The co-formulation of insulin degludec and insulin aspart lowers fasting plasma glucose and rates of confirmed and nocturnal hypoglycaemia, independent of baseline glycated haemoglobin levels, disease duration or body mass index: A pooled meta-analysis of phase III studies in patients with type 2 diabetes

Martin Haluzík, Greg Fulcher, Thomas R Pieber, Lars Bardtrum, Deniz Tutkunkardas, Helena W Rodbard, Martin Haluzík, Greg Fulcher, Thomas R Pieber, Lars Bardtrum, Deniz Tutkunkardas, Helena W Rodbard

Abstract

Aims: To investigate whether the proven benefits of insulin degludec (IDeg) combined with insulin aspart (IAsp), known as IDegAsp, given twice daily, extend across a wide spectrum of patients with diabetes.

Materials and methods: This was a post hoc pooled analysis of 5 phase III randomized, 26-week, open-label, treat-to-target trials comparing IDegAsp twice daily (n = 1111) with one of two comparators: premixed insulin (biphasic insulin aspart 30 [BIAsp 30]) twice daily (n = 561) or IDeg once daily + IAsp (n = 136). Patient data were stratified according to baseline glycated haemoglobin (HbA1c) or fasting plasma glucose (FPG) categories, as well as by baseline duration of diabetes or body mass index (BMI) categories.

Results: We conducted a meta-analysis of 5 clinical trials: NCT01513590, NCT01009580, NCT01059812, NCT01680341 and NCT01713530. End-of-trial results were broadly consistent, with differences between IDegAsp and comparators observed in phase III trials. HbA1c results were similar for IDegAsp and the comparators in all baseline characteristic (HbA1c, duration of diabetes or BMI) and category groups (number ranges). Significantly lower FPG level was observed with IDegAsp vs comparators in all baseline characteristic and most category groups (excluding FPG <5.5 mmol/L). Significantly lower insulin doses were observed with IDegAsp vs comparators in all baseline characteristic and half of the category groups, and significantly lower rates of confirmed and nocturnal confirmed hypoglycaemia were observed with IDegAsp vs comparators in all baseline variable and category groups.

Conclusions: IDegAsp retains a consistent safety and efficacy profile in patients with different baseline characteristics.

Keywords: glycaemic control; hypoglycaemia; insulin analogues; meta-analysis; randomized trial; type 2 diabetes.

Conflict of interest statement

M.H. has received research support from Eli Lilly, Bristol‐Myers Squibb and AstraZeneca, and personal fees as consultant or lecturer from AstraZeneca, Eli Lilly, Sanofi Aventis, Novartis and Novo Nordisk. G.F. has received honoraria, teaching and research sponsorship/grants from AstraZeneca, Boehringer Ingelheim, Janssen, MSD, Novartis, Novo Nordisk, Sanofi Aventis and Servier SA. T.R.P. has received research support from Novo Nordisk (paid directly to the Medical University of Graz), and personal fees as a consultant from AstraZeneca, Bristol‐Myers Squibb, Eli Lilly, Novo Nordisk and Roche Diabetes Care. He is also the CSO of CBmed (Center for Biomarker Research in Medicine), a public‐funded research company. L.B. is an employee of, and holds stock in, Novo Nordisk A/S. D.T. is an employee of, and holds stock in, Novo Nordisk A/S. H.W.R. has served on advisory panels for Amylin Pharmaceuticals Inc., AstraZeneca Pharmaceuticals LP, Biodel Inc., Bayer Health Care LLC, Merck, Novo Nordisk A/S, Roche Pharmaceuticals and Sanofi, as a consultant for Biodel Inc., Merck, Roche Pharmaceuticals and Takeda Pharmaceuticals USA Inc, Merck and Sanofi, has received research support from AstraZeneca Pharmaceuticals LP, Biodel Inc., Boehringer Ingelheim Pharmaceuticals Inc., Hamni, Janssen Pharmaceuticals, Eli Lilly and Company, Merck, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Roche Pharmaceuticals and Sanofi, and has served as a speaker for AstraZeneca Pharmaceuticals LP, BMS, Boehringer Ingelheim Pharmaceuticals Inc., Janssen, Eli Lilly and Company, Merck, Novo Nordisk A/S, Sanofi and Takeda Pharmaceuticals USA Inc.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Glycated haemoglobin (HbA1c) at end of trial stratified by: A, HbA1c category (mmol/mol); B, diabetes duration (years); and C, BMI (kg/m2). Data are mean (SEM) from full analysis set, LOCF. Comparators: biphasic insulin aspart 30 (BIAsp 30; NCT01009580, NCT01059812, NCT01513590), insulin degludec (IDeg) once daily + insulin aspart (IAsp; NCT01713530); Trial NCT01680341: insulin degludec/insulin aspart (IDegAsp) Simple and IDegAsp Step‐wise arms are considered within the IDegAsp group. EOT, end of trial
Figure 2
Figure 2
Fasting plasma glucose (FPG, mmol/L) at end of trial (EOT) by: A, baseline FPG (mmol/L), B, diabetes duration (years) and C, body mass index (BMI, kg/m2). Data are mean (SEM) from the full analysis set, LOCF. **P < .001; ***P < .0001. Comparator: biphasic insulin aspart 30 (BIAsp 30; NCT01009580, NCT01059812, NCT01513590), insulin degludec (IDeg) once daily + insulin aspart (IAsp; NCT01713530). Trial NCT01680341: IDegAsp Simple and IDegAsp Step‐wise arms are considered within the IDegAsp group
Figure 3
Figure 3
Rate ratios and 95% confidence intervals (CIs) for confirmed hypoglycaemia (per 100 patient‐years of exposure) stratified by: A, glycated haemoglobin (HbA1c) category (mmol/mol); B, diabetes duration (years); and C, body mass index (BMI, kg/m2). Data are rate ratios, insulin degludec/insulin aspart (IDegAsp) vs comparator (95% CI), and are from the full analysis set, LOCF. *P < .05; **P < .01; ***P < .0001. Comparator: biphasic insulin aspart 30 (BIAsp 30; NCT01009580, NCT01059812, NCT01513590), insulin degludec (IDeg) once daily + insulin aspart (IAsp; NCT01713530). Trial NCT01680341: IDegAsp Simple and IDegAsp Step‐wise arms are considered within the IDegAsp group. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or has a recorded plasma glucose <3.1 mmol/L (56 mg/dL)
Figure 4
Figure 4
Rate ratios and 95% confidence intervals (CIs) for nocturnal confirmed hypoglycaemia (per 100 patient‐years of exposure) stratified by: A, glycated haemoglobin (HbA1c) category (mmol/mol); B, diabetes duration (years); and C, body mass index (BMI, kg/m2). Data are rate ratios, insulin degludec/insulin aspart (IDegAsp) vs comparator (95% CI), and are from the full analysis set, LOCF. *P < .05; **P < .01; ***P < .0001. Comparators: biphasic insulin aspart 30 (BIAsp 30; NCT01009580, NCT01059812, NCT01513590), insulin degludec (IDeg) once daily + insulin aspart (IAsp; NCT01713530). Trial NCT01680341: IDegAsp Simple and IDegAsp Step‐wise arms are considered within the IDegAsp group. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or has a recorded plasma glucose <3.1 mmol/L (56 mg/dL). Nocturnal period: the period between 12:01 am and 5:59 am (both inclusive)

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