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

Abstract

BackgroundIn the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, randomization of diabetic patients with stable ischemic heart disease to insulin provision (IP) therapy, as opposed to insulin sensitization (IS) therapy, resulted in biochemical evidence of impaired fibrinolysis but no increase in adverse clinical outcomes. We hypothesized that the prothrombotic effect of IP therapy in combination with the hypercoagulable state induced by active smoking would result in an increased risk of myocardial infarction (MI).Methods and ResultsWe analyzed BARI 2D patients who were active smokers randomized to IP or IS therapy. The primary end point was fatal or nonfatal MI. PAI‐1 (plasminogen activator inhibitor 1) activity was analyzed at 1, 3, and 5 years. Of 295 active smokers, MI occurred in 15.4% randomized to IP and in 6.8% randomized to IS over the 5.3 years (P=0.023). IP therapy was associated with a 3.2‐fold increase in the hazard of MI compared with IS therapy (hazard ratio: 3.23; 95% confidence interval, 1.43–7.28; P=0.005). Baseline PAI‐1 activity (19.0 versus 17.5 Au/mL, P=0.70) was similar in actively smoking patients randomized to IP or IS therapy. However, IP therapy resulted in significantly increased PAI‐1 activity at 1 year (23.0 versus 16.0 Au/mL, P=0.001), 3 years (24.0 versus 18.0 Au/mL, P=0.049), and 5 years (29.0 versus 15.0 Au/mL, P=0.004) compared with IS therapy.ConclusionsAmong diabetic patients with stable ischemic heart disease who were actively smoking, IP therapy was independently associated with a significantly increased hazard of MI. This finding may be explained by higher PAI‐1 activity in active smokers treated with IP therapy.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

The Impact of Cardiac Comorbidity Sequence at Baseline and Mortality Risk in Type 2 Diabetes Mellitus: A Retrospective Population-Based Cohort Study

“…Similar findings were demonstrated in the higher mortality risk amongst first-presentation ST-elevation myocardial infarction patients free of modifiable cardiovascular risk factors than their counterparts with preexisting risk factors, where the risks were attenuated after adjusting for the application of guideline-directed therapy [32]. Current studies that demonstrate higher cardiovascular adverse events and mortality risk amongst insulin users randomized patients with diabetes mellitus into insulin provision and insulin sensitization groups, which did not reflect the more advanced disease state amongst typical insulin users in real life [33,34]. However, given sulphonylurea is a second-line agent, the earlier development of CHD marks for early macrovascular involvement, therefore reflecting a poorer disease prognosis.…”

The Impact of Cardiac Comorbidity Sequence at Baseline and Mortality Risk in Type 2 Diabetes Mellitus: A Retrospective Population-Based Cohort Study

“…23 Current studies that demonstrate a higher cardiovascular adverse event and mortality risk amongst insulin users randomized patients with diabetes mellitus into insulin provision and insulin sensitization groups, which did not reflect the more advanced disease state amongst typical insulin users in real life. 24,25 However, given sulphonylurea is a second-line agent, the earlier development of CHD marks for early macrovascular involvement, therefore reflecting a poorer disease prognosis. In addition, the cardioprotective effect of sulphonylurea is relatively weak compared to other antidiabetic agents, hence further increasing the mortality risk.…”

Sex-specific Mendelian randomization study of genetically predicted insulin and cardiovascular events in the UK Biobank

“…Coagulation factors, which were not examined in this study, may also be a mechanism. Hyperinsulinemia promotes a procoagulant state 47 , increasing in several coagulation factors, such as thrombin generation 47 , and plasminogen activator inhibitor type 1 48 , which have been identified as potential causes of IHD and MI 49,50 .…”

“…Insulin causing MI may also partly explain the unexpected off-target effects of insulin raising treatments, such as sulfonylureas 19 . Similarly, insulin therapy has a relatively higher risk of MI than insulin sensitization therapy 48 . Several medications for type 2 diabetes, such as metformin, thiazolidinediones, sodium-glucose transport inhibitors, and glucagon-like peptide 1 agonists may reduce the need for insulin 52 .…”