Insulin Resistance and Atherosclerosis: Is it Time to Measure HOMA-IR to Predict Coronary Artery Disease?

Atherothrombotic cardiovascular disease (CVD) is the leading cause of death worldwide, despite remarkable advances in detection and management. The American Heart Association estimates that by 2030 at least 40% of the US population will have some form of CVD. Well-established modifiable risk factors include dyslipidemia, hypertension, obesity, diabetes mellitus, the metabolic syndrome and physical inactivity. Of these, insulin resistance (IR) is common to metabolic syndrome, diabetes mellitus and obesity. In this issue of North American Journal of Medical Sciences, Srinivasan et al., have provided data that relates the severity of insulin resistance to the severity of coronary artery disease.[1]

Insulin resistance is mediated by the interplay of a person's genetic substrate and acquired pathophysiologic insults. Molecular studies have established that insulin resistance has a key role in every stage of atherosclerosis from the initiation and progression of early atherosclerosis to the formation of clinically significant plaques. In the early stages, insulin resistance appears to affect various molecular pathways at the cellular level in endothelial cells, macrophages and vascular smooth muscle cells.[2] Despite a wealth of data linking insulin resistance and atherosclerosis at the molecular level, the relation between the two in clinical settings has remained uncertain. A multi-center study reported an association between IR and multi-vessel coronary artery disease (CAD) in non-diabetic post-myocardial infarction survivors that was independent of other metabolic risk factors.[3] Another cross-sectional study from Europe reported that IR mediates subclinical atherosclerosis by increasing abdominal adiposity.[4] In an analysis of NHANES population data, we were able to demonstrate that IR was a greater risk for CVD than diabetes itself and that IR was associated with a higher risk of CVD in non-diabetics than in diabetics.[5]

In the current study, the authors have taken this a step further and examined the relationship between insulin resistance and the severity of clinically apparent coronary artery disease. HOMA-IR was used to indicate insulin resistance while the Gensini score denoted CAD severity. They found statistically significant correlations between the HOMA-IR and the Gensini scores in their population. Interestingly in their multivariate analysis they did not find statistically significant associations with other known risk factors for CAD. In this way the authors have demonstrated a significant correlation between the insulin resistance and CAD. Though this positive correlation was small in statistical terms, it is a significant addition to the growing knowledge of the key role of insulin resistance in atherosclerosis. They conclude that they might be able to predict severity of CAD by measuring HOMA-IR. This is in contrast to other studies that have questioned the relative contribution of IR to clinically significant atherosclerotic disease. For example, a multiethnic study concluded that determination of the HOMA-IR is unlikely to improve detection of sub-clinical atherosclerosis.[6]

The question then remains: Are we approaching primary prevention of coronary artery disease correctly by just screening for and treating diabetes mellitus and hyperlipidemia, while ignoring insulin resistance?