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Aims: Cognitive decline disproportionately affects older adult type 2 diabetes. We tested whether randomized intensive glucose-lowering reduces the rate(s) of cognitive decline in adults with advanced type 2 diabetes (mean: age, 60 years; diabetes duration, 11 years) from the Veterans Affairs Diabetes Trial. Methods: A battery of neuropsychological tests (digit span, digit symbol substitution (DSym), and Trails-making Part B (TMT-B)) was administered at baseline in ~1700 participants and repeated at year 5. Thirty-six risk factors were evaluated as predictors of cognitive decline in multivariable regression analyses.Results: The mean age-adjusted, DSym or TMT-B declined significantly in all study participants (P < 0.001). Randomized intensive glucose-lowering did not significantly alter the rate of cognitive decline. The final model of risk factors associated with 5-year decline in age-adjusted TMT-B included as significant predictors: longer baseline diabetes duration (beta = -0.028; P = 0.0057), lower baseline diastolic blood pressure (beta = 0.028; P < 0.001), and baseline calcium channel blocker medication use (beta = -0.639; P < 0.001). Higher baseline pulse pressure was significantly associated with decline in age-adjusted TMT-B suggesting a role for both higher systolic and lower diastolic blood pressure. Baseline thiazide diuretic use (beta= -0.549; P =0.015) was an additional significant predictor of 5-year decline in age-adjusted digit symbol score. Post-baseline systolic blood pressure-lowering was significantly associated (P < 0.001) with decline in TMT-B performance. There was a significant inverse association between post-baseline plasma triglyceride- lowering (P = 0.045) and decline in digit symbol substitution task performance.Conclusions: A five-year period of randomized intensive glucose-lowering did not significantly reduce the rate of cognitive decline in older-aged adults with type 2 diabetes. Systolic and diastolic blood pressure as well as plasma triglycerides were modifiable risk factors of the rate of cognitive decline in older adult type 2 diabetes.

Objective: Although blood pressure variability is increasingly appreciated as a risk factor for cardiovascular disease, its relationship with heart failure (HF) is less clear. We examined the relationship between blood pressure variability and risk of HF in two cohorts of type 2 diabetes participating in trials of glucose and/or other risk factor management.Research Design and Methods: Data were drawn from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Veterans Affairs Diabetes Trial (VADT). Coefficient of variation (CV) and average real variability (ARV) were calculated for systolic (SBP) and diastolic blood pressure (DBP) along with maximum and cumulative mean SBP and DBP during both trials.Results: In ACCORD, CV and ARV of SBP and DBP were associated with increased risk of HF, even after adjusting for other risk factors and mean blood pressure (e.g., CV-SBP: hazard ratio [HR] 1.15, P = 0.01; CV-DBP: HR 1.18, P = 0.003). In the VADT, DBP variability was associated with increased risk of HF (ARV-DBP: HR 1.16, P = 0.001; CV-DBP: HR 1.09, P = 0.04). Further, in ACCORD, those with progressively lower baseline blood pressure demonstrated a stepwise increase in risk of HF with higher CV-SBP, ARV-SBP, and CV-DBP. Effects of blood pressure variability were related to dips, not elevations, in blood pressure.Conclusions: Blood pressure variability is associated with HF risk in individuals with type 2 diabetes, possibly a consequence of periods of ischemia during diastole. These results may have implications for optimizing blood pressure treatment strategies in those with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: There is uncertainty about the importance of glycemic variability in cardiovascular complications in patients with type 2 diabetes. Using the Veterans Affairs Diabetes Trial (VADT), we investigated the association between variation in fasting glucose and glycated hemoglobin (HbA1c) over time and the incidence of cardiovascular disease (CVD) and assessed whether this is influenced by intensive or standard glycemic control.Research Design and Methods: During the VADT, fasting glucose and HbA1c were measured every 3 months for up to 84 months in 1,791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose and HbA1c. Overall mean glucose and HbA1c measures as well as their maximum and the most recent measurement were also examined.Results: Variability measures (CV and ARV) of fasting glucose were significantly associated with CVD even after adjusting for other risk factors, including mean fasting glucose. When considering separately groups receiving intensive and standard glycemic control, this relationship was evident in the intensive treatment group but not in the standard group. Additional adjustment for severe hypoglycemic episodes did not alter the relationship between fasting glucose variability and CVD. Interestingly, no HbA1c measures were associated with CVD after adjusting for multiple baseline risk factors.Conclusions: Our analysis indicates that in the VADT, variability of fasting glucose plays a role in the development of CVD complications beyond the influence of standard fasting glucose measures. The adverse consequences of fasting glucose variability on CVD appear greatest in those receiving intensive glucose control. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.Methods: We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.Results: There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).Conclusions: Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.). [ABSTRACT FROM AUTHOR]

Background: To determine if serum pigment epithelium-derived factor (PEDF) levels predict cardiovascular events, renal dysfunction and mortality in the Veterans Affairs Diabetes Study (VADT).Methods: PEDF was evaluated in relation to subsequent cardiovascular outcomes, mortality, and renal dysfunction (defined as urinary albumin creatinine ratio (ACR) ≥300 mg/g), or chronic kidney disease (CKD) stages 3 (eGFR<60 ml/min) or 4 (eGFR<60 and <30 ml/min respectively). PEDF was measured by ELISA on sera from 881 participants collected a median (range) of 1.7 (0-5.0) years post-baseline, and later, from 832 participants 4.0 (1.5-6.9) years post-baseline.Results: In 743 participants, PEDF was measured at both time-points. PEDF increased over time from (mean ± SD) 10.5 ± 4.03 to 11.0 ± 4.86 ng/ml (paired t-test p = 0.0092). Lower eGFR (p < 0.01), higher serum creatinine (p < 0.01) and urinary ACR (p < 0.01) were associated with increasing PEDF. Multivariate event time models included either one or two follow-up windows (i.e., between first and second PEDF measures; and, when available, from second PEDF measure until study-end). PEDF tertiles were not associated with cardiovascular events, but were significantly associated with all-cause mortality [HR = 2.00 (1.03, 3.89) comparing first to third tertile] in models adjusted for age, minority status, VADT treatment arm and prior cardiovascular event status. Higher PEDF levels also associated with development of kidney dysfunction with adjusted HRs (95% CI comparing third to first PEDF tertiles: 2.74 (1.71, 4.39) for stage 3 CKD; and 3.84 (95% CI: 1.17, 12.5) for stage 4 CKD.Conclusions: Over 2-years, higher serum PEDF levels predicted advanced nephropathy in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]