Coverage Policy Manual
Policy #: 2010003
Category: Laboratory
Initiated: January 2010
Last Review: August 2018
  Measurement of Serum Intermediate Density Lipoproteins (Remnant-like Particles)

Description:
Triglyceride-rich proteins (TRL) consist of a great variety of lipoproteins differing in size, density, and apolipoprotein content. Based on their size and ability to enter the arterial wall, certain TRLs are considered atherogenic while others are not. Remnant lipoproteins, which are considered atherogenic, consist of partially catabolized intestinal chylomicrons or hepatic very low density lipoproteins (VLDLs) that are reduced in size, partially depleted of triglycerides, and enriched with cholesteryl esters. Remnant lipoproteins are also referred to as intermediate density lipoproteins (IDLs) based on how they separate on ultracentrifugation; IDLs are lipoproteins with a density that falls between low density lipoproteins (LDLs) and VLDLs.
 
Measurement of IDLs has been technically difficult and largely confined to a research setting because IDLs vary in size and contain varying proportions of triglycerides and cholesterol, with no available direct method of testing. However, recently, an immunoseparation assay has received approval from the U.S. Food and Drug Administration (FDA) for the direct measurement of IDL. Measurement of IDLs has been investigated in 2 settings:
 
    • As a tool for risk assessment for coronary heart disease
 
IDLs are considered atherogenic, and a variety of studies have suggested that IDL are associated with an increase in coronary heart disease risk; e.g., elevated IDLs may be a predictor of progression of coronary atherosclerosis and coronary events. Elevated IDLs may also be associated with a high triglyceride level (from 200-499 mg/dL), which is also a cardiac risk factor.
 
    • As a technique to diagnose type III hyperlipoproteinemia (also called dysbetalipoproteinemia)
 
Type III hyperlipoproteinemia is an uncommon familial disorder characterized by tuboeruptive and pathognomonic planar xanthomas and a marked predisposition to severe premature atherosclerosis. The disorder is characterized by elevated plasma cholesterol and triglyceride levels, both typically greater than 300 mg/dL. The hyperlipidemia is caused by the accumulation of remnant lipoproteins. Receptor-binding defective forms of apolipoprotein E are typically found. Apo E mediates binding of remnant lipoproteins to their hepatic receptors, and, therefore, when dysfunctional apo E is present, these remnants accumulate in the plasma. Diagnosis of this abnormality is usually based on apo E pheno- or genotyping.
 
 

Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Measurement of serum intermediate density lipoproteins (remnant-like particles) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, measurement of serum intermediate density lipoproteins (remnant-like particles) is considered investigational.  Investigational services are exclusions in the member certificate of coverage.

Rationale:
Measurement of intermediate density lipoproteins (IDLs) has been widely investigated as a cardiac risk factor, principally in an effort to further understand the association between trigylcerides and cardiac risk. For example, trigylcerides are carried in virtually all plasma lipoprotein and thus are highly heterogeneous. Triglycerides may also carry a different risk when present in the postprandial or fasting state. Thus the relationship between plasma triglycerides and cardiac risk is extremely complex. It has been hypothesized that serum levels of remnant lipoproteins, i.e., IDLs, may be a more specific cardiac risk factor compared to triglycerides per se. A variety of epidemiologic studies have been published that have compared the cardiac risk associated with triglycerides and IDLs. For example, in 1999, Kugiyama and colleagues measured remnant lipoprotein levels in 135 patients with coronary artery disease (CAD) (Kugiyama, 1999).  Patients were followed up for 3 years for additional clinical coronary events, such as revascularization procedures, nonfatal myocardial infarction, or cardiac death. The study demonstrated that higher levels of remnant lipoproteins in the fasting serum predicted the development of clinical coronary events in patients with CAD independently of other risk factors. Other studies using indirect measurements of IDLs have also shown that serum IDL levels are independently correlated with coronary artery lesion progression, as evidenced by serial cardiac imaging and clinical events.
 
While measurement of IDLs has emerged as an important research tool in evaluating cardiac risk factors and understanding how different components of plasma triglycerides contribute to cardiac risk, it is unclear how the management of IDLs can be used in the management of the patient. As noted in a prior Technology Evaluation Center (TEC) special report on high-sensitivity C-reactive protein, improved risk prediction does not by itself result in better health outcomes.   To improve outcomes, clinicians must have the tools to translate this information into clinical practice. Management of cardiac risk factors is largely based on the recommendations of the National Cholesterol Education Program, which published the Adult Treatment Panel III Report in May 2001.  ATP III defines target levels of LDL cholesterol based on risk as assessed by measurements of LDL cholesterol, total cholesterol, and HDL cholesterol, in addition to other factors, such as history of cigarette smoking, hypertension, family history of premature coronary heart disease, and age. The LDL cholesterol level may be reduced by diet, exercise, and various pharmacologic therapies, most prominently HMC-CoA reductase drugs, also referred to as statins. The ATP III also identified borderline (150–99 mg/dl), high (200–499 mg/dl), and very high triglyceride levels (>500 mg/dl) and suggested treatment strategies for those with high triglycerides. For example, patients with elevated triglycerides typically have an associated increase in remnant lipoproteins, which are reflected by higher serum levels of VLDL remnants. The ATP III guidelines suggest that in patients with high triglycerides, "VLDL cholesterol can be added to LDL cholesterol to become a secondary target of therapy. VLDL + LDL, termed non-HDL cholesterol, equals total cholesterol minus HDL cholesterol. A normal VLDL cholesterol can be considered to be a level <30 mg/dL. Thus a therapeutic goal for non-HDL cholesterol can be 30 mg/dL higher than the goal for LDL cholesterol." Suggested treatment of elevated triglycerides focuses on changes in life habits, such as body weight control, regular physical activity, smoking cessation, restriction of alcohol use, and avoidance of high carbohydrate diets. Pharmacologic therapy focuses on statin drugs or nicotinic acid. The ATP III supporting document includes the following discussion of remnant lipoproteins:
 
"Many lines of evidence point to the atherogenic potential of lipoprotein remnants. Although no single finding confirms remnant lipoproteins as independent risk factors, circumstantial evidence is strong.… Several assays are available for identification and measurement of remnant lipoproteins; these include ultracentrifugation, electrophoreses, and immunological techniques. Remnant-like particles measured immunologically appear to be promising risk predictor. Even so, prospective studies relating various remnant measures to CHD risk are limited, and measurement with specific assays cannot be recommended for routine practice. Nonetheless, ATP III identified elevated VLDL cholesterol as the surrogate for elevated atherogenic remnants in persons with triglycerides > 200 mg/dL."
 
In 2005 Tzou and colleagues examined the clinical value of “advanced lipoprotein testing” in 311 randomly selected adults participating in the Bogalusa Heart Study (Tzou, 2005).   Advanced lipoprotein testing consisted of subclass patterns of LDL, lipoprotein(a) cholesterol, intermediate density lipoprotein cholesterol, high density lipoprotein cholesterol subclasses, and very low density lipoprotein subclasses. These measurements were used to predict the presence of subclinical atherosclerosis, as measured ultrasonographically by carotid intima-media thickness. In multivariate logistic regression models, substituting advanced lipoprotein testing for corresponding traditional lipoprotein values did not improve prediction of the highest quartile of carotid intima-media thickness.
 
In July 2004, Grundy and colleagues published an article outlining the implications of recent clinical trials of statin therapy (Grundy, 2004).   The authors recommended a further lowering of the target LDL-C for some populations of patients. For example, the LDL-C target of 100 mg/dL in high-risk patients was lowered to 70 mg/dL. In addition, the authors recommend that consideration be given to combining a fibrate or nicotinic acid with an LDL-lowering drug in patients with high triglycerides or low HDL-C concentration. For moderately high-risk patients, the target LDL-C has been lowered from 130 mg/dL to 100 mg/dl. While not an explicit update of the ATP III recommendations, the conclusions were endorsed by the National Heart, Lung, and Blood Institute, the American College of Cardiology Foundation, and the American Heart Association. These new more aggressive targets of therapy create additional questions of how measurements of intermediate density lipoproteins can be used to improve patient management.
 
The majority of publications identified during this period focused on the pathophysiology and basic science aspects of IDL, with a smaller number of research studies reporting data with potential clinical relevance. There were no prospective, large-scale cohort studies that evaluated IDLs as a predictor of cardiovascular risk, nor were there any large diagnostic studies that evaluated the utility of IDLs in diagnosing type III hyperlipidemia.
 
Three, small to moderate-sized cross-sectional studies evaluated IDLs as a predictor of cardiovascular risk. The largest study compared 126 women without CAD to 256 women with CAD (Lamon-fava, 2008). IDL levels were higher in patients with CAD, and the IDL level was positively correlated with the extent of CAD on angiography. Nakajima and co-workers compared IDL levels in 165 Japanese patients with sudden cardiac death (SCD) with 93 patients who had died of other causes (Nakajima, 2007). IDL levels were higher in patients with SCD compared with non-SCD patients.  In patients with CAD, there was a weak correlation between LDL-C and IDL levels. A third cross-sectional study examined 64 patients who had undergone successful percutaneous coronary interventions (PCI) and stenting, 15 of whom had in-stent stenosis and 49 without restenosis (Kato, 2007).  Patients with in-stent stenosis had higher IDL levels compared to patients without restenosis.  In multivariate analysis, an IDL level above the 75th percentile was the strongest independent predictor of restenosis.
 
Two small cross-sectional studies provided evidence on the potential utility of IDL level in diagnosing familial hypercholesterolemia (Nakajima, 2007) (de Graaf, 2007).  Both of these studies compared IDL levels in patients with familial hypercholesterolemia to patients without familial hypercholesterolemia. IDL levels were higher in patients with familial hypercholesterolemia compared to controls in both instances. However, neither study provided clinically useful data such as the sensitivity and specificity of the test and/or the optimal threshold values for discriminating between patients with and without familial hypercholesterolemia.
 
None of the available studies provides guidance on the clinical use of IDL measurements, nor does this evidence suggest that health outcomes are improved as a result of measuring IDL level.
 
2012 Update
A search of the MEDLINE database was conducted through August 2012. There was no new information identified that would prompt a change in the coverage statement.
 
2013 Update
This policy was reviewed with a literature search using the MEDLINE database through August 2013 did not reveal any new literature that would prompt a change in the coverage statement.
   
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2018. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
84999Unlisted chemistry procedure

References: de Graaf J, van der Vleuten GM, ter Avest E et al.(2007) High plasma level of remnant-like particles cholesterol in familial combined hyperlipidemia. J Clin Endocrinol Metab 2007; 92(4):1269-75.

Grundy SM, Cleeman JI, Merz CN et al.(2004) . Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110(2):227-39.

Havel RJ.(2000) Remnant lipoproteins as therapeutic targets. Curr Opin Lipidol 2000; 11(6):615-20.

Hodis HM, Mack WJ, Dunn M et al.(1997) Intermediate-density lipoproteins and progression of carotid arterial wall intima-media thickness. Circulation 1997; 95(8):2022-6.

Imke C, Rodriguez BL, Grove JS et al.(2005) Are remnant-like particles independent predictors of coronary heart disease incidence? The Honolulu Heart Study. Arterioscler Thromb Vasc Biol 2005; 25(8):1718-22.

Kato T, Inoue T, Inagaki H et al.(2007) Remnant-like lipoprotein particle level and insulin resistance are associated with in-stent restenosis in patients with stable angina. Coron Artery Dis 2007; 18(4):319-22.

Koba S, Hirano T, Murayama S et al.(2003) Small dense LDL phenotype is associated with postprandial increases of large VLDL and remnant-like particles in patients with acute myocardial infarction. Atherosclerosis 2003; 170(1):131-40.

Kugiyama K, Doi H, Takazoe K et al.(1999) Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease. Circulation 1999; 99(22):2858-60.

Lamon-Fava S, Herrington DM, Reboussin DM et al.(2008) Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically-defined coronary artery disease in postmenopausal women. Arterioscler Thromb Vasc Biol 2008; 28(3):575-9.

Lee SJ, Sacks FM.(2003) Effect of pravastatin on intermediate density and low density lipoproteins containing apolipoprotein CIII in patients with diabetes mellitus. Am J Cardiol 2003;92(2):121-4.

Mack WJ, Krauss RM, Hodis HN.(1996) Lipoprotein subclasses in the Monitored Atherosclerosis Regression Studies (MARS). Treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol 1996; 16(5):697-704.

Nakajima K, Daimon M, Kamiyama K et al.(2007) Serum remnant lipoprotein cholesterol/triglyceride ratio as an index for screening familial type III hyperlipidaemia. Ann Clin Biochem 2007; 44(pt 4):353-9.

Nakajima K, Nakajima Y, Takeichi S et al.(2007) . Plasma remnant-like lipoprotein particles or LDL-C as major pathologic factors in sudden cardiac death cases. Atherosclerosis 2007 Oct 29 {Epub ahead of print].

Nakamura T, Kugiyama K.(2006) Triglycerides and remnant particles as risk factors for coronary artery disease. . Curr Atheroscler Rep 2006; 8(2):107-10.

National Cholesterol Education Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf

Ooi TC, Cousins M, Ooi DS et al.(2004) Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia. Atherosclerosis 2004; 172(2):375-82.

Phillips NR, Waters D, Havel RJ.(1993) Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation 1993; 88(6):2762-70.

Tzou WS, Douglas PS, Srinivasan SR et al.(2005) Advanced lipoprotein testing does not improve indentificaiton of subclinical atherosclerosis in young adults: The Bogalusa Heart Study. . Ann Intern Med 2005;142(9):742-50.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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