Preventative Cardiology
Emerging Cardiovascular Disease Biomarkers and Incident Diabetes Mellitus Risk in Statin-Treated Patients With Coronary Artery Disease (from the Treating to New Targets [TNT] Study)

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Whether biomarkers associated with cardiovascular disease risk also predict incident diabetes mellitus (DM) is unknown. Our objective was to determine if a panel of 18 biomarkers previously associated with risk of cardiovascular disease also predicts incident DM in statin-treated patients with coronary artery disease (CAD). The Treating to New Targets (TNT) study is a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of coronary heart disease events. Fasting plasma levels of standard lipids and of 18 emerging CAD risk biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in a random sample of 1,424 TNT patients. After exclusion of patients with DM at baseline (n = 253), 101 patients developed DM during the median follow-up of 4.9 years. Patients with incident DM had lower levels of total and high-molecular weight adiponectin, lipoprotein-associated phospholipase A2 (Lp-PLA2), soluble receptor of advanced glycation end products, and vitamin D compared with patients without incident DM. In contrast, insulin, soluble CD40 ligand, and soluble intercellular adhesion molecule-1 levels were higher in patients with incident DM compared with those without. Plasma levels of C-reactive protein, cystatin C, lipoprotein(a), monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, neopterin, N-terminal fragment of pro–B-type natriuretic peptide, osteopontin, and soluble vascular cell adhesion molecule-1 were comparable in patients with and without incident DM. After multivariate adjustment, total and high-molecular weight adiponectin as well as Lp-PLA2 were negatively associated with incident DM. Results of this study suggest that plasma lipids and some emerging CAD risk biomarkers, such as adiponectin and Lp-PLA2, may be useful for predicting incident DM in statin-treated patients with stable CAD.

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Methods

The study protocol and outcome measures for the Treating to New Targets (TNT) study have been published previously.5 In brief, patients with clinically manifest CAD commenced 8 weeks of open-label treatment with atorvastatin 10 mg/day. After this run-in period, 10,001 patients with low-density lipoprotein cholesterol levels <130 mg/dl (<3.4 mmol/L) were randomized in a double-blind design to therapy with either 10 mg or 80 mg of atorvastatin per day and followed for a median of 4.9 years.

Results

The clinical characteristics of the 3 study groups are presented in Table 1. Patients with incident DM during follow-up and those with DM at baseline had a higher mean BMI, mean systolic blood pressure, and higher prevalence of metabolic syndrome than those without DM at baseline and without incident DM during follow-up. These differences in clinical characteristics of study patients who did versus those who did not develop incident DM were comparable to what we have previously reported in the

Discussion

Our results suggest that plasma levels of several emerging biomarkers are either higher or lower in patients with incident DM compared with those without incident DM. However, after adjusting for DM risk factors, we found that only adiponectin and Lp-PLA2 remained independently associated with incident DM.

Many studies have tested the hypothesis that circulating biomarkers may predict incident DM.6 However, very few, if any, have tested this hypothesis in statin-treated patients with CAD. A

Disclosures

Dr. Arsenault holds a junior scholar award from the Fonds de recherche du Québec: Santé (FRQS). Dr. Arsenault has received consulting fees/honoraria from Pfizer. Dr. Kohli has received consulting fees/honoraria from Summer Street Research Partners, Consultant Live, Amgen, and Pfizer. Dr. Lambert has received consulting fees/honoraria from Pfizer Inc, Sanofi/Regerenon and Amgen. Dr. Waters has received consulting fees/honoraria from Pfizer Inc, Servier, Roche, Merck/Schering Plough, Biosante,

References (14)

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This study was funded by Pfizer.

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