Effect of interactions between C peptide levels and insulin treatment on clinical outcomes among patients with type 2 diabetes mellitus.

BACKGROUND A recently halted clinical trial showed that intensive treatment of type 2 diabetes mellitus was associated with increased mortality. Given the phenotypic heterogeneity of diabetes, therapy targeted at insulin status may maximize benefits and minimize harm. METHODS In this longitudinal cohort study, we followed 503 patients with type 2 diabetes who were free of cardiovascular disease from 1996 until data on mortality and cardiovascular outcomes were censored in 2005. Phenotype-targeted therapy was defined as use of insulin therapy in patients with a fasting plasma C peptide level of 0.2 nmol/L or less and no insulin therapy in patients with higher C peptide levels. RESULTS The mean age of the cohort was 54.4 (standard deviation 13.1) years, and 56% were women. The mean duration of diabetes was 4.6 years (range 0-35.9 years). Of the 503 patients, 110 (21.9%) had a low C peptide level and 111 (22.1%) were given insulin. Based on their C peptide status, 338 patients (67.2%) received phenotype-targeted therapy (non-insulin-treated, high C peptide level [n = 310] or insulin-treated, low C peptide level [n = 28]), and 165 patients (32.8%) received non-phenotype-targeted therapy (non-insulin-treated, low C peptide level [n = 82] or insulin-treated, high C peptide level [n = 83]). Compared with the insulin-treated, low-C-peptide referent group, the insulin-treated, high-C-peptide group was at a significantly higher risk of cardiovascular events (hazard ratio [HR] 2.85, p = 0.049) and death (HR 3.43, p = 0.043); the risk was not significantly higher in the other 2 groups. These differences were no longer significant after adjusting for age, sex and diabetes duration. INTERPRETATION Patients with low C peptide levels who received insulin had the best clinical outcomes. Patients with normal to high C peptide levels who received insulin had the worst clinical outcomes. The results suggest that phenotype-targeted insulin therapy may be important in treating diabetes.