Relationship of Glycemic Control, Exogenous Insulin, and C-Peptide Levels to Ischemic Heart Disease Mortality Over a 16-Year Period in People With Older-Onset Diabetes: The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)

OBJECTIVE:--The purpose of this study was to examine the relationship of glycemic control and exogenous and endogenous insulin levels with all-cause and cause-specific mortality (ischemic heart disease and stroke) in an older-onset diabetic population. RESEARCH DESIGN AND METHODS--The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) is an ongoing, prospective, population-based cohort study of individuals with diabetes first examined in 1980-1982. A stratified sample of all individuals with diabetes diagnosed at 30 years of age or older was labeled "older-onset" (n = 1,370). Those participating in the 1984-1986 examination phase (n = 1,007) were included in the analysis. Endogenous insulin was determined by measurements of plasma C-peptide (in nanomoles per liter), and exogenous insulin was calculated in units per kilogram per day. Glycemic control was determined by levels of glycosylated hemoglobin (HbA₁). RESULTS:--After 16 years of follow-up, 824 individuals died (all-cause mortality); 358 deaths involved ischemic heart disease and 137 involved stroke. C-peptide and HbA₁ were significantly associated with all-cause and ischemic heart disease mortality in our study. The hazard ratio (95% CI) values for all-cause mortality were 1.12 (1.07-1.17) per 1% increase in HbA₁, 1.20 (0.85-1.69) per 1 unit · kg⁻¹ · day⁻¹ increase in exogenous insulin, and 1.15 (1.04-1.29) per 1 nmol/l increase in C-peptide and for ischemic heart disease mortality were 1.14 (1.06-1.22), 1.50 (0.92-2.46), and 1.19 (1.02-1.39) for HbA₁, exogenous insulin, and C-peptide, respectively, after adjusting for relevant confounders. C-peptide was associated with stroke mortality only among men (1.65 [1.07-2.53]). CONCLUSIONS:--Our results show that individuals with higher endogenous insulin levels are at higher risk of all-cause, ischemic heart disease, and stroke mortality.