A signal suggesting neurocognitive effects from the use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy emerged in a new meta-analysis, supporting some past concerns that there may be such a risk from the drugs, which can profoundly lower LDL-cholesterol levels.
The review also suggests that use of PCSK9 inhibitors is not associated with cumulative serious adverse events, musculoskeletal effects, or stroke.
"PCSK9 inhibitors have considerable therapeutic potential and are safe as demonstrated by the studies performed to date," Dr Roberto Bolli (Institute of Molecular Cardiology, University of Kentucky) told heartwire from Medscape.
"The signal toward adverse neurocognitive effects does not preclude their use in the appropriate population because the evidence is not conclusive," he said. "However, we should be aware of this possible side effect and monitor our patients closely for any signs or symptoms during follow-up."
The US Food and Drug administration recently approved PCSK9 inhibitors for treating hypercholesterolemia in adults, and studies have shown them to decrease LDL cholesterol and improve cardiovascular outcomes, the researchers write in an article published online January 10, 2017 in Circulation: Cardiovascular Quality and Outcomes.
Bolli and colleagues conducted a meta-analysis of randomized controlled trials to assess the long-term safety of PCSK9 inhibitors. They included in their analysis 11 studies (only two large ones) that evaluated PCSK9 inhibitors and reported safety outcomes for at least 6 months of follow-up.
The researchers found the overall incidence of serious adverse events to be similar among studies.
Serious Adverse Events Among Those Taking and Not Taking PCSK9-Inhibitors
|Type of incidence||PCSK9-inhibitor patients, n (%)||Non–PCSK9-inhibitor patients, n (%)|
|Serious adverse events||741/6760 (11)||403/3896 (10.3)|
|Musculoskeletal events||957/6760 (14.2)||494/3896 (12.7)|
|Stroke||16/6760 (0.2)||5/3896 (0.1)|
|Neurocognitive||56/6760 (0.8)||20/3896 (0.5)|
However, when they only looked at the two large studies (ODYSSEY LONG TERM and OSLER), which accounted for about 65% of all patients, they found a more than twofold increase in incidence of neurocognitive events (odds ratio 2.81, 95% CI 1.32–5.99; P=0.007). These events included delirium (including confusion), cognitive and attention disorders and disturbances, dementia and amnestic conditions, disturbances in thinking and perception, and mental-impairment disorders.
The researchers pointed out that in all studies analyzed, neurocognitive events were self-reported and no study had information on baseline cognition in patients.
Among the research questions now, they write, are what the lower limit for LDL cholesterol should be and what subgroups of patients might be at greater risk for neurocognitive events.
"As is the case for any medication or therapeutic strategy, we should discuss the risks and benefits with the patient and any available alternatives," Bolli told heartwire . "In our opinion, we should share the results of this meta-analysis with patients and make them and their caregivers aware of this potential adverse effect. At the same time, they should be made aware that the data are not conclusive and studies are ongoing that will resolve this issue.
"We don't think any new study needs to be initiated solely to assess neurocognitive events," he continued. "We should be able to assess the risk of neurocognitive events from the ongoing large outcome studies. Moreover, as recommended by the FDA, data are being gathered by drug developers/manufacturers to assess the effect of PCSK9 inhibitors on cognition."