ApoB and the Next Generation of Lipid Management: Lessons from the FOURIER and ODYSSEY Trials

By Dr. Steven Long, DO, MHA, CPT
Beyond Health | Precision Medicine for High-Performance Living

Cholesterol management has entered a new era — one that goes beyond LDL-C alone.

For decades, LDL cholesterol has been the main target for cardiovascular risk reduction. But modern evidence shows that ApoB (apolipoprotein B) — the protein that represents the actual number of atherogenic particles — is a more precise predictor of risk.

The FOURIER and ODYSSEY OUTCOMES trials redefined lipid management by showing that lowering ApoB to unprecedented levels leads to measurable reductions in cardiovascular events — without compromising safety.

At Beyond Health, these studies help shape our advanced approach to lipid management, emphasizing particle count, inflammation, and endothelial health — not just cholesterol numbers.

1. ApoB: The True Marker of Atherogenic Risk

Every atherogenic lipoprotein particle (LDL, VLDL, IDL, Lp(a)) carries one molecule of ApoB.
That means ApoB reflects the total number of particles capable of entering the arterial wall — the key step in atherosclerosis.

• High ApoB → More particles → More arterial injury → Greater plaque formation.
• LDL-C can appear “normal” while ApoB remains high (especially in insulin resistance or metabolic syndrome).

Large-scale evidence shows ApoB correlates more closely with cardiovascular outcomes than LDL-C (Sniderman et al., JAMA, 2019).

This insight set the stage for PCSK9 inhibitor trials like FOURIER and ODYSSEY — which directly tested whether pushing ApoB even lower could further reduce cardiovascular risk.

2. The FOURIER Trial: Lower Is Better

Overview

• Full Name: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk.
• Published: New England Journal of Medicine, 2017.
• Drug: Evolocumab (Repatha), a monoclonal antibody against PCSK9.
• Participants: 27,564 adults with atherosclerotic cardiovascular disease (ASCVD) on statins.
• Baseline LDL-C: ~92 mg/dL.
• ApoB: Median 80 mg/dL at baseline.

Design

Patients were randomized to Evolocumab vs. placebo, on top of maximally tolerated statin therapy.

Results (Median 2.2 years follow-up)

• LDL-C reduced by 59% (to a median of 30 mg/dL).
• ApoB reduced by 50%.
• Primary endpoint (CV death, MI, stroke, revascularization, or unstable angina):
  • 15% relative risk reduction (p<0.001).
• Key secondary endpoint (CV death, MI, or stroke):
  • 20% relative risk reduction.
• Safety: No increase in diabetes, neurocognitive effects, or new safety signals at very low LDL levels (down to 19 mg/dL).

(Sabatine MS et al., NEJM, 2017)

Mechanistic Significance

FOURIER proved that lowering ApoB below traditional LDL targets provides incremental benefit — reinforcing the “lower is better” paradigm.

Plaque imaging studies later confirmed regression of atherosclerosis at these levels (Nicholls SJ et al., JAMA Cardiol, 2019).

3. The ODYSSEY OUTCOMES Trial: Confirming the Benefit

Overview

• Published: New England Journal of Medicine, 2018.
• Drug: Alirocumab (Praluent), another PCSK9 inhibitor.
• Participants: 18,924 adults 1–12 months after acute coronary syndrome (ACS), all on statins.
• Baseline LDL-C: ~87 mg/dL.
• Target LDL-C range: 25–50 mg/dL (dose adjusted).

Results (Median 2.8 years follow-up)

• LDL-C reduced by 62% (to a median of 53 → 40 mg/dL).
• ApoB reductions similar to FOURIER (~50%).
• Primary composite endpoint (CHD death, nonfatal MI, ischemic stroke, unstable angina hospitalization):
  • 15% relative risk reduction.
• All-cause mortality:
  • 15% reduction (HR 0.85; 95% CI, 0.73–0.98).

(Schwartz GG et al., NEJM, 2018)

Post-Hoc Analyses

Patients who achieved LDL-C <25 mg/dL or ApoB <40 mg/dL had the lowest event rates without adverse effects (Ray KK et al., Eur Heart J, 2019).

This reinforced that the benefit was driven by the particle number reduction (ApoB), not LDL cholesterol concentration alone.

4. Why ApoB Matters More Than LDL-C

Traditional LDL-C measures mass of cholesterol within particles, not particle number.
ApoB directly measures atherogenic particle burden — the root cause of plaque formation.

In practice:

Two patients may have the same LDL-C (e.g., 100 mg/dL), but:

• Patient A (metabolically healthy): ApoB 80 mg/dL.
• Patient B (insulin resistant): ApoB 120 mg/dL.

Patient B’s higher particle count drives higher cardiovascular risk — even if total cholesterol looks “normal.”

ApoB is now endorsed by multiple organizations (e.g., European Society of Cardiology, AHA) as a superior metric of atherogenic risk and treatment target (<65 mg/dL in high risk, <55 mg/dL in very high risk).

5. Translating the Trials: What This Means for You

The FOURIER and ODYSSEY trials collectively prove:

1. ApoB is the key driver of atherosclerotic risk.
2. PCSK9 inhibition is safe and effective when added to statin therapy.
3. There is no lower threshold for LDL-C or ApoB at which harm emerges — lower consistently means less risk.

6. Beyond Health Action Plan

At Beyond Health, we take a precision lipidology approach that integrates lessons from FOURIER and ODYSSEY into personalized care.

1. Advanced Lipid Testing

We measure:

• ApoB for particle count.
• Lp(a) for inherited risk.
• hs-CRP, fasting insulin, and triglycerides to assess inflammation and metabolic contributors.

2. Targeted Interventions

• Lifestyle: DASH or Mediterranean diet, resistance and Zone 2 training, weight optimization.
• Pharmacology:
  • Statins remain first-line for reducing ApoB production.
  • PCSK9 inhibitors (Evolocumab or Alirocumab) for residual risk or statin intolerance.
  • Ezetimibe for additional absorption blockade.
• Goal: ApoB <60 mg/dL (or <50 mg/dL in established ASCVD).

3. Continuous Monitoring

We track improvements not just in labs, but in VO? max, endothelial function, and vascular imaging, tying metabolic and cardiovascular health into a unified longevity framework.

7. Beyond Health’s Perspective

The FOURIER and ODYSSEY trials marked a pivotal shift in cardiovascular medicine: from cholesterol mass to particle biology.

At Beyond Health, we view ApoB not as a “cholesterol number,” but as a longevity biomarker — reflecting the health of your vascular system, metabolism, and inflammation control.

Reducing ApoB isn’t just about preventing heart attacks — it’s about extending healthspan, protecting the brain, and maintaining vascular youth for decades.

Conclusion

The FOURIER and ODYSSEY trials proved that aggressive ApoB lowering through PCSK9 inhibition significantly reduces cardiovascular events — and that there’s no penalty for optimal numbers.

When we combine this science with lifestyle and metabolic optimization, the results extend beyond survival — they enhance function, cognition, and quality of life.

At Beyond Health, our philosophy mirrors these findings:
We don’t treat cholesterol; we treat vascular aging.
 And ApoB is one of its most reliable gauges.

References

1. Sabatine MS, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (FOURIER). N Engl J Med. 2017;376(18):1713–1722.
2. Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes After Acute Coronary Syndrome (ODYSSEY OUTCOMES). N Engl J Med. 2018;379(22):2097–2107.
3. Ray KK, et al. Safety and Efficacy of Very Low LDL Cholesterol Levels in the ODYSSEY OUTCOMES Trial. Eur Heart J. 2019;40(33):2760–2772.
4. Nicholls SJ, et al. Effect of PCSK9 Inhibition on Coronary Plaque Composition. JAMA Cardiol. 2019;4(12):1230–1239.
5. Sniderman AD, et al. Apolipoprotein B Particles and Cardiovascular Disease: A Better Measure of Risk Than LDL Cholesterol. JAMA. 2019;321(5):451–452.
6. Mach F, et al. 2021 ESC Guidelines on Cardiovascular Disease Prevention. Eur Heart J. 2021;42(34):3227–3337.
7. Whelton PK, et al. 2017 ACC/AHA Guideline for the Management of Blood Cholesterol. J Am Coll Cardiol. 2018;73(24):e285–e350.