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Rosiglitazone & Pioglitazone Treatment for Lipodystrophy, diabetes, effects on lipids
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Jules Levin
NATAP
This report contains several published studies looking the affect of -glytazone drugs on body changes. In particular I draw your attention to this study summarized below:
"Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients"
The authors say:
--These results suggest that the improvement in glucose homeostasis after thiazolidinedione treatment may in some way be related to an alteration in fat metabolism and/or fat topography
--After pioglitazone treatment, subcutaneous fat area...increased, whereas visceral fat area...and the ratio of visceral to subcutaneous fat...decreased.
--These results suggest that the improvement in glucose homeostasis after thiazolidinedione treatment may in some way be related to an alteration in fat metabolism and/or fat topography...thiazolidinediones promote the differentiation of preadipocytes into mature fat cells in sc, but not visceral, fat depots in humans
Nonhypoglycemic Effects of Thiazolidinediones
Akhil A. Parulkar, MD; Merri L. Pendergrass, MD, PhD; Ramona Granda-Ayala, MD; Tri Richard Lee, MD; and Vivian A. Fonseca, MD
Annals of Internal Medicine 2 January 2001, Volume 134, Issue 1
Thiazolidinediones have been shown to substantially increase levels of total cholesterol and LDL cholesterol. However, the increase is predominantly in the larger buoyant particles of LDL cholesterol, which may be less atherogenic than small, dense LDL cholesterol particles. Levels of the latter have been shown to decrease with troglitazone therapy. These data were confirmed in other studies demonstrating that troglitazone increased the resistance of LDL cholesterol to oxidation. Whether these effects are produced by the other thiazolidinediones or were related to vitamin E moiety in the troglitazone molecule is unclear and warrants further study. Although the effects of the thiazolidinediones on LDL cholesterol oxidation are in theory appealing, their role in preventing cardiovascular events is unclear. Of note, vitamin E, which also has antioxidant and free radical--scavenging properties, did not reduce cardiovascular outcomes in the Heart Outcomes and Prevention Evaluation study.
In summary, all of the thiazolidinediones appear to substantially increase HDL cholesterol levels. Troglitazone and pioglitazone have been shown to decrease triglyceride levels. All of the thiazolidinediones increase LDL cholesterol levels, although changes in the size of LDL cholesterol particles may make the cholesterol less susceptible to oxidation. The differences between the thiazolidinediones in their lipid effects may reflect the fact that different populations have been studied; a randomized comparative trial is needed to determine whether a true difference exists.
The thiazolidinediones are a new class of compounds for treatment of type 2 diabetes. Troglitazone became available in the United States in 1997 but was withdrawn from the market in March 2000 because it caused severe idiosyncratic liver injury. Rosiglitazone and pioglitazone have been available since 1999. Because these drugs directly improve insulin resistance and decrease plasma insulin levels (a risk factor for coronary artery disease), they may decrease risk for cardiovascular disease in patients with type 2 diabetes. Research on the non--glucose lowering effects of troglitazone and, to a lesser extent, of rosiglitazone and pioglitazone have demonstrated changes in several cardiovascular risk factors associated with the insulin resistance syndrome. These beneficial effects include a decrease in blood pressure, correction of diabetic dyslipidemia, improvement of fibrinolysis, and decrease in carotid artery intima--media thickness. Other in vitro effects related to the ability of these agents to bind a newly described class of receptors (peroxisome proliferator--activated receptors) may also have implications for atherosclerosis. However, these drugs increase low-density lipoprotein (LDL) cholesterol levels and may favorably change LDL particle size and susceptibility to oxidation (although the implications of the latter changes are not clear). Furthermore, these drugs tend to cause weight gain. The authors' enthusiasm for these drugs has diminished somewhat because of reported adverse events, including rare liver failure. Nevertheless, because of the mechanism of action of the thiazolidinediones, clinical trials designed to determine whether they (or similar "insulin sensitizers") decrease cardiovascular events in people with type 2 diabetes will be of interest.
In summary, all of the thiazolidinediones appear to substantially increase HDL cholesterol levels. Troglitazone and pioglitazone have been shown to decrease triglyceride levels. All of the thiazolidinediones increase LDL cholesterol levels, although changes in the size of LDL cholesterol particles may make the cholesterol less susceptible to oxidation. The differences between the thiazolidinediones in their lipid effects may reflect the fact that different populations have been studied; a randomized comparative trial is needed to determine whether a true difference exists.
Treatment with troglitazone is associated with abnormalities in liver function test results in approximately 2% of patients. Occasional severe liver failure led to its withdrawal from clinical use. In contrast, in clinical trials, rosiglitazone and pioglitazone have not been associated with an excessive rate of abnormalities on liver function tests. Nevertheless, severe liver injury was reported in two patients treated with rosiglitazone. The exact mechanism of this reaction is poorly understood. Further investigation is needed to determine whether PPAR-{gamma} activation in the liver produced these effects. Elucidation of the mechanism may enable the design of drugs that do not produce hepatic toxicity. Until the pathogenesis of this idiosyncratic liver injury is better understood, U.S. Food and Drug Administration guidelines for liver function monitoring in patients receiving rosiglitazone and pioglitazone should be followed. These include avoiding use of thiazolidinediones in patients with abnormal liver function test results and monitoring liver function test results bimonthly in patients receiving rosiglitazone and pioglitazone.
Another side effect of the thiazolidinediones is a decrease in hematocrit attributable to an increase in plasma volume, weight gain, and edema.
Rosiglitazone for Treatment of HIV Lipodystrophy
Annals of Internal Medicine
Nasser Mikhail, MD, MSc
From Olive View--UCLA Medical Center, Sylmar, CA 91342.
LETTER TO THE EDITOR:
I disagree with Hadigan and colleagues (1) that rosiglitazone had positive effects on metabolic indices in HIV lipodystrophy in their study. In fact, mean plasma levels of total and low-density lipoprotein (LDL) cholesterol increased significantly, approximately 13%, with 4 mg of rosiglitazone per day. Surprisingly, Hadigan and colleagues (1) did not comment on the important study by Carr and associates (2) that evaluated rosiglitazone for the same objective. However, compared with Hadigan and colleagues' study (1), the trial by Carr and associates (2) was larger (108 patients) and longer-term (48 weeks) and used maximum rosiglitazone dosages (4 mg twice daily). Carr and associates (2) also reported significant increases in total and LDL cholesterol levels in the rosiglitazone group. Moreover, plasma triglyceride levels increased significantly in Carr and associates' study but not in the study by Hadigan and colleagues (1), probably because the latter used submaximal doses of rosiglitazone. Clearly, deterioration of the lipid profile during rosiglitazone therapy can increase the cardiovascular risk of HIV-infected patients, who may already be at high risk mainly because of adverse metabolic effects of antiretroviral therapy (3).
Unlike Hadigan and colleagues (1), Carr and associates (2) found no beneficial effects of rosiglitazone on lipoatrophy. The improvement of lipoatrophy noted by Hadigan and colleagues (1) could be attributed, at least in part, to the fact that lipoatrophy was significantly milder in the rosiglitazone group than in the placebo group at baseline. Chance may also be a factor given the small number of patients. Taken together, the previous data indicate that rosiglitazone can worsen lipid variables in HIV lipodystrophy without clear beneficial effects on fat redistribution. Accordingly, rosiglitazone should be used with caution, if at all, in HIV-infected patients receiving antiretroviral therapy and should be accompanied by close monitoring of the lipid profile.
REFERENCES
1. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial. Ann Intern Med. 2004;140:786-94. [PMID: 15148065].
2. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, et al.. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet. 2004;363:429-38.
3. Friis-Moller N, Sabin CA, Weber R, d'ArminioMonforte A, El-Sadr WM, Reiss P, et al.. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993-2003. [PMID: 14627784].
REPLY
Rosiglitazone for Treatment of HIV Lipodystrophy
Colleen Hadigan, MD, MPH, and Steven Grinspoon, MD
From Massachusetts General Hospital, Boston, MA 02114.
IN RESPONSE:
We acknowledge that rosiglitazone was associated with modest but statistically significant increases in total cholesterol and LDL cholesterol levels in our study, similar to findings seen in the non-HIV diabetes literature regarding the use of this agent. It is important to recognize, however, that insulin resistance, elevated free fatty acid levels, and hypoadiponectinemia are also significant independent predictors of cardiovascular disease; all of these improved with rosiglitazone therapy in our study sample. Furthermore, evidence shows that peroxisome proliferator--activated receptor-{gamma} (PPAR-{gamma}) agonists increase LDL particle size and increase small high-density lipoprotein particles, thereby creating a less atherogenic lipid profile (1). In addition, PPAR-{gamma} agonists such as pioglitazone may have more favorable effects on lipid levels while improving insulin sensitivity and adipogenesis. We agree that the long-term cardiovascular effects of thiazolidinediones are not known for this population and warrant further investigation.
In contrast to our study, the report by Carr and associates (2) did not demonstrate significant increases in subcutaneous fat after 48 weeks of rosiglitazone therapy compared with placebo in HIV-infected patients with lipoatrophy. There are several important differences between our study and theirs. Hyperinsulinemia, a surrogate marker for insulin resistance, was required in our study and in the study by Gelato and coworkers (3), which also showed increased subcutaneous fat in response to rosiglitazone. The observed increase in subcutaneous fat in our study is consistent with known biological effects of PPAR-{gamma} agonists in stimulating adipogenesis. Carr and associates (2) showed a 5% mean increase in limb fat with rosiglitazone but a 7% increase with placebo. In contrast, in our study, subcutaneous fat decreased over time in the placebo group but increased in response to rosiglitazone. In Carr and associates' study, negative findings on limb fat may have been related to the spontaneous improvement in limb fat seen in the placebo group. Furthermore, in their study, use of stavudine, a medication associated with progression of lipoatrophy (4), was disproportionate in the rosiglitazone and placebo groups (53% vs. 26%, respectively). In addition to having less severe lipoatrophy, 25% of the patients in our study were women, compared with only 2% in the study by Carr and associates (2). This may also contribute to differences in study results. Although further study is needed, our data indicate a net potential benefit in metabolic variables and body composition in HIV-infected patients with insulin resistance.
References
1. Bavirti S, Ghanaat F, Tayek JA. Peroxisome proliferator-activated receptor-gamma agonist increases both low-density lipoprotein cholesterol particle size and small high-density lipoprotein cholesterol in patients with type 2 diabetes independent of diabetic control. Endocr Pract. 2003;9:487-93.
2. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, et al.. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet. 2004;363:429-38.
3. Gelato MC, Mynarcik DC, Quick JL, Steigbigel RT, Fuhrer J, Brathwaite CE, et al.. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study. J Acquir Immune Defic Syndr. 2002;31:163-70. [PMID: 12394794].
4. Dube M, Zackin R, Tebas P, Roubenoff R, Mulligan K, Robbins G, et al.. Prospective study of regional body composition in antiretroviral-naive subjects randomized to receive zidovudine + lamivudine or didanosine + stavudine combined with nelfinavir, efavirenz, or both: A5005s, a study of ACTG 384. Antiviral Therapy. 2002;7:18.
ARTICLE
Metabolic Effects of Rosiglitazone in HIV Lipodystrophy
A Randomized, Controlled Trial
Colleen Hadigan, MD, MPH; Sigal Yawetz, MD; Abraham Thomas, MD; Fiona Havers, MA; Paul E. Sax, MD; and Steven Grinspoon, MD
ANNALS, 18 May 2004, Volume 140, Issue 10
Background: Patients with HIV infection who are treated with antiretroviral agents often lose subcutaneous fat and have metabolic abnormalities, including insulin resistance and reduced adiponectin levels, which may be related to disrupted subcutaneous adipogenesis and altered peroxisome proliferator--activated receptor-{gamma} signaling.
Objective: To investigate the effects of rosiglitazone (4 mg/d), a peroxisome proliferator--activated receptor-{gamma} agonist, in HIV-infected men and women with hyperinsulinemia and lipoatrophy.
Design: A randomized, double-blind, placebo-controlled, 3-month study.
Setting: University hospital.
Patients: 28 HIV-infected men and women with hyperinsulinemia and lipoatrophy.
Measurements: Insulin sensitivity measured by euglycemic hyperinsulinemic clamp testing; subcutaneous leg fat area measured by computed tomography; adiponectin, free fatty acid, and lipid levels; and safety variables.
Results: Rosiglitazone, when compared with placebo, improved insulin sensitivity (mean [±SD] change, 1.5 ± 2.1 mg of glucose/kg of lean body mass per minute vs. --0.4 ± 1.6 mg/kg per minute; P = 0.02), increased adiponectin levels (mean [±SD], 2.2 ± 2.2 µg/mL vs. 0.1 ± 1.1 µg/mL; P = 0.006), and reduced free fatty acid levels (mean [±SD], --0.09 ± 0.1 mmol/L vs. 0.01 ± 0.1 mmol/L; P = 0.02). Mean percentage (±SD) of body fat (1.38% ± 3.03% vs. --0.83% ± 2.76%; P = 0.03) and subcubaneous leg fat area (2.3 ± 8.4 cm2 vs. --0.9 ± 1.9 cm2; P = 0.02) increased significantly with rosiglitazone compared with placebo. Mean total cholesterol levels (±SD) also increased with rosiglitazone compared with placebo (0.6 ± 1.0 mmol/L [25 ± 37 mg/dL] vs. --0.4 ± 0.6 mmol/L [--15 ± 25 mg/dL]; P = 0.007).
Limitations: The study was relatively small and of short duration.
Conclusions: The authors demonstrated positive effects of rosiglitazone on lipoatrophy; insulin sensitivity; and metabolic indices, including adiponectin levels, in HIV-infected patients with lipoatrophy and insulin resistance. Peroxisome proliferator--activated receptor-{gamma} agonists may correct the metabolic abnormalities associated with disrupted adipogenesis in this population. Further studies must determine the clinical utility of such agents in HIV-infected patients.
Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients
The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2784-2791
Yoshinori Miyazaki, Archana Mahankali, Masafumi Matsuda, Srikanth Mahankali, Jean Hardies, Kenneth Cusi, Lawrence J. Mandarino and Ralph A. DeFronzo
University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas 78229
After 16 wk of pioglitazone treatment, body weight, body mass index, and fat mass all increased significantly. The increase in fat mass (3.0 kg) precisely equaled the increase in body weight (3.0 kg). No change in lean body mass was observed during pioglitazone treatment. Pioglitazone treatment was associated with a significant increase in sc fat area and a significant decrease in visceral fat area. As a result, the visceral to sc fat ratio decreased significantly.
Plasma Lipids
Fasting plasma triglyceride (P < 0.01) and FFA (P < 0.05) concentrations decreased significantly after pioglitazone treatment. Total cholesterol, HDL cholesterol, and LDL cholesterol concentrations did not change.
Abstract
We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 ± 3 yr; body mass index, 29.0 ± 1.1 kg/m2), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m2·min) with [3H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4--5.
After 16 wk of pioglitazone treatment, fasting plasma glucose (179 ± 10 to 140 ± 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 ± 13 to 233 ± 14 mg/dl; P < 0.01), and hemoglobin A1c (8.6 ± 0.4% to 7.2 ± 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 ± 38 to 569 ± 31 µEq/liter; P < 0.05) and mean plasma FFA (539 ± 20 to 396 ± 29 µEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) x basal plasma insulin concentration] decreased from 41 ± 7 to 25 ± 3 mg/kg fat-free mass (FFM)·min x µU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 ± 0.1 to 0.6 ± 0.2 mg/kg FFM·min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 ± 0.5 to 4.4 ± 0.4 ml/kg FFM·min (P < 0.05); second MCR, 8.7 ± 1.0 to 11.3 ± 1.1 ml/kg FFM·min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 ± 4 to 85 ± 4 kg; P < 0.05) and fat mass (27 ± 2 to 30 ± 3 kg; P < 0.05).
After pioglitazone treatment, sc fat area at L4--5 (301 ± 44 to 342 ± 44 cm2; P < 0.01) increased, whereas visceral fat area at L4--5 (144 ± 13 to 131 ± 16 cm2; P < 0.05) and the ratio of visceral to sc fat (0.59 ± 0.08 to 0.44 ± 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP x basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = -0.45; P < 0.05) and second (r = -0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.
THIAZOLIDINEDIONES, a new class of insulin-sensitizing agents, have recently been introduced for the treatment of patients with type 2 diabetic mellitus. Early studies showed that troglitazone ameliorates insulin resistance and improves hyperglycemia, hyperinsulinemia, and dyslipidemia in type 2 diabetic patients. Although the precise mechanism of action of the thiazolidinediones remains to be determined, their glucose-lowering effect seems to depend on the presence of insulin (6). It is known that thiazolidinediones activate specific receptors, termed PPAR{gamma}. PPAR{gamma} activation causes preadipocytes to differentiate into mature fat cells and causes the induction of key enzymes involved in lipogenesis. Consistent with these observations, clinical studies have demonstrated that thiazolidinedione therapy in type 2 diabetic patients is associated with weight gain, yet glycemic control improves. The increase in body weight is positively related to the reduction in hemoglobin A1c (HbA1c). These results suggest that the improvement in glucose homeostasis after thiazolidinedione treatment may in some way be related to an alteration in fat metabolism and/or fat topography. With respect to the later, Adams et al. reported that thiazolidinediones promote the differentiation of preadipocytes into mature fat cells in sc, but not visceral, fat depots in humans. Numerous studies have shown that increased visceral fat is associated with insulin resistance and the development of macrovascular complications. Several recent studies have demonstrated that the thiazolidinedione, troglitazone, decreases visceral fat content in type 2 diabetic patients, but no previous study has examined whether the alterations in abdominal fat distribution after thiazolidinedione treatment are related to the improvement in glycemic control and/or insulin sensitivity.
In the present study we have evaluated the effect of pioglitazone therapy on glucose tolerance, insulin secretion, hepatic and peripheral tissue sensitivity to insulin, plasma lipid levels, and abdominal fat distribution in type 2 diabetic individuals. To the best of our knowledge, this represents the first study that has examined the relationship between changes in abdominal fat distribution and glucose homeostasis/insulin sensitivity after thiazolidinedione treatment in type 2 diabetic subjects.
LETTER
Hepatocellular Injury in a Patient Receiving Pioglitazone
Kenji Maeda, MD
ANNALS 21 August 2001, Volume 135, Issue 4
TO THE EDITOR:
Two new members of the thiazolidinedione family, rosiglitazone and pioglitazone, have been believed to be less harmful than their predecessor troglitazone. A few case reports have described possible hepatocellular injury associated with rosiglitazone (1--3), but no hepatotoxic adverse effects have been previously noted in patients treated with pioglitazone. I describe a patient who developed hepatocellular injury while taking pioglitazone (Actos, Takeda Pharmaceuticals, Osaka, Japan).
A 67-year-old man with type 2 diabetes mellitus visited our outpatient clinic for a regular check-up. He was asymptomatic, but laboratory tests showed liver function abnormalities. Total bilirubin level was 10 µ mol/L (0.6 mg/dL), aspartate aminotransferase (AST) level was 1.95 µ kat/L (117 IU/L) (normal range, 0.13 to 0.67 µkat/L [8 to 40 IU/L]), alanine aminotransferase (ALT) level was 5650 nkat/L (339 IU/L) (normal range, 83 to 750 nkat/L [5 to 45 IU/L]), alkaline phosphatase level was 16.69 µkat/L (normal range, 1.92 to 5.98 µ kat/L), and {gamma}-glutamyltransferase level was 8.12 µkat/L (normal range, <1.17 µkat/L). The patient had received pioglitazone, 30 mg/d, for 7 months; an {alpha}-glucosidase inhibitor, voglibose (Basen, Takeda Pharmaceuticals, Osaka, Japan), 0.6 mg/d, for 5 years; and glyburide, 2.5 mg/d, for 10 years. Results of liver function tests were normal before pioglitazone was added to his regimen and during the first 6 months afterward. Ultrasonography of the liver and viral serologic studies showed no other cause of liver injury.
Pioglitazone therapy was discontinued. On the seventh day after discontinuation, results of liver function tests showed remarkable improvement: total bilirubin level, 9 µmol/L (0.5 mg/dL); AST level, 0.32 µkat/L (19 IU/L); ALT level, 867 nkat/L (52 IU/L); alkaline phosphatase level, 9.84 µkat/L; and {gamma}-glutamyltransferase level, 2.99 µkat/L. All values returned to normal in a month.
The most likely cause of this patient's elevated liver enzyme levels was pioglitazone-associated hepatotoxicity. Physicians who prescribe this drug should observe patients closely, even if results of liver function tests are normal during the first 6 months.
BRIEF COMMUNICATION
Hepatocellular Injury in a Patient Receiving Rosiglitazone
A Case Report
Jameela Al-Salman, MD; Heider Arjomand, MD; David G. Kemp, MD; and Manoj Mittal, MD
ANNALS 18 January 2000, Volume 132, Issue 2
Background: Rosiglitazone maleate (Avandia, SmithKline Beecham, Philadelphia, Pennsylvania) is a new oral hypoglycemic agent approved for the treatment of type 2 diabetes. It acts primarily by increasing insulin sensitivity. In controlled trials, there has been no evidence of rosiglitazone-induced hepatocellular injury.
Objective: To report a case of hepatocellular injury in a patient receiving rosiglitazone.
Design: Case report.
Setting: Community teaching hospital.
Patient: 61-year-old man receiving rosiglitazone, 4 mg/d for 2 weeks.
Intervention: Discontinuation of rosiglitazone therapy.
Measurements: Clinical evaluation and assessment of liver function test results were done daily during hospitalization and periodically after discharge. The outpatient record was also reviewed.
Results: After receiving rosiglitazone for 2 weeks, the patient presented with anorexia, vomiting, and abdominal pain. Liver function tests revealed severe hepatocellular injury. Discontinuation of rosiglitazone therapy led to rapid improvement of liver function and resolution of symptoms.
Conclusion: Rosiglitazone may be associated with hepatocellular injury. We believe that patients receiving rosiglitazone should have liver enzyme levels monitored earlier and more frequently than initially recommended.
Rosiglitazone maleate (Avandia, SmithKline Beecham, Philadelphia, Pennsylvania) is a new oral agent that the Food and Drug Administration has recently approved for treatment of type 2 diabetes mellitus. It is a member of the thiazolidinedione class of antidiabetic agents, and it improves glycemic control by increasing insulin sensitivity. Clinical studies of 4598 patients treated with rosiglitazone, encompassing 3600 patient-years of exposure, reported no evidence of drug-induced hepatotoxicity or elevation of alanine aminotransferase (ALT) levels. In controlled trials, 0.2% of patients treated with rosiglitazone had elevations in ALT levels more than three times the upper limit of normal, compared with 0.2% of patients receiving placebo and 0.5% of patients treated with active comparators, including metformin and sulfonylureas. Elevations of ALT levels in patients treated with rosiglitazone were reversible and were not clearly causally related to rosiglitazone therapy. Another drug of the thiazolidinedione class, troglitazone, has been associated with severe hepatotoxicity. Few cases of liver failure, liver transplants, and death have been reported.
We describe a patient who developed hepatocellular injury while receiving rosiglitazone. This case was reported to the U.S. Food and Drug Administration and the manufacturer of rosiglitazone.
A 61-year-old man with a history of poorly controlled type 2 diabetes mellitus presented with anorexia, nausea, vomiting, and abdominal pain that had lasted 3 days. He also had fatigue and chills and noted that his urine was dark. The patient had received rosiglitazone, 4 mg/d, 2 weeks before admission. He noted the onset of his symptoms 8 days after starting rosiglitazone therapy. His ALT level was 670 nkat/L (40 U/L) (normal range, 0 to 670 nkat/L [0 to 40 U/L]) 5 weeks before rosiglitazone therapy was started.
During the previous year, several attempts had been made to control the patient's diabetes with sulfonylureas and metformin. He had started troglitazone therapy 8 months before admission, but it was discontinued after 1 week because of nausea and an upset stomach. The patient had had no clinical signs of hepatic failure at that time, and liver enzyme levels were normal 5 months after troglitazone therapy was discontinued. Seven weeks before admission, he had started repaglinide therapy. Five weeks later, repaglinide therapy was stopped because he developed nausea and dizziness, which he attributed to repaglinide. The patient subsequently started rosiglitazone therapy.
The patient's medical history included chronic obstructive pulmonary disease and a remote history of alcoholism. He reported no recent alcohol intake, history of blood transfusion, or intravenous drug abuse. Other medications that he had been prescribed during the previous 3 years included bronchodilators, theophylline, prednisone, and zafirlukast. The patient had used acetaminophen, up to 4 g/d, intermittently for headache for the previous 2 years, but he had reduced his acetaminophen intake to three to four tablets daily 3 months before admission. He was not using any other over-the-counter medications. The patient had no history of allergy to any medication.
On initial presentation, physical examination revealed an afebrile, icteric, obese man without clinical evidence of ascites, flapping tremor, or hepatosplenomegaly. Results of laboratory tests on admission and over the follow-up period are shown in the Table. Results of tests for anti-hepatitis B core IgM, hepatitis B surface antigen, antibody to hepatitis A virus IgM, anti-hepatitis C virus, hepatitis B virus DNA, and hepatitis C virus RNA were normal, as were serum ceruloplasmin levels, {alpha}-fetoprotein levels, and iron studies. Findings on serologic tests for acute cytomegalovirus and Epstein-Barr virus infection were also negative. The acetaminophen level was 3.2 µg/mL (normal, 10 to 30 µg/mL). Levels of anti-smooth-muscle antibody, antinuclear antibody, and antimitochondrial antibody were normal. The leukocyte count (9.0 x 109 /L) and the peripheral eosinophil count (90 x 106 /L) were normal. Abdominal ultrasonography showed an enlarged liver with a normal gallbladder and pancreas. Computed tomography of the abdomen was consistent with a fatty liver. Rosiglitazone therapy was discontinued on admission.
The patient had developed nausea, vomiting, abdominal pain, and fatigue 2 weeks after starting rosiglitazone therapy. We believe the most likely cause of his symptoms and elevated liver enzyme levels was rosiglitazone-associated hepatotoxicity. Rosiglitazone therapy was discontinued on admission; his symptoms immediately improved, and liver enzyme levels returned to normal over the ensuing weeks. The development of the patient's symptoms 8 days after starting rosiglitazone therapy and the course of liver function test abnormalities were typical of the findings seen in drug-induced hepatotoxicity. Our patient did not have a fever, rash, or eosinophilia; therefore, it is unlikely that it was a classic immune mechanism. In this patient, liver injury caused by rosiglitazone seems to be idiosyncratic.
The patient had been regularly exposed to acetaminophen, but he had reduced his acetaminophen intake to about three to four tablets per day (975 to 1300 mg/d) 3 months before presentation. His acetaminophen level on admission was within the therapeutic range, which made the diagnosis of acetaminophen toxicity unlikely. His history of troglitazone intake in the remote past could not account for hepatotoxicity, especially because his ALT level was normal after troglitazone therapy was discontinued. Although elevated liver enzyme levels are cited as an infrequent side effect of repaglinide therapy (Novo Nordisk Pharmaceuticals, Inc., Princeton, New Jersey), the medical literature contains no reports of severe hepatotoxicity due to repaglinide. Moreover, monitoring of liver enzyme is not recommended during repaglinide therapy. The patient had no history of exposure to other hepatotoxins, and evaluation did not reveal any evidence of viral, metabolic, or autoimmune liver disease.
Drug-induced liver injury is a potential complication of many medications because the liver is central to the metabolic disposition of most drugs and foreign substances. Drug-induced liver injury and viral hepatitis are the most common causes of fulminant hepatic failure. Drugs are often classified as dose-dependent (predictable) hepatotoxins and dose-independent (unpredictable or idiosyncratic) hepatotoxins. Liver injury produced by dose-dependent hepatotoxins usually occurs after a short latent period (hours), whereas dose-independent hepatotoxins exhibit a variable latent period. The patient's medical history and physical examination can provide important clues to the diagnosis of hepatic drug reactions. For most drugs, the chronologic relations among drug ingestion, onset, and resolution of liver injury within days or weeks of discontinuation of treatment with the drug are the most important consideration in diagnosis.
Although available clinical data show no evidence of significant rosiglitazone-induced hepatocellular injury, rosiglitazone is structurally similar to troglitazone, which has been associated with hepatocellular injury. In clinical trials, troglitazone-induced hepatotoxicity (ALT level greater than three times the upper limit of normal) was identified in 1.9% of 2510 patients. These abnormalities were resolved with discontinuation of therapy with the drug. Although the incidence of increases in ALT levels is lower with rosiglitazone than with troglitazone, this may or may not indicate lower risk for the typical delayed hepatic toxicity associated with rosiglitazone.
The mechanism of rosiglitazone-induced hepatotoxicity is not known but could be explained by the same theory postulated for troglitazone-induced hepatotoxicity. Troglitazone is primarily metabolized to sulfate and glucuronide conjugates in the liver. It also induces cytochrome P4503A4 activity, and a small fraction undergoes cytochrome P450 oxidation to a quinone derivative. The molecular structure of the drug is similar to that of vitamin E; thus, it may be subject to oxidation-reduction reactions. It is thought to have protective properties against oxidant stress, but its ability to undergo single-electron reduction could also confer injurious pro-oxidant reactivity.
Current recommendations about the use of rosiglitazone include checking liver enzyme levels before initiation of therapy, every 2 months for the first 12 months, and periodically thereafter. Because hepatic injury developed shortly after our patient started rosiglitazone therapy (and pending the availability of postmarketing safety data), we recommend earlier and more frequent monitoring of liver enzyme levels after initiation of rosiglitazone therapy. We believe that it is prudent to check liver enzyme levels at the beginning of therapy, weekly for the first 2 to 4 weeks, monthly for the subsequent 11 months, and periodically thereafter or if symptoms develop. Moreover, rosiglitazone therapy should be discontinued immediately if liver enzyme levels become elevated.
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