Insulin as an early treatment for type 2 diabetes: ORIGIN or end of an old question?

Abstract

The Emerging Risk Factors Collaboration (1) has recently confirmed that type 2 diabetes remains associated with substantial premature mortality. Compared with nondiabetic individuals, those with diabetes have a hazard ratio (HR) of 1.80 (95% CI 1.71–1.90) for death from any cause, 1.25 (1.19–1.31) for death from cancer, 2.32 (2.11–2.56) for death from vascular causes, and 1.73 (1.62–1.85) for death from other causes. As is apparent, the greater risk is owing to cardiovascular (CV) disease, which accounts for >60% of the years of life lost because of diabetes. Although this increase in CV risk is largely attributable to the coexistence of multiple metabolic and hemodynamic disorders, elevation of plasma glucose levels remains strongly associated with increased CV morbidity and mortality (2–4). In support of a potential direct effect of plasma glucose elevation is the association between fasting plasma glucose levels >100 mg/dL (5.6 mmol/L) and vascular death (1). Since this a near-linear association (1,5) it has been postulated that reduction of plasma glucose levels should exert a positive impact on CV morbidity and mortality. In the UK Prospective Diabetes Study (UKPDS), improvement of glycemic control was associated with a 16% reduction in the risk of myocardial infarction without achieving statistical significance ( P < 0.052) (6). Glycemic control in that seminal trial was, however, relatively unsuccessful. Though intensively treated patients achieved an average A1C of 7%, a progressive worsening in glycemic control occurred after the initial improvement. A more aggressive and successful approach was adopted in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (7) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) (8) trials and Veterans Affairs Diabetes Trial (VADT) (9). In all these three large studies, glycemic control was achieved (A1C 6.5–7.0%) and maintained over a substantial period of …