Management of Diabetes: PHARMACODYNAMICS

In patients with type-2 diabetes, the decreased insulin resistance produced by generic pioglitazone results in lower values of blood glucose, plasma insulin, and glycosylated hemoglobin (HbA1c). Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appeared to persist for at least one year. In controlled clinical trials, pioglita-zone, in combination with sulfonylurea, metformin, or insulin, had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials of pioglitazone.

Overall, patients receiving pioglitazone experienced mean decreases in triglycerides, mean increases in high-density lipoprotein-cholesterol (HDL-C), and no consistent mean changes in low-density lipoprotein-cholesterol (LDL-C) or total cholesterol (TC). However, in a double-blind, randomized trial by Winkler et al., pioglitazone, when compared with placebo, decreased the LDL particle size in patients with normolipidemia and hypertension. It is worth mentioning that insulin resistance is causally related to hypertension, and a correlation exists between plasma insulin concentrations and blood pressure readings.

In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels decreased in patients receiving pioglitazone doses of 15, 30, and 45 mg, compared with a mean increase in triglycerides in the placebo patients. Mean HDL-C levels increased to a greater extent in patients receiving pioglita-zone than in the placebo-treated patients. There were no consistent differences in LDL-C or TC levels with pioglitazone or with placebo. canada drugs online

At the steady state, two of the pharmacologically active metabolites of pioglitazone—metabolites III (m-III) and IV (M-IV)—reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in type-2 diabetic patients, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration time curve.

A study by Lebovitz et al., published in 2001, assessed the efficacy and safety of a monotherapeutic regimen of rosi-glitazone in patients with type-2 diabetes. Compared with placebo, generic rosiglitazone 2 and 4 mg decreased mean HbA1c levels by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations by 3.22 and 4.22 mmol/L, respectively. Rosiglitazone, compared with placebo, also reduced albumin-creatinine ratios by approximately 30%, decreased levels of plasma free fatty acids, and increased plasma HDL-C and LDL-C. Other studies support the findings of Lebovitz et al. by re-emphasizing that rosiglitazone improves insulin sensitivity and lowers blood glucose in patients with type-2 diabetes.

In a randomized double-blind controlled trial in 36 outpatient centers by Fonseca et al. in the U.S., combination therapies of metformin and rosiglitazone in patients with type 2 diabetes mellitus improved glycemic control, insulin sensitivity, and beta-cell function when compared with metformin alone.

Another study by Karter et al. compared the effect of anti-hyperglycemic monotherapies with antihyperglycemic combined therapies from the Kaiser Permanente Northern California Diabetes Registry. Combination therapies that included a TZD or combined therapies of metformin with insulin resulted in a higher proportion of patients with good glycemic control than did monotherapeutic sulfonylurea regimens.

Hanefield et al. conducted a multicenter randomized, double-blind, parallel-group study throughout Europe involving 639 patients with type-2 diabetes. Therapies combining sulfonylurea plus pioglitazone resulted in a reduced urinary albu-min-creatinine ratio, a slight but significant rise in LDL-C, and significantly larger improvements in triglyceride and HDL-C levels, when compared with combination therapies of sulfonylurea plus.

In an open-label study of patients with type-2 diabetes by Freed et al., a slight increase in LDL-C was observed in patients treated. Similar effects were observed with pioglitazone in another open-label study.

Yates suggests that most of the established studies have demonstrated differences in the effects of rosiglitazone and pioglitazone on blood lipid levels. Although rosiglitazone tends to elevate TC and LDL-C, pioglitazone tends to decrease TC and HDL-C without significantly altering LDL-C.

Another recent study by Goldberg et al. found that pioglitazone, when compared with rosiglitazone, was associated with significant improvement in triglycerides, HDL-C, non-HDL-C (TC minus HDL-C), and LDL-C in patients with type-2 diabetes and dyslipidemia.

Miyazaki et al., Bajaj et al., and Tiikkainen et al. have studied the effects of pioglitazone on abdominal and hepatic fat. In the trial by Miyazaki, the decrease in visceral fat after was associated with a higher sensitivity to insulin in the hepatic and peripheral tissues.

In parallel, Bajaj et al. demonstrated that pioglitazone improved splanchnic glucose uptake, enhanced the suppression of endogenous glucose production, and decreased hepatic fat content. In both studies, however, pioglitazone was associated with a significant increase in body weight.

Tiikkainen et al. compared the different effects of rosi-glitazone and metformin alone on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type-2 diabetes. They found that peripheral glucose uptake increased significantly with rosiglitazone but not with drug metformin. Rosiglitazone  was associated with a reduction in hepatic fat and an increase in insulin clearance.

Rosiglitazone is not likely to cause hepatotoxicity, contrary to an idiosyncratic association of other TZDs, such as troglitazone (Rezulin®), with hepatic reactions leading to liver failure. (Warner-Lambert withdrew troglitazone from the market in 2000.) Indeed, in 13 double-blind studies, Lebovitz et al. assessed the association between three TZDs (tro-glitazone, pioglitazone, and rosiglitazone) and liver enzyme levels. They found that 1.91% of 2,510 patients receiving tro-glitazone, 0.26% of 1,526 patients treated with pioglitazone, and 0.17% of 3,503 patients treated with rosiglitazone canadian had ALT levels that were more than three times the upper limits of the reference range.

Protein-binding affinity is also important in determining the amount of drug available for antidiabetic action. It is commonly accepted that only the unbound drug has activity; hence, the more highly bound the drug, the less free it is to exert its effect. Therefore, the extensive protein binding of the TZDs (above 98%) allows for very little of the unbound drug to be available, thus lowering the AUC concentration.

Category: Diabetes

Tags: Diabetes, diabetes mellitus

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