Troglitazone: New Oral Hypoglycemic Agent

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The fda has approved troglitazone, a new oral hypoglycemic agent, for the treatment of type II diabetes. The drug is the first of a new class of antidiabetic agents called thiazolidinediones, drugs that work primarily by reducing insulin resistance at the cellular level. Insulin resistance is thought to be the primary defect in type II diabetes and can be detected in the prediabetic state. Thiazolidinediones in general, and troglitazone in particular, effectively reverse insulin resistance, but the mechanism is unknown. Thiazolidinediones are also being investigated as treatment for other conditions that manifest insulin resistance including obesity, hypertension, polycystic ovary syndrome, and syndrome X.1

Troglitazone goes by the trade name Rezulin and is a joint venture of the Japanese company Sankyo and the American drug company Parke-Davis.

Indications

Troglitazone is indicated for use in patients with type II diabetes currently on insulin therapy whose hyperglycemia is inadequately controlled (HbA1c > 8.5%) despite insulin therapy over 30 units per day given as multiple injections.

Potential Advantages

In a six-month, double-blind, placebo-controlled study in type II diabetics receiving a mean of 73 units/day of insulin (range, 27-143), the addition of troglitazone reduced mean hemoglobin A1c by 9-15% from baseline and decreased insulin dosage by 15-42%.2 Troglitazone also decreases triglyceride levels by as much as 33%, an effect that appears more prominent in patients with high baseline triglyceride levels. The drug may be more effective in obese patients, as these patients often manifest insulin resistance. Troglitazone appears to be well-tolerated.3

Potential Disadvantages

Not everyone responds to troglitazone. In a multicenter clinical trial, about 50% of patients were classified as responders. Response was defined as more than 20% reduction in fasting plasma glucose or more than 1% reduction in HbA1c.3

Troglitazone should be used with caution in patients with liver disease.2 The drug may also induce drug metabolism by cytochrome 3A4. Concomitant use of troglitazone with drugs metabolized by this P450 isoenzyme (cyclosporine, tacrolimus, etc.) should be undertaken with caution. Troglitazone and cholestyramine should not be administered together. Increases in LDL, HDL, and total cholesterol have been reported, although the LDL/HDL ratio did not change.

Dosing Information

Troglitazone is supplied in 200 mg and 400 mg tablets. The initial dose of troglitazone is 200 mg, and the usual dose is 400 mg. The maximum dose is 600 mg. The current insulin dose should be continued upon initiation of troglitazone. For patients not responding adequately, the dose of troglitazone should be increased after approximately 2-4 weeks. The insulin dose should be decreased by 10-25% when fasting plasma glucose concentration decreases to less than 120 mg/dL.

Comments

Troglitazone has been shown to decrease insulin resistance and improve or even normalize impaired glucose tolerance.5,6 It is believed to act by enhancing cellular responsiveness to insulin and by reducing hepatic gluconeogenesis. These are also the proposed actions of metformin.4

The NIH is sponsoring a six-year study (The Diabetes Prevention Program) in which patients with impaired glucose tolerance will be randomized to troglitazone, metformin, placebo, or intensive diet and exercise. The primary outcome will be the development of diabetes. This study is expected to begin mid-1997.

Clinical Implications

The role of troglitazone appears to be in treating insulin-resistant obese patients inadequately controlled on insulin-a group of patients for whom there are currently few options. There may be as many as 2 million diabetics in this country that fall into this category. The benefits of troglitazone treatment are reduced hyperglycemia, hyperinsulinemia, and hypertriglyceridemia.

Thiazolinediones show tremendous promise, but their role will be more clearly defined with broader clinical experience. Parke-Davis is expected to seek FDA approval for the use of troglitazone in combination with a sulfonylurea and as monotherapy. These drugs may also be useful in a number of other conditions characterized by insulin resistance.

The wholesale cost of troglitazone 400 mg is about $135 per month, which is more than twice the cost for metformin.

References

    1. Saltiel AR, et al. Diabetes 1996;45:1661-1669.

    2. Rezulin Product Information. Parke-Davis. January 1997.

    3. Iwamoto Y, et al. Diabetes Care 1996;19:151-155.

    4. Stumvoll M, et al. N Engl J Med 1995;3S3:550-554.

    5. Antonucci T, et al. Diabetes Care 1997;20:188-193

    6. Nolan JJ, et al. N Engl J Med 1994;331:1188-1193.