Sibutramine is a serotonin and norepinephrine reuptake inhibitor which has been used for short- and long-term therapy of obesity, but which was withdrawn from use in 2010 because of increase risk of cardiovascular events. In large clinical trials, sibutramine therapy was not associated with serum enzyme elevations, and it has only rarely been implicated in cases of clinically apparent, acute liver injury.
Sibutramine (si bue' tra meen) is a beta-phenylethylamine that inhibits the synaptic reuptake of both serotonin and norepinephrine. Developed initially as an antidepressant, it had little effect on depression, but its use was associated with weight loss that appeared to be due to decreased appetite and reduced caloric intake. Sibutramine was approved for use as therapy of obesity in the United States in 1997 and was widely prescribed until it was withdrawn in 2010 because of studies demonstrating an increased risk of myocardial infarction and stroke with its use. Sibutramine was previously available as capsules of 5, 10 and 15 mg under the trade name Meridia. The recommended dose was 10 mg once daily, with adjustment up to 15 mg daily or down to 5 mg daily based upon clinical effect and tolerance. Common side effects included dry mouth, headache, insomnia, constipation, nausea and increased blood pressure and heart rate. While no longer available commercially, silbutramine has been found as a contaminant in in some weight loss products available over-the-counter or via the internet.
Sibutramine has not been linked to an increased rate of serum enzyme elevations during therapy, but the results of serum ALT monitoring have been reported only rarely. Despite its long term availability, only a single case report of acute liver injury attributed to sibutramine has been published. The time to onset was 2 weeks and the pattern of liver enzyme elevation was cholestatic. The liver injury was anicteric and self-limited in course. Immunoallergic and autoimmune features were absent. There have been no reports of acute liver failure or chronic liver injury attributed to sibutramine.
Mechanism of Injury
The mechanism by which sibutramine might cause liver injury is not known. Sibutramine undergoes extensive hepatic metabolism, primarily by the cytochrome P450 system (CYP 3A4) to its active metabolite which may be further metabolized and conjugated in the liver. Thus, a possible mode of liver injury is production of a toxic intermediate.
Case 1. Anicteric acute liver injury attributed to sibutramine use.
[Modified from: Chounta A, Tsiodras S, Zouridakis S, Doumas M, Giamarellou H. Sibutramine use associated with reversible hepatotoxicity. Ann Intern Med 2005; 143: 763-4. PubMed Citation]
A 47 year old obese woman with type 2 diabetes developed fatigue, weakness and pruritus followed by dark urine and jaundice arising 2 weeks after starting sibutramine (10 mg daily). She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. Her only other medication was insulin. She drank herbal tea. Sibutramine was taken for a total of 20 days and stopped once liver injury was identified. Laboratory testing showed normal serum bilirubin levels, but moderate elevations in ALT (222 U/L), AST (98 U/L) and alkaline phosphatase (763 U/L) (Table). Serological tests for viral hepatitis were negative as were routine autoantibodies. Abdominal ultrasound, computerized tomography and magnetic resonance imaging showed a small gallbladder polyp, but no evidence of liver enlargement or biliary obstruction. A liver biopsy showed a mixed inflammatory infiltrate without fibrosis or cholestasis. Upon stopping the medication, she began to improve clinically and laboratory tests fell rapidly and were normal when tested 8 months later.
|Medication:|| Sibutramine (10 mg daily)|
|Pattern:|| Cholestatic (R=0.8)|
|| 1+ (enzyme elevations without jaundice)|
||2 weeks to symptoms, 3 weeks to jaundice|
|| 2-3 months|
|Other medications:|| Insulin, herbal tea|
|Time After Starting
||Weeks After Stopping
||Alk P (U/L)
The timing of onset of liver test abnormalities, the cholestatic pattern of enzyme elevations and the liver histology were all compatible with drug induced liver injury, and the only apparent candidate was sibutramine. Normalization of the alkaline phosphatase and GGT were delayed, but this is common after cholestatic liver injury. The lack of bilirubin elevation indicates that the injury, while symptomatic, was mild.
REPRESENTATIVE TRADE NAMES
Sibutramine – Meridia®
Weight Loss Agents
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 02 January 2014
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Chounta A, Tsiodras S, Zouridakis S, Doumas M, Giamarellou H. Sibutramine use associated with reversible hepatotoxicity. Ann Intern Med 2005; 143: 763-4. PubMed Citation (47 year old woman developed fatigue and pruritus 2 weeks after starting a 20 day course of sibutramine [bilirubin normal, ALT 222 U/L, Alk P 763 U/L], resolving 6-8 months after stopping: Case 1).
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