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Efficacy and safety of insulin degludec three times a week versus insulin glargine once a day in insulin-naive patients with type 2 diabetes: results of two phase 3, 26 week, randomised, open-label, treat-to-target, non-inferiority trials

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Summary

Background

Results of an exploratory phase 2 study showed that insulin degludec, a basal insulin with an action profile of longer than 42 h, provided similar glycaemic control when injected three times a week (IDeg 3TW) to once-daily insulin glargine (IGlar OD). To provide further evidence, we did two phase 3 trials to compare the efficacy and safety of IDeg 3TW with IGlar OD in insulin-naive patients with type 2 diabetes.

Methods

In two 26 week, randomised, open-label, parallel group, non-inferiority trials IDeg was injected Monday, Wednesday, and Friday before breakfast (IDeg 3TWAM) in the AM trial (94 sites in seven countries) or with the evening meal (IDeg 3TWPM) in the PM trial (89 sites in seven countries), and compared with IGlar OD. Adults with type 2 diabetes (HbA1c 7·0–10·0%; body-mass index ≤45 kg/m2) were randomly allocated (1:1) without stratification by a central interactive response system to IDeg 3TW or IGlar OD. Both groups continued taking metformin with or without dipeptidyl peptidase-4 inhibitors. Insulin was titrated to achieve a prebreakfast self-monitored blood glucose (SMBG) concentration of between 3·9 and less than 5·0 mmol/L. The primary outcome was non-inferiority of IDeg 3TW compared with IGlar OD, as assessed by change in HbA1c from baseline to 26 weeks (non-inferiority limit of 0·4%) by ANOVA in an intent-to-treat analysis (full analysis set). These trials are registered with ClinicalTrials.gov, numbers NCT01068678 and NCT01076647.

Findings

We recruited 460 patients for the AM trial (IDeg 3TWAM, n=230; IGlar OD, n=230) and 467 patients for the PM trial (IDeg 3TWPM, n=233; IGlar OD, n=234). After 26 weeks, mean HbA decreased by 0·9% (IDeg 3TWAM) and 1·3% (IGlar OD) in the AM trial, and by 1·1% (IDeg 3TWPM) and 1·4% (IGlar OD) in the PM trial. Non-inferiority was not confirmed in either trial (estimated treatment difference [IDeg 3TWAM–IGlar OD] 0·34%, 95% CI 0·18–0·51; [IDeg 3TWPM–IGlar OD] 0·26%, 0·11–0·41). Across the two trials, rates of confirmed hypoglycaemia (SMBG <3·1 mmol/L or severe [needing assistance]) ranged from 1·0 to 1·6 episodes per patient-year and were similar for IDeg 3TWAM and IGlar OD (estimated rate ratio [ERR] 1·04, 95% CI 0·69–1·55), but higher for IDeg 3TWPM than for IGlar OD (ERR 1·58, 1·03–2·43). The rate of nocturnal confirmed hypoglycaemia was higher for IDeg 3TWAM than for IGlar OD (ERR 2·12, 1·08–4·16); we noted no significant difference between IDeg 3TWPM and IGlar OD (ERR 0·60, 0·21–1·69).

Interpretation

The inferior glycaemic control and increased risk of hypoglycaemia with IDeg 3TW compared with IGlar OD do not support a three-times-weekly dosing regimen.

Funding

Novo Nordisk.

Introduction

Insulin degludec is a basal insulin analogue that forms a soluble depot of multihexamers after subcutaneous injection,1 resulting in a long half-life (about 25 h) and a consistent glucose-lowering effect that lasts longer than 42 h.2, 3, 4 Results of phase 3a treat-to-target trials in patients with type 1 and type 2 diabetes have shown that once-daily insulin degludec provides similar glycaemic control to insulin glargine but with lower rates of hypoglycaemia, particularly during the night.5, 6, 7, 8 Insulin degludec is approved for once-daily dosing in the European Union, Japan, and Mexico and is under regulatory review in other countries; the US Food and Drug Administration (FDA) has requested additional cardiovascular data from a dedicated cardiovascular outcomes trial before their review can be completed.

On the basis of the ultra-long pharmacokinetic and pharmacodynamic profile of insulin degludec, a three-times-weekly dosing regimen was explored in a 16 week, proof-of-concept phase 2, treat-to-target trial in patients with type 2 diabetes.9 In that trial, insulin degludec injected three times a week (IDeg 3TW) provided similar glycaemic control to once-daily insulin glargine (IGlar OD), with similar rates of hypoglycaemia.9 Because a three-times-weekly dosing schedule might, for some patients, be an appealing alternative to the once-daily dosing regimens required by basal insulin analogues, larger, phase 3 trials to further test this treatment and dosing schedule were deemed important.

The objective of this study was to analyse the data from two 26 week, phase 3 trials that compared the efficacy and safety of IDeg 3TW with IGlar OD in previously insulin-naive patients with type 2 diabetes inadequately controlled by oral antidiabetic (OAD) treatments.

Section snippets

Study design and participants

Both phase 3 trials were of identical design (26 week, randomised, treat-to-target, two-arm, parallel group, and open-label), differing only in terms of whether insulin degludec was administered in the morning before the first meal of the day (AM trial) or with the main evening meal (PM trial). The AM trial was done at 94 sites in seven countries (Canada, Czech Republic, Israel, Slovakia, South Africa, UK, and USA) from February to November, 2010; the PM trial was done at 89 sites in seven

Results

Of the 705 participants screened in the AM trial, and the 677 participants screened in the PM trial, 460 (AM) and 467 (PM) were randomly assigned to treatment (figure 1). Similar proportions of participants completed treatment in each trial (figure 1). Within each trial, baseline and demographic characteristics in the full analysis set (ie, all randomised patients excluding one patient in the IDeg 3TWAM trial who was randomised in error) were well matched between groups, except for slight

Discussion

In both trials, clinically relevant improvements in long-term glycaemic control (HbA1c) were recorded for IGlar OD and IDeg 3TW, although the HbA1c reduction was greater with IGlar OD. Indeed, irrespective of whether insulin degludec was injected in the morning or evening, non-inferiority to IGlar OD with respect to change in HbA1c from baseline was not established. IDeg 3TW was also inferior to IGlar OD in terms of reductions from baseline in laboratory-measured FPG and SMBG concentrations.

References (17)

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