BOSTON—There is no significant relationship between cognitive decline or adverse cognitive events and the use of any statin drug in either cognitively healthy people or those with dementia, according to a systematic review and meta-analysis presented at the 2013 Alzheimer’s Association International Conference.
On February 28, 2012, the FDA issued a warning regarding potential adverse effects of statins on cognition. The warning was based on a review of the Adverse Events Reporting System database and the medical literature, which contradicts data from randomized controlled trials. Possible explanations for this discrepancy include the following:
• The magnitude of the adverse effect is too small to be detected in randomized controlled trials due to limited sensitivity of the cognitive measures.
• The adverse effects are large enough to be detected, but too infrequent to be noticed in randomized controlled trials due to limited sample size.
• The adverse effects led to subject dropout, and hence were not captured in the analyses of the cognitive data obtained at the completion of the randomized controlled trials.
To further investigate the issue, Brian R. Ott, MD, Director of the Alzheimer’s Disease and Memory Disorders Center at Rhode Island Hospital and Professor of Neurology at the Warren Alpert Medical School of Brown University in Providence, and colleagues performed a systematic review and meta-analysis of cognitive test results and adverse reports from randomized controlled trials of statin treatment in subjects with and without dementia.
The researchers searched MEDLINE and EMBASE from inception to 2012 to identify randomized controlled trials of statins for the prevention of cardiovascular disease or stroke, or for the treatment of Alzheimer’s disease. Trials enrolling adults or children were included in the meta-analysis if they reported at least one cognitive outcome or reported cognition as a study covariate. Inclusion criteria for the meta-analysis also stipulated that the trial must have used a standardized neuropsychologic instrument valid for cognitive assessment. The primary outcome of this meta-analysis was change in cognition, as measured by neuropsychologic tests. The secondary outcome was the number of adverse cognitive events reported during the trials.
With the following exceptions, no adverse cognitive events were noted in the randomized controlled trials included in this meta-analysis:
• In the Jupiter Study, despite increased reports of confusion for rosuvastatin compared with placebo, there was no significant difference for dementia or any adverse nervous system events.
• In the Heart Protection Study, no significant differences were observed for patients classified as cognitively impaired by telephone-administered cognitive assessment at the end of the simvastatin versus placebo study.
None of the other 468 phase II and III randomized controlled studies that were reviewed reported any adverse cognitive events. Two large trials examining the effects of statins on cognitive tests as a major secondary end point in cognitively normal subjects showed no significant negative effects, and two found negative effects on cognitive tests. Nine smaller trials in cognitively normal subjects also showed no significant negative effects, four found positive effects, and one found negative effects. Four additional randomized controlled trials examining cognitive efficacy of statins in subjects with dementia showed small but nonsignificant trends toward opposite effects of simvastatin and lovastatin.
According to the researchers, their systematic review was consistent with previous reviews in finding no significant relationship between cognitive decline or adverse cognitive events and the use of any statin drug.
“These results raise questions regarding the continued merit of the FDA’s warning about potential adverse effects of statins on cognition,” the researchers said. “This issue has major public health implications due to 1) decisions by patients and physicians to discontinue statin therapy based on the warning, and 2) the known health benefits of statin therapy in the primary and secondary prevention of cardiovascular and cerebrovascular death and morbidity.”
—Glenn S. Williams
Vice President/Group Editor