Key Takeaway

This meta-analysis included 254,828 participants from 20 RCTs Reported the association of 6 different classes (statins, ezetimibe, PCSK9-inhibitors, CETP-inhibitors, fibrates, and niacin) of LLT with apoB levels and major CV events and showed that:

  • All 6 classes of LLT were associated with similar reduction in risk of major CV events for the same magnitude and duration of apoB lowering
  • For 30 mg/dL absolute reduction in plasma apoB levels, 6 classes of LLTs were associated with a consistent reduction in major CV events:
    • 10%, 15%, 19% and 20% proportional reduction after 1, 2, 3, and 4 or 5 years of therapy, respectively
  • Regardless of changes in other lipids, the therapeutic benefit of LLT was determined by changes in plasma apoB levels

Why This Matters

  • LDL-C reduction therapies (statins, ezetimibe, and PCSK9 inhibitors) have demonstrated consistent reduction of major CV events in several RCTs
    • However, therapies that do not involve up-regulation of LDL-receptor pathway* or that lower triglycerides† did not show a consistent reduction in risk of CV events
  • Trapping of apoB molecule within the artery wall can cause progression of atherosclerotic plaque
  • This study compared the association between the proportional reduction in major CV events and different classes of LLT for the same magnitude and duration of apoB lowering

Key Highlights

Methods:

  • Meta-analysis of RCTs evaluating 6 different classes of LLTs
  • Databases: MEDLINE and EMBASE were searched from inception to November 2022

Inclusion criteria:

  • Placebo-controlled, double-blind RCTs reporting adjudicated clinical CV outcomes and enrolled ≥1,000 participants with a median follow-up duration of ≥1 year
  • Reported absolute achieved differences in plasma apoB levels between treatment and control groups
  • Provided cumulative event curves figure for the treatment and control groups that included number of participants remaining at risk at beginning of each year of follow-up

Analysis:

  • Association between 30 mg/dL reduction in plasma apoB levels and risk of major CV events across classes of LLTs
  • Summary estimates of the effect for an individual class of therapy were combined in an inverse variance-weighted random-effects meta-analysis iteratively after each year of follow-up
  • Heterogeneity of effect among different LLT classes was assessed using the I2 statistics

Results:

254,828 participants from 20 trials with major CV events (30,175) were included

  • Mean age = 63 years
  • Females = 26%

Association of Reduction in Plasma Apo-b Levels with Llt and Reduction in Major Cv Events

For each 30 mg/dL absolute reduction in plasma apoB levels, the 6 classes of LLT (statins, ezetimibe, PCSK9-inhibitors, CETP-inhibitors, fibrates, and niacin) were associated with a consistent reduction in major CV events after therapy

Duration of therapy Proportional reduction in major
CV events for each 30 mg/dL absolute
reduction in plasma apoB levels		 HR (95% CI)
After 1 year 10% 0.90 (0.86–0.94)
After 2 years 15% 0.85 (0.82–0.88)
After 3 years 19% 0.81 (0.78–0.85)
After 4 or 5 years 20% 0.80 (0.77–0.83)

No evidence of heterogeneity between estimates of the different LLT classes was noted
(I2 = 6.9%; P = 0.364)

    Therapy HR (95% CI) Heterogeneity; HR (95% CI)
    1 year I2 = 0.00%, H2 = 1.00;
    0.90 (0.86–0.94)
    Statins 0.89 (0.82–0.96)
    PCSK9mAB 0.89 (0.84–0.96)
    Ezetimibe 0.90 (0.77–1.05)
    CETP - Inhibitiors 0.97 (0.77–1.24)
    Fibrates 0.87 (0.53–1.43)
    Niacin 0.99 (0.68–1.43)
    2 years I2 = 0.00%, H2 = 1.00;
    0.85 (0.82–0.88)
    Statins 0.83 (0.78–0.88)
    PCSK9mAB 0.86 (0.81–0.90)
    Ezetimibe 0.85 (0.75–0.97)
    CETP - Inhibitiors 0.93 (0.77–1.12)
    Fibrates 0.93 (0.66–1.31)
    Niacin 0.89 (0.68–1.17)
    3 years I2 = 0.00%, H2 = 1.00;
    0.81 (0.78–0.85)
    Statins 0.80 (0.76–0.84)
    Ezetimibe 0.83 (0.74–0.92)
    CETP - Inhibitiors 0.87 (0.74–1.02)
    Fibrates 0.78 (0.58–1.04)
    Niacin 0.86 (0.68–1.09)
    4 years I2 = 0.00%, H2 = 1.00; 0.80 (0.77–0.83)
    Statins 0.80 (0.76–0.83)
    Ezetimibe 0.81 (0.73–0.90)
    CEPT - Inhibitors 0.81 (0.70–0.94)
    Fibrates 0.77 (0.59–0.99)
    Niacin 0.84 (0.68–1.05)
    5 years I2 = 0.00%, H2 = 1.00;
    0.80 (0.77–0.83)
    Statins 0.80 (0.77–0.83)
    Ezetimibe 0.80 (0.73–0.88)
    Fibrates 0.81 (0.64–1.03)

    ABBREVIATIONS:
    CETP, cholesteryl ester transfer protein; CI, confidence interval; HR, hazard ratio; PCSK9, proprotein convertase subtilisin/ kexin 9; PCSK9mAb, PCSK9 monoclonal antibodies.

*LDL-receptor pathway (CETP-inhibitors and niacin); †Lower triglycerides (fibrates).

ABBREVIATIONS:
ApoB, apolipoprotein-B; CETP, cholesteryl ester transfer protein; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; LLTs, lipid-lowering therapies; PCSK9, proprotein convertase subtilisin/kexin 9; RCTs, randomized controlled trials.

    Galimberti F, et al. Meta-analysis of randomized controlled trials evaluating the association between magnitude and duration of apolipoprotein-b lowering and cardiovascular risk reduction among different lipid-lowering therapies. Poster presented at the 91st European Atherosclerosis Society congress (EAS 2023). May 21–24, 2023.

MAT-KW-2300433/V1/NOV2023