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

Study Questions:

What is the effect of two mechanistically different strategies for treatment of hyperglycemia, insulin-sensitizing and insulin-providing strategies, on biomarker profiles reflecting the balance between fibrinolysis and thrombosis, and on the intensity of inflammation?

Methods:

A total of 2,368 patients with type 2 diabetes mellitus and clinically stable, angiographically documented coronary artery disease were randomized to treatment with one of the two 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. Adjusted Cox proportional hazard models with time-varying analytes were used to estimate effects of the analytes on the outcomes of death, death/myocardial infarction/stroke, and subsequent revascularization procedures, and to examine the potentially mediating effects of the analytes in the causal pathway between the randomization treatments and the cardiovascular disease outcomes.

Results:

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 authors concluded that 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.

Perspective:

This study suggests that an insulin-sensitizing as opposed to an insulin-providing strategy led to changes in biomarker profiles indicative of a profibrinolytic, antithrombotic, and anti-inflammatory state. The hypothesis that the improved biomarker profiles with insulin-sensitizing strategy will lead to better clinical outcomes will require comparisons of large numbers of patients over prolonged intervals stratified with respect to changes in biomarker profiles induced by specific treatment strategies.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Interventions and Coronary Artery Disease

Keywords: Inflammation, Prognosis, Coronary Artery Disease, Myocardial Infarction, Hyperglycemia, Follow-Up Studies, Biological Markers, Thrombosis, Plasminogen, Fibrinolysis, Insulin Resistance, Angioplasty


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