Lipoprotein(a), Remnant Cholesterol and Non-HDL-C in Women - Is it Different

INTRODUCTION

Conventionally, assessment of lipids included measurement of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), very LDL (VLDL)-C and total cholesterol (TC).^[1] Recently, there has been a growing interest in residual risk of atherogenic diseases in statin-treated patients.^[2] Though there may be various reasons for recurrent cardiovascular (CV) events in these statin-treated patients significant atherogenic potential of lipids other than LDL-C, which include lipoprotein(a) (Lp[a]), remnant cholesterol, and non-HDL, is of growing interest.^[3] LDL-C, a predominant lipoprotein carrying cholesterol, is a well-established risk factor for atherosclerotic CV disease (ASCVD) and therefore a prime target for lipid-lowering treatment according to various guidelines.^[3,4] Residual atherogenic risk in patients who have achieved target LDL-C on treatment is an important and clinically relevant issue.^[5] Few studies have implicated a stronger association of non-HDL-C, apo-B with residual CV risk.^[6] Various lipid guidelines and consensus statements have already endorsed non-HDL, Apo-B as predominant and secondary targets.^[5,7-10] Indian-specific data on dyslipidemia are scarce and continue to evolve. This review article is a step forward in providing a consensus statement on dyslipidemia and offers research recommendations to enhance health equity among Indian women.

This article discusses the importance of lipoprotein (a), remnant cholesterol, and non-HDL cholesterol in the assessment of dyslipidemia, studies their role in women across their lifetime in various pathological conditions, examines the current evidence and guidelines, comments on their importance, and highlights the clinical value of these parameters. It also provides practical consensus advice and research recommendations on screening, threshold values, and therapies to mitigate CV risk.

WHAT IS “LP(A), REMNANT CHOLESTEROL AND NON-HDL-C”?

Lipoprotein a is structurally LDL-C with Apo a attached to it. It is proatherogenic, prothrombotic, proinflammatory, and an independent risk factor for ASCVD, myocardial infarction, ischemic stroke, valvular aortic stenosis, carotid and femoral artery disease, and all-cause mortality.^[11] It is genetically determined, reaches peak level by 5 years of age, and therefore lifestyle changes have minimal impact on it.^[12] Due to its high CV disease risk, various guidelines suggest Lp(a) level testing at least once in a lifetime.^[13,14] Cascade testing of family members is advised for probands with familial hypercholesterolemia and high Lp(a).^[15] Table 1^[16-21] lists few studies on Lp(a) in women. Studies in the Indian scenario are listed in Table 2.^[22-25]

For triglyceride levels >4.5 mmol/L (400 mg/dL), a direct LDL cholesterol assay is required to estimate remnant cholesterol. Remnant cholesterol is the cholesterol in all triglyceride-rich lipoproteins, not found in LDL or HDL.^[26] It describes the TC content of all triglyceride-rich lipoproteins (TRL) remnants, which include chylomicrons, VLDL.^[27] It has been independently linked to adverse CV events independent of.^[28] It can be calculated from a standard non-fasting lipid profile at no extra cost.^[29,30] In simple terms, it is the total plasma cholesterol except that found in LDL-C and HDL-C. It is also linked to accelerated progression of atherogenesis and coronary heart disease.^[31-33]

Non-HDL cholesterol is calculated by subtracting HDL cholesterol from TC. This value represents the sum of LDL and remnant cholesterol.^[27] It includes all the atherogenic lipoproteins.^[34] It denotes the TC of all Apo B lipoproteins. It includes remnant cholesterol plus all cholesterol in Apo B-containing lipoproteins.^[35] Recent guidelines highlight its importance for predicting CV disease risk. It is valuable for screening because its measurement is simple, can be done in non-fasting state and is a valuable prognostic marker.^[19]

It has an advantage over LDL because it is not affected by triglyceride variability, which is an important risk factor in Indians.^[36]

UNDERSTANDING THE UNIQUE ASPECTS OF LIPID PROFILE IN WOMEN

There are differences in the distribution and levels of lipids from infancy to adulthood between men and women. In the initial life course, girls tend to have high LDL and TC with similar HDL levels compared to boys. Lipid levels also vary during the menstrual cycle, with higher TC and LDL during the follicular phase and a decline during the luteal phase.^[37]

During pregnancy, a physiological increase in LDL and a much higher increase in TG levels have been observed. In the early adulthood to middle age, women have low LDL and high HDL. During perimenopause and post-menopause, women tend to have an adverse lipid profile. These findings emphasize the need for interpretation of lipid profiles based on gender and life course of women.^[37]

The association between remnant cholesterol and metabolic syndrome risk appears to be stronger in women compared to men. This may be due to a relative deficiency of estrogen, particularly after menopause, which affects lipid metabolism and increases risk. After menopause, women usually develop a lipid profile with higher LDL-C, triglycerides, and TC, driving up remnant cholesterol and non-HDL-C. Both remnant cholesterol and non-HDL-C levels tend to rise with age in women, and postmenopausal women face higher correlated risks for CV disease and diabetes than premenopausal women.

In addition, in coronary artery disease, a difference in lipid profile pattern has been observed. A south Indian cross-sectional study done in acute coronary syndrome (ACS) patients showed that males have higher mean TC and LDL-C, whereas females had higher mean triglycerides and HDL-C.^[38]

The causal link between dyslipidemia and CV disease has been well established. High levels of LDL-C have been strongly implicated as a risk factor. However, these findings have largely been derived from studies involving the Caucasian population. Keeping in view the diversity of the human population, genetically, nutritionally, these findings may not be universally.^[39] Asians are the largest population with CV disease worldwide. Almost 25% of acute myocardial infarction patients in Asia have LDL ≤100 mg/dL. Despite lower absolute LDL-C levels, the pattern of higher risk with elevated levels was seen among various groups. They have a distinct lipid profile comprising high TG, low LDL, and low HDL.

High Apo B to Apo a1 ratio has the strongest association with acute myocardial infarction (AMI) among all the lipid parameters.^[40]

DOES LIPID PROFILE CHANGE IN A WOMAN THROUGHOUT THEIR LIFE?

Hormonal status varies in women throughout the life time and these have an effect on lipid metabolism. Endogenous estrogen is known to have a beneficial effect on lipoprotein metabolism and progesterone has a neutral.^[41] During a menstrual cycle, higher lipid levels are observed during ovulation.^[41] Increase in TC, LDL in the immediate preovulatory period, and peaking of HDL at ovulation have a physiological role as these lipoproteins help in steroidogenesis, should pregnancy occur. TC and LDL levels are low during the luteal phase when estrogen and progesterone are highest. HDL is highest during ovulation, coinciding with high estrogen levels. No consistent pattern is noted in triglyceride levels. At menarche Lp(a) levels are not significantly affected by hormonal changes except by supraphysiological progesterone levels. Therefore, fertility therapies with follicle-stimulating hormone (FSH) induce luteal progesterone increase, which increases Lp(a) level. Despite this, no significant increase in CV disease is observed in a registry-based cohort study in Denmark on long-term follow-up for almost 11 years in women who gave birth by assisted reproductive techniques.^[42]

Furthermore, in coronary artery disease, a difference in lipid profile pattern has been observed. A South Indian cross-sectional study done in ACS patients showed that males have higher mean TC and LDL-C, whereas females had higher mean triglycerides and HDL-C.^[1]

PATHOGENESIS OF ATHEROSCLEROSIS AND LIPID HOMEOSTASIS IN WOMEN

Estrogens decrease atherosclerotic plaque volume, increase endothelial nitric oxide production, leading to vasodilation.^[43] Estrogens reduce E-selectin, vascular and intercellular adhesion molecules in endothelial cells, prevent smooth muscle cell proliferation, and extracellular matrix deposition, thereby decreasing.^[44]

Imaging studies have shown that women compared to men have fewer atherosclerotic plaques, smaller necrotic core, less calcification, less intraplaque hemorrhage, and plaque rupture.^[45]

Estrogens decrease LDL-C, increase HDL-C and favorably impact reverse cholesterol transport.^[46]

SCENARIOS SPECIFIC TO WOMEN

CONCLUSION

Residual CV risk persists even among individuals who achieve target LDL-C levels. Non-HDL cholesterol, encompassing LDL and remnant cholesterol, is increasingly recognized as a key contributor to this residual risk and should be considered a co-primary treatment target. As a prognostic marker, non-HDL cholesterol offers practical advantages: It is stable, cost-effective, and can be measured without fasting. Current guidelines recommend that nonHDL cholesterol levels should not exceed 30 mg/dL above the desired LDL-C target.

Recent insights highlight the atherogenic potential of triglycerides, triglyceride-rich remnants, and remnant cholesterol, which may further contribute to CV risk. In addition, elevated Lp(a) – a genetically determined factor – places individuals at high risk, warranting at least one lifetime screening and cascade testing in families with familial hypercholesterolemia.

Given India’s high burden of coronary artery disease (CAD), there is a pressing need for representative national studies, including adequate female participation. Efforts should focus on increasing awareness of dyslipidemia, routine lipid screening, and proactive identification and management of high-risk individuals to reduce CV morbidity and mortality.

In summary, both non-HDL-C and remnant cholesterol are important markers for CV and metabolic risk in women, with some evidence that remnant cholesterol may have particularly strong associations with metabolic syndrome and diabetes risk in postmenopausal women. The levels and impact of these markers do differ by sex, with hormonal changes playing a significant role.