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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The fda has approved a new thiazolidinedione for the treatment of type 2 diabetes mellitus. Eli Lilly and Takeda’s pioglitazone (Actos) is the third drug in this class, joining troglitazone (Rezulin) and the recently approved rosiglitazone (Avandia). Thiazolidinediones improve insulin sensitivity by acting as potent agonists for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) that regulate the transcription of insulin-responsive genes.1 Sites of action include the liver, adipose tissue, and muscle tissue resulting in a decrease in fasting plasma glucose and insulin.
Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. The drug can be used as monotherapy or in combination with sulfonylurea, metformin, or insulin when diet and exercise plus the single agent is inadequate in achieving glycemic control.1
The recommended initial dose for monotherapy is 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg once daily. When used in combination with a sulfonylurea, the initial dose is 15 mg or 30 mg once daily. The dose of the sulfonylurea should be reduced if the patient experiences hypoglycemia. A similar initial dose is recommended for use in combination with metformin or insulin. In patients receiving insulin and pioglitazone, the insulin dose can be reduced by 10-25%.1 The drug may be taken without regard to meals.
Baseline alanine transaminase (ALT) should be determined before initiating therapy and therapy should not be initiated in patients with baseline ALT more than 2.5 × ULN. Therapy should be discontinued if ALT exceeds 3 × ULN or if the patient is jaundiced.
Pioglitazone is supplied as 15 mg, 30 mg, and 45 mg tablets.
In clinical trials involving more than 4500 subjects, no evidence of drug-induced hepatotoxicity or elevation of ALT levels has been reported.1 The incidence of ALT values equal to or greater than 3 × ULN was 0.26% and 0.25% for pioglitazone and placebo, respectively.1 Due to the chemical similarity between pioglitazone and troglitazone, the FDA is still recommending that serum ALT be evaluated prior to initiation of therapy and every two months for the first year, and periodically thereafter.1 Pioglitazone has been reported to produce a modest reduction in triglyceride levels (50 mg/dL and increase in HDL cholesterol (7-8 mg/dL).8
Edema has been reported in 4.8% of pioglitazone-treated patients compared to 1.2% for placebo-treated patients. Edema was more frequently reported in patients on pioglitazone/insulin combinations. Mean hemoglobin values have declined by 2-4%, which generally occurred within the first 4-12 weeks of therapy and may be related to expansion of plasma volume.1 Pioglitazone is not indicated in heart failure patients with NYHA III or IV cardiac status. In clinical trials, weight gain was associated with pioglitazone therapy (0.5 to 3.7 kg), with the greatest increase when used in combination with insulin (2.3 to 3.7 kg). Pioglitazone may cause resumption of ovulation in anovulatory patients with insulin resistance. Contraceptive measures should be considered in these patients. Ketoconazole may inhibit the metabolism of pioglitazone by inhibiting cytochrome P450 isoform 3A4.1
Pioglitazone is the third thiazolidinedione to be approved. Results from clinical trials (16-26 weeks in duration) have not been published. Limited details are available from the manufacturer and abstracts.1,2,3,4,5,6 As monotherapy (n = 865), pioglitazone produced a mean reduction in fasting blood glucose of 30-56 mg/dL from baseline (267-281 mg/dL) and reduction in glycosylated hemoglobin (HbA1c) from 0.3 to 0.9% (10.2-10.8%).1,2,3 In combination with a sulfonylurea (n = 560) or metformin (n = 328), pioglitazone produced a mean reduction in fasting blood glucose of 34-58 mg/dL from baseline (236-259 mg/dL) and 0.8-1.3% reduction (9.8-10%) in HbA1c.1,4,5 In combination with insulin (n = 566), pioglitazone produced reductions of 35-49 mg/dL in fasting blood glucose and 0.7-1% in HbA1c.1,6 A greater HbA1c reduction has been observed in female patients than in male patients (mean difference of 0.5% in HbA1c).1
Thiazolidinediones are the newest class of antihyperglycemic drugs, providing a different mechanism of action from the sulfonylureas, metformin, insulin, and alpha-glucosidase inhibitors (acarbose, miglitol). As monotherapy, the magnitude of the glycemic control achieved with thiazolidinediones is generally less than that seen with sulfonylureas or metformin, making them more suitable for combination therapy. Due to the natural progressive course of type 2 diabetes, combination therapy is usually unavoidable. In the first three years of treatment, about 50% of patients achieve control with monotherapy but this is reduced to only 25% after nine years.7
Troglitazone had wide appeal as a combination drug until reports of drug-induced hepatotoxicity associated with the drug forced it off the market in Europe and led the FDA to impose strict monitoring of liver function tests in this country. Both pioglitazone and rosiglitazone are touted as being safer than troglitazone, as drug-induced hepatotoxicity has not been reported in clinical trials. The two drugs also seemed to be similar in efficacy (the magnitude of reduction in fasting plasma glucose and glycosylated hemoglobin) and in their side effect profiles (e.g., edema, weight gain). Their effect on the lipid profile may offer a point of differentiation. While both drugs increase HDL-cholesterol (7-8 mg/dL), rosiglitazone increased LDL-cholesterol more than pioglitazone (10-15 mg/dL to 5 mg/dL). In addition pioglitazone reduced triglyceride levels by about 50 mg/dL while rosiglitazone had no effect.8 Since these differences are not from direct comparative studies, the exact magnitude of the difference and clinical significance remains to be determined.
Pioglitazone is priced between $2.85 and $4.95 per day, similar to rosiglitazone.
1. Actos Product Information. Eli Lilly Pharmaceutical, Takeda Pharmaceuticals. July 1999.
2. Mathisen A, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 441.
3. Schneider R, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 469.
4. Schneider R, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 458.
5. Egan J, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 504.
6. Rubin C, et al. American Diabetes Association 59th Scientific Session. June 19-22, 1999. Abstract 474.
7. Turner RC, et al. JAMA 1999;281:2005-2012.
8. DeFronzo RA. Ann Intern Med 1999;131:281-303.