Veterans Affairs Diabetes Trial Research Articles

Elevated apolipoprotein C3 augments diabetic kidney disease and associated atherosclerosis in type 2 diabetes.

Diabetes increases the risk of both cardiovascular disease and kidney disease. Notably, most of the excess cardiovascular risk in people with diabetes is in those with kidney disease. Apolipoprotein C3 (APOC3) is a key regulator of plasma triglycerides, and it has recently been suggested to play a role in both type 1 diabetes-accelerated atherosclerosis and kidney disease progression. To investigate if APOC3 plays a role in kidney disease in people with type 2 diabetes, we analyzed plasma levels of APOC3 from the Veterans Affairs Diabetes Trial. Elevated baseline APOC3 levels predicted a greater loss of renal function. To mechanistically test if APOC3 plays a role in diabetic kidney disease and associated atherosclerosis, we treated black and tan, brachyury, WT and leptin-deficient (OB; diabetic) mice, a model of type 2 diabetes, with an antisense oligonucleotide (ASO) to APOC3 or a control ASO, all in the setting of human-like dyslipidemia. Silencing APOC3 prevented diabetes-augmented albuminuria, renal glomerular hypertrophy, monocyte recruitment, and macrophage accumulation, partly driven by reduced ICAM1 expression. Furthermore, reduced levels of APOC3 suppressed atherosclerosis associated with diabetes. This suggests that targeting APOC3 might benefit both diabetes-accelerated atherosclerosis and kidney disease.

Haptoglobin phenotype and intensive glycemic control for coronary artery disease risk reduction in people with type two diabetes: The Veterans Affairs Diabetes Trial

BackgroundIntensive glycemic control reduced the risk of coronary artery disease (CAD) events among White ACCORD study participants with the haptoglobin (Hp)2-2 phenotype, and not among participants without the Hp2-2 phenotype. It is unknown whether these results persist in a population with more severe diabetes. MethodsHaptoglobin phenotype was measured in 1746 (97 %) samples from the Veterans Affairs Diabetes Trial (VADT) randomized controlled trial. Multivariable-adjusted Cox regression models assessed the effect of intensive therapy on CAD risk among participants with and without the Hp2-2 phenotype separately and when stratified within pre-specified race/ethnicity-based subgroups. Time-varying (achieved) HbA1c data (<7.0 % or ≥8.0 % compared to 7.0–7.9, updated every 3 months) were also analyzed in relation to CAD risk within each phenotype. Results567 (32.5 %) participants had the Hp2-2 phenotype. Compared to standard therapy, intensive glycemic control was not associated with risk of CAD among participants with the non-Hp2-2 or the Hp2-2 phenotype or for any race/ethnicity-based group. Compared to HbA1c of 7.0–7.9 %, having HbA1c <7.0 % was not associated with CAD risk for either phenotype or among any race/ethnicity-based group. Having HbA1c ≥8.0 % was associated with an increased risk of CAD among Hispanic participants without the Hp2-2 phenotype (HR= 3.61, 95 % CI: 1.54–8.41, p-interaction=0.53). ConclusionThe effect of intensive glycemic therapy on CAD events was not dependent on Hp phenotype in the VADT study of veterans with severe diabetes who may represent a population where Hp phenotype information would not be useful for personalizing diabetes management. However, further research is needed to determine if these results are conclusive.

Heterogeneous treatment effects of intensive glycemic control on major adverse cardiovascular events in the ACCORD and VADT trials: a machine-learning analysis

BackgroundEvidence to guide type 2 diabetes treatment individualization is limited. We evaluated heterogeneous treatment effects (HTE) of intensive glycemic control in type 2 diabetes patients on major adverse cardiovascular events (MACE) in the Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) and the Veterans Affairs Diabetes Trial (VADT).MethodsCausal forests machine learning analysis was performed using pooled individual data from two randomized trials (n = 12,042) to identify HTE of intensive versus standard glycemic control on MACE in patients with type 2 diabetes. We used variable prioritization from causal forests to build a summary decision tree and examined the risk difference of MACE between treatment arms in the resulting subgroups.ResultsA summary decision tree used five variables (hemoglobin glycation index, estimated glomerular filtration rate, fasting glucose, age, and body mass index) to define eight subgroups in which risk differences of MACE ranged from − 5.1% (95% CI − 8.7, − 1.5) to 3.1% (95% CI 0.2, 6.0) (negative values represent lower MACE associated with intensive glycemic control). Intensive glycemic control was associated with lower MACE in pooled study data in subgroups with low (− 4.2% [95% CI − 8.1, − 1.0]), intermediate (− 5.1% [95% CI − 8.7, − 1.5]), and high (− 4.3% [95% CI − 7.7, − 1.0]) MACE rates with consistent directions of effect in ACCORD and VADT alone.ConclusionsThis data-driven analysis provides evidence supporting the diabetes treatment guideline recommendation of intensive glucose lowering in diabetes patients with low cardiovascular risk and additionally suggests potential benefits of intensive glycemic control in some individuals at higher cardiovascular risk.

Association of low fasting C-peptide levels with cardiovascular risk, visit-to-visit glucose variation and severe hypoglycemia in the Veterans Affairs Diabetes Trial (VADT)

AimsLow C-peptide levels, indicating beta-cell dysfunction, are associated with increased within-day glucose variation and hypoglycemia. In advanced type 2 diabetes, severe hypoglycemia and increased glucose variation predict cardiovascular (CVD) risk. The present study examined the association between C-peptide levels and CVD risk and whether it can be explained by visit-to-visit glucose variation and severe hypoglycemia.Materials and methodsFasting C-peptide levels at baseline, composite CVD outcome, severe hypoglycemia, and visit-to-visit fasting glucose coefficient of variation (CV) and average real variability (ARV) were assessed in 1565 Veterans Affairs Diabetes Trial participants.ResultsThere was a U-shaped relationship between C-peptide and CVD risk with increased risk with declining levels in the low range (< 0.50 nmol/l, HR 1.30 [95%CI 1.05–1.60], p = 0.02) and with rising levels in the high range (> 1.23 nmol/l, 1.27 [1.00–1.63], p = 0.05). C-peptide levels were inversely associated with the risk of severe hypoglycemia (OR 0.68 [0.60–0.77]) and visit-to-visit glucose variation (CV, standardized beta-estimate − 0.12 [SE 0.01]; ARV, − 0.10 [0.01]) (p < 0.0001 all). The association of low C-peptide levels with CVD risk was independent of cardiometabolic risk factors (1.48 [1.17–1.87, p = 0.001) and remained associated with CVD when tested in the same model with severe hypoglycemia and glucose CV.ConclusionsLow C-peptide levels were associated with increased CVD risk in advanced type 2 diabetes. The association was independent of increases in glucose variation or severe hypoglycemia. C-peptide levels may predict future glucose control patterns and CVD risk, and identify phenotypes influencing clinical decision making in advanced type 2 diabetes.

A Clinical Conundrum: Intensifying Glycemic Control in the Presence of Advanced Diabetic Retinopathy.

Diabetic retinopathy (DR) is a potentially devastating complication of diabetes because of the risk of developing blindness. While therapies to prevent blindness are improving, in much of the world visual impairment continues to occur and impact on the lives of people with diabetes and the societies they live in (1,2). Glycemic control has been shown to provide protection from progression of DR (3–5), but there appear to be limits to that protection. Lowering A1C with a goal of achieving A1C <7% was no better than using a goal slightly above that (6.8% vs. 7.3%) when baseline A1C was ∼7.5% at the outset; this small decrement and small continued difference did not further protect the retina (6). Furthermore, if duration of diabetes is sufficiently long, even relatively tight control is eventually associated with development of DR (3–5), suggesting that there are other factors that mediate DR besides glycemia (7,8). Another factor that might limit the effect of improving glycemia to prevent progression is the presence of advanced DR at the time of initiating a glycemic control trial (9). The Veterans Affairs Diabetes Trial (VADT) did not show evidence of protection against DR progression, explained by the severity level of DR at the start of the trial (9), which was greater than in other comparable large trials (3–5). This month's issue of Diabetes Care contains another publication from the VADT with the major outcome focused on eye procedures that were performed subsequent to entry into …

Generalizability of heterogeneous treatment effects based on causal forests applied to two randomized clinical trials of intensive glycemic control

Purpose Machine learning is an attractive tool for identifying heterogeneous treatment effects (HTE) of interventions but generalizability of machine learning derived HTE remains unclear. We examined generalizability of HTE detected using causal forests in two similarly designed randomized trials in type II diabetes patients.Methods We evaluated published HTE of intensive versus standard glycemic control on all-cause mortality from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD) in a second trial, the Veterans Affairs Diabetes Trial (VADT). We then applied causal forests to VADT, ACCORD, and pooled data from both studies and compared variable importance and subgroup effects across samples.Results HTE in ACCORD did not replicate in similar subgroups in VADT, but variable importance was correlated between VADT and ACCORD (Kendall's tau-b 0.75). Applying causal forests to pooled individual-level data yielded seven subgroups with similar HTE across both studies, ranging from risk difference of all-cause mortality of -3.9% (95% CI -7.0, -0.8) to 4.7% (95% CI 1.8, 7.5).Conclusions Machine learning detection of HTE subgroups from randomized trials may not generalize across study samples even when variable importance is correlated. Pooling individual-level data may overcome differences in study populations and/or differences in interventions that limit HTE generalizability.

Eye Outcomes in Veteran Affairs Diabetes Trial (VADT) After 17 Years.

The objective of this study was to assess the long-term role of intensive glycemic control (INT) compared with standard glycemic control in accumulated eye procedures in patients with advanced diabetes. We compared the effect of treatment assignment on the accumulated number of eye procedures during the intervention period of the Veteran Affairs Diabetes Trial (VADT) (2000-2008) (median follow-up 5.6 years), the interim VADT follow-up study (2000-2013), and the full 17 years of VADT follow-up (2000-2017). We further analyzed data using various cardiovascular markers in two models. Model I included total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, systolic and diastolic blood pressure, and BMI. Model II included these covariates plus age and diabetic retinopathy (DR) severity score at baseline of the original trial. The final analysis of the data showed a mild but nonsignificant increase in number of procedures and in retinal or retinal plus cataract surgery during the three periods of the study. We found no significant benefit of INT during the original trial period in eye-related procedures, such as various procedures for DR, or during the 17 years of follow-up in cataract surgery. However, after adjusting data for some known vascular markers, the increase in the number of eye procedures with INT becomes more prevalent. This finding indicates that INT might not have a protective role in events requiring surgery in individuals with advanced diabetes.

375-P: Association of Low Fasting C-Peptide Levels and Visit-to-Visit Glucose Variability with Cardiovascular Risk in Type 2 Diabetes

C-peptide levels and visit to visit glucose variability (GV) are associated with cardiovascular disease (CVD) in both type 1 and type 2 diabetes (T2D). Although low C-peptide levels, reflecting beta cell failure, are associated with greater GV, the relationship between these two risk factors and CVD is unknown. We tested whether excess GV represents a link between low C-peptide levels and CVD in advanced T2D. Fasting C-peptide levels at baseline, GV (between visit coefficient of variation of fasting glucose levels) and composite CVD events were determined in 1,558 participants of the Veterans Affairs Diabetes Trial. Those in the lowest quartile of C-peptide levels had highest GV which persisted after adjustment for study arm (intensive vs. standard glycemic control), and clinical and demographic CVD risk factors (Figure). Higher CVD risk was associated with low baseline C-peptide levels and higher GV (Figure). In a combined multivariate model, low-C-peptide levels and increased GV both remained significant predictors of CVD risk (Figure). The present data indicate that beta-cell dysfunction in advanced T2D is associated with greater GV and increased CVD risk. Increased GV however does not appear to explain the association between beta cell dysfunction and higher CVD risk. Low C-peptide levels may be used as biomarker of both increased CVD risk and GV in individuals with advanced T2D. Disclosure J. Koska: None. D. S. Nuyujukian: None. G. D. Bahn: None. J. Zhou: None. P. Reaven: Research Support; Self; AstraZeneca, Dexcom, Inc. Funding U.S. Department of Veterans Affairs (CSP465); National Institutes of Health (R01067690, 5R01094775)

Fasting Glucose Variation Predicts Microvascular Risk in ACCORD and VADT.

The association of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) has been under-studied and remains unclear. We investigated this relationship using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Veteran Affairs Diabetes Trial (VADT). In ACCORD, fasting plasma glucose (FPG) was measured 1 to 3 times/year for up to 84 months in 10 251 individuals. In the VADT, FPG was measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose. The primary composite outcome was time to either severe nephropathy or retinopathy event and secondary outcomes included each outcome individually. To assess the association, we considered variability measures as time-dependent covariates in Cox proportional hazard models. We conducted a meta-analysis across the 2 trials to estimate the risk of fasting glucose variability as well as to assess the heterogenous effects of FPG variability across treatment arms. In both ACCORD and the VADT, the CV and ARV of FPG were associated with development of future microvascular outcomes even after adjusting for other risk factors, including measures of average glycemic control (ie, cumulative average of HbA1c). Meta-analyses of these 2 trials confirmed these findings and indicated FPG variation may be more harmful in those with less intensive glucose control. This post hoc analysis indicates that variability of FPG plays a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D.

1416-P: Blood Pressure Variability and Risk of Heart Failure Events in ACCORD and the VADT

We examined the relationship between blood pressure variability and risk of heart failure (HF) in two cohorts of type 2 diabetes (T2D) participating in trials of glucose and/or other risk factor management. 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. In ACCORD (Table), 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: 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 (e.g., for CV-SBP: those with baseline SBP ≥ 140, &amp;lt; 140, &amp;lt; 130 and &amp;lt; 120 mmHg, respectively had the following HRs; 1.03, 1.21, 1.50, and 1.69). Blood pressure variability is independently associated with HF risk and this relationship is most robust at low blood pressure in individuals with T2D. These results may have implications for optimizing blood pressure treatment strategies in those with T2D. Disclosure D.S. Nuyujukian: None. J. Koska: None. P. Reaven: Consultant; Self; Boston Heart Diagnostics, Intercept Pharmaceuticals, Inc. Research Support; Self; Bristol-Myers Squibb, Lysulin. J. Zhou: None. Funding National Institutes of Health (R01067690, R01094775)

Review of the veteran affairs diabetes trial: Lessons learned.

Despite robust evidence linking long-term hyperglycemia with cardiovascular complications, several large randomized trials found only modest benefits from intensive compared to standard glucose control. Of these trials, the Veteran Affairs Diabetes Trial (VADT), offers a unique long-term perspective in that there were analyses of outcomes at the end of the intervention trial, 5-years post-trial, and after 10-years post-trial. From the VADT and other large trials, we draw several valuable lessons that are relevant to the care of patients with type 2 diabetes. Intensive glucose control reduces development of nephropathy and retinopathy but not neuropathy, though evaluations of neuropathy are less consistent and conclusions regarding outcomes less reliable. While the VADT did not demonstrate reduction in cardiovascular outcomes at completion of the glucose lowering intervention, it did demonstrate a 17% reduction 5-years post-trial, which waned by 10-years post-trial observation. Of interest, the 5-year post trial period included 3 additional years of HbA1c separation between treatment groups which suggests that longer-term glucose control may be needed before benefits are seen. Other factors including hypoglycemia and increased glucose variation are also associated with cardiovascular events and are more prevalent during intensive glucose control, potentially lessening the benefit of lowering average glucose levels. Finally, intensive glucose control requires substantial effort from both the patient and clinician perspective. All of these factors must be kept in mind when considering the benefits of aggressive glucose control for each patient.

Glucose Variability and Diabetic Complications: Is It Time to Treat?

Increasing evidence is supporting the role of glucose variability (GV) in the development of diabetic complications, particularly cardiovascular (CV) ones (1). Many observational studies (1) and post hoc analyses of trials, such as ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) (2), DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events) (3), VADT (Veterans Affairs Diabetes Trial) (4), ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) (5), and EMPAREG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) (6), confirm that in type 2 diabetes long-term GV, in terms of fasting glucose and/or HbA1c variability, is correlated with an increased risk of both CV and microvascular complications. In this issue of Diabetes Care , a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial adds a further important piece of evidence on this topic (7). This analysis shows that HbA1c variability is a strong predictor of the total mortality in people with type 2 diabetes and a previous CV event or high risk for CV disease (7). It is worth mentioning that, with abundant measurements in the ACCORD trial, it has been possible for the first time to compare GV effects between the standard and intensive treatment arms. As is well known, increased mortality from all causes was reported in the intensive treatment arm of ACCORD, leading to the premature discontinuation of the study (8). In this post hoc analysis it emerges that HbA1c variability, together with a higher mean HbA1c level, is involved in the increased total mortality, particularly in the intensive treatment arm (7). The authors suggest …

Blood Pressure Variability and Risk of Heart Failure in ACCORD and the VADT.

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. 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. 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. 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.

5 Conservative treatment for PAD - Risk factor management.

5 Conservative treatment for PAD - Risk factor management.

Cardiovascular Outcome Trials in Type 2 Diabetes: What Do They Mean for Clinical Practice?

IN BRIEF Cardiovascular disease is the leading cause of morbidity and mortality in people with diabetes, and deaths from heart disease are two to four times higher among adults with type 2 diabetes. Trials such as the U.K. Prospective Diabetes Study, ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and VADT (Veteran's Affairs Diabetes Trial) produced mixed findings regarding whether intensive glycemic control results in improved cardiovascular (CV) outcomes for patients with diabetes. In response to concerns, including the CV safety of the thiazolidinedione rosiglitazone, the U.S. Food and Drug Administration and subsequently the European Medicines Agency issued guidance that trials should be conducted to prove that antihyperglycemic agents have acceptable CV risk profiles. In this article, the authors review the study designs and results of CV outcomes trials conducted with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists and discuss how these may affect clinical practice.

Serum pigment epithelium-derived factor: Relationships with cardiovascular events, renal dysfunction, and mortality in the Veterans Affairs Diabetes Trial (VADT) cohort

BackgroundTo determine if serum pigment epithelium-derived factor (PEDF) levels predict cardiovascular events, renal dysfunction and mortality in the Veterans Affairs Diabetes Study (VADT). MethodsPEDF 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. ResultsIn 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. ConclusionsOver 2-years, higher serum PEDF levels predicted advanced nephropathy in patients with type 2 diabetes.

554-P: Glycemic Variation Predicts Microvascular Risk in both ACCORD and VADT

The relationship of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) is controversial. Using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veteran Affairs Diabetes Trial (VADT), we investigated this relationship. In ACCORD, fasting glucose was measured every 4 months during the first year then annually for up to 84 months in 10251 individuals. In the VADT, fasting glucose were measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV). In Cox proportional hazard models, log CV in both ACCORD and the VADT were associated with development of future microvascular outcomes (composite of nephropathy and retinopathy) even after adjusting for other risk factors, including average glycemic control (Figure 1). Additional adjustment for severe hypoglycemic episodes did not account for the effect of glucose variability. This analysis indicates that variability of fasting glucose may play a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D. Disclosure J. Zhou: None. P. Reaven: Advisory Panel; Self; Boston Heart Diagnostics. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Funding National Institutes of Health

Development and Validation of PREDICT-DM: A New Microsimulation Model to Project and Evaluate Complications and Treatments of Type 2 Diabetes Mellitus.

Background: Type 2 diabetes mellitus (T2DM) affects ∼30 million people in the United States and ∼400 million people worldwide, numbers likely to increase due to the rising prevalence of obesity. We sought to design, develop, and validate PREDICT-DM (PRojection and Evaluation of Disease Interventions, Complications, and Treatments-Diabetes Mellitus), a state-transition microsimulation model of T2DM, incorporating recent data. Methods: PREDICT-DM is populated with natural history, risk factor, and outcome data from large-scale cohort studies and randomized clinical trials. The model projects diabetes-relevant outcomes, including cardiovascular and renal disease outcomes, and 5/10-year survival. We assessed the model validity against 62 endpoints from ACCORD (Action to Control Cardiovascular Risk in Diabetes), VADT (Veterans Affairs Diabetes Trial), and Look AHEAD trials via several comparative statistical methods, including mean absolute percentage error (MAPE), Bland-Altman graphs, and Kaplan-Meier curves. Results: For the comparison between simulated and observed outcomes of the intervention/control arms of the trial, the MAPE was 19%/25% (ACCORD), 29%/20% (VADT), and 42%/10% (Look AHEAD). The Bland-Altman's 95% limit of agreement was 0.02 (ACCORD), 0.03 (VADT), and 0.01 (Look AHEAD), and the mean difference (95% confidence interval) for the comparison between PREDICT-DM and trial endpoints was 0.0025 (-0.0018 to 0.0070) for ACCORD, -0.0067 (-0.0137 to 0.0002) for VADT, and -0.0033 (-0.0067 to 0.00002) for Look AHEAD, indicating an adequate model fit to the data. The model-driven Kaplan-Meier curves were similarly close to those previously published. Conclusions: PREDICT-DM can reasonably predict clinical outcomes from ACCORD and other clinical trials of U.S. patients with T2DM. This model may be leveraged to inform clinical strategy questions related to the management and care of T2DM in the United States.

Glycaemic variation is a predictor of all-cause mortality in the Veteran Affairs Diabetes Trial.

Diabetes is associated with substantially increased mortality. Classic risk factors explain a portion of the excess of mortality in type 2 diabetes. The aim of this study was to examine whether visit-to-visit variation in fasting glucose and haemoglobin A1c values in the Veteran Affairs Diabetes Trial were associated with all-cause mortality in patients with type 2 diabetes in addition to other comorbidity conditions, hypoglycaemic events and adverse lifestyle behaviours. The Veteran Affairs Diabetes Trial was a randomized trial that enrolled 1791 military veterans who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. During the Veteran Affairs Diabetes Trial, fasting glucose and haemoglobin A1c were measured quarterly for up to 84 months. Variability measures included coefficient of variation and average real variability. We found that variability measures (coefficient of variation and average real variability) of fasting glucose were predictors of all-cause mortality, even after adjusting for comorbidity index, mean fasting glucose and adverse lifestyle behaviour during the study. Accounting for severe hypoglycaemia did not weaken this association. Our analysis indicates that in the Veteran Affairs Diabetes Trial, longitudinal variation in fasting glucose was associated with all-cause mortality, even when accounting for standard measures of glucose control as well as comorbidity and lifestyle factors.

Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial.

OBJECTIVETo determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT).RESEARCH DESIGN AND METHODSThis post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 ± 9.0 years) with suboptimally controlled type 2 diabetes (HbA1c 9.4 ± 2.0%) of 11.5 ± 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA1c <7.0%) versus standard (HbA1c <8.5%) glucose control.RESULTSThe rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P < 0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012).CONCLUSIONSSevere hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all-cause mortality after severe hypoglycemia.