Weight maintenance after discontinuation of GLP-1 therapies

Summary

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual/triple co-agonists have revolutionized obesity treatment, producing mean weight losses of 10–30% that were rarely achievable with lifestyle modification or earlier medications. Yet, once GLP-1 therapy is discontinued, most patients experience rapid weight regain, often accompanied by reversal of cardiometabolic improvements. Real-world data show that up to 65% of users discontinue GLP-1 RAs within a year of initiation, and randomized controlled trials demonstrate that two-thirds of lost weight is typically regained within a year of discontinuation. Weight regain following GLP-1 RA discontinuation reflects a powerful interplay of physiological, behavioral, and environmental factors that promote relapse once pharmacological appetite suppression is removed. Sustaining weight loss after GLP-1 RA discontinuation will ultimately depend on integrated, patient-centered frameworks combining ongoing lifestyle, behavioral, and system-level supports.

Introduction

Over the past few years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a transformative option in obesity treatment. In the United States, the percentage of adults without diabetes prescribed a GLP-1 RA for overweight or obesity increased from 3.7% in 2019 to 16.5% in 2024, representing a 344% relative increase.¹ Similarly, global prescription rates for GLP-1 therapies have risen sharply, reflecting growing demand for effective weight management options.2, 3, 4 GLP-1 RAs and emerging dual/triple co-agonists enable average weight losses of approximately 10–30%, outcomes that were previously difficult to attain or sustain with lifestyle modification or earlier pharmacological options.^5,6 However, once these drugs are discontinued, patients frequently regain much of the weight they lost, often within a year.7, 8, 9

Obesity is increasingly recognized as a chronic, relapsing disease that warrants long-term pharmacological management, an approach supported by major professional society guidelines.^10,11 Nonetheless, in real-world practice, a large proportion of patients eventually discontinue GLP-1 RAs due to barriers such as high cost, limited insurance coverage, persistent side effects, injection burden, or uncertainty regarding long-term safety.¹² Despite these realities, there are no established, evidence-based strategies specifically designed to mitigate weight regain following GLP-1 RA discontinuation, representing a major gap in chronic obesity care.

Without structured guidance, patients are often left to navigate this transition alone, risking cycles of repeated weight loss and regain, cardiometabolic destabilization, and demoralization. This review aims to synthesize available evidence across lifestyle, behavioral, pharmacological, and procedural domains to identify potential strategies that may help mitigate weight regain following GLP-1 treatment discontinuation. Importantly, the approaches are largely extrapolated from broader weight maintenance and obesity management literature and should be interpreted as hypothesis-generating rather than definitive, evidence-based recommendations specific to GLP-1 RA discontinuation.

Search strategy and selection criteria

References for this review were identified through searches of PubMed, Google Scholar, and clinicaltrials.gov covering the period from database inception to December 2025. Search terms included but were not limited to: “glucagon-like peptide-1 receptor agonists,” “GLP-1-based therapies,” “semaglutide,” “tirzepatide,” “weight maintenance,” “cardiometabolic outcomes,” “treatment discontinuation,” “weight regain,” and “weight cycling.” Articles were screened for originality, methodological rigor, and clinical relevance, with priority given to large randomized controlled trials (RCTs), observational studies, systematic review/meta-analyses, and consensus guidelines.

Evidence for weight regain after pharmacotherapy discontinuation

GLP-1 therapies

Despite substantial weight loss achieved during active treatment, RCTs consistently demonstrate rapid weight regain following discontinuation of GLP-1 therapies. In the STEP-1 extension study, participants who discontinued semaglutide regained about two-thirds of their lost weight within one year.⁷ In STEP-4, after a 20-week run-in with semaglutide led to a 10.6% mean weight loss, those who switched to placebo regained 6.9% of baseline weight (roughly 65% of prior loss), while those who continued semaglutide lost a further 7.9% over a year.⁸ A similar pattern was observed in SURMOUNT-4: following a 36-week run-in with tirzepatide and a 20.9% mean weight loss, participants randomized to placebo regained 14% of baseline weight, whereas those who continued tirzepatide lost an additional 5.5% (Fig. 1).⁹ Importantly, weight regain after GLP-1 RA discontinuation is accompanied by reversal of improvements in cardiometabolic risk factors, including worsening glycemic control, blood pressure, waist circumference, and lipid parameters.^7,13,14 This pattern highlights that discontinuation leads to loss of therapeutic effects across multiple metabolic domains, rather than isolated weight regain.

Fig. 1.

Mean % change in weight during the (a) STEP-4 and (b) SURMOUNT-4 maintenance trials. Error bars represent 95% confidence intervals for the mean. Reprinted with permission from Rubino et al., 2022 and Aronne et al., 2023.

Real-world data from the United States also show high discontinuation rates outside of trial settings. Analyses of electronic health record and insurance-claims databases indicate that 50–65% of adults without diabetes who are prescribed GLP-1 RAs for obesity management discontinue treatment within the first year of initiation.^15,16 Notably, in a study of commercially insured adults with obesity and without diabetes, discontinuation rates reached 30–50% at one year despite comprehensive health coverage.¹⁷ These findings suggest that factors beyond cost, such as tolerability or treatment fatigue, contribute to early discontinuation.

Alternate pharmacotherapies

Some earlier anti-obesity medications have also been evaluated in maintenance-phase designs. In the STORM trial (2000), participants who lost ≥5% of body weight during a six-month sibutramine run-in were randomized to continue sibutramine or switch to placebo; only 16% of placebo participants maintained ≥80% of their prior weight loss compared to 43% of those randomized to continued therapy at two years.¹⁸ Similarly, in the BLOOM trial extension (2010), participants treated with lorcaserin who achieved clinically meaningful weight loss (≥5% of body weight) were re-randomized after one year; maintenance of weight loss was observed in 67.9% of those who continued therapy compared to 50.3% of those switched to placebo at two years.¹⁹ Subsequent agents such as phentermine-topiramate and naltrexone-bupropion demonstrated improved durability during active treatment, maintaining roughly 9–11% reductions from baseline weight over two years, though long-term outcomes after treatment discontinuation were not examined.^20,21 These historical precedents illustrate that sustained weight loss with pharmacotherapy has generally depended on continued use, highlighting the challenges of long-term weight maintenance once medications are stopped, regardless of drug class or mechanism.

Weight cycling and cardiometabolic implications

The recurrent pattern of weight loss and regain, often termed “weight cycling” or the “yo-yo effect”, has been associated with adverse cardiometabolic outcomes.22, 23, 24, 25 Proposed mechanisms include preferential visceral fat accumulation, impaired insulin sensitivity, and neurohormonal adaptations such as increased sympathetic activation and oxidative stress.²⁵ However, the extent to which weight cycling independently contributes to cardiometabolic risk remains uncertain. Much of the available evidence is observational and subject to important limitations, including confounding by baseline adiposity, duration of obesity, and aging. In addition, many studies lack appropriate comparator groups to distinguish the effects of weight fluctuation from those of persistent obesity. As a result, it remains unclear whether weight cycling confers greater risk than remaining weight-stable at an elevated BMI.

Data from longitudinal analyses further highlight this uncertainty. In the Diabetes Prevention Program, weight cycling was initially associated with adverse cardiometabolic risk factors, including higher fasting glucose, insulin resistance, and systolic blood pressure; however, these associations were no longer significant after adjustment for baseline weight or 2-year weight change, suggesting that they may be largely driven by underlying adiposity rather than weight fluctuation itself.²⁶ More recent evidence following discontinuation of GLP-1-based therapy supports a similar interpretation. In a post hoc analysis of the SURMOUNT-4 trial, greater weight regain after tirzepatide withdrawal was associated with greater reversal of initial cardiometabolic improvements.¹³ Among participants with ≥75% weight regain, cardiometabolic parameters had returned to baseline values by week 88 without exceeding those levels. Consistent with this, a 2026 systematic review and meta-analysis of weight loss pharmacotherapies reported that beneficial changes in HbA1c, fasting glucose, lipids, and blood pressure attenuated over time, with cardiometabolic markers projected to return to baseline within approximately 1.4 years after treatment cessation.²⁷ Taken together, these findings suggest that while cardiometabolic risk factors worsen with weight regain, current evidence does not clearly demonstrate a worsened phenotype beyond pre-treatment baseline levels.

The direct cardiovascular consequences of GLP-1 RA discontinuation are not well defined. Large cardiovascular outcome trials in high-risk patients with type 2 diabetes have consistently demonstrated reductions in major adverse cardiovascular events (MACE) with GLP-1 RAs. In a recent meta-analysis of 10 RCTs including over 71,000 participants, GLP-1 RAs reduced the incidence of MACE by 14%.²⁸ The SELECT trial (semaglutide) extended these findings to adults with overweight or obesity without diabetes, showing a 20% MACE reduction despite minimal changes in HbA1c, underscoring benefits that extend beyond glycemic control.²⁹ In addition, the SURPASS-CVOT trial (tirzepatide) showed comparable cardiovascular outcomes with dual GLP-1/GIP receptor agonism relative to established GLP-1 RAs (dulaglutide).³⁰ Emerging evidence from trials in obesity populations with specific comorbidities, such as STEP-HFpEF (semaglutide) and SUMMIT (tirzepatide) in individuals with obesity and heart failure with preserved ejection fraction, further supports clinically meaningful cardiometabolic benefits of GLP-based therapies beyond traditional populations with diabetes.^31,32

While part of this benefit likely reflects weight loss, mediation analyses suggest that associated improvements in glycemia, blood pressure, and lipid profile account for only a fraction of the observed cardiovascular effect.^33,34 This evidence indicates that additional weight-independent mechanisms may contribute to these benefits, including direct anti-inflammatory, endothelial, and vascular effects, as suggested by preclinical studies.³⁵ This is further supported by evidence from trials such as Harmony Outcomes, in which albiglutide demonstrated cardiovascular benefit despite relatively modest effects on body weight (22% reduction in MACE with <1 kg placebo-adjusted weight loss at 16 months).³⁶ Whether these cardioprotective effects persist after GLP-1 RA discontinuation has not been clearly established. Emerging evidence from a target trial emulation study suggests that discontinuation or interruption of GLP-1 RA therapy may attenuate cardiovascular benefit in a duration-dependent manner; compared with continued use, discontinuation for 0.5, 1, and 2 years was associated with progressively higher risks of MACE, with similar patterns observed for treatment interruptions.³⁷ These findings likely reflect loss of both weight-dependent cardiometabolic improvements and direct weight-independent vascular and anti-inflammatory effects. Clinical trial data in this context remain limited.

Biological drivers of weight regain

The weight rebound that follows GLP-1 RA discontinuation reflects powerful physiological adaptations that defend body weight through multiple, coordinated pathways (Table 1). During active treatment, GLP-1 RAs reduce appetite and enhance satiety, leading to negative energy balance.³⁸ When therapy is discontinued, these effects reverse and a series of counter-regulatory mechanisms act to restore lost weight.

Table 1.

Multilevel drivers of weight regain after GLP-1 therapy discontinuation.

Domain	Key Mechanisms	Clinical Implications
Biological	•Reversal of GLP-1-mediated appetite suppression •↑ ghrelin •↓ leptin, peptide YY, and cholecystokinin •Adaptive thermogenesis •Reduced resting energy expenditure	Increased hunger and reduced energy expenditure promote positive energy balance, predisposing to rapid weight regain after discontinuation
Behavioral/Psychological	•Emotional eating •Stress-related and hedonic eating •Habit relapse (e.g., snacking, portion size) •Low self-efficacy •Weight stigma and psychological burden	Erosion of adherence to dietary and physical activity behaviors, increasing susceptibility to relapse and weight regain
Environmental	•Obesogenic environment •High availability of ultra-processed foods •Sedentary lifestyle patterns •Social norms and marketing influences •Socioeconomic and structural barriers	Persistent external pressures promote overeating and inactivity, making long-term weight maintenance difficult without systemic or policy-level interventions

Studies using indirect calorimetry have shown that weight loss, regardless of method, triggers reductions in resting energy expenditure that often exceed the decline predicted by the decrease in body mass, a phenomenon termed adaptive thermogenesis.^39,40 This metabolic adaptation can persist for months or years after weight loss, making energy balance more difficult to maintain.⁴¹ Simultaneously, hormonal changes favor increased energy intake: circulating levels of leptin, peptide YY, and cholecystokinin fall, whereas ghrelin and other orexigenic signals rise.^42,43 These shifts heighten hunger and reduce satiety, effectively amplifying the drive to eat once pharmacological appetite suppression is removed.

Neuroimaging studies have shown that individuals with obesity exhibit heightened responsiveness to food cues within mesolimbic reward circuits, reinforcing hedonic eating behaviors and weakening inhibitory control.⁴⁴ These neural patterns, when combined with the metabolic and hormonal adaptations that accompany weight loss, may create a potent biological environment that resists sustained weight reduction.

Behavioral, psychological, and environmental drivers of weight regain

Weight regain after discontinuation of GLP-1 therapy is not solely a biological process; it also reflects deep-rooted behavioral and psychological drivers of eating and activity patterns. Emotional eating, characterized by eating in response to stress, negative mood, or boredom, is a well-recognized obesogenic behavior that contributes to the development and persistence of obesity.⁴⁵ Food is frequently used as a coping mechanism to manage emotional states, and highly palatable foods, especially those high in sugar and fat, activate brain reward circuits in ways that parallel addictive behaviors. This reinforcement increases the likelihood of overeating and relapse after drug discontinuation.⁴⁶ Even minor behavioral lapses, such as returning to old habits of snacking, larger portion sizes, or inactivity, can lead to rapid weight regain once pharmacological appetite suppression is removed. These vulnerabilities are compounded by the chronic psychological burden of obesity itself, which is associated with stigma, body dissatisfaction, and reduced quality of life.⁴⁷ Weight stigma not only increases stress but also predicts maladaptive eating behaviors such as uncontrolled or emotional eating, perpetuating cycles of weight gain and loss.⁴⁸ Internal cues such as fatigue, frustration, and low self-efficacy can further undermine adherence to healthy habits.

Broader environmental influences such as food availability, social norms, marketing pressures, and living conditions contribute to an increasingly obesogenic environment that promotes overeating and sedentary behaviors (Fig. 2).⁴⁹ This is reflected in the abundance of ultra-processed foods and daily routines characterized by prolonged sitting, increased screen-based leisure, and fewer opportunities for incidental physical activity in high-income countries, as well as rapid urbanization and dietary westernization in many low- and middle-income regions. In addition to behavioral and social drivers, emerging evidence suggests that environmental exposures such as pollution, may also contribute to metabolic dysregulation and obesity risk.^50,51 Importantly, many of these determinants operate at a structural level and are not easily modified through individual behavior alone. Addressing these upstream contributors will likely require coordinated public health and policy-level interventions, underscoring that sustainable weight management extends beyond individual- and clinician-level strategies.

Fig. 2.

Multilevel determinants of weight regain after GLP-1 therapy discontinuation. Genetic, environmental, and behavioral factors jointly influence body weight regulation. Following discontinuation of GLP-1 therapy, upstream drivers, including diet, physical activity, psychosocial and socioeconomic factors, environmental pollution, and circadian biology, act through central pathways regulating energy intake and expenditure. These interactions shape eating behavior, energy balance, and fuel partitioning, contributing to weight regain. Reprinted with permission from Johansen et al., 2025.

Lifestyle strategies

Lifestyle modification remains a central component of weight management but its effectiveness for sustaining clinically meaningful weight loss, particularly in the absence of continued pharmacotherapy, is limited. Evidence from landmark trials such as the Look AHEAD and the Weight Loss Maintenance trials suggest that continued engagement in structured dietary and physical activity programs can support weight maintenance; however, long-term durability is modest in most populations.^52,53 In Look AHEAD, participants achieved an initial weight loss of 8.6% at 1 year (vs. 0.7% in the control group) which declined to 6.0% (vs. 3.5% in the control group) by the end of the study (median follow-up: 9.6 years), reflecting partial weight regain and modest between-group differences over time. In ancillary analyses of the Look AHEAD trial, substantial heterogeneity in weight trajectories was observed, with 44% of participants classified as weight regainers, 38% as weight cyclers, and only 18% as maintaining or continuing to lose weight over 8 years of follow-up.⁵⁴

In contrast, observational data from the National Weight Control Registry suggest that long-term weight maintenance is achievable, albeit primarily in highly selected and motivated individuals.⁵⁵ This longitudinal study enrolled individuals who had lost a substantial amount of weight and maintained it for at least one year; at both 5 and 10 years, more than 87% of registry members were estimated to sustain a ≥10% weight loss. Participants who successfully maintained weight loss reported sustained high levels of dietary restraint (∼1400 kcal/day), physical activity (∼2400 kcal/week), and frequent self-monitoring (often daily). Taken together, these findings suggest that while durable weight loss is possible, it typically requires sustained, high-intensity behavioral engagement that may not be generalizable to broader clinical populations.

Dietary strategies

Dietary strategies have been widely studied in the context of weight maintenance, including macronutrient composition, caloric restriction, and overall diet quality. Among these, high-protein diets have received particular attention due to their potential to enhance satiety, preserve lean body mass, and attenuate adaptive reductions in resting energy expenditure that accompany weight loss.56, 57, 58, 59 In the DIOGENES study, higher protein intake was associated with reduced weight regain but absolute differences between dietary groups were small (approximately 0.9 kg less regain over 26 weeks compared to lower protein intake, following an initial ∼11 kg weight loss).⁵⁹ Similarly, in the PREVIEW trial, a high-protein, low glycemic index diet improved appetite-related measures but did not result in differences in weight regain compared to a moderate protein diet, with both groups maintaining approximately 4–5 kg weight loss at 3 years following an initial ≥8% reduction.⁶⁰ More broadly, studies comparing dietary composition (e.g., variations in protein content, carbohydrate restriction, or glycemic index) have generally demonstrated modest effects on weight maintenance, with differences between diets attenuating over time, particularly beyond one year.61, 62, 63

Emerging evidence suggests that structured weight loss maintenance programs may yield more durable outcomes. In a 78-week RCT of individuals with prior substantial weight loss (mean ∼15–19 kg), including a subgroup who had previously lost weight on GLP-1 RA therapy, participants were assigned to formula-based low-energy diets delivered either as intermittent total diet replacement (2 days per week; ∼800 kcal/day) or daily meal-replacement strategies (∼200–400 kcal/serving).⁶⁴ Weight loss was largely maintained over time, with participants sustaining approximately 12–14 kg reductions at 78 weeks. However, these findings should be interpreted in the context of the highly structured and intensive nature of the intervention. The degree of caloric restriction (∼800–1200 kcal/day), reliance on formula-based diets, and sustained behavioral support may limit feasibility and long-term adherence in real-world settings.

Beyond macronutrient composition and caloric restriction, overall diet quality is central to long-term weight maintenance. Successful lifestyle programs such as the Diabetes Prevention Program place a strong emphasis on building food literacy and sustained consumption of minimally processed, nutrient-dense foods, including vegetables, fruits, whole grains, and fiber-rich carbohydrates.⁶⁵ In this context, dietary patterns such as the Mediterranean and DASH-style diets may provide broader cardiometabolic benefits, even when long-term weight loss is modest, supporting a shift toward metabolic health rather than weight alone.^66,67

Physical activity

Physical activity is a critical adjunct to dietary strategies, although its role in long-term weight loss maintenance is often underappreciated. In the context of GLP-1-induced weight loss, reductions in lean mass (25–30% of total weight loss) have received considerable attention and are often raised as a potential concern.⁶⁸ However, available evidence suggests that these changes are largely proportional to overall weight loss and may reflect adaptive physiological responses rather than pathological muscle loss.^69,70 Importantly, physical performance and functional outcomes are generally preserved or improved in most studies, particularly when resistance training is maintained.^71,72 Beyond its role in preserving strength and function, skeletal muscle plays a central role in metabolic regulation.^73,74 Loss of lean mass during weight loss contributes to adaptive declines in energy expenditure and reduced metabolic efficiency, thereby promoting positive energy balance and increasing susceptibility to weight regain. Resistance training helps mitigate these effects by maintaining muscle mass and preserving metabolic capacity, including mitochondrial function and glucose utilization.75, 76, 77, 78

Aerobic training, while less effective for preserving lean mass, provides important complementary cardiovascular and psychological benefits. Regular moderate-to-vigorous aerobic activity improves cardiorespiratory fitness, endothelial function, and insulin sensitivity, and may also regulate mood and stress which reduce vulnerability to weight relapse.^79,80 However, maintaining substantial weight loss typically requires levels of physical activity that exceed standard public health recommendations, often in the range of 200–300 min per week of moderate-to-vigorous activity, which may be difficult to sustain in real-world settings.⁸¹

Sustainability and real-world challenges

Despite their importance, conventional diet and exercise programs are notoriously difficult to sustain over time. Population-based observational studies suggest that only approximately one in five individuals with overweight or obesity maintain ≥10% weight loss through lifestyle modification after one year, with maintenance rates declining further by five years.⁸² A key contributor to this limited durability is declining adherence to prescribed behaviors. Physiological hunger rebound, behavioral fatigue, and competing environmental pressures commonly erode dietary adherence over time.⁴³ Exercise adherence is similarly challenging; fewer than half of participants enrolled in structured programs continue to meet recommended physical activity targets beyond six months.⁸³

These challenges are further compounded by structural factors, including limited access to healthy foods, socioeconomic constraints, and environments that promote energy-dense dietary patterns, which collectively undermine the long-term sustainability of lifestyle interventions.⁵⁰ Addressing these barriers may require interventions beyond individual-level counseling, including efforts to improve health literacy, expand access to affordable and nutritious foods, and implement community- or system-level programs that support sustainable behavior change.

Behavioral strategies

Given the strong behavioral and psychological drivers of weight regain, structured behavioral support is essential during and after GLP-1 RA discontinuation. Many of the intensive lifestyle programs discussed above, including the Diabetes Prevention Program, Look AHEAD, and Weight Loss Maintenance, are grounded in cognitive behavioral therapy (CBT) principles. Behavioral strategies may help patients recognize early signs of relapse, manage stress-related or emotional eating, and maintain motivation as pharmacological appetite suppression wanes.

CBT remains the most established framework for long-term weight management.⁸⁴ CBT-based programs emphasize self-monitoring, stimulus control, cognitive restructuring, and relapse prevention skills. By targeting maladaptive thought patterns and reinforcing consistent behavior change, they help patients maintain adherence and resilience once pharmacological support is removed. Mindfulness- and acceptance-based approaches such as acceptance and commitment therapy complement traditional CBT. By cultivating awareness of hunger, satiety, and emotional triggers, mindfulness techniques reduce reactive or stressed-induced eating, while acceptance-commitment strategies teach patients to tolerate cravings without reverting to maladaptive behaviors.⁸⁵

In the Diabetes Prevention Program, participants received intensive, CBT-based lifestyle counseling reinforced through periodic “booster” sessions focused on dietary logging and activity tracking, sustaining partial weight loss and delaying diabetes onset for over a decade.^65,86 Building on similar behavioral principles, the Look AHEAD trial delivered intensive counseling combining calorie restriction, goal-setting, and weekly group and individual sessions; participants who remained engaged achieved an average 6% weight loss at eight years compared with 2% in the usual care arm.⁵³ The Weight Loss Maintenance trial used structured group meetings and telephone coaching focused on relapse prevention and problem-solving, reducing weight regain by roughly one-third compared with minimal follow-up.⁵² Together, these trials suggest that long-term success depends on continuous behavioral engagement rather than time-limited intervention.

Real-world data highlight important limitations in the durability of behavioral interventions, with substantial variability in adherence and reported dropout rates ranging from 5% to over 60%, which likely contributes to the attenuation of weight loss observed outside structured trial settings.^87,88 The resource-intensive nature of these interventions, including the need for trained personnel, repeated contact, and high levels of patient engagement, may limit their scalability in the context of the growing prevalence of obesity. Digital and remotely delivered CBT-based interventions have been proposed as a potential strategy to address these challenges, with studies demonstrating meaningful short-term weight loss (∼8–10%) while offering improved accessibility.⁸⁹

Self-monitoring and accountability mechanisms are consistent predictors of long-term success.⁹⁰ Regular self-weighing, dietary logging, and physical activity tracking enable early detection of weight drift and promote sustained motivation. Digital tools and mobile applications that integrate these functions, enhanced with automated feedback or remote coaching, may improve adherence and scalability.^91,92 Group-based or peer-supported formats may further strengthen motivation through social accountability while reducing cost and clinician burden.^93,94

Although these approaches are well established in obesity management, few have been tailored specifically for the GLP-1 discontinuation phase. Behavioral programs adapted to this context, including education about physiological hunger rebound, coping strategies for increased appetite, and reinforcement of lifestyle skills gained during the active treatment phase, may support patient awareness and facilitate adherence to behavioral strategies after pharmacotherapy is discontinued.

Pharmacological strategies

Pharmacological strategies to mitigate weight regain after GLP-1 RA discontinuation remain largely exploratory. To date, no RCTs have evaluated specific tapering, transition, or maintenance regimens following withdrawal. Theoretically, gradual dose reduction rather than abrupt cessation may ease physiological rebound, possibly by allowing slower re-emergence of appetite and gastrointestinal motility. Small observational studies suggest that individualized or tapered semaglutide dosing strategies, such as those used in a recent real-world digital weight-management program, may help sustain weight loss at lower maintenance doses.^95,96 Mathematical modeling further supports the theoretical feasibility of extended-interval or dose-reduction regimens to reduce cost and preserve efficacy.⁹⁷ These findings remain preliminary and require formal evaluation in RCTs.

Beyond dose-adjustment approaches, several non-incretin pharmacotherapies may offer limited support for weight maintenance following GLP-1 RA discontinuation. Agents such as bupropion-naltrexone and phentermine-topiramate can modestly suppress appetite and increase energy expenditure, although their efficacy is typically lower than that of GLP-1 RAs and their tolerability often limits use.⁶ Amylin analogues like cagrilintide are also under investigation as adjuncts to enhance satiety and reduce energy intake,⁹⁸ but their role after GLP-1 RA discontinuation has not been defined. Given the paucity of evidence, pharmacological management after GLP-1 RA discontinuation should be individualized and pragmatic.

Procedural strategies

For individuals who experience substantial weight regain or difficulty maintaining weight loss despite behavioral and pharmacological strategies, procedural interventions may represent a more durable option. Bariatric surgery remains the most effective long-term treatment for individuals with higher baseline BMI (typically ≥ 40 kg/m², or ≥ 35 kg/m² with obesity-related comorbidities), producing average weight reductions of 20–30% and durable improvements in metabolic health over a decade or more.⁹⁹ Among patients who have previously used GLP-1 RAs, surgery can serve as a definitive next step when medical management fails to achieve sustained control, though perioperative nutritional assessment and adjustment of residual appetite or motility changes are essential. Less invasive endoscopic interventions are options for patients who prefer non-surgical approaches or who do not meet surgical eligibility criteria. Techniques such as endoscopic sleeve gastroplasty, intragastric balloon placement, and duodenal-jejunal bypass liners (e.g., EndoBarrier) induce weight loss by reducing gastric volume or altering nutrient flow and absorption, achieving mean reductions of 10–15% over six to twelve months.^100,101 Although data specific to post-GLP-1 RA populations are limited, these procedures may function as “rescue” tools for patients who experience early rebound or plateau after pharmacotherapy. Choice of procedural approach should be guided by individual risk profile, degree of weight regain, comorbidities, and patient preference.

Hybrid and step-down models

Given the multifactorial nature of weight regain, combining complementary interventions likely offers the most durable protection against relapse after GLP-1 RA discontinuation (Fig. 3). Evidence from long-term lifestyle programs demonstrates that integrating dietary modification, structured exercise, and behavioral counseling achieves greater adherence and durability than any single component alone.^53,86 In clinical practice, hybrid models could pair gradual pharmacological tapering with ongoing lifestyle and behavioral support. Such frameworks allow patients to transition from active pharmacotherapy to self-management while maintaining therapeutic contact.

Fig. 3.

Stepwise approach to mitigating weight regain after GLP-1 therapy discontinuation. This conceptual framework illustrates a hierarchical strategy for weight maintenance following discontinuation of GLP-1 therapy, progressing from lifestyle and behavioral interventions to pharmacological and procedural approaches. A hybrid phase combining pharmacological tapering with ongoing lifestyle and behavioral support may facilitate transition and reduce early weight regain. Long-term sustainability depends on access, affordability, and healthcare system capacity.

Lessons from diabetes and hypertension management highlight how step-down approaches, where treatment intensity is reduced gradually as weight loss improves disease control, can preserve benefits and minimize rebound. For obesity care, this may translate into a “maintenance phase” that combines low-dose pharmacotherapy, scheduled behavioral check-ins, and ongoing dietary oversight. Although empirical data remain limited, these models align with the chronic, relapsing nature of obesity and merit testing in pragmatic RCTs. Future research should examine how best to sequence, taper, and combine lifestyle, behavioral, and procedural strategies to achieve durable outcomes.

Implementation and health system considerations

Limited access to multidisciplinary obesity management services, including dietitians, exercise professionals, and behavioral therapists, may constrain comprehensive follow-up after GLP-1 RA discontinuation. Digital health platforms may help bridge these gaps by delivering individualized nutrition and activity guidance, real-time feedback, and behavioral accountability at scale.^91,92 Remote monitoring, app-based coaching, and telehealth behavioral support can enable periodic check-ins that help clinicians detect early signs of weight regain and intervene before substantial rebound occurs. However, successful implementation will require clinician training, appropriate reimbursement models, and equitable access to digital infrastructure. Structured lifestyle interventions based on models such as the Diabetes Prevention Program have demonstrated favorable economic profiles in real-world settings, with evidence suggesting a high probability of cost-effectiveness and potential cost savings over time.¹⁰² Integrating such approaches with pharmacotherapy may therefore represent a more sustainable strategy for long-term obesity management at the health-system level.

Ultimately, while strategies to mitigate weight regain after GLP-1 RA discontinuation are important, improving long-term treatment persistence remains critical. Sustained weight loss with pharmacotherapy depends on continued use, yet discontinuation remains common in real-world practice due to barriers such as cost, limited access, side effects, and treatment burden.¹² Annual out-of-pocket costs for GLP-1 RAs can exceed several thousand dollars and insurance coverage for obesity treatment varies widely across insurance plans and health systems.^4,103 Many plans deny coverage for individuals without diabetes or impose duration limits, while intermittent supply shortages have further disrupted continuity of care. Expanded insurance coverage, the eventual introduction of generic formulations for earlier GLP-1 RAs, and novel oral agents may improve long-term affordability and access.^104,105 Tolerability may also be improved through patient education, gradual dose escalation, and proactive side-effect management, while newer formulations, including longer-acting and oral agents, may reduce treatment burden and improve adherence.^78,106,107 Although long-term safety data are generally reassuring, continued evaluation will be essential to support sustained use and inform clinical and policy decisions.¹⁰⁸

Conclusions

Weight regain following discontinuation of GLP-1 therapy is a predictable biological and behavioral response, reflecting the reversal of pharmacological effects on appetite and energy balance. Evidence from RCTs and real-world data consistently shows that discontinuation leads to reversal of cardiometabolic improvements and restoration of prior risk factors. These patterns highlight the need to view GLP-1 therapy not as a finite intervention but as one component of an ongoing continuum of care. Long-term success after GLP-1 RA discontinuation will require integrated, patient-centred approaches that address the physiological, psychological, and environmental determinants of weight regain. Lifestyle and behavioral interventions remain foundational, supported when appropriate by pharmacological, procedural, or digital adjuncts. By reframing obesity management as lifelong maintenance rather than temporary treatment, clinicians and policymakers can help ensure that the therapeutic benefits achieved with GLP-1 RAs are sustained well beyond their discontinuation.

Contributors

AM led the review, conducted the literature search, and drafted the manuscript.

KBF and MJE conceived the idea for the review, supervised the project, and contributed to critical revisions of the manuscript. BK, MAT, ASB, TZ, and AL provided critical intellectual input and reviewed the manuscript. All authors approved the final version.

Declaration of interests

KBF has received speaker fees from Regeneron and Statlog, both unrelated to the present work. MAT has received speaker honoraria from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Janssen, and Amgen. The other authors have no conflicts of interest to disclose.