Beyond Efficacy: Behavioral, Nutritional, and Pharmacological Strategies for Sustainable GLP-1–Based Obesity Treatment—A Narrative Review

Ori Scott, M.Sc. NutritionRegistered Dietitian (Israel)Founder, Healthy Habits Coaching

Abstract

Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and related incretin-based therapies have transformed obesity treatment by producing clinically meaningful weight reduction and improvements in obesity-related health outcomes. Their long-term effectiveness, however, depends not only on pharmacological efficacy but also on whether treatment can be sustained in routine clinical practice. Medication persistence commonly declines over time and may be affected by gastrointestinal adverse effects, treatment burden, cost and access, patient expectations, behavioral engagement, formulation, and healthcare-system factors. The development of effective oral GLP-1 therapies further raises the possibility that chronic obesity pharmacotherapy may evolve from a fixed treatment regimen into an individualized longitudinal treatment pathway.

Objective

To examine behavioral, nutritional, physical-activity, and pharmacological strategies that may contribute to sustainable GLP-1–based obesity treatment, with particular attention to medication adherence and persistence, treatment tolerability, weight maintenance, and emerging injectable-to-oral maintenance strategies.

Methods

A narrative review of PubMed/MEDLINE-indexed literature was conducted using combinations of MeSH and free-text terms relating to obesity, GLP-1 receptor agonists, semaglutide, liraglutide, tirzepatide, oral GLP-1 therapy, medication adherence, persistence, discontinuation, cognitive-behavioral therapy (CBT), motivational interviewing, behavioral intervention, medical nutrition therapy, physical activity, exercise, weight maintenance, and treatment sustainability. Recent GLP-1-specific evidence was prioritized. Established behavioral and nutritional obesity literature was incorporated when direct GLP-1-specific intervention evidence was unavailable. Direct evidence was distinguished from extrapolated and hypothesis-generating evidence.

Results

Randomized trials demonstrate that GLP-1 pharmacotherapy can be effectively combined with intensive behavioral treatment, but these studies were generally designed to evaluate weight reduction rather than whether behavioral treatment independently improves medication persistence. Real-world persistence varies substantially and commonly declines during the first 1–2 years of therapy. Gastrointestinal adverse effects, economic and access barriers, formulation, treatment burden, and patient-level factors contribute to discontinuation. Direct evidence that structured CBT, motivational interviewing, or medical nutrition therapy improves persistence with modern obesity pharmacotherapy remains limited. Exercise may contribute to maintenance of weight and body-composition benefits following pharmacotherapy withdrawal, although evidence is limited and should not be generalized across all incretin therapies. Emerging randomized evidence also suggests that oral GLP-1 therapy may preserve a substantial proportion of weight reduction previously achieved with injectable semaglutide or tirzepatide. However, direct comparison with continued injectable treatment is lacking.

Conclusions

Sustainable GLP-1–based obesity treatment should be conceptualized as more than medication adherence. Long-term effectiveness may depend on coordinated medical, nutritional, physical-activity, behavioral, and health-system strategies. Behavioral and nutritional treatment should complement rather than compete with effective pharmacotherapy. Future randomized studies should determine whether structured supportive interventions improve medication persistence and whether individualized transitions between injectable and oral pharmacotherapy can reduce treatment burden while preserving therapeutic benefit.

Keywords: obesity; GLP-1 receptor agonist; semaglutide; tirzepatide; adherence; persistence; cognitive-behavioral therapy; nutrition; physical activity; oral GLP-1; chronic disease; weight maintenance

Abbreviations

BMI: Body mass indexCBT: Cognitive-behavioral therapyCBT-OB: Cognitive-behavioral therapy for obesityGI: GastrointestinalGLP-1: Glucagon-like peptide-1GLP-1 RA: Glucagon-like peptide-1 receptor agonistIBT: Intensive behavioral therapyMI: Motivational interviewingMNT: Medical nutrition therapyRCT: Randomized controlled trialT2DM: Type 2 diabetes mellitus

1. Introduction

Obesity is a chronic, heterogeneous, and relapsing disease influenced by biological, environmental, behavioral, psychological, social, and structural determinants. Effective obesity treatment therefore frequently requires longitudinal management rather than a temporary period of weight reduction followed by treatment withdrawal.

The development of GLP-1 receptor agonists and related incretin-based pharmacotherapies has substantially changed the therapeutic landscape. In STEP 1, once-weekly semaglutide 2.4 mg combined with lifestyle intervention produced substantial weight reduction in adults with overweight or obesity without diabetes [1]. Subsequent trials of incretin-based therapies have reinforced the potential of pharmacotherapy to produce clinically important improvements in body weight and cardiometabolic risk.

Increasing pharmacological efficacy, however, exposes a second problem: efficacy under trial conditions is not synonymous with long-term effectiveness in routine clinical practice.

A medication cannot deliver its expected long-term benefit when treatment becomes inaccessible, adverse effects become unacceptable, medication-taking becomes burdensome, expectations are not appropriately addressed, or therapy is interrupted or discontinued.

Precise terminology is important. Medication adherence refers to the extent to which medication-taking corresponds with the prescribed regimen, whereas persistence refers to continuation of treatment over time. Temporary interruption, permanent discontinuation, switching, dose modification, and subsequent reinitiation represent related but clinically distinct treatment trajectories.

Recent real-world evidence indicates that persistence with GLP-1–based therapy is variable and frequently declines during the first 1–2 years [2]. This does not necessarily indicate unwillingness to receive treatment. Persistence may be influenced by gastrointestinal adverse effects, cost, insurance coverage, shortages, treatment expectations, formulation, dosing schedule, patient preferences, and healthcare-system characteristics.

The relevant question is therefore no longer only:

How effective is GLP-1 pharmacotherapy?

A second question has become increasingly important:

How can highly effective obesity pharmacotherapy be made sustainable over the course of a chronic disease?

The purpose of this narrative review is to examine this question across four interacting domains: medical/pharmacological treatment, nutrition therapy, physical activity, and behavioral support.

2. Methods

2.1 Review Design

A narrative review design was selected because the research question encompasses heterogeneous evidence, including randomized pharmacotherapy trials, observational persistence studies, behavioral obesity interventions, nutritional-support literature, exercise studies, psychological interventions, and emerging studies of oral maintenance pharmacotherapy.

Evidence was conceptually divided into three categories:

1. Direct evidence: interventions evaluated specifically within GLP-1–based obesity treatment;

2. Indirect evidence: findings from behavioral, nutritional, or physical-activity obesity treatment that may plausibly apply to individuals receiving GLP-1 therapy; and

3. Emerging or hypothesis-generating evidence: promising associations or treatment strategies requiring prospective confirmation.

This hierarchy was used to avoid interpreting the effectiveness of behavioral or nutritional treatment in general obesity care as proof that the same intervention improves GLP-1 medication persistence.

2.2 Information Sources and Search Concepts

PubMed/MEDLINE was searched using combinations of MeSH and free-text terminology related to GLP-1 receptor agonists, semaglutide, liraglutide, tirzepatide, incretin therapy, oral GLP-1 therapy, obesity, overweight, medication adherence, persistence, discontinuation, interruption, behavioral therapy, cognitive-behavioral therapy, motivational interviewing, counseling, self-monitoring, goal setting, problem solving, nutrition therapy, medical nutrition therapy, physical activity, exercise, weight maintenance, and treatment sustainability.

Reference lists of highly relevant systematic reviews, narrative reviews, randomized trials, and consensus publications were also examined.

Recent GLP-1-specific evidence was prioritized. Established obesity behavioral-treatment literature was incorporated where direct evidence was unavailable.

This was a narrative rather than systematic review. Formal PRISMA study selection, duplicate independent screening, and quantitative risk-of-bias assessment were therefore not performed.

3. From Pharmacological Efficacy to Treatment Sustainability

GLP-1–based pharmacotherapy modifies physiological processes involved in appetite, satiety, food intake, and energy balance. These effects challenge older obesity-treatment models in which individuals were expected to behaviorally overcome biological drivers of appetite and weight recurrence predominantly through dietary restraint and increased energy expenditure.

This does not make behavioral treatment obsolete.

Rather, it may change its purpose.

Traditional behavioral obesity treatment includes self-monitoring, goal setting, stimulus control, problem solving, cognitive restructuring, social support, dietary regulation, physical activity, and relapse-prevention strategies.

A 2024 scoping review of psychological interventions for weight reduction and sustained weight reduction identified 31 studies and 13 intervention types, with CBT and motivational interviewing among the commonly represented approaches [3].

CBT-OB similarly integrates behavioral strategies—including self-monitoring, goal setting, stimulus control, problem solving, social support, and relapse prevention—with cognitive strategies intended to address processes associated with treatment discontinuation and long-term weight management [4].

These approaches provide a plausible framework for supportive care during pharmacotherapy.

However, plausibility is not evidence of effectiveness for medication persistence.

At present, evidence demonstrating that CBT or CBT-OB specifically increases persistence with semaglutide or tirzepatide remains insufficient.

4. The Persistence Gap

Persistence estimates differ substantially across populations, indications, medications, healthcare systems, reimbursement arrangements, study designs, and definitions of discontinuation.

A recent narrative review identified seven studies examining persistence with GLP-1–based therapy among adults with obesity and T2DM, with follow-up ranging from six months to two years [5]. Persistence generally decreased over time and often fell below 60% at 12–24 months.

Treatment interruption followed by reinitiation was also observed, demonstrating that discontinuation should not always be considered a permanent binary event.

Factors associated with persistence included age, income, gastrointestinal adverse effects, weight reduction, BMI-related characteristics, GLP-1 agent, formulation, and dosing schedule [5].

Most importantly for the present review, none of the studies included in that review described structured behavioral or supportive strategies specifically designed to improve persistence [5].

This represents a clinically important research gap.

Table 1. Selected evidence relevant to GLP-1 treatment sustainability

Evidence	Population/design	Main finding
STEP 3 [6]	611 adults; RCT	Semaglutide + IBT produced greater weight loss than placebo + IBT
Persistence review [5]	7 real-world studies	Persistence often declined below 60% by 12–24 months
Oral vs injectable semaglutide [7]	242 adults with T2DM	Persistence favored weekly injectable semaglutide
STEP 1 extension [8]	Semaglutide withdrawal	Approximately two-thirds of prior weight loss regained within 1 year
SURMOUNT-4 [9]	Randomized withdrawal trial	Continuing tirzepatide maintained/extended weight loss; withdrawal led to regain
Exercise + liraglutide follow-up [10]	Post-treatment RCT analysis	Prior supervised exercise improved post-treatment maintenance vs liraglutide alone
ATTAIN-MAINTAIN [11]	Phase 3b RCT	Oral orforglipron preserved more prior injectable-induced weight reduction than placebo

5. Why Effective Therapy Is Discontinued

Treatment discontinuation is multifactorial and should not be reduced to motivation.

5.1 Gastrointestinal Adverse Effects

Nausea, vomiting, diarrhea, constipation, abdominal discomfort, and related gastrointestinal effects are common during GLP-1 therapy.

In STEP 3, gastrointestinal adverse events were more frequent with semaglutide than placebo, although only a minority discontinued treatment because of these events [6].

This creates a potentially modifiable pathway:

GI symptoms → increased treatment burden → titration/medication-taking difficulty → interruption → possible discontinuation.

Nutrition and behavioral interventions may plausibly intervene at several points in this pathway. However, direct randomized evidence showing that such interventions increase long-term GLP-1 persistence remains limited.

5.2 Cost and Access

Persistence is partly a healthcare-system outcome.

Insurance coverage, out-of-pocket expenditure, medication shortages, prescribing restrictions, availability, and continuity of clinical care can determine whether an individual can continue therapy regardless of willingness to do so.

Behavioral counseling cannot compensate for structural inability to obtain medication.

Persistence studies should therefore distinguish voluntary discontinuation from access-related discontinuation.

5.3 Expectations and Weight Plateaus

High public visibility of modern obesity pharmacotherapy may generate expectations that differ from individual clinical responses.

Behavioral support may help establish realistic treatment goals centered not exclusively on kilograms lost but also on metabolic health, mobility, physical function, quality of life, and management of obesity-related complications.

A weight plateau following substantial therapeutic benefit should not automatically be interpreted as treatment failure.

5.4 Treatment Burden and Preference

Treatment burden includes more than injection discomfort.

Weekly injectable therapy reduces dosing frequency but requires parenteral administration. Oral therapy removes the injection but may require daily medication-taking and, depending on the agent, specific administration conditions.

Consequently:

oral therapy should not automatically be assumed to produce better adherence or persistence than injectable therapy.

6. Behavioral Treatment in the GLP-1 Era

The rationale for behavioral treatment during pharmacotherapy extends beyond producing additional weight reduction.

Behavioral and psychological interventions may address self-efficacy, treatment expectations, problem solving, emotional eating where relevant, body image, self-monitoring, medication routines, physical activity, relapse prevention, and long-term self-management.

The changing biological environment created by GLP-1 therapy may also alter traditional behavioral targets.

When appetite, cravings, food-related preoccupation, or portion size decrease substantially during pharmacotherapy, behavioral treatment may need to shift emphasis from resisting hunger toward:

• maintaining nutritional adequacy;

• developing sustainable eating routines;

• managing adverse effects;

• maintaining physical activity;

• responding adaptively to weight plateaus;

• supporting medication-taking routines;

• managing treatment interruptions;

• maintaining engagement with healthcare;

• addressing emotional or cognitive concerns not resolved by appetite reduction; and

• preparing for long-term chronic-disease management.

This represents an evolution of behavioral obesity treatment rather than its disappearance.

7. What STEP 3 Demonstrates—and What It Does Not

STEP 3 provides strong evidence that intensive behavioral treatment and semaglutide can be delivered together [6].

Participants received 30 intensive behavioral-therapy visits over 68 weeks, including an initial low-calorie diet, and were randomized to semaglutide 2.4 mg or placebo.

Estimated mean body-weight change was −16.0% with semaglutide compared with −5.7% with placebo. At least 5% weight reduction was achieved by 86.6% and 47.6%, respectively [6].

These findings support a complementary rather than competitive model of pharmacotherapy and behavioral intervention.

However, STEP 3 cannot establish that intensive behavioral treatment improves semaglutide persistence because both treatment groups received behavioral therapy.

A trial designed specifically to answer that question would require:

GLP-1 pharmacotherapy + usual care

versus

GLP-1 pharmacotherapy + structured behavioral intervention

with medication adherence, persistence, interruption, and reinitiation defined prospectively.

8. Potential Behavioral Targets for Persistence

Potential intervention components include CBT, motivational interviewing, structured self-monitoring, problem solving, implementation intentions, goal setting, treatment-expectation management, social support, digital monitoring, and relapse-prevention strategies.

The intervention should distinguish modifiable behavioral barriers from structural barriers.

For example, problem-solving skills may help an individual establish medication routines or communicate early gastrointestinal symptoms to the clinical team.

They cannot resolve loss of insurance coverage or medication shortages.

This distinction is essential for non-stigmatizing obesity care.

Table 2. Supportive interventions during GLP-1 treatment

Intervention	Potential role	Evidence status
CBT/CBT-OB	Coping, cognition, problem solving, relapse prevention	Strong obesity rationale; direct GLP-1 persistence evidence insufficient
Motivational interviewing	Engagement and ambivalence	Plausible; GLP-1 persistence effect unproven
Self-monitoring	Medication routines, symptoms, behaviors	Established behavioral tool; direct persistence trials needed
MNT/dietitian support	GI tolerability and nutrient adequacy	Clinically supported; persistence effect not established
Resistance exercise	Strength, function, lean-tissue preservation	Relevant supportive intervention
Shared decision-making	Expectations and treatment preference	Clinically appropriate; limited direct persistence evidence
Access support	Cost/coverage barriers	Essential when discontinuation is structural

Table note: Evidence for a supportive intervention in general obesity management should not be interpreted as proof that the intervention increases persistence with semaglutide or tirzepatide.

9. Nutrition as Supportive Treatment

Nutrition therapy during GLP-1 treatment should not simply intensify energy restriction.

Reduced appetite and food intake can facilitate therapeutic weight reduction but may also create challenges related to gastrointestinal tolerability, dietary quality, protein intake, micronutrient adequacy, and preservation of lean tissue.

A recent multi-society advisory emphasized nutritional assessment, management of gastrointestinal adverse effects, nutrient adequacy, muscle and bone preservation, resistance exercise, and consideration of social determinants during GLP-1 treatment [12].

Nutrition therapy may therefore contribute to a pathway of:

improved tolerability → adequate nutrient intake → preservation of physical function → sustainable treatment experience.

However, the evidence must be interpreted cautiously.

A recent review specifically examining adherence/persistence and nutritional support acknowledged that much of the evidence supporting nutrition strategies is extrapolated rather than derived from GLP-1-specific randomized trials [13].

Therefore, it is scientifically premature to state that MNT has been proven to increase GLP-1 persistence.

A more accurate conclusion is that structured nutrition intervention represents a clinically plausible and testable strategy.

10. Physical Activity and Functional Sustainability

Physical activity during pharmacologically induced weight reduction should not be reduced to additional calorie expenditure.

Preservation of muscle, strength, mobility, cardiorespiratory fitness, and functional capacity is clinically important.

Evidence from a randomized weight-maintenance trial and its post-treatment extension is particularly informative.

Participants first achieved diet-induced weight loss and then received supervised exercise, liraglutide, the combination, or placebo. One year after active treatment ended, participants previously receiving supervised exercise plus liraglutide maintained body weight and body composition better than those previously receiving liraglutide alone [10].

Weight regain during the post-treatment year was approximately 6 kg greater after liraglutide alone than after supervised exercise [10].

These findings suggest that structured exercise may create benefits that persist beyond medication exposure.

However, this evidence involved liraglutide and should not automatically be generalized to semaglutide, tirzepatide, or other incretin therapies.

11. What Happens When GLP-1 Therapy Stops?

The chronic-disease model becomes especially relevant when effective pharmacotherapy is withdrawn.

In the STEP 1 extension, participants who had received semaglutide lost a mean 17.3% of baseline body weight during treatment. One year after withdrawal, they regained 11.6 percentage points—approximately two-thirds of the previous weight loss—and many cardiometabolic improvements moved toward baseline [8].

SURMOUNT-4 produced a similar conceptual finding with tirzepatide. Participants who continued treatment maintained and extended weight reduction, whereas those switched to placebo experienced substantial regain [9].

These findings should not be interpreted as evidence of patient failure.

Rather, they are consistent with obesity being a chronic disease in which biological drivers of weight recurrence persist after pharmacological effects are removed.

Behavioral and nutritional treatment remain valuable for health and long-term self-management, but current evidence does not establish that they can routinely reproduce the physiological effects of continued high-efficacy pharmacotherapy.

12. Persistence May Be a Treatment-Design Problem

Suboptimal persistence may not always be solved by persuading an individual to remain indefinitely on an identical regimen.

Chronic diseases frequently require therapeutic adaptation.

Obesity pharmacotherapy may ultimately follow a longitudinal model:

initiation → titration → therapeutic response → stabilization → individualized maintenance.

Potential maintenance pathways could include continued injectable therapy, modification of pharmacotherapy, switching agents, or transition to oral treatment.

This changes the question from:

“Will the patient keep taking the injection?”

to:

“What long-term treatment configuration is effective, acceptable, accessible, and sustainable for this individual?”

13. Does Oral Therapy Improve Persistence?

It is tempting to assume that avoiding injections will automatically improve medication persistence.

Current evidence does not support this assumption.

A real-world study of 242 adults with T2DM compared oral with subcutaneous semaglutide [7].

Persistence with oral versus injectable semaglutide was:

• 6 months: 85.3% vs 94.8%;

• 12 months: 72.3% vs 92.4%;

• 18 months: 46.0% vs 83.8%.

Gastrointestinal adverse effects were the most common reason for discontinuation [7].

This study was conducted in T2DM rather than an obesity-only population and was observational, so direct extrapolation to obesity treatment is inappropriate.

Nevertheless, it demonstrates an important principle:

removing the injection does not necessarily remove treatment burden.

Once-daily tablets may be preferable for some individuals, whereas once-weekly injections may be easier for others.

Patient preference should therefore be measured rather than assumed.

14. From Injectable Induction to Oral Maintenance

The development of effective oral GLP-1 therapies creates a particularly important research question.

Could a high-efficacy injectable agent be used to achieve substantial initial weight reduction, followed by oral pharmacotherapy for long-term maintenance in selected patients?

The 2026 ATTAIN-MAINTAIN phase 3b trial provides initial randomized evidence for this strategy [11].

Participants previously treated with tirzepatide or semaglutide were randomized to once-daily oral orforglipron or placebo.

Among participants previously treated with tirzepatide who had achieved a body-weight plateau, orforglipron maintained an estimated 74.7% of prior weight reduction compared with 49.2% with placebo at 52 weeks.

Among participants previously treated with semaglutide, corresponding estimates were 79.3% and 37.6% [11].

This provides proof of concept that oral pharmacotherapy can preserve a substantial proportion of weight reduction achieved with injectable therapy.

However, ATTAIN-MAINTAIN did not include continued injectable semaglutide or tirzepatide as an active comparator [11].

It therefore cannot answer the clinically more important question:

Is switching to oral therapy preferable to continuing an effective injectable therapy?

The trial was also limited to approximately one year of follow-up.

Current evidence therefore does not justify a routine recommendation to switch from injectable to oral therapy after 12, 18, or 24 months.

Table 3. Potential long-term pharmacological strategies

Strategy	Current evidence	Main uncertainty
Continue injectable therapy	Strong maintenance evidence	Long-term burden, access and cost
Modify regimen	Individualized clinical option	Optimal maintenance regimen unclear
Switch injectable agent	Used clinically	Comparative persistence uncertain
Injectable → oral maintenance	Emerging RCT evidence	No continued-injectable comparator
Stop pharmacotherapy	Withdrawal evidence shows recurrence	Who can maintain benefits without medication?
Lifestyle support alone after withdrawal	Important for health	Usually cannot be assumed to reproduce drug effect

Table note: No evidence currently establishes 24 months as an optimal time for routine injectable-to-oral transition.

15. Proposed Sustainable GLP-1 Care Framework

Long-term treatment sustainability can be conceptualized across four interacting pillars.

15.1 Medical/Pharmacological Sustainability

Treatment should remain effective, tolerable, accessible, affordable, and acceptable.

Pharmacotherapy need not remain static throughout the disease course.

15.2 Nutritional Sustainability

Reduced food intake should not lead to preventable nutritional inadequacy.

Nutrition therapy should support dietary quality, appropriate protein and micronutrient intake, gastrointestinal tolerability, and sustainable eating patterns.

15.3 Physical Sustainability

Treatment should preserve or improve strength, mobility, fitness, and functional capacity.

Resistance exercise and appropriate aerobic activity should be considered for health and function rather than merely additional weight loss.

15.4 Behavioral Sustainability

Behavioral support may address expectations, self-monitoring, problem solving, treatment engagement, emotional regulation, medication routines, coping, relapse prevention, and chronic-disease self-management.

The four pillars should be complementary rather than competing approaches.

Figure 1. Proposed Framework for Sustainable GLP-1–Based Obesity Treatment

OBESITY AS A CHRONIC DISEASE

↓

Comprehensive assessment and shared decision-making

Medical status • nutrition • physical function • behavioral/psychological factors • patient preferences • access/cost

↓

Initiate appropriate GLP-1/incretin-based pharmacotherapy

↓

Titration and early supportive care

Nutrition supportGI symptom managementBehavioral supportPhysical activity/resistance exerciseExpectation managementMedication-taking support

↓

Evaluate therapeutic response

Weight trajectory • metabolic health • function • quality of life • tolerability • patient-defined goals

↓

LONG-TERM SUSTAINABILITY ASSESSMENT

↙ Continue effective injectable therapy

↓ Individualize/modify regimen or switch agent

↘ Consider oral maintenance when supported by evidence and patient circumstances

↓

Continuous nutrition + physical activity + behavioral support

Surrounding all stages:

Access • affordability • healthcare continuity • tolerability • patient preference • social determinants

Figure legend: Proposed conceptual framework for sustainable GLP-1–based obesity care. Nutrition therapy, physical activity, behavioral support, and medical intervention operate throughout the treatment pathway. The model is hypothesis-generating and should not be interpreted as a validated prescribing algorithm or as a recommendation for routine transition from injectable to oral therapy.

16. Evidence Versus Research Gaps

Table 4. What is established and what remains uncertain?

Question	Current conclusion
Are modern GLP-1/incretin therapies effective for obesity?	Yes; established by multiple RCTs
Does stopping effective therapy commonly result in weight recurrence?	Yes; supported by withdrawal studies
Does behavioral treatment complement pharmacotherapy?	Yes for comprehensive obesity treatment
Does CBT improve semaglutide/tirzepatide persistence?	Unknown
Does MNT improve GLP-1 persistence?	Plausible but not established by direct RCT evidence
Can exercise improve post-treatment maintenance?	Encouraging liraglutide evidence; broader confirmation needed
Are oral GLP-1 therapies necessarily more persistent than injections?	No
Can oral treatment maintain injectable-induced weight loss?	Emerging evidence says partially yes
Is oral maintenance superior to continued injection?	Unknown
Should patients routinely switch after 24 months?	No evidence supports a fixed 24-month threshold

17. Research Agenda

The evidence gaps identified by this review suggest several priorities.

First, randomized trials should directly test whether structured behavioral intervention improves GLP-1 persistence compared with usual obesity care.

Second, trials should identify which behavioral components are effective. Multicomponent interventions combining CBT, motivational interviewing, self-monitoring, dietary counseling, exercise support, and digital monitoring may improve outcomes while obscuring the contribution of individual components.

Third, future studies should distinguish discontinuation caused by adverse effects, inadequate clinical response, patient preference, cost, insurance loss, medication shortages, clinician-directed cessation, switching, and other clinical circumstances.

Fourth, adherence and persistence terminology should be standardized. Medication adherence, persistence, temporary interruption, permanent discontinuation, reinitiation, and switching are not interchangeable outcomes.

Fifth, dietitian-led MNT should be prospectively evaluated for effects on gastrointestinal tolerability, nutritional adequacy, persistence, physical function, and quality of life.

Sixth, behavioral outcomes deserve greater attention. Self-efficacy, eating behavior, emotional regulation, quality of life, treatment satisfaction, body image, treatment burden, and patient preference may be clinically important even when body-weight outcomes are similar.

Seventh, injectable-to-oral maintenance trials require an active continued-injectable comparator.

An informative future trial could randomize clinically stable responders after a predefined period of injectable treatment to:

continued injectable therapy versus oral maintenance therapy, with outcomes including weight maintenance, cardiometabolic health, persistence, adverse effects, treatment burden, patient preference, quality of life, and cost-effectiveness.

Eighth, follow-up should extend substantially beyond 12–24 months.

Finally, economic and equity outcomes must be incorporated. An intervention that improves persistence only among individuals who can afford uninterrupted therapy cannot resolve structural inequities in obesity treatment.

18. Clinical Implications

Current evidence supports integrating behavioral, nutritional, and physical-activity care with GLP-1–based obesity pharmacotherapy.

However, clinicians and researchers should avoid overstating the evidence.

It has not yet been established that CBT, motivational interviewing, or MNT substantially increases persistence with semaglutide or tirzepatide.

Likewise, oral therapy should not automatically be assumed to improve adherence compared with injections.

Emerging oral agents may eventually provide an important maintenance option after injectable therapy, but optimal patient selection, timing, comparative effectiveness, persistence, long-term safety, and health-economic consequences remain uncertain.

Treatment should therefore remain individualized according to efficacy, adverse effects, comorbidities, physical function, patient preference, access, affordability, and therapeutic goals.

19. Obesity-Specific Guidance

Obesity should be recognized as a chronic disease requiring longitudinal rather than episodic management.

Successful weight reduction during pharmacotherapy should therefore not automatically be interpreted as evidence that medical treatment is no longer required.

Comprehensive obesity care should integrate four complementary pillars:

nutrition therapy, physical activity, behavioral modification, and medical intervention.

Behavioral and nutritional interventions should not be framed as tests of whether an individual can control obesity through willpower or earn the right to discontinue medication.

Similarly, weight recurrence after withdrawal of effective pharmacotherapy should not be described as personal failure.

The objective is sustainable improvement in health, physical function, quality of life, and obesity-related disease burden through individualized combinations of evidence-based treatment.

20. Strengths and Limitations

A strength of this review is its integration of pharmacological, behavioral, nutritional, physical-activity, and treatment-delivery perspectives at a time when these literatures are often considered separately.

The review also explicitly distinguishes direct GLP-1 evidence from evidence extrapolated from general obesity treatment.

Several limitations should be recognized.

This is a narrative rather than systematic review and does not provide exhaustive study identification, duplicate screening, formal risk-of-bias assessment, or meta-analysis.

The GLP-1 evidence base is evolving rapidly.

Definitions of adherence, persistence, interruption, and discontinuation vary substantially across studies.

Much of the behavioral evidence predates semaglutide and tirzepatide.

Direct evidence demonstrating that structured behavioral or nutritional interventions improve persistence with modern incretin pharmacotherapy remains limited.

Evidence comparing oral and injectable persistence is partly derived from T2DM populations and should not be assumed to apply directly to obesity-only populations.

Finally, emerging oral-maintenance evidence does not establish optimal sequencing between injectable and oral therapies.

21. Conclusions

The success of modern GLP-1–based obesity pharmacotherapy has created a new clinical challenge: converting highly efficacious treatment into sustainable long-term chronic-disease care.

Real-world persistence remains incomplete and is shaped by considerably more than pharmacological efficacy. Gastrointestinal tolerability, affordability, access, treatment expectations, treatment burden, behavioral engagement, nutritional factors, formulation, patient preference, and healthcare-system characteristics all influence treatment trajectories.

Behavioral treatment may consequently require a changing role in the GLP-1 era.

Its purpose should not primarily be to replace effective pharmacotherapy or enable patients to “get off” medication. Instead, behavioral intervention may support treatment engagement, chronic-disease self-management, realistic expectations, coping, physical activity, nutrition-related behaviors, and potentially medication persistence.

Nutrition and physical activity similarly remain complementary components of comprehensive obesity care rather than alternatives to pharmacotherapy.

Evidence from treatment-withdrawal studies reinforces the chronic nature of obesity and the importance of ongoing treatment for many patients. At the same time, exercise may improve maintenance after pharmacotherapy cessation in selected contexts.

At the pharmacological level, emerging oral agents introduce the possibility that obesity treatment could become longitudinally adaptive, with formulation and treatment intensity changing over time. Initial randomized evidence demonstrates that oral therapy can preserve a substantial proportion of weight reduction previously achieved with injectable therapy.

However, whether switching to oral treatment improves long-term persistence or provides an effective alternative to continued injectable therapy remains unknown.

No current evidence establishes a universal time point—such as 24 months—at which patients responding to injectable treatment should routinely transition to oral therapy.

The next research priority is therefore not simply to determine whether GLP-1–based obesity pharmacotherapy works.

It is to determine how effective pharmacotherapy can be made sustainable across the course of a chronic disease.

Declarations

Funding

This work received no external funding. The author received no financial or commercial support for the preparation of this review.

Conflicts of Interest

The author declares no financial or non-financial conflicts of interest relevant to this manuscript.

Author Contributions

Ori Scott conceived the review topic and scope, defined the research questions and eligibility criteria, evaluated and interpreted the literature, critically revised the manuscript, and approved the final version. The author accepts responsibility for the accuracy, integrity, interpretation, and conclusions of the work.

Ethics Approval

Not applicable. This narrative review evaluates previously published literature and involved no recruitment of human participants, collection of identifiable personal information, or original intervention involving human or animal subjects.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Data Availability

No original participant-level dataset was collected or generated for this narrative review. The evidence discussed in the manuscript is derived from peer-reviewed publications indexed in PubMed/MEDLINE and identified in the reference list.

Acknowledgments

None.

Declaration of AI-Assisted Technologies

An AI-assisted language tool was used during manuscript preparation to assist with organization, drafting, and language refinement. The author retains responsibility for literature selection, evaluation of the evidence, interpretation of findings, verification of scientific claims and references, critical revision, and approval of the final manuscript. The AI tool was not used as a scientific source and is not an author.

The author accepts responsibility for the content of the final manuscript.

Clinical Disclaimer

This narrative review is intended for scientific and educational purposes and does not constitute individualized medical advice. Clinical decisions regarding obesity pharmacotherapy should be based on patient-specific assessment, approved product information, contraindications, adverse effects, comorbidities, patient preferences, accessibility, shared decision-making, and applicable regulatory and professional guidance.

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