Reducing cardiovascular disease risk in patients with type 2 diabetes and concomitant macrovascular disease: can insulin be too much of a good thing?

Abstract

Despite improvement of microvascular outcomes as a consequence of optimal glucose control in patients with type 2 diabetes, prevention of macrovascular complications is still a major challenge. Of interest, large-scale intervention studies (Action to Control Cardiovascular Risk in Diabetes, Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation and Veterans Affairs Diabetes Trial) comparing standard therapy versus more intensive glucose-lowering therapy failed to report beneficial impacts on macrovascular outcomes. Consequently, it is currently under debate whether the high doses of exogenous insulin that were administered in these trials to achieve strict target glucose levels could be responsible for these unexpected outcomes. Additionally, a potential role for plasma insulin levels in predicting macrovascular outcomes has emerged in patients with or without type 2 diabetes. These observations, combined with evidence from in vitro and animal experiments, suggest that insulin might have intrinsic atherogenic effects. In this review, we summarize clinical trials, population-based studies as well as data emerging from basic science experiments that point towards the hypothesis that the administration of high insulin doses might not be beneficial in patients with type 2 diabetes and established macrovascular disease.

Mortality and Other Important Diabetes-Related Outcomes With Insulin vs Other Antihyperglycemic Therapies in Type 2 Diabetes

“…Indeed, we have recently estimated that, in the United Kingdom, the number of people with T2DM treated with insulin increased from 37 000 in 1991 to 277 000 in 2010 (Holden, SE, unpublished data). Early insulization has recently been recommended in guidelines from the American Diabetes Association and European Association for the Study of Diabetes (8), but the risk–benefit profile of exogenous insulin in the management of people with T2DM has also undergone scrutiny (9–12). …”

Cardiovascular safety of type 2 diabetes medications: Review of existing literature and clinical implications

“…7 Some authors believe that individuals with insulin resistance, mainly affecting the PI3K pathway, need greater amounts of insulin to achieve a similar glycemic control, whilst MAPK pathway overstimulation leads to an acceleration of the atherosclerotic process within the vessel wall. 8 Older in vivo animal studies provided evidence of the atherogenic potential of insulin. 9 Conversely, several studies have pointed to a possible anti-atherosclerotic effect of insulin mediated by nitric oxide release 10 as well as inhibition of pro-apoptotic signals 11 and of platelet aggregation.…”

Insulin as an Early Treatment for Type 2 Diabetes

“…Experimental data have shown that modest elevation of plasma insulin levels, mimicking fasting hyperinsulinemia of insulin-resistant states, abrogates endothelium-dependent vasodilation in large conduit arteries, probably by increasing oxidative stress (32). Moreover, in the presence of insulin resistance, hyperinsulinemia, at least in the in vitro setting, can overstimulate the intracellular mitogen (mitogen-activated protein kinase dependent) signaling pathway in endothelial cells, which, together with impaired phosphatidylinositol 3-kinase activation of nitric oxide synthase, could yield an atherogenic state (33). …”