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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.
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.
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).
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.
KeywordsMetformin Rosiglitazone Pioglitazone Glycaemic Control Sulfonylurea
- 1.International Diabetes Federation. Diabetes e-atlas [online]. Available from URL: http://www.eatlas.idf.org [Accessed 2005 Sep 20]
- 3.Buse JB. Overview of current therapeutic options in type 2 diabetes: rationale for combining oral agents with insulin therapy. Diabetes Care 1999 Apr; 22 Suppl. 3: 65–70Google Scholar
- 7.European Medicines Agency. Actos: summary of product characteristics [online]. Available from URL: http://www.emea.eu.int/humandocs/Humans/EPAR/actos/actos.htm [Accessed 2005 Dec 19]
- 8.Takeda Pharmaceuticals America Inc. Actos (pioglitazone hydrochloride) tablets prescribing information [online]. Available from URL: http://www.actos.com/ [Accessed 2005 Dec 19]
- 14.Diani AR, Sawada G, Wyse B, et al. Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes. Am J Physiol Endocrinol Metab 2004 Jan; 286(1): El 16–122Google Scholar
- 20.Hamdy O, Soodini G, Martens J, et al. Pioglitazone preserves pancreatic β-cells in patients with type 2 diabetes and impaired glucose tolerance [abstract no. 592-P]. American Diabetes Association’s 65th Annual Scientific Sessions; 2005 June 10–14; San Diego (CA) [online]. Available from URL: http://scientificsessions.diabetes.org [Accessed 2005 Dec 19]
- 21.Buchanan TS, Xiang AH, Kjos SL, et al. Diabetes rates and β-cell function in the Pioglitazone in prevention of Diabetes (PIPOD) study [abstract no. 157-OR]. American Diabetes Association’s 65th Annual Scientific Sessions; 2005 June 10–14; San Diego (CA) [online]. Available from URL: http://scientificsessions.diabetes.org [Accessed 2005 Dec 19]
- 35.Flemmer M, Scott J. Mechanism of action of thiazolidinediones. Curr Opin Invest Drugs 2001; 2(11): 1564–7Google Scholar
- 37.Göke B. on behalf of the German Pioglitazone Study Group. Improved glycemic control and lipid profile in a randomized study of pioglitazone compared with acarbose in patients with type 2 diabetes mellitus. Treat Endocrinol 2002; 1(5): 329–36Google Scholar
- 43.Aronoff S, Rosenblatt S, Braithwaite S, et al. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000 Nov; 23(11): 1605–11CrossRefGoogle Scholar
- 44.Herz M, Johns D, Reviriego J, et al. A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Clin Ther 2003 Apr; 25(4): 1074–95PubMedCrossRefGoogle Scholar
- 45.Kaneko T, Baba S, Toyota T, et al. Clinical evaluation of an insulin-resistance improver, AD-4833, in NIDDM patients treated with diet alone: a placebo-controlled, double-blind, comparative study [in Japanese]. Rinsho Kenkyo 1997 Jun; 74(5): 1491–509Google Scholar
- 48.Lübben G, Fennenkötter U, Weidenhammer J, et al. The COM-PACT-study®: pioglitazone vs insulin for treatment of patients with type 2 diabetes mellitus-a medical and pharmacoeconomic analysis [abstract no. PDB9 plus poster]. 6th Annual International Society for Pharmacoeconomics and Outcomes Research European Congress; 2003 Nov 9–11; BarcelonaGoogle Scholar
- 51.Goldberg RB, Kendall DM, Deeg MA, et al. for the GLAI study investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005 Jul; 28(7): 1547–54Google Scholar
- 55.Tan MH, Johns D, Strand J, et al. Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with type 2 diabetes. Diabet Med 2004 Aug; 21(8): 859–66Google Scholar
- 56.Mattoo V, Eckland D, Widel M, et al. Metabolic effects of pioglitazone in combination with insulin in patients with type 2 diabetes mellitus whose disease is not adequately controlled with insulin therapy: results of a six-month, randomized, double-blind, prospective, multicenter, parallel-group study. Clin Ther 2005 May; 27(5): 554–67PubMedCrossRefGoogle Scholar
- 58.Einhorn D, Rendell M, Rosenzweig J, et al. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 2000 Dec; 22(12): 1395–409Google Scholar
- 61.Derosa G, Cicero AFG, Gaddi A, et al. Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month multicenter, double-blind, randomized, controlled, parallel-group trial. Clin Ther 2004 May; 26(5): 744–54PubMedCrossRefGoogle Scholar
- 64.Rosenblatt S, Cichy S, Sanes-Miller C, et al. Long-term pioglitazone/insulin combination therapy improves glycemic control in type 2 diabetes [abstract no. 896]. Diabetologia 2001; 44 Suppl. 1: 233Google Scholar
- 68.Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macro Vascular Events): a randomised controlled trial. Lancet 2005 Oct 8; 366(9493): 1279–89PubMedCrossRefGoogle Scholar
- 69.Erdmann E on behalf of the PROactive investigators. The effect of pioglitazone on recurrent myocardial infaction in 2445 patients with type 2 diabetes & previous myocardial infarction: results from the PROactive study. Slide presentation to the American Heart Association; 2005 Nov 16 [online]. Available from URL: http://www.proactive-results.com/ppt [Accessed 2005 December 19]
- 74.FXConverter-164 Currency Converter [online]. Available from URL: http://www.oanda.com/convert/classic [Accessed 2005 Dec 19]
- 75.Actos®: congestive heart failure. Lincolnshire (IL): Takeda Pharmaceuticals North America Inc., 2005. (Data on file)Google Scholar
- 89.Luna B, Feinglos MN. Oral agents in the management of type 2 diabetes mellitus [online]. Available from URL: http://www.aaf-p.org/afp/20010501/1747.html [Accessed 2002 Mar 20]
- 92.UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 1995 Nov; 44: 1249–58Google Scholar
- 94.National Institute for Clinical Excellence. Management of type 2 diabetes: management of blood glucose [online]. Available from URL: http://www.nelh.nhs.uk/ [Accessed 2004 Jun 15]
- 96.Takeda Pharmaceuticals North America Inc. ACTOplus met™ (pioglitazone HCl and metformin HCl) approved by the FDA for type 2 diabetes [online]. Available from URL: http://www.tpna.com [Accessed 2005 Dec 19]
- 98.MedWatch: the FDA safety information and adverse event reporting program. Thiazolidinediones [Actos (pioglitazone, HCL), Avandia [rosiglitazone maleate]) [online]. Available from URL: http://www.fda.gov/medwatch/SAFETY/2002/summary-actos-avandia.PDF [Accessed 2005 Nov 22]