PIOGLITAZONEHYDROCHLORIDE (Page 4 of 9)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pioglitazone hydrochloride is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone hydrochloride decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

12.2 Pharmacodynamics

Clinical studies demonstrate that pioglitazone hydrochloride improves insulin sensitivity in insulin-resistant patients. Pioglitazone hydrochloride enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone hydrochloride results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone hydrochloride had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14.2)].

Patients with lipid abnormalities were included in clinical trials with pioglitazone hydrochloride. Overall, patients treated with pioglitazone hydrochloride had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone hydrochloride or any other antidiabetic medication [see Warnings and Precautions (5.8) and Adverse Reactions (6.1)].

In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg pioglitazone hydrochloride dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone hydrochloride than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone hydrochloride compared to placebo (see Table 14).

* Adjusted for baseline, pooled center, and pooled center by treatment interaction

†p < 0.05 versus placebo

Table 14 . Lipids in a 26 Week Placebo Controlled Monotherapy Dose Ranging Study
Placebo Pioglitazone Hydrochloride 15 mg Once Daily Pioglitazone Hydrochloride 30 mg Once Daily Pioglitazone Hydrochloride 45 mg Once Daily
Triglycerides ( mg / dL ) N=79 N=79 N=84 N=77
Baseline (mean) 263 284 261 260
Percent change from baseline (adjusted mean*) 4.8% -9.0% -9.6% -9.3%
HDL Cholesterol ( mg / dL ) N=79 N=79 N=83 N=77
Baseline (mean) 42 40 41 41
Percent change from baseline (adjusted mean*) 8.1% 14.1% 12.2% 19.1%
LDL Cholesterol ( mg / dL ) N=65 N=63 N=74 N=62
Baseline (mean) 139 132 136 127
Percent change from baseline (adjusted mean*) 4.8% 7.2% 5.2% 6.0%
Total Cholesterol ( mg / dL ) N=79 N=79 N=84 N=77
Baseline (mean) 225 220 223 214
Percent change from baseline (adjusted mean*) 4.4% 4.6% 3.3% 6.4%

In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks) or insulin (16 weeks and 24 weeks), the results were generally consistent with the data above.

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