December 2009 Clinical Laboratory News: Diagnostic Profiles

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December 2009: Volume 35, Number 12

Treatment in New-Onset Diabetes Does Not Reduce Inflammatory Biomarkers

New research indicates that in patients with recent-onset type 2 diabetes, treatment with insulin or metformin compared with placebo does not reduce inflammatory biomarker levels despite substantially improving glucose control (JAMA 2009;302:1186–1194). The findings may provide insight into the outcomes of three other studies in which intensive glycemic control did not lower the risk of incident cardiovascular disease (CVD), according to the authors.

The Lantus for C-reactive Protein Reduction in Early Treatment of Type 2 Diabetes (LANCET) trial involved 500 adult patients who had recently developed type 2 diabetes, with a median time since diagnosis of 2 years. The patients, who were recruited at 73 office practices, had suboptimal glycemic control, defined as HbA1c levels of 7% –10%, and elevated levels of high sensitivity C-reactive Protein (hsCRP) ≥2 mg/L. The study had four arms, with one-quarter of patients randomized respectively to placebo alone, placebo and insulin glargine, metformin alone, or metformin and insulin glargine. The primary endpoint was change in hsCRP level from baseline to 14 weeks. Secondary endpoints included change in HbA1c, interleukin-6 (Il-6) and soluble tumor necrosis factor receptor 2 (sTNFr2) levels, change in weight, and occurrence of marked hypoglycemia.

The researchers found significant reductions in glucose and HbA1c levels among patients who received active treatment versus placebo, with the greatest reductions in glycemic parameters among those allocated to combination therapy. HbA1c levels were almost normalized among patients in the active treatment groups, and all groups except patients who received insulin alone achieved modest weight loss. However, while all four treatment arms had lower hsCRP levels compared with baseline, there was no significant difference in the reductions and no active treatment arm achieved incremental benefits from reductions in hsCRP levels compared with placebo alone. Results were similar for IL-6 and sTNFr2 levels.

According to the authors, the findings offer a potential explanation for other recent studies which did not observe a link between intensive glycemic control and lower risk of incident CVD despite epidemiologic evidence of a graded association between hyperglycemia and future CVD events. The authors speculate that the mechanisms of weight loss may have differed among the groups. Prior studies have found visceral fat to be more closely linked to subclinical inflammation than subcutaneous fat. The authors call for further investigation of the association between various diabetes treatments and change in weight and body fat distribution.

BNP, cTn Predictors of Adverse Outcomes in Acute Pulmonary Embolism

A recent meta-analysis found that raised levels of B-type natriuretic peptides (BNP) identified a subset of patients with acute pulmonary embolism (APE) who were at higher risk of adverse outcomes, and that among patients with elevated BNP levels, raised troponin (cTn) levels were an independent prognostic indicator (Thorax 2009; 64:869–875). The findings could have important implications for management of APE, according to the authors. Increases in BNP and NT-proBNP presumably are related to enhanced right ventricular shear stress and right ventricular dysfunction in patients with APE, while raised cTn T and I have been associated with higher mortality in APE. The goals of the analysis were to assess both the prognostic significance of BNP and NT-proBNP alone or in conjunction with cTn and the diagnostic accuracy of BNP in detecting right ventricular dysfunction in patients with APE.

The researchers analyzed 23 studies with 1,127 patients. They found that raised BNP levels were significantly associated with all-cause mortality, APE-related mortality, and serious adverse events. Among patients with elevated BNP levels, 46% also had raised cTn levels, and in these patients, the increased cTn levels were associated with increased risk for all-cause and APE-related mortality and serious adverse events. In contrast, patients with low BNP and cTn levels were at very low risk of complications.

Overall, 52% of patients with APE had raised BNP levels. About two-thirds of the studies assessed BNP levels using four different assays, while the others assessed NT-proBNP using the same assay. The various studies reported different thresholds, so in the meta-analysis, researchers used a range of thresholds to facilitate between-study comparisons. For BNP, the thresholds were 80–100 ng/mL with the Biosite Diagnostics assay, and 35–75 ng/mL for the Shionogi assay. In the case of NT-proBNP, the thresholds ranged from 600–1,000 ng/mL for the Roche assays. Four studies assessed cTn I levels, and two assessed cTn T levels. Three different assays were used with different thresholds ranging from 0.01–0.1 µg/L.

The researchers’ analysis of the link between BNP levels and risk of right ventricular dysfunction were limited due to significant heterogeneity among the studies evaluated. However, BNP appeared to have better sensitivity and specificity than NT-proBNP. Similar findings have been reported in a recent meta-analysis for the diagnosis of heart failure, according to the researchers.

The findings have implications for the management of APE in enabling risk stratification of APE patients. Those with increased BNP levels on admission are at higher risk, and those with raised levels of both BNP and cTn are “at particularly high risk of adverse outcomes,” according to the authors.

New Prediction Model Improves Diagnosis of Acute Heart Failure

A newly described and validated prediction model incorporating clinical assessment and N-terminal pro B-type natriuretic peptide (NT-pro BNP) levels has robust accuracy in diagnosing acute heart failure (AHF) (J Am Coll Cardiol 2009;54:1515–21). In patients with undifferentiated shortness of breath, the model “appears to quickly and reliably redirect the undecided clinician for diagnosing AHF,” according to the authors. The model also underscores the utility of measuring NT-proBNP as a continuous, rather than discrete, variable.

To develop the model, the researchers used data from a prior study that involved 534 patients who presented to the emergency department with undifferentiated shortness of breath, and who did not have acute myocardial infarction, renal failure, malignancy, or dypsnea that clearly was not AHF. After initial examination and review of chest x-ray and electrocardiogram, the emergency physician assigned a probability of AHF without having knowledge of NT-pro BNP levels and pursued standard clinical management. Two cardiologists subsequently judged the cases for AHF with full access to medical records but were blinded to NT-pro BNP results. The study population was then divided into low, intermediate, and high pre-test probably of AHF, and the clinicians’ impressions were compared with NT-pro BNP values. The researchers then calculated likelihood ratios for the diagnosis of AHF over a number of discrete and continuous NT-pro BNP ranges, with the likelihood ratio computed as the proportion of patients with AHF who had a result in the range divided by the proportion of patients without AHF who had a result in the range.

The investigators used an external data set from the N-Terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study to validate the model. They found that likelihood ratios for AHF with NT-pro BNP were 0.11 for cut-points <300 pg/mL, increasing to 3.43 for values 2,700 to 8,099 pg/mL, and 12.8 for values ≥8,100 pg/mL. When applied to data from the PRIDE study, the model appropriately reclassified 44% of patients with intermediate clinical probability to either low or high probability of AHF, with a minor (2%) inappropriate redirection. The authors suggest the findings demonstrate that the model can be used to appropriately direct physicians in a “significant number” of indeterminate cases.

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