Hepatotoxicity of Antidiabetic Drugs

US Pharm. 2008;33(5)(Diabetes suppl):3-9.

Diabetes mellitus is a group of metabolic disorders in which the body does not produce enough or properly use insulin, resulting in hyperglycemia. Two major types of diabetes mellitus are recognized. Type 1, previously known as juvenile diabetes, is the result of the body's failure to produce enough insulin. This type of diabetes is prevalent in 5% to 10% of the diabetic population and is generally diagnosed in children.¹ Type 2 diabetes is a result of insulin resistance (a condition in which the body cannot properly use insulin). This type of diabetes is more prevalent and is generally diagnosed in adults.

Incidences of diabetes are increasing at epidemic proportions. According to the estimates of the World Health Organization, there are more than 180 million people with diabetes worldwide and this number is likely to more than double by 2030.² The American Diabetes Association estimates that more than 20 million adults and children in the United States (which accounts for approximately 7% of the U.S. population) have diabetes.³ While more than 14 million patients have been diagnosed with diabetes, over six million individuals are estimated to be unaware of the fact that they have the disease and remain untreated.³

Diabetes-Associated Complications
Diabetes is associated with a number of clinical complications such as cardiopathy, nephropathy, and retinopathy. Many individuals are not even aware that they have diabetes until they are diagnosed with one of these complications. Unmanaged diabetes can lead to life-threatening complications such as heart disease, stroke, blindness, and kidney failure.¹ Diabetes is the sixth leading cause of death in the U.S.

Hepatotoxicity in the Diabetic Population
Until now, the link between risk of hepatic failure and diabetic condition was unclear. Recently, a large prospective cohort study was performed to examine whether patients with type 2 diabetes are at an increased risk of developing acute liver failure.⁵ This study suggested that diabetic patients are twice as likely to suffer hepatic failure compared to normal patients. Another study of the same prospective cohort population indicated that diabetes is associated with increased risk of hepatocellular carcinoma and chronic liver diseases. ⁶

Hepatotoxicity did not receive as much attention as other prevalent complications (i.e., cardiopathy, retinopathy, nephropathy) until hepatotoxicity of antidiabetic drugs emerged as a common clinical complication. This article is an attempt to summarize the current understanding of hepatotoxicity of antidiabetic drugs.

Hypoglycemic Agents in the Treatment of Diabetes
Many therapeutic drugs target both fasting and postprandial hyperglycemia and other metabolic parameters involved in the diabetes-associated complications. These drugs are directed towards increasing insulin secretion, decreasing insulin resistance, and increasing insulin penetration into the cells. Antidiabetic drugs with reported cases of hepatotoxicity include sulfonylureas, alpha-glucosidase inhibitors, biguanides, and thiazolidinediones (Table 1).

Sulfonylureas
Sulfonylureas have been used as first-line oral antihyperglycemic agents for type 2 diabetes since 1954. First-generation sulfonylureas include tolbutamide (Orinase), tolazamide (Tolinase), and chlorpropamide (Diabinese). Chlorpropamide and tolbutamide are well recognized as causes of hepatotoxicity.⁷ However, there have been only three reported cases of hepatic injury caused by a third oral hypoglycemic agent, tolazamide.⁷ With the arrival of second-generation sulfonylureas, first-generation sulfonylureas are rarely used. Second-generation sulfonylureas include glipizide (Glucotrol), glyburide (DiaBeta, Micronase, Glynase), and glimepiride (Amaryl). Drug-induced hepatotoxicity has been reported infrequently with second-generation sulfonylureas. For glimepiride, a second-generation sulfonylurea, there have been no reports of hepatotoxicity in English literature; however, hepatotoxicity has been reported in French literature.^8,9

Alpha-Glucosidase Inhibitors
The glucosidase inhibitors are useful adjunctive therapies for type 2 diabetes. The prototype of this class is acarbose (Precose). Because acarbose is minimally absorbed in unchanged form after oral administration, the drug is widely believed to be safe, with only flatulence as a commonly reported complaint. However, cases of severe hepatotoxicity have been reported.^10-12 Although acarbose-induced hepatotoxicity appears to be uncommon, diabetic patients receiving long-term acarbose therapy should be closely monitored for this adverse effect.

Biguanides
Metformin hydrochloride is widely used for the treatment of type 2 diabetes. A serious but rare side effect, lactic acidosis, is caused because of its interference with mitochondrial oxidative processes.¹³ Metformin (Fortamet, Glucophage, Riomet) hepatotoxicity has rarely been reported, with two cases of acute hepatitis and one of bland cholestasis.^13-15 A well-documented case of acute hepatitis caused by an idiosyncratic adverse reaction to metformin or to one of its metabolites, has also been reported. ¹³

Thiazolidinediones
Thiazolidinediones (TZDs, also known as glitazones) are insulin sensitizers now widely used for the treatment of type 2 diabetes. Three TZDs have been used in clinical practice: troglitazone, pioglitazone, and rosiglitazone.

Troglitazone: Troglitazone (Rezulin), a peroxisome proliferators–activated receptor gamma agonist that enhances insulin sensitivity, was approved for the treatment of type 2 diabetes in 1997.¹⁶ It was an effective antidiabetic drug with a fundamentally new mechanism of action. However, within a year after its widespread use, individual cases of liver injury and failure were reported.^16-19 The mounting evidence for the idiosyncratic hepatotoxicity of troglitazone in the following years led to its withdrawal from the market in 2000.

Since then, a considerable effort has been made to elucidate the mechanism of troglitazone-induced hepatotoxicity. A number of hypotheses were brought forward to explain troglitazone-induced cell injury, including the formation and accumulation of toxic metabolites, mitochondrial dysfunction and oxidant stress, inhibition of the bile salt transporter and bile acid toxicity, and the induction of apoptosis.¹⁷

Pioglitazone and Rosiglitazone: After the withdrawal of troglitazone due to hepatotoxicity, only pioglitazone (Actos) and rosiglitazone (Avandia) can be used for the treatment of patients with type 2 diabetes. Fortunately, these two newer drugs in the TZD class have a much larger margin of safety for liver toxicity. Very rare reports of liver toxicity, usually milder and reversible, have been seen with these drugs. Very few case reports have implicated it as a cause of hepatocellular injury and granulomatous hepatitis.^20-22 Severe cholestatic hepatitis caused by rosiglitazone (8 mg/day) was reported in a 56-year-old female patient who had a history of receiving troglitazone treatment; it is indicated that rosiglitazone is not always a safe alternative in patients who had liver injury due to troglitazone.²³ Pioglitazone-induced hepatocellular-cholestatic liver injury in a 49-year-old patient with diabetes who was on this drug for six months. Liver enzyme values returned to normal six weeks after the patient discontinued pioglitazone therapy.²⁴

In conclusion, while pharmacovigilance for hepatotoxicity is probably still warranted, the practitioner and patient can be fairly confident that these drugs are safe from a liver standpoint. Finally, recent work would suggest that these agents may prove useful to reduce hepatic fat in patients with nonalcoholic steatohepatitis and may possibly protect against adverse metabolic consequences and the ultimate development of cirrhosis in patients with fatty livers.

Pioglitazone and rosiglitazone are used either as monotherapy or in combination with metformin, sulfonylureas, or glinides. The combination of TZDs with insulin is also appealing, as it allows improvement of glycemic control while decreasing the daily insulin requirement. Insulin dosage has to be adjusted regularly to avoid hypoglycemic episodes. Recently, a prospective, open-labeled, nonrandomized study was conducted to assess safety and efficacy of rosiglitazone and insulin treatment in combination with poorly controlled insulin-treated patients with type 2 diabetes.²⁵ It was concluded that the rosiglitazone plus insulin combination is safe and effective in this population. However, further studies are warranted.

Sensitivity of Hepatotoxicants in Diabetic Rodent Models
Hepatotoxicity of several structurally and mechanistically diverse chemicals (i.e., acetaminophen; bromobenzene; carbon tetrachloride; chloroform; 1, 1, 2-trichloroethane; D-galactosamine; and thioacetamide) is significantly altered in streptozotocin- or alloxan-induced type 1 diabetic rats.^26-29 The majority of the studies have pointed out that hepatotoxicant-induced liver injury is potentiated in type 1 diabetic rats. Similarly, hepatotoxicity of allyl alcohol, bromobenzene, carbon tetrachloride, and thioacetamide have been shown to potentiate in type 2 diabetic rats.³⁰ Interestingly, chemical-induced liver injury is differently modified by diabetes in murine models. In contrast to the enhanced hepatotoxicity in diabetic rats, diabetic mice (type 1 as well as type 2) are protected from normally lethal hepatotoxicant challenge.^31-34 Current understanding of altered hepatotoxicity of xenobiotics in diabetes is summarized in Table 2.

Remarkable species differences have been observed in rodent models. Diabetic rats exhibit marked sensitivity versus diabetic mice exhibiting equally marked protection from drug-induced hepatotoxicity. Availability of the rodent diabetic models offers a unique opportunity to uncover mechanisms of clinical interest in averting human diabetic sensitivity to drug-induced hepatotoxicities. While the rat diabetic models appear to be suitable, the diabetic mouse models might not be suitable in preclinical testing for potential hepatotoxic effects of drugs or toxicants, because regardless of type 1 or type 2 diabetes, mice are resistant to acute drug-or toxicant-induced toxicities.³⁵

Conclusion
Recent epidemiological studies suggested that patients with diabetes are twice as likely to suffer hepatic failure compared to patients who do not have diabetes. Increased incidences of hepatotoxicity have been observed in patients with diabetes receiving drug therapies. Neither the mechanisms nor the predisposing factors underlying hepatotoxicity in patients with diabetes are clearly understood. While pharmacovigilance for hepatotoxicity is probably still warranted, the practitioner and patient can be fairly confident that these drugs are safe from a liver standpoint. However, it is recommended that liver enzymes such as alanine amino transferase should be monitored in patients with diabetes receiving antidiabetic drugs for which incidences of hepatotoxicity are already reported.

REFERENCES
1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet. United States, 2005. www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed February 12, 2008.

2. World Health Organization. Diabetes fact sheet, No. 312. September 2006. www.who.int/mediacentre/factsheets/fs312/en/index.html. Accessed February 12, 2008.

3. National Diabetes Information Clearinghouse. National diabetes statistics. http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7. Accessed February 12, 2008.

4. Heron MP, Smith BL. Death: leading causes for 2003. Natl Vital Stat Rep. March 2007;55:1-92.

5. El-Serag HB, Everhart JE. Diabetes increases the risk of acute hepatic failure. Gastroenterology. 2002;122:1822-1828.

6. El-Serag HB, Tran T, Everhart J. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460-468.

7. Nakao NL, Gelb AM, Stenger RJ, Siegel JH. A case of chronic liver disease due to tolazamide. Gastroenterology. 1985;89:192-195.

8. Sitruk V, Mohib S, Grando-Lemaire V, et al. Acute cholestatic hepatitis induced by glimepiride. Gastroenterol Clin Biol.2000;24:1233-1234.

9. Heurgue A, Bernard-Chabert B, Higuero T, et al. Glimepiride-induced acute cholestatic hepatitis. Ann Endocrinol. 2004;65:174-175.

10. Madonia S, Pietrosi G, Pagliaro L. Acarbose-induced liver injury in an anti-hepatitis C virus positive patient. Dig Liver Dis. 2001;33:615-616.

11. Hsiao SH, Liao LH, Cheng PN, Wu TJ. Hepatotoxicity associated with acarbose therapy. Ann Pharmacother. 2006;40:151-154.

12. Mennecier D, Zafrani ES, Dhumeaux D, Mallat A. Acarbose-induced acute hepatitis. Gastroenterol Clin Biol. 1999;23:1398-1399.

13. Deutsch MM, Kountouras D, Dourakis SP. Metformin hepatotoxicity. Ann Intern Med. 2004;140:W25.

14. Babich MM, Pike I, Shiffman ML. Metformin-induced acute hepatitis. Am J Med. 1998;104:490-492.

15. Desilets DJ, Shorr AF, Moran KA, Holtzmuller KC. Cholestatic jaundice associated with the use of metformin. Am J Gastroenterol. 2001;96:2257-2258.

16. Watkins PB. Idiosyncratic liver injury: challenges and approaches. Toxicol Pathol. 2005;33:1-5.

17. Chojkier M. Troglitazone and liver injury: in search of answers. Hepatology. 2005;41:237–246.

18. Faich GA, Moseley RH. Troglitazone (Rezulin) and hepatic injury. Pharmacoepidemiol Drug Saf. 2001;10:537-547.

19. Chan KA, Truman A, Gurwitz JH, et al. A cohort study of the incidence of serious acute liver injury in diabetic patients treated with hypoglycemic agents. Arch Intern Med. 2003;163:728-734.

20. Al-Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in a patient receiving rosiglitazone. Ann Intern Med. 2000;132:121-124.

21. Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med. 2000;132:118-121.

22. Dhawan M, Agrawal R, Ravi J, et al. Rosiglitazone induced granulomatous hepatitis. J Clin Gastroenterol . 2002;34:582-584.

23. Bonkovsky HL, Azar R, Bird S, et al. Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for trolitazone. Dig Dis Sci. 2002;47:1632-1637.

24. May LD, Lefkowitch JH, Kram MT, Rubin DE. Mixed hepatocellular–cholestatic liver injury after pioglitazone therapy. Ann Intern Med. 2002;136:449-452.

25. Garg R, Gopal J, Jones GR. Rosiglitazone: safety and efficacy in combination with insulin in poorly controlled type 2 diabetes mellitus patients treated with insulin alone. J Diabetes Complications. 2007;21:1-6.

26. Aniya Y, Ojiri Y, Sunagawa R, et al. Glutathione S-transferases and chloroform toxicity in streptozotocin-induced diabetic rats. Jpn J Pharmacol. 1989;50:263-269.

27. Hanasono GK, Witschi H, Plaa GL. Potentiation of the hepatotoxic responses to chemicals in alloxan-diabetic rats. Proc Soc Exp Biol Med. 1975;149:903-907.

28. El-Hawari AM, Plaa GL. Potentiation of thioacetamide-induced hepatotoxicity in alloxan- and streptozotocin-diabetic rats. Toxicol Lett. 1983;17:293-300.

29. Wang T, Fontenot RD, Soni MG, et al. Enhanced hepatotoxicity and toxic outcome of thioacetamide in streptozotocin-induced diabetic rats. Toxicol Appl Pharmacol. 2000;166:92-100.

30. Sawant SP, Dnyanmote AV, Shankar K, et al. Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats. J Pharmacol Exp Ther. 2004;308:694-704.

31. Gaynes BI, Watkins JB 3rd. Carbon tetrachloride and the sorbitol pathway in the diabetic mouse. Comp Biochem Physiol B. 1989;94:213-217.

32. Jeffery EH, Arndt K, Haschek WM. The role of cytochrome P450IIE1 in bioactivation of acetaminophen in diabetic and acetone-treated mice. Adv Exp Med Biol. 1991;283:249-251.

33. Shankar K, Vaidya VS, Wang T, et al. Streptozotocin-induced diabetic mice are resistant to lethal effects of thioacetamide hepatotoxicity. Toxicol Appl Pharmacol. 2003;188:122-134.

34. Sawant SP, Dnyanmote AV, Mitra MS, et al. Protective effect of type 2 diabetes on acetaminophen-induced hepatotoxicity in male Swiss-Webster mice. J Pharmacol Exp Ther. 2006;316:507-519.

35. Wang T, Shankar K, Ronis MJ, et al. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Crit Rev Toxicol. 2007;37:413-459.

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