September 2010 Clinical Laboratory News: Diagnostic Profiles

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September 2010: Volume 36, Number 9 

HDL-C Not a Predictor of Residual Cardiovascular Risk After Statin Therapy

New research indicates that HDL cholesterol (HDL-C) concentrations are not predictive of residual vascular risk among patients treated aggressively with statins who achieve very low levels of LDL cholesterol (LDL-C) (Lancet 2010;376:333–39). The findings come from a post-hoc analysis of data from the landmark Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which was published in 2008. JUPITER involved >17,800 people with baseline LDL-C levels <130 mg/dL, C- reactive protein levels ≥2.0 mg/L, and no history of cardiovascular disease who were randomly assigned to take daily either 20 mg of rosuvastatin or placebo. The study showed significantly favorable outcomes in the treatment arm, including a 44% reduction in major cardiovascular events at 2 years.

The researchers conducted the post-hoc analysis because even though statin therapy trials have consistently reported significant reductions in cardiovascular events, a residual vascular risk has been found in the active treatment arms of all such trials. Scientists have speculated that this residual risk might be explained in part because many patients have low HDL-C concentrations after statin therapy, suggesting that boosting HDL-C could be a target for therapy. The post-hoc JUPITER analysis sought to examine the relationship between HDL-C and residual cardiovascular risk.

The researchers found that in the placebo arm, HDL-C concentrations were strongly predictive of cardiovascular risk. However, there was no relationship between HDL-C and cardiovascular risk among patients in the treatment arm in whom LDL-C levels were very low, with median levels of 1.42 mmol/L. “Our data should not reduce enthusiasm for measurement of HDL-C concentration as part of an initial cardiovascular risk assessment… However, these primary prevention data… provide little evidence to support the hypothesis that HDL-C-levels predict risk of vascular events in the setting of high-dose statin therapy,” according to the authors.

More Questions About Intensive Glycemic Control in Type 2 Diabetes

A study of intensive glycemic therapy in type 2 diabetics found that this approach did not reduce the risk of advanced microvascular outcomes (Lancet 2010; 376: 419–430). However, it delayed the onset of albuminuria and some measures of eye complications and neuropathy. The findings suggest that “caution should be exercised in pursuit of a strategy of intensive glycemic control in patients with type 2 diabetes,” according to the authors.

The study reported results of predefined secondary microvascular outcomes involving participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which was an investigation of the cardiovascular effects of intense glycemic control in type 2 diabetes. ACCORD involved >10,000 patients with baseline HbA1c levels ≥7.5% who were assigned to intensive or standard glycemic therapy. Intensive therapy was stopped before the study’s end because of excessive mortality in that group, but patients were transitioned to standard therapy and followed for microvascular outcomes.

The researchers found that intensive glycemic therapy did not have a significant effect on advanced renal or eye complications or peripheral neuropathy. However, they observed reductions in albuminuria with intensive glycemic control. This benefit should be weighed against potential negative outcomes associated with intensive glycemic therapy previously reported from ACCORD, including higher total and cardiovascular-related deaths, weight gain, and severe hypoglycemia in patients at high risk of cardiovascular disease. 


DGP/tTG Proposed as Best Initial Test for Celiac Disease Diagnosis

An analysis of the diagnostic performance of serological tests for celiac disease (CD) suggests that the deamidated gliadin peptide (DGP)/tissue transglutaminase (tTG) assay should be considered as the best initial test in the workup of suspected CD (World J Gastroenterol 2010; 16:3144–25). The researchers also found that this assay, in combination with either IgA anti-tissue transglutaminase (a-tTG) or IgA anti-deamidated gliadin peptide antibody (a-DGP) assays, could obviate the need for duodenal biopsy in >92% of individuals with high- and low- pre-test probabilities for CD.

The study involved 679 individuals who underwent duodenal biopsy and had serological analysis using six assays that detect antibodies to tTG and DGP. The patients were designated as having a high- or low- pre-test risk for CD based on symptoms and prior diagnoses. The investigators aimed to determine the performance of a complete panel of CD-specific serological tests versus biopsy, analyze the performance of individual tests and two-test combinations, and explore the performance of serology-based algorithms that might obviate the need for biopsy. While the gold standard for CD diagnosis remains biopsy, the authors pointed out the limitations associated with the histological diagnosis of CD and the demonstrated high sensitivity and specificity of the various CD serological tests.

The researchers confirmed the presence of CD in 39.1% and 3.3% of high- and low-risk patients, respectively. Area under receiver operator characteristic curves (AUROC) for individual assays ranged from 0.968 to 0.999 in high-risk patients, but were not as robust in the low-risk group, ranging from 0.835 to 0.972. In evaluating combinations of the tests, the researchers reported AUROC ranges of 0.952–0.984 and 0.833–0.907 in the high- and low-risk groups, respectively.

The researchers also tested the performance of the various assays using different cutoffs. At lower cutoffs, the positive predictive value of tests in the low-risk group was as low as 17.6%. In addition, 17% of low-risk patients would be missed by all individual or combination serology tests. The researchers called for further validation of CD testing algorithms.


Pilot Study Supports Routine HPV DNA Testing as a Primary Screening Strategy

A feasibility study to evaluate human papillomavirus (HPV) DNA testing coupled with cervical cytology as a primary screening strategy for cervical cancer precursor lesions found that such an approach can improve prevention and control of this disease in populations where the efficacy of Pap cytology screening is inadequate (Cancer Causes Control DOI 10.1007/s10552-010-9598-2). The study, conducted in 12 federal entities in Mexico, could provide evidence for developing diagnosis and clinical management guidelines in high-risk geographical areas, according to the authors.

The study involved >50,000 women who had two cervical specimens collected during an initial recruitment visit, one for Pap testing and one for HPV DNA testing using a commercially available platform that detects 13 types of high-risk DNA. Of these, 89.9% had negative results by both methods; 7.9% had positive HPV-DNA but normal cytology results; 0.7% had both abnormal cytology and positive HPV-DNA results, while 1.5% had abnormal cytology but negative HPV-DNA results. Women in the latter two groups received colposcopy. The investigators found that the sensitivity of cervical cytology for detecting histologically confirmed moderate or severe dysplasia was 40% compared with 93.3% for HPV DNA testing, at a sensitivity of 97% versus 89.2%, respectively. The study supports the rationale for introducing HPV DNA testing into routine screening , according to the authors.

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