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Objective— To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes. Methods and Results— CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly ( P =0.01) lower with pioglitazone treatment (4.76×10 –3 mm/year; 95% CI: 2.39×10 –3 –7.14×10 –3 mm/year) compared with placebo (9.69×10 –3 mm/year; 95% CI: 7.24×10 –3 –12.15×10 –3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA 1c , fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo ( P Conclusion— Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

The association of insulin resistance and hyperinsulinemia to blood pressure has remained controversial. We examined the association of insulinemia to hypertension and blood pressure using baseline measurements for participants of the Diabetes Prevention Program (DPP). The DPP is a multicenter randomized controlled trial of 3819 participants with impaired glucose tolerance, and is designed to evaluate interventions for the delay or prevention of type 2 diabetes. The relationship between hypertension and insulinemia is described overall and by ethnicity. The effects of demographics (age and gender), adiposity, and glucose on the relationship are also presented. Asian Americans and African Americans had a similarly high prevalence of hypertension as did whites; American Indians had a lower prevalence of hypertension. Among participants not on antihypertensive medications, systolic blood pressure was significantly (but weakly) correlated with fasting insulin ( r =0.12), homeostasis model assessment of insulin resistance (HOMA IR; r =0.13), and fasting proinsulin ( r =0.10) when adjusted for age and gender (all, P r =0.06, P =0.002; DBP: r =0.06, P

Background: Advanced glycation end products (AGEs), thought to be a measure of cumulative glycemic exposure and glycemia-induced vascular damage, are increased both in renal disease and diabetes. As AGE formation increases the stiffness of the arterial wall and vascular matrix AGEs interfere with nitric oxide action, AGEs may be an important link between renal and coronary artery disease (CAD). Skin intrinsic fluorescence (SIF) is a noninvasive marker of AGEs. We sought to determine if SIF was associated with CAD in type 1 diabetes and whether this relationship was independent of renal function and renal disease. Methods: SIF was measured on the volar area of the forearm of 112 subjects from the Pittsburgh Epidemiology of Diabetes Complications study and 60 subjects from MedStar Health Research Institute when mean age and diabetes duration were 48 and 36years, respectively. CAD was defined as a history of myocardial infarction, bypass surgery/revascularization, percutaneous coronary intervention or stenosis >50%. Overt nephropathy (ON) was defined as albumin excretion rate > 200 µg/min, spot urine albumin/creatinine > 300 ug/mg, or history of dialysis/ renal transplant. Cumulative glycemic exposure (updated mean A1c) was determined by averaging HbA1c values collected over follow-up (mean of 18 years in EDC and 10.3 years in MedStar). SIF and serum creatinine were natural log transformed before analyses. Odds ratios (OR) are expressed as per standard deviation change in a given variable. Results: Of the 172 participants, 30 had CAD, with an equal number in each sex. SIF levels were higher in those with CAD (p Conclusion: Skin intrinsic fluorescence is cross-sectionally associated with CAD, independent of renal function and updated mean A1c in subjects with type 1 diabetes.

Background: Concern has been raised that aggressive lowering of LDL-C may not be accompanied by reductions in particle number or apoB lipoprotein concentrations. The SANDS trial demonstrated that a group treated for 3 years to aggressive (AGG) targets of LDL-C ≤ 70 mg/dL and non-HDL-C ≤ 100 mg/dL had a decrease in atherosclerosis, as measured by regression of carotid intimal medial thickness (CIMT) and decreased mean arterial mass, compared with a standard group (STD) treated to LDL-C and non-HDL-C of 100 and 130 mg/dL, respectively. Methods: Participants were 499 type 2 diabetic men and women (average age 56 y) with no previous CVD events; 426 had all baseline and 36-mo lipoprotein variables. Mean baseline BMI (33kg/m 2 ), A1c (8.0%), and HDL-C (46mg/dl) did not change during the study. A standardized algorithm for lipid lowering was used in both groups; the number of hypolipidemic drugs (mean [SD]) was 1.5 [.75] and 1.2 [.73] in the AGG and STD groups, respectively. At baseline and 36 months, lipoprotein particle number (LDL-P and VLDL-P) was quantified by nuclear magnetic resonance, and plasma apoB by immunoassay. Results: There were significant decreases in apoB, LDL-P, VLDL-P, and VLDL size but not LDL size in the AGG vs STD groups. The decrease in LDL-P was reflected in all LDL fractions. In an ordered logit analyses, the probability of a decrease in CIMT was significantly related to decrease in LDL-C and separately to non-HDL-C (p Conclusion: Aggressively lowering LDL-C and non-HDL-C to targets of 70 and 100 mg/dL, respectively, was accompanied by a significant decrease in LDL-P and VLDL-P and a decline in total plasma apoB; changes in LDL-C and non-HDL-C were separately the best predictors of IMT decrease. The relationship of the associated decrease in carotid atherosclerosis to CVD events awaits longer term observation.