Pioglitazone: A Review of its Use in Type 2 Diabetes Mellitus

Drugs 2006; 66 (1): 85-109ADIS DRUG EVALUATION 0012-6667/06/0001-0085/$44.95/0

2006 Adis Data Information BV. All rights reserved.

PioglitazoneA Review of its Use in Type 2 Diabetes Mellitus

John Waugh, Gillian M. Keating, Greg L. Plosker, Stephanie Easthope andDean M. Robinson

Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:R. Balkrishnan, University of Texas School of Public Health, Houston, Texas, USA; J.D. Best, Department ofMedicine, University of Melbourne, Melbourne, Australia; I.W. Campbell, Victoria Hospital, Kirkcaldy,Scotland; D. Chishom, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, Australia; M.Hanefeld, Centre for Clinical Studies, Technical University Dresden, Dresden, Germany; J.M. Lawrence,Department of Diabetes and Endocrinology, Southampton General Hospital, Southampton, UK; C. Otto,Medical Department 2, Grosshadern, University of Munich, Munich, Germany; C.A. Reasner, Texas DiabetesInstitute, University of Texas Health and Science Center, San Antonio, Texas, USA; B. Yeap, Department ofEndocrinology and Diabetes, Fremantle Hospital, University of Western Australia, Fremantle, Australia.

Data SelectionSources: Medical literature published in any language since 1980 on pioglitazone, identified using MEDLINE and EMBASE, supplementedby AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of publishedarticles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.Search strategy: MEDLINE, EMBASE and Adisbase search terms were ’pioglitazone’ or ’AD-4833’. Searches last updated 13 December2005.Selection: Studies in patients with type 2 diabetes mellitus who received pioglitazone. Inclusion of studies was based mainly on themethods section of the trials. When available, large, well controlled, peer reviewed clinical trials with appropriate statistical methodologywere preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.Index terms: Pioglitazone, type 2 diabetes mellitus, thiazolidinedione, pharmacodynamics, pharmacokinetics, therapeutic use,pharmacoeconomics, tolerability.

ContentsSummary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882.2 Metabolic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

2.2.1 Insulin Resistance and Glucose Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882.2.2 Diabetic Dyslipidaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892.2.3 Adipocyte Differentiation and Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

2.3 Cardiovascular Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913.3 Special Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914.1 Glycaemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

4.1.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924.1.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

4.2 Lipid Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

86 Waugh et al.

4.2.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964.2.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

4.3 Cardiovascular Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995. Pharmacoeconomic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

6.1 General Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016.2 Weight Gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026.3 Oedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026.4 Congestive Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026.5 Hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038. Place of Pioglitazone in the Management of Type 2 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . 103

SummaryPioglitazone is an antihyperglycaemic agent that, in the presence of insulinAbstractresistance, increases hepatic and peripheral insulin sensitivity, thereby inhibitinghepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake.

Pioglitazone is generally well tolerated, weight gain and oedema are the mostcommon emergent adverse events, and there are no known drug interactionsbetween pioglitazone and other drugs. In clinical trials in patients with type 2diabetes mellitus, pioglitazone as monotherapy, or in combination withmetformin, repaglinide, insulin or a sulfonylurea, induced both long- andshort-term improvements in glycaemic control and serum lipid profiles. Piog-litazone was also effective in reducing some measures of cardiovascular risk andarteriosclerosis. Pioglitazone thus offers an effective treatment option for themanagement of patients with type 2 diabetes.Pioglitazone activates a specific nuclear receptor, the peroxisome-proliferatorPharmacologicalactivated receptor-γ, which increases insulin sensitivity in liver, fat and skeletalPropertiesmuscle cells, increases peripheral and splanchnic glucose uptake and decreaseshepatic glucose output. Pioglitazone is dependent on the presence of insulin inorder to exert its beneficial effects and may help preserve β-cells of the islets ofLangerhans, but does not act as an insulin secretagogue.

Pioglitazone promotes lipid storage and redistribution from visceral to subcu-taneous deposits, resulting in an increase in whole body adiposity, while promot-ing the differentiation of adipocytes. It also appears to have protective effectsagainst 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. Plasmaconcentrations are dose dependent and steady state is achieved after 4–7 days’treatment. Bioavailability is 83% and there is no accumulation of pioglitazone orits metabolites after repeated administration. Pioglitazone is metabolised in theliver predominantly via the cytochrome P450 enzyme system. About 15–30% of adose is renally excreted, mainly as metabolites and their conjugates, with theremainder eliminated in faeces.In well designed, randomised, controlled monotherapy trials of up to 2 years’Therapeutic Efficacyduration in patients with type 2 diabetes, glycaemic control improved withpioglitazone 15, 30 or 45 mg/day versus baseline and placebo. Improvements inglycaemic 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.

2006 Adis Data Information BV. All rights reserved. Drugs 2006; 66 (1)

Pioglitazone in Type 2 Diabetes Mellitus: A Review 87

Additive effects on glycaemic profiles occurred when pioglitazone was used incombination 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 piog-litazone versus baseline and placebo in monotherapy trials and in trials incombination with metformin, insulin and sulfonylureas. Furthermore pioglitazoneproduced greater reductions in serum triglycerides and greater increases inhigh-density lipoprotein-cholesterol than metformin, sulfonylureas or rosig-litazone.

Pioglitazone also reduced a cardiovascular risk parameter (carotidintima-media thickness), inflammatory biomarkers of arteriosclerosis (high sensi-tivity C-reactive protein, matrix metalloproteinase and monocyte chemoattractantprotein levels) and a secondary composite measure of the risk of macrovascularevents (all-cause mortality, nonfatal myocardial infarct, stroke), but not theprimary 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 inTolerabilityclinical trials of up to 2.5 years’ duration when used as monotherapy and incombination with other drugs including metformin, a sulfonylurea, repaglinide orinsulin. The most commonly reported treatment-emergent adverse events wereweight gain, oedema, arthralgia, headache and decreases in haemoglobin andhaematocrit levels.

Hepatocellular dysfunction and of hepatic enzyme elevations of three or moretimes the upper limit of normal have rarely been reported, and very rarely haveinvolved hepatic failure with and without fatal outcome, although a causal link hasnot been established. Overall, small reductions in mean liver enzyme levels withpioglitazone treatment have been observed.

1. Introduction tions) account for a substantial proportion of manynational health budgets.[1]

Diabetes mellitus is a progressive, debilitating Insulin resistance is associated with hypergly-disease that is among the five leading causes of caemia, diabetic dyslipidaemia, abnormal coagula-death in most developed countries.[1] In 2003, it was tion and hypertension,[2] and typical treatment in-estimated that 194 million people worldwide had cludes sequential and combined use of lifestylediabetes, and type 2 diabetes, characterised by insu- changes and pharmacological therapies. Diet andlin deficiency and resistance, accounts for ≈85–95% exercise reduce weight and increase insulin sensitiv-of all cases of diabetes in developed countries and ity, while pharmacotherapeutic interventions can en-nearly all diabetes cases in developing countries.[1] hance insulin secretion by β-cells of the islets of

Langerhans (e.g. sulfonylureas, repaglinide), in-This growing pandemic is brought about by ag-crease insulin sensitivity (e.g. metformin,ing populations with a genetic predisposition to typethiazolidinediones), impede the uptake of carbohy-2 diabetes, as well as by changes in lifestyle, includ-drates from the digestive tract (acarbose), or supplying low physical activity, obesity and a high caloricexogenous insulin.[3-5]intake.[1] The disease and its complications (corona-

ry artery and peripheral vascular disease, stroke, Pioglitazone (Actos)1 [figure 1] is an insulinneuropathy, retinopathy, nephropathy and amputa- sensitising thiazolidinedione that activates a specific

1 The use of trade names is for product identification purposes only and does not imply endorsement.


88 Waugh et al.

signalling factors, especially adiponectin, to modu-late the insulin sensitivity of nonadipose tissue.[2]

Pioglitazone is dependent on the presence of insulinin order to exert its beneficial effects, and while itmay also aid in the preservation of the function of β-

N O N

S

O

O

H

Fig. 1. Structure of pioglitazonecells of the islets of Langerhans[13-15] it is not aninsulin secretagogue.[8]

nuclear receptor (peroxisome-proliferator activated Pioglitazone and its active metabolites, the hy-receptor-γ [PPAR-γ])[6] found in adipose tissue, pan- droxy derivatives MII and MIV and the keto deriva-creatic β-cells, vascular endothelium and macro- tive MIII, improve dysfunctional glucose homeosta-phages.[2] The focus of this review is its approved sis by decreasing insulin resistance in the liver anduse in the EU and the US in the treatment of type 2 peripheral tissues, thus increasing insulin-dependentdiabetes in patients whose condition is inadequately glucose disposal and decreasing hepatic glucosecontrolled by diet and exercise.[7,8]

output.[8] In animal models, MII, MIII and MIVexert an antihyperglycaemic effect ≈40–60% of that2. Pharmacodynamic Propertiesof pioglitazone.[16] In addition, the triglyceride(TG)-lowering potency of MII is 2-fold greater than

2.1 Mechanism of Action that of the parent compound, while MIII and MIVhave a slightly lesser TG-lowering effect than piog-Thiazolidinediones, including pioglitazone, arelitazone.high-affinity ligands for PPARγ, a member of the

nuclear receptor superfamily of ligand-activated2.2 Metabolic Effectstranscription factors.[6,9] Once activated by a ligand,

PPARγ forms a heterodimer with another nuclear2.2.1 Insulin Resistance and Glucose Levelsreceptor, the retinoid-X receptor. This heterodimerPioglitazone reduces hyperglycaemia and hyper-then binds to specific DNA sequences and regulates

insulinaemia in patients with type 2 diabetes. Piog-the transcriptional activity of target genes that play alitazone increased peripheral insulin sensitivity, en-role in the metabolism of glucose and lipids.[6,10,11]

hancing both splanchnic and peripheral glucose up-Different PPARγ agonists, including troglitazone,take, in patients with type 2 diabetes in randomised,rosiglitazone and pioglitazone, appear to have dif-placebo-controlled, 12- to 26-week trials.[17-19]ferent effects on the regulation of >100 PPARγ-

The beneficial glycaemic effects of pioglitazoneresponsive genes,[2] possibly due to different con-on glucose uptake and metabolism were demonstrat-formational changes in the receptor[12] and the abili-ed in euglycaemic-hyperinsulinaemic clampingty of different ligands to interact with coactivatorstudies.[17,18] For example, in a 12-week trial,[17] theproteins.[2] An additional mechanism, transrepres-mean glucose infusion rate (a measure of peripheralsion, may regulate the anti-inflammatory actions ofglucose uptake) significantly increased from base-PPARs by interfering with the actions of other tran-line in 21 patients receiving pioglitazone 30 mg/dayscription factors, such as the nuclear factor (NF)-κB(1.0 mg/kg • min; p = 0.003), but not in nine placebopathway.[2]

recipients (0.4 mg/kg • min).[17] Furthermore, whenThe activation of PPARγ by pioglitazone leads toeuglycaemic-hyperinsulinaemic clamping was com-increased peripheral, hepatic and adipocyte insulinbined with oral glucose loading, splanchnic glucosesensitivity;[2] however, the exact mechanism has notuptake increased from baseline by a significantlybeen fully elucidated. Thiazolidinediones promotegreater margin in pioglitazone recipients than inthe differentiation and proliferation of adipocytesplacebo recipients (+30.9% vs –0.9%; p < 0.05 vsand the uptake and storage of free fatty acids (FFA),placebo and baseline).which may protect other insulin-sensitive tissues,

and possibly pancreatic β-cells,[13] from the harmful An in vitro study in human β-cells indicates thatmetabolic effects of high FFA levels.[2] Other mech- the inhibition of the NF-κB pathway by pioglitazoneanisms may involve altered release of adipocyte may prevent β-cell apoptosis,[15] while in vivo data



from murine models of type 2 diabetes suggest tin levels were negatively correlated with hepatic fatpreservation of pancreatic islet structure and insulin content.[23]

levels with pioglitazone.[14]

2.2.3 Adipocyte Differentiation and WeightIn humans, improvements in β-cell function were Accumulation of excessive visceral adipose tis-

suggested by results of a 26-week trial in 58 patients sue is a common feature of insulin resistance.[25]

with type 2 diabetes.[18] Changes in the plasma insu- Thiazolidinediones, including pioglitazone, pro-lin area under the concentration time curve from 0 to mote lipid storage and redistribution from visceral to2 hours (AUC2) were significantly greater after an subcutaneous deposits, resulting in an increase inoral glucose tolerance test in pioglitazone 30 or 45 whole body adiposity.[25] Increases in weightmg/day recipients than in placebo recipients (+5144 (0.3–3.6kg) have been reported in patients with typeand +10 239 versus –6041 pmol/L; p < 0.05), but not 2 diabetes receiving pioglitazone monotherapy (sec-in pioglitazone 7.5 or 15 mg/day recipients. In addition 6.2); such increases appear to be due to in-tion, in a 12-week trial in 30 patients with type 2 creased subcutaneous fat accompanied by decreasesdiabetes,[19] improvements from baseline in β-cell in visceral fat.[26]

function (homeostasis model assessment [HOMA]- In vitro[10,27] and in vivo[28,29] studies indicate thatB) and insulin sensitivity (HOMA-S) were signifi- PPARγ plays an important role in adipocyte differ-cantly greater with pioglitazone 30 mg/day entiation and lipid storage. Forced expression ofmonotherapy than with placebo (11.5% vs –1.9% PPARγ in cultured fibroblasts or myoblasts resultedand 24.7% vs 2.1%; both p < 0.05). in their differentiation into mature white adipo-

Preliminary reports of two trials in 38[20] and cytes.[27] In insulin-resistant rats treated with86[21] patients with type 2 diabetes,[20] impaired glu- thiazolidinediones, an increase in the number ofcose tolerance[20] or prior gestational diabetes,[21] small adipocytes and a reduction in the number ofindicate that pioglitazone may reduce β-cell stress large adipocytes in white adipose tissue indicate thatand prevent deterioration of β-cell function. PPARγ is a regulator of adipocyte differentia-

tion.[28,29]These improvements in β-cell function may re-sult directly from activation of PPARγ present in β-

2.3 Cardiovascular Effectscells, and/or indirectly through decreases in lipotox-icity and reductions in β-cell stress associated with

Type 2 diabetes is a risk factor for the develop-reduced insulin resistance.[13]

ment of atherosclerotic conditions such as coronaryheart disease and coronary restenosis after stenting

2.2.2 Diabetic Dyslipidaemia or angioplasty.[30] Despite the fact that PPARγ is A risk factor for cardiovascular disease com- involved in the conversion of macrophages embed-

monly observed in diabetic patients is diabetic dys- ded in the intima of arterial walls to cholesterol-lipidaemia, characterised by increased TG levels, laden foam cells, a critical step in the progression ofdecreased high-density lipoprotein-cholesterol atherosclerosis,[31] data from clinical studies suggest(HDL-C) levels and small, dense low-density lipo- that thiazolidinediones, may protect patients withprotein-cholesterol (LDL-C) particles.[22] In several type 2 diabetes from atherosclerosis, as reflected bysmall (n ≤ 23) trials in patients with type 2 diabe- a decrease in carotid medial intima thickness.[32]

tes,[22-24] pioglitazone 30–45 mg/day for 16 weeks In addition, neointimal tissue proliferation afterreduced TG levels by 22–31%. In one trial,[22] sig- coronary stent implantation was significantly less innificant (p ≤ 0.01) reductions in very low-density patients with type 2 diabetes receiving pioglitazonelipoprotein TG levels (≈30%) and increases in HDL- 30 mg/day than in control patients,[33] while neoin-C levels (14%) were also observed. timal tissue volume and the incidence of restenosis

were less in nondiabetic pioglitazone recipients thanIn addition, increases in plasma adiponectinin placebo recipients.[34]levels (9[24] and 14 µg/mL[23]) and decreases in FFA

levels (163[23] and 168 µmol/L[24]) and hepatic fat The exact mechanism(s) of the protective effectscontent (10%) were observed, and plasma adiponec- of thiazolidinediones against atherosclerosis are un-


90 Waugh et al.

clear; however, it has been suggested that PPARγ is 3.1 Absorption and Distributioninvolved in the expression of ATP binding cassetteA1, an energy-dependent transporter protein in- Overall, the pharmacokinetics of pioglitazone involved in the removal of oxidised LDL-C from patients with type 2 diabetes are similar to those inmacrophages.[9] PPARγ also increases serum levels healthy volunteers.[16] Orally administered piog-of larger LDL-C particles and HDL-C, and lowers litazone is rapidly absorbed (table I) and is firstTG levels. measurable in serum within 30 minutes.[8,16] Serum

Other protective mechanisms include reductions concentrations of both the parent drug and metabo-in endothelial stickiness, reduced Ca2+ uptake by lites (section 3.2) are dose dependent, with steadyvascular smooth muscle (causing vasodilation), re- state usually reached after 4–7 days’ treatment.[8,16]

ductions in intimal thickness of blood vessels by Two pharmacologically active metabolites (MIIIreducing smooth muscle cell migration and in-

and MIV) reach serum concentrations greater thancreases in collateral blood flow.[35] The antiather-or equal to that of pioglitazone (section 3.2).[8]

ogenic effects of pioglitazone appear to be indepen-Absorption is slightly delayed by food intake,dent of its antidiabetic actions, as high sensitivity C-

peak serum concentrations were reached after 3–4reactive protein levels, a marker of inflammation,hours with food compared with ≈2 hours withoutand pulse-wave velocity, a measure of arterial dis-food.[16] However, the area under the serum-concen-tensibility, are reduced by pioglitazone treatmenttration time curve (indicating systemic exposure) isirrespective of changes in glucose regulatory param-similar between fed and fasted states and piog-eters.[30]

litazone can, therefore, be taken with or withoutPioglitazone also has antihypertensive effects inpatients with type 2 diabetes, reducing mean systolic meals.[16] Pioglitazone is highly protein-bound withblood pressure (SBP) from a baseline of 140[36] or a resulting low volume of distribution (table I). The145mm Hg[37] by ≈6mm Hg and diastolic blood volumes of distribution of the metabolites have notpressure (DBP) by 3[37] or 4mm Hg[36] from a base- been measured; however, these are also likely to beline of 85[37] or 87mm Hg.[36] In 234 patients receiv-ing pioglitazone 30–45 mg/day for 20 weeks, over-all changes in mean SBP and DBP were not signifi-cant (–1 to 3 and –2mm Hg), but in 83 patients whowere hypertensive at entry (SBP >140mm Hg orDBP >90mm Hg) changes in SBP and DBP weresubstantial (–10 and –8mm Hg; p < 0.001).[38]

In two small studies in patients with type 2 diabe-tes and microalbuminuria, an early sign of damageto the renal and cardiovascular systems, piog-litazone (n = 15[39] or 19[40]) for 3 months reducedurinary albumin excretion rate by 70%, urinary en-dothelin excretion by 60%[39] and urinary albumin tocreatinine excretion ratio by ≈50% (data estimatedfrom a graph).[40]

3. Pharmacokinetic Properties

Data on the pharmacokinetics of pioglitazonehave been obtained from a review of studies inhealthy volunteers or patients with type 2 diabe-tes,[16] the manufacturer’s prescribing information[8]

and a study of drug interactions.[41]

Table I. Summary of pharmacokinetic parameters of oral piog-litazone (PIO). Data from a review of pharmacokinetics in healthyvolunteers or in patients (pts) with type 2 diabetes mellitus,[16] themanufacturer’s prescribing information[8] and data from a study ofdrug interactions[41]

Mean values in pts with type 2 diabetes receiving a singledose of PIO 15 or 30mg[16]

Cmax (µg/L) 327, 715

tmax (h) 2.1, 2.5

AUC24 (µg • h/L) 3425, 7652

CL/F (L/h) 4.93, 4.64

Other parameters

Bioavailability (%)[16] 83

Vd/F (L/kg)[8] 0.63 (single dose)

Active metabolites[8] Hydroxy (MII, MIV) keto (MIII)

Plasma protein binding (%)[8] >99 (PIO); >98 (MIII, MIV)

t1/2β (h) [5mg IV][8] 3–7 (PIO); 16–24 (PIO + MI-VI)

Elimination[8] Mostly in faeces, 15–30% renal

Drug interactions[8,41] None knownAUC24 = area under the concentration-time curve from 0–24h; CL/F = apparent clearance rate; Cmax = maximum plasmaconcentration; IV = intravenous administration; tmax = time to Cmax;t1/2β = mean terminal elimination half-life; Vd/F = apparentdistribution volume.


https://www.researchgate.net/publication/11594964_Mechanism_of_action_of_thiazolidinediones?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=


low, as the metabolites are also highly protein- elderly[16] or adolescent[42] patients, and therefore nobound.[8,16] age-related dosage adjustment is necessary.

3.4 Drug Interactions3.2 Metabolism and Elimination

Pioglitazone has a favourable drug interaction Pioglitazone is metabolised in the liver by oxida- profile. In healthy volunteers, no significant changes

tion and hydroxylation of aliphatic methylene have been reported in the pharmacokinetics of piog-groups, predominantly via cytochrome P450 (CYP) litazone or coadministered drugs, including atorvas-isoenzymes, the most important being CYP2C8/9 tatin, digoxin, ethinylestradiol, fexofenadine, glipi-and CYP3A4.[16] Five primary metabolites are zide, ketoconazole, metformin, midazolam, nifedip-formed (MI, MII, MIV, MV and MVI); MIV is ine, norethisterone, ranitidine, simvastatin,further metabolised to MIII and MV is metabolised theophylline and warfarin.[8,41]

to MVI.Following oral administration, about 15–30% of 4. Therapeutic Efficacy

the pioglitazone dose is recovered in the urine asmetabolites.[8] Renal elimination of unchanged piog- The efficacy of pioglitazone in the treatment oflitazone is negligible. It is presumed that the remain- type 2 diabetes has been investigated in trials of upder is excreted in bile either unchanged or as metab- to 2.5 years’ duration. Trials evaluated the efficacyolites, and eliminated in the faeces.[8,16] The mean of pioglitazone monotherapy[36,37,43-55] or combina-terminal elimination half-life (t1/2β) of pioglitazone is tion therapy[56-63] compared with placebo or an3–7 hours; however, its active metabolites have a active comparator. Results from long-term com-much longer t1/2β (table I)[16] and are likely to con- parative monotherapy[49,53,55] and combinationtribute to the pharmacological activity that allows therapy[59,61,62] trials and nonblind extensions[64]

for once-daily administration of pioglitazone.[16] of shorter trials[57,58] were reported after1[49,53,55,58,59,61,62,64] or more[65,66] years. Charbonnelet al.[65] present 2-year results of two trials, and data3.3 Special Patient Groupsfrom one study was obtained from a poster.[48] Addi-tional data are available from a meta-analysis,[67]In healthy volunteers (mean creatinine clearanceand from PROactive (PROspective pioglitAzone[CLCR] 100 mL/min; n = 6) and patients with mod-Clinical Trial In macroVascular Events), a trial as-erate (CLCR 46 mL/min; n = 9) or severe (meansessing the effect of pioglitazone on the secondaryCLCR 14 mL/min; n = 12) renal impairment, Cmaxprevention of macrovascular events in patients withand AUC values of pioglitazone, MIII and MIVtype 2 diabetes receiving pioglitazone in addition towere reduced in patients with renal insufficiency.[16]

other glucose-lowering drugs and other medicationsHowever, t1/2β values did not differ between groupsfor >2.5 years.[68,69]and dosage adjustments are not considered necessa-

Clinical trials used various measures to examinery in these patients.[16]

the efficacy of pioglitazone in three main areas:The Cmax of pioglitazone and its metabolites in• glycaemic control (HbA1c, fasting plasma glu-12 male patients with chronic liver insufficiency

cose [FPG], fasting plasma insulin [FPI] or fast-(Child-Pugh class B or C) was ≈57% of that in 12ing serum insulin [FSI], C-peptide levels,healthy male volunteers after oral administration ofHOMA-S and HOMA-B, section 4.1)a single 30mg dose, but the AUC and total clearance

were similar between groups.[16] However, use of • lipid control (TG, LDL-C, HDL-C, total choles-pioglitazone is not recommended in patients with terol [TC], section 4.2)active liver disease or with a serum transaminase • cardiovascular risk (carotid intima-media thick-level >2.5-fold the upper limit of normal (ULN) ness, macrovascular events) or inflammatory bi-[section 7].[8] omarkers of arteriosclerosis [high sensitivity C-

No clinically significant differences in the reactive protein, matrix metalloproteinase, mon-pharmacokinetics of pioglitazone have been seen in ocyte chemoattractant protein], section 4.3).


92 Waugh et al.

Table II. Effects of oral pioglitazone (PIO) monotherapy on glycaemic control in adults with type 2 diabetes mellitus. Mean change frombaseline in glycaemic parameters in patients (pts) with type 2 diabetes in randomised, double-blind, placebo (PL)-controlled, multicentretrials[43-47]

Study Duration Treatment No. of ptsa HbA1c FPG FPI[45,46] /FSI[44]

(wk) (mg/day) (%) (mmol/L) (pmol/L)

baseline change baseline change baseline change

Aronoff et al.[43] 26 PIO 7.5 80 10.0 +0.2 14.6 –1.0*†

PIO 15 79 10.2 –0.3*† 14.8 –1.6*†

PIO 30 85 10.2 –0.3*† 15.0 –1.8*†

PIO 45 77 10.3 –0.9*† 15.3 –3.1*†

PL 79 10.4 +0.7* 14.9 +0.5

Herz et al.[44] 16 PIO 30 99 7.5 –0.8***††† 8.9 –1.4***††† 117 –31***††

PIO 45 99 7.6 –0.9***††† 8.6 –1.6***††† 107 –32***††

PL 99 7.5 –0.2* 8.8 –0.1 99 –13**

Kaneko et al.[45] 12 PIO 30 68 9.3 –1.0**††b 10.3 –1.6**††b 81 –16

PL 66 9.2 0.0b 10.0 +0.3b 73 –6

Rosenblatt et al.[46] 16 PIO 30 101 10.7 –0.6*††† 15.5 –2.8*† 91 –12*†

PL 96 10.4 +0.76* 15.2 +0.4 90 +11

Scherbaum & Goke[47] 26 PIO 15 89 9.3 –0.9*b 13.0 –1.9*††

PIO 30 78 9.1 –1.1*††b 12.3 –2.0*†††

PL 84 8.8 –0.3*b 11.5 –0.1

a No. for whom data were reported.

b Primary endpoint where clearly specified.

FPG = fasting plasma glucose; FPI = fasting plasma insulin; FSI = fasting serum insulin; HbA1c = glycosylated haemoglobin; * p ≤ 0.05, **p ≤ 0.01, *** p ≤ 0.001 vs baseline; † p ≤ 0.05, †† p ≤ 0.01, ††† p ≤ 0.001 vs PL.

Inclusion criteria generally included HbA1c following a washout period of between 1 and 10weeks,[36,37,43-47,50,51,55,57,58,60,62,63] during which otherlevels of ≥6.5 to <12%;[36,37,43-49,51,53-55,57-63,65,68] inmedications were stopped or stabilised. One studysome studies minimum and/or maximum body massincluded a pioglitazone 7.5 mg/day group;[43] how-index (BMI) [≥25,[36,37,44,46,47,58,63] <40,[36] <43[37] orever, as there was no significant reduction in HbA1c<45 kg/m2[60]], minimum FPG levels (≥7.8 mmol/levels from baseline at this dosage (table II) and it isL)[37,43,45,47] and/or minimum C-peptide levelsnot recommended in current prescribing informa-(>0.33,[43,46,55,58,63] ≥0.5[59,62,65] or ≥1 nmol/L[63])tion,[7,8] this dosage is not discussed further.were also specified. The mean age of patients en-

rolled was 55–63 years.[36,37,43-55,57-63,68] In combina-4.1 Glycaemic Controltion-therapy trials, patients were required to have

been treated with an antihyperglycaemic agent for atPioglitazone had generally beneficial effects onleast 30 days (metformin[58] or a sulfonylurea[63]), 3

glycaemic control parameters both as monotherapymonths (metformin[59,60] or a sulfonylurea[60,62]) or 4(section 4.1.1) and when combined with other anti-months (troglitazone[50] or insulin[57]) prior to enrol-hyperglycaemic agents (section 4.1.2).ment.

4.1.1 MonotherapyWhere described, patients were excluded for va-rious reasons, including unstable or rapidly progres- Versus Placebosive diabetic retinopathy, neuropathy or nephropa- Pioglitazone was generally more effective thanthy, unstable cardiovascular conditions, impaired placebo in improving glycaemic control (table II). Inhepatic or renal function, anaemia or a history of five large (n > 100) randomised, double-blind, pla-ketoacidosis.[36,37,43-47,51,53-55,57-59,61-63,65,68]

cebo-controlled, multicentre trials of 12–26 weeks’In the majority of trials,[36,37,43-55,57-63,65,68] piog- duration[43-47] in previously treated[43,45-47]

litazone 15, 30 or 45mg was administered once daily and[43,45,46]/or[44] treatment-naive patients with type 2



diabetes, pioglitazone 15, 30 or 45 mg/day reduced bose[37] or metformin,[36] and greater improvementsHbA1c levels from baseline to a significantly greater in C-peptide levels than with acarbose.[37]

extent than placebo, with the exception of the 15 Long-term treatment with pioglitazone providedmg/day dosage arm in one study.[47]

greater glycaemic control than the sulfonylureaSimilarly, reductions from baseline in FPG levels gliclazide in patients completing 2 years of treat-

were significantly greater in pioglitazone than pla- ment.[66] Greater reductions in HbA1c levels werecebo recipients at all dosages (table II).[43-47] Fur- observed in gliclazide recipients for the first 32thermore, in two[44,46] of three[44-46] trials, FPI/FSI weeks of treatment; however, by week 52, this situa-levels declined to a significantly greater extent in tion had reversed and, thereafter, pioglitazone recip-pioglitazone than in placebo recipients (table II). ients had significantly lower HbA1c levels than

Reductions in fasting serum C-peptide levels, an gliclazide recipients (difference –0.45; p < 0.0001 atindicator of insulin production, were similar after week 104).treatment with pioglitazone or placebo in two tri- Greater reductions in FPG levels were also ob-als,[43,47] but underwent significantly (p ≤ 0.05 vs served in pioglitazone than in gliclazide recipientsplacebo) greater changes in pioglitazone than place- after 104 weeks (difference –0.83 mmol/L).[66] Insu-bo recipients in a third trial[46] (–0.076 vs +0.023 lin sensitivity, measured by HOMA-S, increasednmol/L), as did HOMA-S values (+30% vs during this period in pioglitazone recipients but de-–12%).[46]

creased in gliclazide recipients (difference 36.2% atweek 104; p < 0.0001 vs gliclazide at each timepoint

Versus Active Comparators from week 4 to week 104).[66] By contrast, HOMA-B score improved more in gliclazide than piog-Pioglitazone monotherapy provided glycaemiclitazone recipients throughout the same period (dif-control as good as, or superior to, that of activeference 9.1% at week 104; p < 0.05 vs pioglitazonecomparators (table III) including acarbose,[37] insu-at each timepoint from week 4 to week 104), al-lin,[48] metformin,[36,49] rosiglitazone,[50-52,67] and thethough the difference between treatments decreasedsulfonylureas gliclazide,[53,66] glimepiride[54] andover time.[66]glibenclamide (glyburide).[55]

Reductions in HbA1c levels with pioglitazone4.1.2 Combination Therapytreatment were no different to those induced by

rosiglitazone,[50-52] insulin[48] or glimepiride;[54] The efficacy of glycaemic control with piog-noninferior to those induced by metformin[36,49] and litazone in combination with insulin,[57]

gliclazide;[53] and superior to those induced by acar- metformin,[58,59,65] repaglinide[60] or a sulfony-bose[37] and glibenclamide[55] in 16- to 52-week tri- lurea[61-63] was generally similar or superior to thatals (table III). of other drug combinations (table IV).

Similarly, reductions in mean FPG levels did not The addition of pioglitazone to insulin therapydiffer between pioglitazone, rosiglitazone[51] and in- significantly improved glycaemic control in patientssulin[48] recipients, but were significantly greater with type 2 diabetes in placebo-controlled 16-with pioglitazone than with acarbose,[37] sulfony- week[57] and 6-month trials[56] (table IV) and in alurea[53-55] and, in one[36] of two trials, met- nonblind 72-week extension involving 150 pa-formin.[36,49]

tients[64] of the 16-week trial.[57] In the 16-weekFurthermore, while reductions in FPI/FSI levels trial,[57] patients receiving pioglitazone or placebo in

were similar in pioglitazone and rosiglitazone recip- addition to a stable insulin regimen had significantients, pioglitazone-induced reductions (table III) reductions in HbA1c levels from baseline, but signif-were greater than those with acarbose,[37] icantly greater reductions occurred in pioglitazonemetformin[36,49] or sulfonylureas.[53,54,66] than placebo recipients (table IV). Furthermore, re-

ductions from baseline in FPG levels occurred inAdditional reflections of improved glycaemicboth pioglitazone treatment groups, but not in thecontrol with pioglitazone were the greater increasesplacebo group.[57]in insulin sensitivity (HOMA-S) than with acar-


94 Waugh et al.

Table III. Effects of pioglitazone (PIO) monotherapy on glycaemic control in adults with type 2 diabetes mellitus. Mean change from baselinein glycaemic parameters in patients (pts) with type 2 diabetes receiving PIO or an active comparator in randomised[36,37,49-55] or non-randomised,[48] double-blind[36,49,51,53] or nonblind,[37,48,50,52,54,55] multicentre trials

Study Duration Treatment No. of HbA1c FPG FPI[37,49,51,53]/FSI[36,54,55]

(wk) (mg/day) ptsa (%) (mmol/L) (pmol/L)

baseline change baseline change baseline change

Vs ACA

Goke[37] 26 PIO 45 129 9.0 –1.2††† NR –3.1††† NR –52†††

ACA 50–300 136 9.0 –0.5 NR –1.3 NR –27

Vs INS

Lubben et al.[48]b 26 PIO 437 NR –0.7c NR –1.4

INS 290 NR –0.4c NR –0.9

Vs MET

Pavo et al.[36] 32 PIO 30–45 105 8.6 –1.3***§c 11.8 –3.0*** 101 –23***††

MET 850–2550 100 8.6 –1.5*** c 12.4 –2.8*** 118 –1

Schernthaner et al.[49] 52 PIO 30–45 588 8.7 –1.4§c 11.4 –2.5† 104 –17†††

MET 850–2550 588 8.7 –1.5c 11.3 –2.2 103 –2

Vs ROS

Gegick & Altheimer[50] ≤20 PIO 15–45d 60 7.1 –0.1

ROS 4–8 65 7.0 –0.1

Goldberg et al.[51] 24 PIO 30–45 363 7.6 –0.7 10.0 –1.8 141 –32

ROS 4–8 356 7.5 –0.6 9.8 –2.0 128 –33

Khan et al.[52] 16 PIO 15–45 67 8.0 –0.3c,e

ROS 2–8 60 7.9 –0.2c,e

Vs a sulfonylurea (GLB, GLC, GLM)

Charbonnel et al.[53] 52 PIO ≤45 624 8.7 –1.4§c 11.1 –2.4†† 104 –19†††

GLC ≤320 626 8.7 –1.4c 11.2 –2.0 103 +15

Pfutzner et al.[54] 26 PIO 45 89 7.5 –0.8 8.1 –1.1†† 122 –36†††

GLM 1–6 84 7.4 –0.6 8.0 –0.3 115 +7

Tan et al.[55] 52 PIO 30–45 109 8.4 –0.5*** 10.6 –0.7*† 87 –1††

GLB 1.75–10.5 91 8.5 –0.4** 10.7 +0.2 76 +24***


b Data from a poster.

c Primary endpoint where clearly specified.

d Some patients also received other antihyperglycaemic drugs.

e Estimated from a graph.

ACA = acarbose; FPG = fasting plasma glucose; FPI = fasting plasma insulin; FSI = fasting serum insulin; GLB = glibenclamide (glyburide);GLC = gliclazide; GLM = glimepiride; HbA1c = glycosylated haemoglobin; INS = insulin; MET = metformin; NR = not reported; ROS =rosiglitazone; * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 vs baseline; † p ≤ 0.05, †† p ≤ 0.01, ††† p ≤ 0.001 vs comparator; § noninferior (upper limitof the 90% Cl <0.2%[49,53] or the 95% CI <0.6%[36]) vs comparator.

In the 6-month trial in patients with inadequately FPG levels throughout the extension period in pa-controlled type 2 diabetes, greater reductions in tients who had initially received pioglitazone plusHbA1c and FPG levels occurred in pioglitazone plus insulin (–3.28 mmol/L; p < 0.01 vs baseline and endinsulin recipients than in placebo plus insulin recipi-

of double-blind treatment). Patients initially treatedents (table IV), despite a reduction in insulin dosewith placebo plus insulin in the double-blind study(0.16 U/mL).[56]

showed a significant improvement in HbA1c levelsThe 72-week nonblind extension,[64] showed nochange in HbA1c levels and continued decreases in (–1.17%; p ≤ 0.01 vs end of double-blind treatment),



but not FPG levels (–1.33 mmol/L) when subse- FPG –3.50 mmol/L) throughout a nonblind 56-weekquently treated with pioglitazone plus insulin.[64] extension, in which all patients received piog-

litazone plus metformin.[58]Pioglitazone added to metformin improved gly-

caemic control (table IV) in patients with type 2 In a long-term trial in patients with type 2 diabe-diabetes inadequately controlled with metformin in tes inadequately controlled with metformin, similarplacebo-controlled[58] and active comparator[59,65] reductions in HbA1c and FPG and greater reductionstrials. Significantly greater reductions in HbA1c and in FPI levels were observed after 1 year when piog-FPG levels occurred in pioglitazone plus metformin litazone, rather than gliclazide, was added to contin-than placebo plus metformin recipients in a 16-week ued metformin treatment (table IV).[59] The im-trial (table IV)[58] and the improvement was main- provement in HbA1c level was maintained over 2tained (difference from baseline HbA1c –1.36%; years of treatment, while differences from baseline

Table IV. Effects of pioglitazone (PIO)-based combination therapy on glycaemic control in adult with type 2 diabetes mellitus. Mean (unlessotherwise specified) change from baseline in glycaemic parameters in adult patients (pts) with type 2 diabetes receiving oral PIO, or placebo(PL), plus other antihyperglycaemic comparators in randomised, double-blind[56-59,61-63,65] or nonblind[60] multicentre trials

Study Duration Treatment No. HbA1c FPG FPI(wk) (mg/day) of (%) (mmol/L) (pmol/L)

ptsa baseline change baseline change baseline change

Plus INS

Mattoo et al.[56] 26 PIO 30 + INS 142 8.9 –0.7**††b 11.4 –1.5**††

PL + INS 147 8.8 –0.1b 11.3 +0.7

Rosenstock et al.[57] 16 PIO 15 + INS 191 9.8 –1.0***†††e 12.3 –1.9***†††e

PIO 30 + INS 188 9.8 –1.3***†††e 12.7 –2.7***†††e

PL + INS 187 9.8 –0.3**e 12.2 0.0

Plus MET

Einhorn et al.[58] 16 PIO 30 + MET 161 9.9 –0.7*†c 14.0 –2.3*†c

PL+ MET 149 9.8 +0.20*c 14.4 –0.3c

Matthews et al.[59] & 52 PIO 15–45 + MET 317 8.7 –1.0b [–0.89] 11.8 –1.9 [–1.8†††] 106 –24††† [–18†††]

Charbonnel et al.[65] [104]d GLC 80–320 + MET 313 8.5 –1.0b [–0.77] 11.3 –1.7 [–1.1] 104 –8 [+13.2 ]

Plus REP

Jovanovic et al.[60] 24 PIO 30 + REP 0.5–4.0 123 9.3 –1.8††† b 14.0 –4.6†††

REP 0.5–4.0 61 9.0 –0.2b 13.8 –1.9

PIO 30 62 9.1 +0.32b 13.7 –1.0

Plus a sulfonylurea (GLM or SU)

Derosa et al.[61] 52 PIO 15 + GLM 4 45 8.2 –1.4** 9.1 –1.7** 177 –71**

ROS 4 + GLM 4 42 8.0 –1.3** 8.8 –1.7** 173 –77**

Hanefeld et al.[62] & 52 PIO 15–45 + SU 319 8.8 –1.2b [–1.0] 11.8 –2.2 [–2.0] 92 –9 [–8]

Charbonnel et al.[65] [104]d MET 850–2550 + SU 320 8.8 –1.4b [–1.2] 12.0 –2.3 [–1.9] 89 –6 [–1]

Kipnes et al.[63] 16 PIO 15 + SU 184 10.0 –0.8*†e 13.7 –1.9*†e 128 –14e

PIO 30 + SU 189 9.9 –1.2*†e 13.3 –2.9*†e 127 –21*†e

PL + SU 187 9.9 +0.1e 13.1 +0.3e 146 +1e


b Primary endpoint where clearly specified.

c Estimated from a graph.

d Data from the same population after 2 years of treatment.[65]

e Least squares mean change from baseline.

FPG = fasting plasma glucose; FPI = fasting plasma insulin; GLC = gliclazide; GLM = glimepiride; HbA1c = glycosylated haemoglobin; INS= insulin; MET = metformin; REP = repaglinide; SU = unspecified sulfonylurea; * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 vs baseline; † p ≤ 0.05, ††

p ≤ 0.01, ††† p ≤ 0.001 vs comparator(s).


96 Waugh et al.

in other glycaemic parameters were greater in piog- beneficial effects on lipid parameters both aslitazone than gliclazide combination recipients (ta- monotherapy (section 4.2.1) and in combinationble IV). [65] with other antihyperglycaemic agents (section

4.2.2).When combined with repaglinide 0.5–4.0 mg permeal, pioglitazone 30 mg/day provided greater gly- 4.2.1 Monotherapycaemic control than monotherapy with either repag-

Versus Placebolinide or pioglitazone in a 24-week trial (table IV),Lipid profiles generally improved in pioglitazoneinducing larger reductions in HbA1c and FPG values

recipients in four placebo-controlled 12- to 26-weekin patients receiving repaglinide plus pioglitazonetrials (table V).[43-46] Significantly greater reductionsthan in patients receiving repaglinide or piog-from baseline in TG levels were observed in piog-litazone monotherapy.[60]

litazone than placebo recipients in two trials,[44,46]When combined with a stable sulfonylurea (in-

although not at a pioglitazone dosage of 30 mg/daycluding glibenclamide, glipizide, gliclazide, andin one of these trials.[44] Increases from baseline inglimepiride[62,63,65]) regimen, pioglitazone producedTC and LDL-C levels occurred at some dosages, butgreater glycaemic control (HbA1c and FPG levels)a significant difference between placebo and piog-than placebo,[63] and similar glycaemic control tolitazone recipients in LDL-C level was not ob-metformin plus a sulfonylurea in patients with typeserved.[43,44] Favourable increases in HDL-C were2 diabetes[62] for up to 2 years (table IV).[65] Ingreater in pioglitazone than placebo recipients inaddition, pioglitazone 15 or 30mg plus a sulfony-three trials (table V).[44-46]

lurea was associated with modest, but statisticallysignificant (p < 0.05), decreases (–0.07 and –0.10 Versus Active Comparatorsnmol/L) in C-peptide levels (baseline values Pioglitazone monotherapy provided generally su-0.80–0.83 nmol/L); in contrast, a small increase in perior lipid control to monotherapy with acar-C-peptide levels was shown with placebo plus bose,[37] metformin,[36,49] rosiglitazone,[50-52] and thesulfonylurea (+0.03 nmol/L; p ≤ 0.05) in the 16- sulfonylureas gliclazide[53,66] and glibenclamide (ta-week trial.[63]

ble VI).[55]

Patients with type 2 diabetes and the metabolic Pioglitazone produced greater improvements insyndrome showed similar glycaemic control when lipid parameters than acarbose, causing greater re-pioglitazone or rosiglitazone were combined with ductions in TG and increases in HDL-C valuesthe sulfonylurea glimepiride in a 12-month trial (table VI),[37] and was also superior to(table IV).[61] Glycaemic parameters, including metformin,[36,49] causing greater increases fromHbA1c, FPG, and FPI levels (table IV) and HOMA- baseline in mean HDL-C levels after 32[36] or 52S index score (–5.1 vs –5.3) all improved signifi- weeks,[49] and greater reductions in TG levels in thecantly versus baseline, but did not differ between 52-week trial (table VI).[49] However, an un-treatment groups. favourable increase in mean LDL-C levels with

In a randomised trial in patients (n = 5238) with pioglitazone treatment differed significantly fromtype 2 diabetes already receiving treatment with a the decline observed with metformin treatment (ta-variety of medications (including antihypergly- ble VI).[36,49]

caemic agents),[68] reductions from baseline HbA1c Mean LDL-C particle size was increased fromlevels in patients receiving concomitant piog- baseline (20.0 vs 20.5nm; p = 0.017) and the meanlitazone 45 mg/day for at least 2.5 years were greater particle concentration decreased (1394 vs 1341than in those receiving placebo (0.8% vs 0.3%; p ≤ nmol/L; p < 0.001) by pioglitazone treatment,0.001).[68]

whereas rosiglitazone induced a smaller increase inparticle size (0.3nm; p < 0.005 between groups) andan increase in particle concentration (120 nmol/L; p4.2 Lipid Control< 0.005 between groups).[51]

In addition to its effects on glycaemic control, Changes in TG, TC and HDL-C levels in piog-pioglitazone was found to have small but generally litazone recipients were superior to those in rosig-



Table V. Effects of oral pioglitazone (PIO) monotherapy on serum lipid profiles in adults with type 2 diabetes mellitus. Mean change frombaseline in serum lipid parameters in patients (pts) with type 2 diabetes in randomised, double-blind, placebo (PL)-controlled, multicentretrials[43-46]

Study Duration Treatment No. of TG TC HDL-C LDL-C(wk) (mg/day) ptsa (mmol/L) (mmol/L) (mmol/L) (mmol/L)

baseline change baseline change baseline change baseline change

Aronoff et al.[43] 26 PIO 7.5 80 3.60 –0.62 5.55 +0.05 1.05 +0.07* 3.18 +0.11

PIO 15 79 3.20 –0.65* 5.70 +0.16* 1.05 +0.13* 3.41 +0.16*

PIO 30 85 2.95 –0.41* 5.77 +0.12 1.06 +0.11* 3.51 +0.10

PIO 45 77 2.93 –0.46* 5.53 +0.32* 1.05 +0.18* 3.28 +0.22*

PL 79 2.97 –0.11 5.81 +0.18* 1.08 +0.07* 3.59 +0.08

Herz et al.[44] 16 PIO 30 99 1.91 –0.10 NR +4%*b 1.14 +0.18***† NR +7%*b

PIO 45 99 1.99 –0.32***†† NR 0%b 1.13 +0.23***††† NR +2%b

PL 99 1.72 +0.04b NR +2%b 1.20 +0.11*** NR +3%b

Kaneko et al.[45] 12 PIO 30 68 1.70 –0.38** 5.62 +0.16 1.29 +0.22**††

PL 66 1.61 –0.09 5.45 –0.02 1.33 +0.04

Rosenblatt et al.[46] 16 PIO 30 101 4.02 –0.59**† 5.75 +0.23b 1.03 +0.16**† 3.33 +0.17b

PL 96 3.16 +0.06 5.72 0.00b 1.02 +0.04b 3.46 +0.21b


b Estimated from a graph.

HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; NR = not reported; TC = total cholesterol; TG =triglycerides; * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 vs baseline; † p ≤ 0.05, †† p ≤ 0.01, ††† p ≤ 0.001 vs PL.

litazone recipients in three trials (table VI).[50-52] than gliclazide[53] in the 52-week trials.[53,55] Howev-er, changes in LDL-C levels favoured gliclazideMoreover, in a meta-analysis of 19 double-blindover pioglitazone.[53]trials comparing the effects of pioglitazone and

rosiglitazone on lipid profiles in a total of 5304patients, data from ten monotherapy trials indicated 4.2.2 Combination Therapyimprovements in blood lipid profile in patients treat- Lipid control with pioglitazone in combinationed with pioglitazone were greater than in those who with insulin,[57] metformin,[58,59,65] repaglinide[60] orreceived rosiglitazone.[67] A significant (p < 0.05) a sulfonylurea[61-63] was generally superior to otherdecrease in TG level versus an increase with rosig- drug combinations (table VII).litazone, smaller increases in TC and LDL-C levels The addition of pioglitazone to insulin therapyand larger increases in HDL-C levels were observed improved lipid profiles in patients with type 2 diabe-(figure 2). While these data should be interpreted tes in two placebo-controlled trials (table VII).[56,57]

with caution, as at baseline, pioglitazone recipients Lower TG levels (table VII)[57] or a significant (p <were significantly younger, more obese, and had 0.01) geometric mean TG pioglitazone : placebo ra-more pronounced hyperglycaemia and dys- tio of 0.871,[56] and higher HDL-C levels (table VII)lipidaemia than their counterparts in rosiglitazone were observed with pioglitazone plus insulin thantrials,[67] similar results were obtained in a study in with placebo plus insulin in trials of 16[57] or 26[56]

patients who were well matched at initiation.[51]weeks’ duration; however, in one trial,[57] LDL-Clevels significantly increased in patients receivingPioglitazone was significantly more effectivepioglitazone 15 mg/day, but not in those receivingthan the sulfonylureas gliclazide[53,66] and gliben-pioglitazone 30 mg/day or placebo plus insulin.clamide,[55] but no more effective than glimepi-

ride,[54] in controlling lipid parameters in patients Pioglitazone added to metformin improved thewith type 2 diabetes (table VI). Pioglitazone induced lipid profile in patients with type 2 diabetes inade-greater reductions in TG and greater increases in quately controlled with metformin (table VII).[58,59]

HDL-C levels than glibenclamide[55] and greater When combined with metformin (at pre-study dos-reductions in TC and increases in HDL-C levels ages), pioglitazone 30 mg/day reduced TG levels


98 Waugh et al.

Table VI. Effects of oral pioglitazone (PIO) monotherapy on serum lipid profiles in adults with type 2 diabetes mellitus. Mean change frombaseline in serum lipid parameters in patients (pts) with type 2 diabetes receiving PIO or an active comparator in randomised,[36,37,49-55]

double-blind[36,49,51,53] or nonblind,[37,50,52,54,55] multicentre trials

Study Duration Treatment No. TG TC HDL-C LDL-C(wk) (mg/day) of (mmol/L) (mmol/L) (mmol/L) (mmol/L)

ptsa baseline change baseline change baseline change baseline change

Vs ACA

Goke[37] 26 PIO 45 129 3.11 –0.80††† 5.91 –0.08 1.07 +0.21††† 3.55 +0.01

ACA 50–300 136 3.64 –0.43 6.20 –0.02 1.12 –0.02 3.67 –0.11

Vs MET

Pavo et al.[36] 32 PIO 30–45 105 NR –0.91*** NR 0.00† NR +0.22***† NR +0.16**††

MET 850–2550 100 NR –0.63* NR –0.37** NR +0.13*** NR –0.18*

Schernthaner et al.[49] 52 PIO 30–45 588 NR –0.61††† NR +0.25 NR +0.16††† NR +0.27†††

MET 850–2550 588 NR –0.30 NR +0.11 NR +0.08 NR –0.12

Vs ROS

Gegick & Altheimer[50] ≤20 PIO 15–45b 60 2.35 –0.27† 4.93 –0.23*† 1.21 +0.03† 2.70 –0.20†

ROS 4–8 65 2.02 +0.78* 4.66 +0.39* 1.14 –0.07 2.59 +0.21*

Goldberg et al.[51] 24 PIO 30–45 363 2.91 –0.59*†††c 5.01 +0.23*††† 1.00 +0.13*††† 2.77 +0.32*†††

ROS 4–8 356 2.66 +0.15c 5.01 +0.73* 1.03 +0.06* 2.82 +0.55*

Khan et al.[52] 16 PIO 15–45 67 2.05 –0.17c,d 5.10 –0.51**††c,d 1.16 +0.05c,d 3.01 –0.45**††c

ROS 2–8 60 2.66 +0.08c,d 4.94 +0.12c,d 1.17 +0.05c,d 2.74 –0.05c

Vs a sulfonylurea (GLB, GLC, GLM)

Charbonnel et al.[53] 52 PIO ≤45 565 2.61 –0.51 5.72e –0.78†††e 1.03 +0.22††† 3.52 +0.12†††

GLC ≤320 656 2.80 –0.44 5.67e –0.58e 1.04 +0.06 3.50 –0.17

Pfutzner et al.[54] 26 PIO 45 89 2.15 –0.25 5.88 +0.03 1.19 +0.21 3.52 –0.08

GLM 1–6 84 2.28 –0.19 5.90 –0.34 1.19 +0.03 3.54 –0.21

Tan et al.[55] 52 PIO 30–45 109 2.05 –0.36***† 5.74 +0.20* 1.18 +0.21***††† 3.62 +0.14

GLB 1.75–10.5 91 2.27 –0.03 5.61 +0.05* 1.12 +0.03 3.48 –0.03


b Some patients also received other antihyperglycaemic drugs.


d Estimated from a graph.

e TC/HDL-C.

ACA = acarbose; GLB = glibenclamide (glyburide); GLC = gliclazide; GLM = glimeprimide; HDL-C = high-density lipoprotein-cholesterol;LDL-C = low-density lipoprotein-cholesterol; NR = not reported; MET = metformin; ROS = rosiglitazone; TC = total cholesterol; TG =triglycerides; * p ≤ 0.05; ** p ≤ 0.01, *** p ≤ 0.001 vs baseline; † p ≤ 0.05, †† p ≤ 0.01, ††† p ≤ 0.001 vs comparator.

and increased HDL-C levels significantly more than baseline levels at the end of year 2, although thedifference between treatment groups remained sig-placebo in a 16-week trial.[58]

nificant (table VII).[65]In a long-term trial,[59] greater improvements in

Pioglitazone in combination with repaglinide didthe lipid profile were obtained when pioglitazonenot induce changes in lipid parameters significantly15–45 mg/day, rather than gliclazide 80–320 mg/different from those induced by monotherapy withday, was added to continued metformin treatmentrepaglinide or pioglitazone (table VII).[60]

(table VII). The 2-year results from this studyshowed sustained improvements in lipid parameters When added to a sulfonylurea, pioglitazone im-that were greater in pioglitazone than gliclazide proved the serum lipid profile (decreasing plasmarecipients.[65] Notably, increases in LDL-C levels TG and increasing HDL-C) significantly more thanduring year 1 in patients receiving the pioglitazone placebo plus a sulfonylurea (table VII),[62,63] al-plus metformin combination had almost returned to though a small rise in LDL-C levels was observed



4.3 Cardiovascular Effects

Pioglitazone was significantly (p < 0.05) moreeffective than the sulfonylurea glimepiride in reduc-ing cardiovascular risk parameters and inflammato-ry biomarkers of arteriosclerosis, such as carotidintima-media thickness and high sensitivity C-reac-tive protein, matrix metalloproteinase and monocytechemoattractant protein levels.[54] These markerswere reduced by 6–28% in a manner independent ofimprovements in glycaemic control in pioglitazonerecipients, but did not change in glimepiride recipi-ents (+2 to –4%) in a randomised, nonblind, con-trolled 6-month study (n = 173).

Similar reductions in nonlipid cardiovascular riskfactors associated with insulin resistance and type 2diabetes were observed in pioglitazone and rosig-litazone recipients in one trial, including reductionsin plasminogen activator inhibitor-1 (17% and 20%)and C reactive protein levels (29% and 38%).[51]

While pioglitazone was associated with a 10%

−0.6

−0.4

−0.2

0

0.2

0.4

0.6

0.8

Cha

nge

from

bas

elin

e (m

mol

/L)

PioglitazoneRosiglitazone

TG

*

LDL-C

**

HDL-C

*

TC

Fig. 2. Comparative effects of oral pioglitazone and rosiglitazonemonotherapy in patients with type 2 diabetes mellitus. Results froma meta-analysis of ten double-blind trials of 12–26 weeks’ durationcomparing the effects of pioglitazone 15, 30 or 45 mg/day (n = 561)with those of rosiglitazone 4 or 8 mg/day (n = 2104) on serum lipidprofiles in patients with type 2 diabetes.[67] HDL-C = high-densitylipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol;TC = total cholesterol; TG = triglycerides; * p < 0.05 vs rosig-litazone. risk reduction in the 3-year Kaplan-Meier estimate

of the primary composite endpoint of PROactiveafter 52 weeks in all treatment groups.[62] After 2 (all-cause mortality, nonfatal myocardial infarctyears of treatment, LDL-C levels in pioglitazone- [MI] including silent MI, stroke, major leg amputa-combination recipients had decreased, but the be- tion, acute coronary syndrome, cardiac interventiontween-treatment difference was still significant, or leg revascularisation), the difference between pi-while improvements in HDL-C and TG levels were oglitazone and placebo in the proportion of patientsmaintained during the second year of the trial and experiencing this endpoint (21% vs 23.5%) was notcontinued to favour the pioglitazone combination significant,[68] possibly due to the inclusion of less(table VII).[65] sensitive procedure endpoints in the primary com-

posite endpoint.[70] The proportion of patients exper-In patients with type 2 diabetes and the metaboliciencing a secondary composite endpoint (all-causesyndrome, significantly greater improvements in themortality, nonfatal MI excluding silent MI, stroke)

lipid profile were observed in pioglitazone thanwas significantly different between pioglitazone and

rosiglitazone recipients when combined with the placebo (12.3% vs 14.4%; relative risk reductionsulfonylurea glimepiride (table VII).[61]

16%; p = 0.027).[68]

In the PROactive trial in patients already receiv- In a prespecified subgroup analysis of 2445 pa-ing a variety of medications, the group randomised tients (47%) from the PROactive trial who had anto concomitant treatment with pioglitazone 45 mg/ MI ≥6 months prior to randomisation, the hazardday had greater reductions in TG levels (0.2 vs 0.0 ratio (HR) for a fatal or nonfatal MI, excluding silentmmol/L; p < 0.001) and greater increases in HDL-C MI, was 0.72 (95% confidence interval [CI] 0.52,(0.2 vs 0.1 mmol/L; p < 0.001) and LDL-C (0.2 vs 0.99; p = 0.045).[69] An exploratory post hoc analysis0.1 mmol/L; p < 0.01) levels than the group receiv- of this subgroup suggested a significant reduction in

acute coronary syndrome (38%; p = 0.035).ing placebo.[68]


100W

augh et al.

2006 A

dis D

ata

Info

rma

tion

BV. A

ll righ

ts rese

rved

.D

rug

s 2006; 66 (1)

Table VII. Effects of pioglitazone (PIO)-based combination therapy on serum lipid profile in adult with type 2 diabetes mellitus. Mean (unless otherwise specified) change frombaseline in serum lipid parameters in adult patients (pts) with type 2 diabetes receiving oral PIO, or placebo (PL), plus other antihyperglycaemic comparators in randomised,double-blind[56-59,61-63,65] or nonblind[60] trials

Study Duration Treatment No. of TG TC HDL-C LDL-C(wk) (mg/day) ptsa (mmol/L) (mmol/L) (mmol/L) (mmol/L)

baseline change baseline change baseline change baseline change

Plus INS

Mattoo et al.[56] 26 PIO 30 + INS 142 1.99 NR 5.31 NR 1.23 +0.12**†† 3.20 –0.02

PL + INS 147 1.58 NR 5.14 NR 1.24 –0.03 3.10 –0.08

Rosenstock et al.[57] 16 PIO 15 + INS 191 2.61 +0.14 5.52 +0.01 1.12 +0.08**†† 3.29 +0.17*†

PIO 30 + INS 188 2.96 –0.31† 5.37 +0.02 1.10 +0.10**†† 3.15 +0.09

PL + INS 187 2.74 +0.36* 5.54 –0.04 1.10 0.00 3.39 –0.05

Plus MET

Einhorn et al.[58] 16 PIO 30 + MET 161 3.37 –0.33* 5.51 +0.23* 1.11 +0.11*† 3.09 +0.24*

PL+ MET 149 3.39 +0.29 5.49 +0.06 1.09 +0.02 3.05 +0.36

Matthews et al.[59] & 52 PIO 15–45 + MET 317 2.90 –0.60††† [–0.74†††] 5.64 NR 1.10 +0.18††† [+0.25†††] 3.34 +0.27††† [+0.07†††]

Charbonnel et al.[65] [104]b GLC 80–320 + MET 313 2.78 –0.22 [–0.20] 5.58 NR 1.09 0.00 [+0.08] 3.28 –0.11 [–0.20]

Plus REP

Jovanovic et al.[60] 24 PIO 30 + REP 0.5–4.0 123 3.52 –0.87 5.46 –0.16 1.08 +0.12 3.18 0.00

REP 0.5–4.0 61 1.96 +0.06 5.28 –0.13 1.17 –0.02 3.21 –0.16

PIO 30 62 3.29 –1.03 5.18 +0.21 1.06 +0.16 2.74 +0.26

Plus a sulfonylurea (GLM or SU)

Derosa et al.[61] 52 PIO 15 + GLM 4 45 1.76 –0.40*†c 4.92 –0.28*†c 1.03 +0.16*†c 3.23 –0.39*†c

ROS 4 + GLM 4 42 1.83 +0.33*c 5.05 +0.75*c 1.09 +0.03c 3.13 +0.52*c

Hanefeld et al.[62] & 52 PIO 15–45 + SU 319 2.47 –0.42†† [–0.50††] 1.09 +0.16††† [+0.23†††] 3.57 +0.08††† [–0.13†††]

Charbonnel et al.[65] [104]b MET 850–2550 + SU 320 2.38 –0.28 [–0.26] 1.11 +0.09 [+0.16] 3.58 –0.16 [–0.37]

Kipnes et al.[63] 16 PIO 15 + SU 184 3.07 –0.47*†d 5.49 +0.05 1.06 +0.08*†d 3.21 +0.10*d

PIO 30 + SU 189 2.94 –0.70*†d 5.54 +0.05d 1.09 +0.10*†d 3.28 +0.08*d

PL + SU 187 2.92 +0.09*d 5.49 +0.23*d 1.11 –0.05d 3.21 +0.18*d


b Data from the same population after 2 years of treatment.[65]


d Least squares mean change from baseline.

GLC = gliclazide; GLM = glimepiride; HDL-C = high-density lipoprotein-cholesterol; INS = insulin; LDL-C = low-density lipoprotein-cholesterol; MET = metformin; NR = not reported;REP = repaglinide; SU = unspecified sulfonylurea; TC = total cholesterol; TG = triglycerides; * p ≤ 0.05, ** p ≤ 0.01 vs baseline; † p ≤ 0.05, †† p ≤ 0.01, ††† p ≤ 0.001 vs comparator.


Table VIII. Cost effectiveness of oral pioglitazone (PIO) therapy in patients with type 2 diabetes mellitus from a third-party (healthcaresystem) perspective. Average patient total direct lifetime cost, life expectancy and incremental cost effectiveness (expressed as cost per lifeyear gained [LYG]) predicted by Markov microsimulation models based on published efficacy data. Costs and benefits were undiscounted(0%)[71-73] or discounted at 3%[71,72] and/or 5%[71,73]

Study Country Regimen Direct costs Life expectancy Incremental cost per LYG (discount rate)

(year of costing) (mg/day) (y) (0%) (3%) (5%)

Coyle et al.[71] Canada (1999) PIO vs $Can50 923 11.48

MET $Can43 896 11.35 $Can28 000 $Can41 000 $Can52 000

GLB $Can42 644 11.28 $Can24 000 $Can33 000 $Can41 000

DIET + EX $Can41 616 11.14 $Can15 000 $Can22 000 $Can27 000

Henriksson[72] Sweden (1999) PIO 30 + MET vs SEK386 617 15.59

SU + MET SEK328 214 14.92 SEK86 440 SEK146 196

ROS 8 + MET SEK374 655 15.50 SEK123 313 SEK148 561

PIO 30 + SU vs SEK397 086 15.81

MET + SU SEK329 265 14.95 SEK79 038 SEK129 673

PIO 15 + SU vs SEK361 962 15.49

MET + SU SEK329 265 14.95 SEK60 705 SEK123 029

ROS 4 + SU SEK353 471 15.26 SEK36 878 SEK42 401

Nesser et al.[73] Germany (2002)a PIO 30 + SU vs €78 062 15.19

SU + MET €71 424 14.86 €20 002 €47 636

AC + MET €72 250 14.71 €5 860 €13 386

PIO 30 + MET vs €76 660 15.46

SU + MET €71 424 14.86 €8 707 €19 745

AC + SU €73 617 14.77 €4 443 €9 672

a Mid-year interbank exchange rate (2002 Jul 1) €1 = $US0.99160.[74]

$Can = Canadian dollars (mid-year interbank exchange rate [1999 Jul 1] $Can1 = $US0.68287[74]); AC = acarbose; DIET + EX = diet plusexercise; GLB = glibenclamide (glyburide); MET = metformin; ROS = rosiglitazone; SEK = Swedish kroner (mid-year interbank exchangerate [1999 Jul 1] SEK1 = $US0.11784[74]); SU = sulfonylurea.

5. Pharmacoeconomic Studies 6. Tolerability

Economic models have been used to analyse the 6.1 General Profile

incremental cost effectiveness of pioglitazone as Pioglitazone was generally well tolerated asmonotherapy[71] or as combination therapy[72,73] rela- monotherapy[36,37,43-49,52,67] or in combination with

other drugs[68] including insulin,[57] metformin,[58,65]tive to other treatment regimens in the managementrepaglinide,[60] or a sulfonylurea[61-63,65] in trials ofof type 2 diabetes from a third-party perspectiveup to 2.5 years’ duration in patients with type 2

based on direct medical costs (table VIII). These diabetes. Of the patients treated with pioglitazonemodels predict that the direct medical cost of piog- 15, 30 or 45 mg/day, 14–76% reported at least one

adverse event, as did 7–85% of placebo recipi-litazone treatment is higher than that of other treat-ents.[43,45,63] Few patients receiving pioglitazonements; however, the higher cost is partly offset bystopped treatment because of an adverse event other

increases in life expectancy and reductions in the than hypoglycaemia during clinical trials (3.3%) andincidence and costs of complications.[71-73] As a the rate was similar to that observed in placebo

recipients (2.8%).[8]result, the predicted incremental cost-effectiveness

The most common adverse events (≥5% of pa-ratios per life-year gained[72,73] are below commonlytients) reported in placebo-controlled monotherapy

recognised thresholds of acceptability (between trials were upper respiratory tract infection (13.2%$US50 000 and $US60 000).[72,73] vs 8.5% in placebo recipients), headache (9% vs


102 Waugh et al.

7%), sinusitis (6% vs 5%), myalgia (5% vs 3%), with pioglitazone reported oedema versus 1.2% oftooth disorder (5% vs 2%) and pharyngitis (5% vs patients receiving placebo.[8]

1%).[8] The incidences of these events were similar In PROactive,[68] oedema in the absence of heartin patients receiving pioglitazone in combination failure was experienced by 21% of pioglitazonewith a sulfonylurea, metformin or insulin. versus 13.0% of placebo recipients.

Hypoglycaemia occurred in significantly (p < In combination-therapy studies with sulfony-0.0001) more pioglitazone (28%) than placebo lureas, 7.2% of patients treated with pioglitazone(20%) recipients in PROactive, although there was plus a sulfonylurea reported oedema compared withno difference in the number of patients requiring 2.1% of patients receiving a sulfonylurea alone.[63]

hospital admission for hypoglycaemia (19 vs 11).[68] Similar results were obtained when pioglitazoneIn studies in which patients received pioglitazone in was combined with metformin; oedema was report-combination with another hypoglycaemic agent, hy- ed in 5.9% of pioglitazone plus metformin recipientspoglycaemia occurred with an incidence of <1% to compared with 2.5% of patients receiving15% versus <1% to 11% with comparators, and was metformin alone.[58] When combined with insulin,most commonly experienced in patients receiving oedema was reported in 15.3% of pioglitazone re-concomitant insulin.[57-60,62,63,65] cipients compared with 7.0% of patients treated with

A small dose-related reduction in haemoglobin insulin alone.[57]

(2–4%) and haematocrit levels with pioglitazonetherapy is thought to be a result of haemodilution.[8]

6.4 Congestive Heart Failure

6.2 Weight Gain One concern with thiazolidinediones is that fluidretention may lead to or exacerbate heart failure.[8]

Weight gain is expected in patients treated withIn PROactive,[68] diagnosed heart failure as an ad-thiazolidinediones (section 2.2.3); however, thisverse event occurred in significantly more piog-does not appear to be associated with a reduction inlitazone (11%) than placebo (8%; p < 0.0001) recipi-glycaemic control.[61] Increases in average weightents, however the prevalence of fatal heart failureappeared to be dose-related among patients treatedwas the same in both treatment groups (1%).with pioglitazone 15, 30 or 45 mg/day and ranged

In a 24-week dose controlled study in whichfrom 0.3 to 3.6kg in monotherapy trials and from 0.9pioglitazone was coadministered with insulin, 1 ofto 5.5kg in combination with other antidiabetic345 patients receiving pioglitazone 30 mg/day and 3agents.[8,43-45,47,49,57,59,60,64,65,68] By contrast, patientsof 345 receiving 45 mg/day reported congestivereceiving placebo alone or in combination with oth-heart failure as a serious adverse event.[8]

er drugs had a reduction in mean weight of 0–1.9kg.In a 24-week, post-marketing, safety study inIn the head-to-head trial of pioglitazone and

uncontrolled diabetic patients with New York Heartrosiglitazone in combination with glimepiride, re-Association (NYHA) Class II and III heart failurecipients of both regimens experienced significantand ejection fraction less than 40% receiving piog-increases from baseline in BMI at 12 months (piog-litazone (n = 262 ) or glyburide (n = 256), overnightlitazone plus glimepiride 4.7% and rosiglitazonehospitalization for congestive heart failure was re-plus glimepiride 5.8%; both p < 0.05 vs baseline).[61]

ported in 26 (10%) pioglitazone and 12 (5%) glybu-ride recipients with a treatment difference observed6.3 Oedemafrom 6 weeks.[8]

Central and peripheral oedemas were observed in In another study,[57] 2 of 191 patients treated withpatients treated with pioglitazone either as pioglitazone 15mg plus insulin and 2 of 188 patientsmonotherapy[36,43-45,48,49,59,60,64,65] or in combination treated with pioglitazone 30 mg/day plus insulinwith other drugs[68] including metformin,[58] a developed congestive heart failure compared withsulfonylurea,[62,63,65] repaglinide[60] or insulin.[57] In a none of the 187 patients treated with placebo pluspooled descriptive analysis of monotherapy trials in insulin; however, all four patients had a history ofthe prescribing information, 4.8% of patients treated cardiovascular conditions.[57]



In addition, in other double-blind clinical trials, In Europe, pioglitazone is approved for oralone case of congestive heart failure was reported in a monotherapy in patients with type 2 diabetes, partic-patient receiving pioglitazone plus metformin and ularly overweight patients, whose condition is inad-two in patients receiving placebo plus sulfony- equately controlled by diet and exercise and forlurea.[75] whom metformin is inappropriate because of contra-

indications or intolerance.[7] It is also approved for6.5 Hepatotoxicity oral combination treatment of type 2 diabetes in

patients with insufficient glycaemic control despiteUnlike troglitazone, pioglitazone has rarely been the maximum tolerated dose of metformin, or in

associated with drug-induced hepatotoxicity and el- combination with a sulfonylurea in patients whoevated ALT levels. A total of 14 of 4780 (0.30%) show intolerance to metformin or for whompatients who received pioglitazone in clinical trials metformin is contraindicated.[7]

in the US had ALT levels ≥3-fold ULN.[8] TherePioglitazone is taken orally once daily with orhave been reports of patients who have experienced

without food at a dosage of 15 or 30 mg/day, withhepatoinjury while being treated with piog-titration to 45 mg/day if necessary during monother-litazone,[76-81] including a recent death;[79] however,apy.[7,8] During combination therapy, the dosage of adirect causality has not been established.sulfonylurea may be maintained, but should be de-In PROactive, no cases of acute liver toxicitycreased if hypoglycaemia is reported, while the dos-were noted and a small decline in median ALTage of metformin is unlikely to need adjustment.levels in pioglitazone recipients (–5%) and rise inThe current insulin dosage can be continued afterplacebo recipients (+8%) was reported.[68] Increasesstarting pioglitazone therapy, but dosage should bein ALT levels >3-fold ULN occurred in 20 piog-reduced by 10–25% if hypoglycaemia is reported orlitazone and 33 placebo recipients.if FPG levels decrease to <5.6 mmol/L.[7,8]

In a combined descriptive analysis[82] of dataPioglitazone is contraindicated in patients withfrom four randomised, double-blind, 1-year tri-

cardiac failure (NYHA class I–IV[7] or III–IV[8]) orals[49,53,59,62] comparing pioglitazone (n = 1857) withhepatic impairment (serum ALT level >2.5-foldmetformin (n = 917) or gliclazide (n = 939), reduc-ULN); liver enzymes should be tested prior to treat-tions of 3–18% in mean hepatic enzyme levels werement and periodically thereafter.[7,8]

reported with pioglitazone compared with small in-Local prescribing information should be con-creases of 3–13% with gliclazide and changes of

sulted for dosage reduction guidelines in patients–12% to +2% with metformin. In addition, moreexperiencing toxicity, dosage recommendations inpioglitazone recipients had hepatic enzyme levels inspecial populations, contraindications and precau-the normal ranges at trial end (≥87%) thantions.metformin (≥80%) or gliclazide (≥75%) recipi-

ents.[82]

In addition, data from two small trials 8. Place of Pioglitazone in the(n = 18–20) suggest that pioglitazone may provide Management of Type 2protection against hepatic injury in patients with Diabetes Mellitusnon-alcoholic steatohepatitis, reducing hepatic fatand improving liver histology.[83]

The UKPDS (United Kingdom Prospective Dia-betes Study) found that intensive blood glucose con-7. Dosage and Administrationtrol, involving early pharmacotherapeutic interven-

Pioglitazone monotherapy is approved in the US tion, reduces or delays the onset of diabetes-relatedas an adjunct to diet and exercise to improve gly- complications when compared with diet, exercisecaemic control in patients with type 2 diabetes, and and pharmacological intervention at higher bloodin combination with a sulfonylurea, metformin or glucose thresholds.[84] Improvements in glycaemicinsulin when diet and exercise plus monotherapy is control were associated with sustained reductions ininsufficient.[8] the rate of nephropathy, retinopathy and neuropathy


https://www.researchgate.net/publication/8389960_Drug_Points_Fatal_liver_failure_associated_with_pioglitazone?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=


https://www.researchgate.net/publication/7719233_Changes_in_liver_tests_during_1-year_treatment_of_patients_with_Type_2_diabetes_with_pioglitazone_metformin_or_gliclazide?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=


https://www.researchgate.net/publication/298970464_Mixed_hepatocellular-cholestatic_liver_injury_after_pioglitazone_therapy?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=

104 Waugh et al.

and in the long-term microvascular complications of efficacy than gliclazide (section 4.1.1). In general,type 2 diabetes.[84-86] treatment-naive patients showed greater reductions

in glycaemic parameters than patients who had pre-Thus, treatment for type 2 diabetes should aim toviously received oral antihyperglycaemics.achieve stable normoglycaemia as early as possible.

Pioglitazone has a complimentary mode of ac-Conventional therapeutic strategies (diet and exer-tion to metformin, the sulfonylureas, repaglinidecise) increase insulin sensitivity and reduce cardio-and insulin, maintaining or improving glycaemicvascular risk factors; however, compliance withcontrol and increasing insulin sensitivity when ad-these regimens is frequently poor.[87] Furthermore,ded to monotherapy with these agents (sectiontype 2 diabetes is a progressive disease (4–5% re-4.1.2). Simplifying the use of the pioglitazone/duction in pancreatic β-cell function per year[84,88])metformin combination is the recent US FDA ap-and eventually most patients will require glucose-proval of a single tablet combining these twolowering drugs.agents.[96]Six classes of antihyperglycaemic agent are

Pioglitazone also produced greater glycaemicavailable for the treatment of type 2 diabetes; bigua-control than placebo when combined with anides, sulfonylureas, meglitinides, α-glucosidase in-sulfonylurea, and similar glycaemic control tohibitors, insulins and thiazolidinediones.[89,90] Themetformin plus a sulfonylurea in patients with typediffering, often complementary, modes of action of2 diabetes. Moreover, the complementary mecha-these drug classes offer a range of treatment optionsnisms of pioglitazone and sulfonylureas mean thatto suit the changing needs of patients.[89-91] Thesulfonylurea dosage may be reduced in this combi-progressive nature of the disease means that treat-nation because of increased insulin sensitivity.ment must be regularly adjusted to compensate for

deteriorating glycaemic control. For example, When combined with insulin (approved in the USmonotherapy with sulfonylurea, although initially only), pioglitazone improved glycaemic control, al-effective, has a high primary (20–25% within the though an FDA-mandated warning relating to thefirst year) and secondary (5–10% per year thereaf- incidence of congestive heart failure with this com-ter) failure rate.[91] In the UKPDS, 30% of patients bination (section 6.3) has been added to the manu-who commenced sulfonylurea monotherapy re- facturer’s prescribing information.[8]

quired additional insulin within 6 years.[92] The lipid profile of patients receiving piog- Current US[93] and European[94] guidelines for litazone was improved when compared with those

the management of type 2 diabetes recommend life- receiving rosiglitazone, metformin, acarbose, insu-style changes (weight-loss diet and exercise) in the lin or a sulfonylurea (section 4.2.1) and when usedearly stages of the disease, followed by monother- in combination with metformin, insulin or aapy and then combination therapy as the disease sulfonylurea (section 4.2.2) generally reduced TGprogresses. However, many patients with type 2 and TC and increased HDL-C levels, although at thediabetes eventually require injected insulin, as a expense of modest increases in LDL-C values. Theresult of a decline in endogenous insulin production pioglitazone plus sulfonylurea combination alsoand increasing insulin resistance.[95] produced significantly greater improvements in se-

rum lipid profiles than other sulfonylurea combina-From the moment that pharmacological interven-tions. It should be noted that the clinical impact oftion is necessary, pioglitazone may play a role in thethe changes in lipid profile are not fully understoodtreatment of type 2 diabetes that can extend through-and thus do not substitute for the use of major lipidout the treatment of this chronic disease.controlling therapy.Pioglitazone monotherapy has demonstrated sig-

Cost-effectiveness ratios from pharmacoeconom-nificantly greater antihyperglycaemic effects thanic models are favourable when pioglitazone combi-placebo in treatment-naive and previously treatednation therapies are compared with other antihyper-patients with type 2 diabetes in well designedglycaemic drug combinations (section 5).clinical trials (section 4.1.1). It also provides similar

glycaemic control to rosiglitazone and metformin, Some evidence exists to suggest that long-termgreater efficacy than acarbose and greater long-term treatment with pioglitazone may be associated with


https://www.researchgate.net/publication/292829525_Lessons_from_the_glitazones_A_story_of_drug_development?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=


a slowing of the progression of β-cell failure.[97] For ment, in that pioglitazone induced greater reductionsexample, in a long-term comparison of pioglitazone than placebo in the secondary composite endpointwith gliclazide,[66] insulin sensitivity measured by (risk of all-cause mortality, nonfatal myocardial in-HOMA-S and the reduction in FPI levels were con- farct and stroke), although this result should besistently greater in pioglitazone recipients through- interpreted with caution, as an advantage was notout 2 years (section 4.1.1) and reductions in FPI observed in the primary composite endpoint (sectionlevels were also seen when pioglitazone was used in 4.3).combination with metformin (section 4.1.2).[59] Al- Increases in oedema (section 6.3) and congestivethough it is uncertain whether changes in FPI levels heart failure (section 6.4) have been observed inreflect improved insulin sensitivity, a lower gly- trials with pioglitazone. Because of concerns regard-caemic stimulus, or a decline in β-cell function, ing oedema with thiazolidinediones in general theHOMA-B measurement of β-cell function indicated FDA has issued precautionary warnings for their usea sustained improvement in pioglitazone recipients in patients with advanced heart failure.[98] A retro-over 2 years.[66] Initial improvements with gliclazide spective analysis of a health insurance claimswere followed by a steady decline, although database (n = 33 544) suggested that both thiazo-HOMA-B score remained higher in gliclazide than lidinedione use in general (adjusted HR 1.76 95% CIpioglitazone recipients throughout the 2-year period 1.43, 2.18; n = 5441, p < 0.001), and pioglitazone(section 4.1.1). use at recommended dosages (HR 1.81 95% CI 1.12,

While there appears to be little difference in the 2.94; n = 1150, p < 0.001) were predictive of heartglycaemic effects or the tolerability of the two avail- failure.[99] However, a retrospective analysis ofable thiazolidinediones, pioglitazone induced Medicare patients with diabetes discharged aftergreater improvements in lipid profile than rosig- hospitalisation with heart failure suggested that thelitazone in the one well designed head-to-head trial adjusted 1-year mortality was lower in patients re-to report this,[51] and in two nonblind trials (section ceiving thiazolidinediones (HR 0.87 95% CI 0.80,4.2.1).[50,52] These results were supported by a meta- 0.94; n = 2226) than in those not receiving an insulinanalysis,[67] indicating that TG and HDL-C levels sensitiser (n = 12 069).[100] There was a marginallywere significantly improved in patients treated with higher risk for hospital readmission for heart failurepioglitazone versus those who received rosig- with thiazolidinediones (HR 1.06 95% CI 1.00,litazone. While unfavourable increases in LDL-C 1.12), although this was nonsignificant in a subanal-levels were observed in pioglitazone recipients, this ysis of the period (2000–2001) after pioglitazonemay be partially compensated for by a shift to larger, and rosiglitazone became available and troglitazonemore buoyant LDL-C particles that are thought to be had been removed from the market (HR 1.06 95%less atherogenic.[67] The clinical significance of dif- CI 0. 98, 1.15). In addition, a recent retrospectiveferences between the thiazolidinediones is not yet cohort analysis[101] of 23 440 patients with type 2known and potential confounding factors identified diabetes initiating monotherapy indicated no signifi-in some studies included baseline differences[67] and cant increase in the incidence of hospitalisation forconcurrent lipid reducing medications.[52] In addi- congestive heart failure (HR 1.28; 95% CI 0.85,tion, loss of enzyme induction following conversion 1.92) in those receiving pioglitazone (n = 3356).to pioglitazone after discontinuation of troglitazone The tolerability profiles of thiazolidinedionesin patients receiving statins in one study may have differ from those of other antihyperglycaemic clas-enhanced lipid reduction, while blunting the re- ses, allowing them to be substituted where tolerancesponse to rosiglitazone.[52]

of other drugs is an issue. For example, pioglitazone,While improvements in glycaemic and lipid pa- unlike metformin, can be used as monotherapy in

rameters with pioglitazone therapy are promising, patients with impaired renal function.[7] Further-they are primarily surrogate endpoints for reduc- more, pioglitazone has a favourable drug-interactiontions in the microvascular and macrovascular com- profile, allowing concomitant administration withplications of type 2 diabetes. In this regard, the many other drugs likely to be used in patients withresults of PROactive[68] provide some encourage- type 2 diabetes (section 3.4).


https://www.researchgate.net/publication/227945580_Long-term_glycaemic_control_with_pioglitazone_in_patients_with_type_2_diabetes?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=

106 Waugh et al.

The hepatotoxic nature of troglitazone has cast a References1. International Diabetes Federation. Diabetes e-atlas [online].shadow over thiazolidinediones in general; howev-

Available from URL: http://www.eatlas.idf.org [Accesseder, to date, there have been no reports of severe 2005 Sep 20]

2. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004 Sep 9;hepatotoxicity in clinical trials with either piog-351 (11): 1106-18litazone or rosiglitazone,[102-105] and ALT levels in

3. Buse JB. Overview of current therapeutic options in type 2pioglitazone recipients were generally similar to, or diabetes: rationale for combining oral agents with insulin

therapy. Diabetes Care 1999 Apr; 22 Suppl. 3: 65-70better than, those of patients receiving placebo or4. Brown DL, Brillon D. New directions in type 2 diabetes mel-active comparators (section 6.5). Some isolated litus: an update of current oral antidiabetic therapy. J Natl Med

Assoc 1999 Jul; 91 (7): 389-95cases of reversible hepatoinjury[76-78,80,81] and one5. Campbell IW. Antidiabetic drugs present and future: will im-death[79] have been reported; however, a causal rela-

proving insulin resistance benefit cardiovascular risk in type 2tionship has not been established.[8] Current clinical diabetes mellitus? Drugs 2000 Nov; 60 (5): 1017-28

6. Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabet-evidence suggests that the more recent thiazolidine-ic thiazolidinedione is a high affinity ligand for peroxisome-diones do not share the hepatotoxic profile of trog- proliferator-activated receptor γ (PPARγ). J Biol Chem 1995;

litazone;[103] however, there is a need for long-term 270 (22): 12953-67. European Medicines Agency. Actos: summary of product char-monitoring of hepatotoxicity. As a precautionary

acteristics [online]. Available from URL: http://ww-measure, it is recommended that monitoring of liver w.emea.eu.int/humandocs/Humans/EPAR/actos/actos.htm

[Accessed 2005 Dec 19]enzymes should be carried out prior to the initiation8. Takeda Pharmaceuticals America Inc. Actos (pioglitazone hy-of treatment and periodically thereafter.[8]

drochloride) tablets prescribing information [online]. Availa-ble from URL: www.actos.com/ [Accessed 2005 Dec 19]Trials investigating the efficacy of pioglitazone

9. Willson TM, Lambert MH, Kliewer SA. Peroxisome prolifer-in paediatric patients with type 2 diabetes would be ator-activated receptor γ and metabolic disease. Annu RevBiochem 2001; 70: 341-67beneficial in determining its role in the treatment of

10. Sakamoto J, Kimura H, Moriyama S, et al. Activation of humanthis patient population. In addition, an examinationperoxisome proliferator-activated receptor (PPAR) subtypes

of the effects of prior treatment on the efficacy of the by pioglitazone. Biochem Biophys Res Commun 2000 Nov30; 278 (3): 704-11thiazolidinediones may help in determining the most

11. Lambe KG, Tugwood JD. A human peroxisome-proliferator-suitable treatment choice for each patient. activated receptor-γ is activated by inducers of adipogenesis,including thiazolidinedione drugs. Eur J Biochem 1996; 239:In conclusion, pioglitazone is generally well tol-1-7

erated, weight gain and oedema are the most com- 12. Camp HS, Li O, Wise SC, et al. Differential activation ofperoxisome proliferator-activated receptor-γ by troglitazonemon emergent adverse events, and there are noand rosiglitazone. Diabetes 2000 Apr; 49 (4): 539-47known drug interactions between pioglitazone and 13. Walter H, Lubben G. Potential role of oral thiazolidinedione

other drugs. In clinical trials in patients with type 2 therapy in preserving β-cell function in type 2 diabetes mel-litus. Drugs 2005; 65 (1): 1-13diabetes mellitus, pioglitazone as monotherapy, or

14. Diani AR, Sawada G, Wyse B, et al. Pioglitazone preservesin combination with metformin, repaglinide, insulin pancreatic islet structure and insulin secretory function in three

murine models of type 2 diabetes. Am J Physiol Endocrinolor a sulfonylurea, induced both long- and short-termMetab 2004 Jan; 286 (1): E116-122improvements in glycaemic control and serum lipid 15. Zeender E, Maedler K, Bosco D, et al. Pioglitazone and sodium

profiles. Pioglitazone was also effective in reducing salicylate protect human β-cells against apoptosis and im-paired function induced by glucose and interleukin-1β. J Clinsome measures of cardiovascular risk and arterio-Endocrinol Metab 2004 Oct; 89 (10): 5059-66

sclerosis. Pioglitazone thus offers an effective treat- 16. Eckland DA, Danhof M. Clinical pharmacokinetics of piog-litazone. Exp Clin Endocrinol Diabetes 2000; 108 Suppl. 2:ment option for the management of patients withS234-242type 2 diabetes.

17. Kawamori R, Matsuhisa M, Kinoshita J, et al. Pioglitazoneenhances splanchnic glucose uptake as well as peripheralglucose uptake in non-insulin-dependent diabetes mellitus.Diabetes Res Clin Pract 1998; 41: 35-43Disclosure

18. Miyazaki Y, Matsuda M, DeFronzo RA. Dose-response effectof pioglitazone on insulin sensitivity and insulin secretion intype 2 diabetes. Diabetes Care 2002 Mar; 25 (3): 517-23During the peer review process, the manufacturer

19. Wallace TM, Levy JC, Matthews DR. An increase in insulinof the agent under review was offered an opportuni- sensitivity and basal β-cell function in diabetic subjects treatedty to comment on this article; changes based on any with pioglitazone in a placebo-controlled randomized study.

Diabet Med 2004; 21: 568-76comments received were made on the basis of scien-20. Hamdy O, Soodini G, Martens J, et al. Pioglitazone preserves

tific and editorial merit. pancreatic β-cells in patients with type 2 diabetes and impaired



glucose tolerance [abstract no. 592-P]. American Diabetes study of pioglitazone compared with acarbose in patients withAssociation’s 65th Annual Scientific Sessions; 2005 June type 2 diabetes mellitus. Treat Endocrinol 2002; 1 (5): 329-3610-14; San Diego (CA) [online]. Available from URL: http:// 38. Gerber P, Lubben G, Heusler S, et al. Effects of pioglitazone onscientificsessions.diabetes.org [Accessed 2005 Dec 19] metabolic control and blood pressure: a randomised study in

21. Buchanan TS, Xiang AH, Kjos SL, et al. Diabetes rates and β- patients with type 2 diabetes mellitus. Curr Med Res Opincell function in the Pioglitazone in prevention of Diabetes 2003; 19 (6): 532-9(PIPOD) study [abstract no. 157-OR]. American Diabetes 39. Nakamura T, Ushiyama C, Shimada N, et al. ComparativeAssociation’s 65th Annual Scientific Sessions; 2005 June effects of pioglitazone, glibenclamide, and voglibose on urina-10-14; San Diego (CA) [online]. Available from URL: http:// ry endothelin-1 and albumin excretion in diabetes patients. Jscientificsessions.diabetes.org [Accessed 2005 Dec 19] Diabetes Complications 2000; 14 (5): 250-4

22. Nagashima K, Lopez C, Donovan D, et al. Effects of the PPARγ 40. Yanagawa T, Araki A, Sasamoto K, et al. Effect of antidiabeticagonist pioglitazone on lipoprotein metabolism in patients medications on microalbuminuria in patients with type 2 dia-with type 2 diabetes mellitus. J Clin Invest 2005 May 2; 115 betes. Metabolism 2004 Mar; 53 (3): 353-7(5): 1323-32 41. Prueksaritanont T, Vega JM, Zhao J, et al. Interactions between

23. Bajaj M, Suraamornkul S, Piper P, et al. Decreased plasma simvastatin and troglitazone or pioglitazone in healthy sub-adiponectin concentrations are closely related to hepatic fat jects. J Clin Pharmacol 2001 May; 41 (5): 573-81content and hepatic insulin resistance in pioglitazone-treated 42. Christensen ML, Meibohm B, Capparelli EV, et al. Single- andtype 2 diabetic patients. J Clin Endocrinol Metab 2004 Jan; 89 multiple-dose pharmacokinetics of pioglitazone in adolescents(1): 200-6 with type 2 diabetes. J Clin Pharmacol 2005 Oct; 45 (10):

24. Miyazaki Y, Mahankali A, Wajcberg E, et al. Effect of piog- 1137-44litazone on circulating adipocytokine levels and insulin sensi- 43. Aronoff S, Rosenblatt S, Braithwaite S, et al. Pioglitazonetivity in type 2 diabetic patients. J Clin Endocrinol Metab 2004 hydrochloride monotherapy improves glycemic control in theSep; 89 (9): 4312-9 treatment of patients with type 2 diabetes: a 6-month random-

25. de Souza CJ, Eckhardt M, Gagen K, et al. Effects of piog- ized placebo-controlled dose-response study. The Pioglitazonelitazone on adipose tissue remodeling within the setting of 001 Study Group. Diabetes Care 2000 Nov; 23 (11): 1605-11obesity and insulin resistance. Diabetes 2001 Aug; 50 (8): 44. Herz M, Johns D, Reviriego J, et al. A randomized, double-1863-71 blind, placebo-controlled, clinical trial of the effects of piog-

26. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on glycemic control and dyslipidemia in oral an-litazone on abdominal fat distribution and insulin sensitivity in tihyperglycemic medication-naive patients with type 2 diabe-type 2 diabetic patients. J Clin Endocrinol Metab 2002 Jun 1; tes mellitus. Clin Ther 2003 Apr; 25 (4): 1074-9587 (6): 2784-91 45. Kaneko T, Baba S, Toyota T, et al. Clinical evaluation of an

27. Hu E, Tontonez P, Spiegelman BM. Transdifferentiation of insulin-resistance improver, AD-4833, in NIDDM patientsmyoblasts by the adipogenic transcription factors PPARγ and treated with diet alone: a placebo-controlled, double-blind,C/EBPα. Proc Natl Acad Sci USA 1995 Oct; 92: 9856-60 comparative study [in Japanese]. Rinsho Kenkyo 1997 Jun; 74

28. Hallakou S, Doare L, Foufelle F, et al. Pioglitazone induces in (5): 1491-509vivo adipocyte differentiation in the obese Zucker fa/fa rat. 46. Rosenblatt S, Miskin B, Glazer NB, et al. The impact of piog-Diabetes 1997 Sep; 46: 1393-9 litazone on glycemic control and atherogenic dyslipidemia in

29. Okuno A, Tamemoto H, Tobe K, et al. Troglitazone increases patients with type 2 diabetes mellitus. Coron Artery Dis 2001the number of small adipocytes without the change of white Aug; 12 (5): 413-23adipose tissue mass in obese Zucker rats. J Clin Invest 1998 47. Scherbaum WA, Goke B. and the German Pioglitazone StudyMar; 101 (6): 1354-61 Group. Metabolic efficacy and safety of once-daily piog-

30. Satoh N, Ogawa Y, Usui T, et al. Antiatherogenic effect of litazone monotherapy in patients with type 2 diabetes: a doub-pioglitazone in type 2 diabetic patients irrespective of the le-blind, placebo-controlled study. Horm Metab Res 2002 Oct;responsiveness to its antidiabetic effect. Diabetes Care 2003 34 (10): 589-95Sep; 26 (9): 2493-9 48. Lubben G, Fennenkotter U, Weidenhammer J, et al. The COM-

31. Tontonoz P, Nagy L, Alvarez JGA, et al. PPARγ promotes PACT-study: pioglitazone vs insulin for treatment of patientsmonocyte/macrophage differentiation and uptake of oxidised with type 2 diabetes mellitus- a medical and pharmacoeconom-LDL. Cell 1998 Apr; 93: 241-52 ic analysis [abstract no. PDB9 plus poster]. 6th Annual Inter-

national Society for Pharmacoeconomics and Outcomes Re-32. Koshiyama H, Shimono D, Kuwamura N, et al. Rapid commu-search European Congress; 2003 Nov 9-11; Barcelonanication: inhibitory effect of pioglitazone on carotid arterial

wall thickness in type 2 diabetes. J Clin Endocrinol Metab 49. Schernthaner G, Matthews DR, Charbonnel B, et al. Efficacy2001 Jul; 86 (7): 3452-6 and safety of pioglitazone versus metformin in patients with

type 2 diabetes mellitus: a double-blind, randomized trial. J33. Takagi T, Yamamuro A, Tamita K, et al. Pioglitazone reducesClin Endocrinol Metab 2004 Dec; 89 (12): 6068-76neointimal tissue proliferation after coronary stent implanta-

tion in patients with type 2 diabetes mellitus: an intravascular 50. Gegick CG, Altheimer MD. Comparison of effects ofultrasound scanning study. Am Heart J 2003 Aug; 146 (2): E5 thiazolidinediones on cardiovascular risk factors: observations

from a clinical practice. Endocr Pract 2001; 7 (3): 162-934. Marx N, Wohrle J, Nusser T, et al. Pioglitazone reduces neoin-tima volume after coronary stent implantation: a randomized, 51. Goldberg RB, Kendall DM, Deeg MA, et al. for the GLAI studyplacebo-controlled, double-blind trial in nondiabetic patients. investigators. A comparison of lipid and glycemic effects ofCirculation 2005 Nov 1; 112 (18): 2792-8 pioglitazone and rosiglitazone in patients with type 2 diabetes

and dyslipidemia. Diabetes Care 2005 Jul; 28 (7): 1547-5435. Flemmer M, Scott J. Mechanism of action of thiazolidinediones.Curr Opin Invest Drugs 2001; 2 (11): 1564-7 52. Khan MA, St Peter JV, Xue JL. A prospective, randomized

comparison of the metabolic effects of pioglitazone or rosig-36. Pavo I, Jermendy G, Varkonyi TT, et al. Effect of pioglitazonelitazone in patients with type 2 diabetes who were previouslycompared with metformin on glycemic control and indicatorstreated with troglitazone. Diabetes Care 2002 Apr; 25 (4): 708-of insulin sensitivity in recently diagnosed patients with type 211diabetes. J Clin Endocrinol Metab 2003 Apr; 88 (4): 1637-45

37. Goke B. on behalf of the German Pioglitazone Study Group. 53. Charbonnel BH, Matthews DR, Schernthaner G, et al. A long-Improved glycemic control and lipid profile in a randomized term comparison of pioglitazone and gliclazide in patients with


https://www.researchgate.net/publication/11852526_Pioglitazone_026_Study_Group_The_impact_of_pioglitazone_on_glycemic_control_and_atherogenic_dyslipidemia_in_patients_with_type_2_diabetes_mellitus?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=










108 Waugh et al.

type 2 diabetes mellitus: a randomized, double-blind, parallel- 69. Erdmann E on behalf of the PROactive investigators. The effectgroup comparison trial. Diabet Med 2005 Apr; 22 (4): 399-405 of pioglitazone on recurrent myocardial infaction in 2445

patients with type 2 diabetes & previous myocardial infarction:54. Pfutzner A, Marx N, Lubben G, et al. Improvement of cardio-results from the PROactive study. Slide presentation to thevascular risk markers by pioglitazone is independent fromAmerican Heart Association; 2005 Nov 16 [online]. Availableglycemic control: results from the Pioneer study. J Am Collfrom URL: http://www.proactive-results.com/ppt [AccessedCardiol 2005 Jun 21; 45 (12): 1925-312005 December 19]55. Tan MH, Johns D, Strand J, et al. Sustained effects of piog-

70. Yki-Jarvinen H. The PROactive study: some answers, manylitazone vs. glibenclamide on insulin sensitivity, glycaemicquestions. Lancet 2005 Oct 8; 366 (9493): 1241-2control, and lipid profiles in patients with type 2 diabetes.

71. Coyle D, Palmer AJ, Tam R. Economic evaluation of piog-Diabet Med 2004 Aug; 21 (8): 859-66litazone hydrochloride in the management of type 2 diabetes56. Mattoo V, Eckland D, Widel M, et al. Metabolic effects ofmellitus in Canada. Pharmacoeconomics 2002; 20 Suppl. 1:pioglitazone in combination with insulin in patients with type 231-42diabetes mellitus whose disease is not adequately controlled

72. Henriksson F. Applications of economic models in healthcare:with insulin therapy: results of a six-month, randomized, doub-the introduction of pioglitazone in Sweden. Pharmacoeco-le-blind, prospective, multicenter, parallel-group study. Clinnomics 2002; 20 Suppl. 1: 43-53Ther 2005 May; 27 (5): 554-67

73. Neeser K, Lubben G, Siebert U, et al. Cost effectiveness of57. Rosenstock J, Einhorn D, Hershon K, et al. Efficacy and safetycombination therapy with pioglitazone for type 2 diabetesof pioglitazone in type 2 diabetes: a randomised, placebo-mellitus from a German statutory healthcare perspective.controlled study in patients receiving stable insulin therapy. IntPharmacoeconomics 2004; 22 (5): 321-41J Clin Pract 2002 May; 56 (4): 251-7

74. FXConverter-164 Currency Converter [online]. Available from58. Einhorn D, Rendell M, Rosenzweig J, et al. Pioglitazone hydro-URL: http://www.oanda.com/convert/classic [Accessed 2005chloride in combination with metformin in the treatment ofDec 19]type 2 diabetes mellitus: a randomized, placebo-controlled

75. Actos: congestive heart failure. Lincolnshire (IL): Takedastudy. The Pioglitazone 027 Study Group. Clin Ther 2000 Dec;Pharmaceuticals North America Inc., 2005. (Data on file)22 (12): 1395-409

76. Chase MP, Yarze JC. Pioglitazone-associated fulminant hepatic59. Matthews DR, Charbonnel BH, Hanefeld M, et al. Long-termfailure [letter]. Am J Gastroenterol 2002 Feb; 97 (2): 502-3therapy with addition of pioglitazone to metformin compared

77. Maeda K. Hepatocellular injury in a patient receiving piog-with the addition of gliclazide to metformin in patients withlitazone [letter]. Ann Intern Med 2001 Aug 21; 135 (4): 306type 2 diabetes: a randomized, comparative study. Diabetes

Metab Res Rev 2005; 21 (2): 167-74 78. May LD, Lefkowitch JH, Kram MT, et al. Mixed hepatocellu-lar-cholestatic liver injury after pioglitazone therapy. Ann In-60. Jovanovic L, Hassman DR, Gooch B, et al. Treatment of type 2tern Med 2002 Mar 19; 136 (6): 449-52diabetes with a combination regimen of repaglinide plus piog-

litazone. Diabetes Res Clin Pract 2004 Feb; 63 (2): 127-34 79. Farley-Hills E, Sivasankar R, Martin M. Fatal liver failureassociated with pioglitazone. BMJ 2004 Aug 21; 329 (7463):61. Derosa G, Cicero AFG, Gaddi A, et al. Metabolic effects of429pioglitazone and rosiglitazone in patients with diabetes and

80. Nagasaka S, Abe T, Kawakami A, et al. Pioglitazone-inducedmetabolic syndrome treated with glimepiride: a twelve-monthhepatic injury in a patient previously receiving troglitazonemulticenter, double-blind, randomized, controlled, parallel-with success. Diabet Med 2002 Apr; 19 (4): 347-8group trial. Clin Ther 2004 May; 26 (5): 744-54

81. Marcy TR, Britton ML, Blevins SM. Second-generation62. Hanefeld M, Brunetti P, Schernthaner GH, et al. One-yearthiazolidinediones and hepatotoxicity. Ann Pharmacotherglycemic control with a sulfonylurea plus pioglitazone versus a2004 Sep; 38 (9): 1419-23sulfonylurea plus metformin in patients with type 2 diabetes.

Diabetes Care 2004 Jan; 27 (1): 141-7 82. Belcher G, Schernthaner G. Changes in liver tests during 1-yeartreatment of patients with type 2 diabetes with pioglitazone,63. Kipnes MS, Krosnick A, Rendell MS, et al. Pioglitazone hydro-metformin or gliclazide. Diabet Med 2005 Aug; 22 (8): 973-9chloride in combination with sulfonylurea therapy improves

glycemic control in patients with type 2 diabetes mellitus: a 83. Reynaert H, Geerts A, Henrion J. Review article: the treatmentrandomized, placebo-controlled study. Am J Med 2001 Jul; of non-alcoholic steatohepatitis with thiazolidinediones. Ali-111 (1): 10-7 ment Pharmacol Ther 2005 Nov 15; 22 (10): 897-905

64. Rosenblatt S, Cichy S, Sanes-Miller C, et al. Long-term piog- 84. UK Prospective Diabetes Study (UKPDS) Group. Intensivelitazone/insulin combination therapy improves glycemic con- blood-glucose control with sulphonylureas or insulin com-trol in type 2 diabetes [abstract no. 896]. Diabetologia 2001; 44 pared with conventional treatment and risk of complications inSuppl. 1: 233 patients with type 2 diabetes (UKPDS 33). Lancet 1998 Sep;

352: 837-5365. Charbonnel B, Schernthaner G, Brunetti P, et al. Long-term85. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemiaefficacy and tolerability of add-on pioglitazone therapy to

with macrovascular and microvascular complications of type 2failing monotherapy compared with addition of gliclazide ordiabetes (UKPDS 35): prospective observational study. BMJmetformin in patients with type 2 diabetes. Diabetologia 20052000; 321: 405-12May 12; 48: 1093-104

86. UK Prospective Diabetes Study (UKPDS) Group. Effect of66. Tan MH, Baksi A, Krahulec B, et al. Comparison of piog-intensive blood-glucose control with metformin on complica-litazone and gliclazide in sustaining glycemic control over 2tions in overweight patients with type 2 diabetes (UKPDS 34).years in patients with type 2 diabetes. Diabetes Care 2005 Mar;Lancet 1998; 352: 854-6528 (3): 544-50

87. Gale EA. Lessons from the glitazones: a story of drug develop-67. Van Wijk JP, De Koning EJ, Martens EP, et al. Thiazolidine-ment. Lancet 2001 Jun 9; 357 (9271): 1870-5diones and blood lipids in type 2 diabetes. Arterioscler Thromb

Vasc Biol 2003 Oct 1; 23 (10): 1744-9 88. Mooradian AD, Chehade J, Thurmann J.E.. The role ofthiazolidinediones in the treatment of patients with type 268. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondarydiabetes mellitus. Treat Endocrinol 2002; 1 (1): 13-20prevention of macrovascular events in patients with type 2

diabetes in the PROactive Study (PROspective pioglitAzone 89. Luna B, Feinglos MN. Oral agents in the management of type 2Clinical Trial In macroVascular Events): a randomised con- diabetes mellitus [online]. Available from URL: www.aaf-trolled trial. Lancet 2005 Oct 8; 366 (9493): 1279-89 p.org/afp/20010501/1747.html [Accessed 2002 Mar 20]




https://www.researchgate.net/publication/7968230_The_Role_of_Thiazolidinediones_in_the_Treatment_of_Patients_with_Type_2_Diabetes_Mellitus?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=






https://www.researchgate.net/publication/292829525_Lessons_from_the_glitazones_A_story_of_drug_development?el=1_x_8&enrichId=rgreq-6d8627943783431cb62410371151e473-XXX&enrichSource=Y292ZXJQYWdlOzczNzIzNTE7QVM6MTkyMjE2OTA5NTc0MTUwQDE0MjI4Mzk0OTA2MDc=




90. Flemmer MC, Vinik AI. Evidence based therapy for type 2 from URL: http://www.fda.gov/medwatch/SAFETY/2002/diabetes: the best and worst of times. Postgrad Med 2000 May; summary-actos-avandia.PDF [Accessed 2005 Nov 22]107 (5): 27-40 99. Delea TE, Edelsberg JS, Hagiwara M, et al. Use of thiazolidine-

91. Hanefeld M, Goke B. Combining pioglitazone with a diones and risk of heart failure in people with type 2 diabetes: asulphonylurea or metformin in the management of type 2 retrospective cohort study. Diabetes Care 2003 Nov; 26 (11):diabetes. Exp Clin Endocrinol Diabetes 2000; 108 Suppl. 2: 2983-9S256-266

100. Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones,92. UK Prospective Diabetes Study Group. UK Prospective Diabe- metformin, and outcomes in older patients with diabetes and

tes Study 16. Overview of 6 years’ therapy of type II diabetes: heart failure: an observational study. Circulation 2005 Feb 8;a progressive disease. Diabetes 1995 Nov; 44: 1249-58 111 (5): 583-90

93. American Diabetes Association. Clinical practice recommenda- 101. Karter AJ, Ahmed AT, Liu J, et al. Pioglitazone initiation andtions for the treatment of type 2 diabetes. Diabetes Care 2004 subsequent hospitalization for congestive heart failure. DiabetJan; 27 Suppl. 1: S1-150 Med 2005 Aug; 22 (8): 986-93

94. National Institute for Clinical Excellence. Management of type 102. Lebovitz HE. Differentiating members of the thiazolidinedione2 diabetes: management of blood glucose [online]. Available class: a focus on safety. Diabetes Metab Res Rev 2002 Mar; 18from URL: http://www.nelh.nhs.uk/ [Accessed 2004 Jun 15]

Suppl. 2: S23-2995. Gray A, Raikou M, Mcguire A, et al. Cost effectiveness of an 103. Scheen AJ. Thiazolidinediones and liver toxicity. Diabetes

intensive blood glucose control policy in patients with type 2 Metab 2001 Jun; 27 (3): 305-13diabetes: economic analysis alongside randomised controlled

104. Hanefeld M, Belcher G. Safety profile of pioglitazone. Int J Clintrial (UKPDS 41). BMJ 2000 May; 320: 1373-8Pract Suppl 2001 Sep; 121: 27-31

96. Takeda Pharmaceuticals North America Inc. ACTOplus met105. Wagstaff AJ, Goa KL. Rosiglitazone: a review of its use in the(pioglitazone HCl and metformin HCl) approved by the FDA

management of type 2 diabetes mellitus. Drugs 2002; 62 (12):for type 2 diabetes [online]. Available from URL: http://1805-37www.tpna.com [Accessed 2005 Dec 19]

97. Campbell IW. Long-term glycaemic control with pioglitazonein patients with type 2 diabetes. Int J Clin Pract 2004 Feb; 58

Correspondence: Dean M. Robinson, Adis International(2): 192-200Limited, 41 Centorian Drive, Private Bag 65901, Mairangi

98. MedWatch: the FDA safety information and adverse eventBay, Auckland 1311, New Zealand.reporting program. Thiazolidinediones [Actos (pioglitazone,E-mail: [email protected]), Avandia [rosiglitazone maleate]) [online]. Available




Pioglitazone: A Review of its Use in Type 2 Diabetes Mellitus

Documents

Transcript of Pioglitazone: A Review of its Use in Type 2 Diabetes Mellitus