APOLIPOPROTEIN B: Bridging the gap between evidence and clinical practice

Abstract

Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol (LDL-C) in predicting atherosclerotic cardiovascular disease risk, it has not become widely adopted into routine clinical practice. One barrier for use of apoB is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. While guidelines have often provided clear LDL-C targets and/or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we seek to synthesize existing data regarding the epidemiology of apoB by 1) comparing guideline recommendations regarding utilization of apoB, 2) describing population percentiles of apoB relative to LDL-C, 3) summarizing studies of discordance between LDL-C and apoB, and 4) evaluating apoB levels in clinical trials of lipid lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care.

Rationale for Measurement of apoB

Lipid measurement is done with the main goal of identifying and treating individuals with or at risk for atherosclerotic cardiovascular disease (ASCVD).(1) Cholesterol circulates in plasma within lipoprotein particles, of which apolipoproteins are essential structural and functional components. There are two main isoforms of apoB found on lipoproteins: apoB-48, which is present in lipoproteins of intestinal origin including chylomicrons and chylomicron remnants, and apoB100, which is found in lipoproteins of hepatic origin including very-low-density lipoprotein (VLDL), intermediate-density lipoproteins (IDL), low-density lipoprotein (LDL), and lipoprotein (lp(a)).(2) While chylomicrons are too large to enter the arterial wall, the other apoB containing lipoproteins, including chylomicron remnants, can be trapped in the arterial wall and deposit cholesterol, therefore driving the atherogenesis process.(3) High-density lipoprotein (HDL) particles do not contain apoB. Because each atherogenic lipoprotein particle only contains one molecule of apoB, the plasma apoB measurement provides a measurement of the total number of atherogenic particles in plasma (Figure 1).(4)

Figure 1.

Schematic illustration of apoB-48 and apoB-100 containing lipoproteins.

LDL-C particles derived from the VLDL lipolysis, contain different types of lipids and proteins -including apoB- in a micelle-like arrangement (Figure 1). Different types of assays have been developed to quantify LDL in plasma, the most widely used being LDL-C, which quantifies the amount of cholesterol carried collectively by the LDL lipoproteins.(5)

All atherogenic lipoproteins, including VLDL and LDL, contain a single apoB molecule (Figure 1). Accordingly, measurement of apoB provides a direct assessment of the number of atherogenic lipoprotein particles. The use of apoB clinically, however, remains low. Rather, mass-based estimates of LDL-C (the total mass of cholesterol carried collectively by all LDL particles) have been, and remain, the primary measure used to guide treatment.(6–11) LDL-C can be measured directly with ultracentrifugation, but is usually calculated indirectly based on total cholesterol, HDL-C, and triglycerides (TG) using one of several formulas.

There are multiple reasons for apoB to be used clinically. Although LDL-C, and apoB are highly correlated, a large body of prior research indicates that apoB is a better predictor of ASCVD risk than LDL-C for several reasons.(3, 12, 13) First, the cholesterol mass per LDL particle is variable – as shown in figure 2-, which can lead to cholesterol-depleted or cholesterol-enriched lipoproteins which vary in their atherogenicity. Persons with large number of cholesterol-depleted lipoproteins (and a high apoB) may have an apparently low LDL-C despite being at higher risk of ASCVD.(14) Similarly, patients may have high LDL-C levels but low apoB due to the presence of cholesterol-enriched lipoproteins. In these patients, ASCVD risk is over-estimated by LDL-C.(2) Second, LDL-C measurements fail to capture the risk conferred by VLDL and IDL particles, which are also atherogenic.(15) As illustrated in Figure 2 with two hypothetical cases, patients with the same level of LDL-C can have different risk profiles based on the number of atherogenic particles in plasma, therefore the importance of measuring apoB.

Figure 2.

Cholesterol mass and particle measures.

This is a hypothetical representation of two patients with the same level of LDL-C but different levels of apoB. The patient with higher apoB has more atherogenic particles and therefore more cardiovascular risk.

Another reason for using apoB clinically is that it does not suffer the same challenges related to measurement as LDL-C. LDL-C is usually estimated from total cholesterol, HDL cholesterol, and TG, based on a formula. The most commonly used formula, the Friedewald equation, has known limitations, particularly in patients with hypertriglyceridemia. Newer formulas including the Martin/Hopkins equation and the Sampson method have been proposed, but there remains uncertainty about the ideal method. Further, all methods have limited performance at very low levels of LDL-C, which is now increasingly common with the introduction of novel lipid lowering therapies,(16–18) and in the presence of severe hypertriglyceridemia (in whom fasting LDL-C measurements are recommended).(19) In contrast, the measurement of apoB is standardized, accurate, inexpensive, and can be applied on automated chemistry platforms widely available in the clinical laboratories.(20) The International Federation of Clinical Chemistry and the World Health Organization endorsed the standardization of apoB measurement in 1994, introducing a reference material that minimized variability across laboratories.(21) Nevertheless, to further enhance the standardization, there are ongoing efforts to develop a new Reference Measurement System employing direct apoB measurement through mass spectrometry.(22)

ApoB is also unaffected by fasting state. Although the apoB immunoassay measures both apoB100 (which is found on VLDL, IDL, and LDL particles) and apoB48 (which is found on chylomicrons), even in a postprandial state the number of chylomicrons relative to apoB100 containing particles is low.(10) On average, there are 9 LDL apoB100 particles for every VLDL apoB100 particle. Likewise, there are 9 VLDL apoB100 particles for each apoB48 particle. This ratio underlines why total apoB, even in a postprandial state, essentially equates to total apoB100 and is largely unaffected by fasting.(3)

In epidemiologic studies, apoB outperforms LDL-C to predict ASCVD. The first evidence that apoB serves as a more precise indicator of risk emerged in 1980, with a study showing that apoB, particularly LDL apoB, more effectively distinguished between patients with and without coronary atherosclerosis.(23) Since then, the evidence supporting superiority of apoB has grown significantly. A meta-analysis by Sniderman et al of 12 epidemiological studies containing estimates of relative risk of ischemic cardiovascular events of different lipid markers, found that apoB was the most potent marker of cardiovascular relative risk ratio compared to non-HDL.(24) Additionally, changes in apoB may better capture the potential benefit of lipid lowering therapy. A meta-analysis of 29 randomized clinical trials involving 332,912 patients on lipid-lowering therapy (statins, ezetimibe, PSCK9 inhibitors, cholesterylester transfer protein inhibitors, fibrates, niacin, and n-3 fatty acids) demonstrated that absolute reduction in apoB was associated with decreased all-cause and cardiovascular mortality (relative risk for every 10mg/dL decrease in apoB of 0.95: 0.92–0.99 and 0.93:0.88–0.98, respectively).(25) Moreover, Thanassoulis et al., using a frequentist and a Bayesian approach with data from 7 placebo-controlled statin trials, found that mean relative risk reduction of cardiovascular events per standard deviation change in lipid marker from statin therapy was more closely related to reductions in apoB than to reductions in either non-HDL-C or LDL-C.(26) In the ODYSSEY-Outcomes trial, achieved levels of LDL-C or non–HDL-C were not predictive of major adverse cardiovascular events (MACE) after taking achieved apoB into account.(18) Data from other trials have also supported the superiority of apoB over LDL-C as predictor of cardiovascular events. For example, an analysis that included individuals from the UK biobank (primary prevention cohort) and FOURIER and IMPROVE-IT trials (secondary prevention cohort) demonstrated that apoB was the only lipid parameter independently associated with incident myocardial infarction.(13) The risk captured by apoB was independent from the type of lipid (cholesterol or TG) or lipoprotein (either LDL or TG-rich as VLDL and IDL) across both cohorts.(13) Furthermore, data from the Copenhagen General Population Study, showed that in statin-treated patients, apoB was a superior marker for all-cause mortality risk than both non-HDL-C and LDL-C.(27)

Using non-HDL-C instead of LDL-C can help improve risk prediction by capturing the burden of non-LDL, apoB containing lipoproteins such as VLDL and IDL particles. However, there are still a significant proportion of individuals (ranging between 8–23%) in whom apoB and non-HDL-C remain discordant, and in whom apoB remains a better predictor of ASCVD risk.(28) Welsh et al., analyzing data from the UK biobank for patients without cardiovascular disease and not taking statins, found that 18% of participants had discordant apoB and LDL-C values (defined as ≥10% absolute difference in baseline percentile of direct LDL and apoB). In those patients, only apoB was associated with increased ASCVD risk (adjusted hazard ratio per standard deviation, 1.23: 1.12–1.35, P<0.001), but not directly measured or calculated LDL-C (by either Friedewald or Martin-Hopkins formula), nor non-HD-CL.(29)

Measurement of apoB is also needed for accurate differential diagnoses and targeted treatment of hypertriglyceridemia, i.e. to differentiate hypertriglyceridemia due to excess VLDL particles vs hyperchylomicronemia.(30) Furthermore, for the identification of Familial Dysbetalipoproteinemia, also known as Type III Hyperlipoproteinemia, apoB measurement is necessary. This is a highly atherogenic and treatable dyslipoproteinemia characterized by elevated levels of both cholesterol and triglycerides due to a significant increase in cholesterol-rich chylomicron and VLDL remnant lipoprotein particles.(30) Utilizing apoB alongside a traditional lipid panel allows for the reliable diagnosis of Type III Hyperlipoproteinemia and its differentiation from mixed hyperlipidemia.(31)

1. How have guidelines incorporated apoB?

1.a. On measurement of apoB

Although major clinical guidelines for management of blood cholesterol focus on LDL-C, measurement of apoB is increasingly recommended in certain populations, in particular those with elevated TG.(6, 8) Specific apoB measurement recommendations and statements about apoB measurement by the principal lipid guidelines are shown in Table 1.

Table 1:

Guideline/Statement recommendations for measurement of apoB.

Guideline/Statement (year)	Guideline/Statement name	Recommendation	Strength	Other statements about apoB
CCS (2021) (6)	2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults.	For any patient with triglycerides > 1.5 mmol/L, non-HDL-C or apoB be used instead of LDL-C as the preferred lipid parameter for screening.	Strong Recommendation, High-Quality Evidence	-Non-HDL-C (indirectly) and apoB (directly) provide a more accurate assessment of the total concentration of atherogenic particles than LDL-C. Non-HDL-C and apoB are, for this reason, both better predictors of cardiovascular event risk and benefit of lipid-lowering therapy compared with LDL-C. -In Canada, the approach has been to allow clinicians to use either non-HDL-C or apoB as their preferred parameter for assessment of risk and achievement of treatment targets, depending on their comfort level with the two measurements, availability of apoB testing in their region, and when there might be a concern about discordance between the two measurements.
ESC/EAS (2019) (8)	2019 ESC/EAS Guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk.	ApoB analysis is recommended for risk assessment, particularly in people with high TG, DM, obesity or metabolic syndrome, or very low LDL-C. It can be used as an alternative to LDL-C, if available, as the primary measurement for screening, diagnosis, and management, and may be preferred over non-HDL-C in people with high TG, DM, obesity, or very low LDL-C.	Class I, level C	-Given the central causal role of apoB-containing lipoproteins in the initiation and progression of atherosclerosis, direct measurement of the circulating concentration of atherogenic apoB-containing lipoproteins to both estimate risk and guide treatment decisions would be ideal. -In general, LDL-C, non-HDL-C, and apoB concentrations are very highly correlated. As a result, under most circumstances, they provide very similar information about ASCVD risk. -Non-HDL-C or apoB are good markers of TRLs and remnants and are a secondary objective of therapy. -Because apoB provides an accurate estimate of the total concentration of atherogenic particles under all circumstances, it is the preferred measurement to further refine the estimate of ASCVD risk that is modifiable by lipid-lowering therapy. -There are no outcome-based comparisons of LDL-C vs. apoB as primary measurement methods for screening, diagnosis, and management
AHA/ACC Multisociety (2018) (7)	2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.	A relative indication for its measurement would be triglyceride ≥200 mg/dL. A level >130 mg/dL corresponds to an LDL-C >160 mg/dL and constitutes a risk-enhancing factor.	N/A	-In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy. Risk-enhancing factors include -among others- if measured in selected individuals, apolipoprotein B >130. -Risk-enhancing factors may favor statin therapy in patients at 10-year risk of 5% to 7.5% (borderline risk).
AACE/ACE (2020) (9)	Consensus Statement By The American Association Of Clinical Endocrinologists And American College Of Endocrinology On The Management Of Dyslipidemia And Prevention Of Cardiovascular Disease Algorithm –2020 Executive Summary.	Assessment of apoB or LDL particles, Lp(a), and high-sensitivity C reactive protein should also be considered based on individual patient clinical circumstances.	N/A	-Because an isolated focus on LDL-C is not always sufficient to prevent ASCVD in at-risk individuals or to treat existing atherosclerosis, goals for non-HDL-C, apo B, and triglycerides are also included in the risk assessment and goals. -Apo B-100 measurement may provide a more accurate assessment of atherogenicity because all atherogenic particles (i.e., VLDL, IDL, and LDL) contain 1 apo B-100 molecule measurement of apo B is useful in assessing the success of lipid-lowering therapy, since apo B may remain above goal after achieving the LDL-C goal.
AACC (2009) (10)	Apolipoprotein B and Cardiovascular Disease Risk: Position Statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices.	Addition of apoB to the routine lipid panel for assessing and monitoring patients at risk for adverse outcomes should enhance patient management.	N/A	-A wealth of evidence has now accumulated demonstrating the superiority of apoB measurement over that of LDL cholesterol for assessment of cardiovascular risk. The next logical step is the addition of apoB to guidelines in the US. - Changing perceptions and practice will not be easy, considering that physicians and patients are accustomed to LDL-C. Significant education efforts will be required, and it appears prudent at this point to consider using both apoB (or LDL-P) and LDL-C to assess LDL-related risk for an interim period until the superiority of apo B is generally recognized.
NLA (2021) (32)	Lipid measurements in the management of cardiovascular diseases: Practical recommendations a scientific statement from the national lipid association writing group.	ApoB measurement may be reasonable for initial evaluation.	IIb (B-NR)	- Unfortunately, apoB assays have not yet been formally standardized. - Measurements of apoB or LDL-P may effectively identify a patient with an increased ASCVD risk due to a higher atherogenic lipoprotein burden. These patients may benefit from additional therapy to lower apoB/LDL-P by taking higher doses of statins, adding eze- timibe or PCSK9 inhibitors, but data from clinical trials are lacking on this topic. - The development of a primary reference method is a logical next step to increase confidence in apoB measurement. - LDL-C, non- HDL-C or apoB are all well documented to be worthy targets of therapy and their reduction predicts lower risk for major cardiovascular clinical events in proportion to the decrease in concentration.
		ApoB measurement is reasonable on lipid therapy.	IIa (B-NR)
		ApoB measurement is recommended to facilitate the diagnosis of Familial Dysbetalipoproteinemia and Familial Combined Hyperlipidemia.	IIa (B-NR)

Abbreviations: AACC: American Association for Clinical Chemistry; AACE/ACE: American Association of Clinical Endocrinologists/ American College of Endocrinology; AHA/ACC: American Heart Association/American College of Cardiology; ASCVD: Atherosclerotic Cardiovascular Disease; ApoB: apolipoprotein B; CCS: Canadian Cardiovascular Society; DM: diabetes; ESC/EAS: European Society of Cardiology/ European Atherosclerosis Society; IDL: intermediate-density lipoproteins; LDL-C: low-density lipoprotein cholesterol; LDL-P: low-density lipoprotein particle number; Lp(a): lipoprotein (a); non-HDL-C: non-high-density cholesterol; NLA: National Lipid Association; TG: triglycerides; TRLs: triglyceride-rich lipoproteins; VLDL: Very low-density lipoproteins.

Canadian and European guidelines have recommended apoB measurement in certain populations for many years. Since 2012, the Canadian Cardiovascular Society (CCS) guideline for the diagnosis and treatment of dyslipidemia has recognized the utility of measuring apoB in people with high TG (defined as TG>1.5mmol/L – 131mg/dl- in the CCS guideline).(33) In the last (2021) guideline, the CCS strongly recommended using either apoB or non-HDL-C instead of LDL-C as the preferred lipid parameter for screening in any patient with TG > 1.5mmol/L (133mg/dL).(6) The guideline further recognized that there could be discordance between apoB and non-HDLC in some patients, and suggested that the decision on which to use should be guided by availability and clinical expertise. Meanwhile, since 2016, the European Society of Cardiology and the European Atherosclerosis Society (ESC/EAS) recommended considering apoB, when available, in patients with high TG, and expanded this recommendation in the 2019 guideline.(8, 34) In this most recent document, ESC/EAS recommend apoB measurement as an alternative to LDL-C (and may even be preferred over non-HDL-C) as the primary marker for screening, diagnosis, and management in people with high TG levels, diabetes (DM), obesity, or very low LDL-C (Class I Level C). The 2019 ESC/EAS guideline stated that in the aforementioned individuals, LDL-C may underestimate ASCVD risk by underestimating both the total concentration of cholesterol carried by LDL and the total concentration of apoB-containing lipoproteins Compared with Canadian and European guidelines, American guidelines have been more limited in recommending measurement of apoB.(7) One of the oldest recommendations for utilization of apoB in the United States comes from the American Association for Clinical Chemistry (AACC), whose 2009 Lipoproteins and Vascular Diseases Division Working Group on Best Practices statement supported the use of apoB for assessing and monitoring patients at risk for cardiovascular disease. In that statement, the authors state that “changing perceptions and practice will not be easy, considering that physicians and patients are accustomed to LDL-C. Significant education efforts will be required”.(10) Indeed, over the subsequent decade, LDL-C remained the main recommended measure of lipid related risk by US Guidelines. The 2018 American Heart Association and the American College of Cardiology, in collaboration with multiple leading medical organizations (AHA/ACC Multisociety Guideline) state that those with TG ≥200 mg/dL have a “relative indication” for apoB measurement.(7) The guideline also states that an apoB >130mg/dL should be considered a “risk enhancing factor” for considering lipid-lowering therapy but do not recommend universal testing. The 2020 American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) guideline stated that apoB may provide a more accurate assessment of atherogenicity as apoB can be elevated in individuals with normal LDL-C, particularly in those with insulin resistance who could often have small-dense LDL.(9) It also recognized that apoB is useful in assessing the success of lipid-lowering therapy, as it may remain above the goal after achieving the LDL-C target. However, the recommendation to measure apoB– or LDL particles, lp(a), and high sensitivity C reactive protein-was only made “based on individual patient clinical circumstances”. In 2021 a scientific statement from the National Lipid Association (NLA) endorsed that the measurement of apoB is reasonable, not only as part of the initial lipid evaluation, but also in patients on lipid therapy.(32) The document recognized that in high-risk patients with LDL-C <70mg/dL on lipid-lowering therapy, apoB measurement may effectively identify a patient with an increased ASCVD risk due to residual atherogenic lipoprotein burden who could benefit from additional therapy. While various guidelines have recognized value in measuring apoB, there is considerably less agreement in apoB thresholds for risk/treatment.

Guidelines consistently support that apoB is a more accurate predictor of cardiovascular risk, particularly in the presence of cholesterol-depleted apoB particles and is recommended as the marker of choice for individuals with high TG levels. However, it should be noted that there is still no unanimous agreement on the specific TG levels that define hypertriglyceridemia. Evidence also indicates that cholesterol-depleted apoB lipoproteins can occur outside of cases with high TG levels. In further exploring the link between TG, apoB, and LDL-C, De Marco et al., analyzed LDL-C/apoB ratios in a cohort of 6,272 participants from National Health and Nutrition Examination Survey (NHANES).(35) They found that cholesterol-depleted apoB particles, as indicated by a low LDL-C/apoB ratio, can be present across all TG levels, reporting that 21.4% of individuals with TG levels <100 mg/dL exhibited a low LDL-C/apoB ratio.(35) These findings reinforce the argument for the routine inclusion of apoB in clinical assessments for all patients, not just those with elevated TG levels.

1.b. Guideline recommendations for apoB Targets/Triggers

Guideline-based LDL-C targets vary significantly, partly based on guideline publication year and temporal updates from iterative trial data, and partly due to differences between guidelines. However, even when the same LDL-C target is used, (i.e. <70 mg/dL) guidelines vary in the corresponding apoB level. This reflects the lack of a universally agreed upon conversion between apoB and LDL-C and different possible ways to establish an apoB target. Table 2 synthesizes the target/trigger levels present in different guidelines.

Table 2:

Guideline LDL-C, and apoB triggers/targets.

	ApoB trigger/targets (mg/dl)
Guideline/Statement	CCS (2021) (6)	ESC/EAS (2019) (8)	AHA/ACC (2018) (7)	AACE/ACE (2020) (9)	AACC ††† (2009) (10)	NLA (2015) (11)
Mechanism to establish apoB Target	Percentile equivalents for each LDL-C threshold from NHANES.	Evidence from CARDS study and Meta-analysis (26, 36)	Not indicated	Evidence from trials, (37–40) ADA,(41), and an expert report. (42)	Population distributions in the Framingham Offspring Study.	Population distributions in NHANES III.
LDL-C Goal
40		55#
55		65**		70||||
70	70*	80††		80##		80‡‡‡
77	80†
96	85‡
100		100‡‡		90***	80	90§§§
130					100
135	105§
160			130§§
193	145||

^*Recommendation to intensify f lipid-lowering therapy (with PCSK9 inhibitors/ezetimibe) in patients with ASCVD receiving maximally tolerated statin dose in whom apoB remains ≥70mg/Dl (or LDL-C ≥ 1.8 mmol/L).

^†Recommendation of adding-on therapy (ezetimibe as first line or bile-acid sequestrant as alternative) for primary prevention, in patients on maximally tolerated statin dose and apoB≥80mg/dL.

^‡Recommendation to intensify lipid-lowering with PCSK9 inhibitors in patients with heterozygous familial hypercholesterolemia without clinical ASCVD and receiving maximally tolerated statin therapy with or without ezetimibe therapy whose apoB remains ≥ 0.85 mg/dL (or LDL-C ≥ 2.5 mmol/L or < 50% reduction from baseline).

^§Recommendation to initiate of statin therapy with apoB>105mg/dL (or LDL≥3.5 mmol/L) in patients at intermediate risk FRS: 10%−19.9%), or low risk (FRS of 5%−9%) with other cardiovascular risk modifiers (e.g., family history of premature coronary artery disease, Lp(a) ≥ 50 mg/dL [or ≥ 100 nmol/L] or CAC > 0 AU).

^||Recommendation to initiate statin therapy with apoB≥145mg/dL (or LDL≥5.0 mmol/L) in low-risk patients (FRS < 10%) who have a statin-indicated condition, likely a genetic dyslipidemia such as familial hypercholesterolemia.

^#very high-risk with recurrent ASCVD events.

^**Very high total cardiovascular risk: Documented ASCVD, either clinical or unequivocal on imaging; diabetes with target organ damage, or at least three major risk factors, or early onset of type 1 diabetes of long duration (>20 years); severe chronic kidney disease (eGFR <30 m198L/min/1.73 m2); a calculated SCORE >_10% for 10-year risk of fatal cardiovascular disease; familial hypercholesterolemia with ASCVD or with another major risk factor.

^††High total cardiovascular risk: Markedly elevated single risk factors, in particular total cholesterol>8 mmol/L (>310 mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or blood pressure >_180/110 mmHg; patients with familial hypercholesterolemia without other major risk factors; patients with diabetes without target organ damage, diabetes duration >_10 years or another additional risk factor; moderate chronic kidney disease (eGFR 3059 mL/min/1.73 m2); a calculated SCORE >_5% and <10%.

^‡‡Moderate total cardiovascular risk: Young patients (type 1 diabetes <35 years; type 2 diabetes <50 years) with diabetes duration <10 years, without other risk factors; a calculated SCORE >_1 % and <5%.

^§§An apoB level ≥130 mg/dl constitutes a risk enhancing factor (particularly when accompanied by persistently elevated triglycerides), denotes high lifetime risk for ASCVD and favor initiation of statin therapy.

^||||Treatment goal for subjects at extreme high-risk: Progressive ASCVD including unstable angina, established clinical ASCVD plus diabetes or chronic kidney disease ≥3 or familial hypercholesterolemia, or history of premature ASCVD.

^##Treatment goal for subjects at very high-risk: Established clinical ASCVD or recent hospitalization for acute coronary syndrome, carotid, or peripheral vascular disease, or 10-year risk >20%; diabetes with ≥1 risk factor(s), chronic kidney disease ≥3 with albuminuria, familial hypercholesterolemia.

^***Treatment goal for subjects at high risk (≥2 risk factors and 10-year risk 10–20%; diabetes or chronic kidney disease ≥3 with no other risk factors) and moderate risk (<2 risk factors and 10-year risk <10%).

^†††Provides apoB cut points equivalent to LDL-C cut points of Framingham Offspring Study. Does not specify risk stratification of subjects.

^‡‡‡Optional target for treatment goals for those with very high risk: Clinical ASCVD; diabetes (type 1 or 2) with ≥2 major ASCVD risk factors or evidence of end-organ damage (eGFR <60 mL/min/1.73 m2).

^§§§Optional target for treatment goals for primary prevention.

Abbreviations:

AACC: American Association for Clinical Chemistry; AACE/ACE: American Association of Clinical Endocrinologists/ American College of Endocrinology; AHA/ACC: American Heart Association/American College of Cardiology; ASCVD: Atherosclerotic Cardiovascular Disease; ApoB: apolipoprotein B; CAC: Coronary artery calcium; CCS: Canadian Cardiovascular Society; eGFR: estimated glomerular filtration rate; ESC/EAS: European Society of Cardiology/ European Atherosclerosis Society; FRS: Framingham Risk Score; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein (a); NLA: National Lipid Association; SCORE: Systematic Coronary Risk Estimation.

The 2021 CCS guideline established apoB-based recommendations by generating percentile equivalents of apoB and non-HDL-C for each of their recommended LDL-C target using data from NHANES and UK Biobank.(6) They recommend starting statin treatment with an LDL-C ≥5.0mmol/L (193.35mg/dL) or an apoB≥145mg/dL in low-risk patients, and an LDL-C ≥3.5mmol/L (135.34mg/dL) or an apoB of ≥105mg/dL in intermediate or low-risk patients with other cardiovascular risk factors. The CCS also recommended using an LDL-C or apoB level of ≥70mg/dL as a threshold to intensify lipid-lowering treatment in patients with ASCVD. On the other hand, the 2019 ESC/EAS guideline establishes secondary apoB goals of <65, <80, and <100 mg/dL for very-high-, high-, and moderate-risk patients, respectively, which corresponded to LDL-C targets of <55 mg/dL, <70 mg/dL and <100 mg/dL.(8)

In the USA, the AHA/ACC Multi-Society Cholesterol Guideline states that an apoB level ≥130 mg/dL corresponds to an LDL-C ≥160 mg/dl and constitutes a risk-enhancing factor (particularly when accompanied by persistently elevated TG) for which statin initiation or intensification can be considered.(7) Meanwhile, the AACE/ACE suggests an apoB goal of <70, <80, and <90 mg/dl for individuals at extremely high-risk (persistent ASCVD), very high-risk (established ASCVD or DM plus ≥1 additional risk factor), and high and moderate-risk (risk of ASCVD, including those with DM), respectively.(9) In the 2015 NLA Recommendations for Patient-Centered Management of Dyslipidemia, the apoB recommendations are < 80 mg/dL for high-risk patients and < 90 mg/dL in primary prevention, both based on NHANES III data.(11) In 2009, an AACC working group established apoB cut points equivalent to LDL- cut points based on Framingham Offspring Study.(10) In this document, apoB levels of 80 and 100 mg/dL are considered equivalent to LDL-C levels of 100 and 130mg/dL.

2. Population percentiles of apoB relative to LDL-C

ApoB equivalents for LDL-C have been determined through various approaches using population percentiles. One method involves determining corresponding apoB values in individuals with a particular LDL-C level, while the other involves aligning the LDL-C percentile corresponding to a particular LDL-C value and determining the same percentile value for apoB in that population. One challenge to this approach globally is that the population distribution of apoB in a population varies by region. Figure 3 shows the levels of apoB corresponding to the 10^th, 50^th, and 90^th population percentiles based on studies from the United States, Canada, South Korea, India, Mexico, Finland, and Sweden.(43–49) Not only do apoB levels vary in different populations, so do the levels of LDL-C and non-HDL-C.(50, 51) The CCS was the only guideline that established the apoB triggers based on LDL-C population percentiles equivalents using data from NHANES and the UK Biobank.(6) In contrast, the other guidelines, the equivalent apoB level suggested relative to LDL-C, can be significantly higher in terms of population percentile.(52) For example, the ESC/EAS, AACE/ACE, and NLA guidelines all use an apoB of 80 mg/dL to correspond to an LDL-C of 70 mg/dL. However, based on NHANES and the Very Large Database of Lipids, a LDL-C of 70 mg/dL corresponded to a population-percentile–equivalent apoB value of 60 mg/dL (≈7th–9th percentile), while an apoB of 80 mg/dL corresponded to a population-percentile–equivalent LDL-C value of 100 mg/dL (≈31st–36th percentile).(52)

Figure 3:

Illustration of apoB 10^th, 50^th and 90^th percentiles in different countries.

Data from the USA obtained from NHANES 1988–1991. (43) Data from Canada obtained from random sample of men and women aged 18 to 74 years selected from Saskatchewan and Quebec 1989–1990. (49) Data from South Korea obtained from subjects residing in Seoul and Kyung-gee Do with an average age of 43.5 ± 8.3 years. (44) Data from India obtained from the health checkup program at Hinduja National Hospital. (48) Data from Mexico obtained from the 1990 National Census. (45) Data from Finland obtained from the population registers of the city of Turku and some adjacent rural and urban communities in southwestern Finland. (47) Data from Sweden obtained from Swedish population sample from 1985–1996 males and females, ages <20 to >80 years. (46)

3. Discordance between LDL and apoB

As mentioned above, there can be significant variability in the amount of cholesterol carried by every lipoprotein, hence; apoB, LDL-C, and non-HDL-C are not equivalent cardiovascular risk markers.(53) For most patients, apoB and LDL-C are highly correlated, such that using LDL-C accurately captures the majority of the patient’s atherogenic risk. Multiple “discordance analyses” have attempted to identify patients with discordant apoB and LDL-C levels and analyze their risk of cardiovascular events. As there is no definitive ratio between LDL-C and apoB that defines a cholesterol-depleted vs cholesterol-enriched lipoprotein phenotype, most of the discordance studies have used median values of LDL-C and apoB to establish four different groups (concordantly high and low, and discordantly high and low apoB in relation to LDL-C or non-HDL-C) to compare cardiovascular outcomes between them. Other studies have used a variety of other methods. The manner of defining discordance, as well as the results of these discordance analyses are summarized in Table 3.(27, 28, 54–61)

Table 3:

Concordance/Discordance analysis of apoB and LDL-C

Study (Country, N)	Methods to define discordance	Outcome	Groups	OR	Median of apoB (mg/dL)	Median of LDL-C (mg/dL)	Delta (apoB-LDL-C)	% discordant high apoB	Characteristics of subjects with discordant high apoB
CARDIA (USA, 2794) (28)	Median	OR of having CAC >0 at Year 25	Concordant Low	1.00	70.5 ± 11.2	83.4 ± 15.2	− 12.9	8.6	Higher triglycerides, waist circumference, BMI, and obesity.
			Concordant High	1.94 (1.58–2.40)	110.9±17.1	137.2 ± 22.7	−.3
			Discordant Low	1.29 (0.91–1.83)	79.9 ± 7.9	119.0±12.5	−39.1
			Discordant High	1.55 (1.10–2.18)	99.3 ± 18.1	96.1 ± 8.5	3.2
Copenhagen General Population Study (Denmark, 13015) (27)	Median	HR of all-cause mortality / myocardial infarction	Concordant Low	1.00 / 1.00	73 (64–81)	70 (58–82)	3	13	Higher smokers and diabetes.
			Concordant High	1.10 (1.00–1.21) / 1.24 (1.01–1.52)	116 (105–136)	116 (103–135)	0
			Discordant Low	0.86 (0.75–0.99) / 0.94 (0.69–1.29)	84 (79–89)	101 (93–108)	−17
			Discordant High	1.21 (1.07–1.36) / 1.49 (1.15–1.92)	107 (98–121)	78 (66–85)	29
Quebec Cardiovascular Study (Canada, 2103) (54)	More than one quintile difference	Risk of CAD over 5 years	Concordant	1.00				~15	Higher BMI and triglycerides.
			Discordant Low	3.0 (1.1 – 7.8)	107	153	−46
			Discordant High	3.2 (1.2 – 8.1)	128	129	−1
MESA (USA, 4623) (55)	Residuals and percentile rankings (>5/10/15 percentile)	OR of CAC>0 at baseline / CAC incidence	Concordant	1.00	106.1	118.4	−12.3	14.1	Higher hypertension, diabetes, metabolic syndrome, BMI and triglycerides. Lower HDL-C levels. Hispanics were also more likely to have discordantly high apoB levels
			Discordant low	0.98 (0.92– 1.04) / 0.86 (0.73– 1.01)	96.1	120.7	−24.6
			Discordant high	1.02 (0.95– 1.08) / 1.00 (0.84–1.19)	127.0	121.1	5.9
		OR of CAC progression (absolute change/year) relative to no progression: >0 - <75th percentile / >75th percentile	Concordant	1.00	106.1	118.4	−12.3
			Discordant low	0.90 (0.75– 1.10) / 1.03 (0.82, 1.29)	96.1	120.7	−24.6
			Discordant high	1.00 (0.80–1.25) / 1.10 (0.85, 1.41)	127.0	121.1	5.9
Kangbuk Samsung Health Study (South Korea, 14205) (56)	Median	Risk of CAC progression	Concordant Low	1.00	83.3	105.3	−22	5.3	Higher hypertension and diabetes and the lowest levels of HDL-C.
			Concordant High	1.49 (1.34–1.66)	124.9	160.6	−35.7
			Discordant low	1.02 (0.84–1.26)	97.3	139.5	−42.2
			Discordant high	1.26 (1.02–1.56)	110.0	121.5	−11.5
Women’s Health Study (USA, 27533) (57)	Median	Cumulative probability of incident coronary heart disease	Low LDL-C:					9.3	Higher triglycerides, BMI, and high-sensitivity C-reactive protein. Lower HDL cholesterol, and smaller LDL particles.
			Concordant Low apoB	1.00	81	98	−17
			Discordant High apoB	2.98 (2.41–3.68)	112	111	1
			High LDL-C:
			Concordant High apoB	1.00	124	148	−24
			Discordant Low apoB	0.31 (0.23–0.41)	93	130	−37
Framingham Offspring Cohort (USA, 2966) (58)	Tertiles established by Residuals.	New onset coronary heart disease	Tertiles of discordant apoB					NR	Men>Women. Older, higher obesity, diabetes, hypertension and metabolic syndrome.
			Lowest	0.70 (0.51–0.96)	86.7	134	−47.3
			Middle	1.00	97.6	132	−34.4
			Highest	1.46 (1.14–1.86)	116	136	−20
Qu et al (China, 402) (59)	Median	Arterial stiffness risk	Concordant Low	1.00	58	58.39	−0.39	9.2	Higher systolic and diastolic blood pressure, triglycerides.
			Concordant High	3.062 (1.147–8.179)	98	114.85	−16.85
			Discordant Low	1.214 (0.408–3.609)	72	88.55	−16.55
			Discordant high	13.054 (2.385–71.454)	95	61.48	33.52
PRECISE (China, 3043) (60)	Residual and Median	Presence and burden of coronary atherosclerotic plaques Plaque/SIS/SSS	Concordant	1.00	97	106.73	−9.73	24.9	Men>Women. Higher BMI, smokers, drinking.
			Discordant Low	0.85 (0.70–1.03) / 0.85 (0.71–1.02)/ 0.79 (0.65–0.95)	87	94.74	−7.74
			Discordant High	1.13 (0.94–1.37) / 1.21 (1.02–1.44)/ 1.28 (1.08–1.53)	114	121.8	−7.8

Abbreviations: BMI: Body mass index; CARDIA: Coronary Artery Risk Development in Young Adults; MESA: Multi-Ethnic Study of Atherosclerosis; LDL: low-density lipoproteiN; PRECISE: PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events; SIS: segment involvement score; SSS: segment stenosis score.

Because of differences in the populations studied as well as the definition of discordance, the cutoffs used to identify adults with “discordantly high” and “discordantly low” apoB varied. Most of the studies utilized median values to define discordance, therefore there was not a specific difference between apoB and LDL-C to consider someone “discordantly high”, and the difference between apoB and LDL-C levels in these groups ranged from −11.5 to 33.52. The percentage of people with discordantly high apoB also ranged from 5.3–24.9%. Overall, men, people with metabolic syndrome, DM, hypertension, smokers, higher BMI, higher levels of TG, and lower levels of HDL were most likely to have discordantly high apoB relative to LDL-C, highlighting the need to test apoB in these populations as LDL-C can be insufficient to fully capture ASCVD risk.

4. ApoB levels achieved in randomized clinical trials.

While LDL-C has been the main target for clinical trials of lipid lowering therapy, many trials have also measured apoB both at baseline and on-treatment. Data from trials that reported apoB at baseline and achieved apoB levels are presented in Table 4 and Figure 4. While the degree of LDL-C lowering varied across and within therapeutic classes, in statin, ezetimibe, PCSK9i, inclisiran and bempedoic acid trials the proportional reduction in LDL-C was greater than the proportional reduction in apoB. The degree of apoB reduction was highly correlated with the degree of LDL-C reduction, and the correlation between the % reduction in apoB and the % reduction in LDL-C across all other trials is high (R²=0.85). Overall, across all trials, the % reduction of apoB was slightly lower than LDL-C. For statin, PCSK-9i, inclisiran, and bempedoic acid trials, the mean reduction in apoB was ~6–8% lower than the mean reduction in LDL-C, meanwhile, for the ezetimibe trials, the mean reduction in LDL-C was 16% higher than the apoB reduction. This difference could be explained by the mechanism of action of ezetimibe – inhibiting cholesterol absorption from the small intestine – or due to differences in the populations enrolled in trials.

Table 4:

ApoB and LDL-C baseline and achieved levels in different randomized clinical trials of lipid-lowering drugs including statins, ezetimibe, PCSK-9 inhibitors, inclisiran and bempedoic acid.

Study (Year)	Population Studied	Active Agent	Baseline apoB, (mg/dl)	Achieved apoB (mg/dl)	% Decrease In apoB*	Baseline LDL-C, (mg/dl)	Achieved LDL-C (mg/dl)	% Decrease In LDL-C*
STATIN TRIALS
ASTEROID (62)	Patients who required coronary angiography for a clinical indication with at least one obstruction >20%.	Rosuvastatin 40mg	127.9	74.5	41.75	130.4	60.8	53.37
REVERSAL (63)	Patients who required coronary angiography for a clinical indication with at least one obstruction >20%.	Pravastatin 40mg	153.0	118.1	22.81	150.2	110.4	26.50
		Atorvastatin 80mg	152.4	91.8	39.76	150.2	78.9	47.47
CARDS (64)	Patients with type 2 diabetes, no history of cardiovascular disease and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension.	Atorvastatin 10mg	117.0	80.0	31.62	117.5	81.6	30.55
ACCESS (65)	Patients categorized using the coronary heart disease risk categories defined in the U.S. National Cholesterol Education Program guidelines. From patients with no coronary or peripheral vascular disease and 1 or no risk factors, to patients with clinically evident coronary and peripheral vascular disease.	Atorvastatin 10–80mg	170	114	32.94	178	102	42.70
		Fluvastatin 20–80mg	168	136	19.05	179	126	29.61
		Lovastatin 20–80mg	170	126	25.88	178	114	35.96
		Pravastatin 10–40mg	168	136	19.05	179	128	28.49
		Simvastatin 10–40mg	166	124	25.30	176	112	36.36
MERCURY II (66)	Patients with high risk of coronary heart disease events, including established ASCVD, diabetes, or high Adult Treatment Panel III defined risk.	Rosuvastatin 20mg	159.0	93.97	40.90	167.1	80.04	52.1
		Atorvastatin 10mg	160.6	114.19	28.90	169.0	106.30	37.1
		Atorvastatin 20mg	160.3	104.36	34.90	168.1	95.31	43.3
		Simvastatin 20mg	162.6	119.02	26.80	169.4	111.47	34.2
		Simvastatin 40mg	161.8	109.70	32.2	168.8	99.25	41.2
ADVOCATE (67)	Patients with and without coronary artery disease.	Atorvastatin 10–40mg	140	84	40	196	99.96	49
		Simvastatin 10–40mg	137	94.53	31	192	117.12	39
AFCAPS/TEXCAPS (68)	Patients with no prior history or signs or symptoms of definite myocardial infarction, angina, claudication, cerebrovascular accident, or transient ischemic attack.	Lovastatin 20 mg	120	96.0	20.00	149.27	114.4	23.36
LIPID (69)	Patients with history of acute myocardial infarction or a diagnosis of unstable. angina 3 to 36 months before registration	Pravastatin 40 mg	133	101.0	24.06	150	107	28.67
IDEAL (70)	Patients with a history of confirmed acute myocardial infarction.	Atorvastatin 80 mg	119	81	31.93	121.4	78.5	35.34
		Simvastatin 20–40mg	119	106	10.92	121.4	105.2	13.34
JUPITER (71)	Patients without diabetes or cardiovascular disease.	Rosuvastatin 20 mg	109	66	39.45	108	55	49.07
STATIN AND EZETIMIBE TRIALS
IMPROVE IT (38)	Patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days	Simvastatin 40 mg	92.7	81.3	12.30	93.8	69.9	25.48
		Simvastatin 40 mg + ezetimibe 10 mg	92.7	70.3	24.16	93.8	53.2	43.28
COMPELL (72)	Patients eligible for treatment based on U.S. National Cholesterol Education Program Adult Treatment Panel III Guidelines.	Simvastatin 20–40 + Ezetemibe 10mg	141	83.19	41	202	86	57.43
		Rosuvastatin 10–40 mg	139	84.79	39	198	91	54.04
EXPLORER (73)	Patients with hypercholesterolemia and a history of coronary heart disease or clinical evidence of atherosclerosis or a coronary heart disease risk equivalent (10-year risk score 20%)	Rosuvastatin 40mg	173	95	45.09	191	82	57.07
		Rosuvastatin 40mg + Ezetimibe 10mg	176	76	56.82	189	57	69.84
PCSK9 INHIBITOR TRIALS
SPIRE 1 (74)	Patients with previous cardiovascular event (secondary prevention cohort) or a history of diabetes, chronic kidney disease, or peripheral vascular disease with additional cardiovascular risk conditions or a history of familial hypercholesterolemia (high-risk primary prevention cohort).	Bococizumab 150 mg	80.1	41.33	48.4	93.8	51.68	44.9
SPIRE 2 (74)		Bococizumab 150 mg	105.8	62.42	41.0	133.9	79.54	40.6
ODYSSEY OUTCOMES (18)	Patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy.	Alirocumab 75–150 mg	79	39	50.63	87	37.6	56.78
ODYSSEY LONG TERM (75)	Patients with heterozygous familial hypercholesterolemia (as determined by genotyping or clinical criteria) or with established coronary heart disease or a coronary heart disease risk equivalent.	Alirocumab 150 mg	101.9	48.10	52.8	122.8	48.3	61
FOURIER TRIAL (76, 77)	Patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol who were receiving statin therapy.	Evolocumab 140 mg	83	44.82	46	92	30	67.4
INCLISIRAN
ORION-10( 78 )	Patients with atherosclerotic cardiovascular disease.	Inclisiran 284 mg	94.1	51.94	44.8	104.5	50.89	51.3
ORION-11( 78 )	Patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent.	Inclisiran 284 mg	97.1	60.01	38.2	107.2	58.10	45.8
BEMPEODIC ACID TRIAL
CLEAR (79)	Patients with hypercholesterolemia and a history of intolerance to at least 2 statins.	Bempedoic acid 180 mg	141	119.85	15	158.5	124.90	21.2

^*Values were calculated

Abbreviations: ACCESS: Atorvastatin Comparative Cholesterol Efficacy and Safety Study; ADVOCATE: ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation; AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study; Apolipoprotein B (apoB); ASCVD: Atherosclerotic Cardiovascular Disease; ASTEROID: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden; CARDS: Collaborative Atorvastatin Diabetes Study; CLEAR: Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-Inhibiting Regimen; COMPELL: COMParative Effects on Lipid Levels of Niaspan and statins versus other lipid therapies; EXPLORER: EXamination of Potential Lipid-modifying effects Of Rosuvastatin in combination with Ezetimibe versus Rosuvastatin alone; FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; IDEAL: Incremental Decrease in End P oints Through Aggressive Lipid Lowering; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy Inter-national Trial; JUPITER: Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin; LIPID: The Long-Term Intervention with Pravastatin in Ischemic Disease; MERCURY II: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II; ODYSSEY LONG TERM: Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy; ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; ORION: Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol; REVERSAL: Reversal of Atherosclerosis with Aggressive Lipid Lowering; SPIRE: Studies of PCSK9 Inhibition and the Reduction of Vascular Events.

Figure 4:

Proportional reduction in LDL-C and apoB seen in lipid lowering therapy trials.

Dotted line: best fit across all trials.

With respect to what the actual target apoB level should be, trial data can provide further evidence. Figure 5 shows the achieved LDL-C and apoB levels across statin, ezetimibe, PCSK9i, inclisiran and bempedoic acid trials from Table 3. Across all trials, the on-treatment LDL-C and apoB levels attained are highly correlated (R²=0.85). For most trials of statins, ezetimibe, and inclisiran on-treatment LDL-C levels were slightly lower than on-treatment apoB levels, while for PCSK9i and bempedoic acid, on-treatment LDL-C levels were slightly higher than on-treatment apoB levels. However, across all trials, the on-treatment LDL-C levels and on-treatment apoB levels were roughly equivalent.

Figure 5:

Achieved LDL-C and apoB levels in lipid lowering therapy trials.

Dotted line: best fit across all trials.

Across clinical trials, the levels of apoB achieved in the treatment arms has varied based on the population being studied and the type of treatment used, though trial data have consistently shown that with respect to apoB and LDL-C, lower is better. For instance, in statin trials, apoB levels ranged from 119 mg/dL in the REVERSAL trial (Pravastatin 40 mg) to 66 mg/dL in the JUPITER trial (Rosuvastatin 20 mg).(63, 71) When ezetimibe was combined with simvastatin in the IMPROVE-IT trial, the apoB level reached 70 mg/dL.(38) Contemporary outcomes trials of PSCK-9 inhibitor monoclonal antibodies achieved the lowest on-treatment apoB levels, with the ODYSSEY and FOURIER trials averaging 39 mg/dL and 45 mg/dL, respectively.(75–77) The latter two trials would suggest a target apoB level in secondary prevention of at least <55 mg/dL, consistent with current European guideline recommendations.(7)

5. Summary of Results and apo B Targets

The totality of data suggests that apoB may be a superior marker not only of risk of ASCVD but also of the benefit of lipid lowering therapy compared with LDL-C. The use of apoB has also practical benefits worth mentioning, including that patients don’t need to fast, and is more accurate than LDL-C in patients with high TG or very low LDL-C levels. As guidelines are increasingly recommending more aggressive lipid reduction, obtaining precise lipid measurements is essential. This has led many to call for the preferential use of apoB over LDL-C. However, to date, consistent recommendations for how clinicians should use apoB results remain lacking, and different guidelines have provided variable apoB targets for given LDL-C levels.

Previously, some guidelines have compared population or study-specific percentiles of LDL-C and apoB to identify equivalent levels. While this approach has a benefit of potentially identifying similar numbers of individuals for treatment, variability across populations in the distribution of LDL-C and apoB could lead to continued variability in global guidelines for optimal apoB targets. Discordance analyses have confirmed that persons with metabolic syndrome and hypertriglyceridemia are at highest risk of discordantly high apoB and reinforce current guideline recommendations to measure apoB in these populations. Unfortunately, variability across analyses in how discordance was defined limits their utility in guiding clinical management. However, all discordance analyses demonstrated that regardless of LDL-C, those with elevated apoB are at increased risk of ASCVD, reinforcing the importance of measurement of apoB.

Percentage reductions in apoB

Given this, trial data appear to be most useful in developing clinical recommendations for how to implement apoB to guide treatment recommendations. In terms of proportional reduction, all the lipid lowering therapy included appear to reduce apoB slightly less than LDL-C. Thus, if targeting a 50% or more LDL-C reduction (as recommended by many guidelines) with statins, ezetimibe, PSCK-9i, inclisiran, or bempedoic acid, a comparable apoB reduction would be 40–45%.

ApoB Treatment targets

To guide treatment targets, the trial data provide a very straightforward path. As the on-treatment LDL-C levels and on-treatment apoB levels were nearly identical, the same number can be used for apoB as LDL-C. Thus, if a target LDL-C level is <70 mg/dL, the target apoB should also be <70 mg/dL (0.70 g/L). In high-risk patients with a target of LDL-C <55mg/dL, the corresponding goal for apoB should be <55mg/dL (0.55 g/L). This simple approach can be easily communicated to patients and treating physicians and could eliminate confusion between guidelines.

Conclusions

The use of apoB offers a standardized, accurate, and cost-effective measurement of the total number of atherogenic lipoprotein particles in plasma, providing a more accurate assessment of ASCVD risk and effectiveness of lipid lowering therapy. Unlike LDL-C, apoB is particularly advantageous in patients with discordant lipid profiles, such as those with high TG, and insulin resistance, who are more likely to have cholesterol depleted apoB particles. ApoB is also more accurate when the levels of LDL-C are lower, a situation very common now days in clinical practice when guidelines suggest more aggressive treatment targets. Despite this, apoB faces barriers to widespread adoption in clinical practice, primarily due to the absence of consistent guidance on its interpretation and application. To address the existing challenges and based on evidence in RCT, this review suggests the use of the same number for LDL-C as for apoB when establishing treatment targets. The simplification of the interpretation of apoB, by aligning apoB targets with LDL-C levels, could enhance its integration into routine practice. The use of apoB in clinical decision-making holds promise for more accurate ASCVD risk prediction and tailored lipid-lowering strategies.

Non-standard Abbreviations and Acronyms

AACC

American Association for Clinical Chemistry

AACE/ACE

American Association of Clinical Endocrinologists and the American College of Endocrinology

AHA/ACC

American Heart Association and the American College of Cardiology

apoB

Apolipoprotein B

ASCVD

Atherosclerotic cardiovascular disease

CCS

Canadian Cardiovascular Society

DM

Diabetes

ESC/EAS

European Society of Cardiology and the European Atherosclerosis Society

HDL

High-density lipoprotein

IDL

Intermediate-density lipoproteins

lp(a)

Lipoprotein (a)

LDL

Low-density lipoprotein

LDL-C

Low-density lipoprotein cholesterol

MACE

Major adverse cardiovascular events

NHANES

National Health and Nutrition Examination Survey

NLA

National Lipid Association

TG

Triglycerides

VLDL

Very-low-density lipoprotein