Rosiglitazone
July 30, 1999 5 minutes read
Pharmacology Update
Rosiglitazone
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The fda has approved smithkline beecham’s rosiglitazone for the treatment of type 2 diabetes mellitus. The drug is the second thiazolidinedione to be approved by the FDA. The first drug of this class is troglitazone (Rezulin), which has recently been associated with rare, but highly publicized hepatotoxicity. In clinical trials in about 5000 patients, rosiglitazone has not been associated with drug-induced hepatoxicity or elevation of liver enzymes, but whether rosiglitazone represents a safer thiazolidinedione remains to be established.
Rosiglitazone is marketed as Avandia by SmithKline Beecham and Bristol-Myers Squibb. A third drug in this class, Lilly and Takeda’s pioglitazone (Actos), is expected to be approved soon.
Indications
Rosiglitazone is approved for monotherapy, as an adjunct to diet and exercise, to improve glycemic control in type 2 diabetes. It is also indicated for use in combination with metformin when diet, exercise, and either drug alone do not provide adequate control.1
Dosage
The recommended starting dose for rosiglitazone is 4 mg daily administered qid or bid. The dose may be increased to 8 mg if there is insufficient glycemic control after 12 weeks of therapy.1 Higher doses of rosiglitazone tend to be more effective administered twice daily compared to once daily. The difference in glycosylated hemoglobin was significantly greater with 8 mg qid vs. 4 mg bid but not statistically different at 4 mg qid vs. 2 mg bid.1
Rosiglitazone may be taken without regard to meals. No dosage adjustment is required in patients with mild to severe renal impairment or in the elderly.1
Rosiglitazone is supplied as 2-mg, 4-mg, and 8-mg tablets.
Potential Advantages
Clinical trial results reported no significant difference between placebo in the frequency of ALT elevations more than three times the upper limits of normal (0.2% for both groups).1 The manufacturer reported no evidence of drug-induced hepatotoxicity in 4598 patients (3600 patient years). However, due to the chemical similarity between rosiglitazone and troglitazone, the FDA is recommending that liver enzymes be checked prior to initiation of therapy and monitored every two months for the first 12 months and periodically thereafter.1 In vitro data suggest that rosiglitazone does not inhibit any of the major cytochrome P450 enzymes.1
Potential Disadvantages
Edema has been reported in 4.8% of patients administered rosiglitazone; thus, the drug should be used with caution in patients with heart failure.1 Dose-related decreases in hemoglobin (£ 1.0 g/dL) and hematocrit (£ 3.3%) have also been reported.1 Anemia has been reported in 1.9% of patients compared to 0.7% for placebo and 0.6% for sulfonylurea.1 Mean weight gains of 1.75-2.95 kg were reported in patients treated with 4-8 mg of rosiglitazone for 52 weeks.1 Rosiglitazone increases LDL-cholesterol mainly during the first 1-2 months of therapy. HDL-cholesterol is also elevated and continues to rise over time. The net result is an increase in the LDL to HDL ratio, which peaks after two months and tends to decrease over time.1 The FDA’s analysis of the data showed an increase in VLDL-cholesterol of 11.5 mg/dL from a baseline of 20.6 after 26 weeks.7 Contraception may need to be considered in premenopausal anovulatory women with insulin resistance as rosiglitazone may cause resumption of ovulation.1
Comments
Rosiglitazone and troglitazone are both members of the thiazolidinedione class of antihyperglycemic drugs. These agents are thought to improve insulin sensitivity by acting as a potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARg). These receptors are expressed primarily in tissues such as liver, skeletal muscle, and adipose tissue and regulate the control of glucose production, transport, and use.1 In animal adipose tissue models, thiazolidinedones may act by increasing the number of small adipocytes and decreasing the number of large adipocytes.2
Results from clinical trials on the drug have not been published and limited data are available from the manufacturer and/or in abstract forms only.1,4,5,6,8 In placebo-controlled 26-week studies (n = 1400), rosiglitazone (4-8 mg daily) produced a reduction (difference from placebo) in fasting plasma glucose (FPG) of 31-76 mg/dL in patients with a baseline FPG of 220-229 mg/dL.1 Corresponding reductions of glycosylated hemoglobin were 0.8-1.5% with baseline values of 8.9-9.0%. Rosiglitazone was generally more effective when administered twice daily compared to once daily.1 In a 52-week comparative trial (n = 587) with glyburide (mean dose of 7.5 mg/d), rosiglitazone (4 mg bid) produced a mean change from baseline of 41 mg/dL vs. 30 mg/dL in FPG and 0.53-0.72% in glycosylated hemoglobin. Initial reductions in FPG and glycosylated hemoglobin were greater with glyburide; however, values at 52 weeks appeared to be comparable. In contrast to placebo-controlled trials, patients in the active-controlled trial had lower baseline FPG (190-196) and glycosylated hemoglobin (8.07-8.21). Unpublished data indicate that the addition of rosiglitazone to metformin, sulfonyurea, and insulin in type 2 patients has resulted in added improvement in glycemic control.4-6 Currently only the combination with metformin is FDA approved.
The daily cost of rosiglitazone (4-8mg) ranges from $2.50 to $5 per day. This compares favorably to troglitazone (200-800 mg/d), which ranges from $3 to $9.50 per day.
Clinical Implications
Thiazolidinediones are the newest class of antihyperglycemic agents approved for use in type 2 diabetics. Members of this class, which currently include troglitazone and now rosiglitazone, seem to work by increasing insulin sensitivity. These agents offer a different mechanism of action from the sulfonylureas, metformin, insulin, and acarbose. Thiazolidinediones also offer the potential for combination therapy with these other agents. Toxicity is a concern, with liver toxicity leading the FDA to recently change the labeling for troglitazone. On the other hand, animal studies have suggested that these drugs may protect the vasculature from diabetes-enhanced injury.3 While clinical trial data are encouraging, whether rosiglitazone will be safer for the liver than troglitazone remains to be determined.
References
1. Avandia Product Information. SmithKline Beecham Pharmaceuticals. May 1999.
2. Okuno A, et al. J Clin Invest 1998;101(16):1354-1361.
3. Goetze S, et al. J Cardiovas Pharmacol 1999; 33(5):798-806.
4. Raskin P, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 0404.
5. Gomis R, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 0266.
6. Charbonnel B, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 0494.
7. FDC Report "The Pink Sheet" 1999;61(17):8.
8. Grunberger G, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 0439.
Which of the following is not true for rosiglitazone?
a. It raises LDL and HDL cholesterol
b. Higher doses are more effective administered twice a day
c. It has not been associated with liver dysfunction in clinical trials
d. The FDA is not recommending monitoring liver functions when the drug is started.
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