Measurement of Small, Dense Lipoprotein Particles
Small, dense lipoprotein particles have been extensively investigated in three different clinical contexts:
1. An independent risk factor for coronary artery disease:
A nested case-control study from the Physician’s Health Study, prospective cohort study of almost 15,000 men, investigated whether low-density lipoprotein (LDL) particle size was an independent predictor of coronary artery disease (CAD) risk, particularly in comparison to triglyceride levels. This study concluded that while LDL particle diameter was associated with risk of myocardial infarction, this association was not present after adjustment for triglyceride level. Only triglyceride level was significant independently. The Quebec Cardiovascular Study evaluated the ability of “nontraditional” lipid risk factors, including LDL size, to predict subsequent CAD events in a prospective cohort study of 2,155 men followed up for five years. The presence of small LDL was associated with a 2.5-times increased risk for ischemic heart disease after adjustment for traditional lipid values, indicating a level of risk similar to total LDL. This study also suggested an interaction in atherogenic risk between LDL size and apolipoprotein B levels. In the presence of small LDL particles, elevated apolipoprotein B levels were associated with a six-fold increased risk of CAD, whereas when small LDL particles were not present, elevated apolipoprotein B levels were associated with only a two-fold increase in risk.
2. A risk factor in patients with “normal” total LDL and cholesterol levels:
A number of randomized trials have evaluated lipid-lowering therapy in patients with dyslipidemia, but normal total cholesterol and total LDL levels. However, LDL size was not used as a selection criterion or as an outcome measure in these trials. Rather, other lipid parameters associated with dyslipidemia, such as high triglycerides and/or low HDL were used as patient selection factors and outcome measures.
3. A predictor of response to treatment:
Patients with subclass pattern B have been reported to respond more favorably to diet therapy compared to those with subclass pattern A. Subclass pattern B has also been shown to respond more favorably to the drugs gemfibrozil and niacin, with a shift from small, dense LDL particles to larger LDL particles. While statin drugs lower the overall concentration of LDL cholesterol, there is no shift to the larger LDL particles.
Several trials with angiographic outcomes have examined the change in LDL particle size in relation to angiographic progression of CAD. The Stanford Coronary Risk Intervention Program (SCRIP) trial studied the relationship between small, dense LDL and the benefit of diet, counseling, and drug therapy in patients with coronary artery disease, as identified by initial coronary angiogram. Patients with subclass pattern B showed a significantly greater reduction in CAD progression compared to those with subclass pattern A. The Familial Atherosclerosis Treatment Study (FATS) randomized patients from families with premature CAD and elevated apolipoprotein B levels. Change in LDL particle size was significantly correlated with angiographic progression of CAD in this study. Fewer studies have evaluated clinical outcomes in relation to LDL particle size. In the Cholesterol and Recurrent Events (CARE) trial, survivors of myocardial infarction with normal cholesterol levels were randomized to lipid-lowering therapy or placebo. A post-hoc analysis from this trial failed to demonstrate a correlation between change in particle size and treatment benefit.
In summary, small LDL size is one component of an atherogenic lipid profile that also includes increased triglycerides, increased apolipoprotein B, and decreased HDL. Some studies have reported that LDL size is an independent risk factor for CAD, and others have reported that a shift in LDL size may be useful marker of treatment response. However, the direct clinical application of measuring small, dense lipoprotein particles is still unclear. An improved ability to predict risk and/or treatment response does not by itself result in better health outcomes. To improve outcomes, clinicians must have the tools to translate this information into clinical practice. This requires guidelines that incorporate emerging risk factors into existing risk prediction models, and that have been demonstrated to classify patients into risk categories with greater accuracy. Predictive models also need to be accompanied by treatment guidelines that target interventions toward patients who will get the most benefit.
Tools for linking levels of small, dense LDL to clinical decision making, both in risk assessment and treatment response, are currently not available. Published data are inadequate to determine how such measurements should guide treatment decisions and whether these treatment decisions result in beneficial patient outcomes. Other associated lipid parameters, such as triglycerides and HDL levels may be more useful than LDL size in assessing risk and treatment response. The ATP III practice guidelines consider the metabolic syndrome to be an important risk factor that should be addressed, but continues to tie clinical decision making to conventional lipid measures, such as total cholesterol, LDL-C, and HDL-C.
Measurement of LDL Particle Concentration
Similar to small dense lipoprotein particles, several epidemiologic studies have shown that the lipoprotein particle concentration is also associated with cardiac risk. For example, the data derived from the Cardiovascular Health Study, Women’s Health Study, and PLAC-1 trial suggest that the number of LDL particles is an independent predictor of cardiac risk. Translating these findings into clinical practice requires setting target values for lipoprotein number. Proposed target values have been derived from the same data set (i.e., the Framingham study) that was used to set the ATP III target goals for LDL-C. For example, the ATP III targets for LDL-C correspond to the 20th, 50th, and 80th percentile values in the Framingham Offspring Study, depending on the number of risk factors present. Proposed target goals for lipoprotein number correspond to the same percentile values, and LDL particle concentration corresponding to the 20th, 50th, and 80th percentile is 1,100 nmol/L, 1,400 nmol/L, and 1,800 nmol/L, respectively. Therefore, one proposed clinical application is to assess the lipoprotein particle concentration in patients who have met their LDL-C goal. For example, assessment of LDL particle number may be assessed in individuals with known CHD risk equivalents or the metabolic syndrome who are near or have reached the ATP III LDL-C goals. If NMR-measured LDL particle concentration is at a corresponding population goal, there is no residual risk arising from LDL particle excess, and treatment is optimized. However, if the LDL particle concentration is elevated, then residual risk from LDL particle excess may exist and these patients may benefit from further therapy. However, at the present time, there have been no controlled trials that have directly assessed how measurements of particle number can be used in the management of the patient. As noted here, an improved ability to predict risk and/or treatment response does not by itself result in better health outcomes.
In July 2004, Grundy and colleagues published an article outlining the implications of recent clinical trials of statin therapy. 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 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, American College of Cardiology Foundation, and American Heart Association. These new, more aggressive targets of therapy create additional questions of how either measurements of either LDL concentration or LDL size can be used to improve patient management.
In 2005, Tzou and colleagues examined the clinical value of “advanced lipoprotein testing” in 311 randomly selected adults participating in the Bogalusa Heart Study. Advanced lipoprotein testing consisted of subclass patterns of LDL, i.e., the presence of large buoyant particles, intermediate particles, or small dense particles. These measurements were used to predict the presence of subclinical atherosclerosis, as measured ultrasonographically by carotid intimal-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 intimal-media thickness. Other studies further explore the role of subclass patterns of LDL in the pathogenesis of coronary artery disease or the metabolic syndrome, or continue to include subclass patterns of LDL as intermediate outcomes in clinical studies, but no studies were identified in which identification of subclass patterns of LDL were used to direct patient management.
January 2006– April 2007 Update
A literature search was performed for the period of July 2005 through April 2007. A number of studies were published during this time that continued to evaluate whether LDL size was a clinically important, independent predictor of cardiovascular events. The majority of this evidence concluded that measurement of LDL size provided independent predictive information above that provided by standard lipid measurements. However, other authors have suggested that this additional risk is a function of LDL particle number (as measured by apo B), and reported that LDL size has no additional predictive value beyond that of apo B.
Other studies have further evaluated the use of LDL particle size as a measure of treatment response. Superko and colleagues reported that the response to gemfibrozil differed in patients with LDL subclass A compared to those with LDL subclass B. There was a greater reduction in the small, low-density LDL levels for patients with subclass B, but this was not correlated with clinical outcomes. Another study reported that atorvastatin treatment led to an increase in mean LDL size, while pravastatin treatment led to a decrease in LDL size.
None of these published studies provided evidence that measurement of LDL size led to improved clinical outcomes. Tools for linking levels of small, dense LDL to clinical decision making, both in risk assessment and treatment response, are currently not available. Therefore, no new evidence has been identified that would prompt reconsideration of the policy statement, which remains unchanged.
Using NMR techniques, Cromwell and Otvos reported that patients with type 2 diabetes mellitus and LDL cholesterol levels below 100 mg/dL were heterogeneous with regard to concentrations of LDL particles. Among 871 patients with LDL cholesterol below 70 mg/dL, 40% had LDL particle levels above 1000 nmol/L (the 20th percentile). Otvos and colleagues also reported that changes in NMR-measured LDL and HDL subclasses, which were not reflected in conventional lipid measures, helped to explain the effect of gemfibrozil in patients with low HDL cholesterol.
None of these published studies provided evidence that measurement of LDL concentration led to improved clinical outcomes. Tools for linking concentration of LDL particles to clinical decision making, both in risk assessment and treatment response, are currently not available. Therefore, the coverage position of this medical policy remains unchanged.
Measurement of LDL Particle Concentration (Number)
A recent consensus statement from the American Diabetes Association (ADA) and American College of Cardiology (ACC) commented on the use of LDL particle number in patients with cardiometabolic risk. This article comments on the limitations of the clinical utility of Nuclear Magnetic Resonance (NMR) measurement of LDL particle number or size, including lack of widespread availability. This article also comments that there is a need for more independent data confirming the accuracy of the method and whether its predictive power is consistent across various patient populations.
Mora et al. evaluated the predictive ability of LDL particle size and number measured by NMR in participants of the Women’s Health Study, a prospective cohort study of 27,673 women followed up over an 11-year period. After controlling for nonlipid factors, LDL particle number was a significant predictor of incident cardiovascular disease, with a hazard ratio of 2.51 (95% CI: 1.91–3.30) for the highest compared to the lowest quintile. LDL particle size was similarly predictive of cardiovascular risk, with a hazard ratio of 0.64 (0.52–0.79). Cardiovascular disease (CVD) risk prediction associated with NMR lipoprotein profiles in this study was comparable but not superior to standard lipids or immunoassay-measured apolipoproteins. When compared to standard lipid measures and apolipoproteins, LDL particle size and number showed similar predictive ability, but were not superior in predicting cardiovascular events.
A relatively small number of studies have evaluated the predictive ability of LDL particle size and number as measured by NMR. These studies do not demonstrate that NMR-measured particle size and/or number offer additional predictive ability beyond that provided by traditional lipid measures. NMR measures have been proposed as indicators of residual cardiovascular risk in patients treated with statins who have met LDL goals, but there is no evidence that these measures improve health outcomes when used for this purpose. Therefore, none of the available evidence is sufficient to prompt reconsideration of the current coverage statement, which remains unchanged.
Measurement of LDL Particle Size
In a retrospective cohort study (McAna, 2012) conducted over a 2-year period, outcomes were compared between patients with a standard lipid profile to those evaluated with a comprehensive lipid profile. All adult members of the WellMed Medical Management, Inc. managed care health plan diagnosed with IHD or CHF, and continuously enrolled between July 1, 2006 and June 30, 2008, were included in the study. Cases were defined as those who had at least one comprehensive lipid test (the VAP [vertical auto profile] ultracentrifuge test) during this period (n=1767); they were compared to those who had no lipid testing or traditional standard lipid testing only (controls, n=289). The VAP test provides standard profile results along with LDL density (i.e., Pattern A buoyant vs. Pattern B dense), intermediate-density lipoprotein, HDL subtypes, very-low-density lipoprotein density, and Lp(a). In this study univariate statistics were analyzed to describe the groups, and bivariate tests or chi-squares examined differences between the two cohorts. Multivariate regression analyses were performed to control for potential confounders. Despite the several limitations addressed in this study the authors noted that prescription use and frequency of lipid measurement suggested improved control resulting from a targeted approach to managing specific dyslipidemias. The authors also note that further studies using prospective and randomized controlled designs are needed to further assess the impact of comprehensive lipid profiling on care management, and to better understand what aspects of therapy appear to be most influenced by lipid findings and lead to the greatest improvement in health and economic outcomes.
Measurement of LDL Particle Concentration (Number of particles)
Otvos et al. (2011) used data from the Multi-Ethnic Study of Atherosclerosis (MESA) a multicenter cohort initiated by the National Heart, Lung and Blood Institute to characterize subclinical atherosclerosis and its progression. The cohort included 6814 study participants. Differences between LDL cholesterol and particle concentration and their relationship to incident cardiac events among those with concordant and discordant levels were evaluated. The cohort was followed for incident CVD events a mean of 5.5 years. Incident cardiac disease included myocardial infarction, coronary heart disease death, angina, stroke, stroke death, other atherosclerotic or cardiovascular death. Both LDL and LDL particles were associated with incident disease overall; when the levels disagreed only the LDL particle was associated with incident CVD. A consistent relationship was noted with intima media thickness and LDL particle rather than with LDL. The authors note that the relevance of these findings to the management of risk for CVD deserves additional study.
The National Lipid Association (NLA) (Davidson, 2011), convened a panel of clinical experts to evaluate the use of selected biomarkers in clinical practice as either tools to improve risk assessment or as markers to adjust therapy once a decision to treat had been made. The authors note that the greatest usefulness of LDL-P (and Apo B) appears to be in patients for whom LDL-C, and to a lesser degree, non-HDL-C, do not provide a reliable indication of the burden of circulating atherogenic particles. In such patients, available data and expert panel recommendations support consideration of LDL-P (or Apo B) as a target of therapy (in addition to LDL-C and non-HDL-C) to adjudicate the adequacy of LDL-lowering therapy. The authors note: “Additional research is needed to more clearly define optimal treatment targets for LDL-P. Given the prevalence and magnitude of discordance between cholesterol and particle number measures of LDL burden, additional research is needed to more clearly define settings in which a policy of treating to LDL-P (or Apo B) goals might produce more favorable outcomes than the alternative of treating to LDL-C and non-HDL-C goals.”
The American College of Cardiology/American Heart Association (ACCF/AHA) (Greenland; 2010)
ACCF/AHA published guidelines in 2010 for the assessment of cardiovascular risk in asymptomatic patients. These guidelines included recommendations on measurement of some non-traditional lipid and apolipoproteins in cardiovascular risk assessment. Apo-B, apo-A, the ratio of apoB/apo-A, lipoprotein(a), lipid particle size and lipid density were specifically addressed. Measurement of these specific lipid parameters were not recommended for cardiovascular risk assessment in asymptomatic adults. Class III: No Benefit. Level of Evidence: C.
Academy of the American Association for Clinical Chemistry (NACB) – (Myers, 2009)
Recommendations for LDL Subclasses and Particle Size
- Lipoprotein subclasses, especially the number or concentration of small, dense LDL particles, have been shown to be related to the development of initial CHD events, but the data analyses of existing studies are generally not adequate to show added benefit over standard risk assessment for primary prevention. Classification of recommendation: III (lipoprotein subclass determination is not recommended). Level of evidence: A
- There are insufficient data that measurement of lipoprotein subclasses over time is useful to evaluate the effects of treatments. Classification of recommendation: III Level of evidence: C
- Several methods are available to assess lipoprotein subclasses. Standardization is needed for this technology. Classification of recommendation: IIa Level of evidence: C
Adult Treatment Panel III (ATP III) recommendations for cholesterol management developed by the National Cholesterol Education Program (NCEP)
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) launched the National Cholesterol Education Program (NCEP) in November 1985 with the most recent update released in 2004. Current guidelines maintain that total LDL is the primary target of therapy in the ATP III recommendations. Presently, the NHLBI has convened expert panels to develop new clinical practice guidelines on high blood cholesterol as well as high blood pressure, and obesity, and three work groups to examine the crosscutting issues of risk assessment, lifestyle, and implementation. Common methods are being used by each of the groups to enable future development of integrated cardiovascular risk reduction guidelines. The draft guidelines are expected to be available for public review and comment in 2012.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.