On a busy emergency shift, you have a series of patients with atypical presentations. Your first patient, Patient A, is a 38-year-old female with a distant history of anorexia nervosa, presenting with persistent, diffuse, abdominal pain, nausea, intractable vomiting, inability to tolerate oral intake, and fatigue for four days. She experienced a syncopal episode at work today. Her vital signs are within normal limits. Her lab work reveals a new metabolic alkalosis with hyponatremia, hypokalemia, hypochloremia, a lactate of 10.1 mmol/L, and an acute kidney injury with a creatinine of 1.78 mg/dL (from 0.72 mg/dL at baseline).

Patient B, a 62-year-old male with a history of obesity and diabetes, walks in for daily headaches without sudden onset but associated with nausea, generalized weakness, and lightheadedness, worsening over one month. His heart rate and blood pressure are elevated from his baseline. Given the fact that he has not had these headaches before and has diffuse symptoms including weakness, lab work and head imaging are obtained. There were no acute findings on head CT. His lab values demonstrate no anemia, leukocytosis, or electrolyte abnormalities except for an elevated creatinine.

Patient C, a 27-year-old female with a history of epilepsy, taking valproate and endorsing adherence, is then brought in by ambulance for a witnessed seizure. This is her first seizure in six years. She is postictal at the time of your assessment, but when she becomes more alert, your review of systems is pertinent only for her stating she has noticed oily stains on her underwear. She is highly concerned that when she passes stool, she has loose bowel movements, and her stools are surrounded by mucus.

Of note, you learn that all three of these patients recently started medications to lose weight.

The proliferation of medications available to the public for weight loss has resulted in increased prevalence of their use.¹ Many of these medications contain pharmacologic agents that have been used for other indications. Regulatory and pharmaceutical availability barriers have even resulted in changing of such medications while in treatment, incomplete usage, and alternative patterns of administration.² As such, the increased popularity of such medications ushers in a new era of challenges and presentations, particularly for the emergency physician.

Each of the aforementioned patients represents chief complaints secondary to the use of antiobesity medications. In each case, a detailed history of what medications were used, dosage, and frequency of use is imperative.

Patient A: Semaglutide

The mechanism of many antiobesity medications relies upon the glucagon-like peptide-1, or GLP-1, molecule, which is, in part, responsible for enhancing the secretion of insulin. Ozempic, Wegovy, and Rybelsus are the brand names of drugs with different formulations of semaglutide. Its major side effects include gastrointestinal symptoms: abdominal pain, constipation, diarrhea, nausea, and vomiting.³ It has been found to be correlated with acute kidney injury, usually prerenal in the setting of volume contraction, syncope, biliary pathology, and pancreatitis.⁴ It is believed that substantial gastrointestinal loss causes chloride and potassium depletion, as well as hypovolemia, acute kidney injury, and renal potassium loss. Patients may consequently present with vague symptoms of weakness and fatigue.

The management for this case included full labs, including a metabolic panel to assess for electrolyte abnormalities, liver function tests to assess for possible hepatic and biliary involvement, lipase to stratify risk for pancreatitis, creatine kinase to assess for potential rhabdomyolysis, urine studies, infusion of potassium chloride, analgesia and symptom control including antiemetics, and careful consideration of intravenous fluids given her hypokalemia, which represents a risk factor for over-correction of sodium and risk for osmotic demyelination. This patient’s syncope is most likely due to metabolic disruptions and fluid-status physiology; nevertheless, assessment of cardiogenic etiologies through an EKG, troponin, and cardiac risk factors should be considered as appropriate.

Similar electrolyte abnormalities can be found in refeeding syndrome, where shifts in fluids, electrolytes, and hormones may cause further deficiencies including hypophosphatemia. Patients with history of anorexia nervosa, chronic alcoholism, uncontrolled diabetes, older age, and chronic malnutrition may be at higher risk.⁴ Different agents, even with the same underlying drug, may have different formulations and effects on patients. At times, patients may also be taking other diabetes medications such as sulfonylureas or insulin, which could precipitate worsening persistent hypoglycemia. Semaglutide has a half-life of approximately one week; as such, it is long-acting and requires supportive measures. There have been documented cases of overdose, and of note, there is no known antidote.⁵ Supportive care includes dextrose infusion and consideration of reversal agents for other medications used in combination (such as glucagon for insulin and octreotide for sulfonylureas).

Patient A’s symptoms improved with intravenous fluids, antiemetics, and over-the-counter analgesia in the acute setting. Similarly to management of intractable nausea and vomiting, labs to assess for metabolic function, renal function, and acute infection should be considered. The differential should include broad infectious etiologies, electrolyte abnormalities such as those secondary to refeeding syndrome, and hyperemesis secondary to etiologies such as cannabinoid use or pregnancy. Management of symptoms is the same for all of these, relying upon fluid resuscitation, antiemetics, and electrolyte repletion. However, if a patient has such side effects of this antiobesity medication, they should discontinue taking it and follow up with their primary care physician promptly for longitudinal management of dosage and tracking of laboratory results to ensure appropriate improvement, or be admitted for this workup if there are persistent lab electrolyte abnormalities and inability to tolerate oral intake.

Patient B: Buproprion-Naltrexone

Patient B stated he has been taking buproprion-naltrexone (Contrave) for symptoms and has been titrating his dosage up to take two tablets, twice daily. Buproprion-naltrexone is a combination of an opioid antagonist and a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. Its mechanism for weight loss is not fully understood, but it is approved for use in chronic weight management.⁶ It is contraindicated with concurrent use of bupropion-containing medications or other opioid antagonists, as well as in acute opioid withdrawal, uncontrolled hypertension, eating disorders, and seizure disorders. Buproprion-naltrexone can be associated with nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, diarrhea, and renal impairment. It has also been associated with increases in heart rate and blood pressure.⁷ Patients are expected to titrate the medication up over time; however, they require guidance on therapeutic ceiling and to ensure they do not continue taking this medication if not efficacious. Patient B’s symptoms improved with intravenous fluids, antiemetics, and over-the-counter analgesia in the acute setting. Similarly to the management of other causes of nausea and vomiting, labs to assess for metabolic function, renal function, and acute infection should be considered. Risk stratification of headache, including a full neurological examination to assess central versus peripheral etiologies, and appropriate imaging should also be considered.

Patient B’s symptoms improved with intravenous fluids, antiemetics, and over-the-counter analgesia. On follow-up with his primary care physician, titrating his buproprion-naltrexone dose down resulted in normalization of his creatinine and resolution of his symptoms.

Patient C: Orlistat

Oily stool, also known as steatorrhea, is associated with the secretion of lipids in the gastrointestinal tract. The differential includes any intraabdominal process, such as celiac disease, tropical sprue, exocrine pancreatic insufficiency, malabsorption due to small intestinal disease, and bariatric surgery.⁸ However, medications can also cause this. Orlistat (Xeical, Alli) is a reversible inhibitor of gastric and pancreatic lipases. It inhibits absorption of dietary fats; thus, they are secreted in the stool and can frequently cause steatorrhea, fecal spotting, and diarrhea.⁹ Orlistat can also cause diffuse abdominal pain, anal fissures, hepatotoxicity, and acute kidney injury. It is contraindicated in chronic malabsorption syndromes, cholestasis, and patients with existing absorption issues secondary to prior surgical resection, such as bariatric surgery. This patient had her first seizure in years despite adherence to her valproate for management of her epilepsy. One side effect of this medication is that it can reduce the absorption of antiepileptic medications such as valproate, vigabatrin, and lamotrigine and reduce their plasma concentration, thus putting patients taking these medications at higher risk of seizure.¹⁰ Patients taking orlistat should have regular assessment of their levels of antiepileptic medications and dosing adjustments as needed. It also has the potential to decrease absorption of other medications such as amiodarone, warfarin, levothyroxine, cyclosporine, and antiretroviral medications. Similarly, consideration of subtherapeutic dosing should be considered for patients with relevant history. A high suspicion for toxic and metabolic impacts of orlistat in caring for patients with multiple comorbidities and polypharmacy is needed.

For Patient C’s steatorrhea, labs to assess metabolic function, and lipase helps. Her seizure is more concerning and warrants full assessment of possible infectious, toxic, and metabolic etiologies that may be contributing. Obtaining a serum level of the antiepileptic medication may assist in diagnostic certainty. Ultimately, stopping orlistat is the treatment.

Conclusion

Antiobesity medications present a new challenge to emergency medicine. This practice update underscores the importance of controlling symptoms, investigating potential electrolyte abnormalities, toxicity, hypoglycemia, and co-ingestion with other medications, and ensuring close outpatient follow-up. Asking patients about their use of such agents can help us better care for them when they present for acute, unscheduled care.

Dr. Sanky is an emergency medicine physician at the Mount Sinai Health System in New York.

Dr. Lin is an emergency medicine physician at Mount Sinai Health System in New York.

References

1. Suran M. As Ozempic’s popularity soars, here’s what to know about semaglutide and weight loss. JAMA. 2023;329(19):1627-1629.
2. Wright DR, Guo J, Hernandez I. A prescription for achieving equitable access to antiobesity medications. JAMA Health Forum. 2023;4(4):e230493.
3. Sodhi M, Rezaeianzadeh R, Kezouh A, et al. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA. 2023;330(18):1795-1797.
4. Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care. 2018;41:258–66.
5. Goodman B. Poison centers see nearly 1,500% increase in calls related to injected weight-loss drugs as people accidentally overdose. CNN website. Published December 18, 2023. Accessed January 11, 2024.
6. Contrave (naltrexone HCl/bupropion HCl) prescribing information. Deerfield, Illinois: Takeda Pharmaceuticals America Inc; 2014.
7. Mercer S. ACS chemical neuroscience molecule spotlight on Contrave. ACS Chem Neurosci. 2011;2(9):484-486.
8. Azer SA, Sankararaman S. Steatorrhea. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541055/. Published January 2023.Updated May 16, 2023.
9. Bansal AB, Al Khalili Y. Orlistat. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Available from: https://www.ncbi.nlm.nih.gov/books/NBK542202/. Published January 2023. Updated December 11, 2022.
10. Bigham S, McGuigan C, MacDonald BK. Reduced absorption of lipophilic anti-epileptic medications when used concomitantly with the anti-obesity drug orlistat. Epilepsia. 2006;47(12):2207.

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