Lipoprotein(a): A New Treatment Target?

July 1, 2007

Lp(a) is a fascinating variant of low-density lipoprotein (LDL). It is basically an LDL molecule that has been modified by the covalent addition of apoprotein(a). Elevated levels of Lp(a) correlate with increased risk of acute coronary syndromes, cerebrovascular accident, peripheral arterial disease, and coronary mortality. This Q&A session answers some curiosities about Lipoprotein(a).

 

Q: Should I prescribe niacin for a patient whose lipoprotein(a) (Lp[a]) level is 65 mg/dL?

A: Lp(a) is a fascinating variant of low-density lipoprotein (LDL). It is basically an LDL molecule that has been modified by the covalent addition of apoprotein(a).1 Elevated levels of Lp(a) correlate with increased risk of acute coronary syndromes, cerebrovascular accident, peripheral arterial disease, and coronary mortality.2-4

However, much work remains to be done to fully understand the variety and frequency of allelic variation in the gene for apoprotein(a), the mechanism by which LDL is modified by apo(a), and the pathways for Lp(a) catabolism and elimination.

Purported mechanism of action of Lp(a). It is believed that Lp(a) increases the risk of acute cardiovascular events because it is both thrombogenic and atherogenic. Apoprotein(a) is homologous in some of its sequencing with the fibrinolytic enzyme plasminogen.5 By interfering with the generation of plasmin from plasminogen, Lp(a) inhibits fibrinolysis and allows for clot propagation. In addition, Lp(a), like LDL, functions as a transport vehicle for cholesterol. It is believed to traverse the arterial endothelium and deliver cholesterol into the subendothelial space where it can be oxidatively modified and taken up by macrophages, forming foam cells and an atherogenic nidus. Lp(a) is found in atheromatous plaques.

Significance of Lp(a) levels. Lp(a) is considered elevated when serum levels exceed 30 mg/dL. Approximately one third of patients at high risk for cardiovascular disease have elevated levels of Lp(a). However, because there are many antigenic variants of the apoprotein(a) moiety, there is wide variation in the accuracy of currently available assay methods of measuring serum levels of this lipoprotein.6 Improved assays are currently in development.

The National Cholesterol Education Program recognizes Lp(a) as an emerging risk factor but makes no specific recommendations about its management.7 Professional societies such as the American College of Cardiology, the American Heart Association, the American Academy of Family Physicians, and the American College of Physicians do not recommend routine screening for Lp(a).

How should elevated Lp(a) levels be treated? There is no drug currently available that specifically and reproducibly reduces circulating levels of Lp(a). Niacin used at pharmacologic doses (2 g/d) has been shown to reduce serum levels of Lp(a) by 20% to 25%. However, no prospective trials are currently available to show that treating patients who have elevated Lp(a) levels with high-dose niacin reduces the risk of cardiovascular events.

Estrogen can reduce Lp(a) levels by about 50%. In the Heart and Estrogen/Progestin Replacement Study (HERS), the only subgroup of women to derive benefit from estrogen therapy for reducing coronary heart disease (CHD)-related events were those with elevated levels of Lp(a).8 However, given the results of other trials, such as the Women's Health Initiative, it is not currently recommended that estrogen be used to reduce the risk of cardiovascular events in postmenopausal women.9

Statin therapy is not associated with reduction in the serum concentration of Lp(a). However, these drugs have been shown, in a wide range of primary and secondary prevention trials, to unequivocally reduce the risk of cardiovascular morbidity and mortality. Multivariate analysis of data from the Familial Atherosclerosis Treatment Study shows that in patients with coronary artery disease, once LDL cholesterol levels are reduced below 100 mg/dL, Lp(a) is no longer a significant predictor of risk.10

Latest thinking on Lp(a) and prevention of heart disease. So how is Lp(a) currently integrated into cardiovascular disease prevention? Although widespread screening is not recommended, measurement of Lp(a) levels can be helpful for assessing risk in patients with CHD who have no other significant risk factors for atherosclerotic disease and in those with a family history of premature CHD. In these patients, established risk factors should be treated aggressively to the goal levels specified in current guidelines. In a patient with coronary artery disease, this would mean reduction of the LDL cholesterol level to less than 100 mg/dL (or less than 70 mg/dL in a patient meeting criteria for very high risk), reduction of the non-HDL cholesterol level to less than 130 mg/dL, an effort to raise the high-density lipoprotein (HDL) cholesterol level if it is less than 40 mg/dL, lowering of blood pressure to less than 130/80 mm Hg, smoking cessation, weight loss, and lifestyle modification as appropriate; the patient should also be evaluated for any evidence of insulin resistance or diabetes mellitus.

In patients who have a high Lp(a) level in conjunction with a low HDL cholesterol level and/or an elevated triglyceride level, niacin in addition to lifestyle modification is a very effective adjunctive therapy that can help normalize the lipid profile.

References:

REFERENCES:


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