Drug Warning: Beware of Troglitazone (Rezulin)
Drug Warning: Beware of Troglitazone (Rezulin)
By Patricia McGinley, RNP, MSN
Summary—Although more than 800,000 patients in the United States and in Japan have received troglitazone for control of type 2 diabetes, reports of severe hepatic dysfunction resulting in hepatic failure in several patients causes concern.1 New drugs are now advertised in consumer magazines as well as professional journals, and patients come into the office requesting them to control their diseases. Clinicians must be knowledgeable about adverse affects of medications, especially those newly approved, and exercise caution when initiating therapy. Troglitazone underwent clinical trials at several medical centers and reported only a 2% incidence of adverse liver function. It was deemed safe by the U.S. Food and Drug Administration (FDA) after the six-month trial period. Since the release of troglitazone (Rezulin, Parke-Davis, Morris Plains, NJ), the drug manufacturer, the FDA, a major newspaper, and medical journal letters and editorials have expressed concern about serious adverse affects following its use.2,3,4,5 Clinicians are well-advised to abide by recommended liver function monitoring and patient education parameters.
Recently, the Sunday Los Angeles Times ran a front-page article holding troglitazone, (Rezulin), responsible for the deaths of 33 diabetic patients due to acute liver failure. Some of the 33 deaths occurred within the first month of taking this drug.1 This is alarming news for patients and for practitioners prescribing the new drug who need reliable data from controlled research studies to respond to clients’ questions.
Troglitazone came on the market in March 1997. It is a member of a new class of drugs called the thiazolidinediones, which improve the function of insulin through activation of the perioxisome-activated insulin receptors found in muscle, adipose tissue, and the large intestine. These receptors regulate insulin action, lipid homeostasis, and adiposcyte differentiation. Troglitazone improves insulin action within the muscle and reduces basal glucose production in the liver.6,7 Initially, the FDA approved troglitazone for patients with type 2 diabetics in poor control and/or those on two injections of insulin daily. Later in 1997, the FDA approved troglitazone for use as monotherapy or in combination with oral sulfonylureas.
Study Methodology
A 26-week multicenter double-blind, placebo-controlled study with open-label extension recruited 222 subjects who had failed prior oral antidiabetic medication and took 30-150 U of insulin daily.8 The study was designed to determine the maximum reductions in insulin dose achievable with troglitazone without causing an increase in the mean fasting blood glucose (FBG). Subjects were randomly assigned to one of three treatment groups:
1. 200 mg of troglitazone;
2. 400 mg of troglitazone;
3. or matching placebo.
Subjects completing the double-blind phase entered the open-label extension trial using 200 mg troglitazone with an option of titrating to 400 mg. Eligibility criteria for the trial included the following:
• type 2 diabetes;
• HbA1c > 7%;
• C-peptide >= 0.5 nmol/l;
• FBG > 7.8mmol/l at the end of a 2-4 week placebo baseline phase, which preceded the study;
• mean daily insulin dose 30-150 U;
• and failure on oral medication before initiating insulin.
Exclusion criteria included:
• subjects with hepatic enzymes elevated ³ two times normal;
• serum creatinine elevations >= 177 mmol/l;
• history of ketoacidosis;
• symptomatic angina pectoris;
• cardiac insufficiency;
• uncontrolled hypertension;
• and active cancer within five years of screening.
Women of child-bearing potential were required to use contraception (barrier or hormonal) provided they were not pregnant or lactating. Antidiabetic medications other than the study medications and insulin were not permitted.
Study Results
Of 222 enrolled subjects, 194 (87%) completed the double-blind phase. Of these, 70% using 400 mg of troglitazone and 51% of those treated with 200 mg troglitazone reduced the amount of insulin required to control FBS up to 50%. The placebo group had only a 19% reduction. Reductions in daily insulin dose were as follows:
• placebo — 18%;
• troglitazone 200 mg — 41%;
• and troglitazone 400 mg — 57%.
Sixteen patients were able to discontinue insulin completely. The 400 mg troglitazone subjects had a 0.4% decrease in HbA1c compared with 0.1% for placebo group subjects. Reductions also were noted in the FBG and FSG (fasting serum glucose). No notable trends or differences with regard to adverse events were found among troglitazone-treated patients and placebo subjects. Twenty-eight patients did report serious adverse events; however, none were believed to be associated with the study medication. The incidence of hypoglycemia was 17% higher in troglitazone patients when compared with placebo patients; however, there was no severe hypoglycemia. Modest increases were found in high-density lipoprotein (HDL), low-density lipoprotein, and total cholesterol (TC) without changes in TC/HDL ratio.
Less than 2% of patients were found to have abnormalities of liver function, and all abnormalities reversed upon discontinuation of the drug.8
In another study, researchers reported a 52-week clinical study of 552 poorly controlled diabetics on oral sulfonylureas randomized into three groups:
• micronized glyburide only;
• troglitazone monotherapy;
• and combined troglitazone and glyburide.
Seven patients were withdrawn from the study at the investigator’s discretion due to an elevation of liver enzymes. All enzyme levels returned to baseline or normal levels after withdrawal of troglitazone.8
Another author notes that 48 out of 2510 patients who received troglitazone (1.9%) experienced hepatic dysfunction with serum aminotransferase concentrations more than three times the upper limit of normal as compared with three of 475 placebo patients (0.6%).9
Practice Implications
Although numerous trials have demonstrated that troglitazone increases insulin action, improves dyslipidemia, and enhances oral glucose utilization for type 2 diabetes, practitioners must remain wary and alert for indicators of possible adverse affects upon the liver.
In a series of warnings,1,2,3,4,5 Parke Davis and the FDA published recommendations for clinicians, including the following:
• Check serum transaminase levels for the first two months and then every two months during the first year of troglitazone therapy.
• Any patient with symptoms suggesting liver dysfunction should receive liver function tests.
• Patients with a 1.5 or > elevation in ALT (serum alanine aminotransaminase) levels should not begin troglitazone.
• ALT levels should be measured at the initiation of troglitazone, monthly for eight months, every two months for the remainder of the first year, and periodically thereafter.
• Patients with ALT levels > 1.5-2 times normal during troglitazone therapy need to be retested within one week then weekly until back to normal.
• If ALT levels rise above three times normal, discontinue the drug.
In December 1998, the FDA strongly recommended liver function testing for patients on troglitazone at the start of therapy, at monthly intervals for the first six months, every other month for the next six months, and periodically thereafter.7,8,9,10
It is vitally important for the clinician to be knowledgeable about contraindications for using the drug. Practitioners must carefully educate each patient who is prescribed troglitazone about signs and symptoms such as jaundice, nausea, vomiting, loss of appetite, fatigue, or dark urine that may indicate liver dysfunction.
References
1. Willman D. Fast-track’ drug to treat diabetes tied to 33 deaths. Los Angeles Times, Dec. 6, 1998:A-l.
2. U.S. Food and Drug Administration. Retyped text of a letter from Parke-Davis. Oct. 28, 1997:1-3. Http://www.fda.gov/medwatch/safety/1997/rezuli.html.
3. U.S. Food and Drug Administration. Rezulin labeling changes. FDA Talk Paper Nov. 3, 1997:1-2. Http://www.fda.gov/bbs/topics/ANSWERS/ANS00831.html.
4. Imura H. A novel antidiabetic drug, troglitazone — reason for hope and concern. NEJM 1998;338:908-909.
5. Watkins P, Whitcomb R. Hepatic dysfunction associated with troglitazone. (Letter). NEJM 1998;338:916-917.
6. Medical Economics Co. Physicians’ Desk Reference. Montvale, NJ; 1998:2118-2121.
7. Zimmerman B, Hagen M. An evaluation of new agents in the treatment of type 2 diabetes. J Fam Pract 47:S37-S43.
8. Buse J, Gumbiner B, Mathias N, et al. Troglitazone use in insulin-treated type 2 diabetic patients. Diabetes Care 1998;21:1455-1460.
9. Horton E, Whitehouse F, Ghazzi M, et al. Venable, troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. Diabetes Care 1998;21:1462-1469.
10. Diabetes Monitor. Troglitazone. Aug. 25, 1998:1-14. http://www.mdcc.com/rezulin.htm.
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