The Trojan horse of off-label glucagon-like peptide-1 receptor agonist use: Protecting patients through responsible practice

Reports on postmarketing safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have assumed particular importance, urgency, and global relevance at a time when clinical innovation is rapidly outpacing regulatory and societal safeguards. Although these agents exemplify the transformative potential of incretin-based therapies in diabetes and obesity care, emerging safety signals underscore the need for mechanism-aware pharmacovigilance and agent-specific monitoring. ¹ Postauthorization data not only complement trial evidence but also illuminate patterns of use, misuse, and harm that remain invisible in controlled settings. The aim of this commentary is to examine the challenges posed by the widespread off-label use of GLP-1RAs and to articulate a shared perspective on the implications for clinical practice, public health, and patient safety. We argue that failure to address these challenges risks undermining both the scientific credibility and long-term societal benefit of this therapeutic class.

GLP-1RAs have revolutionized the management of type 2 diabetes and obesity, delivering significant weight reduction and cardio-kidney-metabolic benefits.^2–4 However, prescribers should strictly follow the Summary of Product Characteristics (SmPC) and limit use to approved indications—diabetes, obesity, and overweight with complications—because off-label and aesthetic use has created a new “zone of danger.” Social media influence, celebrity endorsement, and the allure of rapid weight loss continue to drive this trend, undermining evidence-based practice, contributing to drug shortages, and exposing low-risk individuals to preventable adverse effects. This supply–demand imbalance has also facilitated the emergence of counterfeit GLP-1RAs, extending the problem from inappropriate prescribing to supply-chain distortion. These falsified products may contain incorrect dosages, harmful constituents, or no active ingredient at all, posing serious risks to patient safety while undermining trust in regulated pharmaceutical systems. ⁵

The risk extends beyond transient gastrointestinal symptoms to include metabolic, nutritional, musculoskeletal, and psychological complications, including worsened body image and disordered eating. Pharmacovigilance data reinforce this concern, with semaglutide adverse event reports increasing 67.1% compared with previous periods (p < 0.001). ⁶ This pharmacovigilance signal is further supported by Chiappini et al., ⁷ who, using FAERS data, demonstrated stronger signals of misuse and abuse potential for semaglutide than for other GLP-1RAs and the phentermine–topiramate combination, alongside a progressive increase in adverse-event reports. The current “Ozempic off-label era” demands urgent attention.^6–8

The extent and visibility of off-label GLP-1RA use are reflected in the findings from Callaghan et al., ⁹ who reported that 46.3% of respondents supported physician discretion to prescribe these agents off-label, while 58% expressed concern about potential supply shortages and 63% about safety in this context. Notably, an embedded survey experiment demonstrated that safety-framed messaging significantly reduced public support for off-label prescribing, whereas supply-focused framing had no comparable effect, underscoring the sensitivity of public opinion to risk communication. More importantly, this pattern is not confined to the general population. A recent multicountry cross-sectional study involving 657 healthcare professionals identified semaglutide as the most commonly used GLP-1RA, with its use frequently influenced by peer recommendations and social media exposure. These findings highlight the growing normalization of off-label GLP-1RA use even within the medical workforce and signal a troubling erosion of evidence-based prescribing practices and professional responsibility. ¹⁰

This disconnect between perceived acceptability and clinically appropriate prescribing is reflected in real-world risk scenarios. For instance, prescribing a GLP-1RA off-label to an individual with known or unassessed gallstone disease, in the absence of an approved indication, may expose the patient to avoidable risks such as biliary complications or pancreatitis. ¹¹ Similarly, off-label use in metabolically healthy individuals seeking to lose a small amount of weight for aesthetic reasons may result in a disproportionate loss of lean mass, potentially accelerating sarcopenia and long-term functional impairment. ¹² Most concerning is the off-label prescription of GLP-1RAs to individuals with subclinical eating disorders or distorted body image, where appetite suppression may exacerbate underlying psychopathology and reinforce harmful behaviors. ¹³ In each of these scenarios, harm is driven not primarily by patient demand but by the clinical decision to prescribe outside evidence-based indications, without appropriate clinical evaluation, risk stratification, and adherence to fundamental medical principles—particularly “first, do no harm.” Furthermore, failure to educate patients regarding the indispensable role of lifestyle interventions constitutes a critical lapse in responsible care.

Aesthetic-driven use also distorts public understanding of obesity as a chronic, relapsing disease that requires sustained lifestyle modification and multidisciplinary management.^3,14,15 When pharmacotherapy is framed as a cosmetic shortcut, the principles of long-term disease management become obscured. Engagement with preventive and therapeutic interventions may diminish, while treatment availability for patients with medically indicated needs becomes constrained. This phenomenon, which we term the “red carpet syndrome,” reflects a concerning shift toward cosmetic pharmacotherapy. The “red carpet syndrome” also exemplifies how media narratives can reframe prescription medications as lifestyle enhancers, blurring the boundary between medical necessity and consumer desire.

This glamorization risks trivializing the complexity of obesity as a chronic, multifactorial disease and may discourage patients from engaging in essential lifestyle modifications and multidisciplinary care. Moreover, it can perpetuate unrealistic expectations regarding weight loss, fostering cycles of disappointment and potential psychological harm. Changing societal ideals of body image and popular weight-loss trends further exacerbate this issue, normalizing the pursuit of rapid cosmetic outcomes over sustained health improvements. The societal embrace of quick pharmacologic fixes threatens to undermine comprehensive public health strategies aimed at sustainable disease management.

Education regarding prescribers, stricter regulatory oversight, and rational pharmacotherapy are essential. This includes reinforcing guideline-based prescribing, enhancing continuing medical education, and ensuring complete transparency in promotional activities. Without such measures, there is a risk of loss of therapeutic value of GLP-1RAs through misuse, converting a medical breakthrough into a public health liability. ⁸ Encouragingly, semaglutide and tirzepatide, initially developed as antihyperglycemic agents, have redefined obesity care, demonstrating weight reductions of up to 14.9% (STEP 1) and 20.9% (SURMOUNT-1), respectively, while conferring cardiovascular, osteoarticular, hepatic, and sleep apnea benefits.^3,4,14 These outcomes underscore the legitimate and profound impact of GLP-1-based therapies when used appropriately.

However, these powerful pharmacologic tools should be used responsibly. GLP-1RAs and dual agonists should complement—not replace—lifestyle interventions, thereby avoiding the “couch potato syndrome” that undermines their true potential. Sustainable benefit depends on behavioral, nutritional, and physical activity changes that pharmacotherapy alone cannot provide. Off-label aesthetic use raises ethical, safety, and long-term psychological concerns. Regulators must continue rigorous safety evaluations, integrating mechanistic insights with pharmacovigilance, while clinicians conduct timely monitoring and ongoing risk–benefit assessments.^6,8 Such oversight is particularly important because treatment durations may extend beyond those evaluated in clinical trials.

Clinical outcomes alone will not determine the success of GLP-1RAs and dual agonists; their true value depends on responsible and judicious use in everyday practice, as off-label and inappropriate application risks compromising both their favorable safety profile and high effectiveness. “Primum non nocere” remains the guiding principle for all stakeholders involved in GLP-1RA use. Responsibility extends far beyond clinicians—patients must engage thoughtfully with treatment; prescribers must exercise careful, evidence-based judgment; marketers must actively discourage inappropriate or off-label use; and media coverage should convey evidence-based information rather than rely on glamorized “red carpet” portrayals. A shared framework of accountability is therefore essential.

Structured and transparent implementation is essential to preserve therapeutic efficacy, protect patients, and maintain public trust. Addressing the challenges posed by off-label GLP-1RA use requires coordinated action among all stakeholders. Regulatory bodies must enforce stricter oversight; healthcare systems should support prescriber education and access to multidisciplinary care; and patient advocacy groups can play a vital role in disseminating balanced information. Such collective responsibility can help implement these therapies safely and equitably.

In this new era of antiobesity pharmacotherapy, the failure of any stakeholder to act responsibly risks transforming one of medicine’s most powerful therapeutic tools into a societal hazard (Figure 1).

Figure 1.

Conceptual illustration of the risks and hazards associated with off-label and aesthetic use of GLP-1RAs. GLP-1RAs: glucagon-like peptide-1 receptor agonists.