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Published on: July 29, 2018
Proprotein convertase subtilisn/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk
Tasnim F Imran1,2,3, Ali A Khan3, Phinnara Has2,3
1Providence VA Medical Center, Providence, Rhode Island, United States of America.
Insights
Proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitors and siRNA therapy significantly lower LDL-c in high-risk patients. Alirocumab and Evolocumab also reduced major adverse cardiac events and mortality, demonstrating their clinical benefit.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of mortality, driven by LDL-c accumulation.
- Lipid-lowering therapies are crucial for ASCVD prevention.
- PCSK9 inhibitors and siRNA therapies show promise but their impact on MACE and mortality requires further investigation.
Approach:
- A meta-analysis of randomized controlled trials (RCTs) was conducted using data from major databases until April 2023.
- RCTs involving PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) for lipid lowering and MACE risk were extracted.
- Random-effects models were used to pool data on LDL-c reduction, MACE, and mortality.
Key Points:
- Evolocumab reduced LDL-c by 61.09%, Alirocumab by 46.35%, and Inclisiran by up to 54.83%.
- Evolocumab reduced the risk of myocardial infarction, revascularization, stroke, and overall MACE.
- Alirocumab significantly reduced myocardial infarction, cardiovascular mortality, all-cause mortality, and overall MACE.
Conclusions:
- PCSK9 inhibitors and siRNA therapy achieve significant LDL-c reduction (>40%) in high-risk individuals.
- Both Alirocumab and Evolocumab demonstrated a reduction in major adverse cardiac events.
- Alirocumab showed a significant reduction in both cardiovascular and all-cause mortality.
Background:
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Atherosclerosis occurs due to accumulation of low-density lipoprotein cholesterol (LDL-c) in the arterial system. Thus, lipid lowering therapy is essential for both primary and secondary prevention. Proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitors (Evolocumab, Alirocumab) and small interfering RNA (siRNA) therapy (Inclisiran) have been demonstrated to lower LDL-c and ASCVD events in conjunction with maximally tolerated statin therapy. However, the degree of LDL-c reduction and the impact on reducing major adverse cardiac events, including their impact on mortality, remains unclear.
Objective:
The purpose of this study is to examine the effects of PCSK9 inhibitors and small interfering RNA (siRNA) therapy on LDL-c reduction and major adverse cardiac events (MACE) and mortality by conducting a meta-analysis of randomized controlled trials.
Methods:
Using Pubmed, Embase, Cochrane Library and clinicaltrials.gov until April 2023, we extracted randomized controlled trials (RCTs) of PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) for lipid lowering and risk of MACE. Using random-effects models, we pooled the relative risks and 95% CIs and weighted least-squares mean difference in LDL-c levels. We estimated odds ratios with 95% CIs among MACE subtypes and all-cause mortality. Fixed-effect model was used, and heterogeneity was assessed using the I2 statistic.
Results:
In all, 54 studies with 87,669 participants (142,262 person-years) met criteria for inclusion. LDL-c percent change was reported in 47 studies (n = 62,634) evaluating two PCSK9 inhibitors and siRNA therapy. Of those, 21 studies (n = 41,361) included treatment with Evolocumab (140mg), 22 (n = 11,751) included Alirocumab (75mg), and 4 studies (n = 9,522) included Inclisiran (284mg and 300mg). Compared with placebo, after a median of 24 weeks (IQR 12-52), Evolocumab reduced LDL-c by -61.09% (95% CI: -64.81, -57.38, p<0.01) and Alirocumab reduced LDL-c by -46.35% (95% CI: -51.75, -41.13, p<0.01). Inclisiran 284mg reduced LDL-c by -54.83% (95% CI: -59.04, -50.62, p = 0.05) and Inclisiran 300mg reduced LDL-c by -43.11% (95% CI: -52.42, -33.80, p = 0.01). After a median of 8 months (IQR 6-15), Evolocumab reduced the risk of myocardial infarction (MI), OR 0.72 (95% CI: 0.64, 0.81, p<0.01), coronary revascularization, 0.77 (95% CI: 0.70, 0.84, p<0.01), stroke, 0.79 (95% CI: 0.66, 0.94, p = 0.01) and overall MACE 0.85 (95% CI: 0.80, 0.89, p<0.01). Alirocumab reduced MI, 0.57 (0.38, 0.86, p = 0.01), cardiovascular mortality 0.35 (95% CI: 0.16, 0.77, p = 0.01), all-cause mortality 0.60 (95% CI: 0.43, 0.84, p<0.01), and overall MACE 0.35 (0.16, 0.77, p = 0.01).
Conclusion:
PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) significantly reduced LDL-c by >40% in high-risk individuals. Additionally, both Alirocumab and Evolocumab reduced the risk of MACE, and Alirocumab reduced cardiovascular and all-cause mortality.
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