In 2014 in response to early trial evidence, the U.S. Food and Drug Administration (FDA) asked developers of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to assess for cognitive adverse events (CAEs) in ongoing late-stage trials.¹ It seems inevitable that concern would eventually carry over to PCSK9 inhibitors as the newest class of lipid-lowering therapy with the ability to lower low-density lipoprotein cholesterol (LDL-C) to a greater degree than seen with even the strongest statin therapy. Recently, two phase III efficacy and safety trials^2,3 reported a greater incidence of CAEs in the PCSK9 treatment group. This article reviews these results, discusses ongoing studies, and proposes one potential solution to the continued question of whether lipid-lowering therapy can cause CAEs.

The Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) study⁴ was the first to report increased CAEs in the PCSK9 treatment group and likely prompted the FDA directive. The study enrolled 1,104 hypercholesterolemic patients, randomized them to receive 420 mg of evolocumab + standard of care or standard of care alone, and monitored the incidence of adverse events over one year. CAEs were more common in the evolocumab group with three reporting amnesia (<1%) and five with memory or mental impairment (<1%). No events were reported in the standard of care group. CAEs were ascertained by self report, and patients were not blinded to treatment, raising the possibility of responder bias. Additionally, patients randomized to the evolcoumab + standard of care group were followed every four weeks while patients in the standard of care (control) group were seen every 12 weeks. As such, ascertainment bias, whereby patients in the evolocumab + standard of care group had three times the number of opportunities to report adverse events, is a possible factor in this study design.

Earlier in 2015, the OSLER program released additional data² from 4,465 participants with 11-month follow-up also that showed increased CAEs in the evolocumab group (0.9%) relative to the standard of care group (0.3%). These events were heterogeneous, including delirium, cognitive and attention disorders and disturbances, dementia, disturbances in thinking and perception, and mental impairment disorders. Importantly, in both OSLER studies, CAEs were not related to the degree of LDL-C lowering; clustering did not occur in the LDL-C <25 mg/dL group relative to the 25-50 mg/dL or >50 mg/dL groups.

Available data from alirocumab³ also suggests a higher incidence of CAEs in those allocated to the PCSK9 group. In the Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) trial, CAEs were reported in 1.2% of patients taking alirocumab versus 0.5% in the placebo group (p = 0.17). The prevalence of CAEs is similar to the OSLER trials, but patients in ODYSSEY LONG TERM were blinded to treatment and followed for nearly 18 months.

All four companies developing PCSK9 inhibitors — Pfizer (bococizumab), Amgen (evolocumab), and Sanofi/Regeneron (alirocumab) — plan to monitor for CAEs in their phase III trials,^5-8 but it remains unclear whether these events will be subjectively reported, as in OSLER and ODYSSEY LONG TERM, or objectively determined via neurocognitive testing. Perhaps most informative will be a dedicated neurocognitive substudy:⁹ Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects (EBBINGHAUS) (ClinicalTrials.gov Identifier: NCT02207634). Participants without dementia or mild cognitive impairment at baseline will be randomized in a double-blind, placebo-controlled, multicenter study to evaluate evolocumab + background statin therapy versus statin therapy alone. The primary outcome will be the Spatial Working Memory test, an assessment of executive function. Results are expected in September 2017 with an enrollment of 4,000 subjects.

If EBBINGHAUS shows no increased incidence of CAEs in the PCSK9 group, will that go far enough to belay concerns among providers and patients? This possibility seems unlikely. After all, statins have faced concern for years regarding CAEs despite multiple systematic reviews^10-12 showing a lack of conclusive evidence tying them to CAEs. The problem in accepting systematic reviews of randomized trials as definitive is multi-fold:

1. There may be vulnerable subgroups diluted when analyzed with large groups.
2. Formal neurocognitive tests such as the Mini-Mental Status Examination (MMSE) may be too blunt to detect the changes perceived by patients.

This may explain why patients taking statins continue to report CAEs,¹³ while studies with neurocognitive testing are largely negative. On the other hand, correlation does not equal causation and subjectively-reported adverse events are potentially fraught with bias. It is especially worth remembering that coronary heart disease has also been shown to impair cognition^14,15 and may confound patients' perceptions of the root cause of their confusion.

For PCSK9 inhibitors, if past performance is a predictor of future controversy, there may be disparate results from trials such as OSLER or ODYSSEY LONG TERM and EBBINGHAUS again. If that is the case, how should health care providers monitor for CAEs? One way to satisfy methodological purists while concentrating on patients perhaps most vulnerable to CAEs would be to employ n-of-1 trials. With this format, a patient reporting a CAE would be enrolled into a series of cross-over trials with randomization to PCSK9 inhibitor or placebo in a blinded fashion for specified periods of time. The patient would serve as his or her own control, and there would also be washout periods between cross-over stages. Patients could receive both formal neurocognitive testing and maintain subjective reporting, such as through a symptom diary. Such a design would be patient-centered, financially efficient, and methodologically sound.

Further reporting of CAEs with PCSK9 inhibitors is forthcoming over the next two to three years.^9,5-8 It will be interesting to see if results repeat the statin experience or if the data conclusively implies causality between lipid-lowering therapy and CAEs. Regardless, providers and patients must take care to avoid missing the forest through the trees; both OSLER² and ODYSSEY LONG TERM³ reported an approximate 50% relative risk reduction in cardiovascular events, all the more impressive when one considers the majority of control groups were already taking statin therapy. As with any complex decision, the relative pros and cons of treatment should be discussed and interpreted through each patient's unique value system.

References

1. Walker J. FDA Advises of Adverse Effects from New Cholesterol Drugs. (Wall Street Journal website). 2014. Available at: http://www.wsj.com/articles/SB10001424052702304732804579425612487904436. Accessed 2/20/15.
2. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
3. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372;1489-99.
4. Koren MJ, Giugliano R P, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234-43.
5. US National Institutes of Health. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727) (ClinicalTrials.gov website). 2012-2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01663402. Accessed 4/23/15.
6. US National Institutes of Health. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) (ClinicalTrials.gov website). 2013-2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01764633. Accessed 4/23/15.
7. US National Institutes of Health. The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-1) (ClinicalTrials.gov website). 2013-2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01975376. Accessed 4/23/15.
8. US National Institutes of Health. The Evaluation of Bococizumab (PF-04950615; RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-2) (ClinicalTrials.gov website). 2013-2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01975389. Accessed 4/23/15.
9. US National Institutes of Health. (ClinicalTrials.gov website). 2014. Available at: https://clinicaltrials.gov/ct2/show/NCT02207634. Accessed 4/23/15.
10. Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: A systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 2013;88:1213-21.
11. Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med 2013;159:688-97.
12. Ott BR, Daiello LA, Dahabreh IJ, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med 2015;30:348-58.
13. Golomb BA, Dimsdale JE, White HL, Criqui MH. Abstract 1501: do low dose statins affect cognition? Results of the UCSD Statin Study. Circulation 2006;114:II_289.
14. Gharacholou SM, Reid KJ, Arnold SV, et al. Cognitive impairment and outcomes in older adult survivors of acute myocardial infarction: findings from the translational research investigating underlying disparities in acute myocardial infarction patients' health status registry. Am Heart J 2011;162:860-869.e1.
15. Breteler MM, Claus JJ, Grobbee DE, Hofman A. Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam Study. BMJ 1994;308:1604-8.

Keywords: Amnesia, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cognition, Confusion, Control Groups, Coronary Disease, Delirium, Dementia, Double-Blind Method, Executive Function, Follow-Up Studies, Health Personnel, Hypercholesterolemia, Incidence, Lipoproteins, LDL, Memory, Short-Term, Mental Disorders, Cognitive Dysfunction, Prevalence, Proprotein Convertases, Random Allocation, Risk, Risk Factors, Standard of Care, Subtilisins, United States Food and Drug Administration

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