Aramesh Saremi

Progression of Vascular Calcification Is Increased With Statin Use in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE To determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Progression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM. RESULTS After adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.2 ± 0.5 mm3 vs. 4.2 ± 1.1 mm3; P < 0.01). AAC progression was in general not significantly increased with more frequent statin use; in a subgroup of participants initially not receiving statins, however, progression of both CAC and AAC was significantly increased in frequent statin users. CONCLUSIONS More frequent statin use is associated with accelerated CAC in T2DM patients with advanced atherosclerosis.

Association between IL-6 and the extent of coronary atherosclerosis in the veterans affairs diabetes trial (VADT)

AIMS The aim of the present study was to investigate the association of high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6) and lipoprotein-associated phospholipase A2 (Lp-PLA2) with the extent of calcified coronary atherosclerosis in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND RESULTS This is a cross-sectional study of 306 subjects aged 40years or older who were enrolled into the veterans affairs diabetes trial (VADT). Calcified coronary atherosclerosis was assessed using electron beam computed tomography scored by the Agatston method. Clinical parameters, traditional cardiovascular risk factors and plasma levels of CRP, IL-6 and Lp-PLA2 were measured at the time of the scan. Coronary artery calcium (CAC) scores increased stepwise across increasing categories of IL-6, but did not change across increasing categories of CRP and Lp-PLA2. After adjustment for traditional cardiovascular risk factors, IL-6 was significantly associated with CAC scores (p=0.05). The association between IL-6 and CAC was largely in those with lower (below the median) abdominal artery calcium (AAC) levels (p=0.04). CONCLUSIONS Despite a generally higher level of systemic inflammation in T2DM, the inflammatory marker IL-6 remained significantly associated with CAC score, particularly in those subjects with lower AAC scores.

Rates and Determinants of Coronary and Abdominal Aortic Artery Calcium Progression in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE To determine the predictors of progression of calcified atherosclerosis and the effect of intensive glycemic control on this process in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS As part of the Risk Factors, Atherosclerosis, and Clinical Events in Diabetes (RACED) substudy of the Veterans Affairs Diabetes Trial (VADT), 197 and 189 individuals with type 2 diabetes received baseline and follow-up computed tomographic scans for measurement of coronary and abdominal artery calcium, respectively. Standard and novel risk factors were assessed at baseline, and progression of calcified atherosclerosis was determined by several methods. Progression was defined both as a categorical (square root increase of volumetric scores ≥2.5 mm3) and continuous variable. In addition, annualized percent change of volume scores was determined. RESULTS After an average follow-up of 4.6 years, >75% of individuals demonstrated coronary (CAC) and abdominal artery calcification (AAC) progression. Progression increased with higher baseline calcium categories but was not influenced by standard risk factors. However, the albumin-to-creatinine ratio (ACR) (P = 0.02) and lipoprotein-associated phospholipase A2 (Lp-PLA2) (P = 0.01) predicted progression of CAC, and these results were not altered by adjustment for age and other traditional risk factors. Treatment assignment (intensive versus standard) within the VADT did not influence CAC or AAC progression, irrespective of baseline calcium category. CONCLUSIONS In patients with long-standing type 2 diabetes, baseline CAC, Lp-PLA2, and ACR predicted progression of CAC. Intensive glycemic control during the VADT did not reduce progression of calcified atherosclerosis.

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.

A Link Between Hypoglycemia and Progression of Atherosclerosis in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE To determine whether a link exists between serious hypoglycemia and progression of atherosclerosis in a substudy of the Veterans Affairs Diabetes Trial (VADT) and to examine whether glycemic control during the VADT modified the association between serious hypoglycemia and coronary artery calcium (CAC) progression. RESEARCH DESIGN AND METHODS Serious hypoglycemia was defined as severe episodes with loss of consciousness or requiring assistance or documented glucose <50 mg/dL. Progression of CAC was determined in 197 participants with baseline and follow-up computed tomography scans. RESULTS During an average follow-up of 4.5 years between scans, 97 participants reported severe hypoglycemia (n = 23) or glucose <50 mg/dL (n = 74). Serious hypoglycemia occurred more frequently in the intensive therapy group than in the standard treatment group (74% vs. 21%, P < 0.01). Serious hypoglycemia was not associated with progression of CAC in the entire cohort, but the interaction between serious hypoglycemia and treatment was significant (P < 0.01). Participants with serious hypoglycemia in the standard therapy group, but not in the intensive therapy group, had ∼50% greater progression of CAC than those without serious hypoglycemia (median 11.15 vs. 5.4 mm3, P = 0.02). Adjustment for all baseline differences, including CAC, or time-varying risk factors during the trial, did not change the results. Examining the effect of serious hypoglycemia by on-trial HbA1c levels (cutoff 7.5%) yielded similar results. In addition, a dose-response relationship was found between serious hypoglycemia and CAC progression in the standard therapy group only. CONCLUSIONS Despite a higher frequency of serious hypoglycemia in the intensive therapy group, serious hypoglycemia was associated with progression of CAC in only the standard therapy group.

Validity of the SMAST in two American Indian tribal populations.

The standardized evaluation of alcoholism and other psychopathologies in minority populations, particularly American Indians, has long been questioned. This study investigated the validity of one of the most commonly applied assessments for alcoholism—the Short Michigan Alcohol Screening Test (SMAST)—in two distinct American Indian tribal groups. We analyzed data collected from 1989 to 1995 from largely community representative samples of 456 Southwestern and 214 Plains Indians ages 21 or older. For comparison, alcohol dependence was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Third Edition–Revised (DSM-III-R) criteria from a detailed, modified version of the Schedule for Affective Disorders and Schizophrenia—Lifetime (SADS-L). Accuracy of the SMAST was quantified as sensitivity, specificity, likelihood ratios, and the area under the curve for receiver operating characteristics, using the DSM-III-R diagnosis as the reference. The standard SMAST cutoff score of ≥3 had a demonstrated sensitivity 86% to 95%, but did not perform well in terms of specificity (23%–47%). Significantly higher cutoff scores (≥5 for both genders in the Southwestern tribe and 8 and ≥6 for men and women in the Plains tribe) were required to demonstrate acceptable levels of specificity in both tribes. The findings suggest that the SMAST is not a valid tool to screen for alcohol misuse in these two tribal populations. The highly elevated and different thresholds required from one population to the next and from one gender to the next constitute a significant obstacle to the use of the instrument.

Advanced Glycation End Products, Oxidation Products, and the Extent of Atherosclerosis During the VA Diabetes Trial and Follow-up Study*

OBJECTIVE To determine whether plasma levels of advanced glycation end products and oxidation products play a role in the development of atherosclerosis in patients with type 2 diabetes (T2D) over nearly 10 years of the VA Diabetes Trial and Follow-up Study. RESEARCH DESIGN AND METHODS Baseline plasma levels of methylglyoxal hydroimidazolone, Nε-carboxymethyl lysine, Nε-carboxyethyl lysine (CEL), 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone (G-H1), 2-aminoadipic acid (2-AAA), and methionine sulfoxide were measured in a total of 411 participants, who underwent ultrasound assessment of carotid intima-media thickness (CIMT), and computed tomography scanning of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) after an average of 10 years of follow-up. RESULTS In risk factor–adjusted multivariable regression models, G-H1 was associated with the extent of CIMT and CAC. In addition, 2-AAA was strongly associated with the extent of CAC, and CEL was strongly associated with the extent of AAC. The combination of specific advanced glycation end products and oxidation products (G-H1 and 2-AAA) was strongly associated with all measures of subclinical atherosclerosis. CONCLUSIONS Specific advanced glycation end products and metabolic oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing T2D.

Advanced Glycation End Products, Oxidation Products, and Incident Cardiovascular Events in Patients With Type 2 Diabetes

OBJECTIVE The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone, and glyoxal hydroimidazolone) and two OP (2-aminoadipic acid and methionine sulfoxide [MetSO]) were measured at baseline in two intensive glucose-lowering studies: 1) a subcohort of the Veterans Affairs Diabetes Trial (VADT) (n = 445) and 2) a nested case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (n = 271). RESULTS Increased levels of several AGE and OP were associated with older age, decreased kidney function, previous CVD, and longer diabetes duration, but not with hemoglobin A1c. In the VADT, increased risk of incident CVD events (n = 107) was associated with lower MetSO after adjusting for age, race/ethnicity, sex, prior CVD event, kidney function, treatment assignment, and diabetes duration (hazard ratio [HR] 0.53; 95% CI 0.28–0.99; P = 0.047). Individuals with both low MetSO and high 3-deoxyglucosone hydroimidazolone concentrations were at highest risk for CVD (HR 1.70; P = 0.01). In the ACCORD study, those with incident CVD events (n = 136) had lower MetSO (by 14%; P = 0.007) and higher glyoxal hydroimidazolone and carboxymethyl lysine (by 18% and 15%, respectively; P = 0.04 for both); however, only the difference in MetSO remained significant after adjustment for prior CVD event (P = 0.002). CONCLUSIONS Lower levels of MetSO and higher levels of select AGE are associated with increased incident CVD and may help account for the limited benefit of intensive glucose lowering in type 2 diabetes.

The effect of intensive glucose lowering therapy among major racial/ethnic groups in the Veterans Affairs Diabetes Trial

OBJECTIVE To examine the effect of intensive glycemic control on cardiovascular disease events (CVD) among the major race/ethnic groups in a post-hoc analysis of the VADT. MATERIALS AND METHODS Participants included 1111 non-Hispanic Whites, 307 Hispanics and 306 non-Hispanic Blacks randomized to intensive or standard glucose treatment in VADT. Multivariable Cox proportional hazards models were constructed to assess the effect of intensive glucose treatment on CVD events among race/ethnic groups. RESULTS Mean age was 60.4 years and median follow-up was 5.6 years. By design, modifiable risk factors were managed equally well in both treatment arms and only differed modestly between race/ethnic groups. HbA(1c) decreased significantly from baseline with intensive glucose treatment in each race/ethnic group, with a trend for a greater response in Hispanics (P=0.02 for overall comparison between groups). Intensive glucose treatment was associated with reduced risk of CVD events for Hispanics but not for others (hazard ratios ranged from 0.54 to 0.75 for Hispanics whereas they were consistently close to 1 for others). Sensitivity analyses with different definitions of race/ethnicity or limited to individuals free of previous known CVD yielded similar results. CONCLUSIONS The results of these analyses support the hypothesis that race/ethnicity is worthy of consideration when tailoring intensive treatment for individuals with long-standing type 2 diabetes. However, additional studies are needed to confirm the findings of this post-hoc analysis.

Preliminary report: hepatic fat and inflammation in type 2 diabetes mellitus.

Although the association between inflammation and hepatic fat is fairly established, it remains unclear whether this association is independent of general measures of obesity and standard cardiovascular risk factors. Therefore, the aim of this study was to investigate the contribution of hepatic steatosis as an independent predictor of chronic inflammation in 281 subjects with type 2 diabetes mellitus. Reduced hepatic steatosis significantly (P < .01) correlated with C-reactive protein (r = -0.16) and adiponectin (r = 0.23). The association of hepatic steatosis with both C-reactive protein and adiponectin remained significant after adjustment for age, ethnicity, body mass index (or waist circumference), triglycerides, high-density lipoprotein, and total cholesterol. These data support the concept that accumulation of hepatic fat is related to enhanced inflammation in type 2 diabetes mellitus independent of general measures of obesity and standard cardiovascular risk factors.