WASHINGTON, DC — Adding evolocumab to statin therapy does not cause memory loss or other cognitive issues, according to the results of the EBBINGHAUS study presented at the 66th Annual Scientific Session & Expo of the American College of Cardiology (ACC).1
EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects; Clinicaltrials.gov identifier: NCT02207634) was a substudy of the FOURIER clinical trial, also presented at ACC. Researchers enrolled 1974 patients from FOURIER to evaluate the relationship between a PCSK9 inhibitor (evolocumab) and changes in cognition. Patients were excluded if they had a diagnosis of dementia, cognitive impairment, or other significant mental or neurological disorder.
The question of neurocognitive function with statins first surfaced several years ago when some studies suggested a potential association between high doses of the agents and memory problems.2,3 The US Food and Drug Administration (FDA) then added a safety alert label to statins4 in 2012, but 2 years later, a medical expert panel5 concluded the evidence was weak to nonexistent. The question was then raised again in 2015 when PCSK9 inhibitors were reported to cause potential cognitive side effects.6
Validated neurocognitive tests, including the Cambridge Neuropsychological Test Automated Battery, were conducted at baseline, after 24, 48, and 96 weeks; and at the conclusion of the study (median follow-up, 19 months). The primary end point was a measure of executive function known as the Spatial Working Memory Strategy Index. Questionnaires were also used to assess “everyday cognition” before, during, and at the end of the study.
In the group that received evolocumab, the change in executive function (by raw scores) was -0.29 compared with -0.21 in the placebo group (P noninferiority <.001). Furthermore, there were no statistically significant differences in cognitive test scores among different low-density lipoprotein cholesterol (LDL-C) values, even in patients who achieved levels <25 mg/dL.
One of the investigators, Robert P. Giugliano, MD, SM, associate professor at Harvard Medical School and staff physician at Brigham and Women’s Hospital in Boston, noted that FOURIER will have an open-label extension and the patients included in EBBINGHAUS will also roll over to that extension. The study may continue for several more years, possibly up to a decade. Dr Giugliano also addressed the issue of short follow-up by referencing neurocognitive experts he consulted who stated that 2 years is considered a lengthy period in the field.1
- Giugliano RP; on behalf of the EBBINGHAUS Investigators. EBBINGHAUS: a cognitive study of patients enrolled in the FOURIER trial. Joint ACC/JAMA Late-Breaking Clinical Trials. Presented at: the 66th Annual Scientific Session & Expo of the American College of Cardiology. March 17-19, 2017; Washington, DC.
- Rojas-Fernandez CH, Cameron JC. Is statin-associated cognitive impairment clinically relevant? A narrative review and clinical recommendations. Ann Pharmacother. 2012;46:549-557.
- Padala KP, Padala PR, McNeilly DP, Geske JA, Sullivan DH, Potter JF. The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer’s dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother. 2012;10:296-302.
- US Food and Drug Administration. FDA Drug Safety Communication: important label changes to cholesterol-lowering statin drugs. http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed March 19, 2017. Last updated January 19, 2016.
- Rojas-Fernandez CH, Goldstein LB, Levey AI, Taylor BA, Bittner V, The National Lipid Association’s Safety Task Force. An assessment by the Statin Cognitive Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S5-S16. doi:10.1016/j.jacl.2014.02.013
- Lipinski MJ, Benedetto U, Escarcega RO, et al. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2016;37(6):536-545. doi:10.1093/eurheartj/ehv563.