In a patient on tirzepatide (Mounjaro) who develops biliary obstruction, how should the medication be managed and what alternative glucose‑lowering therapies are recommended?

Management of Tirzepatide in Patients with Biliary Obstruction

Immediate Medication Management

Tirzepatide must be discontinued immediately upon diagnosis of biliary obstruction. 1, 2 Recent meta-analysis data demonstrate that tirzepatide is associated with a 52% increased risk of gallbladder/biliary diseases (RR=1.52,95% CI: 1.17-1.98) and a 67% increased risk of cholelithiasis (RR=1.67,95% CI: 1.14-2.44), with most adverse events occurring within 1-6 months of treatment initiation. 1, 2

• Do not rechallenge with tirzepatide after resolution of biliary obstruction, as case reports show that 15 of 18 patients with serious adverse events discontinued the medication permanently. 2
• The temporal relationship between tirzepatide initiation and biliary complications, coupled with clinical resolution upon discontinuation, strongly suggests a causal relationship. 3, 4

Acute Management of Biliary Obstruction

Endoscopic retrograde cholangiopancreatography (ERCP) is the treatment of choice for biliary decompression in patients with moderate to severe acute cholangitis. 5

• ERCP should be performed within 24-72 hours of diagnosis to prevent ascending cholangitis and irreversible liver damage. 6
• If ultrasound demonstrates common bile duct stones, proceed directly to ERCP without further imaging. 6
• Percutaneous transhepatic biliary drainage (PTBD) should be reserved only for patients in whom ERCP fails due to unsuccessful biliary cannulation or inaccessible papilla. 5

Initiate broad-spectrum antibiotics immediately (within 1 hour) if signs of cholangitis or infected fluid collections are present. 5

• Recommended regimens include piperacillin/tazobactam, imipenem/cilastatin, meropenem, or ertapenem. 5
• Add fluconazole in fragile patients or cases of delayed diagnosis. 5

Alternative Glucose-Lowering Therapies

First-Line Alternatives

GLP-1 receptor agonists (excluding tirzepatide) remain viable options after biliary obstruction has been definitively treated and resolved. 5

• Semaglutide demonstrated resolution of steatohepatitis in 59% of patients at the higher dose (equivalent to 2.4 mg/week) compared with 17% in placebo (P<0.001). 5
• Liraglutide improved features of NASH and delayed progression of fibrosis in randomized controlled trials. 5
• Critical caveat: GLP-1 RAs should only be reintroduced after complete resolution of biliary obstruction and cholecystectomy if indicated, given the class-wide association with biliary complications. 1, 2

Alternative Non-Incretin Options

Insulin is the preferred glucose-lowering agent in patients with decompensated cirrhosis or acute biliary complications. 5

• Insulin provides reliable glycemic control without hepatobiliary safety concerns during the acute phase. 5
• Once biliary obstruction is resolved and liver function stabilizes, transition to other agents can be considered. 5

SGLT-2 inhibitors reduce hepatic steatosis but their effects on steatohepatitis remain unknown. 5

• These agents offer cardiovascular and renal benefits without direct biliary tract effects. 5
• Can be safely continued or initiated after resolution of biliary obstruction. 5

Pioglitazone may be considered for patients with concurrent NASH, though it causes dose-dependent weight gain (3-5% at 45 mg/day) and increases fracture risk. 5

Agents to Avoid or Use with Caution

Metformin has failed to improve steatohepatitis in paired-biopsy studies and offers no specific advantage in this clinical context. 5

Sulfonylureas, glitinides, DPP-4 inhibitors, and acarbose have no randomized controlled trials with liver histological endpoints and should not be prioritized. 5

Monitoring and Follow-Up

Monitor liver enzymes at 48-72 hours post-ERCP and again at 1-3 months to confirm resolution of obstruction. 6

• Repeat alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) to document normalization. 6
• Persistent elevation of ALP >1.5× upper limit of normal warrants repeat imaging with MRCP. 6

Plan elective laparoscopic cholecystectomy after acute inflammation resolves to prevent recurrent biliary complications. 6

• This is particularly important given the patient's exposure to tirzepatide, which increases cholelithiasis risk. 1

Critical Clinical Pitfalls

Do not assume elevated transaminases exclude biliary obstruction – in acute choledocholithiasis, ALT can surpass ALP, mimicking acute hepatitis. 6

Do not delay ERCP waiting for further tests when clinical and laboratory findings are diagnostic of biliary obstruction. 6

Enhanced monitoring of liver and kidney function is warranted when restarting any glucose-lowering therapy, especially in patients concurrently taking other potentially hepatotoxic medications. 2

Do not underestimate biliary sludge or "mud" on imaging – these are precursors to stones and can cause obstruction. 6