Atherosclerosis, a leading cause of cardiovascular disease (CVD), begins early in life and progresses gradually, providing a wide window for screening and early detection.¹ CV risk is not uniformly distributed across populations; South Asians are 1.5 times more likely to die from coronary artery disease than White Caucasians.² The focus of ASCVD risk assessment, followed by treatment decision-making, has traditionally been LDL-C. However, significant residual CV risk persists despite optimal LDL-C reduction. ³ Growing evidence suggests that nontraditional lipid markers including lipoprotein(a) [Lp(a)], apolipoprotein B (ApoB), and non-high-density lipoprotein cholesterol (non-HDL-C) as well as high-sensitivity C-reactive protein (hs-CRP) may contribute to this residual risk, independent of LDL-C. ^4,5

Hence, it is important to look beyond LDL-C levels and determine CV risk based on a host of biomarkers for greater predictive accuracy. ³

Atherogenic risk markers

LDL-C: A sub-optimal marker

LDL-C is the major circulating atherogenic lipoprotein; but, it no longer enjoys the numero uno status as the atherosclerotic risk marker. ² Small, dense LDL particles are often predominant in South Asians, so LDL particle number may be elevated even with a normal LDL-C level. ⁶ Its usefulness as the sole marker is also limited by inaccurate estimation especially in the presence of hypertriglyceridemia, inability to capture other atherogenic lipoprotein fractions, and the need for fasting samples, which can be inconvenient for both patients and clinicians and may delay reporting. ⁷

HDL-C: Functional vs dysfunctional HDL

HDL has been viewed as the “protective” or the “good” cholesterol; higher the levels, lower the risk. HDL quality and functionality, rather than quantity, have now come to the forefront. Functional HDL has significant antioxidant, anti-inflammatory, and cholesterol efflux activities including vascular endothelial protective and anti-thrombotic actions. ⁸ Dysfunctional HDL particles have smaller size, ambiguous shape, reduced apoA-I content, and lower antioxidant ability. ⁹ 

Apolipoprotein A1

ApoA1, the major protein component of HDL, has anti-inflammatory, antiatherogenic, and antithrombotic properties. A linear relationship exists between ApoA1 and HDL-C across racial groups; but, South Asians have the lowest ApoA1 levels for a given HDL-C concentration. ⁶

ApoB: A more accurate measure of atherogenic burden

ApoB is the primary structural protein in all atherogenic lipoproteins and directly quantifies the total number of circulating atherogenic particles unlike LDL-C. It therefore provides a more accurate assessment of atherogenic burden, particularly in hypertriglyceridemia, metabolic syndrome, diabetes, and obesity. ¹⁰ Among statin-treated patients, ApoB was the strongest predictor of significant CAD and the only biomarker independently associated with left main and three-vessel disease. Left main disease assumes clinical significance due to its association with higher mortality and multivessel
disease. ¹⁰

ACC-AHA and LAI advise universal measurement of Apo B to assess the true CV risk and guide treatment.^11,12

ApoB/ApoA1 ratio

This ratio depicts the balance between atherogenic and antiatherogenic lipoproteins.¹³ A lower ratio indicates a more favorable lipid profile; a higher ratio points to an increased risk of ASCVD, including type 2 diabetes. South Asians have higher ApoB/ApoA1 ratios than Caucasians, despite lower total cholesterol levels. ^6,14

Lp(a): A genetically determined biomarker

A positive linear relationship exists between the Lp(a) level and ASCVD risk. ¹⁵ As ~90% of serum Lp(a) is genetic⁶, levels remain same throughout life. It should be measured at least once, especially in those with a family history of premature ASCVD or a personal history of ASCVD not explained by major risk factors.¹¹ Extremely high Lp(a) levels > 430 nmol/L convey a lifetime CVD risk similar to those with heterozygous familial hypercholesterolemia. ²

Triglycerides

Hypertriglyceridemia often co-occurs with low HDL-C and increased small dense LDL-C.¹¹ In type 2 diabetes, high TGs may lead to falsely low LDL-C levels. Hence, LDL-C should be interpreted cautiously to avoid underestimating CV risk as ApoB continues to be high. ¹⁴

Non-HDL-C

HDL-C is the only anti-atherogenic lipoprotein; therefore, like ApoB, non-HDL-C is also an indirect indicator of the total atherogenic particle burden.¹¹ It can be easily calculated from a standard lipid profile as total cholesterol minus HDL-C.¹⁶

ApoB is superior to non-HDL cholesterol as a secondary target in patients with mild-to-moderate hypertriglyceridemia (175-880 mg/dL), diabetes, obesity or metabolic syndrome, or very low LDL cholesterol < 70 mg/dL. But when apoB is not available, non-HDL cholesterol should be used to supplement LDL-C. ¹⁶

LDL/ApoB ratio

Since LDL particle size is not easy to measure, the LDL/ApoB ratio acts as a surrogate marker of LDL particle size and composition. ¹⁰ LDL/ApoB ratio ≤1.2 indicates a high prevalence of small, dense particles, which are more atherogenic as they penetrate the subendothelial space more easily and are more likely to be retained within the arterial wall. ^10,17

Inflammatory risk marker

hs-CRP: The inflammatory marker of ASCVD risk

Raised hs-CRP levels, tested on at least two distinct occasions, are used for CV risk assessment in asymptomatic persons. ¹⁸ Its predictive ability is comparable to or greater than the traditional risk factors such as LDL-C or systolic BP. ⁵ Persistently elevated hsCRP level should lead to consideration of initiation or intensification of statin therapy, regardless of LDL-C. ¹⁹

Emerging risk marker

Oxidized LDL-C

Foam cell formation, the critical step in atherosclerotic plaque build-up, is triggered by the uptake of oxidized LDL by macrophages. Oxidized LDL is pro-inflammatory and pro-atherogenic,²⁰ and occurs independent of LDL-C. Raised levels may indicate ongoing atherosclerotic disease progression even when LDL-C is within target range. ¹⁴

Toward integrated CV risk mapping

No single biomarker can adequately predict CVD risk. LDL-C alone underestimates risk in many patients. Risk assessment should extend beyond LDL-C to capture the multifactorial nature of ASCVD. Although LDL-C remains a key therapeutic target, residual risk may persist despite achieving guideline-recommended levels. A more integrated approach incorporates additional atherogenic markers, including ApoB, non-HDL-C, Lp(a), TGs, and small dense LDL, alongside inflammatory markers such as hsCRP. Patient-specific factors, including diabetes, obesity, metabolic syndrome, hypertension, and family history, should also be considered. This multidimensional risk mapping facilitates a more comprehensive assessment of atherogenic burden and eases personalized intervention strategies.

Guidelines now advocate nonfasting lipid profiles for CV risk assessment, as fasting status has little effect on LDL-C, HDL-C, and ApoB levels. It improves convenience, particularly in children, older adults, patients with diabetes, and those with acute coronary syndrome. Fasting is needed when nonfasting triglycerides are >400 mg/dL, in known hypertriglyceridemia, during recovery from hypertriglyceridemia-related acute pancreatitis, or when other fasting tests (such as glucose) are required.²¹

Clinical Thresholds and Action Points: Quick Reckoner

*In Indians, Lp (a) ≥20 mg/dL indicates heightened ASCVD risk; Lp(a) 20-49 mg/dL is moderate risk, while ≥50 mg/dL is high-risk.

** Optimum levels in Indians are <100 mg/dL.

Case scenario:  A 46-year-old South Asian man with hypertension and a family history of premature coronary artery disease has an LDL-C of 82 mg/dL but persistently elevated ApoB (118 mg/dL) and Lp(a) of 95 mg/dL. He has no history of GI bleeding, is not on anticoagulants, and has normal platelet count.  . Management: Despite the “at-goal” LDL-C, the high ApoB indicates an increased burden of atherogenic particles and residual cardiovascular risk along with elevated Lp(a) levels. Intensify lipid-lowering therapy (high-intensity statin ± ezetimibe), reinforce lifestyle modification, consider low-dose aspirin (75-100 mg)and monitor ApoB as a treatment target.

References

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