|Year : 2012 | Volume
| Issue : 3 | Page : 372-376
Improvement of abnormal liver enzymes after rosiglitazone treatment in Chinese type 2 diabetes
Jing-Quan Zheng1, Kun Wang1, Dee Pei1, Yen-Lin Chen2, Yen-Lin Chang3, Chun-Hsien Hsu3, Tsan-Ming Huang1, Mei-Yu Lin1, Pao-Ying Lin1, Jiunn-Diann Lin4
1 Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Catholic Fu-Jen University, Taipei, Taiwan, China
2 Department of Pathology, Cardinal Tien Hospital, School of Medicine, Catholic Fu-Jen University, Taipei, Taiwan, China
3 Department of Family Medicine, Cardinal Tien Hospital, School of Medicine, Catholic Fu-Jen University, Taipei, Taiwan, China
4 Department of Internal Medicine, Division of Endocrinology and Metabolism, Shuang Ho Hospital, School of Medicine, Taipei Medical University, Taipei, Taiwan, China
|Date of Submission||06-Jun-2011|
|Date of Decision||20-Feb-2012|
|Date of Acceptance||28-Feb-2012|
|Date of Web Publication||17-May-2012|
Department of Internal Medicine, Division of Endocrinology and Metabolism, Shuang Ho Hospital, School of Medicine, Taipei Medical University, Taipei, Taiwan
Source of Support: None, Conflict of Interest: None
Objectives: Insulin resistance is one of the important underlying abnormalities of type 2 diabetes. The effect of thiazolidinedione on liver functions has been controversial in different studies. In this study, we evaluated the effect of rosiglitazone on liver enzymes in subjects with type 2 diabetes with and without abnormal liver function.
Materials and Methods: Seventy-three patients with type 2 diabetes taking rosiglitazone 4 mg daily were enrolled in this 3-month study. Forty-two of them had normal liver function (NLF), and 31 had abnormal liver function (ABLF). Blood biochemistries were collected monthly during the treatment period.
Results: At baseline, other than age and liver enzymes, there were no differences in body mass index, fasting plasma glucose, hemoglobin A1c (HbA1c), and lipid profiles between the NLF and ABLF groups. At the end of the treatment, HbA1c was lowered in both groups, but only significantly in the ABLF group ( P = 0.027). More importantly, serum concentrations of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the ABLF group decreased significantly (AST: 57.8 ± 26.5 to 47.5 ± 20.2 U/L, P = 0.006; ALT 66.6 ± 35.0 to 51.9 ± 23.5 UL, P = 0.004), while in the NLF group, a similar change was not found.
Conclusion: After 3-month rosiglitazone treatment in subjects with type 2 diabetes with mildly elevated liver enzymes, significant improvement in AST and ALT were observed. Our study provides some hints that rosiglitazone might not be contraindicated in subjects with diabetes with abnormal liver function as previously thought, but further well-designed studies are necessary to clarify this issue.
Keywords: Rosiglitazone, type 2 diabetes, liver function
|How to cite this article:|
Zheng JQ, Wang K, Pei D, Chen YL, Chang YL, Hsu CH, Huang TM, Lin MY, Lin PY, Lin JD. Improvement of abnormal liver enzymes after rosiglitazone treatment in Chinese type 2 diabetes. Indian J Pharmacol 2012;44:372-6
|How to cite this URL:|
Zheng JQ, Wang K, Pei D, Chen YL, Chang YL, Hsu CH, Huang TM, Lin MY, Lin PY, Lin JD. Improvement of abnormal liver enzymes after rosiglitazone treatment in Chinese type 2 diabetes. Indian J Pharmacol [serial online] 2012 [cited 2021 May 11];44:372-6. Available from: https://www.ijp-online.com/text.asp?2012/44/3/372/96340
| » Introduction|| |
It is well-documented that insulin resistance is one of the major pathophysiology of type 2 diabetes. Thiazolidinedione (TZD), a category of antidiabetic medication, can regulate genes expression to improve insulin sensitivity through binding with the peroxisome proliferation activation receptor - g (PPAR-g).  It was regarded as the only treatment to improve insulin resistance in type 2 diabetes. Unfortunately, the first generation, troglitazone, was withdrawn 3 years later due to episodes of severe liver injury.  The second-generation rosiglitazone and pioglitazone were then launched in 1999. The postmarketing studies showed no increased risk of hepatotoxicity with these drugs.  Sporadic case reports of acute hepatitis, including one death, which may be attributed to rosiglitazone, although alternative causes cannot be entirely excluded in these cases. ,,,, Thus, the United States Food and Drug Administration suggested that rosiglitazone should not be initiated in patients with active liver disease or moderate-to-severe liver function impairment. Nonetheless, in some clinical trials, rosiglitazone and pioglitazone were found not to be associated with increased abnormalities of liver function.  On the contrary, some studies even showed a substantial number of patients with non-alcoholic steatohepatitis (NASH), a disease related with insulin resistance, who had improved steatosis, inflammation, and liver fibrosis after administration of TZD. ,, These findings, therefore, suggest the potential role of TZD in the treatment of patients of type 2 diabetes with NASH.
Although there are a large number of studies on the role of rosiglitazone in hepatitis, controversies exist. This is an open-labeled, 2-arm study designed to evaluate the effect of rosiglitazone in type 2 diabetes with normal and abnormal liver function at the baseline.
| » Materials and Methods|| |
Subjects and study design
Seventy-three patients with type 2 diabetes mellitus, diagnosed for more than six months from the outpatient clinic, were enrolled. Other inclusion criteria were age between 50 and 70 years and body mass index (BMI) 23-30 kg/m. 2 Subjects with significant comorbidities, such as congestive heart failure, significant peripheral edema, chronic renal failure, peripheral arterial occlusive disease, decompensated liver cirrhosis or those taking medication that might affect the liver function were excluded. Subjects with a history of alcoholism and either hepatitis B or C were also excluded. The study was approved by the hospital's institutional review board and ethics committee and all subjects provided written informed consent prior to participation.
After 10 hours of fasting, the subjects visited the clinic and underwent complete physical examination. The BMI was calculated as body weight/height  (kg/m 2 ), while systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured on the right arm of seated subjects using standard mercury sphygmomanometer. Blood samples were drawn from the antecubital vein for biochemical analysis. Patients were divided into two groups based on their initial liver function tests: those with both normal serum aspartate aminotransferase (AST, reference ranges £ 40 U/L) and alanine aminotransferase (ALT, reference range £ 40 U/L) levels were defined as normal liver function group (NLF, n=42), \ while, subjects with either elevated serum ALT (>40 U/L) or AST (>40 U/L) levels were defined as abnormal liver function group (ABLF, n=31).
These patients were treated with glibenclamide and/or metformin and the doses were maintained throughout the study period. Other medications such as antihypertensive or lipid-lowering agents were maintained. The patients were prescribed rosiglitazone 4mg daily for 3 months. They were instructed to continue their previous lifestyle, including diet and exercise throughout the study period. The blood biochemistries were examined at monthly intervals.
Plasma was separated from blood within one hour and stored at -30°C. Fasting plasma glucose (FPG) was determined using the glucose oxidase method (YSI 203glucose analyzer, Scientific Division, Yellow Spring Instrument Company, Inc., Yellow Spring, OH). Both triglyceride (TG) and total cholesterol (TC) levels were measured using the dry, multilayer analytical slide method (Fuji Dri-Chem 3000 analyzer, Fuji Photo Film Corporation, Minato-Ku, Tokyo, Japan). Serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) concentrations were determined using an enzymatic assay following dextran sulfate precipitation, while the level of hemoglobin A1c (HbA1c) was evaluated by the ion-exchange high-pressure liquid chromatography method (Variant II; Bio-Rad, Hercules, CA). Serum levels of both AST and ALT were measured using the kinetic rate method (Synchron LX System).
Data were tested for normal distribution using the Kolmogorov-Smirnov test and for homogeneity of variances by Levene's test. Continuous variables were expressed as mean ± standard deviation. Independent t-test was used to evaluate liver function between the two groups. Paired t-test was used to assess the alterations of liver function of subjects in the two groups before and after rosiglitazone treatment. All statistical data were two-sided and a P value <0.05 was considered to be statistically significant. All analyses were performed using the SPSS statistical package (version 16.0) for Windows (SPSS, Chicago, IL).
| » Results|| |
The baseline demographic characteristics of subjects in the NLF and ABLF groups are shown in [Table 1]. Subjects in the NLF group were older than those in the ABLF group. BMI, FPG, HbA1c, and lipid profiles were not significantly different between the two groups, except for higher levels of baseline liver function in the ABLF group.
|Table 1: The clinical and biochemical characteristics of the patients at baseline|
Click here to view
Glycemic control and lipids changes before and after 3 months of rosiglitazone treatment in the NLF and ABLF groups are presented in [Table 2]. Both FPG and HbA1c were lowered after the treatment with rosiglitazone. However, only the differences of FPG in the NLF group (P=0.002) and HbA1c in the ABLF group (P=0.027) reached statistical significance. AST and ALT decreased significantly in the ABLF group, while in the NLF group, only mild, nonsignificant decreases were noted. As for the lipids levels, there were no significant differences before and after treatment.
|Table 2: Glycemic control and lipids of the patients with normal and abnormal liver function at baseline and after 3 months of rosiglitazone treatment|
Click here to view
Monthly AST and ALT changes in the two groups are shown in [Figure 1]A and 1B, respectively. In comparison with the baseline, serum concentrations of both AST and ALT in the ABLF group decreased significantly at the end of the third month of treatment (AST: 57.8 ± 26.5 to 47.5 ± 20.2 U/L, P=0.006; ALT: 66.6 ± 35.0 to 51.9 ± 23.5 U/L, P=0.004, respectively). In the NLF group, the monthly concentrations of AST and ALT showed no significant difference. The incidence of hepatic injury in each group was also assessed. After 3 months of treatment, 21 out of 31 (67.7%) patients in the ABLF group had either abnormal ALT or AST levels while 2 out of 42 (4.8%) patients in the NLF group had abnormal ALT or AST levels.
|Figure 1: The changes of aspartate aminotransferase (AST, panel A) and alanine aminotransferase (ALT, panel B) after 3-month treatment with rosiglitazone in the normal liver function (NLF) and abnormal liver function (ABLF) groups. The data is shown as mean ± standard error. * P<0.05 as compared with baseline|
Click here to view
Since ad hoc sample size estimation was not conducted, post hoc power analysis of the AST and ALT levels was performed using the formula proposed by Dupont et al.  In this study, the differences in AST and ALT were 10.25 and 14.67 and their corresponding standard deviations were 21.32 and 30.06, respectively. Under the presupposition of two-tailed significance, the estimated power of the differences in AST and ALT would be 0.73 and 0.74, respectively.
| » Discussion|| |
At present, pioglitazone and rosiglitazone are widely used in the clinical setting. In comparison to their predecessor, troglitazone, they are believed to be safer and not to be associated with a higher risk of hepatotoxicity. Lebovitz et al. found that in 22 studies and more than 6,000 patients, rosiglitazone did not show any hepatotoxic effects.  In another study done in Taiwan, Wang et al. observed that around 30% of type 2 diabetic patients with elevated AST and/or ALT had an improvement in the liver enzymes. However, the cohort was small and there was no control group.  In the present study, we investigated the changes of serum ALT and AST after 3 months of rosiglitazone treatment in diabetic Chinese population. Compared to the baseline, both serum ALT and AST concentrations decreased significantly at the end of treatment in the ABLF group, while there was no similar change in the NLF group [Figure 1]. It should be stressed that although the results are not surprising and similar studies were done, our study is still the first one to have a control group (NLF group) which further confirmed that rosiglitazone does not increase liver enzymes, but could reduce them.
The mechanism of TZD in the improvement of liver function in diabetic patients remains unclear. However, two mechanisms might be involved; first, decreased insulin resistance and, second, the anti-inflammatory effect of TZD. Nowadays, more and more studies demonstrate that there is a strong association between obesity, insulin resistance and inflammatory mediators. ,, These inflammatory mediators play an important role in the development of NASH. , For instance, the plasma tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) are increased in insulin resistant states. Consequently, high levels of these inflammatory markers, mostly seen in obese people and type 2 diabetes, might further interfere with insulin action by suppressing the insulin signal transduction.  Through activation of PPAR-γ, a nuclear transcription factor, rosiglitazone increases insulin sensitivity, which not only inhibits lipolysis and decreases free fatty acid release but also facilitates free fatty acid uptake and triglyceride accumulation in the muscle, and consequently inhibits the inflammatory response of hepatocyte to dietary lipid overload. , In addition, rosiglitazone also promotes the uptake and storage of free fatty acid in adipocytes and facilitates the redistribution of fat from liver to peripheral adipocytes, which not only decreases insulin resistance since peripheral fat is less insulin resistant, but also reduces the liver steatosis and concurrent hepatic cell injury. 
In addition to the effect of increased insulin sensitivity, some studies also showed that rosiglitazone could directly suppress inflammatory mediators, such as IL-6, interleukin-1β, resistin, and TNF-α. ,,, Hong et al. reported that rosiglitazone could directly inhibit the secretion of TNF-a from primary human monocytes.  Similarly, Tahan et al. demonstrated that rosiglitazone affected cytokines, including interleukin-6, interleukin-1β and TNF-α, which led to improved inflammation in NASH.  Further, some studies reported that rosiglitazone exerted the anti-inflammatory effect through regulating some pathways such as NF-kB. ,,, In addition to the direct anti-inflammatory effect, the decrease in inflammatory cytokines also increase insulin sensitivity, which can further diminish the liver inflammation. These anti-inflammatory effects through different mechanisms attenuate the inflammation of hepatocytes and finally lead to the improvement of liver function.
In comparison with the results observed in the ABLF group, there were no significant changes of liver function in the NLF group during the 3 months follow-up period in our study. The different findings may be attributed to an initial lower BMI, higher insulin sensitivity and lower inflammatory mediators in the NLF than those in the ABLF group.
The strength of our study is that we could compare the effect of rosiglitazone on the NLF and ABLF groups at the same time. However, there are several limitations in our study. First, only serum ALT and AST were evaluated. One may argue that these two liver markers are not accurate for evaluating liver function. However, since they are routine laboratory tests in primary health settings, our study provides information that may prove practical for clinicians. Also, ALT and AST reflect the acute hepatocellular damage, hence may predict acute liver injury after short-term use of rosiglitazone. Although we do not have data of other liver functions, we believe that these findings are useful. Further evaluation of liver function with abdominal sonogram, liver biopsy and other markers such as alkaline phosphate, γ-glutamyl transpeptidase, albumin, bilirubin, prothrombin time will further confirm our results. The short duration of the study and a small study population were other limitations. Further investigation with a larger population and longer follow-up period is warranted.
In conclusion, after 3-month rosiglitazone treatment in type 2 diabetes with elevated liver enzymes, significant improvement of ALT and AST levels were observed in this study. Although our results provides some evidence that rosiglitazone might not be contraindicated in diabetes with abnormal liver function as previously thought, further studies are needed to evaluate whether rosiglitazone is beneficial for diabetic patients with elevated liver enzymes.
| » Acknowledgment|| |
The authors thank all investigators and subjects who participated in the study.
| » References|| |
|1.||Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001;134:61-71. |
|2.||Henrion HR. The Treatment of Non-Alcoholic Steatohepatitis With Thiazolidinediones; Review Article. Aliment Pharmacol Ther 2005;22:897-5. |
|3.||Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med 2000;132:118-21. |
|4.||Al-Salman JA, Kemp DG, Mittal M. Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Intern Med 2000;132:121-4. |
|5.||Dhawan M, Agrawal R, Ravi J, Gulati S, Silverman J, Nathan G, et al. Rosiglitazone-induced granulomatous hepatitis. J Clin Gastroenterol 2002;34:582-4. |
|6.||Gouda HE, Khan A, Schwartz J, Cohen RI. Liver failure in a patient treated with long-term rosiglitazone therapy. Am J Med 2001;111:584-5. |
|7.||Bonkovsky HL, Azar R, Bird S, Szabo G, Banner B. Severe cholestatic hepatitis caused by thiazolidinediones: Risks associated with substituting rosiglitazone for troglitazone. Dig Dis Sci 2002;47:1632-7. |
|8.||Rajagopalan R, Iyer S, Perez A. Comparison of pioglitazone with other antidiabetic drugs for associated incidence of liver failure: No evidence of increased risk of liver failure with pioglitazone. Diabetes Obes Metab 2005;7:161-9. |
|9.||Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003;38:1008-17. |
|10.||Wang CH, Leung CH, Liu SC, Chung CH. Safety and effectiveness of rosiglitazone in type 2 diabetes patients with nonalcoholic Fatty liver disease. J Formos Med Assoc 2006;105:743-52. |
|11.||Dupont WD, Plummer WD Jr. Power and sample size calculations. A review and computer program. Control Clin Trials 1990;11:116-28. |
|12.||Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials: Evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care 2002;25:815-21. |
|13.||Civera M, Urios A, Garcia-Torres ML, Ortega J, Martinez-Valls J, Cassinello N, et al. Relationship between insulin resistance, inflammation and liver cell apoptosis in patients with severe obesity. Diabetes Metab Res Rev 2010;26:187-92. |
|14.||Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010;72:219-46. |
|15.||Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006;17:4-12. |
|16.||Day CP. Non-alcoholic steatohepatitis (NASH): Where are we now and where are we going? Gut 2002;50:585-8. |
|17.||Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002;51:797-802. |
|18.||Dandona P, Aljada A, Bandyopadhyay A. Inflammation: The link between insulin resistance, obesity and diabetes. Trends Immunol 2004;25:4-7. |
|19.||Todd MK, Watt MJ, Le J, Hevener AL, Turcotte LP. Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance. Am J Physiol Endocrinol Metab 2007;292: E485-93. |
|20.||Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards JC, Biswas N, et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 2002;10:1008-15. |
|21.||Hong G, Davis B, Khatoon N, Baker SF, Brown J. PPAR gamma-dependent anti-inflammatory action of rosiglitazone in human monocytes: Suppression of TNF alpha secretion is not mediated by PTEN regulation. Biochem Biophys Res Commun 2003;303:782-7. |
|22.||Tahan V, Eren F, Avsar E, Yavuz D, Yuksel M, Emekli E, et al. Rosiglitazone attenuates liver inflammation in a rat model of nonalcoholic steatohepatitis. Dig Dis Sci 2007;52:3465-72. |
|23.||Hernandez R, Teruel T, de Alvaro C, Lorenzo M. Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-alpha induction of p38 and p42/p44 mitogen-activated protein kinases. Diabetologia 2004;47:1615-24. |
|24.||Jung HS, Youn BS, Cho YM, Yu KY, Park HJ, Shin CS, et al. The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus. Metabolism 2005;54:314-20. |
|25.||Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391:82-6. |
|26.||Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391:79-82. |
|27.||Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, et al. Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab 2004;89:2728-35. |
|28.||Asada K, Sasaki S, Suda T, Chida K, Nakamura H. Antiinflammatory roles of peroxisome proliferator-activated receptor gamma in human alveolar macrophages. Am J Respir Crit Care Med 2004;169:195-200. |
[Table 1], [Table 2]