Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized controlled trials

Abstract

Aim: To evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and ADJUNCT TWO trials.

Materials and methods: ADJUNCT ONE and ADJUNCT TWO were randomized controlled phase 3 trials in 1398 and 835 participants with T1D treated with liraglutide (1.8, 1.2, or 0.6 mg) or placebo (adjuncts to insulin). This post hoc analysis evaluated treatment effects by subgroups: HbA1c (< or ≥8.5%), body mass index (BMI; < or ≥27 kg/m2 ), and insulin regimen (basal bolus or continuous subcutaneous insulin infusion).

Results: In both trials at week 26, reductions in HbA1c, body weight, and daily insulin dose did not differ significantly (P > .05) by baseline HbA1c or BMI. Risk of clinically significant hypoglycaemia or hyperglycaemia with ketosis did not differ significantly (P > .05) by baseline HbA1c, BMI, or insulin regimen. At week 26 in ADJUNCT ONE, these risks did not differ (P > .05) between treatment groups. Placebo-adjusted reductions in HbA1c, body weight, and insulin dose (-0.30%-points, -5.0 kg, and -12%, respectively, with liraglutide 1.8 mg), were significant (P < .05), greater than at week 52, and similar to those in ADJUNCT TWO (-0.35%, -4.8 kg, and -10%, respectively, with liraglutide 1.8 mg).

Conclusions: In ADJUNCT ONE and ADJUNCT TWO, the efficacy and glycaemic safety of liraglutide did not depend on subgroups, leaving residual beta-cell function as the only identified variable impacting the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in T1D. These findings support a role for GLP-1 RAs as adjuncts to insulin in T1D, warranting further study.

Trial registration: ClinicalTrials.gov NCT02098395 NCT01836523.

Keywords: clinical trial; incretin therapy; liraglutide; type 1 diabetes.

Conflict of interest statement

Five of the authors of this report are employees of the sponsor and, as such, were involved in the preparation, review, and approval of the manuscript. TFD: Advisory board for Novo Nordisk; lecture fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi; research grant from Novo Nordisk and AstraZeneca. BJvS: Employee and shareholder of Novo Nordisk A/S. EC: Employee and shareholder of Novo Nordisk A/S. FFK: Employee and shareholder of Novo Nordisk A/S. LB: Employee and shareholder of Novo Nordisk A/S. MvH: Employee and shareholder of Novo Nordisk A/S. CM: serves or has served on the advisory panel for Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet, and Zealand Pharma. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for CM from Medtronic, Novo Nordisk, Sanofi, and ActoBio Therapeutics; CM serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca, and Novartis. Financial compensation for these activities has been received by KU Leuven. SM: Advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, and Bayer; lecture fees from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, and Sanofi; research grant from Novo Nordisk and Boehringer Ingelheim.

© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

HbA1c and insulin use: week 26. Data are estimated mean changes from baseline (bars) and estimated treatment differences versus placebo with 95% confidence intervals at week 26 in ADJUNCT ONE (left panels) and in ADJUNCT TWO (right panels). Estimates are shown for change in HbA1c (panels A‐D) and total daily insulin dose (panels E‐H) by subgroups by baseline HbA1c level (HbA1c 2). Estimates were derived from a mixed model for repeated measurements with treatment, subgroup, stratification, visit, and country as fixed factors, and baseline value as a fixed covariate; the model also included the interaction between subgroup and treatment group, and the interactions between each model term and visit, and group mean estimates were adjusted according to the observed baseline distribution in each subgroup. Postbaseline on‐treatment data (data collected on or after the first day on treatment and no later than the day after the last day on treatment) were included in the analysis. Unless indicated (*), the estimated placebo‐adjusted treatment effect did not differ statistically significantly within subgroups for all liraglutide dose levels (all tests for interaction between treatment and group were not statistically significant). *Indicates a statistically significant test for interaction between treatment and group. BMI, body mass index; N, number of participants

FIGURE 2

Body weight: week 26. Data are estimated mean changes from baseline (bars) and estimated treatment differences versus placebo with 95% confidence intervals at week 26 in ADJUNCT ONE (left panels) and in ADJUNCT TWO (right panels). Panels A‐D, estimates are shown for change in body weight, by subgroups, by baseline HbA1c level (2). Estimates were derived from a mixed model for repeated measurements with treatment, subgroup, stratification, visit, and country as fixed factors, and baseline value as a fixed covariate; the model also included the interaction between subgroup and treatment group, and the interactions between each model term and visit, and group mean estimates were adjusted according to the observed baseline distribution in each subgroup. Postbaseline on‐treatment data (data collected on or after the first day on treatment and no later than the day after the last day on treatment) were included in the analysis. The estimated placebo‐adjusted treatment effect did not differ statistically significantly within subgroups for all liraglutide dose levels (all tests for interaction between treatment group and subgroup were not statistically significant). BMI, body mass index; N, number of participants

FIGURE 3

Hyperglycaemia with ketosis and hypoglycaemia (clinically significant): week 26. Data are estimated mean rate ratios versus placebo with 95% confidence intervals at week 26 in ADJUNCT ONE (left panels) and in ADJUNCT TWO (right panels). Estimates are shown for hyperglycaemic episodes with ketosis (episodes with plasma glucose >16.7 mmol/L and plasma ketone >1.5 mmol/L) (panels A‐F), and clinically significant hypoglycaemic episodes (symptomatic hypoglycaemic episodes as defined by Novo Nordisk as severe according to the American Diabetes Association and a plasma glucose value 20 ) (panels G‐L), by subgroups, by baseline HbA1c level (< or ≥8.5% [69 mmol/mol]), by baseline BMI (< or ≥27 kg/m2), and by type of insulin treatment used at baseline (basal bolus or CSII). Episodes are treatment‐emergent (onset on or after the first day on treatment and no later than the day after the last day on treatment). Estimates were derived from a negative binomial regression model with a log‐link and with treatment, subgroup, country, stratification factor, and the interaction between treatment and subgroup as factors, baseline HbA1c as a covariate, and the logarithm of the exposure time as offset. Unless indicated (*), the episode rate ratio did not differ statistically significantly within subgroups for all liraglutide dose levels. *Indicates a statistically significant test for interaction between treatment and group. BMI, body mass index; CSII, continuous subcutaneous insulin infusion