach also showed trends—but not statistically significant changes—with atorvastatin.
In a post hoc analysis, differences in cognitive responses were noted according to gender. “Males had a significant benefit on the ADAS-Cog,” said Dr. Feldman, while there was no significant benefit in women. He noted that the finding, although “intriguing,” could only be considered as hypothesis generating, requiring further exploration.
Whole brain and hippocampal volumes were also assessed with MRI at baseline and at end point. There was no significant difference in whole brain volume changes between the two study groups; however, in the hippocampal volumetric analysis, there was a significant difference in favor of the atorvastatin arm.
“We do not know yet … the significance of this finding,” Dr. Feldman told Neurology Reviews. “A finding of reduced rates of hippocampal volume loss could reflect on a good biologic effect, although clinical significance is also going to be needed [to be proved].”
Safety of Atorvastatin
Dr. Feldman said that there was initial uncertainty around the tolerability of atorvastatin in the geriatric population when the LEADe study was initiated. “It was interesting to see that the adverse event rates were similar between the treatment arms, the serious adverse event rates were similar, and the death rates were similar in the two arms, with only a few more in the atorvastatin arm than in the placebo arm over the 18-month study,” he reported.
The most common side effect of elevated liver enzymes was expected from prior studies, noted Dr. Feldman. He also reported that 2.6% of participants in the atorvastatin arm showed at least a threefold increase in serum aspartate aminotransferase, although this was not associated with any untoward clinical effects.
—Jessica Dziedzic