Aims/hypothesis The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. Methods This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA 1c 7.5-10%) and combination therapy (7.0-10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA 1c . Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n=232), liraglutide placebo (n=115) and open-label insulin glargine (n=234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times.Electronic supplementary material The online version of this article (doi:10.1007/s00125-009-1472-y) contains a list of members of the LEAD-5 Study Group, which is available to authorised users. Results The number of patients analysed as intention to treat were: liraglutide n=230, placebo n=114, insulin glargine n= 232. Liraglutide reduced HbA 1c significantly vs glargine (1.33% vs 1.09%; −0.24% difference, 95% CI 0.08, 0.39; p= 0.0015) and placebo (−1.09% difference, 95% CI 0.90, 1.28; p<0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference -1.39 kg, 95% CI 2.10, 0.69; p=0.0001), and vs glargine (treatment difference −3.43 kg, 95% CI 4.00, 2.86; p<0.0001). Liraglutide reduced systolic BP (−4.0 mmHg) vs glargine (+0.5 mmHg; −4.5 mmHg difference, 95% CI 6.8, −2.2; p=0.0001) but not vs placebo (p=0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies. Conclusions/interpretation Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA 1c was within the predefined non-inferiority margin.

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Objective:This study investigated the efficacy and safety of insulin degludec (IDeg) once daily (OD), varying injection timing day to day in subjects with type 1 diabetes.Research Design and Methods:This 26-week, open-label, treat-to-target, noninferiority trial compared IDeg forced flexible (Forced-Flex) OD (given in a fixed schedule with a minimum 8 and maximum 40 hours between doses) with IDeg or insulin glargine (IGlar) given at the same time daily OD. In the 26-week extension, all IDeg subjects were transferred to a free-flexible (Free-Flex) regimen, which allowed any-time-of-day dosing, and compared with subjects continued on IGlar.Results:After 26 treatment weeks, mean glycosylated hemoglobin was reduced with IDeg Forced- Flex (−0.40%), IDeg (−0.41%), and IGlar (−0.58%). IDeg Forced-Flex noninferiority was achieved. Fasting plasma glucose reductions were similar with IDeg Forced-Flex and IGlar but greater with IDeg (−2.54 mmol/L) than IDeg Forced-Flex (−1.28 mmol/L) (P = .021). At week 52, IDeg Free-Flex subjects had similar glycosylated hemoglobin but greater fasting plasma glucose reductions than IGlar subjects (−1.07 mmol/L) (P = .005). Confirmed hypoglycemia rates (plasma glucose <3.1 mmol/L or severe hypoglycemia) were similar at weeks 26 and 52. Nocturnal confirmed hypoglycemia was lower with IDeg Forced-Flex vs IDeg (37%; P = .003) and IGlar (40%; P = .001) at week 26 and 25% lower with IDeg Free-Flex vs IGlar (P = .026) at week 52.Conclusions:IDeg can be administered OD at any time of day, with injection timing varied without compromising glycemic control or safety vs same-time-daily IDeg or IGlar. This may improve basal insulin adherence by allowing injection-time adjustment according to individual needs.

OBJECTIVE -Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA 1c , prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration.RESEARCH DESIGN AND METHODS -People with type 1 diabetes (n ϭ 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDet mornϩbed ) or at a 12-h interval (IDet 12h ). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart.RESULTS -With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet 12h vs. NPH, Ϫ1.5 mmol/l [95% CI Ϫ2.51 to Ϫ0.48], P ϭ 0.004; IDet mornϩbed vs. NPH, Ϫ2.3 mmol/l (Ϫ3.32 to Ϫ1.29), P Ͻ 0.001), as was self-measured prebreakfast plasma glucose (P ϭ 0.006 and P ϭ 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P ϭ 0.046; 32%, P ϭ 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDet mornϩbed group (P Ͻ 0.001). Although HbA 1c for each insulin detemir group was not different from the NPH group, HbA 1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference Ϫ0.18% [Ϫ0.34 to Ϫ0.02], P ϭ 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P Ͻ 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet 12h vs. NPH, Ϫ0.8 kg [Ϫ1.44 to Ϫ0.24], P ϭ 0.006; IDet mornϩbed vs. NPH, Ϫ0.6 kg [Ϫ1.23 to Ϫ0.03], P ϭ 0.040).CONCLUSIONS -Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person's needs. Diabetes Care 27:1081-1087, 2004L andmark studies show that intensive diabetes management delays progression of the late complications of type 1 diabetes (1,2). Although the introduction of rapid-acting insulin analogs has given improvement in postprandial blood glucose control, these analogs are not ideal for use with NPH insulin, which has inadequate duration of action to cover nighttime requirements and an undesirable peak effect ϳ5 h after administration (3). These problems, together with the high day-to-day variability in absorption (4,5), present a major barrier to achieving appropriate targets of blood glucose control.These limitations have stimulated the development of a soluble basal insulin analog that does not require resuspension before injection ...