Intensive Glycemic Control Improves Long-term Renal Outcomes in Type 2 Diabetes in the Veterans Affairs Diabetes Trial (VADT).
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ABSTRACT:
SUBMITTER: Agrawal L
PROVIDER: S-EPMC6804611 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
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Intensive Glycemic Control Improves Long-term Renal Outcomes in Type 2 Diabetes in the Veterans Affairs Diabetes Trial (VADT).
Agrawal Lily L Azad Nasrin N Bahn Gideon D GD Reaven Peter D PD Hayward Rodney A RA Reda Domenic J DJ Emanuele Nicholas V NV
Diabetes care 20190923 11
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Project description:AIMS/HYPOTHESIS:We conducted an analysis of data collected during the Veterans Affairs Diabetes Trial (VADT) and the follow-up study (VADT-F) to determine whether intensive (INT) compared with standard (STD) glycaemic control during the VADT resulted in better long-term kidney outcomes. METHODS:VADT randomly assigned 1791 veterans from 20 Veterans Affairs (VA) medical centres who had type 2 diabetes mellitus and a mean HbA1c of 9.4 ± 2% (79.2 mmol/mol) at baseline to receive either INT or STD glucose control for a median of 5.6 years (randomisation December 2000 to May 2003; intervention ending in May 2008). After the trial, participants received routine care through their own physicians within the VA. This is an interim analysis of the VADT-F (June 2008 to December 2013). We collected data using VA and National databases and report renal outcomes based on serum creatinine, eGFR and urine albumin to creatinine ratio (ACR) in 1033 people who provided informed consent to participate in the VADT-F. RESULTS:By the end of the VADT-F, significantly more people who received INT treatment during the VADT maintained an eGFR >60 ml min-1 1.73 m-2 (OR 1.34 [95% CI 1.05, 1.71], p = 0.02). This benefit was most evident in those who were classified as at moderate risk (INT vs STD, RR 1.3, p = 0.03) or high risk (RR 2.3, p = 0.04) of chronic kidney disease on the Kidney Disease Improving Global Outcomes (KDIGO-CKD) at the beginning of VADT. At the end of VADT-F, significantly more people from the INT group improved to a low KDIGO risk category (RR 6.1, p = 0.002). During the VADT-F there were no significant differences between INT and STD for average HbA1c, blood pressure or lipid levels. CONCLUSIONS/INTERPRETATION:After just over 11 years of follow-up, there was a 34% greater odds of maintaining an eGFR of >60 ml min-1 1.73 m-2 and of improving the KDIGO category in individuals with type 2 diabetes who had received INT for a median of 5.6 years. VADT clinical trials.gov number: NCT 00032487.
| S-EPMC5747983 | biostudies-literature
Project description:ObjectiveBlood pressure (BP) control for renal protection is essential for patients with type 2 diabetes. Our objective in this analysis of Veterans Affairs Diabetes Trial (VADT) data was to learn whether on-study systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) affected renal outcomes measured as albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR).Research design and methodsThe VADT was a prospective, randomized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events. In this post hoc study, time-varying covariate survival analyses and hazard ratios (HR) were used to determine worsening of renal outcomes.ResultsCompared with SBP 105-129 mmHg, the risk of ACR worsening increased significantly for SBP 130-139 mmHg (HR 1.88 [95% CI 1.28-2.77]; P = 0.001) and for SBP ≥140 mmHg (2.51 [1.66-3.78]; P < 0.0001). Compared with a PP range of 40-49 mmHg, PP <40 was associated with significantly lowered risk of worsening ACR (0.36 [0.15-0.87]; P = 0.022) and PP ≥60 with significantly increased risk (2.38 [1.58-3.59]; P < 0.0001). Analyses of BP ranges associated with eGFR worsening showed significantly increased risk with rising baseline SBP and an interaction effect between SBP ≥140 mmHg and on-study A1C. These patients were 15% more likely than those with SBP <140 mmHg to experience eGFR worsening (1.15 [1.00-1.32]; P = 0.045) for each 1% (10.9 mmol/mol) A1C increase.ConclusionsSBP ≥130 mmHg and PP >60 mmHg were associated with worsening ACR. The results suggest that treatment of SBP to <130 mmHg may lessen ACR worsening. The interaction between SBP ≥140 mmHg and A1C suggests that the effect of glycemic control on reducing progression of renal disease may be greater in hypertensive patients.
| S-EPMC4170129 | biostudies-literature
Project description:ObjectiveIntensive 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 methodsStandard 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.ResultsINT 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.ConclusionsINT 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.
| S-EPMC3714508 | biostudies-literature
Project description:ObjectiveTo 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 methodsSerious 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.ResultsDuring 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 mm(3), 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.ConclusionsDespite 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.
| S-EPMC5317238 | biostudies-literature
Project description:ObjectiveTo test the hypothesis that high levels of plasminogen-activating inhibitor (PAI)-1 and fibrinogen at baseline were associated with the onset or progression of diabetic retinopathy (DR) during the Veterans Affairs Diabetes Trial (VADT).Research design and methodsThe VADT was an open-label, prospective, randomized controlled trial to test the effect of standard glycemic control (STD) compared with intensive control (INT) on cardiovascular events in patients with advanced type 2 diabetes mellitus (T2DM). Diabetic retinopathy (DR) outcomes were also collected. Incidence and progression of DR were assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later taken in 858 of a total of 1,791 participants who completed both eye examinations.ResultsAssignment to INT was not independently associated with decreased risk of onset of DR. However, after adjustment for multiple covariates, baseline level of PAI-1 was an independent risk factor for the onset of DR. The risk for incidence of DR increased by 12% for each 10 ng/dL increase in baseline PAI-1 concentration (odds ratio [OR] 1.012 [95% CI 1.00-1.024], P = 0.042). Assignment to INT was not independently associated with decreased risk of progression of DR. However, there was an interaction between glycemic treatment assignment and fibrinogen level at baseline. INT was associated with decreased progression of retinopathy in those with fibrinogen <296 mg/dL (OR 0.55 [95% CI 0.31-1.00], P = 0.03).ConclusionsThe results require confirmation but are consistent with greater hypercoagulabilty and inflammation, as measured by higher levels of PAI-1 and fibrinogen, being related to DR and responsiveness to INT.
| S-EPMC3898766 | biostudies-literature
Project description:ObjectiveThere 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 methodsDuring 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.ResultsVariability 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.ConclusionsOur 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.
| S-EPMC6150432 | biostudies-literature
Project description: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).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).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.
| S-EPMC2688903 | biostudies-literature
Project description: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.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 mm(3)) and continuous variable. In addition, annualized percent change of volume scores was determined.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 A(2) (Lp-PLA(2)) (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.In patients with long-standing type 2 diabetes, baseline CAC, Lp-PLA(2), and ACR predicted progression of CAC. Intensive glycemic control during the VADT did not reduce progression of calcified atherosclerosis.
| S-EPMC2992205 | biostudies-literature
Project description:ObjectiveThe Veterans Affairs Diabetes Trial (VADT) was a randomized, prospective, controlled trial of 1,791 patients with type 2 diabetes to determine whether intensive glycemic control would reduce cardiovascular events compared with standard control. The effect of intensive glycemic control and selected baseline variables on renal outcomes is reported.Research design and methodsBaseline mean age was 60.4 years, mean duration of diabetes was 11.5 years, HbA(1c) was 9.4%, and blood pressure was 132/76 mmHg. The renal exclusion was serum creatinine >1.6 mg/dL. Renal outcomes were sustained worsening of the urine albumin-to-creatinine ratio (ACR) and sustained worsening by one or more stages in the estimated glomerular filtration rate (eGFR).ResultsIntensive glycemic control did not independently reduce ACR progression but was associated with a significant attenuation in the progression of ACR in those who had baseline photocoagulation, cataract surgery, or both. The beneficial effect of intensive glycemic control increased with increasing BMI and with decreasing diastolic blood pressure (DBP). Intensive glycemic control was associated with less worsening of eGFR with increasing baseline ACR and insulin use. Baseline systolic blood pressure, triglycerides, and photocoagulation were associated with worsening of eGFR.ConclusionsIntensive glycemic control had no significant effect on the progression of renal disease in the whole cohort but was associated with some protection against increasing ACR in those with more advanced microvascular disease, lower baseline DBP, or higher baseline BMI and on worsening of eGFR in those with high baseline ACR.
| S-EPMC3161270 | biostudies-literature
Project description:OBJECTIVE:Connective tissue growth factor (CTGF), also known as CCN2, is a potent chemotactic and extracellular matrix-inducing matricellular protein that has been implicated in progression of inflammatory and fibroproliferative disorders. An emerging role of CTGF/CCN2 is that of a prosclerotic factor implicated in the development of cardiac disease. Our objective was to determine the role of CTGF/CCN2 as a predictor of cardiovascular events in type 2 diabetes in the Veterans Affairs Diabetes Trial (VADT) cohort. RESEARCH DESIGN AND METHODS:Levels of CTGF/CCN2 were measured in 952 VADT patients a median of 1.9 years after entry into the study. Participants were followed for an average of 3.3 years for vascular outcomes. CTGF/CCN2 categories were defined as below the detectable limit (referent, 54.5%), lower half of detectable values (22.8%), and upper half of detectable values (22.7%). Hazard ratios (HRs) for cardiovascular end points in relation to CTGF/CCN2 categories were calculated by Cox proportional hazards models. RESULTS:During follow-up, 4.8% had a myocardial infarction (MI), 6.9% had an MI or cardiovascular death, and 6.9% died. After adjustments by conventional risk factors, individuals in the highest category of CTGF/CCN2 were at higher risk of MI (HR 2.43 [95% CI 1.15, 5.14]), MI or cardiovascular death (HR 2.71 [95% CI 1.44, 5.08]), and all-cause mortality (HR 2.70 [95% CI 1.43, 5.08]) relative to individuals with CTGF below the detectable limit. CONCLUSIONS:Our study indicates that high levels of CTGF/CCN2 predict future MI and cardiovascular death in patients with type 2 diabetes.
| S-EPMC5860844 | biostudies-other