The largest ever clinical trial of cholesterol-lowering statins as a treatment for Alzheimer’s disease has drawn a blank.

Presented at the recent annual American Academy of Neurology meeting in Chicago, the results of the 18-month Lipitor’s Effect on Alzheimer’s Dementia (LEADe) study put a question mark over previous research that has linked high cholesterol levels to Alzheimer’s.

They also deliver a blow to Pfizer’s efforts to fortify Lipitor (atorvastatin), its blockbuster cholesterol-lowering drug, against flagging sales and a looming patent expiry in 2010.

In the study of 640 patients with mild-to-moderate Alzheimer’s disease (AD), adding Lipitor (atorvastatin calcium tablets) 80 mg to Aricept (donepezil HCl) 10 mg, the AD therapy that Pfizer co-promotes with the licence holder Eisai, produced no significant differences in cognition or global function – key measures of Alzheimer’s progression –compared with placebo plus Aricept 10 mg.

Nor were any statistically significant differences seen in various cognitive, behavioural and functional secondary endpoints, Pfizer reported.
Previous – although not all – clinical studies have suggested that taking statins prophylactically could markedly lower the risk of developing Alzheimer’s disease. One such US trial at Boston University, published last August in the journal Neurology, indicated that statins might cut the risk of Alzheimer’s by as much as 79%.

In a recent paper published in the Journal of Alzheimer’s Disease, researchers at the University of Groningen in the Netherlands showed that lovastatin (Mevacor, Merck & Co) can activate a neuroprotective mechanism by stimulating nerve cells to produce the receptor tumour necrosis factor (TNF)-alpha. The death of nerve cells is thought to be a major cause of the symptoms found in Alzheimer’s and other neurological diseases such as Parkinson’s.

Interesting findings

While rates of decline in cognition and global function were similar for the Lipitor and placebo groups, the LEADe study did generate “some interesting findings”, Pfizer noted.

In a subset of 64 patients for whom magnetic resonance imaging (MRI) scans were available, those taking Lipitor showed markedly less of a decline in hippocampal volume in the brain than the patients on placebo. “While the clinical significance of this result is not yet fully understood, less decline in hippocampal volume may be beneficial since declines have been associated with the progression of Alzheimer’s disease,” Pfizer commented.

Moreover, in a sub-analysis completed after the trial, men taking Lipitor had a significantly slower rate of decline in cognition than those in the placebo arm. No comparable effect was observed in women taking Lipitor, though.
Pfizer said it was not planning any more studies with Lipitor in Alzheimer’s patients “at this time”, although it did remain committed to advancing research and treatment in Alzheimer’s disease.

The company saw a happier outcome in the five-year Treating to New Targets (TNT) study with Lipitor, results of which have just been published in the Journal of the American College of Cardiology. These showed that Lipitor 80mg reduced the risk of heart attack and stroke by 32% in patients who had heart disease and chronic kidney disease, compared with patients taking the 10mg dose of the drug.

Sales of Lipitor dropped by 7% year on year to $3.14 billion in the first quarter of 2008.