Large randomized controlled trials such as UKPDS [122] or the Outcome Reduction With Initial Glargine Intervention (ORIGIN) Trial [123] did not observe an increased incidence of cardiovascular disease with insulin therapy, but these trials focused on low-dose insulin therapy of up to a median of 40 IU/day (or 0.4 IU/kg/day), respectively. This evidence concerns the gene INS and cardiovascular disorder.