The Effect of Intensive Glucose Lowering on Lipoprotein Particle Profiles and Inflammatory Markers in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE: Intensive glucose-lowering therapy (INT) did not reduce macrovascular events in the recent randomized trials, possibly because it did not improve or worsen other traditional or novel cardiovascular risk factors. RESEARCH DESIGN AND METHODS: Standard plasma lipids, cholesterol content of lipoprotein subfractions, and plasma inflammatory and prothrombotic markers were determined in a subgroup of the Veterans Affairs Diabetes Trial (VADT) participants (n = 266) at baseline and after 9 months of INT or standard therapy. RESULTS: INT lowered glycated hemoglobin (by a median of 2% vs. a median of 0.7% by standard treatment; P < 0.0001); increased BMI (4 vs. 1%; P < 0.001), total HDL (9 vs. 4%; P < 0.05), HDL2 (14 vs. 0%; P = 0.009), LDL2 (36 vs. 1%; P < 0.0001), and plasma adiponectin (130 vs. 80%; P < 0.01); and reduced triglycerides (−13 vs. −4%; P = 0.02) and small, dense LDL4 (−39 vs. −13%; P < 0.001), but had no effect on levels of plasma apolipoproteins B-100 and B-48, C-reactive protein, interleukin-6, lipoprotein-associated phospholipase A2, myeloperoxidase, fibrinogen, and plasminogen activator inhibitor 1. Incident macrovascular events were associated with baseline interleukin-6 (hazard ratio per each quartile increase 1.33 [95% CI 1.06–1.66]), total LDL (1.25 [1.01–1.55]), apolipoprotein B-100 (1.29 [1.01–1.65]), and fibrinogen (1.26 [1.01–1.57]) but not changes in any cardiovascular risk factors at 9 months. CONCLUSIONS: INT was associated with improved adiponectin, lipid levels, and a favorable shift in LDL and HDL subfractions after 9 months. These data suggest that the failure of INT to lower cardiovascular outcomes occurred despite generally favorable changes in standard and novel risk factors early in the study.