Adding fast-acting insulin aspart to basal insulin significantly improved glycaemic control in patients with type 2 diabetes: A randomized, 18-week, open-label, phase 3 trial (onset 3)

Abstract

Aim: To confirm glycaemic control superiority of mealtime fast-acting insulin aspart (faster aspart) in a basal-bolus (BB) regimen vs basal-only insulin.

Materials and methods: In this open-label, randomized, 18-week trial (51 sites; 6 countries), adults (n = 236) with inadequately controlled type 2 diabetes (T2D; mean glycosylated haemoglobin [HbA1c] ± SD: 7.9% ± 0.7% [63.1 ± 7.5 mmol/mol]) receiving basal insulin and oral antidiabetic drugs underwent 8-week optimization of prior once-daily basal insulin followed by randomization 1:1 to either a BB regimen with faster aspart (n = 116) or continuation of once-daily basal insulin (n = 120), both with metformin. Primary endpoint was HbA1c change from baseline after 18 weeks of treatment. Secondary endpoints included: postprandial plasma glucose (PPG) change and overall PPG increment (all meals); weight; treatment-emergent adverse events; hypoglycaemic episodes.

Results: HbA1c decreased from 7.9% (63.2 mmol/mol) to 6.8% (50.7 mmol/mol; BB group) and from 7.9% (63.2 mmol/mol) to 7.7% (60.7 mmol/mol; basal-only group); estimated treatment difference [95% confidence interval] -0.94% [-1.17; -0.72]; -10.3 mmol/mol [-12.8; -7.8]; P < .0001. Reductions from baseline in overall mean 2-hour PPG and overall PPG increment for all meals (self-measured plasma glucose profiles) were statistically significant in favour of BB treatment ( P < .0001). Severe/blood glucose confirmed hypoglycaemia rate (12.8 vs 2.0 episodes per patient-years of exposure), total daily insulin (1.2 vs 0.6 U/kg) and weight gain (1.8 vs 0.2 kg) were greater with BB than with basal-only treatment.

Conclusions: In T2D, faster aspart in a BB regimen provided superior glycaemic control as compared with basal-only insulin, but with an increase in the frequency of hypoglycaemia and modest weight gain.

Trial registration: ClinicalTrials.gov NCT01850615.

Keywords: glycaemic control; hypoglycaemia; insulin therapy; phase 3 study; randomized trial; type 2 diabetes.

Conflict of interest statement

H. W. R. reports receipt of grants and personal fees from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, Sanofi and Regeneron. M. D. and S. T. are employees of Novo Nordisk. M. P. reports receipt of personal fees from Aventis, Lilly and Novo Nordisk. D. T. and M. V. V. have no conflicts of interest to disclose.

© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Participant disposition. A total of 323 participants entered the run‐in period of the trial; the most common reason for failure during the run‐in period was failure to meet randomization criteria (HbA1c 7.0%‐9.0% [53‐75 mmol/mol]) at Visit 9 (Week –1). The pattern of withdrawal was low and comparable between groups, with 94.1% of participants completing the trial. HbA1c, glycosylated haemoglobin

Figure 2

Observed mean HbA1c change from baseline to Week 18 (A), participants who achieved target HbA1c (B) and PPG levels (C) at Week 18. *P < .0001. Error bars: ± standard error of the mean. HbA1c targets: <7.0% (53.0 mmol/mol) and ≤6.5% (47.5 mmol/mol), and <7.0% (53.0 mmol/mol) and ≤6.5% (47.5 mmol/mol) without SH. PPG (based on SMPG) target: 2‐hour PPG ≤ 7.8 mmol/L (140 mg/dL) and 2‐hour PPG ≤7.8 mmol/L (140 mg/dL) without SH. Basal insulin: insulin detemir, insulin glargine U100 or NPH insulin. CI, confidence interval; faster aspart, fast‐acting insulin aspart; HbA1c, glycosylated haemoglobin; NPH, neutral protamine Hagedorn; OR, estimated odds ratio; PPG, postprandial plasma glucose; SH, severe hypoglycaemia during treatment period; SMPG, self‐measured plasma glucose. The conversion factor used for glucose between mmol/L and mg/dL was 0.0555

Figure 3

Eight‐point SMPG profiles at baseline (A) and Week 18 (B). Values are based on the full analysis set and averaged for each time point ± standard error of the mean. Basal insulin: insulin detemir, insulin glargine U100 or NPH insulin. Faster aspart, fast‐acting insulin aspart; NPH, neutral protamine Hagedorn; SMPG, self‐measured plasma glucose. The conversion factor used for glucose between mmol/L and mg/dL was 0.0555