Determinants of Liraglutide Treatment Discontinuation in Type 1 Diabetes: A Post Hoc Analysis of ADJUNCT ONE and ADJUNCT TWO Randomized Placebo-Controlled Clinical Studies

Abstract

Introduction: Two phase 3 randomized controlled studies (ADJUNCT ONE (Clinicaltrials.gov: NCT01836523), ADJUNCT TWO (Clinicaltrials.gov: NCT02098395)) evaluated liraglutide (1.8, 1.2 or 0.6 mg) vs placebo in participants with type 1 diabetes (T1D) as an adjunct to insulin therapy. This paper aims to improve our understanding of the potential mechanisms leading to premature discontinuation of this treatment regimen.

Methods: Post hoc comparisons were conducted on baseline characteristics and adverse event (AE) rates of participants completing and not completing the ADJUNCT studies due to AEs/lack of tolerance using summary tables and variance analysis.

Results: Non-completers (liraglutide and placebo combined) had lower baseline body mass index (BMI) (ADJUNCT ONE: 27.8 kg/m² vs 29.8 kg/m², P < .0001; ADJUNCT TWO: 26.3 kg/m² vs 29.2 kg/m², P < .0001), longer duration of T1D (25.8 years vs 21.0 years, P < .0001; 24.1 years vs 21.0 years, P = .04), lower daily insulin doses by continuous infusion (46.4 U vs 57.3 U, P = .01; 40.9 U vs 57.4 U, P = .12) or multiple injections (58.4 U vs 68.5 U, P = .006; 56.0 U vs 65.8 U, P =.03) and a higher proportion of participants with undetectable C-peptide (91.5% vs 81.3%; 87.0% vs 84.9%) compared to completers. When analyzed by treatment group, only duration of T1D and C-peptide differed between completers and non-completers among liraglutide (and not placebo) participants. The AE rates were higher for non-completers.

Conclusion: Individuals with longer-standing T1D and low levels of C-peptide at baseline were more likely to discontinue adjunctive liraglutide treatment due to AEs/lack of tolerance than individuals with residual insulin production. Lower BMI predicted a greater likelihood of non-completion for the included participants, regardless of treatment. These new findings may be relevant for clinical practice.

Keywords: GLP-1 receptor agonist; adjunctive therapy; baseline data; discontinuation; liraglutide; type 1 diabetes.

Figure 1.

Participant disposition of ADJUNCT ONE (A) and ADJUNCT TWO (B) across the three liraglutide dose groups (1.8 mg, 1.2 mg, 0.6 mg) and placebo. Bars show number N of all randomized participants (blue), completers defined as participants completing the last scheduled visit (week 52 in ADJUNCT ONE and week 26 in ADJUNCT TWO) (green), and non-completers defined as participants discontinuing treatment prematurely due to AEs/lack of tolerance before the last visit (red). The numbers (N) and percentages out of all randomized participants (%) were added above each graph. Note that non-completers in this study were defined as participants withdrawn from the study prematurely due to AEs/lack of tolerance only. Participants withdrawn from the study for other reasons and participants discontinued without being withdrawn were not included in the non-completer definition used here. The details of participant disposition are presented in section “Methods.”

Figure 2.

Box plots of ADJUNCT ONE completers (dark blue) vs ADJUNCT ONE non-completers (light blue) and for ADJUNCT TWO completers (dark green) and ADJUNCT TWO non-completers (light green) for body weight (A), BMI (B), age (C), duration of T1D (D), CSII—total daily insulin dose (E), MDI—total daily insulin dose, (F). Data were combined across all three liraglutide dose groups (1.8 mg, 1.2 mg, and 0.6 mg) and placebo. Lower and upper bounds of the boxes denote 25th and 75th percentiles of the data sets and the line inside the box denotes the median value (50th percentile). The whiskers mark the 10th and 90th percentiles, respectively. Values beyond these lower and upper bounds are denoted by individual dots. Proportion of C-peptide below the LLOQ is presented as a bar plot (G). Statistically significant differences for non-completers vs completers within each of the ADJUNCT studies added according to: *P < .05, **P < .01, ***P < .001, ****P < .0001. No statistical analysis was possible to perform for the C-peptide proportion as this was a single digit. Abbreviations: BMI, body mass index; CSII, continuous subcutaneous insulin infusions; LLOQ, lower level of quantification; MDI, multiple daily insulin injections; SD, standard deviation; T1D, type 1 diabetes.

Figure 3.

Boxplots of completers vs non-completers for ADJUNCT ONE (left column of figures) and ADJUNCT TWO (right column of figures) across all three liraglutide dose groups (1.8 mg, 1.2 mg, and 0.6 mg) and placebo for BMI (A, B), body weight (C, D), duration of T1D (E, F), CSII—total daily insulin dose (G, H), and MDI—total daily insulin dose (I, J). Lower and upper bounds of the boxes denote 25th and 75th percentiles of the data sets, and the line inside the box denotes the median value (50th percentile). The whiskers mark the 10th and 90th percentiles, respectively. Values beyond these lower and upper bounds are denoted by individual dots. Abbreviations: BMI, body mass index; CSII, continuous subcutaneous insulin infusions; MDI, multiple daily insulin injections; SD, standard deviation; T1D, type 1 diabetes.

Figure 4.

Percentage of participants in ADJUNCT ONE (a) and ADJUNCT TWO (b) with C-peptide below LLOQ of 0.03 nmol/L at baseline for completers vs non-completers. Abbreviations: LLOQ, lower level of quantification.