Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan.

AIMS: To compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan. METHODS: In this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ±â€¯oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8-20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30-50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose <3.1 mmol/L [56 mg/dL]), nocturnal (00:01-05:59) or severe (requiring assistance of another person). RESULTS: During the treatment period, IDegAsp (n = 131) had significantly lower overall and nocturnal hypoglycaemia rates with similar glycaemic efficacy, versus BIAsp 30 (n = 132). During Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: -0.54 mmol/L [-1.02; -0.07]95% CI, p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30. CONCLUSIONS: IDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue.

Day-to-Day and Within-Day Variability in Glucose-Lowering Effect Between Insulin Degludec and Insulin Glargine (100 U/mL and 300 U/mL): A Comparison Across Studies.

BACKGROUND: Insulin degludec (IDeg) has significantly lower day-to-day and within-day variability compared to insulin glargine (IGlar) 100U/mL (U100) and 300U/mL (U300). Here, we report post hoc assessments to confirm the robustness of these observations while accounting for potential experimental confounders. METHODS: Two euglycemic clamp studies in type 1 diabetes patients, comparing IDeg to IGlar-U100 (Study A, parallel design, 54 patients; Study B, crossover, 22 patients) and one study comparing IDeg to IGlar-U300 (Study C, crossover, 57 patients), all dosed at 0.4U/kg, were evaluated. Pharmacodynamic parameters were assessed at steady state from glucose infusion rate (GIR) profiles following three 24-hour euglycemic clamps in Studies A (162 clamps) and C (342 clamps), and one 42-hour clamp in Study B (44 clamps). RESULTS: Pooled data (Studies A and B) showed that IDeg had an even distribution of glucose-lowering effect over the 24-hour dosing interval that was consistent with Study C. IGlar-U100 showed a constant decrease in glucose-lowering effect over 24 hours while IGlar-U300 had a lower effect in the middle of the dosing interval (6-18 hours). Relative within-day variability of IDeg was 40% and 37% lower than IGlar-U100 and -U300, respectively. Exclusion of profiles with low response in Study C (19/342 clamps) did not impact the difference in the distribution of glucose-lowering effect or within-day variability. Day-to-day variability was significantly lower with IDeg compared to IGlar-U100 and -U300 based on smoothed and unsmoothed GIR data. CONCLUSIONS: Significantly lower relative within-day and day-to-day variability was confirmed irrespective of experimental considerations for IDeg compared to IGlar-U100 and IGlar-U300.

Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes.

AIM: To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes. MATERIALS AND METHODS: In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period. RESULTS: Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P < .0001). The distribution of glucose-lowering effect was stable across 6-hour intervals (24%-26%) for IDeg, while IGlar-U300 had greater effects in the first (35%) and last (28%) intervals compared with 6 to 12 hours (20%) and 12 to 18 hours (17%). Within-day variability (relative fluctuation) was 37% lower with IDeg than with IGlar-U300 (estimated ratio IDeg/IGlar-U300: 0.63, 95% CI 0.54; 0.73; P < .0001). The day-to-day variability in glucose-lowering effect with IDeg was approximately 4 times lower than IGlar-U300 (variance ratio IGlar-U300/IDeg: 3.70, 95% CI 2.42; 5.67; P < .0001). The day-to-day variability in glucose-lowering effect assessed in 2-hour intervals was consistently low with IDeg over 24 hours, but steadily increased with IGlar-U300 to a maximum at 10 to 12 hours and 12 to 14 hours after dosing (variance ratios 12.4 and 11.4, respectively). CONCLUSION: IDeg has lower day-to-day and within-day variability than IGlar-U300 and a more stable glucose-lowering effect, which might facilitate titration and enable tighter glycaemic control with a reduced risk of hypoglycaemia.