William C. Duckworth’s research while affiliated with U.S. Department of Veterans Affairs and other places

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.).

Objective: To 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 methods: This 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. Results: The 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). Conclusions: Severe 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.

The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants. After the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality. The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years). After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. (Funded by the VA Cooperative Studies Program and others; VADT ClinicalTrials.gov number, NCT00032487.).

Rosiglitazone may be associated with increased risk of cardiovascular (CV) disease in patients with type 2 diabetes (T2D). We evaluated the relationship between patterns of rosiglitazone use and CV outcomes in the Veterans Affairs Diabetes Trial (VADT). Time-dependent survival analyses, case-control and 1:1 propensity matching approaches were used to examine this relationship in the VADT, a randomized controlled study that assessed the effect of intensive glycemic control on CV outcomes in 1791 T2D patients (mean age of 60.4 ± 9 years). Participants were recruited from December 1, 2000, through May 31, 2003, and were followed for 5 to 7.5 years (median 5.6) with the final visit by May 31, 2008. Rosiglitazone (4 mg and 8 mg daily) was initiated per protocol in both intensive-therapy and standard-therapy groups. Main outcomes include a composite CV outcome, CV death, and myocardial infarction (MI). Both daily doses of rosiglitazone were associated with lower risk for the primary composite CV outcome (HR 0.63; 95% CI 0.49-0.81 and HR 0.60; 95% CI 0.49-0.75, respectively) after adjusting for demographic and clinical covariates. A reduction of CV death was also observed (HR 0.25, p < 0.001, for both 4 and 8 mg/day rosiglitazone), however the effect on MI was less evident for 8 mg/day and not significant for 4 mg/day. In older patients with T2D the use of rosiglitazone was associated with decreased risk of the primary CV composite outcome and CV death. Rosiglitazone use did not lead to higher risk of MI. This article is protected by copyright. All rights reserved.