Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression

Raccah, Bruria Hirsh; Yanovsky, A; Treves, Nir; Rotshild, Victoria; Renoux, Christel; Danenberg, Haim; Eliaz, Ran; Matok, Ilan

doi:10.1016/j.ijcard.2021.04.025

Cited by 16 publications

(13 citation statements)

References 52 publications

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“…At the same time, PCSK9i has been reported in many meta-analysis as associated with neurocognitive disorder ( Harvey et al, 2018 ; Gouverneur et al, 2021 ). However, Khan and Raccah et al performed that evidence of neurocognitive adverse events was found during follow-up periods ( Hirsh Raccah et al, 2021 ; Khan et al, 2017 ). In our network meta-analysis, we were unable to analyze the adverse neurological events due to the few studies that reported relevant events.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis

Pan

et al. 2021

Front. Pharmacol.

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There have been many meta-analyses for statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) to evaluate clinical outcomes, but the efficacy and safety of different intensity of these three drugs on clinical outcomes was absent. PCSK9i, ezetimibe, and statins were divided into seven interventions as follows: including PCSK9i + high-intensity statins (P9i+HT), PCSK9i + moderate-intensity statins (P9i+MT), ezetimibe + high-intensity statins (Eze+HT), ezetimibe + moderate-intensity statins (Eze+MT), high-intensity statins (HT), moderate-intensity statins (MT), and low-intensity statins (LT). The risk ratios (RR) and 95% confidence intervals (CI) were calculated to evaluate the clinical outcomes in all randomized controlled trials included. In traditional meta-analysis, the more intensive treatment had a lower risk of all-cause mortality (RR 0.91, 95% CI 0.88–0.95), cardiovascular mortality (RR 0.89, 95% CI 0.86–0.92), myocardial infarction (RR 0.79, 95% CI 0.77–0.81), coronary revascularization (RR 0.80, 95% CI 0.76-0.84), and cerebrovascular events (RR 0.84, 95% CI 0.80–0.88) compared with the less intensive treatment. However, the more intensive treatment had a higher risk of new-onset diabetes (RR 1.08, 95% CI 1.04-1.12). The network meta-analysis demonstrated that P9i+HT, P9i+MT, HT, and MT were significantly associated with a risk reduction in coronary revascularization and cerebrovascular events compared with PLBO. LT could effectively reduce the risk of cardiovascular mortality (RR 0.71, 95% CI 0.54–0.92), MI (RR 0.67, 95% CI 0.54-0.82), and coronary revascularization (RR 0.77, 95% CI 0.65–0.91) compared with PLBO. P9i+HT was superior to HT in reducing the risk of MI (RR 0.78, 95% CI 0.68–0.90), coronary revascularization (RR 0.84, 95% CI 0.73–0.96), and cerebrovascular events (RR 0.78, 95% CI 0.64–0.95). However, compared with PLBO, P9i+HT, HT, and MT could increase the risk of new-onset diabetes (RR 1.23, 95% CI 1.11–1.37; RR 1.23, 95% CI 1.14–1.33; RR 1.09, 95% CI 1.02–1.15, respectively). In conclusion, PCSK9i added to background statins may be recommended as preferred lipid-lowering therapy, and did not increase the additional risk of new-onset diabetes. The safety and efficacy of ezetimibe was not superior to that of statins. LT can be recommended as the initial therapy.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis

Pan

et al. 2021

Front. Pharmacol.

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Section: Side Effectsmentioning

confidence: 95%

“…64 A meta-analysis of 59,733 patients pooling data from RCTs on the impact of PCSK9 inhibitors on neurocognitive adverse events found no significant increase in risk of neurocognitive adverse effects with PCSK9 inhibitors. 65 Meanwhile, among older adults, subgroup analysis from both the FOURIER and ODDYSSEY-OUTCOMES trials found no significant interaction for efficacy and no additional increase in safety outcomes when stratified by age. [66][67][68] A Mendelian randomization study of PCSK9 variants showed an increased risk for diabetes (odds ratio 1.11, 95% CI: 1.04-1.19) in the setting of impaired fasting glucose, which was comparable with variants for HMGCR.…”

Section: Side Effectsmentioning

confidence: 95%

PCSK9 Inhibitors in the Management of Cardiovascular Risk: A Practical Guidance

Jia¹,

Rifai²,

Saeed³

et al. 2022

VHRM

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“…Subsequent meta-analyses found no increased risk of NCEs in the groups treated with PCSK9 inhibitors. 10,11…”

Section: Pcsk9 Inhibitors and Cognitionmentioning

confidence: 99%

“…Subsequent metaanalyses found no increased risk of NCEs in the groups treated with PCSK9 inhibitors. 10,11 Furthermore, the Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects (EBBINGHAUS) trial assessed cognitive function across a wide range of domains, including memory and attention, prospectively. Executive function and episodic memory were assessed and were similar in the evolocumab group compared to the placebo group in the subgroups of patients stratified according to their lowest-attained LDL-C levels.…”

Section: Pcsk9 Inhibitors and Cognitionmentioning

confidence: 99%

Safety Issues Associated With the Clinical Application of PCSK9 Inhibitors: Current Findings

Wang

Zhang

2022

Cardiology in Review

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Reduction in low-density lipoprotein cholesterol levels is the cornerstone of treatment and prevention of atherosclerotic cardiovascular diseases. Currently, high-intensity statins are being used as the first-line therapy to lower low-density lipoprotein cholesterol levels, as they improve the prognosis of patients with atherosclerotic cardiovascular disease and those in high-risk groups. However, in some patients, the expected reduction in cholesterol is not achieved despite aggressive treatment with statins. Moreover, some patients cannot tolerate the dosage or show poor response or compliance to statins. Therefore, combination therapies with statins and other medications should be considered. Recently, several clinical trials have shown that the use of proprotein convertase subtilisin/kexin type 9 inhibitors with or without statins and/or other lipid-lowering drugs can significantly reduce low-density lipoprotein cholesterol levels, sometimes to extremely low levels. Therefore, to facilitate appropriate prescription of these new lipid-lowering drugs, we systemically evaluated the safety issues associated with these inhibitors and extremely low low-density lipoprotein cholesterol levels.

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Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression

Cited by 16 publications

References 52 publications

Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis

Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis

PCSK9 Inhibitors in the Management of Cardiovascular Risk: A Practical Guidance

Safety Issues Associated With the Clinical Application of PCSK9 Inhibitors: Current Findings

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