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1.  Favorable Effects of Insulin Sensitizers Pertinent to Peripheral Arterial Disease in Type 2 Diabetes 
Diabetes Care  2013;36(10):3269-3275.
OBJECTIVE
The aim of this manuscript was to report the risk of incident peripheral arterial disease (PAD) in a large randomized clinical trial that enrolled participants with stable coronary artery disease and type 2 diabetes and compare the risk between assigned treatment arms.
RESEARCH DESIGN AND METHODS
The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomly assigned participants to insulin sensitization (IS) therapy versus insulin-providing (IP) therapy for glycemic control. Results showed similar 5-year mortality in the two glycemic treatment arms. In secondary analyses reported here, we examine the effects of treatment assignment on the incidence of PAD. A total of 1,479 BARI 2D participants with normal ankle-brachial index (ABI) (0.91–1.30) were eligible for analysis. The following PAD-related outcomes are evaluated in this article: new low ABI ≤0.9, a lower-extremity revascularization, lower-extremity amputation, and a composite of the three outcomes.
RESULTS
During an average 4.6 years of follow-up, 303 participants experienced one or more of the outcomes listed above. Incidence of the composite outcome was significantly lower among participants assigned to IS therapy than those assigned to IP therapy (16.9 vs. 24.1%; P < 0.001). The difference was significant in time-to-event analysis (hazard ratio 0.66 [95% CI 0.51–0.83], P < 0.001) and remained significant after adjustment for in-trial HbA1c (0.76 [0.59–0.96], P = 0.02).
CONCLUSIONS
In participants with type 2 diabetes who are free from PAD, a glycemic control strategy of insulin sensitization may be the preferred therapeutic strategy to reduce the incidence of PAD and subsequent outcomes.
doi:10.2337/dc12-2265
PMCID: PMC3781574  PMID: 23735723
2.  Race/Ethnic Disparities in Risk Factor Control and Survival in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial 
The American journal of cardiology  2013;112(9):10.1016/j.amjcard.2013.05.071.
This study sought to evaluate the impact of race/ethnicity on cardiovascular risk factor control and on clinical outcomes in a setting of comparable access to medical care. The BARI 2D trial enrolled 1,750 participants from the United States and Canada that self-reported either White non-Hispanic (n = 1,189), Black non-Hispanic (n = 349), or Hispanic (n = 212) race/ethnicity. Participants had type 2 diabetes and coronary artery disease and were randomized to cardiac and glycemic treatment strategies. All patients received intensive target-based medical treatment for cardiac risk factors. Average follow-up was 5.3 years. Kaplan-Meier survival curves and Cox proportional hazards regression models were constructed to assess potential differences in mortality and cardiovascular outcomes across racial/ethnic groups. Long-term risk of death and death/myocardial infarction/stroke did not vary significantly by race/ethnicity (5-year death: 11.0% Whites, 13.7% Blacks, 8.7% Hispanics, p = 0.19; adjusted hazard ratio 1.18 Black versus White, 95% confidence interval 0.84 to 1.67, p = 0.33 and 0.82 Hispanic versus White, 95% confidence interval 0.51 to 1.34, p = 0.43). Among the 1,168 patients with suboptimal risk factor control at baseline, the ability to attain better risk factor control during the trial was associated with higher 5-year survival (71%, 86% and 95% for patients with 0 or 1, 2, and 3 factors in control, respectively, p <0.001); this pattern was observed within each race/ethnic group. In conclusion, significant race/ethnic differences in cardiac risk profiles that persisted during follow-up did not translate into significant differences in 5-year death or death/MI/stroke.
doi:10.1016/j.amjcard.2013.05.071
PMCID: PMC3837550  PMID: 23910429
3.  Impact of Glycemic Control Strategies on the Progression of Diabetic Peripheral Neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort 
Diabetes Care  2013;36(10):3208-3215.
OBJECTIVE
The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN).
RESEARCH DESIGN AND METHODS
DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score >2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates.
RESULTS
Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P < 0.01).
CONCLUSIONS
Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.
doi:10.2337/dc13-0012
PMCID: PMC3781573  PMID: 23757426
4.  The effect of exercise training on ankle-brachial index in type 2 diabetes 
Atherosclerosis  2013;230(1):125-130.
Introduction
Though being physically active has associated with a healthier ankle-brachial index (ABI) in observational studies, ABI usually does not change with exercise training in patients with peripheral artery disease (PAD). Less is known about the effect of exercise training on ABI in patients without PAD but at high risk due to the presence of type 2 diabetes (T2DM).
Methods
Participants (n=140) with uncomplicated T2DM, and without known cardiovascular disease or PAD, aged 40–65 years, were randomized to supervised aerobic and resistance training 3 times per week for 6 months or to a usual care control group. ABI was measured before and after the intervention.
Results
Baseline ABI was 1.02±0.02 in exercisers and 1.03±0.01 in controls (p=0.57). At 6 months, exercisers vs. controls improved ABI by 0.04±0.02 vs. −0.03±0.02 (p=0.001). This change was driven by an increase in ankle pressures (p<0.01) with no change in brachial pressures (p=0.747). In subgroup analysis, ABI increased in exercisers vs. controls among those with baseline ABI<1.0 (0.14±0.03 vs. 0.02±0.02, p=0.004), but not in those with a baseline ABI≥1.0 (p=0.085). The prevalence of ABI between 1.0–1.3 increased from 63% to 78% in exercisers and decreased from 62% to 53% in controls. Increased ABI correlated with decreased HbA1c, systolic and diastolic blood pressure, but the effect of exercise on ABI change remained significant after adjustment for these changes (β=0.061, p=0.004).
Conclusion
These data suggest a possible role for exercise training in the prevention or delay of PAD in T2DM, particularly among those starting with an ABI <1.0.
doi:10.1016/j.atherosclerosis.2013.07.002
PMCID: PMC3775271  PMID: 23958264
exercise; peripheral artery disease; ankle-brachial index; type 2 diabetes
5.  Impact of left ventricular function and the extent of ischemia and scar by stress myocardial perfusion imaging on prognosis and therapeutic risk reduction in diabetic patients with coronary artery disease: Results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial 
Background
The Bypass Angioplasty Revascularization Investigation 2 Diabetes trial demonstrated similar long-term clinical effectiveness of revascularization (REV) and intensive medical (MED) therapy. Comparisons of post-intervention ischemic burden have not been explored but are relevant to treatment decisions. This study examined differences in 1-year stress myocardial perfusion SPECT (MPS) abnormalities by randomized treatment.
Methods
MPS was performed in 1,505 patients at 1-year following randomization. MPS images were analyzed (masked to treatment) by a Nuclear Core Laboratory using a quantitative percent (%) of total, ischemic, and scarred myocardium. Cox proportional hazards models were used to estimate the relationship between MPS variables and trial endpoints.
Results
At 1-year, nearly all REV patients underwent the assigned procedure; while 16% of those randomized to MED received coronary REV. Patients randomized to REV exhibited fewer stress perfusion abnormalities than MED patients (P < .001). CABG patients had more frequent ischemic and scarred myocardium encumbering ≥5% of the myocardium when compared to those receiving PCI. Patients randomized to MED had more extensive ischemia and the median % of the myocardium with perfusion abnormalities was lower following REV (3% vs 9%, P = .01). A total of 59% of REV patients had no inducible ischemia at 1-year compared to 49% of MED patients (P < .001). Within the CABG stratum, those randomized to MED had the greatest rate of ischemic (P = .032) and scarred (P = .017) perfusion abnormalities. At 1-year, more extensive and severe stress myocardial perfusion abnormalities were associated with higher 5-year rates of death and a combined endpoint of cardiac death or myocardial infarction (MI) rates (11.3%, 8.1%, 6.8%, for ≥10%, 5%-9.9%, and 1-4.9% abnormal myocardium at stress, respectively, P < .001). In adjusted models, selected MPS variables were significantly associated with an increased hazard of cardiac death or MI (hazard ratio = 1.11 per 5% increase in abnormal myocardium at stress, P = .004).
Conclusions
Patient management strategies that focus on ischemia resolution can be useful to guide the efficacy of near-term therapeutic approaches. A 1-year post-therapeutic intervention myocardial perfusion scan provides important information regarding prognosis in stable CAD patients with diabetes. (J Nucl Cardiol 2012;19:658–69.)
doi:10.1007/s12350-012-9548-3
PMCID: PMC4135719  PMID: 22527794
Diabetes; clinical trials; myocardial perfusion imaging; ischemia
6.  Effects of weight loss and insulin reduction on arterial stiffness in the SAVE trial 
Background
Chronic arterial stiffness contributes to the negative health effects of obesity and insulin resistance, which include hypertension, stroke, and increased cardiovascular and all-cause mortality. Weight loss and improved insulin sensitivity are individually associated with improved central arterial stiffness; however, their combined effects on arterial stiffness are poorly understood. The purpose of this study was to determine how insulin levels modify the improvements in arterial stiffness seen with weight loss in overweight and obese young adults.
Methods
To assess the effects of weight loss and decreased fasting insulin on vascular stiffness, we studied 339 participants in the Slow the Adverse Effects of Vascular Aging (SAVE) trial. At study entry, the participants were aged 20–45, normotensive, non-diabetic, and had a body-mass index of 25–39.9 kg/m2. Measures of pulse wave velocity (PWV) in the central (carotid-femoral (cfPWV)), peripheral (femoral-ankle (faPWV)), and mixed (brachial-ankle (baPWV)) vascular beds were collected at baseline and 6 months. The effects of 6-month change in weight and insulin on measures of PWV were estimated using multivariate regression.
Results
After adjustment for baseline risk factors and change in systolic blood pressure, 6-month weight loss and 6-month change in fasting insulin independently predicted improvement in baPWV but not faPWV or cfPWV. There was a significant interaction between 6-month weight change and change in fasting insulin when predicting changes in baPWV (p < 0.001). Individuals experiencing both weight loss and insulin reductions showed the greatest improvement in baPWV.
Conclusions
Young adults with excess weight who both lower their insulin levels and lose weight see the greatest improvement in vascular stiffness. This improvement in vascular stiffness with weight loss and insulin declines may occur throughout the vasculature and may not be limited to individual vascular beds.
Trial registration
NCT00366990
doi:10.1186/1475-2840-11-114
PMCID: PMC3468408  PMID: 22998737
Pulse wave velocity; Insulin; Weight loss and arterial stiffness

Results 1-6 (6)