Acarbose is an alpha glucosidase inhibitor which decreases intestinal absorption of carbohydrates and is used as an adjunctive therapy in the management of type 2 diabetes. Acarbose has been linked to rare instances of clinically apparent acute liver injury.
Acarbose (ay' kar bose) is an inhibitor of intestinal alpha-glucosidase, an enzyme responsible for digestion and absorption of starch, disaccharides and dextrin. The inhibition of the glucosidase activity in the intestinal brush border blocks the breakdown of starch and disaccharides to absorbable monosaccharides, leading to carbohydrate malabsorption and blunting of the postprandial rise in blood glucose. Acarbose was approved for use in the United States in 1995 and was the first alpha-glucosidase inhibitor introduced into clinical practice. A similar alpha glucosidase inhibitor, miglitol, was approved the following year. The current indications for acarbose are for management of glycemic control in type 2 diabetes used in combination with diet and exercise, with or without other oral hypoglycemic agents or insulin. Acarbose is available generically and under the brand name Precose in tablets of 25, 50 and 100 mg. The typical initial dose in adults is 25 mg with each meal (with the first bite), followed by a gradual increase to a maximum of 100 mg three times daily. Acarbose causes malabsorption and gastrointestinal side effects of flatulence, diarrhea and abdominal boating are not uncommon.
In several large clinical trials, serum enzyme elevations above 3 times the upper limit of normal were more common with acarbose therapy (2% to 5%) than with placebo, but all elevations were asymptomatic and resolved rapidly with stopping therapy. These studies reported no instances of clinically apparent liver injury. Subsequent to approval and with wide clinical use, however, at least a dozen instances of clinically apparent liver injury have been linked to acarbose use. The liver injury typically arises 2 to 8 months after starting therapy and is associated with a hepatocellular pattern of serum enzyme elevations with marked increases in serum ALT levels, suggestive of acute viral hepatitis. Immunoallergic features and autoantibody formation are not typical. While most cases are mild, some are associated with marked jaundice. No cases of acute liver failure or chronic liver injury have been linked to acarbose use, and most large series of cases of drug induced liver injury and acute liver failure have not identified cases due to acarbose. Rechallenge has been carried out in several instances and resulted in recurrence with a shortening of the time to onset.
Likelihood score: B (highly likely cause of clinically apparent liver injury).
Mechanism of Injury
The cause of liver injury during acarbose therapy is not known. Acarbose is an oligosaccharide of microbial origin and is minimally absorbed, so that systemic toxicity and liver injury were not expected and remain unexplained. Liver injury from acarbose is clearly idiosyncratic and may relate to an immunological reaction to the bacterially derived oligosaccharide molecule.
Outcome and Management
The liver injury caused by acarbose has generally been mild and self-limited with the injury resolving rapidly once acarbose is discontinued. Cross sensitivity with other hypoglycemic agents has not been described. Furthermore, liver injury has not been described in patients taking the other currently available alpha glucosidase inhibitor, miglitol. Recurrence of injury with reintroduction of acarbose has been reported and should be avoided.
Case 1. Acute hepatocellular injury due to acarbose.
[Modified from: Diaz-Gutierrez FL, Ladero JM, Diaz-Rubio M. Acarbose-induced acute hepatitis. Am J Gastroenterol 1998; 93: 481. PubMed Citation]
A 57 year old woman with type 2 diabetes developed nausea, right upper quadrant pain, dark urine and jaundice 2 months after starting acarbose (50 mg three times daily before meals). She was taking no other medications for diabetes, but had been on a laxative (cyclobutyrol) intermittently for several years. She had no history of liver disease or drug reactions, had no risk factors for viral hepatitis and did not drink alcohol. Examination showed jaundice and hepatic tenderness, but no fever or rash or signs of chronic liver disease. Laboratory results demonstrated hyperbilirubinemia (3.8 mg/dL) and marked elevations in serum aminotransferase levels (ALT 1580 U/L, AST 1090 U/L), with minimal increase in alkaline phosphatase (220 U/L). Tests for acute hepatitis A and B, cytomegalovirus and Epstein Barr virus infection were negative as were autoantibodies. An abdominal ultrasound was normal. Acarbose was discontinued and she improved within the next 10 days (Table). In follow up, all liver tests had returned to normal and she later tolerated glipizide without evidence of liver injury.
|Medication:||Acarbose (150 mg daily)|
|Pattern:|| Hepatocellular (R=~20)|
||3+ (jaundice, hospitalization)
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Started on glipizide
| Normal Values
Acarbose therapy has been linked to rare instances of an acute hepatitis-like injury arising 2 to 8 months after starting treatment. This case is typical of the injury described, with marked elevations in serum aminotransferase levels and mild jaundice, rapid improvement on stopping acarbose and lack of cross sensitivity with other antidiabetic medications.
REPRESENTATIVE TRADE NAMES
Acarbose – Generic, Precose®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 15 January 2016
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Holman RR, Cull CA, Turner RC. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44). Diabetes Care 1999; 22: 960-4. PubMed Citation (Controlled trial of acarbose vs placebo for up to 3 years in 3309 patients with diabetes; side effects and ALT results were not discussed).
Gentile S, Turco S, Guarino G, Sasso FC, Torella R. Aminotransferase activity and acarbose treatment in patients with type 2 diabetes. Diabetes Care 1999; 22: 1217-8. PubMed Citation (Among 770 patients with diabetes treated with acarbose, preexisting liver disease was common and mild de novo ALT elevations occurred in 1.9%, usually near the beginning of therapy and none were clinically apparent).
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Madonia S, Pietrosi G, Pagliaro L. Acarbose-induced liver injury in an anti-hepatitis C virus positive patient. Dig Liver Dis 2001; 33: 615-6. PubMed Citation (74 year old woman developed jaundice 3 months after adding acarbose to glyburide [bilirubin 8.9 mg/dL, ALT 519 U/L, Alk P 258 U/L], resolving within 1 month of stopping; patient was also positive for anti-HCV and HCV RNA and no follow up provided).
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controlled trial. J Evid Based Med 2012; 5: 134-8. PubMed Citation (Among 207 patients with type 2 diabetes treated with a standard or chewable tablet of acarbose three times daily for 12 weeks, there were no "clinically relevant changes in biochemical parameters").
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diabetes. Diabetes Res Clin Pract 2013; 102: 16-24. PubMed Citation (Among 233 patients with type 2 diabetes treated with acarbose alone or acarbose and metformin for 16 weeks,serious adverse events were rare [~3%] and none were hepatic; no mention of ALT elevations).
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trial. Lancet Diabetes Endocrinol 2014; 2 (1): 46-55. PubMed Citation (Among 784 patients with type 2 diabetes treated with either metformin or acarbose for 24-48 weeks, serious adverse events were rare [2%] and none were hepatic; no mention of ALT elevations).
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