What are the management steps for a patient with a suspected semaglutide (GLP-1 receptor agonist) overdose, considering potential risks of severe hypoglycemia and pancreatitis?

Management of Semaglutide Overdose

In the event of semaglutide overdose, initiate supportive care focused on managing gastrointestinal symptoms with antiemetics and fluid/electrolyte replacement, monitor for hypoglycemia (though risk is low), and observe for complications including pancreatitis, acute kidney injury, and gallbladder disease over an extended period given the drug's one-week half-life. 1

Immediate Assessment and Monitoring

The FDA label explicitly states that appropriate supportive treatment should be initiated according to clinical signs and symptoms, with prolonged observation necessary due to semaglutide's approximately one-week half-life. 1

Initial Evaluation

• Assess the dose ingested and timing of administration, as overdoses ranging from 2-20 times the recommended dose have been reported with variable presentations 2, 3
• Check blood glucose immediately and serially, though hypoglycemia is unlikely to occur with semaglutide alone due to its glucose-dependent mechanism of action 2, 3
• Obtain baseline renal function (creatinine, BUN), hepatic function (AST, ALT, alkaline phosphatase), pancreatic enzymes (lipase, amylase), and electrolytes 2, 4

Critical Monitoring Parameters

• Monitor for severe gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain) which are the most common manifestations of overdose and can lead to dehydration and acute kidney injury 2, 3, 4
• Observe for at least 7 days given the prolonged half-life, with extended monitoring if symptoms develop 1, 2
• Serial glucose monitoring is warranted, particularly if the patient is on concurrent insulin or sulfonylureas, which increase hypoglycemia risk 5, 3

Supportive Care Interventions

Gastrointestinal Management

• Provide antiemetics for nausea and vomiting, which are dose-dependent and the predominant adverse effects 6, 2, 3
• Aggressively replace fluids and electrolytes to prevent dehydration-related complications, particularly acute kidney injury 6, 2, 4
• Monitor for severe constipation, small bowel obstruction, or ileus progression, which can occur with GLP-1 receptor agonists 6

Hypoglycemia Prevention

• While semaglutide alone rarely causes hypoglycemia due to glucose-dependent insulin secretion, monitor closely if patient is on concurrent insulin or sulfonylureas 5, 2, 3
• Consider reducing or holding doses of insulin or sulfonylureas during the overdose period 5, 6
• Maintain glucose monitoring for the duration of observation given the prolonged drug half-life 1, 2

Serious Complications to Monitor

Pancreatitis

• The American Diabetes Association recommends discontinuing semaglutide immediately if pancreatitis is suspected, as acute pancreatitis has been reported with GLP-1 receptor agonists and can be fatal 5, 6, 7, 8
• Monitor for severe epigastric pain radiating to the back, persistent nausea/vomiting, and elevated lipase/amylase 6, 7, 8
• Obtain imaging (CT abdomen) if clinical suspicion is high, as one case report documented fatal pancreatitis after semaglutide dose increase 8

Acute Kidney Injury

• Monitor renal function closely, as dehydration from severe gastrointestinal effects is the primary mechanism for acute kidney injury and worsening chronic renal failure 6, 2, 4
• Ensure adequate fluid intake and consider IV hydration if oral intake is compromised 6, 2
• One case report documented multiorgan failure including renal failure requiring continuous renal replacement therapy following overdose 4

Gallbladder Disease

• Monitor for right upper quadrant pain, fever, and signs of cholecystitis or cholelithiasis, as GLP-1 receptor agonists increase this risk 5, 6, 9
• Check GGT in addition to standard liver enzymes if biliary symptoms develop 9
• Consider ultrasound if clinical suspicion for acute cholecystitis arises 6, 9

Special Considerations

Multiorgan Failure Risk

• One case report documented multiorgan failure, hypoglycemia, cholestatic liver dysfunction, and duodenal ulcers following intentional overdose (4 times the weekly dose) 4
• Monitor for distributive shock requiring vasopressors, ARDS requiring intubation, and cardiac complications in severe cases 8, 4

Psychiatric Assessment

• Screen for suicidal ideation, as one case involved intentional overdose with dysphoric mood preceding the event 6, 4
• The American Gastroenterological Association notes that suicidal ideation has been reported in clinical trials 6

Delayed Gastric Emptying

• Be aware that semaglutide delays gastric emptying, which may affect absorption of concomitantly administered oral medications 5, 6
• Consider this when managing other medications during the overdose period 5, 6

Clinical Pearls

• No specific antidote exists for semaglutide overdose; management is entirely supportive 1, 2
• Case reports demonstrate that patients may remain asymptomatic despite significant overdoses (7-fold daily dosing for 7 days), while others develop severe complications 2, 3, 4
• The glucose-dependent mechanism of action makes isolated hypoglycemia unlikely, but concurrent use of insulin or sulfonylureas substantially increases this risk 5, 2, 3
• Extended observation beyond typical emergency department timeframes is necessary due to the one-week half-life 1, 2