WASHINGTON (FRONTLINE MEDICAL NEWS) – Concerns about possible adverse cognitive effects from the new lipid-lowering drug evolocumab and from aggressive lowering of LDL cholesterol were largely put to rest with results from a nearly 2,000-patient study showing that a median 20 months of treatment with evolocumab caused no cognitive or memory decline, either compared with baseline measures or compared with similar patients randomized to placebo treatment.

Early reports during development of the PCSK9-inhibitor antibodies had hinted at a possible adverse effect on cognition with these drugs, a finding that played into already existing concerns perpetuated largely on the Internet that treatment with statins and lowering of LDL cholesterol in general can lead to memory and cognition problems. On the basis of these new results from a large placebo-controlled trial of patients treated for a relatively prolonged period, “I wouldn’t be concerned about adverse cognitive effects” in patients treated with evolocumab (Repatha) or, for the time being, any other PCSK9 inhibitor, said Robert P. Giugliano, MD , in a video interview .

A subgroup analysis in the study also showed that, even among patients who achieved and sustained LDL cholesterol below 25 mg/dL, no hint arose of an adverse effect on memory or cognition, said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.

“This trial is extremely important because it is out there on the Internet that statins make you stupid,” commented Deepak L. Bhatt, MD , a designated discussant for the study. The results “reassure us that pharmacologically achieved very low LDL cholesterol levels appear safe,” added Dr. Bhatt, a professor of medicine at Harvard University in Boston and a cardiologist at Brigham and Women’s Hospital.

“Every day in my office, patients tell me that statins make you dumb. Now I can comfortably tell my patients that we studied whether this drug [evolocumab] makes you dumb, and it doesn’t; nor did having an LDL cholesterol level below 25 mg/dL,” commented Sandra J. Lewis, MD , chief of cardiology at Legacy Good Samaritan Hospital in Portland, Ore.

The Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects ( EBBINGHAUS ) study ran as a nested substudy within the larger FOURIER trial of more than 27,000 patients that established the efficacy and safety of evolocumab treatment to significantly reduce adverse cardiovascular events, compared with placebo, in high-risk patients who were already on statin treatment (N Engl J Med. 2017 Mar 17. doi:10.1056/NEJMoa1615664 ). EBBINGHAUS randomly selected 1,974 of the FOURIER placebo and evolocumab patients and subjected them to a battery of cognitive and memory tests at baseline, then after 6, 12, 24, and 48 months on treatment, and also at the end of the study. The EBBINGHAUS patients averaged 63 years of age; 72% were men.

The primary assessment tool Dr. Giugliano and his associates used in EBBINGHAUS was the Cambridge Neuropsychological Test Automated Battery ( CANTAB ) Assessments, a computer-based test of spatial working memory strategy index of executive function, and 1,204 patients underwent CANTAB testing both before they received their first dose of their assigned agent and also at the end of treatment. The scores of the patients on evolocumab virtually superimposed on those of patients in the placebo group, both at baseline and at the end of treatment, easily meeting the study’s prespecified definition of noninferiority, Dr. Giugliano reported at the annual meeting of the American College of Cardiology.

The CANTAB scores also showed no change from baseline over time in the individual subgroups of both evolocumab-treated and placebo-treated patients. The total absence of a signal of mental deterioration in the placebo patients who remained on statin treatment throughout the study provided new evidence that medium-term treatment with a statin was not linked with any change in memory or cognition.

EBBINGHAUS also assessed participants using several other memory and cognition tests, had patients complete an end-of-study survey of their perceptions of their mental function, and questioned participating physicians about patients’ mental performance. None of these measures showed any signals of impairment. A full description of the range of assessments used in EBBINGHAUS appeared recently in a published article ( Clin Cardiol. 2017 Feb;40[2]:59-65 ).

Dr. Giugliano conceded that what remains unknown at this point is the possible impact of further prolonged treatment with a PCSK9 drug or from extended maintenance of LDL cholesterol levels at very low levels, effects that could continue for decades in the routine treatment of selected patients. He noted that patients who participated in FOURIER and in EBBINGHAUS are undergoing continued follow-up to gain better insight into the longer-term effects of their treatment.

EBBINGHAUS was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has been a consultant to and received research support from Amgen and from several other drug companies. Dr. Bhatt has received research support from Amgen, from Sanofi Regeneron associated with research on another PCSK9 inhibitor, and from several other drug companies, Dr. Lewis had no disclosures.

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