LDL-C or apoB as the Best Target for Reducing Coronary Heart Disease

Should Apob be Implemented into Clinical Practice?

Helena Vaverkova

Disclosures

Clin Lipidology. 2011;6(1):35-48. 

In This Article

Conclusion & Future Perspective

It is usually argued that the introduction of apoB as a marker of risk and target of therapy would lead to confusion of both physicians and patients. For more than two decades, a great effort was devoted to education on the issue of the role of 'bad cholesterol' (LDL-C) in the development of atherosclerosis and the necessity of cholesterol-lowering therapy in the prevention of CVD. Thus, most authorities in this field think that it is necessary, at least for an interim period of time, to introduce apoB assessment to the routine lipid profile.

ApoB is a marker of the risk of atherogenic particles, especially LDL risk, and cannot substitute the whole lipid profile, especially at baseline examination. Thus, as this article suggests, apoB should be a part of the routine lipid panel at baseline. However, when apoB is the target, total cholesterol, LDL-C and non-HDL-C need not be measured on routine follow-up visits. Thus, apoB could unify all lipid targets representing the proatherogenic lipoprotein particle risk into one parameter.

Estimation of baseline TGs is useful, as a mild-to-moderate increase in TGs is a good marker of insulin resistance and its associated risk factors and also as a marker of increased risk of CVD.[38] Even in patients treated with statins to achieve very low levels of LDL-C of less than 70 mg/dl, high TG levels represent a considerable residual risk.[69] Severe hypertriglyceridemia is a marker of the risk of acute pancreatitis. Nevertheless, especially in hypertriglyceridemia, CVD risk is influenced by concomitant apoB levels. High apoB levels in hypertriglyceridemia indicate an increase in potentially atherogenic particles such as sdLDL and smaller TG-rich particles, such as IDL and smaller VLDL, while low apoB levels instead indicate an increase in larger TG-rich lipoprotein species such as chylomicrons and large VLDLs, which are less atherogenic (owing to their volume, they do not easily enter the artery wall). Thus, increased TG levels of greater than or equal to 150 mg/dl (≥1.7 mmol/l) are markers of increased cardiovascular risk, and very high levels of greater than or equal to 900 mg/dl (~10 mmol/l) are markers of acute pancreatitis risk. However, there is not enough evidence to set TG goals at present.

The aforementioned heterogeneity of lipoprotein particles also influences non-HDL-C levels and produces discordance in the levels of non-HDL-C and apoB, which results in differences in the accuracy with which they measure the number of atherogenic particles. In this respect, apoB is a better marker than non-HDL-C.

Estimation of HDL-C is also important for the evaluation of CVD risk, as it is an independent risk factor for CVD.[70] Even in patients treated with statins to achieve very low levels of LDL-C of less than 70 mg/dl, low HDL-C significantly contributed to macrovascular risk.[71]

At present, many HDL-raising therapies aimed at lower residual risk are in development, and several interventional studies with HDL-increasing drugs are underway.

The research in recent years has shown that the functionality of HDL and its specific subpopulations may be even more important than HDL-C levels. Nevertheless, at present, we do not have a useful method for measuring HDL functionality in clinical practice. Various drugs can influence different HDL species and various HDL functions. Thus, the results of clinical end point trials and not HDL-C levels should be decisive in this respect. However, as most drugs used for the treatment of lipid disorders usually influence more than one lipoprotein class, it will be very difficult to decide which part of the outcome is an HDL-related effect.

Several observations have shown that for many antiatherogenic roles of HDL, apoA-I is more important than HDL particle cholesterol content. Thus, in future, HDL-C assessment could probably be substituted with apoA-I assessment until better methods for the evaluation of HDL functionality are developed.

At present, the apoB:apoA-I ratio seems to be the best marker of cholesterol balance. It was shown to be the best marker of risk of MI and CVD in the AMORIS[24] and INTERHEART[72] studies, and also the best marker of treatment effects in the AFCAPS/TexCAPS study[45] and in combined data from the TNT and IDEAL studies.[48] Thus, for the future, the apoB:apoA-I ratio is a promising marker of both risk and treatment effect.

Where should our Research be Directed in Connection with apoB?

Statin therapy represents a great development in the treatment of dyslipidemias and associated cardiovascular risk. This therapy is based on increasing the activity of the LDL receptor pathway. Although this approach is very efficient, many patients remain undertreated.

Recently, Sniderman et al. suggested the 'apoB paradigm', which points to a different model of how the hepatocyte achieves cholesterol homeostasis in a complex metabolic environment.[73] This paradigm states that the rate at which LDL particles are produced is at least as important a determinant of their concentration in plasma as the rate at which they are cleared from plasma. According to this paradigm, secretion of VLDL (which is the precursor of LDL) is an important mechanism for maintaining cholesterol homeostasis within the hepatocyte.

Thus, novel therapeutic strategies to lower LDL-C through diminishing hepatic assembly of VLDL (such as apoB mRNA antisense oligonucleotide therapy) should be investigated vigorously in the future.[74]

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