Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors

Abstract

Background-There is encouraging evidence of the efficacy of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors; however, their long-term safety remains unclear. We performed a meta-analysis of studies to evaluate the longterm safety of PCSK9 inhibitors. Methods and Results-Our search strategy yielded 11 studies (9 smaller early-phase and 2 larger outcome trials). The outcomes assessed were cumulative serious adverse events, musculoskeletal adverse events, neurocognitive adverse events, and stroke. Odds ratio (OR) was calculated using the Mantel-Haenszel method. Subgroup analysis was done to assess the difference in safety between the smaller early-phase studies and the larger outcome studies. Our meta-analysis suggested no difference in the incidence of serious adverse events (OR, 1.00; 95% confidence interval [CI], 0.88−1.15), musculoskeletal adverse events (OR, 1.01; 95% CI, 0.87−1.13), neurocognitive adverse events (OR, 1.29; 95% CI, 0.64−2.59), or stroke (OR, 1.44; 95% CI, 0.57−3.65) with the use of PCSK9 inhibitors. Subgroup analysis of the 2 large outcome studies did suggest an increased incidence of neurocognitive adverse events (OR, 2.85; 95% CI, 1.34−6.06) with the use of PCSK9 inhibitors. However, the overall incidence of neurocognitive adverse events and stroke was <1%, whereas the cumulative incidence of serious adverse events and musculoskeletal events was >10% in both the groups. Conclusions-Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in the outcome studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and post-marketing surveillance. (Circ Cardiovasc Qual Outcomes. 2017;10:e003153.

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

“…De novo glial synthesis of cholesterol in the brain is postulated to be important for synapse formation and function; observational studies and RCTs of statins have been inconsistent in their demonstration of an association between statin utilization and impaired neurocognitive function 52, 53, 54, 55. PCSK9 inhibitors are not known to inhibit de novo cholesterol synthesis or to cross the blood–brain barrier; nevertheless, imbalances in neurocognitive side effects between PCSK9 inhibitors and control groups were detected in OSLER (Open‐Label Study of Long‐Term Evaluation Against LDL‐C) 1 and 2 (pooled rate: 0.9% versus 0.3%) and in ODYSSEY LONG‐TERM (1.2% versus 0.5%), as well as 2 large meta‐analyses of lipid‐lowering trials 46, 56. However, these findings were limited by heterogeneity of the examined populations, small numbers of events, and differences in the definition and assessment of neurocognitive events.…”

Neurological effects of proprotein convertase subtilisin/kexin type 9 inhibitors: direct comparisons

“…Khan et al . 18 also published a meta-analysis evaluating the rates of ischaemic stroke with the use of PCSK9 inhibitors. The authors have divided the studies into two groups, early Phase II–III studies and long-term studies, and concluded that the incidence of ischaemic strokes were similar.…”

“…The authors have divided the studies into two groups, early Phase II–III studies and long-term studies, and concluded that the incidence of ischaemic strokes were similar. 18 Both of these investigations also lack the cohorts included in the FOURIER/EBBINGHAUS and GLAGOV trials. 8,15 …”

“…Lipinski et al ., 19 Robinson et al ., 39 and Khan et al . 18 published the meta-analyses that estimated the rates of neurocognitive deficits with the use of PCSK9 inhibitors, albeit in a subgroup fashion. Lipinski et al .…”

“…5,8,10–17 Prior meta-analyses have contributed to the notion that PCSK9 inhibitors are ‘neurologically unsafe’ due to the increase in the incidence of neurocognitive adverse events with use of these inhibitors when compared with the controls. 18,19 …”