ApoB: An Overrated Marker of Risk

ApoB: An Overrated Marker of Risk

May 01, 2024

Some researchers recommend the use of apoB (or LDL particle number) to assess cardiovascular/mortality risk. But this is an error for three reasons:

Reason #1: ApoB does not always associate with risk.

Reason #2: ApoB does not improve prediction and is not better than many other risk markers.

Reason #3: ApoB particles in themselves do not cause atherosclerosis.

In future posts, I will examine the evidence specific to atherosclerosis (my book in this link already deals with the atherosclerosis issue). But for now, let us look at 80+ papers on cardiovascular events or mortality, all demonstrating that apoB is not superior and often inferior to other risk markers.

The Studies (With Comments and Quotes)

1) In the AURORA study, there was no relation between apoB and major cardiovascular events. Nor any relation between apoB and atherosclerotic cardiac events. Moreover, apoB was not found among the six factors associated with cardiovascular death (https://www.karger.com/Article/Abstract/346710):

In the multivariate analysis, six factors independently predicted CV death: age (HR 1.03), phosphate (HR 1.56), albumin (HR 0.93), diabetes (HR 1.32), history of pre-existing CHD (HR 1.70) and log CRP (HR 1.16).

2) Based on 15 years follow-up, there was no relation between apoB and CHD events in HeFH individuals (https://pubmed.ncbi.nlm.nih.gov/12755140/):

In this study, we found that smoking, hypertension increased LDL/HDL ratio and fibrinogen levels are the strongest predictors of CHD events, during the 15-year follow-up. No associations were found between Lp(a), triglycerides, apolipoprotein levels and cardiovascular events, after controlling for several potential confounders.

3) The Hortega-Liposcale Follow-up Study: Baseline LDL particle number did not have a stronger relation to CVD events than the TC/HDL ratio. It was concluded that particle composition may be more important than particle number (https://www.sciencedirect.com/science/article/abs/pii/S0167527317378841):

Medium LDL particles were associated with incident cardiovascular disease. LDL particles showed the strongest association with cardiovascular events when the particle composition, rather than the total concentration, was investigated. A change in baseline composition of LDL particles from large to medium and small LDL particles was associated with an increased cardiovascular risk, especially for CHD.

4) The Nurses' Health Study: HDL was described as the "key discriminator" of CHD events, not apoB (https://pubmed.ncbi.nlm.nih.gov/15492318/):

We observed that the association of apoB100 with CHD was more attenuated by lipid and nonlipid risk factors than was LDL-C . . . HDL-C appeared to be the primary lipid predictor.

5) The Physicians' Health Study: ApoB was not predictive of risk after standard risk factors and the ratio of total to HDL cholesterol were considered (https://pubmed.ncbi.nlm.nih.gov/2062328/):

Third, the levels of the HDL subfractions, the levels of apolipoproteins A-I and B-100 . . . were significantly related to the risk of myocardial infarction, but none were independently predictive of infarction after standard risk factors and the ratio of total to HDL cholesterol had been considered.

6) Health Professionals' Follow-up Study: The TC/HDL ratio was a better predictor of cardiovascular events than apoB (https://pubmed.ncbi.nlm.nih.gov/15277429/):

Non-HDL cholesterol and apoB are more potent predictors of CVD incidence among diabetic men than LDL cholesterol. Statistically, the ratio of total to HDL cholesterol is the best predictor of CVD in this cohort of diabetic men.

7) The Multi-Ethnic Study of Atherosclerosis: LDL-P was not associated with risk after adjustments for lipid + non-lipid factors. Also, there were no significant improvements for addition of any lipid or lipoprotein to the AHA/ACC baseline model (https://pubmed.ncbi.nlm.nih.gov/25477346/):

Upon adjusting for traditional lipid panel variables of TC, LDL-C, HDL-C, and triglycerides, no associations remained significant . . . C-statistics revealed that neither apolipoproteins nor NMR measures significantly improved event prediction.

8) PROSPER: There was no relation between apoB and cardiovascular events (https://pubmed.ncbi.nlm.nih.gov/16275871/):

In people >70 years old, HDLc appears to be a predictor not only of coronary risk but also of those who will benefit most from statin treatment. . . . ApoB, which has been reported to predict risk in circumstances where plasma cholesterol or LDLc does not, also did not show any relation to coronary events.

9) Women's Health Study: The TC/HDL ratio had a stronger association with cardiovascular risk than apoB. ApoB also added nothing in prediction models (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2663974/):

The total/HDL cholesterol ratio had the largest hazard ratio of any lipid or lipoprotein measure with CVD. . . . when LDLNMR was examined as a continuous variable, no significant association was found after inclusion of the total/HDL cholesterol ratio. . . . No statistically significant difference was found in the c-index for the models that added LDLNMR or apolipoprotein B100 to the referent model.

10) The ATTICA study: ApoB had no relation with all-cause mortality and cardiovascular events. Again, ratios were better (https://pubmed.ncbi.nlm.nih.gov/26370413/):

The model with the highest explanatory ability was the one included the total cholesterol/HDL-cholesterol ratio . . . the model containing the Apolipoprotein-B/-A1 ratio was the one with the best correct reclassification ability.

11) Malmö Prevention Project Study: In the full group, the relation between LDL particle number and cardiovascular events weakened after adjustment for other risk factors and became non-significant. But HDL remained associated (https://pubmed.ncbi.nlm.nih.gov/28728064/):

The current study did not find that total number of LDL particles (LDL-P) was associated with CVD after adjustment for standard lipids.

12) The FIELD trial: The TC/HDL ratio was more strongly associated with cardiovascular events and was a better predictor than apoB (https://pubmed.ncbi.nlm.nih.gov/20526762/):

Our analysis of 9,795 people with type 2 diabetes in the FIELD study cohort showed that baseline lipid and apolipoprotein ratios performed better than any single lipid or apolipoprotein in predicting CVD risk . . . these analyses provide little support for replacing traditional lipids and their ratios with measures of ApoB and ApoA-I.

13) TNT/IDEAL analysis: Ratios were more strongly associated with risk than apoB (https://pubmed.ncbi.nlm.nih.gov/18519851/):

Evaluation of the ratios revealed a greater statistical association with cardiovascular disease than single measurements of non-HDL cholesterol or apolipoprotein B, with apolipoprotein B/A-I showing the strongest relationship.

14) AFCAPS: Often cited for use of apoB, but there was no association for change in apoB and events. On the other hand, change in ApoA1 did have a relation (https://ncbi.nlm.nih.gov/pubmed/10662743):

At year 1, there were inverse relations between the change in concentrations of apoAI and HDL-C and the subsequent risk for developing a primary end point among those treated with lovastatin, although only on-treatment apoAI achieved statistical significance as a predictor of outcome.

15) ACTIVE/ADIPOSE cohort: In this population, apoB was not associated with cardiovascular disease and inversely associated with all-cause death (https://europepmc.org/article/PMC/5880742):

We found no significant association between lipoprotein concentrations and hospitalization or mortality related to cardiovascular events. Generally, higher lipoprotein concentrations were associated with lower all-cause mortality.

16) The Casale Monferrato study: The ApoB/ApoA1 ratio had the strongest association for cardiovascular mortality in this study. Also, apoB had no association with total mortality (https://pubmed.ncbi.nlm.nih.gov/16525840/):

ApoB had no association with mortality from all causes (HR=1.03; 95% CI 0.79–1.34 for the upper quartile).

17) Dubbo Study: ApoB was not related to coronary heart events in women and was not associated with all-cause mortality (https://pubmed.ncbi.nlm.nih.gov/8546747/) -- -- https://pubmed.ncbi.nlm.nih.gov/19849748/):

Total and LDL cholesterol (and apo B) are significant predictors of CHD in men 60-74 years, but not in older men or in any women over 60 years. . . . [there was] no significant prediction of ACM by various lipid and lipoprotein parameters.

18) PREVEND: ApoB was not better than the TC/HDL ratio and worse than the apoB/apoA1 ratio and non-HDL (https://pubmed.ncbi.nlm.nih.gov/21129046/):

When ratios were compared with single measures, the apoB/apoA-I ratio was better than apo B and LDL-C.

19) Uppsala Longitudinal Study of Adult Men: ApoA1 was the best predictor in this elderly population, not apoB (https://pubmed.ncbi.nlm.nih.gov/17234819/):

Serum ApoA1 is a better risk marker than are ApoB, ApoB/ApoA1 ratio, HDL-C, and LDL-C for cardiovascular disease and mortality in elderly men.

20) The South-Western Finland study: ApoB failed to associate with mortality, unlike markers of oxidative stress (https://pubmed.ncbi.nlm.nih.gov/22693160/):

Circulating ox-LDL lipids, when proportioned to LDL-c, HDL-c or apoaA1, stand out as a risk factor for all-cause mortality independent of major confounding attributes. In the prospective survival and increasing disease burden caused by accumulating age, oxidative stress may have a considerable role.

21) The Chin-Shan Community Cardiovascular Cohort Study: The TC/HDL ratio was more strongly associated with coronary heart events and was a better predictor than apoB (greater risk ratios and if anything a greater c-statistic). There was also no increased risk for apoB in the lowest TC/HDL tertile (https://pubmed.ncbi.nlm.nih.gov/17698856/):

After multivariate adjustment, the lipid ratios, such as TC/HDL-C and apoB/apoA-I, had the strongest associations with CHD.

22) Framingham: ApoB was no better than the TC/HDL ratio (https://pubmed.ncbi.nlm.nih.gov/17699011/):

These data do not support measurement of apo B or apo A-I in clinical practice when total cholesterol and HDL-C measurements are available.

23) LIPID: Analyses generally showed better associations for the TC/HDL ratio than apoB. Also, apoB did not associate with cardiovascular mortality in a 2020 analysis (https://pubmed.ncbi.nlm.nih.gov/11889008/ -- https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3931993/ -- https://pubmed.ncbi.nlm.nih.gov/31209498/):

The total/HDL cholesterol ratio was the strongest predictor of risk and the only significant lipid factor in a multivariate model.

24) Survey in the city of Turku, Finland: ApoB was not related to vascular or nonvascular death (https://pubmed.ncbi.nlm.nih.gov/9261250/):

Concentrations of HDL-C, LDL-C, triglyceride, or apo B were not associated with vascular or nonvascular mortality. On the other hand, a low concentration of apo A-1 predicted vascular death.

25) CORONA: ApoB was neither associated with increased atherothrombotic events nor increased mortality. It was even associated with better prognosis. Furthermore, ApoA1 was the best predictor (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2645061/):

We found that higher baseline LDL, HDL, apoA1, ApoB, and TG were each associated with a better prognosis.

26) The Caerphilly Study: In this cohort, apoB could not survive a simple cholesterol adjustment (https://pubmed.ncbi.nlm.nih.gov/11114956/):

Apolipoproteins B and AI do not improve on the prediction of risk of IHD provided by total and HDL cholesterol, respectively.

27) ARIC: ApoB was not better than the non-HDL/HDL ratio (HRs greater for the lipid ratio). In obese subjects, apoB even lost its relation to coronary events in models adjusted for non-HDL-C and HDL-C (https://pubmed.ncbi.nlm.nih.gov/23109406/):

Among obese participants, we also assessed the association of apolipoproteins with incident CHD in regression models simultaneously adjusted for non-HDL-C and HDL-C. In this lipoprotein cholesterol-adjusted model, a 1-SD higher apoB level was not significantly associated with CHD (HR 1.01, 95% CI 0.82–1.24), while non-HDL-C continued to demonstrate an association.

28) Women's Health Study: In an early report of this study, apoB was clearly a weaker marker than the TC/HDL ratio and far inferior to CRP (https://jamanetwork.com/journals/jama/article-abstract/201996):

As reported for our primary end point, non–HDL cholesterol and the ratio of total cholesterol to HDL cholesterol were superior to apolipoprotein B100 for the end point of “hard” cardiovascular events, and high-sensitivity C-reactive protein remained the single strongest predictor of risk.

29) Showa University Hospital cohort: Small-dense LDL (sdLDL-C) and apoA1 related to cardiovascular events, whereas apoB lost significance in multivariate models (https://pubmed.ncbi.nlm.nih.gov/29512264/):

This study, which compared LDL-C, sdLDL-C, RLP-C, non-HDL-C and ApoB in patients with stable CAD, found that only sdLDL-C was independently associated with CE in patients treated with statins.

30) Multi-Ethnic Study of Atherosclerosis: In those without diabetes or metabolic syndrome, neither LDL nor LDL-P associated with cardiovascular events after adjustments (https://www.sciencedirect.com/science/article/abs/pii/S0002914916304271):

LDL-P did not predict CHD or CVD (despite a trend) for those with DM, the neither disease group, or the overall sample (Table 2). Similarly, LDL-P was not found to be significant within these groups in sensitivity analyses.

31) UK BioBank: ApoB and apoA1 did not improve cardiovascular risk prediction beyond total cholesterol and HDL cholesterol. Furthermore, HDL-C and ApoA1 had the strongest (inverse) associations for cardiovascular mortality (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.041149):

In conclusion, data from UK Biobank show that the predictive ability of total cholesterol and HDL-C, in the context of other classical risk factors, are not improved by the addition or replacement with apolipoproteins in the assessment of CVD risk . . . Our findings suggest its measurement is unlikely to be beneficial for predictive purposes, either in the whole population or in those with discordance.

Also, see the reply to Sniderman:

Our findings suggest its [apoB] measurement is unlikely to be beneficial for predictive purposes, either in the whole population or in those with discordance . . .

32) JUPITER: In the placebo group, apoB had no relation to 'CVD + all-cause mortality,' but smaller LDL particles were (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4674425/):

When examined in relation to the expanded secondary endpoint of CVD and all-cause death that occurred in the placebo group, the smaller LDL-p subfractions remained significantly associated with increased risk, in particular LDL-IVc (1.36, 1.23-1.52, p<0.001), which remained significant after additionally adjusting for standard lipids.

33) The Epidemiology of Diabetes Interventions and Complications cohort: ApoB lost its relation with cardiovascular events after adjustments for age, mean HbA1c and triglycerides (https://pubmed.ncbi.nlm.nih.gov/31203233/):

Among the other apolipoproteins measured in our cohort, APOB showed a positive association with “any CVD” event but not with MACEs after adjusting for age and mean HbA1c.

34) MIRACL trial: HDL was inversely associated with outcomes, but no association was seen for apoB (https://pubmed.ncbi.nlm.nih.gov/15764620/):

Similar to baseline LDL-C, baseline total cholesterol, triglycerides, and apoB were not significantly related to the 16 week risk of clinical events.

35) ERFC meta-analysis: In this large analysis, apoB added no predictive value to conventional risk factors and had a weaker relation to events than the TC/HDL ratio. In fact, apolipoproteins worsened prediction when replacing total cholesterol and HDL (https://pubmed.ncbi.nlm.nih.gov/22797450/):

Replacement of information on total cholesterol and HDL-C with apolipoprotein B and A-I significantly worsened risk discrimination and risk classification.

Note also that the ERFC analysis used individual participant data, which avoids some biases associated with aggregated data (e.g., see Problems and pitfalls in subgroup analysis and meta-regression)

36) VA-HIT: There was no relation between apoB and heart events (https://jamanetwork.com/journals/jama/article-abstract/193685):

Concentrations of apoB, the component of LDL that has been found to be strongly correlated with a reduction in CHD risk when LDL-C is decreased with therapy, had no significant relation to the development of a CHD event.

37) Sex-based analysis from ATTICA: The relation between apoB and cardiovascular events in men was barely significant (attenuation after adjustment). For women, there was zero relation in adjusted models (https://www.mdpi.com/1420-3049/25/7/1506/htm):

Apolipoproteins seem to have the lowest discriminative ability against CVD in both men and women, which comes in line a meta-analysis of cohort studies implemented by the Emerging Risk Factors Collaboration.

38) The CATHGEN biorepository cohort: For the endpoint of 'death or incident MI,' LDL particle number (LDL-P) was actually associated with a reduced risk (https://www.nature.com/articles/s41598-020-78478-w):

In the current study, higher LDL-P levels were protective against death or MI.

39) ARISTOTLE: ApoB was not associated with the composite cardiovascular outcome and was inversely associated with all-cause death (https://www.ahajournals.org/doi/pdf/10.1161/jaha.117.007444):

ApoB was not statistically significantly associated with the risk of the composite ischemic outcome with an HR of 1.01 (95% CI, 0.92–1.12; P=0.8240; Table 6) . . . lower levels of ApoB were associated with an increased risk of all-cause death.

40) INTERHEART: Although this case-control study is sometimes cited as evidence for apoB alone, it showed that the apoB/apoA1 ratio had the strongest association with heart events (https://www.sciencedirect.com/science/article/abs/pii/S0140673608610764):

The ratio of ApoB/ApoA1 was the most powerful marker associated with acute myocardial infarction in both sexes.

41) Women's Health Study (2021): As with earlier publications of the WHS, the TC/HDL ratio had the strongest association with heart events of all the lipid markers, not apoB. Furthermore, the strongest risk factor overall was diabetes (https://jamanetwork.com/journals/jamacardiology/article-abstract/2775559):

In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD.

42) The Strong Heart Study: The TC/HDL ratio was a better predictor of coronary events than apoB (https://pubmed.ncbi.nlm.nih.gov/11880214/):

Only HDL and LDL cholesterol were significant independent lipoprotein lipid and apoprotein predictors for CHD . . . The ratios of HDL/total cholesterol, HDL/LDL cholesterol, and apo AI/B had higher accuracy for predicting CHD . . . Although the ratios were more accurate than the individual lipoprotein lipids and apoproteins, they were still not accurate enough to be clinically conclusive.

43) FINRISK and Health 2000: Of all the markers assessed, including apoB, an inflammatory marker (GlycA) had the strongest association with both peripheral artery disease and coronary artery disease (https://www.medrxiv.org/content/10.1101/2020.07.24.20158675v1):

GlycA displayed the single strongest hazard ratio per SD-change for both CAD (1.31, 1.26-1.37) and PAD (1.53, 1.42-1.65) risk among all the metabolic biomarkers analysed in this study.

44) SMART: Unlike other lipid markers, apoB was not associated with cardiovascular mortality (https://www.sciencedirect.com/science/article/pii/S0002914916311195):

None of the apoB quartiles were associated with any of the end points compared with the lowest quartile.

45) Nishiyama et al.: In this analysis, apoB was not associated with cardiovascular mortality, only apoA1 (https://www.ahajournals.org/doi/abs/10.1161/circ.134.suppl_1.17747):

Multivariate analysis using Cox proportional hazard model demonstrated low ApoA1 (1st quartile) is a significant indicator for cardiovascular mortality (Hazard ratio: 1.60, 95% confidential interval: 1.18-2.15, p=0.002), while high ApoB100, and high ApoB100/ApoA1 ratio were not.

46) NHANES: ApoB did not associate with cardiovascular events (http://clsjournal.ascls.org/content/early/2019/10/09/ascls.119.002063):

Logistic regression results indicated that cases were 3 times more likely to have an increased LDL value but not likely to have an increased ApoB when compared to controls. The study concluded that LDL is an independent predictor of ASCVD and is a better marker than ApoB.

47) HPS: LDL particles and apolipoproteins were not better associated with risk than conventional markers. Moreover, all markers were poorly associated with strokes (https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.111.073684):

The present results indicate that LDL lipoprotein particle measurements provide little additional predictive value over traditional measures for occlusive vascular events . . . Associations of these different LDL-related measures were much weaker or nonexistent with ischemic stroke and other cardiac events (mainly heart failure).

48) Zimmermann et al.: For this cohort of hemodialysis patients, apoB was neither associated with cardiovascular mortality nor all-cause mortality (https://core.ac.uk/reader/82812860):

Cardiovascular mortality was only dependent of age, CRP, BMI, presence of diabetes, and male sex.

49) EPIC–Heidelberg: While apoB was associated with some endpoints, its association with cardiovascular mortality weakened and became non-significant after adjustments for other risk factors (https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0976-4):

"ApoB-100 and TG were positively associated with CVD mortality. However, none of the hazard ratios for CVD mortality remained statistically significant after multivariable adjustments, whereby waist circumference and BMI had the largest effects on risks."

50) TwinGene: Unlike markers such as glucose metabolism, inflammation, and HDL, apoB did not associate with "healthspan." In fact, apoB was inversely associated with all-cause mortality (https://www.sciencedirect.com/science/article/pii/S2352396421001110):

Higher circulating levels of HbA1c, FBG, CRP, and TG were indicative of a higher risk of healthspan ending; in contrast, increased levels of HDL-C, ApoA1, TC were associated with a lower risk of any chronic disease; no statistically significant evidence of association was observed after multiple testing correction for LDL-C, Hb and ApoB . . . Hb, ApoB, and LDL-C were inversely associated with death risks.

51) EDC Study: In a type 1 diabetes population, apoB was not associated with coronary heart disease (CHD) or lower-extremity arterial disease (LEAD)(https://www.sciencedirect.com/science/article/abs/pii/S0021915099002178):

In multivariate analysis, neither ApoA1 or ApoB was associated with CHD or LEAD . . . hypertension, low HDL cholesterol level, high white cell count, depression, and nephropathy were the independent risk factors for CHD (including morbidity and mortality).

52) The BIP study: After multivariate adjustment, the association between apoB and mortality was no better than conventional lipid markers. Moreover, the hazard ratio for apoB was one of the weakest (https://www.sciencedirect.com/science/article/abs/pii/S0002870308007151):

In both male and female CHD patients, the antiatherogenic lipoprotein subfraction (measured as either HDL-C or apolipoprotein A-I) had a slight advantage over to the atherogenic subfraction (non–HDL-C or apolipoprotein B) in predicting all-cause mortality over the long-term followup.

53) ECAT: HDL-C and apoA1 had the strongest relations to heart events in angina patients, but apoB did not remain associated after adjustments (https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0037-1614155):

ApoB did not remain associated with the occurrence of coronary events if adjusted for triglycerides. Similarly to triglycerides, apoB was neither independent of HDL cholesterol nor tPA. These findings do not support those of a recent study in healthy French-Canadian men and may argue against the role of elevated apoB as an independent risk marker for coronary events at least in secondary prevention.

54) Schlitt et al.: ApoB did not predict cardiovascular events, only apoA1 (https://www.sciencedirect.com/science/article/abs/pii/S0167527304005522):

In summary, apoB, triglycerides, and LDL-C did not predict the risk for cardiovascular events in patients with CAD in our population. In this study, apoA-I is the only (apo)lipoprotein with independent predictive value for patients with CAD.

55) Teresa Subirana et al.: ApoB was not associated with risk in multivariate analysis (https://www.sciencedirect.com/science/article/abs/pii/S0002914910021119):

From the multivariate regression analysis, only male gender, older age, smoking, and an LDL/HDL cholesterol ratio of ≥3 were significantly associated with CHD.

56) Manickam et al.: LDL particle number was not a better predictor of coronary events than the TC/HDL ratio https://www.sciencedirect.com/science/article/abs/pii/S1933287410004587:

Our data do not support the routine use of lipid subfractions (particle concentration and LDL subfractions) to assess future coronary risk.

57) Reykjavik Study: ApoB did not contribute anything beyond total cholesterol (https://www.sciencedirect.com/science/article/abs/pii/000291499291215P):

The present study indicates that measurements of apo-AI (equivalent of high-density lipoprotein) and apo(a) (equivalent of Lp[a]) add significantly to the estimate of future risk of coronary artery disease in men, whereas apo-B does not contribute more than serum cholesterol, at least in this age group.

58) ARIC (2001): ApoB was not associated with heart events (https://www.ahajournals.org/doi/full/10.1161/hc3501.095214):

When added to models including LDL-C, HDL-C, and TG, Lp(a) was a significant independent CHD predictor and apolipoproteins were not.

59) AMORIS: As with INTERHEART, this cohort found that the apoB/apoA1 ratio was the strongest predictor of heart attacks in multivariate analyses (https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2008.01925.x):

The best predictor, as evident in paired multivariate analyses, was the apoB⁄apoA-I ratio.

60) Akintoye et al.: ApoB ≥ 130 mg/dL alone (an alleged 'risk enhancer') did not provide any meaningful added value to prediction. Also, when assessed as a continuous variable, apoB was not significantly associated with cardiovascular events [1.06 (0.96, 1.16)](https://www.ahajournals.org/doi/pdf/10.1161/JAHA.120.019589):

The individual risk enhancers evaluated in this study provided no or only marginal incremental information added to the pooled cohort equation.

61) Johansson et al.: ApoB was not associated with cardiac events (https://www.ahajournals.org/doi/abs/10.1161/01.atv.8.6.742):

Cigarette smoking, history of hypertension, high serum triglycerides, and age remained associated with infarction, as did low levels of apo A-l and high levels of apo E. HDL cholesterol and apo B did not contribute independently to infarction.

62) Jin et al.: In this cohort, LDL-TG associated with cardiovascular events, but not apoB (https://link.springer.com/article/10.1186/s12933-020-01125-1):

Compared with other lipid parameters including TG, LDL-C, HDL-C, non-HDL-C, and ApoB, the prognostic value of LDL-TG was more significant.

63) For an older community with no history of cardiovascular disease, apoB did not add any predictive value. ApoB was also no different between those who experienced a cardiovascular event and those who did not (https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jch.13617):

Age, sex, smoking status, T2DM, polypharmacy, and symptoms of apathy were predictors for CVD, whereas total cholesterol, HDL‐cholesterol, SBP, and other additional factors were not.

64) 4D: There was no relation between apoB and atherosclerotic cardiovascular events (https://pubmed.ncbi.nlm.nih.gov/34108090/):

In conclusion, we found no evidence that triglycerides, triglyceride–rich lipoproteins, or apolipoproteins B or C–III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis.

65) Dong et al.: In this cohort, a lower apoB level was not beneficially associated with mortality outcomes and was actually associated with an increased risk of coronary heart events (https://www.frontiersin.org/articles/10.3389/fcvm.2021.745539/full):

Unexpectedly, we observed that low ApoB level (<0.7 g/l) also increased the risk of CHD . . .

66) A Taiwanese cohort found that higher apoB levels were not associated with a greater cardiovascular risk and did not increase all-cause mortality. If anything, the point estimates for all-cause mortality were in a beneficial direction for an increasing apoB change (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8016969/):

A novel finding in our study was that increasing apo B level showed no higher cardiovascular risks . . . our study showed that those with decreasing lipid change had increased mortality risk.

67) In a cohort of type 2 diabetics, the TC/HDL ratio was associated with PAD (peripheral artery disease), but apoB was not (https://pubmed.ncbi.nlm.nih.gov/33409569/):

Our study also highlights the total cholesterol/HDL-cholesterol ratio as a strong and consistent lipid biomarker for the risk of major PAD. . . . We did not observe significant association between triacylglycerol, ApoB-100 or Lp(a) and major PAD.

68) CASABLANCA: Unlike age and diabetes, no association was seen between apoB and CVD mortality (supplementary Table 9). An unusual HDL "apolipoproteomic score" was related to CVD mortality in those with CAD (https://www.sciencedirect.com/science/article/pii/S0735109719339270):

An HDL apolipoproteomic score is associated with the presence of CAD, independent of circulating apoA-1 and apoB concentrations and other conventional cardiovascular risk factors. Among individuals with CAD, this score may be independently associated cardiovascular death.

69) The KIHD cohort: This study assessed the risk of cardiometabolic multimorbidity (CMM) in relation to various lipids/lipoproteins. CMM is characterized by the "coexistence of two or more diseases including type 2 diabetes (T2D), chronic heart disease (CHD), and stroke." Notably, apoB was not associated with an increased risk of "CHD + stroke" (see table 2) (https://aocs.onlinelibrary.wiley.com/doi/10.1002/lipd.12337):

No statistically significant associations were observed between serum apoB concentration and coexisting CMM conditions when introducing categorical or continuous variables.

70) Zhan et al.: In PD patients, apoB did not associate with mortality or cardiovascular events (https://assets.researchsquare.com/files/rs-1334091/v1/1cfcf7f7-dcf0-4faf-8df2-e16e85c62211.pdf?c=1644440173):

Our study showed that apo B was not significantly associated with all-cause mortality or cardiovascular events.

71) UK Biobank: In a large sample, Julkunen et al. (2022) looked at relations between various biomarkers and multiple diseases. Estimates for higher apoB levels were generally in the direction of benefit. For the important outcomes of all-cause mortality, heart disease mortality, and cancer mortality, the study did not show evidence of a harmful association (https://www.medrxiv.org/content/10.1101/2022.06.13.22276332v2):

We note that low-density lipoprotein (LDL) cholesterol and apolipoprotein B displayed inverse associations across a wide range of diseases, i.e. higher concentration was associated with lower risk for disease incidence.

72) Cheang and colleagues published a study on almost 15,000 individuals assessing the relation between lipids/lipoproteins and mortality outcomes. There was no evidence of an association between lower apoB levels and lower cardiovascular mortality or all-cause mortality (https://www.sciencedirect.com/science/article/pii/S240584402201338X):

ApoB and NHDL-C did not show a significant association in CV mortality, whereas [they] showed a U-shape association with all-cause mortality.

73) There was no robust association between apoB and stroke in the China Health and Nutrition Survey. The ApoB/ApoA-1 ratio had the strongest association in the full population (https://www.sciencedirect.com/science/article/pii/S0939475321004737):

ApoA-I, ApoB, TC, HDL-C, LDL-C, TC/HDL-C, and LDL-C/HDL-C were not significantly associated with stroke risk after multivariable adjustments.

74) WHI (hormone): No clear evidence of an association between LDL particle number and CHD risk was demonstrated, including for lipoprotein changes (https://www.ahajournals.org/doi/full/10.1161/atvbaha.108.170431):

For none of the lipoproteins was change from baseline to year 1 significantly associated with CHD after adjustment for treatment arm.

75) CARDS: The ApoB:ApoA-1 ratio more strongly associated with cardiovascular events than apoB, but no association was found between lipids/lipoproteins and stroke (https://link.springer.com/article/10.1007/s00125-008-1176-8):

Neither the ApoB:ApoA-I nor any other lipoprotein concentration or ratio predicted the stroke outcome. . . . The ApoB:ApoA-I ratio was more closely associated with cardiovascular and CHD risk than other lipoprotein variables as judged by the Cox proportional hazard model.

76) REGICOR: ApoB lost its association with the incidence of coronary events after statistical adjustments for classical risk factors. Increased albumin showed the most robust (protective) association with risk (https://www.sciencedirect.com/science/article/abs/pii/S1885585718301373):

The 25-OH-vitamin D, apoA1, and apoB concentrations and the apoA1:apoB ratio showed no independent association with the risk of coronary events.

77) Drexel et al.: A surrogate marker of LDL particle size was associated with major cardiovascular events (and remained so after adjustments for apoB). The researchers also found no evidence of an association between apoB and cardiovascular events (1.02 [0.91–1.15]; p = 0.788) (https://pubmed.ncbi.nlm.nih.gov/34183170/):

Following this adjustment [for apoB], higher LDL-C serum levels reflect a higher cholesterol content of individual LDL particles – and with that larger LDL particle size, a well-established indicator of lower cardiovascular risk.

78) D-EPESE: In this cohort, researchers examined 186 clinical and molecular measures (including apoB) and their relationships with survival. Physical function and HDL particle measures were consistently strong predictors of longevity. On the other hand, there was no evidence of an association for apoB (https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00474-1/fulltext):

It was notable in our study that total lipid concentrations (triglyceride, cholesterol) and cholesterol subfractions (including TRL-C, LDL-C and HDL-C), whether measured by NMR or by standard clinic-ordered lipid panel, were not among the most predictive and direct factors of longevity, contrary to numbers of small HDL particles that were highly predictive.

79) Helgadottir et al.: In this genetic (associative) study, the researchers concluded that non-HDL-C was a better predictor than apoB. They also noted that apoB may be confounded by other factors (https://academic.oup.com/eurjpc/article/29/18/2374/6705598):

Some epidemiological studies indicate that among people with the same non-HDL-C levels, the ones with higher apoB particle count would be at greater CAD risk. However, our study indicates that higher observed risk would not be due to apoB particle concentration, but because of confounding with other risk factors.

80) Cao et al.: Researchers found that TG-rich lipoprotein (TRL)-related biomarkers were associated with cardiovascular events, but not apoB (https://www.jlr.org/article/S0022-2275(20)43690-9/fulltext):

Moreover, non-HDL-C and apoB showed no association with CVEs [cardiovascular events] in the univariate Cox analysis, while TRL-C and RLPC still predicted future CVEs even after being adjusted for non-HDL-C or apoB.

81) PURE: While apoB was associated with cardiovascular events in men, there was no evidence of an association in women [1·03 (0·95–1·11) per 1 SD increase]. Increased ApoA1, on the other hand, was associated with a similar decreased risk in both men and women (https://www.sciencedirect.com/science/article/abs/pii/S0140673622014416):

ApoB (per 1 SD increase) was also more strongly associated with major cardiovascular disease in men than in women. By contrast, the association of ApoA1 (per 1 SD increase) with major cardiovascular disease was similar in women and in men.

82) Yixing City: In this prospective cohort study, the splines in the supplement of the paper clearly show that low apoB levels were not associated with a lower risk of cardiovascular events. For those with normal CRP levels, the relationship for apoB even appeared non-linear with a harmful association at lower levels (https://lipidworld.biomedcentral.com/articles/10.1186/s12944-023-01836-w#Abs1):

ApoB displayed a non-linear pattern with stroke, TC and LDL-C displayed a non-linear pattern with CHD, and ApoB displayed a non-linear pattern with CHD and CVD.

83) UK Biobank (type 2 diabetics): Li and colleagues assessed the association between LDL particles and mortality outcomes in those with type 2 diabetes. For both all-cause mortality and cardiovascular mortality, LDL particles did not display any harmful relationships (https://pubmed.ncbi.nlm.nih.gov/37492984/):

We found that the NMR-derived medium LDL particle was inversely associated with all-cause mortality among patients with T2D, but large and small LDL particles were not.

84) Deelen et al.: An analysis on metabolic biomarkers and all-cause mortality was conducted using 12 cohorts comprising 44168 individuals. Although apoB was not mentioned in the main paper, a look at the supplement shows that apoB was not associated with all-cause mortality [0.98 (0.94 - 1.02) for the full model - https://www.nature.com/articles/s41467-019-11311-9]:

In conclusion, we identified a set of 14 metabolic biomarkers [but not apoB] that independently associate with all-cause mortality.

85) Leiherer et al.: In an Austrian cohort with up to 16 years follow-up, the researchers could not find an association between apoB and cardiovascular mortality. Moreover, higher apoB was associated with a lower risk of death (https://academic.oup.com/ehjopen/advance-article/doi/10.1093/ehjopen/oeae001/7513112):

Apart from remnant cholesterol, none of the other lipid species namely Lp(a), HDL-C, total C, triglycerides, ApoA-1, and ApoB-100 were successful in predicting the outcome . . .

86) NHANES: Zhang and colleagues observed that the non-HDL-C/apoB ratio, a marker for LDL particle size, was associated with all-cause mortality. But the same was not observed for apoB particles (https://www.cell.com/heliyon/pdf/S2405-8440(24)04186-0.pdf):

Our study confirms the negative linear association of this ratio with long-term mortality, with a relatively higher risk of death at low ratio (< 1.4). This effect was not observed for non-HDL-C or apoB . . . Therefore, non-HDL-C/apoB ratio is more predictive of long-term mortality than non-HDL-C or apoB alone.

87) PAVD cohort: Unlike apoB, investigators found that the "ceramide score" was associated with clinical outcomes:

In this population, we found that both LDL-C and ApoB were not significantly associated with stroke/MI or MACE/death after adjusting for traditional risk factors. However, consistent with our previous work, our findings indicate that ceramide score may be useful in predicting ASCVD risk, even after adjusting for traditional risk factors.


When we consider both "strength of association" and prediction, apoB is no better than many other risk factors. In fact, it is often worse. Therefore, apoB should not be used in place of traditional lipids (e.g., lipid ratios) and other risk factors.

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