Insulin resistance but not beta-cell secretory dysfunction predicts adverse cardiovascular outcome in non-diabetic men with stable coronary artery disease: a 20-year single-centre study

Purpose: Insulin resistance, an underlying cause of the metabolic syndrome, has been implicated in the pathogenesis of atherosclerosis. Both insulin resistance and beta-cell secretory dysfunction contribute to the progressive deterioration of glucose tolerance with a concomitant rise in cardiovascular (CV) risk. Our aim was to estimate prognostic effects of insulin resistance and insulin secretory dysfunction on CV outcome in men with stable coronary artery disease (CAD) and without diabetes. Methods: We studied 102 consecutive non-diabetic men with stable angina (age 49±10 years), significant angiographic CAD and without heart failure who were hospitalized in our department in 1992-1993. Measures of insulin resistance and beta-cell secretory function were calculated by means of the homeostasis model assessment from fasting levels of insulin and glucose as HOMA-IR and HOMA-B, respectively. The study subjects were followed for 20 years. Major adverse CV events were defined as death from a CV cause, non-fatal, non-procedure-related myocardial infarction, resuscitation after cardiac arrest and stroke. Results: Fifty-seven major adverse CV events were recorded over a 20-year follow-up, including 16 deaths from CAD and 12 strokes. By a univariate Cox regression, adverse CV outcome during the first 10 years after index hospitalization was related to HOMA-IR (hazard ratio [HR] per 1-SD increment: 1.47 [95% confidence interval (CI), 1.10–1.96], p=0.009) but not HOMA-B (HR: 0.84 [0.65–1.08], p=0.17). Neither HOMA-IR (HR: 1.14 [0.77–1.69], p=0.5) nor HOMA-B (HR: 0.95 [0.48–1.88], p=0.9) was associated with adverse outcome between 10 and 20 years after the index hospitalization. The significant relationship between HOMA-IR and a 10-year adverse CV prognosis was maintained upon adjustment for the diagnostic components of the metabolic syndrome (HR: 1.38 [1.04–1.83], p=0.03). Conclusions: Insulin resistance, in contrast to beta-cell secretory dysfunction, predicts major adverse CV events in non-diabetic men with stable CAD. This association appears independent of clustering of the metabolic syndrome diagnostic components and may suggest a detrimental effect of insulin resistance by itself on CV outcome, which weakens with lengthening follow-up time.