How troglitazone affects insulin resistance
How troglitazone affects insulin resistance
The following information on troglitazone was supplied by Warner Lambert in Morris Plains, NJ, makers of the drug, in lieu of product information, which won’t be available until the drug is fully approved:
• Mechanism of action.
Troglitazone works primarily by direct and potent reduction in insulin resistance. It enhances the effects of circulating insulin by decreasing insulin resistance without increasing the secretion of insulin.
Troglitazone works at the cellular level to treat the mechanism of insulin resistance through an insulin-binding defect at the plasma membrane that prevents glucose transport into a muscle cell. Troglitazone is unique because its site of action is at the hepatic and muscle cells, not the pancreas. It modulates target cell responses to insulin, resulting in improved glycemic control and decreasing circulating insulin. Troglitazone is effective only in the presence of insulin produced by the body or by injection. It should not be used as monotherapy in patients with type I diabetes or in the treatment of diabetic keto-acidosis.
• Study protocols.
There were two pivotal clinical studies for troglitazone. The first study was a six-month, placebo-controlled trial of 350 patients randomly assigned to receive either placebo, 200 mg troglitazone, or 600 mg troglitazone. The main objective of the study was to determine the effect of troglitazone therapy on parameters of glycemic control. Thirty percent of patients taking 200 mg of troglitazone and 47% of patients taking 600 mg of the drug achieved HbA1c levels of less than 8%. Those reductions occurred in the presence of clinically significant reductions in exogenous insulin doses of 15% for the 200 mg group and 42% for the 600 mg group. Patients receiving 200 mg or 600 mg of the drug experienced clinically significant (p < 0.0001) drops in fasting serum glucose levels.
The second study was a 26-week, double-blind, placebo-controlled trial of 222 patients randomly assigned to receive either placebo, 200 mg troglitazone, or 400 mg troglitazone. The objective of the study was to determine if troglitazone therapy would reduce insulin requirements in type II patients while providing evidence of improved glycemic control as measured by capillary blood glucose. In insulin-requiring type II patients taking 15 to 35 units of insulin per day, troglitazone patients were able to maintain or improve glycemic control and decrease injected insulin requirements by 41% in the 200 mg group and 58% in the 400 mg group vs. 14% in the placebo group.
In addition, 51% of the 200 mg group and 70% of the 400 mg group were able to reduce their insulin doses by more than 50%. Some patients — 15% in the 400 mg group and 7% in the 200 mg group — were able to completely eliminate insulin injections altogether from their treatment regimens.
• Safety and tolerability.
Patients on troglitazone had side effects comparable to patients on placebo. The incidence of withdrawal from the drug was the same for patients on troglitazone or placebo (4%). Overall, adverse events were comparable to placebo except for nausea, which was 2% higher than among patients on placebo. Those effects didn’t interfere with therapy.
There were small decreases noted in hemoglobin, hematocrit, and neutrophil counts in patients on troglitazone, but the levels remained within normal range.
When used as monotherapy, troglitazone doesn’t cause hypoglycemia or insulin secretion. But because troglitazone acts to reduce insulin resistance, when it is used in combination with sulfonylureas or insulin, some patients experienced hypoglycemia related to the effects of those agents and required dose adjustment of concomitant medications.
No dosage adjustment is necessary in patients with renal dysfunction. Troglitazone must be used with caution in patients with hepatic diseases, however.
In early trials, cardiac enlargement occurred in rodents at 14 to 47 times human exposure to the drug, but similar exposures to monkeys, dogs, and humans didn’t induce cardiac enlargement. Vascular tumors also occurred in mice during early trials in doses 14 times higher than normal, but no such tumors were found in human studies.
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