Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

Abstract

BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.

Keywords: Addiction; Clinical Trials; Neuroimaging; Neuroscience; Pharmacology.

Conflict of interest statement

Conflict of interest: AFJ has received an unrestricted research grant from Novo Nordisk A/S to investigate the effects of GLP-1 receptor stimulation on weight gain and metabolic disturbances in patients with schizophrenia treated with an antipsychotic. TV has served on scientific advisory panels for, been part of speaker’s bureaus for, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, Mundipharma, MSD/Merck, Novo Nordisk, and Sun Pharmaceutical Industries. HB has received honoraria from Washington University Seminar. JJH has received consulting fees from Novo Nordisk A/S and grants from the Novo Nordisk Foundation. GMK has received personal honoraria from Sage Biogen, H. Lundbeck A/S, and Sanos and serves as president of the European College of Neuropsychopharmacology (unpaid) and chair of the Science and Infrastructure Advisory Board for the Human Brain Project (personal honorarium). SVK has received grants from the German Research Foundation. JM has received honoraria from H. Lundbeck A/S. KWM has received honoraria from H. Lundbeck A/S and Janssen. The funding sources and the manufacturer of exenatide once weekly (Bydureon, AstraZeneca) had no influence on the trial design or data analysis.

Figures

Figure 1. CONSORT flow diagram.

Study diagram of patient flow according to CONSORT 2010 statement. Details regarding initial meetings and ineligibility for screening can be found in Supplemental Figure 3, and a flowchart for the 6-month follow-up can be found in Supplemental Figure 1. Of the 127 patients included in the study, 65 patients were randomized to 2 mg exenatide once weekly, and 62 patients were randomized to placebo. Thirty-two patients from the exenatide group and 26 patients from the placebo group completed the study after 26 weeks of trial participation. AUDIT, Alcohol Use Disorders Identification Test; CIWA-Ar, Clinical Institute Withdrawal Assessment for Alcohol, Revised.

Figure 2. Kaplan-Meier survival curve of patients who withdrew from the trial or were lost to follow-up.

The time to discontinuation was not significantly different in the 2 groups (P = 0.46). Input data are the number of injections + 1 because patients were registered as discontinued in the week after the last injection was received. All patients are included (n = 127). Censoring is indicated by the + mark.

Figure 3. Reduction in heavy drinking days.

Mean percentage heavy drinking days in the last 30 days, measured with the Time-Line Follow Back (TLFB) method, at all assessments (week 0, week 4, week 12, week 20, week 26). Data were analyzed with an ANOVA adjusted for baseline, and missing data were imputed with the use of multiple imputations as described in the text (n = 127). Data represent mean ± SEM.

Figure 4. Reduction in heavy drinking days in BMI subgroups.

Exploratory analysis of mean percentage heavy drinking days in the last 30 days, measured with the TLFB method, at all assessments (week 0, week 4, week 12, week 20, week 26) within the BMI subgroups. Normal weight, n = 52; BMI > 30, n = 30. Only significant findings from Supplemental Table 7 are included. Data were analyzed with an ANOVA adjusted for baseline, and missing data were imputed with the use of multiple imputations as described in the text. Data represent mean ± SEM.

Figure 5. Reduction in total alcohol intake in BMI subgroups.

Exploratory analysis of mean total alcohol intake in the last 30 days, measured with the TLFB method, at all assessments (week 0, week 4, week 12, week 20, week 26) within the BMI subgroups. BMI > 25, n = 75; BMI > 30, n = 30. Only significant findings from Supplemental Table 7 are included. Data were analyzed with an ANOVA adjusted for baseline, and missing data were imputed with the use of multiple imputations as described in the text. Data represent mean ± SEM.

Figure 6. fMRI ALCUE ROI results.

(A) Key fMRI findings showed reduced cue reactivity after 26 weeks of treatment with exenatide compared with placebo. Analysis revealed statistically significant interaction between the treatment and time on fMRI response in all 3 ROIs: ventral striatum [F(1,31) = 4.744, P = 0.037, partial η2 =0.133], dorsal striatum [F(1,31) = 6.124, P = 0.019, partial η2 = 0.165], putamen [F(1,31) = 4.730, P = 0.037, partial η2 = 0.132]. *P < 0.05. (B) In more detail, we found that at week 26, cue-induced activity was significantly lower in ventral striatum after treatment with exenatide compared with placebo (M = –0.176, SE = 0.075, P = 0.025), but not in dorsal striatum (M = –0.142, SE = 0.076, P = 0.073) nor in putamen (M = –0.123, SE = 0.084, P = 0.153). At baseline, cue-induced activity did not differ significantly between groups. Within the exenatide group, cue-induced activity was significantly reduced from baseline to week 26 in ventral striatum (M = –0.254, SE = 0.116, P = 0.044) and in dorsal striatum (M = –0.351, SE = 0.156, P = 0.039), but not in putamen (M = –0.405, SE = 0.202, P = 0.063). Within the placebo group, no statistically significant differences were found. (A and B) ROI data were analyzed using a repeated-measures ANOVA including factors group and time and an independent sample 2-tailed t test comparing groups (placebo and exenatide). Placebo, n = 16; exenatide, n = 17. Boxes represent upper and lower quartiles, the line represents the median, and the X represents the mean. Horizontal lines indicate significant interactions between treatment and time (*P < 0.05), and brackets indicate significant simple effects (*P < 0.05).

Figure 7. fMRI ALCUE whole-brain results.

Reduced cue-induced activation in the exenatide group compared with the placebo group after 26 weeks of treatment in the left caudate and septal area (x, y, z coordinates = 0, 0, 4) (A) and right middle frontal gyrus (x, y, z coordinates = 36, 20, 48) (B). A 2-sample 2-tailed t test was performed for the post hoc analyses to compare groups (placebo, exenatide) and within a group across time (placebo/exenatide: T1, T2). For the group comparisons, the contrast of interest used was ‘alcohol > neutral stimuli’, where the probability of a family wise error (FWE) was set to 0.05 to control for multiple statistical testing. Using the AlphaSim (3dClustSim) method, a combined voxel wise threshold of P < 0.001 and a cluster extent threshold of 101 voxels were calculated (n = 22).

Figure 8. fMRI spatial working memory task (N-back task).

The exenatide group showed a reduction at follow-up in the response to the 2-back > 1-back task compared with the placebo group (2-way mixed-effect ANOVA; placebo, n = 16; exenatide, n = 17; control, n = 25) in 2 prefrontal clusters (frontal pole x, y, z = 34, 54, 20, corrected P < 0.002; superior frontal gyrus x, y, z = 4, 46, 46, corrected P < 0.001). Boxes represent upper and lower quartiles, the line represents the median, and the X represents the mean. dlPFC, dorsolateral prefrontal cortex; dmPFC, dorsomedial prefrontal cortex.

Figure 9. SPECT DAT results combined.

(A) Baseline DAT availability in striatum, caudate, and putamen in AUD patients did not differ from that in healthy controls. Data were analyzed with a 1-way ANCOVA, adjusted for baseline DAT availability. Healthy controls, n = 21; patients at baseline, n = 45. (B) At the week 26 rescan, DAT availability in striatum, caudate, and putamen was significantly lower in the exenatide group compared with the placebo group [striatum, F(1,13) = 4.978, P = 0.044; caudate, F(1,13) = 8.066, P = 0.014; putamen, F(1,13) = 6.571, P = 0.024]. Data were analyzed with an ANCOVA adjusted for age. Placebo, n = 9; exenatide, n = 7. *P < 0.05. (A and B) Boxes represent upper and lower quartiles, the line represents the median, and the X represents the mean.