Introduction

Obesity is a complex and chronic disease of epidemic proportions in the USA and worldwide. Over 40% of US adults over the age of 20 live with obesity (body mass index (BMI) of 30 kg/m2 or greater), and 18.5% of US children and adolescents live with obesity (BMI at 95th percentile or higher by age and sex). Additionally, 9% of adults and 6% of youth live with severe obesity, defined as BMI of 40 or greater in adults and 120% or more of the 95th percentile for youth [1, 2]. At the individual level, obesity is a disease driven by myriad complex interactions between environmental, humoral, and genetic factors. It also predisposes patients to many other chronic and fatal comorbidities, such as cardiovascular disease, type 2 diabetes mellitus, obstructive sleep apnea, and several forms of cancer. The rapid global rise in obesity therefore has tremendous ramifications for morbidity, mortality, and economic costs for both individuals and society, and the access to and availability of effective treatment options is paramount [3].

While lifestyle management and pharmacotherapy are common therapeutic options for obesity, bariatric surgery has superior efficacy and demonstrated safety in producing long-term weight control in both pediatric and adult populations [4]. Studies show decreases in body weight ranging from 16 to 23% over the first 10 years post-surgery, in addition to significant reductions in comorbidities [5]. Currently, over 250,000 bariatric surgeries are performed in the USA annually, with nearly two-fold increases in adolescent and ten-fold increases in adult bariatric surgical volume in recent years [6,7,8].

Indications for bariatric surgery are different in pediatric and adult populations. The American Society for Metabolic and Bariatric Surgery (ASMBS) Pediatric Committee recommends children and adolescents with class II obesity (BMI ≥ 120% of the 95th percentile for age and sex) and a comorbidity, or class III obesity (BMI ≥ 140% of the 95th percentile for age and sex) be considered surgical candidates [9]. Adults are considered candidates if they have (1) severe obesity (BMI≥40) or more than 100 lbs. overweight, (2) BMI≥35 and at least one obesity-related comorbidity, or (3) if they have been unable to achieve healthy, sustained weight loss for a period of time with prior efforts [10]. ASMBS does not specify a minimum time frame needed for sustained prior efforts at weight loss.

Several safe metabolic and bariatric surgical options are available to adult and pediatric patients. For pediatric and adult patients, sleeve gastrectomy is the most common bariatric operation and involves the laparoscopic removal of 80% of the stomach to induce metabolic and restrictive effects [11]. Gastric bypass operations also induce restrictive and metabolic effects through creation of a small stomach pouch followed by anastomosis of the remaining bypassed portion of the stomach and upper small intestine with the middle portion of the small intestine. Roux-en-Y gastric bypass (RYGB) is the second most common surgical procedure performed in the USA and internationally [4, 8, 12]. On average, at 36-month post-procedure, the expected decrease in BMI after sleeve gastrectomy (SG) is approximately 13 kg/m2, whereas after gastric bypass, it is approximately 14 kg/m2 and approximately 10 kg/m2 after gastric banding [4, 13].

Despite these clinically significant postoperative weight reduction outcomes, studies have shown that 20–30% of bariatric surgical patients have significant weight regain (≥15% of initial post-surgical weight loss) within 2–5 years of their surgery [14, 15•, 16••]. Additionally, an estimated 15–35% of patients have inadequate weight loss (<50% of excess weight) by 12-month post-operation [17•]. Weight regain after surgery is multifactorial and is often driven by hormonal and metabolic changes, dietary non-adherence, changes in physical activity and mental health, and anatomic surgical changes [18••]. While various options such as revisional surgeries and endoscopic procedures are available, pharmacotherapy has emerged as a leading non-invasive and effective option to assist pediatric and adult populations to achieve and sustain recurrent weight loss after bariatric surgery. This review seeks to examine the most recent evidence underpinning the use of pharmacotherapeutic agents in treating weight regain in pediatric and adult bariatric surgical patients.

Methods

A literature search of PubMed and MEDLINE electronic databases was conducted to identify studies examining pharmacotherapeutic options for weight regain after bariatric surgery in pediatric and adult populations. The following keyword search terms were used: “bariatric surgery,” “obesity,” “weight gain,” “weight regain,” “pediatric,” “adolescence,” “adult,” “anti-obesity medication,” “weight loss medication,” and “bariatric pharmacotherapy”. Inclusion of studies was limited to publications in English and those with human subjects. The primary outcome of interest among included articles was the use of pharmacotherapy among pediatric and/or adult bariatric surgery patients. Clinical trials, case reports, case series, reviews, systematic reviews, scoping reviews, and meta-analyses were all considered. Studies published prior to 2017 and those not directly relevant to the primary outcome of interest were excluded. Articles were screened by title and abstract review.

An initial search of English language articles published between 2017 and 2021 yielded 1376 results, which were screened for eligibility and inclusion as depicted in Figure 1.

Figure 1
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Article screening for eligibility and inclusion

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Pharmacotherapeutic options for weight regain after bariatric surgery in children and adolescents

The prevalence of pediatric obesity is increasing at an alarming rate in the USA and throughout the world with no countries experiencing a decreased rate over the past 3 decades [19, 20]. In the USA, prevalence rates are 18.4% among children aged 6–11 years and 20.6% among adolescents aged 12–19 years [21]. Obesity is associated with significant consequences in health and quality of life, and the presence of obesity in youth increases the risk of obesity as an adult [22]. Therefore, effectively treating pediatric obesity is paramount.

The cornerstone of current pediatric and adolescent management focuses on lifestyle interventions including optimizing physical activity and nutrition. Currently, there are only four anti-obesity medications that have been approved by the Food and Drug Administration (FDA) for the treatment of obesity in pediatric patients: orlistat for patients ≥12 years, phentermine for those >16 years, liraglutide for those ≥12 years, and setmelanotide for those ≥6 years [23, 24, 25•]. Several anti-obesity medications (AOM) are approved in adults and are used “off label” to treat pediatric obesity. For pediatric and adolescent patients with severe obesity, metabolic and bariatric surgery (MBS) is a safe and effective treatment option that reduces the risk of persistence of obesity into adulthood and improves or leads to remission of several clinically important comorbidities. Use of MBS in adolescents is supported in clinical practice guidelines by the Endocrine Society and the American Society for Metabolic and Bariatric Surgery (ASMBS) [9, 23•]. In December 2019, the American Academy of Pediatrics (AAP) also published its first ever policy statement regarding the expanded use of MBS for adolescent and pediatric patients with severe obesity [26]. The 2018 ASMBS pediatric metabolic and bariatric surgery guidelines recommend MBS for adolescents with class II obesity (120% BMI percentile for age and sex) along with an obesity-related comorbidity or with class III obesity (140% BMI percentile for age and sex), defining pediatric obesity based on the Centers for Disease Control and Prevention age- and sex-matched growth charts [9]. These proposed BMI criteria for MBS in adolescents are similar to those employed in adult guidelines. However, the approach to anti-obesity pharmacotherapy in adolescents does not have the same level of support in clinical practice guidelines. This is evidenced by the Endocrine Society’s suggestion that anti-obesity medications should be restricted to clinical trials during childhood and adolescence, and there is no guidance offered regarding the use of pharmacotherapy to treat inadequate weight loss or weight regain following MBS [23•]. A multidisciplinary expert committee published a position statement that recommends applying similar, but modified BMI criteria for the consideration of anti-obesity pharmacotherapy in adolescents with a BMI ≥95th percentile (or BMI ≥30 kg/m2, whichever is lower) plus the presence of at least one obesity-related comorbidity, or BMI ≥120% of 95th percentile (or BMI ≥35 kg/m2, whichever is lower) irrespective of co-morbidity, or if criteria for MBS are met [27]. Yet, guidance on the use of AOM for the treatment of weight regain following MBS is lacking.

There are three landmark studies which assess the outcomes of MBS in adolescents: Follow-up of Adolescent Bariatric Surgery (FABS-5+) [28], Adolescent Morbid Obesity Surgery (AMOS) [29], and Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) [30] (Table 1). All of these are prospective observational studies with follow up of 3–5+ years and demonstrated that weight regain relative to lowest weight observed occurs between 1 and 2 years postoperatively; participants tend to regain 13–25% of the maximum observed weight lost, and persistence of obesity at the same or lower classification is common [28,29,30]. When weight regain does occur in adolescent patients following MBS, there are no clear guidelines, position statements, or studies to provide guidance on the safety and efficacy of anti-obesity pharmacotherapy in this patient population. Stanford et al studied weight regain after bariatric surgery in young adults aged 21 to 30 years; they found that the ideal time to start anti-obesity pharmacotherapy is at the post-surgical nadir weight and patients who underwent RYGB lost a larger percent of weight with medications than SG groups although both groups had weight loss benefits [31••].

Table 1 Comparison of long-term outcomes of prospective trials of bariatric surgeries in adolescents
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With a lack of data guiding post-bariatric surgical weight regain in young populations, clinicians are currently limited to the use of the current FDA-approved and non-approved adult AOM medications (off-label), summarized below (Table 2), to treat weight regain or augment weight loss in adolescents after MBS. As such, there is an urgent need for studies to evaluate the safety and efficacy of anti-obesity medications for the treatment of weight regain following MBS in adolescent patients to provide continued treatment for this increasingly prevalent disease.

Table 2 Medication options for obesity pharmacotherapy in pediatric, adolescent, and adult patients
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A potential barrier to conducting such studies is that there are low utilization rates of MBS in adolescents and young adults at academic healthcare institutions within the USA [32]. Additionally, many pediatric patients who pursue MBS may be adults at the time of having significant weight regain following MBS given that the mean baseline age in FABS-5+, AMOS, and Teen-LABS is 17.1 years (SD 1.7), 16.5 years (SD1.2), and 17 years (SD 1.6), respectively, with lowest mean observed weight occurring at 1–2 years postoperatively [28,29,30]. The patient’s age at the time of weight regain is important because if they are ≥ 18 years of age, adult guidelines may be applied. There are more FDA-approved medications available at older ages, and, although scarce, studies have previously shown the benefits and safety of pharmacotherapy for weight regain following MBS in adult patients. Until further studies are available, pediatric obesity medicine specialists may need to look towards the available adult literature to attempt to make inferences from the data to guide their decisions for treating weight regain following MBS in pediatric patients.

Pharmacotherapeutic options for weight regain after bariatric surgery in adults

Bariatric surgery, as a part of a comprehensive weight management treatment plan, continues to be one of the most effective interventions in the treatment of obesity. Weight regain after bariatric surgery is an undesired outcome and is usually caused in adults by a combination of medical, psychosocial, and behavioral factors. Pharmacotherapy has emerged as a first-line therapy to halt weight regain and achieve additional weight loss following bariatric surgery. For patients with challenges meeting lifestyle modification goals, or for those at high risk for complications from revisional surgery, pharmacotherapy is a particularly effective initial interventional choice to support behavioral changes and dietary intervention.

Anti-obesity pharmacotherapy has been recommended for the treatment of obesity in adult patients with BMI ≥ 30 or a BMI ≥ 27 with comorbid conditions. For many patients with weight regain following bariatric surgery, their BMI remains in the obesity category (BMI ≥ 30) [33••]. However, most currently approved medications were not originally tested in patients with prior bariatric surgery. To date, the majority of evidence for the use of weight loss pharmacotherapy in these patients has been reported in retrospective studies. In a multicenter study by Stanford et al., patients were identified following Roux-en-Y gastric bypass or sleeve gastrectomy who received anti-obesity pharmacotherapy postoperatively for weight regain or inadequate weight loss [16••]. In this study, over 50% of patients achieved >5% total body weight loss with medications postoperatively, while 30.3% and 15% of patients lost ≥10% or ≥15% of total body weight, respectively. It was also reported that patients with higher pre-operative BMI achieved greater weight loss after use of weight loss pharmacotherapy. Additional studies have supported these findings [34••].

Medications such as phentermine and topiramate, used individually and in combination as a part of a comprehensive treatment plan post-bariatric surgery, have been studied in adult patients. Phentermine, a centrally acting sympathomimetic drug, stimulates secretion and inhibits reuptake of norepinephrine in the hypothalamus, thus suppressing appetite and promoting weight loss. Topiramate, an anticonvulsant also used for migraine prophylaxis, also suppresses appetite and may have an effect on energy balance [35•]. In the aforementioned multicenter study by Stanford et al., topiramate was the only medication that was associated with a statistically significant response for weight loss of the pharmacotherapy studied, which also included phentermine, metformin, and bupropion. In this study, patients were twice as likely to achieve at least 10% total body weight loss when treated with topiramate [16••]. When the young adults (age 21–30) of this study were examined separately, topiramate and phentermine had a similar level of effectiveness [31••].

Glucagon-like peptide-1 (GLP-1) receptor agonists such as liraglutide have also been shown to be effective in treating weight regain following bariatric surgery. The primary action of GLP-1 receptor agonists is the glucose-dependent inhibition of glucagon secretion and increase in insulin secretion [36]. They also reduce food intake and promote satiety by their actions on appetite-regulating neuronal activity: inhibiting the activity of neuropeptide Y (NPT)/agouti-related peptide (AgRP) neurons and directly stimulating the proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons. Finally, GLP1 receptor agonists have also shown additional effects of decreasing the rate of gastric emptying and stimulating activity of brown adipose tissue to increase thermogenesis [36, 37]. In non-surgical patients, liraglutide 3.0 mg has been associated with significant weight loss and appetite reduction [38]. This effect has also been shown in studies including post-bariatric surgery patients.

In a study by Suliman et. al, 60% and 23% of patients treated with liraglutide 3.0 mg lost >5% and >10%, respectively, of their total body weight, without a difference in percentage weight loss seen between patients with a history of bariatric surgery and non-surgical patients [39•]. Gazda et al demonstrated that GLP1 receptor agonists are more effective than non-GLP1 receptor agonist medications at 3, 6, and 9 months of follow up for treating post-bariatric weight regain [40••]. At 9 months after medication initiation, those receiving GLP-1 class medications had lost 6.9% body weight vs. 5.7% body weight reduction in those receiving non-GLP-1 medications, while those on intensive lifestyle modification experienced 1.6% weight gain [40••]. Additional studies have shown significant weight loss of 5.5–7.1% of body weight in post-bariatric surgery patients treated with liraglutide, and the degree of weight loss remained statistically significant 1 year after initiation of liraglutide [41••, 42••]. There are several pharmacotherapeutic agents pending regulatory approval (including 2.4mg dose GLP-1, combination amylin analog/2.4mg GLP1, and combination GIP/GLP1) for which clinical trials have shown even greater weight loss benefits than GLP1 alone [43,44,45]; we anticipate that these agents will be studied more extensively in post-surgical weight regain populations in the future.

An additional consideration for the use of weight loss pharmacotherapy in patients with weight regain following bariatric surgery is the number of agents used. Postoperative bariatric patients treated with two or more anti-obesity medications have been shown to have significant weight loss [46••]. These findings suggest that for the greatest effect, regimens including two or more agents in combination should be considered. The timing of weight loss pharmacotherapy initiation should also be considered. Stanford et al reported that weight loss medications are particularly useful in adults 60 years of age and older following inadequate weight loss or weight regain after bariatric surgery [47••], while Gutt et al reported that initiation of anti-obesity pharmacotherapy at the time the weight plateau is reached, as opposed to after weight regain, may result in higher total body weight loss [48••].

Conclusion

Anti-obesity pharmacotherapy is severely underutilized for treating primary obesity and only marginally less underutilized in treating recurrent obesity following bariatric surgery [40••]. Due to a lack of evidence-based guidelines for initiation and monitoring of pharmacotherapy in those with weight regain following bariatric surgery, obesity specialists and other clinicians who seek to treat this patient population often face significant challenges and uncertainty. This review represents a compilation of the recently published data on efficacy of anti-obesity pharmacotherapy in the treatment of weight regain after bariatric surgery for children, adolescents, and adults.

The key finding of this review are as follow:

  • A number of small, non-randomized, retrospective, and prospective studies provide evidence that multiple pharmacological options, both FDA approved and off-label, are effective in mitigating and managing weight regain after bariatric surgery [78••].

  • Randomized controlled trials addressing pharmacotherapeutic management of post-bariatric surgical weight regain are lacking.

  • There is much excitement and anticipation among those in the fields of obesity medicine for the pending regulatory approval of additional pharmacotherapeutic anti-obesity agents which will likely provide additional therapeutic options for managing post-bariatric surgical weight regain.

  • Despite many promising developments in this clinical area, there is a significant need for future studies to fully characterize and quantify the utility of pharmacotherapeutic treatment options for weight regain after bariatric surgery in children, adolescents, and adults.