Elsevier

The Lancet

Volume 379, Issue 9825, 21–27 April 2012, Pages 1489-1497
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(12)60204-9Get rights and content

Summary

Background

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.

Methods

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 [HbA1c] ≤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 HbA1c after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228.

Findings

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, HbA1c 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 HbA1c 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.

Interpretation

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.

Funding

Novo Nordisk.

Introduction

The physiological replacement of insulin in patients with type 1 diabetes mellitus is challenging because exogenous insulin needs to cover both basal and meal-related (bolus) insulin requirements. In landmark trials, intensive basal-bolus therapy was successful in improving glycaemic control and reducing the risk of long-term complications that are associated with type 1 diabetes mellitus.1, 2

The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend a glycated haemoglobin (HbA1c) target of less than 7% (<53 mmol/mol), without substantial hypoglycaemia.3, 4 A history of hypoglycaemia and the fear of further episodes, particularly at night, can lead to poor adherence to treatment and compromise glycaemic control.5, 6, 7, 8 Nocturnal hypoglycaemia is associated with poor quality of sleep, decreased sense of wellbeing, fatigue, and reduced productivity.5, 7, 9, 10

The risk of hypoglycaemia is partly due to impaired protective endocrine and physiological responses but limitations in subcutaneous insulin delivery contribute substantially to hypoglycaemic risk. Subcutaneous absorption is not reproducible and insulin entry directly into the peripheral circulation (bypassing portal circulation) is not linked to glucose sensing. Insulin analogues have been developed to improve the physiological coverage of the need for insulin. Basal insulin analogues such as insulin glargine and insulin detemir have longer duration of action and lower risks of hypoglycaemia than neutral protamine Hagedorn insulin, especially at night.11 However, neither insulin reliably provides 24 h basal insulin replacement on all days in all patients with type 1 diabetes mellitus, and once-daily dosing with these analogues can be inadequate; thus, an insulin with a more predictable and longer duration of action is needed.12

Insulin degludec is an ultra-longacting insulin that is in clinical development. On subcutaneous injection, it forms a depot of soluble multihexamers from which insulin is slowly and continuously absorbed into the circulation.13 Pharmacokinetic data show that insulin degludec has a flat, stable profile at steady state and a terminal half-life of more than 25 h, which is twice that of insulin glargine, and a duration of action greater than 40 h.13, 14 In a phase 2 trial, glycaemic control with insulin degludec in patients with type 1 diabetes mellitus was similar to that with insulin glargine but the rate of hypoglycaemia was lower,15 perhaps because in pharmacodynamic studies the day-to-day variability with insulin degludec was four times lower.16

We compared the efficacy and safety of insulin degludec with that of insulin glargine, both administered once daily in a basal-bolus regimen with rapid-acting insulin aspart as meal-time insulin in participants with type 1 diabetes mellitus in this BEGIN Basal-Bolus Type 1 trial.

Section snippets

Study design and participants

In a 52 week, randomised, controlled, open-label, multinational, parallel design, treat-to-target, non-inferiority trial, participants with type 1 diabetes mellitus were given insulin degludec or insulin glargine, with insulin aspart as the meal-time insulin. The trial was undertaken at 79 sites that were university-affiliated, public and private hospitals and clinical research centres in six countries (France, Germany, Russia, South Africa, the UK, and the USA).

Adults (aged ≥18 years) who had

Results

626 of 629 participants who were randomly assigned to treatment between Sept 1, 2009, and Nov 8, 2010, were given one of the trial drugs, and most (404 [86%] of 472 in insulin degludec group and 137 [87%] of 157 in insulin glargine group) completed the trial (figure 1). The overall withdrawal pattern was similar in the two groups.

Baseline characteristics were representative of a population with type 1 diabetes mellitus with reasonably good glycaemic control (mean HbA1c 7·7%, 60·7 mmol/mol,

Discussion

Reduction in HbA1c concentration from baseline with insulin degludec and insulin glargine was similar, thus establishing non-inferiority of insulin degludec to insulin glargine in improving long-term glycaemic control in type 1 diabetes. Further evidence of improved glycaemic control with both insulins was the reduction in FPG and SMPG. Mean SMPG before breakfast was significantly lower with insulin degludec than with insulin glargine; reduction in laboratory-reported FPG tended to be greater

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