Adding Evolocumab to a Statin Shows No Evidence of Cognitive Issues
March 19, 2017—Washington, DC—Adding evolocumab to treatment with a statin shows no evidence of causing memory or cognitive loss.
This conclusion, based on results of the prospective EBBINGHAUS study, was presented at the American College of Cardiology’s 66th Annual Scientific Session, from March 17 – 19.
Robert P. Giugliano, MD, SM, of Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, explained that cholesterol is important for normal memory and brain functioning, but the brain should be able to generate sufficient amount of cholesterol.
Studies have suggested a possible link between high doses of statins and memory difficulties. In 2012, the FDA added a safety alert to statin labeling, noting that some patients had experienced memory loss and confusion. In 2014, however, a medical expert panel concluded that the evidence that statins cause cognitive side effects was weak to nonexistent.
The question resurfaced in 2015 in two studies of proprotein convertase subtilisin-kexin 9 (PCSK9) inhibitors, which block the PCSK9 protein. The two studies reported infrequent cognitive side effects (<1% of patients) but occurred more frequently in patients taking a PCSK9 inhibitor than in those who received placebo.
Dr. Giugliano said, “EBBINGHAUS was the largest, most rigorously designed study to address this issue to date. It was the first prospectively designed study to evaluate the relationship between a PCSK9 inhibitor and changes in cognition, including memory, attention, and reaction time.”
The trial enrolled 1974 patients who were taking part in the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, a large double-blind, randomized trial conducted in 30 countries to evaluate evolocumab or placebo + statin therapy to reduce LDL cholesterol in high-risk patients with cardiovascular or peripheral artery disease.
Patients were 63 years of age on average. Seventy-five percent had suffered an MI; 20% an ischemic stroke; and 19%, peripheral arterial disease. All were receiving moderate- or high-intensity statin therapy. Patients were excluded if they had been diagnosed with dementia, cognitive impairment, or another significant mental or neurological disorder.
Patients completed the validated neurocognitive Cambridge Neuropsychological Test Automated Battery, when they enrolled, and after 24, 48, and 96 weeks, and at the end of the study.
Median follow-up duration was approximately 19 months. The tests, performed on a tablet computer, assessed executive function (ability to pay attention, manage time, plan, organize, and remember details) as well as working memory, memory function, and reaction time.
The primary endpoint was the Spatial Working Memory strategy index. Patients also completed a questionnaire assessing their everyday cognition before, during, and at the end of the study.
Dr. Giugliano said, “We found no important differences between patients taking evolocumab and those receiving placebo on any of the four measures of cognitive functioning, in the patient questionnaires, or in the physician report of adverse cognitive events. We also looked at patients according to how low their LDL cholesterol levels dropped. Patients who reached very low LDL values–<25 mg/dL–displayed had cognitive function similar to those with higher LDL values.”
He added that the findings should “enable physicians to feel more secure about adding evolocumab to a statin to achieve very low levels of LDL cholesterol, without worrying that memory or cognitive functioning will be affected.”
A limitation of the study was that patients were followed for <2 years on average. Long-term follow-up in a subset of the EBBINGHAUS patients, however, is ongoing. A further limitation was the possibility that patients were experiencing cognitive problems that were not picked up by the tests.
The tests were validated, however, in more than 160 clinical trials over the past 30 years, in both cognitively normal subjects and those with neuropsychiatric disorders such as schizophrenia and Alzheimer’s disease. The tests are sensitive to both positive and negative drug-related cognitive effects
Dr. Giugliano concluded, “Our findings were reassuring in that we found no apparent effect on any of these cognitive domains despite achieving very low blood levels of LDL cholesterol.”Click on any of these tags to subscribe to Topic Alerts. Once subscribed, you can get a single, daily email any time PracticeUpdate publishes content on the topics that interest you.
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