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Blue Cross and Blue Shield of Montana (BCBSMT) considers determination of the apolipoprotein E (apo E) genotype or phenotype in the risk assessment and management of cardiovascular disease experimental, investigational and unproven.
This policy was developed in 2013 with searches of scientific literature through January 2013. This section of the current policy has been substantially revised. The following is a summary of the key literature to date.
Apo E as a Predictor of Cardiovascular Disease
A large body of research has established a correlation between lipid levels and the underlying apo E genotype. For example, in population studies, the presence of an apo e2 allele is associated with the lowest cholesterol levels and the apo e4 allele is associated with the highest levels. (1)
Numerous studies have focused on the relationship between genotype and physiologic markers of atherosclerotic disease. A number of small- to medium-sized cross-sectional and case-control studies have correlated apo E with surrogate outcomes such as cholesterol levels, markers of inflammation, or carotid intima-media thickness. (2-7) These studies have generally shown a relationship between apo E and these surrogate outcomes. Other studies have suggested that carriers of apo e4 are more likely to develop signs of atherosclerosis independent of total and LDL-cholesterol levels. (8-11)
Some larger observational studies have correlated apo E genotype with clinical disease. The Atherosclerosis Risk in Communities (ARIC) study followed up 12,000 middle-aged individuals free of coronary artery disease (CAD) at baseline for 10 years. (12) This study reported that the e3/2 genotype was associated with carotid artery atherosclerosis after controlling for other atherosclerotic risk factors. Volcik et al. reported that apo E polymorphisms were associated with LDL levels and carotid intima-media thickness but were not predictive of incident CAD. (13)
A meta-analysis published by Bennet and colleagues (14) summarized the evidence from 147 studies on the association of apo E genotypes with lipid levels and cardiac risk. Eighty-two studies included data on the association of apo E with lipid levels, and 121 studies reported the association with clinical outcomes. The authors estimated that patients with the apo e2 allele had LDL levels that were approximately 31% less compared to patients with the apo e4 allele. When compared to patients with the apo e3 allele, patients with apo e2 had an approximately 20% decreased risk for coronary events (OR: 0.80; 95% CI: 0.70–0.90). Patients with the apo e4 had an estimated 6% higher risk of coronary events that was of marginal statistical significance (OR: 1.06; 95% CI: 0.99–1.13).
Apo E as a Predictor of Response to Therapy
Apo E has been investigated as a predictor of response to therapy by examining apo E alleles in the intervention arm(s) of lipid-lowering trials. Some data suggest that patients with an apo e4 allele may respond better to diet-modification strategies. (15, 16) Other studies have suggested that response to statin therapy may vary with apo E genotype and that the e2 allele indicates greater responsiveness to statins. (15, 17)
Chiodini et al. (18) examined differential response to statin therapy according to apo E genotype, by reanalyzing data from the GISSI study according to apo E genotype. GISSI was an RCT comparing pravastatin with placebo in 3,304 Italian patients with previous myocardial infarction (MI). Patients with the apo e4 allele treated with statins had a greater response to treatment as evidenced by lower overall mortality (1.85% vs. 5.28%, respectively, p=0.023), while there was no difference in mortality for patients who were not treated with statins (2.81% vs. 3.67%, respectively, p=0.21). This study corroborates results reported in previous studies but does not provide evidence to suggest that changes in treatment should be made as a result of apo E genotype.
For the 2009 policy update, additional published studies were identified that evaluated apo E genetic status as a predictor of response to lipid-lowering therapy. Donnelly et al. (19) reported on 1,383 patients treated with statins from the Genetics of Diabetes Audit and Research in Tayside, Scotland (Go-DARTS) database. The researchers reported on the final LDL levels and percent of patients achieving target LDL according to apo E genetic status. LDL levels following treatment were lower for patients who were homozygous for apo e2, compared to patients homozygous for apo e4 (0.6 +/- 0.5 mmol/L vs. 1.7 +/- 0.3 mmol/L, p<0.001). All patients who were homozygous for apo e2 reached their target LDL level, compared to 68% of patients homozygous for apo e4 (p<0.001).
Vossen et al. (20) evaluated response to diet and statin therapy by apo e status in 981 patients with CAD who were enrolled in a cardiac rehabilitation program. These authors reported that patients with an apo e4 allele were more responsive to both diet and statin therapy than were patients with an apo e2 allele. The overall response to treatment was more dependent on baseline LDL levels than apo e genetic status, with 30–47% of the variation in response to treatment explained by baseline LDL, compared to only 1% of the variation explained by apo E status.
The evidence suggests that apo E genotype may be associated with lipid levels and CAD but is probably not useful in providing additional clinically relevant information beyond established risk factors. Apo E is considered a relatively poor predictor of CAD, especially when compared to other established and emerging clinical variables and does not explain a large percent of the inter-individual variation in total cholesterol (TC) and LDL levels. Moreover, apo E has not been incorporated into standardized cardiac risk assessment models and was not identified as one of the important “emerging risk factors” in the most recent ATP III recommendations.
The evidence on response to treatment indicates that apo E genotype may be a predictor of response to statins and may allow clinicians to better gauge an individual’s chance of successful treatment, although not all studies are consistent in reporting this relationship. At present, it is unclear how this type of information will change clinical management. Dietary modifications are a universal recommendation for those with elevated cholesterol or LDL levels, and statin drugs are the overwhelmingly preferred agents for lipid-lowering therapy. It is unlikely that a clinician will choose alternative therapies, even in the presence of an apo E phenotype that indicates diminished response.
None of the available evidence provides adequate data to establish that apo E genotype or phenotype improves outcomes when used in clinical care. Thus, given the uncertain impact on clinical outcomes, this testing is considered experimental, investigational and unproven.
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