Highway to the danger zone? A cautionary account that GLP-1 receptor agonists may be too effective for unmonitored weight loss

Abstract

Glucagon-like peptide 1 (GLP-1) receptor agonists are revolutionizing obesity and type 2 diabetes treatment, delivering remarkable weight loss outcomes. These medications, leveraging the effects of the insulin-regulating hormone GLP-1 via actions on peripheral and central nervous system targets, have raised hopes with their bariatric surgery-rivaling results. However, questions remain about their long-term safety and efficacy. Drawing from our expertise in obesity medicine and psychiatry, we reflect upon our experiences with the clinical use of these medications and delve into the nuanced challenges and risks they pose, particularly for those prone to disordered eating or those diagnosed with rare genetic diseases of obesity. We contend that effectively managing weight loss within this ‘danger zone’ necessitates (1) proactive screening and continuous monitoring for disordered eating; (2) vigilant monitoring for appetite-related maladaptive responses, including food aversion and dehydration; and (3) ongoing assessment for broader health impacts. A multifaceted, interdisciplinary approach that melds medical, psychological, dietary, and behavioral strategies is crucial to deliver tailored and thorough care to each patient.

Introduction: Sounding the Alarm on GLP-1 Agonist Therapy in Obesity Management

GLP-1 (glucagon-like peptide 1) agonists, such as semaglutide, liraglutide, dulaglutide and tirzepatide, are FDA-approved medications obesity and type 2 diabetes treatment.^1–3 These drugs mimic GLP-1, a hormone that is released from intestinal L cells after food intake, which promotes insulin release from the pancreas and reduces glucagon secretion.⁴ They also induce satiety by activating GLP-1 receptors in brain centers that regulate appetite, such as the hypothalamus, brainstem nucleus tractus solitarius, and amygdala⁵, and slow gastric emptying, which aids in glycemic control and weight loss.⁶ Notably, GLP-1 agonists are typically part of a broader weight reduction treatment plan that includes diet and exercise, and they may be used in conjunction with bariatric surgery for weight reduction.

GLP-1 agonists have demonstrated powerful impacts on weight loss. Research, including meta-analyses of randomized controlled trials, indicates these medications can achieve an average weight reduction of approximately 3 to 5% of initial body weight after 6 to 12 months of treatment.^6,7 Newer agents like semaglutide and tirzepatide are showing even more remarkable results—up to 15%⁸ and over 20% of total bodyweight⁹, respectively. In some cases, patients experience weight reductions comparable to those achieved through bariatric surgery.^3,10 While these results underscore the potential of GLP-1 agonists as a treatment for obesity, due to the unprecedented efficacy of these medications there is also a significant risk of excessive weight loss in patients utilizing them.¹¹ Furthermore, their long-term tolerability and efficacy beyond 2 years of treatment are unknown.¹²

The rapid acceptance of GLP-1 agonists, driven by their effectiveness against obesity, has gained substantial traction among medical professionals and patients, simultaneously igniting significant public and media interest. High-profile celebrity endorsements, media portrayals such as humorous takes in pop culture¹³, and consistent advertising to the general public reflect a growing societal trend toward their use beyond traditional medical indications. This expanding use of GLP-1 agonists suggests the need for prudence in their broad application, as reflected by recent societal¹⁴ and individual¹⁵ commentaries. It is therefore essential to maintain a balance between the promise these medications hold and a rigorous assessment of their proper use and potential risks.

Clinical Experiences with GLP1 Agonists in a Weight Management Program

In the context of a weight management program, we present a series of case studies that illustrate the potential for GLP-1 agonists to trigger or exacerbate restrictive eating behaviors. These cases highlight the complexity of appetite regulation and the need for careful monitoring when using these medications.

Case 1:

A female with a history of Roux-en-Y Gastric Bypass surgery, pre-surgical BMI of 68, and metabolic syndrome, was prescribed GLP-1 therapy to aid further weight loss post-surgery. She began demonstrating restrictive food intake behaviors after transitioning to semaglutide 1 milligram (mg), reporting severe aversion to food to the point of consuming 400 Calories a day. This resulted in an additional 20-pound weight loss over a 3-month period, raising concerns from her dietician about lean body mass depletion. As a result semaglutide was discontinued, and the patient was referred to a psychiatrist who treated her for obsessive compulsive disorder with high dose fluoxetine 60 mg daily and psychotherapy.

Case 2:

Due to a national shortage of 1.0 mg semaglutide, a female whose weight was previously stable on phentermine 15mg/topiramate 25mg twice daily plus GLP-1 agonist therapy (i.e., semaglutide) was switched to 5mg tirzepatide in-between clinic visits. On the day after taking the first dose, she suddenly decided to start a liquid diet comprised only of water and Diet Coke and did not eat any solid food for 13 days until her next clinic appointment. Over the previous 12 months, the patient had lost 25 pounds on gradually increasing doses of the phentermine/topiramate combination medication, with very slow weight loss and with an absence of weight loss in the preceding 3 months. After initiating tirzepatide she lost 21 pounds in 13 days. The patient felt such a strong absence of hunger that she described a dietary plan of “fasting for six days and eating one time a week” as her stated plan for long-term weight reduction. Alarmed by her extreme fasting behaviors, tirzepatide and other medications were discontinued, and close dietician follow up was instituted as well as additional referral to a psychiatrist and clinical psychologist for evaluation and treatment of potential psychiatric comorbidities.

Case 3:

An individual with obesity and hypertension received a prescription for tirzepatide through a telemedicine app, with blind titration and no dietary counseling. The patient experienced a strong hunger reduction, nausea, and some diarrhea on 2.5mg and was increased to 5mg on refill. After increasing the dose to 5mg they had severe diarrhea and reported the loss of almost all sense of hunger and thirst, stopping nearly all liquid intake and only eating 400–600 Calories of unhealthy high-density (i.e., junk) food per day. The patient was also taking a diuretic medication for hypertension, and after 2 weeks of minimal intake, reported severe leg cramps to their primary care physician and disclosed they had started tirzepatide. Laboratory evaluation of renal function revealed their creatinine had increased from 0.6 to 3.6 mg/dL, prompting hospitalization for acute kidney injury and treatment for dehydration and electrolyte deficiencies.

Case 4:

After a sleeve gastrectomy, a female patient with type 2 diabetes mellitus discontinued tirzepatide 7.5 mg as advised but resumed it independently due to rising fasting blood glucose levels. This led to excessive satiety, such that she reduced her daily intake to 300–350 Calories due to disinterest in food. Upon discovery of this outcome, her medical team stopped the tirzepatide, and she was transitioned to low dose insulin for blood sugar control.

Integration of GLP-1 Agonists With Other Weight Loss Management Drugs in a Rare Genetic Disorders of Obesity Clinic

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved drug for managing weight in rare genetic disorders of obesity, such as pro-opiomelanocortin (POMC) deficiency, leptin receptor deficiency, proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, and Bardet-Biedl syndrome. By targeting MC4R in the brain, it counteracts the excessive hunger caused by mutations in the MC4R pathway, aiding in appetite control and weight reduction.¹⁶ Based on this pharmacology setmelanotide is prescribed alongside diet and exercise to facilitate weight loss and enhance quality of life in patients with genetic disorders of obesity.¹⁷ When combined with minimal doses of GLP-1 agonists, setmelanotide has shown promise in reversing hyperphagia from conditions such as Bardet-Biedl syndrome. We present case studies that illustrate the effectiveness of this combination therapy in patients with these unique genetic conditions.

Case series 1:

Under medical oversight, two individuals with Bardet-Biedl syndrome and type 2 diabetes mellitus lost 15% of their total body weight in a 3- and 5-month period, respectively, following a combination therapy of tirzepatide and setmelanotide. Significant appetite suppression and aversion to solid foods prompted a dosage reduction from 5mg tirzepatide and 3mg setmelanotide, alleviating these symptoms. Subsequently, one patient needed psychoeducational support to understand and accept the return of hunger sensations as a normal physiological response during weekly GLP-1 treatment intervals.

Case 2:

A Bardet-Biedl syndrome patient with lifelong hyperphagia underwent combination therapy with 3mg setmelanotide and 5mg tirzepatide, leading to a severe food aversion, even to protein shakes, limiting their intake to fewer than 800 Calories daily. Reducing the GLP-1 agonists’ dosage mitigated these aversions. Afterwards, nutritional counseling was necessary to help the patient recognize and accept hunger 3 to 4 hours after eating as a normal physiological response.

Navigating the Danger Zone in Weight Loss Management

The “danger zone” metaphor aptly characterizes the precariousness of situations that are fraught with risk and uncertainty; where the stakes are high, and the consequences of failure are severe. The obesity epidemic in the US, and the worldwide obesity pandemic^18,19, represent one of human society’s most visible and yet most ignored health problems. Given the many health risks associated with obesity and the unprecedented increase in human obesity rates over the past century, substantive action is imperative. GLP-1 agonists represent a potentially transformative advancement in combating obesity. However, our clinical experience warns of a need for intensive monitoring and deeper understanding, as their potent efficacy could also inadvertently lead to extreme dietary restriction and weight loss in some patients. Consequently, we stand at a critical juncture in weight loss management, calling for a well-defined strategy to approach this challenging terrain.

As we navigate this “danger zone” in weight loss management with GLP-1 agonists, history offers valuable lessons. For instance, angiotensin converting enzyme inhibitors (ACEI), now a cornerstone for hypertension treatment, initially led to severe hypotension in dehydrated patients due to a lack of understanding of their potent effects.²⁰ With the recognition of ACEI-induced renal failure risks²¹, tailored titration algorithms were developed for vulnerable patients.²² Similarly, the introduction of denosumab for life-threatening hypercalcemia required adjustments after some patients developed life-threatening hypocalcemia.²³ These precedents remind us that with groundbreaking treatments come the responsibility to anticipate, detect, and address potential risks through attentive monitoring and patient and provider education. In the case of GLP-1 agonists, we must apply this wisdom to prevent over-suppression of appetite and the resultant complications, crafting a careful approach that draws from past insights to avoid the dangers of improper or indiscriminate prescription.

With obesity recognized globally as a prevalent and preventable health risk²⁴, the need for effective treatments to alter its course is clear. Yet, the conventional approach of maximizing medication dosages proves unsuitable for potent GLP-1 agonists aimed at weight loss. Such medications risk suppressing appetite excessively, which can potentially lead to conditions mimicking Avoidant/Restrictive Food Intake Disorder (ARFID).²⁵ The clinical observations highlighted above suggest that patients, particularly those undergoing bariatric surgery, may suffer from significant disruptions in eating behaviors, exhibit rapid and unsafe weight loss, and face mood disturbances or even organ damage due to dehydration and malnutrition. The current danger level associated with GLP-1 agonist use in at-risk populations is elevated, with potential for severe consequences if not managed appropriately. In light of this, we propose a set of recommendations for clinical practice (Figure 1), which are informed by these observations and take into account critical patient characteristics.

Figure 1. A Flowchart for Managing the Dangers Associated with GLP-1 Agonist Therapy from the Standpoint of Disordered Eating.

This diagram outlines a structured approach, beginning with initial patient assessment, followed by proactive screening for disordered eating behaviors, vigilant monitoring for appetite-related maladaptive responses, and ongoing evaluation of broader health impacts. The flowchart emphasizes the importance of these steps in optimizing the safety and efficacy of GLP-1 agonist treatment in patients with obesity. See text for definitions of SCOFF, EDE-Q, and BES scales.

Recommendation 1: Proactive Screening and Continuous Monitoring for Disordered Eating

Caution is advised when prescribing GLP-1 agonists to individuals with a history or risk of disordered eating. All patients should be screened for disordered eating behaviors before starting GLP-1 agonists (for example, via the SCOFF²⁶ questionnaire for abbreviated five-question screening, the Eating Disorder Examination Questionnaire²⁷ for a more comprehensive evaluation, or the Binge Eating Scale²⁸, which assesses cognitive, behavioral, and emotional aspects of eating). Continuous monitoring for signs of eating disorders or undue weight loss is also paramount during treatment. Where necessary, preemptive, or timely mental health referrals should be made to address potential exacerbations of disordered eating patterns.

Recommendation 2: Vigilant Monitoring for Appetite-related Maladaptive Responses

GLP-1 agonists can significantly aid weight reduction when lifestyle modifications are insufficient for individuals with obesity. Nevertheless, it is crucial for healthcare providers to diligently monitor for adverse appetite-related responses to these medications. This includes observing for restrictive eating patterns, such as severe food or fluid limitation, diminished food appeal or aversions, unusually rapid or excessive weight loss, and medical complications like dehydration-induced renal issues or fluctuating blood glucose levels. Psychiatric side effects, though rare with GLP-1 agonists, warrant prompt attention. These effects may pertain to the psychological challenges of adjusting to rapid physical changes, including altered self-appearance perception²⁹ or changes in inhibitory cognitive control during alcohol use that have been observed following bariatric surgery³⁰ which could potentially lead to increased risk taking. Dosage adjustments or cessation of the medication may be necessary to safeguard patient well-being.

Recommendation 3: Ongoing Assessment of GLP-1 Agonists’ Broader Health Impacts

Given the limited research on GLP-1 agonists in psychiatric populations, there remains uncertainty about their safety and efficacy for these individuals. While there has been no clear association with certain psychiatric side effects, such as depression or suicidal ideation in research-based³¹ or real-world³² samples, the potential modulation of reward pathways by these drugs necessitates vigilant monitoring in patients with psychiatric histories, particularly in the setting of treatment with a medication that can substantially modulate the response of appetitive neurocircuitry to natural rewards such as food and water. Additionally, GLP-1 agonists influence gastric emptying, which could interact with psychiatric medication pharmacokinetics, altering their effectiveness or safety, especially those with weight-based dosing. It is essential to conduct basic and translational research to investigate the neural and systemic effects of GLP-1 agonists further, particularly in people with obesity, disordered eating³³, or addiction. Notably, although GLP-1 agonists do not independently cause hypoglycemia, their combination with other glucose-lowering drugs may pose a risk, which is compounded in psychiatric patients who may struggle to manage their blood sugar or recognize symptoms of hypoglycemia.

Thus, healthcare providers must thoroughly assess the advantages and possible risks of GLP-1 agonists before prescribing these medications. Vigilant monitoring for new side effects and drug interactions is essential. Prescribers should ensure that GLP-1 agonists are prescribed and administered properly, and that their patients receive adequate education and counseling regarding their potential effects. Implementing preemptive nutritional counseling and support is also crucial and could be an important means of avoiding severe food aversion and potentially serious medical complications.

Conclusion: Optimizing GLP-1 Agonist Use in Obesity Management

GLP-1 agonists have emerged as highly effective tools against the obesity epidemic, with marked efficacy in reducing body weight. Nonetheless, their impact on appetite can be profound, occasionally leading to the development or exacerbation of restrictive eating behaviors. Careful monitoring for such adverse effects is crucial, and these medications should be integrated with lifestyle interventions for holistic obesity treatment. Special consideration is necessary when prescribing GLP-1 agonists in individuals with a history of eating disorders or other forms of psychiatric conditions, emphasizing pre-treatment screening akin to bariatric surgery protocols. Close monitoring for exacerbation or triggering of abnormal eating patterns is critical, as well as prompt referral to a mental health professional when deemed necessary.

We are acutely aware of the societal stigma surrounding obesity³⁴ and strongly oppose any form of weight- or body-related discrimination. Acknowledging obesity’s potential health repercussions and impact on quality of life, we recognize that GLP-1 agonists can significantly enhance health outcomes when used judiciously, even in individuals with certain forms of eating disorders³⁵ or addiction.^36,37 We advocate for a multidisciplinary approach to obesity treatment, involving close collaboration among various healthcare specialists (psychiatrists, psychologists, psychotherapists, and other healthcare professionals) to ensure tailored and comprehensive care. By adopting such strategies, we believe that it is possible to navigate the danger zone for weight loss management safely and effectively.