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Neuropsychiatric safety with liraglutide 3.0 mg for weight management: Results from randomized controlled phase 2 and 3a trials

Aims Liraglutide, a GLP‐1 receptor agonist, regulates appetite via receptors in the brain. Because of concerns regarding the potential of centrally‐acting anti‐obesity medications to affect mental health, pooled neuropsychiatric safety data from all phase 2 and 3a randomized, double‐blind trials with liraglutide 3.0 mg were evaluated post hoc. Methods Data from the liraglutide weight‐management programme were pooled. Across trials, individuals with a body mass index ≥30 or ≥27 kg/m2 with weight‐related comorbidities were randomized to once‐daily subcutaneous liraglutide 3.0 mg (n = 3384) or placebo (n = 1941), both with a 500 kcal/d deficit diet, plus exercise. Adverse events related to neuropsychiatric safety were collected in all trials. Additionally, in the phase 3a trials, validated mental‐health questionnaires were prospectively and systematically administered. Results In the pooled analysis of 5325 randomized and exposed individuals, rates of depression (2.1 vs 2.1 events/100 person‐years) and anxiety (1.9 vs 1.7 events/100 person‐years) through adverse event reporting were similarly low in liraglutide and placebo groups. Nine (0.3%) individuals receiving liraglutide and 2 (0.1%) receiving placebo reported adverse events of suicidal ideation or behaviour. In phase 3a trials, mean baseline Patient Health Questionnaire‐9 scores of 2.8 ± 3.0 vs 2.9 ± 3.1 for liraglutide vs placebo improved to 1.8 ± 2.7 vs 1.9 ± 2.7, respectively, at treatment end; 34/3291 individuals (1.0%) receiving liraglutide 3.0 mg vs 19/1843 (1.0%) receiving placebo reported suicidal ideation on the Columbia‐Suicide Severity Rating Scale. Conclusions Results of this exploratory pooled analysis provide no cause for concern regarding the neuropsychiatric safety of treatment with liraglutide 3.0 mg in patients similar to those included in the examined trials. Although there was a small numerical imbalance in suicidal ideation with liraglutide through adverse event reporting, no between‐treatment imbalances in suicidal ideation/behaviour or depression were noted through prospective questionnaire assessments.


| INTRODUCTION
Obesity is a global health problem 1 and is associated with multiple comorbidities, 2,3 premature mortality, 4 impaired health-related quality of life 5 and individual, societal and economic costs. 6 While initially effective for many individuals, diet or behaviour modification alone is often difficult to sustain and many individuals regain weight upon discontinuation. 2 Pharmacotherapy for chronic weight management may serve as an adjunct to lifestyle intervention in enabling individuals to achieve and sustain clinically relevant weight loss.
Given that many of the approved anti-obesity medications are centrally-acting appetite suppressants, neuropsychiatric safety has become an area of interest. [7][8][9] Rimonabant, the first selective central cannabinoid (CB1) receptor antagonist, was never approved by the Food and Drug Administration (FDA) because of concerns regarding psychiatric adverse events, including depression, anxiety and suicidal ideation. 10 Rimonabant was withdrawn by the European Medicines Agency (EMA) in 2009, leading to termination of development of several CB1-receptor blockers for the treatment of obesity. 11,12 However, many potential treatments aimed at varied molecular targets in the central nervous system (CNS) are still under development. 8,9,11 Adding to the complexity of the situation is the fact that, in general, obese individuals have a higher prevalence of neuropsychiatric disorders, such as depression, compared to the general population. 13,14 Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that regulates appetite centrally via receptors in the hypothalamus and other areas of the brain. 15 Weight loss with liraglutide is mediated by reduced appetite and energy intake rather than by increased energy expenditure. 16 The clinical development programme for liraglutide concerning weight management comprised one phase 2 dose-finding trial, which demonstrated weight loss with liraglutide doses up to 3.0 mg over 2 years, 17 and a large global phase 3a programme called SCALE (Satiety and Clinical Adiposity -Liraglutide Evidence in individuals with and without diabetes). The SCALE programme was designed to investigate the efficacy and safety of liraglutide 3.0 mg in 4 randomized, double-blind, placebo-controlled trials (1 during 3 years, 2 during 56 weeks and 1 during 32 weeks) in over 5300 adults. Treatment with liraglutide 3.0 mg led to observed mean weight loss from baseline, ranging from 5.7% to 8.0% (6.0-8.4 kg) depending on the SCALE trial, whereas mean weight loss in the placebo group ranged from 0.1% to 2.6% (0.1-2.8 kg). [18][19][20][21][22] Liraglutide, administered at a once-daily subcutaneous dose of 3.0 mg, is now approved for weight management in several regions, including North America and Europe.
This post hoc analysis evaluates pooled neuropsychiatric safety data from the 5 randomized, double-blind and placebo-controlled trials described above, including data from 2 mental health questionnaires that were used in the 4 SCALE trials. Because of the evolving regulatory and safety concerns described above, psychiatric disorders were identified as medical events of special interest in the phase 3a liraglutide 3.0 mg clinical development programme, providing an opportunity for prospective evaluation of depression and suicidality.

| METHODS
This is a post hoc analysis and comprehensive report of pooled neuropsychiatric safety data from the liraglutide weight management programme. The 5 trials were performed at clinical research sites in accordance with the Declaration of Helsinki 23 and Good Clinical Practice guidelines, 24 and the respective protocols were approved by local institutional review boards or ethics committees. All participants provided written informed consent before the trials began. See Table S1, Supporting Information online, for further information about the trials, including inclusion/exclusion criteria and primary endpoints; full methodology details have been reported previously. 17-22

| Participants
Each trial enrolled men and women with a body mass index (BMI) of ≥27 kg/m 2 and with at least 1 weight-related comorbidity, or a BMI of ≥30 kg/m 2 (Table S1, Supporting Information). Key exclusion criteria included type 1 or 2 diabetes (except for the SCALE Diabetes trial which specifically enrolled individuals with type 2 diabetes), the use of medications causing significant weight gain or loss, previous bariatric surgery, or a history of chronic pancreatitis or idiopathic acute pancreatitis. Psychiatric illness was not excluded in the phase 2 trial, as this was not a regulatory requirement at the time, but individuals were excluded from the phase 3a trials for the following reasons: history of major depressive disorder within the last 2 years; a Patient Health Questionnaire-9 (PHQ-9) score ≥ 15 (indicating moderately severe/severe depression) at screening; history of other severe psychiatric disorders; lifetime history of a suicide attempt; or history of suicidal behaviour or suicidal ideation type 4 (active suicidal ideation with some intent to act without specific plan) or type 5 (active suicidal ideation with specific plan and intent) according to the Columbia-Suicide Severity Rating Scale (C-SSRS) during the month before randomization.

| Interventions
All participants self-administered treatment with once-daily subcutaneous liraglutide or placebo in FlexPen devices (Novo Nordisk A/S, Bagsvaerd, Denmark), starting at a dose of 0.6 mg with weekly 0.6mg increments to 3.0 mg. This pooled analysis compared data with liraglutide 3.0 mg and placebo only; additional liraglutide doses were investigated in the phase 2 dose-finding trial (1.2, 1.8 and 2.4 mg) and the SCALE Diabetes trial (1.8 mg), but those doses were not included in this analysis since they are not approved for weight management. Furthermore, for the phase 2 trial, only data up to 1 year were included for liraglutide 3.0 mg and placebo; after that, all liraglutide-or placebo-treated individuals were switched to treatment with liraglutide 2.4 mg and, thereafter, to 3.0 mg. 17 Diet and exercise counselling, provided at approximately monthly intervals, was similar across trials. [17][18][19][20][21][22] Participants were advised (in groups or individually) to follow a reduced-calorie diet with an energy deficit of~500 kcal/d below their estimated total energy expenditure, containing a maximum of 30% energy from fat,~20% from protein and~50% from carbohydrates. The diet was reinforced by the use of 3-day food diaries, and pedometers were provided to encourage participants to achieve a recommended minimum of 150 min/wk of physical activity.

| Neuropsychiatric safety
In each trial, adverse events in the system organ classes of "psychiatric disorders" and "nervous system disorders" were identified using MedDRA (Medical Dictionary for Regulatory Activities) coding. In the phase 3a trials, psychiatric disorders were classified as medical events of special interest to ensure that brief narratives were collected, also for non-serious adverse events. These narratives were limited to a free-text description of the event by the investigator, such as relevant medical history.
In the phase 3a trials, 2 validated mental health questionnaires were employed for detecting possible depression (PHQ-9) 25 or suicidal ideation and behaviour (C-SSRS). 26 These were completed at screening, randomization and each visit to the clinic during treatment (except the dose-titration visits in the SCALE Maintenance trial) and each took approximately 10 minutes to complete. Suicidal behaviour was defined as: (1) death by suicide, (2) suicidal attempts where there was intention to die or (3) nonfatal, self-injurious acts committed without intent to die. The PHQ-9 was self-administered and consisted of 9 questions used for detecting possible depression and monitoring treatment. 25 The C-SSRS (available at http://www.cssrs.columbia.edu/) was administered as an interview by the investigator or sufficiently trained medical personnel. 26 The investigator reviewed the PHQ-9 and C-SSRS questionnaires for completeness, together with any reported adverse events at each visit.

| Statistical analyses
All available randomized individuals who received at least 1 treatment dose of liraglutide 3.0 mg or placebo from the 5 randomized, controlled weight management trials were included in the analyses. For the change from baseline to end-of-treatment in the PHQ-9 total score, a treatment difference was estimated, using an ANCOVA model that included the baseline PHQ-9 total score as a covariate and treatment and trial as factors. None of the trials was powered to identify differences in adverse event rates; hence, adverse events were analysed using descriptive statistics and no testing for significance was undertaken.

| Participant characteristics
Baseline characteristics of the 5325 randomized and exposed individuals are displayed in Table 1, and were generally comparable for lira-  Data are presented as mean (SD), unless otherwise stated, and are reported for randomized individuals who were exposed to at least 1 dose of liraglutide or placebo. Individuals from France were not required to report race. Ethnicity was not collected in the phase 2 trial. Anxiety includes the high-level terms "anxiety symptoms" and "anxiety disorders not elsewhere classified." Dyslipidaemia and hypertension were based on reported medical history. Cardiovascular disease was based on standardized (Medical Dictionary for Regulatory Activities; MedDRA) queries regarding ischaemic heart disease, cardiac failure, central nervous system haemorrhages, cerebrovascular conditions, and embolic and thrombotic events. 3.2 | Neuropsychiatric safety data by adverse event reporting

| Adverse events
Adverse events in the system organ classes of psychiatric and nervous system disorders in the pooled analysis across all 5 trials are shown in Table 2. Overall rates of psychiatric disorder were similar for liraglutide 3.0 mg and placebo. Most events were non-serious and did not lead to participant withdrawal. Rates of depression, anxiety and insomnia were similarly low in both treatment groups (Table 2), though insomnia rates were marginally higher in the liraglutide group.

Treatment groups were similar in terms of proportion of participants
showing improvement or worsening from baseline to their maximum total PHQ-9 score at any time of treatment (Table 3).
Mental health questionnaire information for individuals reporting suicide-related adverse events is shown in Table S3, Supporting Information. PHQ-9 total scores at baseline indicated no depression or mild depression for all 11 individuals. Eight of the 11 individuals showed increases during treatment in maximum PHQ-9 score from baseline, with 2 scores in the moderately severe or severe depression category.
Question 9 of the PHQ-9 asks the respondent to report how often over the previous 2 weeks he or she has "been bothered by thoughts that you would be better off dead or of hurting yourself in some way?" Of the 11 individuals reporting suicide-related events, the maximum post-baseline response to this question was a 0 ("not at all") for 5 in the liraglutide group and both of those in the placebo group, a 1 ("several days") for 3 in the liraglutide group, and a 3 ("nearly every day") for 1 liraglutide group member (see Supporting Information for details).

| Columbia-Suicide Severity Rating Scale (C-SSRS)
On Data were for individuals in the safety analysis set (all exposed individuals), and show the shift from randomization to maximum PHQ-9 total score during treatment. Blue shading represents improvement and grey shading represents worsening. No shading denotes no change. No individuals were in the severe category at randomization. b Three individuals changed to the moderately severe category (which was exclusionary at screening) between screening and baseline.

| Neuropsychiatric safety data following treatment discontinuation
All of the SCALE trials, except the SCALE Sleep Apnoea trial, had a 12-week off-treatment observational follow-up period to evaluate withdrawal or rebound effects of discontinuing liraglutide treatment.
No neuropsychiatric safety signals, through adverse event reporting, PHQ-9 or C-SSRS data collection at the end of the 12-week time period, were evident to indicate any withdrawal or rebound effects. Overall, no evidence suggests that a positive history of these types of events should be a contraindication for treatment with liraglutide.

| DISCUSSION
Several studies have revealed positive associations between BMI and some psychiatric disorders, including depression and anxiety, 14 with some differences between men and women. 13 In one epidemiological study, individuals with obesity were 1.5 times more likely than those of normal weight to report such disorders occurring during their lifetime or in the past year, and anxiety rates were increased not only in individuals with obesity, but also in those who were moderately overweight. 28 Individuals with obesity are also more likely to experience insomnia, according to a recent review. 29 There appears to be a reciprocal link between depression and obesity, 30  We note that the information obtained from adverse-event reporting and that from questionnaires used in the SCALE trials were  Data were for individuals in the safety analysis set (all exposed individuals) and represent responses obtained at any time during treatment. The number and percentage of specific ideation types sum to more than that of any ideation because individuals may have more than 1 type over time.
a Including data from the 4 phase 3a SCALE trials (1 of 160 weeks' duration, 2 of 56 weeks' duration and 1 of 32 weeks' duration). SCALE Obesity and Prediabetes had 2 parts: a 56-week period for individuals with and without prediabetes; individuals with prediabetes at screening continued in the second part of the trial for up to 160 weeks of treatment.
A limitation of this analysis is that it was performed in a population that was selected according to trial-specific eligibility criteria, and does not necessarily cover the full spectrum of patients who might be treated outside of clinical trials, as individuals at high-risk for psychiatric disorders were excluded. Furthermore, the trial was not powered to quantify a treatment effect on the event rate of psychiatric disorders, suggesting the importance of further investigation.
While the PHQ-9 and the C-SSRS are validated mental-health questionnaires and may be useful as rapid assessment screening tools, their limitations, as compared to longer structured assessments, should also be noted. Strengths of the analysis include the overall large sample size and the substantial exposure to liraglutide 3.0 mg in the blinded trials, as well as the systematic prospective collection of neuropsychiatric safety data by trained staff. In