2. Introduction Subcutaneous insulin absorption is not reproducible and insulin entry directly into the circulation is not linked to glucose sensing Basal insulin analogues like Glargine and Detemir have longer duration of action and lower risk for hypoglycemia as compared to NPH; however none provide 24hour basal insulin replacement Insulin Degludec is a ultra-long acting insulin in clinical development It forms soluble multihexamers from which insulin is slowly and continuously absorbed It has a flat, stable profile at steady state and half- life of 25hours, total duration of action 40 hours. Day- to day variability in pharmacologic studies is four times lower than glargine

3. Study design 52 week, randomized, controlled, open label, multinational parallel design, treat- to target non inferiority trial Patients- Type 1 diabetes >18yr, on basal- bolus therapy for at least 1 year with HA1c < 10%, BMI < 35 79 sites in 6 countries- France, Germany, Russia, South Africa, UK and USA Randomization in 3:1 ratio: Group 1- once daily insulin degludec + meal time aspart Group 2- once daily insulin glargine + meal time aspart Primary objective: To confirm the non- inferiority of insulin degludec to insulin glargine in reduction of HbA1c from baseline after 52 weeks of treatment Secondary endpoints: fasting blood glucose, self monitored BG, HRQoL, hypoglycemia, body weight, lipids Confirmed hypoglycemia- plasma glucose <55 or severe episode requiring assistance Nocturnal hypoglycemia- episodes occurring between 0001hr to 0559h Basal insulin doses were titrated to achieve prebreakfast SMBG between 70- 90mg/dl.

4. Total=629

5. Results Mean decrease in HbA1c from baseline was similar - 0.40% for insulin degludec - 0.39 % for insulin glargine Estimated treatment difference= -0.01% which confirms degludec is non- inferioir as compared to glargine in reducing HbA1c

6. Mean FBS decreased by 23.4 mg/dl in glargine group and 25.2 mg/dl in degludec group (p= 0.35) Mean prebreakfast SMPG decreased from baseline to 131 in degludec group and 140 in glargine group (p=0.023)

7. Weight gain : 1.8 kg with degludec 1.6 kg with glargine ( p= 0.62)

8. 25% ↓

9. Limitations Since this is an open- label trial, there is risk of reporting bias Masking of treatment was not possible since the devices are different The time of administration of glargine was not systematically recorded Difficult to achieve uniform titration of bolus insulin

10. Discussion Reduction in HBA1c was similar in both groups, thus establishing the non- inferiority of insulin degludec The flat and stable pharmacokinetic profile of insulin degludec has the potential to lower hypoglycemic events The lower day- to day variability of action of insulin degludec may explain lower nocturnal hypoglycemia which in turn will result in more stringent glycemic control