Influence of the Functionally Selective Insulin Analog NNC-965 vs. Insulin Glargine (IGla) on Cardiac Structure and Function

Abstract

NNC-965 selectively stimulates insulin receptors with greater Akt and less MAPK activation, which improved vascular function, insulin sensitivity (IS), and weight gain versus conventional basal insulin in diabetic rats. We hypothesized that improved vascular function on NNC-965 unloads the heart thereby improving left ventricular (LV) structure and function. We compared the effects of NNC-965 and IGla on flow-mediated dilation (FMD), IS, body weight, vascular function and cardiac function/structure (assessed by MRI) in 86 people with type 2 diabetes on basal insulin ± oral agents in a randomized, double-blind study over 26 weeks. NNC-965 improved FMD and IS versus IGla (table). Glycemic control and liver fat responded similarly to both insulins, but body weight and fat mass increased more with NNC-965. LV ejection fraction and LV stroke volume slightly decreased with NNC-965 and increased with IGla, but the differences were not significant. We observed no clinically relevant changes in LV mass, LV enddiastolic and endsystolic volume by either treatment. In conclusion, NNC-965 showed some characteristics of a functionally selective insulin but increased body weight. The observed improvement in FMD might lead to long-term reductions in cardiovascular risk; however, studies with longer treatment duration may be needed to assess effects on cardiac function and structure.