Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial

Burton E Sobel, Regina M Hardison, Saul Genuth, Maria M Brooks, Robert D McBane 3rd, David J Schneider, Richard E Pratley, Kurt Huber, Robert Wolk, Ashok Krishnaswami, Robert L Frye, BARI 2D Investigators, Burton E Sobel, Regina M Hardison, Saul Genuth, Maria M Brooks, Robert D McBane 3rd, David J Schneider, Richard E Pratley, Kurt Huber, Robert Wolk, Ashok Krishnaswami, Robert L Frye, BARI 2D Investigators

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 A(1c) 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.

Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Figures

Figure 1
Figure 1
Median insulin and mean HbA1c over time of follow-up (months after randomization) in patients treated with an insulin-providing (IP) or insulin-sensitizing (IS) strategy. HbA1c indicates hemoglobin A1c; BL, baseline.
Figure 2
Figure 2
Concentrations in blood or activity of biomarkers over time. tPA indicates tissue plasminogen activator; BL, baseline; IP, insulin-providing treatment strategy; IS, insulin-sensitizing treatment strategy; and PAI-1, plasminogen activator inhibitor type 1.
Figure 3
Figure 3
Median or mean values of the analytes specified over 24 months. CRP indicates C-reactive protein; BL, baseline; FEU, fibrinogen equivalent unit; FPA, fibrinopeptide A; IP, insulin-providing treatment strategy; and IS, insulin-sensitizing treatment strategy.
Figure 4
Figure 4
Kaplan–Meier 5-year rate estimates for mortality and major cardiovascular events stratified by baseline values of the analytes specified. CRP indicates C-reactive protein; Q, quintile; and MI, myocardial infarction.

Source: PubMed

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