Liraglutide 3.0 mg for the management of insufficient weight loss or excessive weight regain post‐bariatric surgery

Summary To assess the effectiveness of liraglutide 3.0 mg in post‐bariatric surgery patients, and to determine whether this would differ based on the type of bariatric surgery. One hundred seventeen post‐bariatric surgery patients from the Wharton Medical Clinic were analysed. Changes in weight while taking liraglutide 3.0 mg were examined for all patients, and by three types of bariatric surgery—Roux‐en‐Y gastric bypass, gastric banding and gastric sleeve. Patients primarily underwent Roux‐en‐Y gastric bypass (n = 53, 45.3%) or gastric banding (n = 50, 42.7%). Over 7.6 ± 7.1 months taking liraglutide 3.0 mg, patients lost a statistically significant amount of weight (−6.3 ± 7.7 kg, P < .05) regardless of the type of surgery they had (P > .05). This decrease in weight remained significant after 1‐year of taking liraglutide 3.0 mg (P < .05). Nausea was the most prevalent side effect, reported by 29.1% patients. While options for excess weight management in post‐bariatric surgery patients are limited, results of this study suggest that post‐bariatric surgery patients can lose a significant amount of weight while taking liraglutide 3.0 mg regardless of the type of surgery they had. Further, similar to non‐surgical populations, post‐bariatric surgery patients taking liraglutide 3.0 mg may experience gastrointestinal side effects such as nausea and can continue to lose weight up to 1 year.


| INTRODUCTION
Bariatric surgery is considered the gold standard treatment for weight loss in patients with obesity and complications of obesity, based on superior long-term weight loss outcomes, and improvements in comorbidities compared to lifestyle and pharmaceutical interventions. 1 Despite the dramatic weight loss achieved with bariatric surgery (30%-45% weight loss 2 ), 10% to 20% of bariatric surgery patients will regain a significant amount of the weight they had lost, 3 which can be defined as a patient regaining 10% to 25% of excess weight or total weight lost. 4 Regardless, as greater number of patients have surgery, the concern of weight regain post-surgery has become significant.
In 2015, liraglutide 3.0 mg was approved for the treatment of excess weight in Canada. 5 In non-surgical populations, liraglutide 3.0 mg has been found to be associated with significant reductions in appetite and weight. 6 However, as surgical patients were excluded from phase III weight management pharmaceuticals trials, the effectiveness of liraglutide 3.0 mg in this population is unknown. Thus, the objective of the current study was to examine the weight loss associated with the use of liraglutide 3.0 mg in post-bariatric surgery patients. There was a total of 649 post-bariatric surgery patients referred to WMC for weight management and who consented for their data to be used for research. Of these, 174 patients were prescribed liraglutide 3.0 mg for weight management. Patients were excluded if they did not initiate liraglutide 3.0 mg, resulting in 117 patients for analysis. Of the 57 patients who did not initiate liraglutide 3.0 mg, 10 were lost to follow-up, and three initiated Contrave (an oral weight management medication). The remaining 44 patients participated in the lifestyle intervention at the clinic without adjunctive therapies.
Over the 14.7 ± 24.0 months these patients attended the clinic, they lost 2.1 ± 9.0 kg (P > .05). The reason for not initiating liraglutide 3.0 mg was recorded for only six patients, and all stated it was due to cost.

| WMC protocol
WMC procedures have been previously discussed in greater detail elsewhere. 7 During the initial visit to the clinic, patients complete a comprehensive intake questionnaire on demographics, and medical and weight management history. Anthropometric measurements are done on all patients by trained technicians. Height is measured by a wall-mounted tape to the nearest 0.1 cm (McArthur Medical Sales, Inc., Ontario), and weight which is measured using a digital scale to the nearest 0.1 kg (Itin Scale Co, Inc., New York). Subsequently, patients attend an introductory educational session about WMC's policies and procedures, followed by an appointment with a bariatric educator and medical doctor. The bariatric educator provides weight management support by establishing dietary changes and exercise regimes. The medical doctor examines and reviews the patient's medical history, discusses pharmaceutical management or surgical intervention where clinically indicated. Patients who choose to initiate liraglutide 3.0 mg are recommended to follow a dosing schedule starting at 0.6 mg that is titrated 0.6 mg/mL until reaching the maximum clinical dosage of 3.0 mg, but this may vary in clinical practice. 8 The physician orders blood work, resting metabolic rate test and other relevant tests for each patient.
Patients are given a meal plan at their third visit which includes a caloric deficit of approximately 500 kcal/day based on their daily energy expenditure. The bariatric educator reviews the meal plan with the patient and discusses food alternatives and snacks. The patient also meets with the physician who examines the patient, reviews the updated anthropometric measurements, and monitors comorbidities and pharmaceuticals.
Following the initial three visits, patients are encouraged to attend monthly appointments at the clinic; however, patients may attend more often if they desire. At all subsequent appointments patients meet with a physician and/or a bariatric educator for continued weight management support.
Weight (kg), height (cm), sex (female/male), age (years), treatment time (months) and type of bariatric surgery (ie, adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RNYGB) and gastric sleeve), maximum dose achieved on liraglutide 3.0 mg, side effects, and reason for discontinuation were extracted from electronic medical records.

| Statistical analysis
Continuous variables are reported as mean ± SD and categorical variables as frequency (prevalence). Independent t test was undertaken to compare weight change between patients who did and did not achieve the recommended clinical dose of liraglutide 3.0 mg. One-way analysis of variance (ANOVA) was used to examine differences in age, body mass index (BMI), treatment time, percent changes in weight, and the side effect nausea and repeated measures ANOVA was used to examine absolute changes in weight based on the type of bariatric surgery patients had underwent. Least-square difference post-hoc was used where indicated. Differences in sex and the proportion of individuals achieving ≥5% and ≥10% weight loss based on the type of bariatric surgery were assessed using chi-square analysis. Changes in weight were compared in 2-month increments from 1-month postinitiation up to 1 year based on the type of bariatric surgery using proc mixed. Changes in weight loss were also compared using proc mixed for patients who were persistent on liraglutide 3.0 mg for ≤2 months, >2 to ≤4 months, and >4 months using proc mixed. All analyses were conducted using SAS version 9.4 (SAS Institute). A P-value ≤.05 was considered statistically significant.

| RESULTS
One hundred seventeen patients were included in the analysis.
Patients who had undergone RNYGB had a lower BMI prior to initiating liraglutide 3.0 mg than patients who had received a AGB or sleeve gastrectomy (P < .05, Table 1). Regardless of the surgery, patients who took liraglutide 3.0 mg lost a similar amount of weight (P > .05). Patients experienced a significant weight loss as early as 1 to 2 months post-initiation of liraglutide 3.0 mg, which remained significant up to 1 year of taking the medication (P < .05) regardless of the type of bariatric surgery they had (P > .05, Figure 1). Further, on average those persistent on liraglutide 3.0 mg lost significantly more weight by 11 to 12 months post-initiation than at 5 to 6 months (2.0 ± 7.4 kg, P = .004). As expected, patients who discontinued liraglutide 3.0 mg within 4 months lost less weight early in the treatment as compared to patients who remained on the drug for greater than 4 months (data not shown, P < .05).
More than half of the participants (n = 73 of 117, 62.4%) achieved the recommended maximum clinical dose of 3.0 mg. Of the participants (n = 94 of 117, 80%) that had taken liraglutide 3.0 mg for long enough (ie, >1 month) to titrate to the recommended maximum clinical dose, 25.5% (n = 24 of 94) did not achieve the recommended maximum clinical dose. The proportion of patients who did not achieve the recommended maximum clinical dose of 3.0 mg was similar regardless of type of bariatric surgery (P = .29). Patients who were persistent on liraglutide 3.0 mg for more than 1 month (n = 94 of 117) lost a similar amount of weight whether or not they achieved the recommended maximum clinical dose (7.4 ± 6.9 vs 6.8 ± 11.4, P = .81).
A total of 92 side effects were reported among 59 of 117 patients (50.4%, Table 2). Gastrointestinal side effects were the most preva-  Overall, the medication appeared to be well tolerated, with only three patients reporting discontinuing due to adverse events (ie, two patients due to an allergic reaction, and one patient due to pancreatitis). Pancreatitis is a known potential side effect of liraglutide 3.0 mg and may occur in 0.1% to 0.3% of patients. 5 In the current study, the proportion was slightly higher but this could be attributed to our smaller sample size. Nonetheless, these results suggest that the side effects experienced by patients with bariatric surgery are similar to those reported in non-bariatric surgery patients taking liraglutide 3.0 mg and supports the notion that this medication may be a safe option to manage excess weight in post-bariatric surgery patients.
Our study has several strengths and limitations that warrant men-   These results are promising as current methods for weight management in post-bariatric surgical patients are limited, and often have greater risks to the patient than the initial procedure itself. More research, using a more rigorous study design, is still necessary to determine the reproducibility of these results and whether certain weight management pharmaceuticals may be more efficacious for post-bariatric surgery patients than others.

ACKNOWLEDGEMENTS
Our sincere thanks to Wali Mir and Maral Dehlehhosseinzadeh for their work in abstracting data for the analyses. In addition, we would also like thank the patients at the Wharton Medical Clinic who consented for their data to be used, and the staff who worked with the patients and collected the data, without which it would not have been possible to conduct this research.

CONFLICTS OF INTEREST
S.W. is the Medical Director of the Wharton Medical Clinic, and an internal medicine specialist with privileges at Toronto East General Hospital, and Hamilton Health Sciences. S.W. has received payment in the past from Novo Nordisk, Eli Lilly, Janssen, and Astra Zeneca for