Elsevier

The Lancet

Volume 379, Issue 9825, 21–27 April 2012, Pages 1498-1507
The Lancet

Articles
Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial

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Summary

Background

Basal insulin therapy does not stop loss of β-cell function, which is the hallmark of type 2 diabetes mellitus, and thus diabetes control inevitably deteriorates. Insulin degludec is a new, ultra-longacting basal insulin. We aimed to assess efficacy and safety of insulin degludec compared with insulin glargine in patients with type 2 diabetes mellitus.

Methods

In this 52 week, phase 3, open-label, treat-to-target, non-inferiority trial, undertaken at 123 sites in 12 countries, we enrolled adults (aged ≥18 years) with type 2 diabetes mellitus and a glycated haemoglobin (HbA1c) of 7·0–10·0% after 3 months or more of any insulin regimen (with or without oral antidiabetic drugs). We randomly allocated eligible participants in a 3:1 ratio to receive once-daily subcutaneous insulin degludec or glargine, stratified by previous insulin regimen, via a central interactive response system. Basal insulin was titrated to a target plasma glucose concentration of 3·9–<5·0 mmol/L self-measured before breakfast. The primary outcome was non-inferiority of degludec to glargine measured by change in HbA1c from baseline to week 52 (non-inferiority limit of 0·4%) by ANOVA in the full analysis set. We assessed rates of hypoglycaemia in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00972283.

Findings

744 (99%) of 755 participants randomly allocated degludec and 248 (99%) of 251 allocated glargine were included in the full analysis set (mean age 58·9 years [SD 9·3], diabetes duration 13·5 years [7·3], HbA1c 8·3% [0·8], and fasting plasma glucose 9·2 mmol/L [3·1]); 618 (82%) and 211 (84%) participants completed the trial. After 1 year, HbA1c decreased by 1·1% in the degludec group and 1·2% in the glargine group (estimated treatment difference [degludec–glargine] 0·08%, 95% CI −0·05 to 0·21), confirming non-inferiority. Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe episodes requiring assistance) were lower with degludec than glargine (11·1 vs 13·6 episodes per patient-year of exposure; estimated rate ratio 0·82, 95% CI 0·69 to 0·99; p=0·0359), as were rates of nocturnal confirmed hypoglycaemia (1·4 vs 1·8 episodes per patient-year of exposure; 0·75, 0·58 to 0·99; p=0·0399). Rates of severe hypoglycaemia seemed similar (0·06 vs 0·05 episodes per patient-year of exposure for degludec and glargine) but were too low for assessment of differences. Rates of other adverse events did not differ between groups.

Interpretation

A policy of suboptimum diabetes control to reduce the risk of hypoglycaemia and its consequences in advanced type 2 diabetes mellitus might be unwarranted with newer basal insulins such as degludec, which are associated with lower risks of hypoglycaemia than insulin glargine.

Funding

Novo Nordisk.

Introduction

The landmark UK Prospective Diabetes Study (UKPDS)1 showed that, because of unremitting loss of β-cell function that characterises type 2 diabetes mellitus, a substantial number of patients need insulin therapy after 9 years or more of disease. Moreover, many patients need intensification to a basal-bolus insulin regimen after 3–5 years of basal insulin treatment.1 Hypoglycaemia is the main restricting factor in glycaemic management of type 2 diabetes mellitus, leading to physical and psychosocial morbidity and perhaps even mortality.2 Variability in absorption and duration of action and time-action profile peaks associated with administration of subcutaneous insulin can contribute to hypoglycaemia. Therefore, we need an effective basal insulin with a long, flat, and stable profile, and a lowered risk of hypoglycaemia.

Insulin degludec is an ultra-longacting basal insulin in clinical development for the treatment of diabetes. Insulin degludec forms soluble multihexamers on subcutaneous injection, resulting in a depot from which monomers are slowly and continuously absorbed into the circulation. This mechanism leads to the reported ultra-long pharmacokinetic and pharmacodynamic profiles and reduced variability in insulin action compared with insulin glargine.3, 4, 5 A previous proof-of-concept phase 2 clinical trial6 comparing once-daily insulin degludec with insulin glargine in patients with type 2 diabetes mellitus not previously treated with insulin showed similar efficacy and suggested lower rates of hypoglycaemia with insulin degludec. In this phase 3, BEGIN Basal-bolus Type 2 study, we aimed to assess the efficacy and safety of insulin degludec compared with insulin glargine in a basal-bolus regimen in patients with longstanding type 2 diabetes mellitus.

Section snippets

Trial design and participants

In our phase 3, 52-week, randomised, treat-to-target, parallel-group, open-label, non-inferiority trial, we compared the efficacy and safety of once-daily insulin degludec with once-daily insulin glargine in a basal-bolus regimen with mealtime insulin aspart, with or without metformin, pioglitazone, or both in participants with type 2 diabetes mellitus. We undertook the trial at 123 sites in 12 countries (Bulgaria, Germany, Hong Kong, Ireland, Italy, Romania, Russia, Slovakia, South Africa,

Results

We enrolled and assessed participants between Sept 1, 2009, and Oct 28, 2010. 618 (82%) of 755 participants randomly assigned insulin degludec and 211 (84%) of 251 randomly assigned insulin glargine completed the trial (figure 1). The proportion of participants who withdrew and reasons for withdrawal were similar in the two groups (figure 1).

Demographic and baseline characteristics were very similar between groups and were representative of a population with type 2 diabetes mellitus requiring

Discussion

In participants with advanced insulin-treated type 2 diabetes mellitus, overall glycaemic reductions as measured by HbA1c concentration resulting from basal-bolus intensive insulin therapy with insulin degludec were non-inferior to those noted for insulin glargine, which was to be expected from the treat-to-target trial design.11 Treat-to-target trials allow investigators to minimise potential differences between treatments in measures of plasma glucose and can show differences in safety

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