Cardiovascular disease and the use of insulin.

Insulin therapy has been used for the treatment of hyperglycemia for decades. Although it is clearly accepted that intensive insulin treatment regimens (multiple daily injections or continuous subcutaneous insulin infusion) represent the optimal and accepted standard of care treatment for patients with type 1 diabetes mellitus (T1DM), the role of insulin therapy in type 2 diabetes mellitus (T2DM) with respect to timing of insulin initiation, the specific regimen to be used, and the potential benefit/adverse effects continues to be debated. Recently the current American Diabetes Association/European Association for the Study of Diabetes position statement for the management of T2DM recommends that consideration be given to using insulin as part of a first-line combination regimen. It is interesting that recent studies have suggested that insulin therapy may improve bcell function when administered early in the course of T2DM. In addition, the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial observed that insulin glargine reduced new-onset diabetes when administered to individuals with impaired fasting glucose or impaired glucose tolerance. These observations suggest that the use of insulin in patients with T2DM might be considered much earlier in the context of the usual continuum of treatment escalation, as opposed to its use after multiple oral agents have failed. Despite significant advances in insulin therapy, concerns remain with respect to long-term safety, particularly as it relates to hypoglycemia, weight gain, and possible cardiovascular (CV) risk. In this editorial we will examine the current evidence supporting both the potential for beneficial and adverse effect of insulin on CV risk. The concept that insulin might be associated with increased risk for CV disease was first proposed in the 1970s. Data from observational studies demonstrated that endogenous hyperinsulinemia is associated with CV disease. In fact, a meta-analysis of 12 observational studies showed that hyperinsulinemia predicts the occurrence of CV events, although this association was statistically weak (odds ratio 1.18 [95% confidence interval 1.08–1.29]). However, as in many observational studies these findings have several limitations. First, in most of these studies, insulin was measured only at one time point, which limits the evaluation of the exposure (i.e., hyperinsulinemia). Second, endogenous hyperinsulinemia is made up of several products (insulin, proinsulin, and split products) and is often accompanied by known risk factors for CV disease, such as obesity, hypertension, and hyperlipidemia, making the evaluation of insulin’s independent effect on CV outcomes difficult to assess. Finally, these studies did not evaluate whether insulin itself is a predictor of future CV disease or just a surrogate for insulin resistance, the true determinant of CV risk. In this context, the results of these observational studies may be affected by several known and unknown important confounders that can lead to uncertain outcomes and conclusions. The uncertainty of the association between insulin and CV disease is further highlighted by experimental studies. In vitro studies evaluating the effect of insulin on the human vasculature have demonstrated that insulin has both protective and deleterious effects. Some studies have demonstrated favorable effects of insulin on endothelium function by showing (1) that insulin stimulates the vasodilator nitric oxide in humans through activation of endothelial nitric oxide synthase, whereas insulin-resistant states are associated with impairment of the insulin-mediated activation of the l-arginine nitric oxide pathway, and (2) that, in addition, insulin has also been shown to exert direct inhibitory effects on mediators of endothelial inflammation, oxidative stress, and thrombogenesis. On the other hand, it has been shown that insulin also can have deleterious effect on the vascular bed by (1) increasing the production of endothelin-1, which is a potent vasoconstrictor and mitogen, and (2) stimulating growth factors, which ultimately decrease fibrinolysis and increase angiogenesis within atherosclerotic plaques (Fig. 1). Clinical trials evaluating the effect on exogenous insulin for the treatment of diabetes have shown neither a clear benefit of the use of insulin treatment on reducing CV disease nor a deleterious effect. In T1DM, the Diabetes Control and Complications Trial (DCCT) show that the intensive-treatment group had a reduction of 42% in macrovascular events compared with the control group. In T2DM, the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive control with either insulin or sulfonylurea resulted in a 16% reduction of macrovascular disease compared with the conventional treatment, although statistical significance was not reached. Following these two landmark studies on