PCSK9-targeted therapies and the risk of stroke and dementia: a meta-analysis of RCTs

Today, I will be presenting my study on the association between PCSK9-targeted therapies and the risk of stroke and dementia, a meta-analysis of randomized controlled trials. In this study, as we know that PCSK is known to lower the LDL-C clearance from the blood and LDL-C and Lp(a) fall sharply after its initiation and led to less atherosclerosis and fewer stroke incidents. The open question is, cholesterol is essential for neuronal membrane and synapses. Does lowering LDL-C aggressively protect the brain from stroke or put cognition at risk? So in this meta-analysis test, we’ve tested both sides, where there’s a cerebrovascular benefit and neurocognitive safety. In this study, a total of 856 records has been identified and out of this 22 randomized controlled trials, Phase III trials have been included. And a total population of 34,808 in PCSK9-targeted therapies and 30,180 in the control group with a median follow-up of 1.2 years. And the agents which have been used in these trials were alirocumab, evolocumab, and inclisiran. We find out that the primary outcome was the risk of any stroke and our meta-analysis demonstrates that there is a 22% reduction in the risk of stroke. And the risk of ischemic stroke has been reduced by 23%. However, the risk of TIA and hemorrhagic stroke were non-significant and was comparable within both groups. And there was no signal of neurocognitive harm like dementia, Alzheimer’s dementia, and Parkinson’s disease, all of them were non-significant and with a wide confidence interval because of the less number of studies, and I think in the future, further randomized trials must evaluate and prospective studies must aim to evaluate the effect of PCSK therapies on patients with hypercholesterolemia, ASCVD, for the risk of dementia and all the neurocognitive endpoints. In 22 trials, a total of 64,000 patients with 0% heterogeneity for stroke has been observed and no publication bias detected. The key clinical take-home messages were that stroke protection is real, 22% lower all-cause stroke, 24% lower ischemic stroke, complement doesn’t replace statin-based ASCVD prevention. No hemorrhagic stroke signal has been observed in this study with a risk ratio of 1.16 and very low LDL-C levels for bleeding risk. Cognition looks unaffected for now. So the bottom line of this study is to consider PCSK9 targeted therapy for stroke risk reduction in patients, not at goal on statins, with reassurance, not certainly on long-term cognitive safety.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.

Today, I will be presenting my study on the association between PCSK9-targeted therapies and the risk of stroke and dementia, a meta-analysis of randomized controlled trials. In this study, as we know that PCSK is known to lower the LDL-C clearance from the blood and LDL-C and Lp(a) fall sharply after its initiation and led to less atherosclerosis and fewer stroke incidents. The open question is, cholesterol is essential for neuronal membrane and synapses. Does lowering LDL-C aggressively protect the brain from stroke or put cognition at risk? So in this meta-analysis test, we’ve tested both sides, where there’s a cerebrovascular benefit and neurocognitive safety. In this study, a total of 856 records has been identified and out of this 22 randomized controlled trials, Phase III trials have been included. And a total population of 34,808 in PCSK9-targeted therapies and 30,180 in the control group with a median follow-up of 1.2 years. And the agents which have been used in these trials were alirocumab, evolocumab, and inclisiran. We find out that the primary outcome was the risk of any stroke and our meta-analysis demonstrates that there is a 22% reduction in the risk of stroke. And the risk of ischemic stroke has been reduced by 23%. However, the risk of TIA and hemorrhagic stroke were non-significant and was comparable within both groups. And there was no signal of neurocognitive harm like dementia, Alzheimer’s dementia, and Parkinson’s disease, all of them were non-significant and with a wide confidence interval because of the less number of studies, and I think in the future, further randomized trials must evaluate and prospective studies must aim to evaluate the effect of PCSK therapies on patients with hypercholesterolemia, ASCVD, for the risk of dementia and all the neurocognitive endpoints. In 22 trials, a total of 64,000 patients with 0% heterogeneity for stroke has been observed and no publication bias detected. The key clinical take-home messages were that stroke protection is real, 22% lower all-cause stroke, 24% lower ischemic stroke, complement doesn’t replace statin-based ASCVD prevention. No hemorrhagic stroke signal has been observed in this study with a risk ratio of 1.16 and very low LDL-C levels for bleeding risk. Cognition looks unaffected for now. So the bottom line of this study is to consider PCSK9 targeted therapy for stroke risk reduction in patients, not at goal on statins, with reassurance, not certainly on long-term cognitive safety.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.