Efficacy and Safety of Insulin Degludec in a Flexible Dosing Regimen vs Insulin Glargine in Patients With Type 1 Diabetes ( BEGIN: Flex T1): A 26-Week Randomized, Treat-to-Target Trial With a 26-Week Extension

and Institute of Life Sciences (S.C.B.), Swansea University, SA2 8QA Swansea, United Kingdom.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 02/2013; 98(3). DOI: 10.1210/jc.2012-3249
Source: PubMed


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.

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.

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.

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Available from:, Sep 14, 2015 · License: CC BY-NC
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    • "There are several plausible explanations for this discrepancy. First, the targeted fasting blood glucose levels were more strictly defined (79–90 mg/dL) in the phase 3 trials678 which would increase the likelihood of nocturnal hypoglycemic events. Second, only symptomatic and self-monitored blood glucose levels under 56 mg/dL were reported as hypoglycemia in the phase 3 trials, while the definition in the current study was any blood glucose value under 70 mg/dL using CGM. "
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    ABSTRACT: To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes.
    Full-text · Article · Nov 2015 · Endocrine Journal
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    • "However, the concentration of IDeg-specific antibodies and antibodies cross-reacting with IDeg and human insulin was found to be low in studies in patients with T1DM [48, 49] or T2DM [50, 53], indicating that the risk of immunogenicity with IDeg is minimal. Furthermore, the studies showed that there was no apparent association between the development of cross-reacting antibodies and hypoglycaemia, HbA1c or insulin dose [48, 49, 53]. "
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    ABSTRACT: Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. To date, a large number of studies have been conducted to investigate the pharmacokinetic and pharmacodynamic properties of IDeg. Standardised methods for collection and analysis of blood samples (for pharmacokinetic endpoints) and euglycaemic clamp procedures (for pharmacodynamic endpoints) were applied across studies to enable cross-study evaluation of important pharmacokinetic and pharmacodynamic parameters. Data show that IDeg has a half-life of >25 h [compared with ~12 h for insulin glargine (IGlar)] and reaches steady state within 3 days of administration in all patient populations investigated. The pharmacokinetic profile of IDeg demonstrates an even distribution of exposure across one dosing interval. The pharmacodynamic profile of IDeg is flat and stable, demonstrated by an even distribution of glucose-lowering effect across all four 6-h intervals in a 24-h period (one dosing day). These properties were consistently demonstrated across different type 1 and type 2 diabetes mellitus patient populations, including those from different ethnic origins (both males and females with type 2 diabetes), the elderly, and patients with hepatic or renal impairment. IDeg has an ultra-long duration of action exceeding 42 h and demonstrates four times lower day-to-day within-subject variability in glucose-lowering effect than IGlar. This review discusses the pharmacokinetic and pharmacodynamic data accumulated thus far, and the relevance of these results from a clinical perspective.
    Full-text · Article · Sep 2014 · Clinical Pharmacokinetics
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    • "Previous studies have shown that insulin degludec and insulin glargine or detemir achieve similar glycemic control, but the frequency of nocturnal hypoglycemia was lower in patients treated with insulin degludec [8–13]. Heise et al. [14] showed that degludec had a significantly more predictable glucose-lowering effect on day-to-day variability than glargine. "
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    ABSTRACT: Objective The aim of this study was to analyze the changes in daily blood glucose fluctuation and insulin dose in patients with type 1 diabetes mellitus (T1DM) undergoing basal-bolus therapy following a switching of basal insulin used from insulin glargine or detemir to insulin degludec. Methods Seven patients with T1DM were enrolled. All patients treated with insulin glargine or detemir twice daily were switched to insulin degludec with 80–90 % of the prior insulin dose. During the study period, the basal insulin doses were adjusted by the attending physician. The patients underwent continuous glucose monitoring before, 3 days after, and 24 weeks after switching to insulin degludec. The daily insulin dose was analyzed before, 3 days after, and 24 weeks after switching. Glycated hemoglobin levels were measured before and 24 weeks after switching. Results The blood glucose profile did not change significantly before and after switching. On the other hand, the total daily insulin dose and total daily basal insulin dose decreased significantly 24 weeks after switching. Discussion In patients with T1DM undergoing insulin glargine or detemir treatment, it is possible to achieve similar glycemic control in the medium term with a once daily, lower dose of insulin degludec.
    Preview · Article · May 2014 · Drugs in R & D
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