Bariatric surgery is a powerful tool for achieving significant long-term weight loss in individuals with obesity. Procedures like sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) have historically been the most popular. However, a considerable percentage of patients experience post-surgical weight regain, and some may not achieve adequate initial weight loss. This article explores the role of weight loss medications in addressing these challenges after bariatric surgery, offering a detailed overview of available options, their effectiveness, and considerations for their use.
The Challenge of Weight Regain After Bariatric Surgery
Multiple definitions exist for significant post-bariatric weight regain and inadequate post-bariatric procedure weight loss, making comparisons across studies difficult. However, research consistently demonstrates that weight regain is a common issue following bariatric surgery.
Studies like the Longitudinal Assessment of Bariatric Surgery (LABS) have shown that weight regain can occur as early as one year after RYGB, with patients regaining a median of 26.8% of their maximum weight loss at 5 years post-surgery, or a median weight regain of 9.7% relative to their pre-surgical weight at 5 years. The Swedish Obese Subjects (SOS) study found that patients experienced gradual weight regain totaling 8-13% before reaching a weight loss plateau at 8-10 years after the procedure. The largest observational study of bariatric surgery patients was conducted by Baig et al. who reviewed 9617 patient charts from 26 weight centers in India to characterize clinically significant post-bariatric WR at 5 years following SG, RYGB, and one-anastomosis gastric bypass (OAGB). Mean WR ranged from 6-22% at 5 years depending on type of bariatric surgery (5).
Weight regain can be a distressing experience and is associated with various health problems, including diabetes, hypertension, hyperlipidemia, asthma, arthritis, depression, coronary heart disease, and malignancies. Therefore, weight management providers must offer interventions to prevent post-bariatric surgery weight regain and optimize patients' weight status.
Medical Management of Obesity: An Overview
Medical management of obesity is recommended for individuals with a body mass index (BMI) of 30 kg/m2 or greater, and for those with a BMI of 27 kg/m2 plus comorbidities. Pharmacologic agents can facilitate weight loss by targeting various physiological mechanisms that contribute to obesity.
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FDA-Approved Medications for Long-Term Weight Management
Currently, five medications are FDA-approved for the long-term treatment of obesity:
- Orlistat: An intestinal lipase inhibitor that reduces fat absorption by approximately 30%.
- Phentermine/Topiramate: A combination medication that suppresses appetite and has central anorexigenic effects.
- Liraglutide 3.0mg: A glucagon-like-peptide-1 receptor agonist (GLP-1-RA) that promotes satiety and slows gastric emptying.
- Naltrexone/Bupropion: A combination medication that affects brain regions involved in appetite and reward.
- Semaglutide 2.4mg: A GLP-1-RA with a higher dose than the formulation used for type 2 diabetes.
Off-Label Medications for Weight Management
Several medications are used off-label for long-term weight management, including:
- Phentermine (>3 months)
- Topiramate
- Liraglutide 1.8mg
- Naltrexone
- Bupropion
- Semaglutide 2.0mg
- Tirzepatide
Weight Loss Medications After Bariatric Surgery: Evidence and Efficacy
Several studies have evaluated the effectiveness of weight loss medications in patients who have undergone bariatric surgery.
Orlistat
Orlistat was associated with weight loss in a non-randomized intervention study of 38 patients experiencing a weight loss plateau (WLP) after adjustable gastric banding, with a weight change of -8 ± 3 kg at 8 months compared to -3 ± 2 kg with dietary intervention alone.
Phentermine, Topiramate, and Phentermine/Topiramate
These medications have a large body of evidence supporting their use in patients with a history of bariatric surgery. In the largest retrospective study of 319 patients, topiramate was associated with the greatest weight change (-20.2lbs) after RYGB or SG as compared to 15 other AOMs (-13.99 lbs. for AOMs other than topiramate). A similar study of 197 post-surgical patients reported that phentermine/topiramate was associated with the greatest odds of achieving 5, 10, and 15% weight loss compared to other AOMs.
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Adherence to topiramate, phentermine, or combination phentermine/topiramate has been consistently associated with greater weight loss. Among 16 patients with binge eating disorder and a history of bariatric surgery, topiramate 12.5-50mg per day was associated with an additional excess weight loss of 13.7%. In a retrospective study of 30 patients, when phentermine 37.5mg was compared with phentermine-topiramate 7.5-46mg, both produced significant weight losses of 6.3 kg and 3.8 kg, respectively, over 90 days, and phentermine 37.5mg was statistically superior.
Liraglutide
The benefit of liraglutide in the post-bariatric surgery setting is supported by a randomized controlled trial and multiple observational studies. The randomized double-blind placebo-controlled trial, which was performed to investigate the effect of liraglutide 1.8mg for the management of patients with a history of bariatric surgery and persistent or recurrent type 2 diabetes, reported as a secondary endpoint a statistically significant mean weight change of -4.23 kg with liraglutide vs. placebo at 26 weeks.
Of the observational studies, the largest included 787 patients treated with liraglutide 3.0 mg for ≥ 16 weeks and demonstrated a weight change of -6.4% for patients with a history of bariatric surgery versus -6.1% for patients without a history of bariatric surgery. Use of liraglutide in patients with a history of bariatric surgery has also been associated with improvements in blood pressure and hemoglobin A1c. In comparing the effect of liraglutide 3.0 mg in patients with different bariatric surgeries, those who had a history of RYGB lost significantly more weight (-5.6%) than patients who had a history of SG (-3.3%); similar results have been replicated (-6.6% with RYGB vs. -3.6% with SG) but were not found to be statistically significant.
Naltrexone/Bupropion
There are no studies evaluating the individual efficacies of naltrexone, bupropion, or naltrexone/bupropion specifically in the post-bariatric surgery population. A few studies have investigated the effectiveness of obesity pharmacotherapy in general, in which monotherapies naltrexone or bupropion and combination naltrexone/bupropion were minimally represented.
Semaglutide and Tirzepatide
There are no studies evaluating semaglutide or tirzepatide specifically in the post-bariatric surgery population. However, several phase 3 randomized controlled trials, which excluded individuals with a history of bariatric surgery, proved superior weight loss with semaglutide 2.4mg compared to placebo in individuals with obesity or metabolically complicated overweight. A recent phase 3 trial of tirzepatide demonstrated weight loss efficacy approaching that of some bariatric surgeries in individuals without prior bariatric surgery.
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Combination Therapies and Factors Influencing Weight Loss
Retrospective studies have investigated weight loss associated with obesity pharmacotherapy in general among patients with a history of bariatric surgery without identifying specific AOM monotherapies or AOM combination therapies. A trend toward greater weight loss has been observed with two or more AOMs compared to patients taking zero or one AOM. GLP-1-RAs were found to produce significantly greater weight loss than regimens with a non-GLP-1-RA or intensive lifestyle modification alone. Other studies identified factors associated with greater weight loss in the population of patients with medically managed obesity after bariatric surgery. Greater weight loss results were observed with use of AOMs for patients with a history of laparoscopic adjustable gastric band vs. SG and RYGB vs. SG, for patients with pre-operative BMI > 36 vs.
GLP-1 Receptor Agonists: A Growing Trend
A recent study analyzing electronic health records found that an increasing proportion of patients who undergo bariatric surgery start taking GLP-1 weight-loss drugs in the years after their surgery. The rate of post-surgery GLP-1 use increased as more powerful GLP-1 drugs such as semaglutide and tirzepatide became available. Factors associated with GLP-1 use included being female, having type 2 diabetes, undergoing sleeve gastrectomy, and having lower post-operative weight loss.
Pre-Operative Weight Optimization
There are no official guidelines on perioperative weight optimization in patients undergoing bariatric surgery, and there is no consensus on the pharmacologic management of weight regain, inadequate weight loss, or weight loss plateau after bariatric surgery. Whether initiation of AOM preoperatively has long-term benefits to mitigate these post-operative weight issues is unknown.
Weight loss in the pre-operative period has proven benefits, including a reduction in the likelihood of post-operative complications after RYGB but not SG. Only one study, conducted in patients with BMI > 50, investigated this question of pre-operative weight optimization and demonstrated significantly greater post-operative weight loss at 24 months with pre-operative phentermine/topiramate 7.5-46mg daily. Although post-operative weight loss outcomes associated with using other AOMs before bariatric surgery have not been assessed, other AOMs should still be considered if phentermine/topiramate is contraindicated or if an obesity-associated co-morbidity can be concomitantly addressed (e.g., GLP-1-RA in a patient with obesity and diabetes).
Timing and Monitoring
Weight regain after bariatric surgery most often begins 1-2 years post-operatively. Patients should monitor their weight changes and follow up with their weight management providers at regular intervals after bariatric surgery, as the timing of weight regain or WLP will vary. When a patient reaches a WLP, providers should assess for any factors responsible for preventing additional weight loss, such as dietary changes, initiation of an obesogenic medication, or a post-operative anatomic etiology (e.g., gastro-gastric fistula). The period when patients reach a weight loss plateau represents an opportunity to intervene, with or without an AOM, to address obesogenic factors. Several studies have suggested that greater weight loss was achieved when AOMs were initiated at the weight loss plateau rather than waiting for weight regain, with one study demonstrating statistical significance.
Practical Considerations
- Individualized Approach: The choice of weight loss medication should be tailored to the individual patient, considering their medical history, specific needs, and potential contraindications.
- Lifestyle Modifications: Weight loss medications are most effective when combined with healthy lifestyle changes, including a balanced diet and regular physical activity.
- Monitoring and Follow-Up: Regular monitoring is essential to assess the effectiveness of the medication and manage any potential side effects.
- Addressing Underlying Factors: It's crucial to identify and address any underlying factors contributing to weight regain, such as dietary changes, obesogenic medications, or anatomical issues.
The Role of GLP-1 Receptor Agonists
Use of GLP-1-RAs for weight optimization after bariatric surgery will likely gain popularity given evidence in the post-surgical population and the proven weight loss efficacy of newer agents in the non-surgical population with obesity. Semaglutide and tirzepatide are the newest additions to the family of GLP-1-RAs, with the latter being a dual GLP-1 and GIP receptor agonist.
A Combined Approach: Medication and Surgery
For a growing number of patients, a combined approach of bariatric surgery and anti-obesity medication is proving to be the most effective strategy for sustainable weight loss. Anti-obesity medications can help patients reach an optimal pre-operative weight, qualify for surgery, and continue to take the medication after surgery to reach their ideal weight.
Lifestyle Changes
Whether patients choose medication, surgery, or both, the lifestyle changes required are similar. Dietary recommendations are clearly spelled out for patients who have bariatric surgery, with plans customized to each patient’s needs. Nutritional guidelines do not currently exist for anti-obesity medications, but efforts are underway to provide sustainable dietary recommendations for patients who take weight-loss medications.