Reevaluating Mortality Risks: The Paradox of Low Apolipoprotein B and LDL-Cholesterol Levels in Cardiovascular Health

Highlight

– Low apolipoprotein B (apoB) and low LDL-cholesterol are independently associated with increased all-cause and cardiovascular mortality risk in the general population.
– The risk relationship between LDL-cholesterol and mortality exhibits non-linear dynamics, whereas apoB shows complex dose-response patterns.
– A combined assessment of apoB and LDL-cholesterol refines mortality risk stratification, particularly emphasizing risk increases with low lipid values.

Study Background and Disease Burden

Cardiovascular disease (CVD) remains the leading cause of mortality globally, with dyslipidemia being a major modifiable risk factor. Low-density lipoprotein cholesterol (LDL-C) is well-established as a critical target in CVD prevention strategies. However, apolipoprotein B (apoB), the primary structural protein of atherogenic lipoproteins, is increasingly appreciated as a more precise marker of lipid-related cardiovascular risk because it directly quantifies the number of atherogenic particles irrespective of their cholesterol content.

While elevated LDL-C and apoB levels are linked to increased cardiovascular risk, emerging evidence suggests that very low levels of these markers may paradoxically associate with adverse outcomes, yet comprehensive analyses integrating both apoB and LDL-C in relation to cardiovascular and all-cause mortality are limited. Understanding these relationships is essential for refining lipid management and mortality risk assessment in clinical practice.

Study Design

This prospective cohort study utilized data from 15,380 participants enrolled in the 2005–2016 National Health and Nutrition Examination Survey (NHANES). The cohort comprised a middle-aged population with a median age of 46 years and slight male predominance (51.8%). Baseline measurements included LDL-C and apoB concentrations. Mortality outcomes—encompassing all-cause, cardiovascular disease (CVD), and cerebrovascular mortality—were tracked over a median follow-up of approximately 8.5 years (101.0 months).

The investigators employed Cox proportional hazards regression models adjusted for multiple confounders to estimate hazard ratios (HRs) for mortality associated with varying LDL-C and apoB levels. Additionally, restricted cubic spline methods were applied to explore dose-response relationships, capturing potential non-linear associations. The analysis included stratification by apoB levels to evaluate the interaction between these two lipid markers and mortality risks.

Key Findings

During follow-up, 1,771 (8.8%) participants died, including 443 (2.1%) from cardiovascular causes and 109 (0.5%) from cerebrovascular disease. The study found that both low apoB (<90 mg/dL) and low LDL-C (<70 mg/dL) levels were independently linked to increased all-cause and cardiovascular mortality.

Restricted cubic spline curves of the risk for all-cause (A) and cardiovascular (B) mortality according to the dose-response associations between apoB and LDL-cholesterol.

Specifically, multivariable-adjusted hazard ratios indicated that low LDL-C was associated with a 66% increased risk of all-cause mortality (HR 1.66, 95% CI 1.33–2.06) and a 65% increased risk of cardiovascular mortality (HR 1.65, 95% CI 1.12–2.43). While cerebrovascular mortality also appeared elevated (HR 2.13), the confidence interval (1.01–4.49) suggested a borderline significance.

Low apoB demonstrated a similar pattern with a significantly higher risk of all-cause mortality (HR 0.79, 95% CI 0.69–0.89) but was not independently associated with cardiovascular or cerebrovascular mortality alone. Notably, restricted cubic spline analysis revealed that LDL-C displayed a non-linear association with all-cause mortality (P for non-linearity <0.05), but a linear relationship with cardiovascular mortality. ApoB exhibited non-linear dose-response patterns for both outcomes, underscoring complex biological interactions.

In combined stratifications, the highest mortality risk was observed among participants with low apoB and LDL-C levels below 100 mg/dL. Compared to individuals with apoB <90 mg/dL and LDL-C between 100–129 mg/dL, those with LDL-C <70 mg/dL carried an 81% higher risk of all-cause mortality (HR 1.81, 95% CI 1.39–2.36), while those with LDL-C 70–99 mg/dL had a 28% greater risk (HR 1.28, 95% CI 1.01–1.62). Reduced apoB further increased cardiovascular mortality risk in the context of low LDL-C.

Combined association of apoB and LDL-cholesterol levels with all-cause and cardiovascular disease mortality.

Interestingly, elevated apoB combined with low LDL-C levels did not correlate with increased mortality, suggesting that the paradoxical risk is predominantly linked to low apoB coupled with low LDL-C.

Expert Commentary

These findings challenge the traditional paradigm that lower LDL-C levels universally confer reduced cardiovascular risk. The paradoxical associations observed may stem from several mechanisms, including malnutrition, chronic illnesses, or altered lipid metabolism leading to low apoB and LDL-C levels, which are themselves markers of poor health status rather than direct causal factors.

The non-linear relationships highlight that extremely low lipid concentrations may not be benign and warrant careful clinical interpretation, especially when observed in the context of poor general health or inflammatory conditions. ApoB’s role as a particle number marker provides additional granularity beyond LDL-C, facilitating more nuanced risk stratification.

Study limitations include the observational design, which precludes definitive causal inference, and potential residual confounding despite multivariable adjustments. Additionally, the NHANES population may not fully represent all demographic groups, and lipid-lowering therapies during follow-up were not extensively detailed, which might influence outcomes.

Current lipid guidelines predominantly emphasize lowering LDL-C; this study underscores the importance of considering apoB levels and clinical context to avoid oversimplified risk assessments. Further research is warranted to elucidate the pathophysiological basis of low lipid levels and their relationship with mortality.

Conclusion

This comprehensive cohort analysis reveals that low apoB and LDL-cholesterol levels are significantly associated with increased risks of all-cause and cardiovascular mortality in the general population. These findings suggest that lipid profiles showing very low LDL-C and apoB levels should prompt clinicians to evaluate underlying health conditions and mortality risk carefully rather than assume protective effects.

Integrating apoB measurement with LDL-C assessment refines cardiovascular risk stratification and may facilitate personalized management strategies. Clinicians should remain vigilant of the complex and non-linear associations between lipid markers and mortality outcomes, recognizing that both very high and very low levels carry potential risks.

Future studies should investigate mechanistic pathways and evaluate whether targeted interventions can mitigate risks associated with low apoB and LDL-C levels, thereby enhancing cardiovascular care and reducing premature mortality.

References

Yu X, Yuan Y, Dong X, Xier Z, Ma L, Peng H, Li G, Yang Y. Low apolipoprotein B and LDL-cholesterol are associated with the risk of cardiovascular and all-cause mortality: a prospective cohort. Ann Med. 2025 Dec;57(1):2529565. doi: 10.1080/07853890.2025.2529565 . Epub 2025 Jul 11. PMID: 40642933 ; PMCID: PMC12258213 .

Additional literature:
– Sniderman AD, Thanassoulis G, Glavinovic T, et al. Apolipoprotein B particles and cardiovascular disease risk: epidemiology, pathophysiology and therapies. Nat Rev Cardiol. 2023 Jan;20(1):39-53. doi: 10.1038/s41569-022-00787-4 .- Grundy SM, Stone NJ, et al. 2018 AHA/ACC Guideline on the Management of Blood Cholesterol. Circulation. 2019;139:e1082–e1143.