PCSK9 Inhibitors in Cardiovascular Disease

PCSK9 inhibitors in cardiovascular disease: A meta-analysis

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are generally safe and well tolerated in patients with cardiovascular disease (CVD), with mild and acceptable adverse events.

Key Takeaway

In patients with atherosclerotic cardiovascular disease (ASCVD):

• PCSK9 inhibitors could ameliorate the lipid profile
  • They could reduce low-density lipoprotein cholesterol (LDL-C) by >50% and increase high-density lipoprotein cholesterol (HDL-C) by >5% as well as markedly reduce total cholesterol (TC) and triglyceride (TG) levels.
• Adverse events of PCSK9 inhibitors were mild and acceptable in patients with CVD. However, attention should be paid to injection-site reactions
• PCSK9 inhibitors were generally safe and well tolerated

Why This Matters

• PCSK9 inhibitors are an effective strategy to reduce LDL-C and other lipid parameters, particularly in patients not achieving optimal LDL-C levels or probably having high residual CVD risk despite high-intensity statin therapy.
• However, physicians are still concerned regarding the efficacy and safety of PCSK9 inhibitors; this knowledge gap has been assessed in this study.

Study Design

• This meta-analysis included randomized controlled trials (RCTs) from PubMed, Cochrane Library database, and Clinicaltrials.gov (March 2012–March 2021), with no language, follow-up, or study size restrictions.
• Inclusion criteria (based on the PICOS schema): (P) Patients with hypercholesterolemia or CVD; (I) PCSK9 inhibitors (assessing efficacy and safety of alirocumab, evolocumab, or bococizumab); (C) control (assessing efficacy and safety of control, i.e., placebo, usual care, or ezetimibe); (S) RCTs
• Exclusion criteria: Abstracts, reviews, and case reports; no efficacy and safety data

Key Results

• Of 1,820 studies, 45 RCTs (alirocumab vs evolocumab vs bococizumab: 21 vs 21 vs 3 RCTs) were included (N = 97,297 patients).

Lipid profile

• In total, 42 RCTs (N = 92,681) reported data on TG, TC, LDL-C, and HDL-C
• PCSK9 inhibitors could significantly reduce LDL-C, TC, and TG and increase HDL-C vs the control.
• Alirocumab vs control:
  • Reduced LDL-C by –51.29% (95% confidence interval [CI]: –55.83 to –46.75, P <0.05), TC by –30.31% (95% CI: –34.26 to –26.36, P <0.05), and TG by –10.31% (95% CI: –13.81 to –6.81, P <0.05)
  • Increased HDL-C by 5.63% (95% CI: 4.86–6.40, P <0.05))
• Evolocumab vs control:
  • Reduced LDL-C by –53.99% (95% CI: –58.45 to –49.54, P <0.05), TC by –34.2% (95% CI: –36.18 to –32.21, P <0.05), and TG by –8.86% (95% CI: –13.17 to –4.55, P <0.05)
  • Increased HDL-C by 7.05% (95% CI: 5.55–8.54, P <0.05)
• Bococizumab vs control:
  • Reduced LDL-C by –56.96% (95% CI: –60.69 to –53.23, P <0.05), TC by –38.96% (95% CI: –43.33 to –34.58, P <0.05), and TG by –17.64% (95% CI: –20.79 to –14.48, P <0.05)
  • Increased HDL-C by 5.98% (95% CI: 4.86–7.11, P <0.05)

Cardiac disorders

• Unstable angina (UA) was reported in 13 studies (N = 57,717) and myocardial infarction (MI) in 16 studies (N = 90,355).
  • UA was less common in the alirocumab group vs control (odds ratio [OR] = 0.69, 95% CI: 0.48–0.98, P <0.05) as was the frequency of MI (OR = 0.85, 95% CI: 0.76–0.95, P <0.05).
  • The risk of UA did not differ significantly between evolocumab and control group (OR = 0.66, 95% CI: 0.42–1.03, P >0.05); however, the risk of MI was lower with evolocumab (OR = 0.73, 95% CI: 0.65–0.82, P <0.05).
  • No statistically significant difference in UA (OR = 0.82, 95% CI: 0.67–1.00, P = 0.05) and MI (OR = 0.94, 95% CI: 0.78–1.14, P >0.05) was found between bococizumab and control groups./span>

Stroke

• Incidence of stroke was significantly lower with PCSK9 inhibitors compared with control: Alirocumab (OR = 0.76, 95% CI: 0.60–0.97, P <0.05), evolocumab (OR = 0.79, 95% CI: 0.66–0.95, P <0.05), and bococizumab (OR = 0.60, 95% CI: 0.42–0.84, P <0.05)

Safety

• Incidence of injection-site reactions was significantly higher with PCSK9 inhibitors vs control: Alirocumab (OR = 1.68, 95% CI: 1.45–1.93, P <0.05), evolocumab (OR = 1.64, 95% CI: 1.41–1.91, P <0.05), and bococizumab (OR = 8.03, 95% CI: 6.85–9.41, P <0.05)
• Incidence of myalgia did not differ significantly between the control and alirocumab (OR = 1.18, 95% CI: 0.92–1.53), evolocumab (OR = 1.09, 95% CI: 0.85–1.38), and bococizumab (OR = 1.05, 95% CI: 0.92–1.20) (all, P >0.05).

Limitations

• PCSK9 inhibitor dose and different follow-up durations may have affected heterogeneity of results.
• Pooling of data in control group was a mixture of placebo or ezetimibe.
• Definitions of efficacy and safety were not uniform in the included studies.