• Insulin
• Diabetes & Endocrinology Clinical Trials
• Hypertensive Disease
• Hyperglycemia/Hypoglycemia
• Lipid Disorders Diabetes Mellitus

• Insulin
• Diabetes & Endocrinology Clinical Trials
• Hypertensive Disease
• Hyperglycemia/Hypoglycemia
• Lipid Disorders
• Endocrinology
• Diabetes & Metabolic Syndrome
• Diabetes Mellitus

Previously published results from the Action to Control Cardiovascular Risk in Diabetes study [ACCORD; ACCORD Study Group. N Engl J Med 2008] showed an increased risk of all-cause and cardiovascular (CV) mortality in the intensive control group (HbA1C target, <6.0%) compared with the less intensive group (HbA1C target, 7.0% to 7.9%). “This brought a huge puzzle to the diabetes community, to figure out why we were seeing this result,” said Elias S. Siraj, MD, Temple University School of Medicine, Philadelphia, Pennsylvania, USA. Several post hoc analyses have been conducted to date to determine what factors may have influenced this outcome [ACCORD Study Group. N Engl J Med 2008; Bonds DE et al. BMJ 2010; Riddle MC et al. Diabetes Care 2010; Seaquist ER et al. Diabetes Care 2012]. These analyses did not find a conclusive link between the ACCORD results and factors such as hypoglycemia, low HbA1C, the rapid decline in HbA1C during the first year of the study, weight gain, and specific medication use.

To better understand the findings of this study, ACCORD investigators hypothesized that higher doses of exogenous insulin may be associated with the CV mortality results from the ACCORD trial. To investigate this idea, data for insulin exposure and CV mortality from 10,163 patients were analyzed. HRs and 95% CIs were calculated, and multivariable Cox regression performed to choose the most appropriate baseline covariates and models.

The updated average total, basal, and bolus insulin doses were significantly higher in the intensive-control arm (all p<0.0001). In addition, there was a significant linear association between the updated average HbA1C level and updated average insulin dose in both groups (both p<0.0001). Four different Cox proportional hazards models were employed to determine HRs for CV mortality. The first model controlled for the following 14 baseline covariates: age, history of CV disease, heart failure, QT-index, baseline HbA1C value, high-density lipoprotein, amputation, presence of peripheral neuropathy, serum creatinine, urinary ratio of albumin to creatinine, use of angiotensin receptor blockers, educational status, presence of integrated health plan, and presence of certified diabetes educator on staff at randomization. Model 2 added assignment to blood pressure or lipid trial, treatment assignment within these, severe hypoglycemia, and weight change. Model 3 added the updated average HbA1C, and Model 4 added the glycemic treatment arm assignment. Results from all 4 models by total, basal, and bolus insulin are presented in Table 1.

Based on the unadjusted HRs, a daily insulin dose increase by 1 unit/kg of body weight was associated with a 1.83- (total insulin), 2.29- (basal insulin) and 3.36-fold increase in risk of CV mortality (all p<0.0001). However, results from the four models did not confirm these findings. After adjustment for baseline covariates in Model 1, the HRs became nonsignificant indicating no association of insulin dose with CV mortality. Additionally, no association between insulin dose and CV mortality emerged after adjustments were made for on-treatment factors.

Dr. Siraj concluded that these results do not support the idea that insulin dose is an independent risk factor for CV mortality in the ACCORD population.

• © 2013 MD Conference Express®