Going to Low LDL Levels With Evolocumab Does Not Affect Memory, Brain Function: EBBINGHAUS

The trial should help dispel the notion that lowering LDL aggressively can “make you stupid,” one expert says.

Going to Low LDL Levels With Evolocumab Does Not Affect Memory, Brain Function: EBBINGHAUS

WASHINGTON, DC—Reducing LDL cholesterol to “unprecedented” low levels with a PCSK9 inhibitor—down to less than 25 mg/dL in some patients—does not adversely affect cognitive function, according to the results of the EBBINGHAUS study.

In a subgroup of patients who underwent cognitive testing in FOURIER, the large cardiovascular morbidity and mortality trial testing evolocumab (Repatha, Amgen), investigators report no differences between evolocumab- and placebo-treated patients in terms of performance on a battery of neuropsychological tests.

Additionally, there was no significant difference in patient- and physician-reported cognitive adverse events between the two study arms.

Speaking with the media following his presentation at the American College of Cardiology 2017 Scientific Session, Robert Giugliano, MD (Brigham and Women’s Hospital, Boston, MA), said physicians can face an uphill battle when dealing with patients fears of lipid-lowering therapy. He said their desire to lower LDL cholesterol levels often clashes with misinformation patients glean from the internet or the misinterpretation of studies.

Moreover, a network meta-analysis led by Michael Lipinski, MD (MedStar Washington Hospital Center, DC), published in the European Heart Journal last year, suggested that LDL-lowering with PCSK9 inhibitors was associated with a more than twofold increase in neurocognitive adverse events.

“The major goal here was to assess cognition—memory and other executive functions—as there had been some preliminary, small observational data with statins and patients who achieved very low LDL to suggest there might be connection between statins and impairments in memory recall and other functions,” said Giugliano.

To address these concerns, researchers conducted a cognitive substudy of patients enrolled in FOURIER. The EBBINGHAUS study included 1,204 patients with baseline cognitive testing on/before the first dose of evolocumab and who had follow-up cognitive testing at 6, 12, and 24 months and at the study’s completion. Within the cohort, 20% of patients had a prior stroke (median time of 3.5 years from the last stroke).

Researchers used a standardized, validated computer tablet-based platform known as the Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessment to test spatial working memory—the study’s primary endpoint. This involved searching for a blue “token” hidden within a red box on the screen, with the number of red boxes increasing each round. Patients were not allowed to return to a box where a blue token was found, a task which tested their memory. 

After 2 years, the researchers saw “absolutely no difference between evolocumab and placebo,” said Giugliano. Other metrics, including assessments of reaction time and memory-matching, were no different between treatments.

Importantly, when investigators stratified patients by achieved LDL cholesterol levels, they observed no impairment in memory and executive function among patients who achieved LDL cholesterol levels less than 25 mg/dL with evolocumab.


Earlier at the ACC conference, the FOURIER trial commanded center stage when investigators showed that treatment with evolocumab (140 mg every 2 weeks or 420 mg monthly) in patients with stable atherosclerotic cardiovascular disease significantly reduced the risk of cardiovascular outcomes compared with placebo.

Aside from the main results, the FOURIER trial broke new ground for LDL-cholesterol lowering. In the trial, adding the PCSK9 inhibitor to patients who were well treated with statin therapy—70% were treated with a high-intensity statin—reduced LDL cholesterol 59%, down from a median of 92 mg/dL at baseline to 30 mg/dL at 48 weeks. More than 25% of patients achieved a final LDL cholesterol level less than 20 mg/dL, said investigators.

While the cardiology community praised the trial, stating the results resolutely confirm the “lower is better” hypothesis, previous studies with statins have raised concerns about cognitive deficits with very low LDL cholesterol levels. This led the US Food and Drug Administration to update the label for statins to warn of the potential for memory loss, confusion, and other cognitive impairments.

Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), who moderated the late-breaking clinical trial session and was not involved in the study, said EBBINGHAUS was one of the most anticipated presentations at the meeting given the questions about the safety of lowering LDL cholesterol to very low levels.

“This trial is extremely important, I think, because it’s out there on the internet and blogosphere that statins make you stupid,” said Bhatt, referencing fears of lowering LDL cholesterol levels. “Newborn babies have LDL cholesterol levels of 20 or 30 [mg/dL] and they’re forming brain tissue. [T]his stuff out there about statins and effects on cognitive function is so widespread but the science behind it is mostly pseudoscience.”

The EBBINGHAUS data, added Bhatt, should reassure physicians that very low levels of LDL cholesterol achieved by pharmacologic means appears to be safe.

Sandra Lewis, MD (Northwest Cardiovascular Institute, Portland, OR), who chaired the morning press conference, agreed, stating the data should reassure patients and physicians that evolocumab is not going to impair cognitive function. 

Study Still Very Short, More to Learn

Speaking with TCTMD, Roger Blumenthal, MD (Johns Hopkins Medical Institute, Baltimore, MD), pointed out that the duration of follow-up in EBBINGHAUS was relatively short. “I think 2 years is not enough to settle this question, and Robert Giugliano alluded to that, and it’s a relative small cohort,” said Blumenthal.

While it was noted that evolocumab, which is a monoclonal antibody, is too large to cross the intact blood-brain barrier, Blumenthal said it’s not known if chronic high blood pressure or diabetes might affect the blood-brain barrier, which might lead to cognitive impairments.

“It’s very reassuring what we have right now, but it’s a very short study,” he said.

Speaking with the media, Giugliano said that patients in FOURIER included in EBBINGHAUS who participate in the open-label extension study will continue to be studied for cognitive changes. “It’s important because we don’t treat patients for just 20 months,” he said. As long as funding is available from the sponsor, Giugliano said he would like to see patients studied for a decade or more.

In 2013, along with lead investigator Kristopher Swiger, MD (Johns Hopkins University School of Medicine), Blumenthal and colleagues performed a large meta-analysis of clinical trials testing statin therapy and showed that in patients without baseline cognitive dysfunction, the short-term data showed no adverse effect of statins on cognition. Additionally, the long-term data suggested statin therapy might even be beneficial for preventing dementia. 

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Giugliano RP, Mach F, Zavitz K, et al. EBBINGHAUS: a cognitive study of patients enrolled in the FOURIER trial. Presented at: ACC 2017. March 18, 2017. Washington, DC.

  • Giugliano reports having received research grants from Merck; having received research grants and honoraria for CME programs from Daiichi Sankyo and the American College of Cardiology; and serving as a compensated consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck, Portola, and Pfizer.
  • Bhatt reports consulting fees/honoraria Elsevier Practice Update Cardiology; Belvoir Publications, Cardax, Clinical Cardiology, Elsevier, HMP communications, Journal of Invasive Cardiology, Medscape Cardiology, Merck & Co, Regado Biosciences, Slack Publications/Cardiology Research Foundation, WebMD. He reports research grant support from Amarin, Amgen Inc., Astra Zeneca, Bristol Myers Squibb, Eisai, Ethicon, FlowCo, Forest Laboratories, Ischemix, Medtronic, Pfizer Inc, PLx Pharma, Roche, Sanofi Aventis, Takeda, and The Medicines Company.
  • Lewis and Blumenthal report no conflicts of interest.