BEGIN Basal-Bolus Type 1 Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): A phase 3, randomised, open-label, treat-to-target non-inferiority trial

University of Sheffield, Sheffield, UK. s.heller@sheffi
The Lancet (Impact Factor: 45.22). 04/2012; 379(9825):1489-97. DOI: 10.1016/S0140-6736(12)60204-9
Source: PubMed


Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes.
In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin [HbA(1c)] ≤10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA(1c) after 52 weeks, with the intention-to-treat analysis. This trial is registered with, number NCT00982228.
Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA(1c) had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference -0·01% points [95% CI -0·14 to 0·11]; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA(1c) of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1·07 [0·89 to 1·28]; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 [0·59 to 0·96]; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups.
Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy.
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    • "Another clinical concern with IDeg includes the potential for immunogenicity. 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.
    Clinical Pharmacokinetics 09/2014; 53(9). DOI:10.1007/s40262-014-0165-y · 5.05 Impact Factor
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    • "In conclusion, the development and introduction of long-acting insulin analogs represented a dramatic step forward in diabetes care, fulfilling the clinical need for a basal insulin analog (which was hinted at by NPH insulin almost half a century previously). Insulin glargine now represents a reference basal insulin against which future developments in long-acting insulin analogs are measured [70, 126, 127]. "
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    ABSTRACT: The epoch-making discovery of insulin heralded a new dawn in the management of diabetes. However, the earliest, unmodified soluble insulin preparations were limited by their short duration of action, necessitating multiple daily injections. Initial attempts to protract the duration of action of insulin involved the use of various additives, including vasoconstrictor substances, which met with limited success. The subsequent elucidation of the chemical and three-dimensional structure of insulin and its chemical synthesis and biosynthesis allowed modification of the insulin molecule itself, resulting in insulin analogs that are designed to mimic normal endogenous insulin secretion during both fasting and prandial conditions. Insulin glargine was the first once-daily, long-acting insulin analog to be introduced into clinical practice more than 10 years ago and is specifically designed to provide basal insulin requirements. It has a prolonged duration of action and no distinct insulin peak, making it suitable for once-daily administration and reducing the risk of nocturnal hypoglycemia that is seen with intermediate-acting insulins. Insulin glargine can be used in combination with prandial insulin preparations and non-insulin anti-diabetic agents according to individual requirements. Electronic supplementary material The online version of this article (doi:10.1007/s40265-014-0226-4) contains supplementary material, which is available to authorized users.
    Drugs 05/2014; 74(8). DOI:10.1007/s40265-014-0226-4 · 4.34 Impact Factor
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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.
    Drugs in R & D 05/2014; 14(2). DOI:10.1007/s40268-014-0048-6 · 1.71 Impact Factor
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