2.  Insulin Degludec  Ultra long action  Due to formation of soluble multihexamers at the injection site from which monomers gradually separate and are absorbed into circulation http://www.diatribe.us/issues/30/new-now-next.php

3.  Insulin Degludec  Results in a flat and stable pharmacokinetic profile at steady state.  These characteristics may reduce risk of hypoglycemia  Possibly may be given 3 times a week in type 2 DM that are insulin-naïve  This could help with initiation and adherence to treatment. www.diabetologica.com

4.  To assess efficacy and safety of insulin degludec when:  injected once daily or three times a week  compared with insulin glargine once daily  in insulin-naïve people with type 2 DM and  Inadequately controlled on oral antidiabetic drugs

5.  16-week randomized, open-label, parallel group phase 2 trial  Participants 18-75 years old  Type 2 DM with A1C= 7-11%  Enrolled and treated at 28 clinical sites (Canada, India, South Africa, USA)

6.  Eligibility:  Type 2DM (>3months)  18-75 years  A1C 7-11%  BMI 23-42 kg/m2  Insulin naïve  on oral agents for >2mos at stable half-maximum to maximum doses  Excluded:  if treated with agents that interfere with insulin metabolism within 3 months of study (TZD, DPP-IV inhibitors)

7.  Randomly allocated in 1:1:1:1: ratio by computer generated block randomization to: receive  insulin degludec 3 times/wk (1U=9nmol) M,W,F  Insulin degludec group A (1U=6nmol) daily  Insulin degludec group B (1U=9nmol)daily  Insulin glargine (1U=6nmol) daily  All groups in combination with metformin.

9.  Before randomization:  Participants discontinued pretrial oral drug and underwent 2-week forced metformin-titration period (up to 2g/day) followed by 1-week metformin maintenance.  Elible if able to maintain metformin 2g (or at least 1.5g/day) + have fasting glucose of >7.5 mmol/L on 3 consecutive days (~135 mg/dL).

10.  Dosing  Starting dose for daily groups: 10U  Starting dose for degludec 3x/wk: 20U  Insulin titrated up  based on blood glucose before breakfast (lowest value on 3 consecutive days)  Used a plasma-calibrated blood glucose meter.  Goal AM glucose = 4-6 mmol/L (~72- 108mg/dL)

11.  Primary outcome= A1C (after 16 weeks of tx)  Goal was to determine a treatment difference in A1C between groups  Secondary Endpoint:  Changes in fasting plasma glucose  Required insulin dose  Nine-point profiles of self monitored glucose.

14.  Mean A1C and fasting plasma glucose the same across treatment groups.  A1C reduction from baseline was -1.3 to -1.5% for all groups (and not different between groups)  At the study end, fasting glucose was the same across groups.  The mean 9-point glucose profiles  lower in all treatment groups compared to baseline  Had the same overall shape for all groups.

15.  Starting dosing was higher in the degludec 3x/wk group and group B (due to formulation)  At 16 weeks, insulin dose was same in all groups except group B (which was higher/kg)

16.  Body weight was slightly elevated in degludec group B and glargine group.

17.  Hypoglycemia did NOT occur in 77-92% of participants.  There were no differences between groups in hypoglycemia.  The proportion of hypoglycemia in degludec group A was lower than that in glargine group or degludec 3x/wk group.

18.  There were only 2 serious adverse events:  Aggravation of a pretrial CAD in the degludec 3x/wk group.  Worsening paroxysmal Afib in degludec group B (daily). ▪ Both were thought not to be related to degludec.  Only 6 participants had side effects possibly related to degludec (headache, dermatitis, rash, diarrhea, edema)

19.  Insulin degludec can provide equivalent glycemic control to insulin glargine without new or increased rates of adverse events in insulin-naïve type 2 DM.  The safety, efficacy and optimum use of treatment regimens needs to be established.