What literature is available on GLP-1 receptor agonists in the setting of bariatric surgery?

Introduction
Defined as a body mass index (BMI) of ≥30 kg/m2 in adults by the World Health Organization (WHO), as of 2022, approximately 890 million adults live with obesity worldwide, with 1 in 8 people considered obese.1 An additional 2.5 billion adults worldwide as of 2022 are considered overweight, which is defined as a BMI of ≥ 25 kg/m2. An increased BMI is considered a risk factor for cardiovascular disease (CVD), diabetes, neurological conditions, chronic respiratory disorders, digestive disorders, and certain cancers. The American Society for Metabolic and Bariatric Surgery (ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) currently recommend metabolic and bariatric surgery (BS) in adults with a BMI of ≥35 kg/m2 in the presence or absence of comorbid conditions, and state that surgery can also be considered in adult patients with a BMI of 30 to 34.9 kg/m2 and metabolic disease.2 The guidelines additionally state that in Asian populations, surgical intervention should be offered at a lower BMI threshold of 27.5 kg/m2. Although surgical interventions are generally more effective than non-surgical interventions for weight loss, insufficient weight loss (IWL) or weight regain (WR) often develops post-procedure.3,4 Insufficent weight loss is defined as an excess weight loss percentage of <50% within 18 months of surgery; however, a standardized definition of WR is not currently available in the literature.3,5 The prevalence of IWL and WR varies depending on the prior type of surgery. After laparoscopic sleeve gastrectomy (LSG), IWL has been reported in 32 to 40% of patients and WR in 27.8% of patients during long-term follow-up. Therapeutic options to reverse WR can include revisional surgery, behavioral and lifestyle interventions, and pharmacotherapy.4 Although revisional surgery has been the primary therapeutic option for patients with a poor response to BS, glucagon-like peptide-1 (GLP-1) receptor agonists have become a promising option.6 This FAQ aims to summarize the emerging evidence on GLP-1 receptor agonists in the setting of BS.

Literature Summary
The available published literature on GLP-1 receptor agonist using in the setting of BS is primarily limited to small observational studies and randomized controlled trials (RCTs), with the majority of evaluating liraglutide and semaglutide for the treatment of WR or IWL after bariatric procedures.7-14 Recently, 2 meta-analyses have been published summarizing the results of these studies for WR or IWL after BS (see Table).7,8 Another small retrospective study by Lautenbach et al that evaluated a lower dose of injectable semaglutide for WR and IWL post-BS, has also been published.9 In the first MA of 8 studies that evaluated injectable semaglutide and liraglutide for WR or IWL post-BS, semaglutide 1 mg weekly was shown to result in a greater percent reduction in body weight when compared to liraglutide (doses of 1.8 to 3 mg daily) at 6 months and at 12 months.7 In 1 study included in the MA, liraglutide use was associated with a significant decrease in fat mass (MD, -4.78 kg; 95% CI, -7.11 to -2.45; p<0.001), lean muscle mass (MD, -3.01 kg; 95% CI, -4.80 to -1.22; p=0.001), and whole-body bone mineral density (MD, -0.02 kg/m2; 95% CI, -0.04 to -0.00; p=0.03).7,10 In the second MA of 6 studies evaluating liraglutide post-BS, liraglutide was associated with a weight loss of 7.9 kg (95% CI, -10.4 to -5.4; p<0.0001) over a treatment period of least 6 months.8 In the studies included in this MA, liraglutide was given at doses ranging from 2 to 3 mg SC daily and was initiated from 6 weeks to 1 year post-surgery. Larger studies (>100 patients) included in these MAs also demonstrated the degree of weight loss with liraglutide to be comparable regardless of the type of prior BS (e.g., adjustable gastric band, laparoscopic gastric banding, one-anastomosis gastric bypass, Roux-en-Y gastric bypass, sleeve gastrectomy, vertical banded gastroplasty), and whether the surgery was primary or revisional.7,8, 10-14 In the study by Lautenbach et al, injectable semaglutide 0.5 mg weekly initiated for IWL or WR after sleeve gastrectomy or Roux-en-Y gastric bypass resulted in a >5% weight loss in 85% of patients, with no differences shown in weight loss based on the previous type of procedure.9 As expected, gastrointestinal side effects such as nausea, vomiting, diarrhea, and constipation were the main adverse effects of GLP-1 receptor agonists across studies, although decreases in fat mass, muscle mass, and bone mineral density were also observed in 1 study.7,9,10

Table 1. Clinical Evidence for GLP-1 Receptor Agonists Post-Bariatric Surgery.7,8
Study design and durationSubjectsInterventionsResultsConclusions
Dutta et al 20247

MA of 8 studies (>8 weeks duration)		N=557 adults with IWL or WR post-BS

Prior surgeries included AGB, LABG, RYGB, SG, VSG		Liraglutide 1.8 mg SC

Liraglutide 3 mg SC

Semaglutide 1 mg SC

PBO

Initiated 6 weeks to 1 year post-surgery
  • Compared to PBO, liraglutide had a significant effect on weight loss after 6 months (MD, -4.29 kg; 95% CI, -8.09 to -0.50)
  • Compared to liraglutide, semaglutide demonstrated a greater percent reduction in body weight at 6 months (MD, -2.57%; 95% CI, -3.91 to -1.23; p<0.001, I2=0%) and 12 months (MD, -4.15%; 95% CI, -6.96 to -1.34; p=0.004)
  • A significant decrease in fat mass (MD, -4.78 kg; 95% CI, -7.11 to -2.45; p<0.001), lean muscle mass (MD, -3.01 kg; 95% CI, -4.80 to -1.22; p=0.001), and whole-body BMD (MD, -0.02 kg/m2; 95% CI, -0.04 to -0.00; p=0.03) was observed after 6 months on liraglutide
  • Semaglutide likely more effective than liraglutide for WR or IWL post-BS
  • Decreased lean muscle mass and BMD associated with liraglutide warrants further study
Vinciguerra et al 20248

MA of 6 studies (>6 months duration)		N=369 adults with IWL or WR after BS

Prior surgeries included AGB, SG, OAGB, RYGB, VBG		Liraglutide 2 mg SC

Liraglutide 2.4 mg SC

Liraglutide 2.9 mg SC

Liraglutide 3 mg SC
  • Weight loss of 7.9 kg (95% CI, -10.4 to -5.4 kg; p<0.0001) with liraglutide observed across studies
  • The change in BMI was - 3.09 kg/m2 (95% CI, -3.89 to -2.28; p<0.0001) with liraglutide observed across studies
  • Safety outcomes from studies not reported
  • Liraglutide effective option for patients responding poorly to BS
Abbreviations: AGB=adjustable gastric band; BMD=bone mineral density; BMI=body mass index; BS=bariatric surgery; CI=confidence interval; DB=double-blind; IWL=insufficient weight loss; LAGB, laparoscopic gastric banding; MA=meta analysis; MD=mean difference; OAGB=one-anastomosis gastric bypass; PBO=placebo; RYGB=Roux-en-Y gastric bypass; SC=subcutaneous; SG=sleeve gastrectomy; VBG=vertical banded gastroplasty; WR=weight regain.

Several small additional studies have evaluated GLP-1 receptor agonists in patients with type 2 diabetes mellitus (T2DM) who are awaiting BS, in patients undergoing swallow balloon therapy, and as an adjunct to BS for weight loss.15-20 Only exenatide has been evaluated in patients awaiting BS, and has demonstrated positive effects on weight loss in 2 observational studies.15,16 In 1 study conducted in 56 patients, exenatide extended-release (ER) plus dapagliflozin in patients with T2DM was shown to reduce the proportion of patients meeting surgical criteria after 24 weeks versus placebo, and in another study, exenatide 10 mg 2 times daily for 6 months was associated with significant effects on weight loss, hemoglobin A1C (HbA1c), triglyceride levels, blood pressure, and waist circumference. In patients undergoing swallow balloon treatment, the addition of oral semaglutide versus control was shown to increase the percentage weight loss in patients through 1 to 4 months post-balloon placement, with no unexpected safety issues detected.17 Several small randomized studies have also shown liraglutide to be effective for enhancing weight loss with BS when initiated after surgery.18-20 In these studies, liraglutide, initiated at doses of 1.8 to 3 mg SC 6 weeks after Roux-en-Y gastric bypass, laparoscopic gastric banding, and laparoscopic sleeve gastrectomy was shown to augment weight loss when continued for 6 months.

Conclusion
Few high-quality studies have been published on the use of GLP-1 receptor agonists in the setting of BS, with the available literature limited to small RCTs (<100 patients) and observational studies primarily in patients who have experienced WR or IWL post-BS. Data in this population are encouraging, although decreased bone health and muscle mass warrant further investigation of this effect in future studies. To date, of the available GLP-1 receptor agonists, only injectable liraglutide and semaglutide have been studied in patients experiencing WR or IWL post-BS, exenatide in patients with T2DM awaiting BS, liraglutide as an adjunct to BS, and oral semaglutide as an adjunct to swallow balloon treatment.

References

  1. World Health Organization. Obesity and overweight. Updated March 1 2024. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed April 25, 2024.
  2. Eisenberg D, Shikora SA, Aarts E, et al. 2022 American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) Indications for Metabolic and Bariatric Surgery. Obes Surg. 2023;33(1):3-14. doi:10.1007/s11695-022-06332-1.
  3. El Ansari W, Elhag W. Weight regain and insufficient weight loss after bariatric surgery: Definitions, prevalence, mechanisms, predictors, prevention and management strategies, and knowledge gaps-a scoping review. Obes Surg. 2021;31(4):1755-1766. doi:10.1007/s11695-020-05160-5.
  4. Noria SF, Shelby RD, Atkins KD, et al. Weight regain after bariatric surgery: Scope of the problem, causes, prevention, and treatment. Curr Diab Rep. 2023;23(3):31-42. doi:10.1007/s11892-023-01498-z.
  5. Nedelcu M, Khwaja HA, Rogula TG. Weight regain after bariatric surgery-how should it be defined?. Surg Obes Relat Dis. 2016;12(5):1129-1130. doi:10.1016/j.soard.2016.04.028.
  6. Çalık Başaran N, Dotan I, Dicker D. Post metabolic bariatric surgery weight regain: the importance of GLP-1 levels. Int J Obes (Lond). doi:10.1038/s41366-024-01461-2.
  7. Dutta D, Nagendra L, Joshi A, et al. Glucagon-like peptide-1 receptor agonists in post-bariatric surgery patients: A systematic review and meta-analysis. Obes Surg. 2024;34(5):1653-1664. doi:10.1007/s11695-024-07175-8.
  8. Vinciguerra F, Di Stefano C, Baratta R, et al. Efficacy of high-dose liraglutide 3.0 mg in patients with poor response to bariatric surgery: real-world experience and updated meta-analysis. Obes Surg. 2024;34(2):303-309. doi:10.1007/s11695-023-07053-9.
  9. Lautenbach A, Wernecke M, Huber TB, et al. The potential of semaglutide once-weekly in patients without type 2 diabetes with weight regain or insufficient weight loss after bariatric surgery-a retrospective analysis. Obes Surg. 2022;32(10):3280-3288. doi:10.1007/s11695-022-06211-9.
  10. Mok J, Adeleke MO, Brown A, et al. Safety and efficacy of liraglutide, 3.0 mg, once daily vs placebo in patients with poor weight loss following metabolic surgery: The BARI-OPTIMISE randomized clinical trial. JAMA Surg. 2023;158(10):1003-1011. doi:10.1001/jamasurg.2023.2930.
  11. Murvelashvili N, Xie L, Schellinger JN, et al. Effectiveness of semaglutide versus liraglutide for treating post-metabolic and bariatric surgery weight recurrence. Obesity (Silver Spring). 2023;31(5):1280-1289. doi:10.1002/oby.23736.
  12. Elhag W, El Ansari W. Effectiveness and safety of liraglutide in managing inadequate weight loss and weight regain after primary and revisional bariatric surgery: anthropometric and cardiometabolic outcomes. Obes Surg. 2022;32(4):1005-1015. doi:10.1007/s11695-021-05884-y.
  13. Suliman M, Buckley A, Al Tikriti A, et al. Routine clinical use of liraglutide 3 mg for the treatment of obesity: Outcomes in non-surgical and bariatric surgery patients. Diabetes Obes Metab. 2019;21(6):1498-1501. doi:10.1111/dom.13672.
  14. Wharton S, Kuk JL, Luszczynski M, et al. Liraglutide 3.0 mg for the management of insufficient weight loss or excessive weight regain post-bariatric surgery. Clin Obes. 2019;9(4):e12323. doi:10.1111/cob.12323.
  15. López-Cano C, Santos MD, Sánchez E, et al. Dapagliflozin plus exenatide on patients with type 2 diabetes awaiting bariatric surgery in the DEXBASU study. Sci Rep. 2022;12(1):3236. doi:10.1038/s41598-022-07250-z.
  16. Iglesias P, Civantos S, Vega B, et al. Clinical effectiveness of exenatide in diabetic patients waiting for bariatric surgery. Obes Surg. 2015;25(3):575-578. doi:10.1007/s11695-014-1563-9.
  17. Mathur W, Kosta S, Reddy M, et al. Effect of swallow balloon therapy with the combination of semaglutide oral formulation: a randomised double-blind single-centre study. Obes Surg. 2024;34(1):198-205. doi:10.1007/s11695-023-06975-8.
  18. Hany M, Torensma B, Ibrahim M, et al. Boosting weight loss after conversional Roux-en-Y gastric bypass with liraglutide and placebo use. A double-blind-randomized controlled trial. Int J Surg. 2024;110(3):1546-1555. doi:10.1097/JS9.0000000000000.
  19. Coelho C, Dobbie LJ, Crane J, et al. Laparoscopic adjustable gastric banding with liraglutide in adults with obesity and type 2 diabetes (GLIDE): a pilot randomised placebo controlled trial. Int J Obes (Lond). 2023;47(11):1132-1142. doi:10.1038/s41366-023-01368-4.
  20. Thakur U, Bhansali A, Gupta R, Rastogi A. Liraglutide augments weight loss after laparoscopic sleeve gastrectomy: a randomised, double-blind, placebo-control study. Obes Surg. 2021;31(1):84-92. doi:10.1007/s11695-020-04850-4.

Prepared by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2024

The information presented is current as April 11, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.