Profibrinolytic, Antithrombotic, and Antiinflammatory Effects of an Insulin-Sensitizing Strategy in Patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial

Abstract

Background Effects were compared in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of 2 mechanistically different strategies for treatment of hyperglycemia, insulin-sensitizing and insulin-providing strategies, on biomarker profiles reflecting the balance between fibrinolysis and thrombosis and the intensity of inflammation implicated in diabetic vasculopathy. Methods and Results A total of 2368 patients with type 2 diabetes mellitus and clinically stable, angiographically documented coronary artery disease were randomized to treatment with 1 of the 2 strategies and followed for an average of 5 years. Plasminogen activator inhibitor type 1 antigen and activity, tissue plasminogen activator antigen, fibrinogen, D-dimer, C-reactive protein, insulin, and hemoglobin A1c were assayed in blood samples acquired at baseline and at 12 regular intervals throughout the follow-up interval. Higher baseline D-dimer, fibrinogen, and C-reactive protein portended a poor prognosis in patients in both groups. In contrast to the insulin-providing strategy, the insulin-sensitizing strategy led to (1) lower plasma insulin; (2) lower plasminogen activator inhibitor type 1 antigen and activity and lower tissue plasminogen activator antigen (known to track with plasminogen activator inhibitor type 1); and (3) lower C-reactive protein and fibrinogen at all intervals after baseline (P<0.001 for each). Conclusions The insulin-sensitizing treatment strategy led to changes in biomarker profiles indicative of decreased insulin resistance, an altered balance between thrombosis and fibrinolysis favoring fibrinolysis, and diminished intensity of the systemic inflammatory state, factors that have been associated with cardiovascular risk.

Change in Albuminuria and eGFR Following Insulin Sensitization Therapy Versus Insulin Provision Therapy in the BARI 2D Study

“…Sobel et al (15) reported that, in BARI 2D subjects, IS as opposed to IP treatment led to changes in biomarker profiles that were indicative of a profibrinolytic, antithrombotic, and antiinflammatory state. Peroxisome proliferator-activated receptors are widely expressed in the kidney, and peroxisome proliferator-activated receptor gamma agonists have renoprotective effects in experimental models of diabetic kidney disease (16,17).…”

Increased Hazard of Myocardial Infarction With Insulin‐Provision Therapy in Actively Smoking Patients With Diabetes Mellitus and Stable Ischemic Heart Disease: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) Trial

“…An analysis of BARI 2D by Chaitman et al found that in the CABG‐stratum patients who had greater atherosclerotic burden, the reduction of MI seen in patients randomized to revascularization was found to be significant only in those randomized to an IS treatment strategy 2. Sobel and colleagues subsequently evaluated the impact of IS and IP treatment strategies on fibrinolytic biomarker profiles in the BARI 2D trial 7. Although IP therapy was associated with greater PAI‐1 antigen and activity, these changes did not translate into any difference in outcomes in the overall trial.…”

“…Insulin, tPA antigen, and PAI‐1 assays were performed by ELISA. The tPA activity was not measured because it complexes with excess PAI‐1 in plasma resulting in activity that is undetectable 7. PAI‐1 activity was assayed with a chromogenic substrate kinetic procedure.…”

“…In the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial of patients with diabetes mellitus and SIHD, PAI‐1 (plasminogen activator inhibitor 1) antigen and activity levels increased in those randomized to an insulin provision (IP) strategy compared with those randomized to an insulin sensitization (IS) strategy. Despite the significant differences in fibrinolytic biomarker profiles, no difference was observed in death or major cardiovascular events between the 2 treatment strategies 7, 8. Active cigarette smoking also induces a multifactorial hypercoagulable state through increased synthesis of PAI‐1, elevation in the blood fibrinogen concentration, increased platelet activity, and increased expression of tissue factor and is associated with an increased risk of MI in both diabetic and nondiabetic patients with SIHD 9.…”

Burton E. Sobel: 1937–2013

“…He played an important role in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial, in which he showed that insulin-sensitizing treatment of diabetic patients altered the balance between thrombosis and fibrinolysis, favoring the latter. 5 At the time of his death, he had 2 peer-reviewed articles in press and 1 under review, the latter in Circulation! Burt was as talented a leader as he was as an investigator, clinician, educator, and editor.…”