Effect of Insulin Glargine and n-3FA on Carotid Intima-Media Thickness in People With Dysglycemia at High Risk for Cardiovascular Events: The Glucose Reduction and Atherosclerosis Continuing Evaluation Study (ORIGIN-GRACE)

OBJECTIVE

To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT).

RESEARCH DESIGN AND METHODS

We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years.

RESULTS

Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups.

CONCLUSIONS

In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.Atherosclerosis is the major cause of death and disability in people with type 2 diabetes and lesser degrees of dysglycemia (1,2). Large epidemiological studies show consistent independent associations between glycemia and cardiovascular (CV) risk (1–4), and the metabolic abnormalities associated with dysglycemia promote atherosclerosis (5). Exogenous insulin can provide effective glycemic control, but its effects on atherosclerosis are unknown. Moreover, some studies suggest possible proatherogenic effects (6,7).Essential long-chain n-3 polyunsaturated fatty acids (n-3FA) may have beneficial effects on atherosclerosis (8). Higher intake of fish or n-3FA supplements is associated with lower rates of coronary heart disease and death (9,10) and lower atherosclerotic burden (11,12), and some, but not all, previous trials reported reduced CV events in patients receiving n-3FA supplements (13–16). The effects of these supplements on human atherosclerosis progression were evaluated in a few small studies, which were inconclusive (17–21).Therefore, we evaluated the effects of insulin glargine and n-3FA supplements on carotid intima-media thickness (CIMT) in people with dysglycemia and additional risk factors for atherosclerosis progression in a substudy of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (22–24).