The Inappropriate Use of GLP-1 Analogs: Reflections from Pharmacoepidemiology

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a potent therapeutic option for the management of obesity, demonstrating exceptional efficacy in several large-scale clinical trials. Despite their promising therapeutic outcomes, the rising popularity of these agents raises significant concerns, particularly regarding their off-label use by individuals seeking weight loss for aesthetic reasons rather than addressing underlying metabolic health conditions. This article critically evaluates the efficacy and safety of GLP-1 RAs in obesity management. Additionally, it explores the economic implications and ethical challenges associated with the increasing demand for GLP-1 RAs. By addressing these dimensions, this article aims to facilitate informed and responsible decision-making in clinical practice, highlighting the need for individualized patient assessments and careful consideration of both short- and long-term safety risks.

1. Introduction

Obesity is a complex, multifactorial chronic disease requiring a multifaceted approach to its management, tailoring a combination of lifestyle modifications, pharmacological interventions, and surgical options to the patient’s clinical profile [1]. Despite these options, many patients fail to achieve substantial and sustained weight loss through conventional methods such as diet and exercise alone, particularly those with a body mass index (BMI) ≥ 27 kg/m² and comorbidities such as type 2 diabetes or hypertension, or with a BMI ≥ 30 kg/m² [1]. For these patients, pharmacological options have become increasingly essential. Among these options, GLP-1 receptor agonists (GLP-1 RAs) have emerged as a particularly important treatment since their FDA approval in 2014, offering a novel mechanism of action distinct from both older pharmacological agents and surgical interventions [2].

GLP-1 RAs, such as semaglutide, liraglutide, and dulaglutide, stand out from traditional weight loss treatments due to their multifaceted effects on glucose metabolism and satiety regulation. By mimicking endogenous GLP-1, they enhance insulin secretion, suppress glucagon release, delay gastric emptying, and act on the central nervous system to increase satiety and reduce caloric intake [3,4,5]. In addition to promoting significant weight loss, GLP-1 RAs have demonstrated broad metabolic and cardiovascular benefits, reducing the risk of cardiovascular disease, renal disease progression, and neuropathy in patients with type 2 diabetes [5,6,7]. These broader health impacts differentiate the GLP-1 RAs from other pharmacological options and underscore their rising prominence in obesity management.

Furthermore, randomized controlled trials have consistently shown that GLP-1 RAs, particularly semaglutide, can achieve weight loss comparable to bariatric surgery, with reductions of up to 10–15% in body weight [8,9,10]. These impressive outcomes highlight their effectiveness where lifestyle interventions alone have failed, but they also raise concerns about their off-label use. In recent years, there has been a growing trend of individuals without obesity or metabolic comorbidities using GLP-1 RAs for cosmetic purposes despite the lack of appropriate clinical indications [11]. Such misuse poses significant risks, including gastrointestinal side effects and potential long-term metabolic consequences, which are not justified in individuals without a medical need for weight reduction [12].

As the off-label use of GLP-1 RAs increases, so too does the urgency for regulatory oversight to prevent inappropriate prescribing. Without clear guidelines, there is a risk of overprescription, leading to unnecessary adverse effects and potentially undermining public trust in these medications for legitimate therapeutic purposes [13,14]. This article aims to explore the growing trend of using off-label GLP-1 RAs for cosmetic weight loss, assess the associated health risks from individual and public health perspectives, and emphasize the need for stringent prescribing guidelines to ensure their appropriate clinical use.

2. Safety Profile and Adverse Effects of GLP-1 RAs

2.1. Gastrointestinal Effects

The most commonly reported adverse effects of GLP-1 receptor agonists (GLP-1 RAs) are gastrointestinal, including nausea, vomiting, and diarrhea, affecting up to 50% of patients, particularly in the early stages of treatment [1,15]. These side effects are generally dose-dependent and tend to diminish with time as the body adjusts to the medication. Gradual dose titration and patient education on managing these symptoms, such as dietary adjustments, can help mitigate their severity [15]. A network meta-analysis of 68 trials showed that GLP-1 RAs were associated with higher rates of treatment discontinuation due to gastrointestinal events compared to oral antidiabetic agents [16]. In the context of weight loss, GLP-1 RAs have also been linked to more severe gastrointestinal complications, such as gastroparesis, bowel obstruction, and delayed gastric emptying, which may complicate surgical procedures requiring anesthesia [17,18]. These effects appear to be more pronounced in patients with preexisting renal impairment, underscoring the need for careful patient selection, monitoring, and dose adjustments to minimize risks [19].

2.2. Pancreatic Effects

Concerns about the potential for acute pancreatitis associated with GLP-1 RAs have been raised, although the evidence remains inconclusive regarding a direct causal relationship [20]. Patients experiencing severe abdominal pain should be promptly evaluated for pancreatitis, and treatment should be discontinued if confirmed [21]. While some studies have suggested an increased risk of hospitalization due to pancreatitis, others, including large-scale meta-analyses, have not consistently demonstrated an elevated risk [20,21]. The current consensus suggests that the risk is low but warrants further investigation. Additionally, GLP-1 RAs have been associated with transient elevations in pancreatic enzymes (amylase and lipase); however, these do not appear to predict the onset of pancreatitis and should not lead to premature discontinuation without other clinical symptoms [21].

Recent studies have also addressed the potential risk of pancreatic cancer. A study by Dankner et al. involving a large population cohort over nine years found no significant increase in pancreatic cancer incidence among GLP-1 RA users compared to basal insulin users during a seven-year follow-up [22]. These findings support the short- to medium-term safety of GLP-1 RAs concerning pancreatic cancer risk, but continued long-term monitoring beyond seven years is necessary to confirm this safety. Other recent studies have similarly ruled out an association between GLP-1 RA use and pancreatic cancer [23,24,25].

2.3. Gallbladder and Biliary Conditions

A meta-analysis of 76 studies reported an increased risk of gallbladder-related conditions, including cholelithiasis and cholecystitis, in patients treated with GLP-1 RAs [26]. This risk appears to be dose-dependent and correlated with longer treatment durations. Therefore, the long-term use of GLP-1 RAs necessitates vigilant monitoring of patients for symptoms suggestive of gallbladder disease. Early detection through routine imaging and laboratory tests can help prevent the progression of these conditions [26].

2.4. Hypersensitivity and Injection Site Reactions

Although hypersensitivity reactions such as angioedema and anaphylaxis are rare, they have been reported with the use of GLP-1 RAs [27,28]. Injection site reactions, including abscess formation, cellulitis, and necrosis, are more common, particularly with weekly formulations such as exenatide compared to daily formulations. Managing these reactions would typically involve rotating the injection sites and providing patients with education on proper injection techniques. In rare cases, patients may develop antibodies to GLP-1 RAs, which can reduce the drug’s efficacy, though this is uncommon and generally does not affect long-term glycemic control [29].

2.5. Renal Effects

Acute kidney injury (AKI) has been reported in association with GLP-1 RA use, particularly exenatide, often in the setting of severe dehydration caused by gastrointestinal side effects [29]. This underscores the importance of monitoring renal function, especially in patients with preexisting kidney disease or those on medications that affect renal function. Adjusting fluid intake and the early management of gastrointestinal symptoms can reduce the risk of AKI [29,30].

2.6. Thrombocytopenia

There have been rare reports of exenatide-induced immune thrombocytopenia, characterized by the development of antibodies that react with platelets in the presence of the drug, leading to a drop in platelet count and an increased risk of bleeding [31]. Immediate discontinuation of GLP-1 RA therapy is required if immune thrombocytopenia is suspected, along with close monitoring and supportive care [31].

2.7. Thyroid C-Cell Tumors

Preclinical studies in rodents have demonstrated a link between GLP-1 RAs and the development of thyroid C-cell tumors. While these findings have not been conclusively observed in human studies, GLP-1 RAs are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 [32,33]. Given the absence of definitive human data, patient screening for risk factors and thorough counseling are essential before initiating GLP-1 RA therapy, especially in high-risk populations [34].

2.8. Neuropsychiatric Adverse Effects

There have been isolated reports suggesting a potential link between GLP-1 RAs and neuropsychiatric effects such as anxiety, insomnia, and depression [35]. However, establishing a direct cause-and-effect relationship between metabolic diseases, mood disorders, and medications is complex due to the interplay of underlying physiological mechanisms and individual variability. Further research is needed to clarify whether these neuropsychiatric effects are directly attributable to GLP-1 RAs or if they result from the broader metabolic improvements induced by the treatment [35]. Until more definitive evidence is available, clinicians should remain vigilant for signs of neuropsychiatric side effects in patients receiving GLP-1 RAs and consider modifying the treatment if necessary.

3. Pharmacoeconomics and Ethical Considerations

The rapid expansion of the use of GLP-1 receptor agonists (GLP-1 RAs) for diabetes management, weight reduction, and other uses, including substance abuse treatment, has introduced significant ethical and economic challenges [35,36]. Driving this trend is the portrayal of GLP-1 RAs as quick weight-loss solutions, often promoted by social media and celebrity endorsements [13,14]. This has resulted in global shortages, disproportionately affecting patients who rely on these medications to manage type 2 diabetes and obesity. Ethical concerns arise from the off-label use of GLP-1 RAs for cosmetic purposes, as many individuals without metabolic comorbidities may not fully understand the associated risks, including gastrointestinal disturbances, pancreatitis, and other adverse effects [13,14,37].

The European Medicines Agency (EMA) has acknowledged these shortages and taken steps to prioritize the use of GLP-1 RAs for patients with medical conditions such as diabetes and obesity [13]. Nevertheless, the off-label demand continues to drive shortages, leaving those needing these medications without access. Additionally, the high cost of GLP-1 RAs, often exceeding $1000 per month, exacerbates healthcare inequities, particularly for lower-income patients. Wealthier individuals can more easily obtain these drugs for non-therapeutic purposes, while vulnerable populations are deprived of essential treatments, deepening healthcare access disparities.

A study among aesthetic plastic surgeons highlights the growing off-label use of GLP-1 RAs for cosmetic weight loss, with nearly 30% of surgeons reporting the personal use of these medications for aesthetic purposes [14]. This study underscores the increasing role of the aesthetic industry in shaping public perceptions of these drugs, highlighting the urgent need for more substantial ethical guidelines within the plastic surgery community. Clear recommendations for healthcare professionals on the responsible and medically appropriate use of GLP-1 RAs are essential to prevent misuse.

3.1. Pharmacoeconomic Impact and Healthcare Inequities

The rapid rise in GLP-1 RA use has placed a significant financial strain on healthcare systems worldwide. With monthly costs ranging from $900 to $1300, these drugs already present a substantial financial burden for patients and healthcare providers. This issue is particularly problematic in low-resource settings, where limited healthcare budgets may restrict access to these life-saving treatments for individuals with type 2 diabetes and obesity [38]. The diversion of GLP-1 RAs for cosmetic purposes further exacerbates these financial pressures, as wealthier individuals access the drugs off-label, leaving those who meet clinical criteria struggling to obtain necessary medications.

These healthcare inequities are further amplified by regional disparities in drug availability. In Spain, for example, the growing demand for semaglutide has led to widespread shortages, leaving many diabetic patients without essential medications [39,40]. In response, the Spanish Agency for Medicines and Health Products (AEMPS) has updated guidelines to prioritize GLP-1 RA prescriptions for patients with documented medical conditions such as type 2 diabetes and obesity [41]. Regional health authorities, such as the Castilla y León Health Portal, have also adjusted treatment protocols to ensure these medications are accessible to high-need patients [42].

3.2. Addressing Pharmacoepidemiological and Pharmacoeconomic Challenges

A multifaceted approach is needed to address the challenges posed by the off-label use of GLP-1 RAs. Promoting rational drug use (RDU) is critical, requiring healthcare professionals to adhere to evidence-based guidelines. This approach ensures that GLP-1 RAs are prescribed only to patients with medical indications, such as obesity and type 2 diabetes. Educational campaigns targeting both healthcare providers and the public are essential to raise awareness about the risks of off-label use and shift the perception of GLP-1 RAs away from their use as cosmetic solutions and onto their use as serious therapeutic interventions.

In addition, regulatory bodies must implement stricter controls on the prescription and distribution of GLP-1 RAs. The AEMPS, for example, has introduced measures to regulate the distribution of GLP-1 analogs, urging healthcare professionals to prioritize prescriptions for patients who meet clinical criteria [41]. Similar regulatory frameworks are needed globally to prevent the misuse of these medications and ensure equitable access for patients with legitimate medical needs.

To alleviate the economic burden caused by GLP-1 RAs, policymakers should consider financial strategies such as subsidies, insurance coverage adjustments, or tiered pricing models based on patient income or regional healthcare resources. These measures would reduce the strain on healthcare systems and ensure that patients with type 2 diabetes and obesity are not deprived of essential treatments due to financial barriers.

4. Discussion

The widespread use of GLP-1 receptor agonists (GLP-1 RAs) for obesity management has opened a promising pharmacotherapeutic pathway. However, the rapid adoption of these medications, particularly for off-label use in cosmetic weight loss, raises significant clinical and ethical concerns. While GLP-1 RAs provide critical treatment options for patients with type 2 diabetes and obesity, their misuse for aesthetic purposes exposes individuals to unnecessary risks and contributes to drug shortages, depriving those with legitimate medical needs of essential treatment.

Clinically, GLP-1 RAs have demonstrated their efficacy in weight loss and glycemic control, but they are also associated with adverse effects, including gastrointestinal disturbances, pancreatitis, and gallbladder disease. These risks are typically manageable in patients with metabolic conditions, who possess compensatory mechanisms to mitigate potential side effects. However, individuals using GLP-1 RAs for cosmetic purposes, without underlying metabolic diseases, may lack these protections, making them more susceptible to adverse events. Such risks highlight the need for cautious prescribing and the importance of adhering to medical guidelines. While the short-term benefits of GLP-1 RAs for weight loss are clear, the long-term safety profile remains insufficiently explored. Ongoing research is necessary to fully assess the risks and benefits, particularly in populations using these drugs off-label.

From a pharmacoepidemiological perspective, the off-label use of GLP-1 RAs also introduces significant public health challenges. The high cost of these medications, ranging from $900 to $1300 per month, creates barriers to access, particularly in low-resource settings. This demand, driven by their viral popularity on social media and celebrity endorsements, places undue pressure on healthcare systems. Inappropriately allocating these drugs for non-medical purposes exacerbates this financial strain, potentially leading to inequities in healthcare access. Those with the financial means to afford GLP-1 RAs may obtain them for cosmetic reasons, while patients with type 2 diabetes and obesity—who meet the clinical criteria—struggle to access these vital treatments.

Addressing these challenges requires a concerted effort to promote the rational drug use (RDU) of GLP-1 RAs. Healthcare professionals must adhere strictly to the established clinical guidelines, ensuring that GLP-1 RAs are prescribed only to patients who meet the criteria for obesity management and type 2 diabetes. This approach is crucial for mitigating the risks of off-label use and ensuring that these medications are reserved for individuals most likely to benefit from their effects. Educating both healthcare providers and patients on the risks of off-label use is essential in curbing the misuse of these powerful drugs. Public health campaigns and patient education programs can raise awareness about the potential dangers of inappropriate use, helping to shift public perception away from cosmetic applications.

On a broader scale, policymakers should consider implementing stricter regulations to ensure responsible prescription and distribution. This approach could include measures such as mandatory provider training on GLP-1 RA prescribing, stricter enforcement of prescribing guidelines, and prioritizing access for high-need patients through regulated distribution channels. In addition, addressing the financial burden associated with GLP-1 RAs is a key aspect. Policymakers could explore options such as price controls, insurance coverage adjustments, or subsidy programs to ensure these medications remain accessible to those who need them most, particularly in lower-income populations.

In conclusion, while GLP-1 RAs offer significant therapeutic benefits for patients with obesity and type 2 diabetes, their misuse for cosmetic purposes presents clinical, ethical, and economic challenges. Promoting rational drug use, educating the public on the risks of off-label use, and implementing targeted policy solutions are essential steps to ensure that GLP-1 RAs are used safely and equitably, preserving their efficacy for those who truly need them.

5. Conclusions

GLP-1 receptor agonists represent a significant breakthrough in the pharmacological management of obesity and type 2 diabetes mellitus. However, their growing popularity for off-label, aesthetic purposes raises important pharmacoepidemiological, ethical, and economic concerns. Promoting the rational use of GLP-1 RAs by adhering to clinical guidelines is essential to prevent inappropriate prescribing and ensure equitable access. The medical community must remain vigilant regarding the long-term safety of these agents and advocate for their use in populations that derive the greatest clinical benefit. Strengthening regulatory oversight is critical to ensure the safe and appropriate use of GLP-1 RAs. This approach includes implementing measures to prevent off-label marketing and enhancing data collection systems to monitor adverse events. Additionally, healthcare providers need to be educated on the appropriate use of GLP-1 RAs and the risks linked to off-label prescribing. Addressing these challenges will help maintain a balance between innovation and ethical responsibility in the management of obesity.