Drugs

, Volume 66, Issue 1, pp 85–109 | Cite as

Pioglitazone

A Review of its Use in Type 2 Diabetes Mellitus
  • John Waugh
  • Gillian M. Keating
  • Greg L. Plosker
  • Stephanie Easthope
  • Dean M. Robinson
Adis Drug Evaluation

Summary

Abstract

Pioglitazone is an antihyperglycaemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake

Pioglitazone is generally well tolerated, weight gain and oedema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin or a sulfonylurea, induced both long- and short-term improvements in glycaemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.

Pharmacological Properties

Pioglitazone activates a specific nuclear receptor, the peroxisome-proliferator activated receptor-γ, which increases insulin sensitivity in liver, fat and skeletal muscle cells, increases peripheral and splanchnic glucose uptake and decreases hepatic glucose output. Pioglitazone is dependent on the presence of insulin in order to exert its beneficial effects and may help preserve β-cells of the islets of Langerhans, but does not act as an insulin secretagogue.

Pioglitazone promotes lipid storage and redistribution from visceral to subcutaneous deposits, resulting in an increase in whole body adiposity, while promoting the differentiation of adipocytes. It also appears to have protective effects against atherosclerosis and antihypertensive actions.

Following oral administration of pioglitazone in patients with type 2 diabetes, peak plasma concentrations of pioglitazone are achieved in 2–2.5 hours. Plasma concentrations are dose dependent and steady state is achieved after 4–7 days’ treatment. Bioavailability is 83% and there is no accumulation of pioglitazone or its metabolites after repeated administration. Pioglitazone is metabolised in the liver predominantly via the cytochrome P450 enzyme system. About 15–30% of a dose is renally excreted, mainly as metabolites and their conjugates, with the remainder eliminated in faeces.

Therapeutic Efficacy

In well designed, randomised, controlled monotherapy trials of up to 2 years’ duration in patients with type 2 diabetes, glycaemic control improved with pioglitazone 15, 30 or 45 mg/day versus baseline and placebo. Improvements in glycaemic control in pioglitazone recipients were similar to those of metformin, insulin and rosiglitazone recipients, and greater than those in recipients of acar-bose or the sulfonylureas gliclazide, glimepiride or glibenclamide.

Additive effects on glycaemic profiles occurred when pioglitazone was used in combination with metformin, repaglinide, insulin or the sulfonylureas gliclazide, glipizide, glimepiride or glibenclamide (glyburide).

In patients with type 2 diabetes, lipid control was also improved with pioglitazone versus baseline and placebo in monotherapy trials and in trials in combination with metformin, insulin and sulfonylureas. Furthermore pioglitazone produced greater reductions in serum triglycerides and greater increases in high-density lipoprotein-cholesterol than metformin, sulfonylureas or rosiglitazone.

Pioglitazone also reduced a cardiovascular risk parameter (carotid intima-media thickness), inflammatory biomarkers of arteriosclerosis (high sensitivity C-reactive protein, matrix metalloproteinase and monocyte chemoattractant protein levels) and a secondary composite measure of the risk of macrovascular events (all-cause mortality, nonfatal myocardial infarct, stroke), but not the primary composite endpoint (all-cause mortality, nonfatal myocardial infarct [MI] including silent MI, stroke, major leg amputation, acute coronary syndrome, cardiac intervention or leg revascularisation).

Tolerability

Pioglitazone was generally well tolerated in patients with type 2 diabetes in clinical trials of up to 2.5 years’ duration when used as monotherapy and in combination with other drugs including metformin, a sulfonylurea, repaglinide or insulin. The most commonly reported treatment-emergent adverse events were weight gain, oedema, arthralgia, headache and decreases in haemoglobin and haematocrit levels.

Hepatocellular dysfunction and of hepatic enzyme elevations of three or more times the upper limit of normal have rarely been reported, and very rarely have involved hepatic failure with and without fatal outcome, although a causal link has not been established. Overall, small reductions in mean liver enzyme levels with pioglitazone treatment have been observed.

Keywords

Metformin Rosiglitazone Pioglitazone Glycaemic Control Sulfonylurea 

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Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • John Waugh
    • 1
  • Gillian M. Keating
    • 1
  • Greg L. Plosker
    • 1
  • Stephanie Easthope
    • 1
  • Dean M. Robinson
    • 1
  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

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