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World J Cardiol. May 26, 2011; 3(5): 144-152
Published online May 26, 2011. doi: 10.4330/wjc.v3.i5.144
PPARγ activator, rosiglitazone: Is it beneficial or harmful to the cardiovascular system?
Siripong Palee, Nipon Chattipakorn, Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
Siripong Palee, Siriporn Chattipakorn, Arintaya Phrommintikul, Nipon Chattipakorn, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
Siriporn Chattipakorn, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand
Arintaya Phrommintikul, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
Author contributions: All authors contributed equally to this review.
Supported by Grants from the Thailand Research Fund RTA 5280006 (NC), BRG (SC), MRG5280169 (AP) and the Commission of Higher Education Thailand (SP, NC)
Correspondence to: Nipon Chattipakorn, MD, PhD, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. nchattip@gmail.com
Telephone: +66-53-945329 Fax: +66-53-945368
Received: March 17, 2011
Revised: April 4, 2011
Accepted: April 11, 2011
Published online: May 26, 2011

Abstract

Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with type II diabetes. Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity. Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction, inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation, and the protection of myocardial injury during ischemic/reperfusion in different animal models. Previous clinical studies in type II diabetes patients demonstrated that rosiglitazone played an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system. Despite these benefits, inconsistent findings have been reported, and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system, including increased risk of acute myocardial infarction, heart failure and chronic heart failure. As a result, rosiglitazone has been recently withdrawn from EU countries. Nevertheless, the effect of rosiglitazone on ischemic heart disease has not yet been firmly established. Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.

Key Words: Rosiglitazone, Ischemic reperfusion injury, Heart disease, Type II diabetic, Thiazolidinediones



INTRODUCTION

Type II diabetes mellitus (T2DM) is a disease whose incidence is dramatically increasing and requires continuing medical management in many countries[1,2]. T2DM is characterized by insulin resistance and impaired glucose tolerance[3]. The development of T2DM involves 3 metabolic defects that include insulin resistance, alterations in hepatic glucose production and β-cell deficiency[4]. The earliest defect seen in the development of T2DM is insulin resistance[4]. In this state, the β-cells produce large amounts of insulin reaching a supraphysiologic level as a compensatory response to peripheral tissue insulin resistance. If insulin resistance is left untreated, the β-cells begin to fail to produce insulin, resulting in a state of relative insulin deficiency[4]. T2DM is known to develop after this phase. T2DM patients have a 2- to 4-fold increased risk of developing coronary artery disease, unstable angina and myocardial infarction (MI)[5,6]. Furthermore, T2DM patients have been shown to have a worse prognosis than non-diabetic patients after a cardiovascular event[7,8].

Thiazolidinediones (TZDs) are an oral medication developed to reduce insulin resistance in T2DM patients and have been used since 1997[9]. TZDs exert their properties by stimulating a nuclear hormone receptor, the peroxisome proliferator-activated receptor γ (PPARγ)[10]. Troglitazone was the first drug developed but was withdrawn from the market due to liver toxicity[9]. Currently, pioglitazone and rosiglitazone are the only compounds that are available for clinical use[9]. However, the effects of rosiglitazone have been controversial regarding cardiovascular effects in both animal and clinical studies[11-59]. On the positive side, rosiglitazone has been shown to exert its potent insulin sensitization by improving insulin resistance in T2DM[10,60]. Various studies demonstrated that the therapeutic effects of rosiglitazone could reach far beyond its action as an insulin sensitizer because it has other therapeutic effects on many organs especially in the cardiovascular system in both animal models and humans[11-59]. Nevertheless, in the past decade growing evidence from both basic and clinical studies indicates that rosiglitazone could be harmful to the heart[11-25]. Because of its serious undesired effects, rosiglitazone has been recently withdrawn from the EU market[61], and is under close monitoring by the US Food and Drug Administration[62,63].

In this review, we aim to summarize and discuss the overall benefits as well as the adverse effects of rosiglitazone on the heart from both pre-clinical and clinical reports. Understanding the inconsistent findings as well as the limitations found in each study using rosiglitazone should allow investigators to carefully design future studies that hopefully can clarify previous inconsistent findings, and to indicate whether rosiglitazone should be used in patients.

BENEFICIAL EFFECTS OF ROSIGLITAZONE ON THE CARDIOVASCULAR SYSTEM

Previous studies reported that rosiglitazone had beneficial effects on the cardiovascular system in in vitro, in vivo and clinical studies. These beneficial effects of rosiglitazone are summarized in Table 1. In rat models of ischemic/reperfusion (I/R) injury, pretreatment with rosiglitazone reduced the infarct size and improved ischemia/reperfusion-induced myocardial contractile dysfunction[26,46,48]. Rosiglitazone treatment also improved left ventricular (LV) systolic pressure and positive and negative maximal values of the first derivative of LV pressure (dP/dt) during I/R injury[32,46]. In addition, in both obese and normal rats rosiglitazone could decrease systolic blood pressure, improve contractile function and normalize the insulin level[31,44,45]. These findings suggested that rosiglitazone could prevent the development of hypertension associated with insulin resistance. This notion was supported by the finding that rosiglitazone treatment could enhance nitric oxide (NO)-mediated arteriolar dilation[28]. Furthermore the accumulation of neutrophils and macrophages and expression of monocyte chemoattractant factor (MCP)-1 in the ischemic heart was diminished by rosiglitazone[46]. Likewise, rosiglitazone treatment in diabetic rat and mouse models reduced the blood levels of glucose, triglycerides, and free fatty acids, and enhanced cardiac glucose oxidation in the ischemic myocardium[26,50]. Rosiglitazone treatment also reduced myocardial apoptosis and infarction size post I/R injury by restoring the balance between the pro-apoptotic and anti-apoptotic mitogen-activated protein kinase (MAPK) signaling pathway, increasing phosphatidylinositol-3-kinase-Akt phosphorylation, and inhibiting p42/44 MAPK[26,35,38,41,59].

Table 1 Reports of the beneficial effects of rosiglitazone on the cardiovascular system in pre-clinical and clinical studies.
ModelsDose of rosiglitazoneMajor findingsInterpretationRef.
Cultured neonatal rat cardiomyocytes5 μmol/L; pretreated for 30 min before stimulation with Ang II (1 μmol/L) for 48 hInhibited Ang II-induced upregulation of skeletal α-actin and ANP genes, and prevent an increase in cell surface areaRosiglitazone involved in the inhibition of cardiac hypertrophy[27]
Isolated and cultured neonatal rat ventricular myocytes1, 5, 10 μmol/L; pretreated for 48 hAccelerated Ca2+ transient decay ratesCardioprotective effects of rosiglitazone may be mediated via NF-κB[43]
Increased SERCA2 mRNA levels
Upregulation of IL-6 secretion
Enhanced TNF-α- and lipopolysaccharide-induced NF-κB-dependent transcription
Isolated and cultured adult rat ventricular myocytes10-8-10-5 mol; pretreated for 24 hDid not increase protein synthesisRosiglitazone did not directly induce cardiomyocyte hypertrophy in cardiomyocytes[30]
Did not attenuate hypertrophic response to noradrenaline, phorbol-12-myristate13-acetate and endothelin-1
Cultured neonatal rat ventricular myocytes10 μmol/L; pretreated for 24 hInhibited the endothelin-1-induced increase in protein synthesis, surface area, calcineurin enzymatic activity, and protein expressionRosiglitazone inhibited endothelin-1-induced cardiac hypertrophy via calcineurin/nuclear factor of activated T-cells pathway[29]
Inhibited the nuclear translocation of NFATc4
Enhanced the association between PPARγ and calcineurin/nuclear factor of activated T-cells
Cultured rat cardiomyoblast cell line H9c2(2-1)100 μmol/L; pretreated for 24 hIncreased expression of heme oxygenase 1Rosiglitazone had cardioprotective effects against oxidative stress[40]
Increased cell viability under oxidative stress induced by H2O2
Cultured neonatal rat cardiac fibroblasts0.1, 1, 10 μmol/L pretreated for 48 hInhibited cardiac fibroblast proliferationRosiglitazone could prevent myocardial fibrosis[37]
Increased connective tissue growth factor expression
Decreased nitric oxide production induced by advanced glycation endproducts
Cultured neonatal rat ventricular myocytes1 μmol/L; pretreated for 30 min prior to H2O2 treatmentDecrease cell apoptosisRosiglitazone protected cells from oxidative stress through upregulating Bcl-2 expression[42]
Increase Bcl-2 protein content
Cultured neonatal rat cardiac myocytes0.1, 1, 3, 10, 30 μmol/L; pretreated for 30 min before hypoxiaDecreased cytoplasmic accumulation of histone-associated DNA fragmentsRosiglitazone protected cardiac myocytes against I/R injury by facilitating Akt rephosphorylation[35]
Increased reoxygenation-induced rephosphorylation of Akt
Did not alter phosphorylation of the MAP kinases ERK1/2 and c-Jun N-terminal kinase
Fatty Zucker rats7-7.5 μmol/L per kilogram po; 9-12 wkDecreased systolic blood pressureRosiglitazone prevented the development of HT and endothelial dysfunction associated with insulin resistance[45]
Decreased fasting hyperinsulinemia
Improved mesenteric arteries contraction and relaxation
Rats with I/R injury3 mg/kg per day po; pretreated for d; 1 and 3 mg/kg iv given during I/RImproved left ventricular systolic pressure, dP/dtmax and dP/dtminRosiglitazone decreased infarct size and improved contractile dysfunction during I/R possibly via inhibition of the inflammatory response[46]
Reduced neutrophils and macrophages accumulation
Reduced the infarct size
Downregulation of CD11b/CD18
Upregulation of L-selectin on neutrophils and monocytes
Fatty Zucker rats with I/R injury (Ex vivo model)3 mg/kg po; 7 or 14 d prior to isolated perfuse heart studyNormalized the insulin resistanceRosiglitazone protected obese rat heart from I/R injury[44]
Restored GLUT4 protein levels
Improved contractile function
Prevented greater loss of ATP
I/R injury in isolated perfused normal and STZ- induced diabetic rat hearts (Ex vivo model)1 μmol/L given prior to ischemia; 10 μmol/kg per day po after STZ injection for 4 wkInhibited activating protein-1 DNA-binding activityRosiglitazone attenuated postischemic myocardial injury in isolated rat heart[34]
Inhibited of Jun NH2-terminal kinase phosphorylation
Reduced lactate levels and lactate dehydrogenase activity
Sprague-Dawley rats5 mg/kg per day po; 7 dReduced systolic blood pressureRosiglitazone prevented the development of hypertension and endothelial dysfunction[31]
Reduced vascular DNA synthesis, expression of cyclin D1 and cdk4, AT1 receptors, vascular cell adhesion molecule-1, and platelet and endothelial cell adhesion molecule, and NF-κB activity
T2DM mice3 mg/kg per day po; 7 dDid not affect serum glucose and insulinRosiglitazone enhanced nitric oxide mediation of coronary arteriolar dilations via attenuating oxidative stress in T2DM mice[28]
Increased serum 8-isoprostane and dihydroethydine-detectable superoxide production
Enhanced catalase and reduced NAD(P)H oxidase activity
Did not affect SOD activity
Hypercholesterolemic New Zealand rabbits with I/R injury3 mg/kg per day po; 5 wk prior to I/RAttenuated postischemic myocardial nitrative stressRosiglitazone attenuated arteriosclerosis and prevented I/R-induced myocardial apoptosis[38]
Restored a beneficial balance between pro- and anti-apoptotic MAPK signaling
Reduced postischemic myocardial apoptosis
Improved cardiac functional recovery
Zucker diabetic fatty rats with I/R injury3 mg/kg per day po; 8 d prior to I/RReduced blood glucose, triglycerides, and free fatty acids levelsRosiglitazone protected heart against I/R injury[26]
Enhanced cardiac glucose oxidation
Increased Akt phosphorylation (Akt-pS473) and its downstream targets (glycogen synthase kinase-3β and FKHR-pS256) (forkhead transcription factor)
Reduced apoptotic cardiomyocytes and myocardial infarct size
Sprague-Dawley rats with I/R injury3 mg/kg per day po; 7 d prior to I/RReduced infarct sizeRosiglitazone attenuated myocardial I/R injury possibly via increase expression of AT2 and inhibition of p42/44 MAPK[41]
Decreased myocardial expression of AT1 receptors
Increased AT2 mRNA and protein expression
Inhibited p42/44 MAPK
Did not alter Akt1 expression
Sprague-Dawley rats with I/R injury3 mg/kg per day po for 8 wk prior to I/RImproved left ventricular dP/dtmax and dP/dtminRosiglitazone had a beneficial effect on post-infarct ventricular remodeling, but had a neutral effect on mortality[32]
Inhibited myocardial angiotensin II and aldosterone
No significant effects on myocardial AT1 and AT2 mRNA
WT and eNOS knockout mice with I/R injury3 mg/kg ip; retreated for 45 min prior to I/RWT mice: increased the recovery of left ventricular function and coronary flow following ischemiaRosiglitazone protected the heart against I/R injury via nitric oxide by phosphorylation of eNOS[48]
eNOS knockout mice: suppressed the recovery of myocardial function following ischemia
Isolated perfused hearts from T2DM mice23 mg/kg per day po; pretreated for 5 wkNormalized plasma glucose and lipid concentrationsRosiglitazone improved cardiac efficiency and ventricular function[50]
Restored rates of cardiac glucose and fatty acid oxidation
Improved cardiac efficiency due to decrease in unloaded myocardial oxygen consumption
Improved functional recovery after low-flow ischemia
WT and APN knockdown/knockout mice with myocardial infarction20 mg/kg per day po; pretreated 72 h prior to MI and continuously treated until 7 and 14 dImproved the postischemic survival rate of WT mice at 14 d of treatmentAPN was crucial for cardioprotective effects of rosiglitazone in myocardial infarction[57]
Increased adipocyte APN expression
Elevated plasma APN levels
Reduced infarct size
Decreased apoptosis and oxidative stress
Improved cardiac function
Hypercholesterolemic rats4 mg/kg per day po; pretreated for 5 moReduced Ang II levelRosiglitazone protected the heart against cardiac hypertrophy via improved lipid profile, reduced Ang-II and increase AT2 expression[54]
Upregulated AT2
Improved lipid metabolism
Mice with I/R injury3 mg/kg per day po; pretreated for 14 d prior to I/RReduced ratio of infarct size to ischemic area (area at risk)Cardioprotective effects of rosiglitazone against I/R injury were mediated via a PI3K/Akt/GSK-3α-dependent pathway[59]
Reduced the occurrence ventricular fibrillation
Attenuated cardiac apoptosis
Increased levels of p-Akt and p-GSK-3α
T2DM patients (n = 21)4 mg/d; 6 moWeight loss (first 12 wk)Rosiglitazone amplified some of the positive benefits of lifestyle intervention[55]
Decreased waist circumference
Decreased systolic and diastolic blood pressure
Reduced HbA1c
Randomized, double-blind, placebo-controlled study in T2DM (n = 357)4 or 8 mg/d; 26 wkReduced C-reactive protein, matrix metalloproteinase-9 and white blood cell levelsRosiglitazone had beneficial effects on overall cardiovascular risk[49]
Did not alter interleukin-6 level
Randomized, double-blind in CAD patients without diabetes (n = 40, control = 44)4 mg/d for 8 wk ollowed by 8 mg/d for 4 wkReduced E-selectinRosiglitazone reduces markers of endothelial cell activation and levels of acute-phase reactants in CAD patients without DM[56]
Reduced von Willebrand
Reduced C-reactive protein & fibrinogen
Reduced homeostasis model of insulin resistance index
Elevation of LDL and triglyceride level
Randomized, double-blind, placebo-controlled study in T2DM with CAD patients (n = 54)4-8 mg/d; 16 wkImproved glycemic control and whole-body insulin sensitivityRosiglitazone facilitated myocardial glucose storage and utilization in T2DM with CAD patients[36]
Increased myocardial glucose uptake in both ischemic and non-ischemic regions
Randomized controlled trial in patients with impaired glucose tolerance (n = 2365, control = 2634)8 mg/d; 3 yrFacilitated normoglycemicRosiglitazone reduced incidence of T2DM and increased normoglycemia[47]
Did not alter cardiovascular event
Randomized, double-blind, placebo-controlled trial in patients with T2DM (n = 70, control =16)8 mg/d; 6 moDecreased plasma glucose and HbA1c with a trend to decrease HOMA indexRosiglitazone improved endothelial function and C-reactive protein in patients with T2DM[51]
Decreased C-peptide and fasting insulin
Reduced C-reactive protein
Improved endothelium-dependent dilation
Randomized, controlled trial in patient with T2DM with CAD (Rosiglitazone; n = 25)4 mg/d; 12 wkDecreased insulin resistanceRosiglitazone prevented arteriosclerosis by normalizing metabolic disorders and reducing chronic inflammation of the vascular system[58]
Decreased pulse wave velocity
Reduced plasma levels of C-reactive protein and monocyte chemoattractant protein 1
Prospective and cross-sectional study in T2DM (Rosiglitazone; n = 22, metformin/rosiglitazone; n = 100)Treated with rosiglitazone 6 moDecreased endotoxinLower endotoxin and higher adiponectin in the groups treated with rosiglitazone may be responsible for the improved insulin sensitivity[39]
Increased adiponectin levels
Comprehensive meta-analysis of randomized clinical trials (n = 42922, control = 45483)Results of 164 trials with duration > 4 wkThe OR for all-cause and cardiovascular mortality with rosiglitazone was 0.93 and 0.94, respectivelyRosiglitazone did not increase risk of MI or cardiovascular mortality[52]
The OR for nonfatal MI and heart failure with rosiglitazone was 1.14 (0.9-1.45) and 1.69 (1.21-2.36), respectively
The risk of heart failure was higher when rosiglitazone was administered as add-on therapy to insulin

In in vitro studies, incubation of a rat cardiomyoblast cell line with rosiglitazone demonstrated cardioprotective effects against oxidative stress, and the antioxidant enzyme heme oxygenase 1 was upregulated in these cells after rosiglitazone treatment[40]. Furthermore, rosiglitazone could inhibit cardiac fibroblast proliferation, increase connective tissue growth factor expression and decrease NO production induced by advanced glycation endproducts in cultured neonatal rat cardiac fibroblasts[37]. In addition, rosiglitazone could prevent cardiac hypertrophy by inhibiting angiotensin II[27,32,54].

Many clinical studies reported that the beneficial effects of rosiglitazone on the cardiovascular system were similar to those from animal studies. Rosiglitazone therapy has been shown to reduce cardiovascular complications associated with T2DM[47,49,58]. Data from preliminary studies in patients who underwent coronary angioplasty and stent implantation demonstrated that rosiglitazone treatment for 6 mo led to a lower occurrence of restenosis and a lower degree of stenosis of the luminal diameter after angioplasty[64]. Furthermore, a study in patients with T2DM demonstrated that treatment with 4 mg/d of rosiglitazone for 12 wk decreased not only insulin resistance but also pulse wave velocity, which is a direct parameter of arterial stiffness in patients with diabetes and coronary arteries disease (CAD)[58]. Rosiglitazone has been shown to reduce plasma levels of C-reactive protein[5,51,56,58], matrix metalloproteinase-9 and MCP-1[58] in T2DM patients, suggesting that rosiglitazone plays an important role in protecting against arteriosclerosis by normalizing metabolic disorders and reducing chronic inflammation of the vascular system. Rosiglitazone treatment in patients with T2DM with/without CAD has also been shown to improve myocardial glucose uptake and utilization[36,47]. Rosiglitazone decreased both systolic and diastolic pressure[53,55], suggesting that this drug could improve systolic and diastolic function. All of these findings indicate that in addition to improving insulin resistance in T2DM patients, rosiglitazone also has the beneficial effects on overall cardiovascular risk.

ADVERSE EFFECTS OF ROSIGLITAZONE ON THE CARDIOVASCULAR SYSTEM

Despite these previously mentioned beneficial effects of rosiglitazone on the cardiovascular system, growing evidence indicates other adverse cardiovascular outcomes. The effect of rosiglitazone in increasing mortality in post-MI rats was first reported by Lygate et al[21] in 2003. Later, more studies, including clinical trials, demonstrated undesirable effects of rosiglitazone on the cardiovascular system. These findings suggested that rosiglitazone treatment may be harmful and should be used with caution in cardiovascular patients. A summary of reports on the adverse effects of rosiglitazone in various models as well as clinical studies are shown in Table 2.

Table 2 Reports of the adverse effects of rosiglitazone on the cardiovascular system in pre-clinical and clinical studies.
ModelDose of rosiglitazoneMajor findingsInterpretationRef.
Isolated and cultured vascular smooth muscle cells1-10 μmol/L; incubated for 24 hInduced cell death in a concentration-dependent mannerRosiglitazone induced apoptotic cell death through an ERK1/2-independent pathway[17]
Increased caspase 3 activity and the cytoplasmic histone-associated DNA fragmentation
PD98059 (MAPKK inhibitor) did not abolish rosiglitazone induced ERK1/2 activation (proapoptotic effects)
Rats with I/R injury3 mg/kg per day po; pretreated for 14 d prior to I/RDid not reduce left ventricular infarct size or hypertrophyRosiglitazone did not prevent left ventricular remodeling, but was associated with increased mortality after myocardial infarction[21]
Increased mortality rate
Improved ejection fraction and prevented an increase left ventricular end diastolic pressure
Swine with I/R injury3 mg/kg per day po; pretreated for 8 d prior to I/RIncreased expression of PPARγRosiglitazone had no cardioprotective effects in a swine model of myocardial I/R injury[25]
Had no effect on myocardial contractile function
Did not alter substrate uptake and proinflammatory cytokines expression
PPARγ-knockout (CM-PGKO) mouse10 mg/kg per day po; 4 wkIncreased phosphorylation of p38 mitogen-activated protein kinaseRosiglitazone caused cardiac hypertrophy at least partially independent of PPARγ in cardiomyocytes[15]
Induced phosphorylation of extracellular signal-related kinase 1/2
Did not affect phosphorylation of c-Jun N-terminal kinases
Induced cardiac hypertrophy
Wild type and PPARγ overexpression mice10 mg/kg per day po; 15 dIncreased lipid accumulationRosiglitazone and PPARγ overexpression could be harmful to cardiac function[24]
Increased size of the heart
Decreased fractional shortening
Increased CD36 expression
Swine with I/R injury0.1, 1.0 10 mg/kg iv; pretreated for 60 minAttenuated MAP shortening during ischemia by blocking cardiac KATP channelsRosiglitazone promoted onset of ventricular fibrillation during cardiac ischemia[20]
Increased propensity for ventricular fibrillation during myocardial ischemia
Sprague-Dawley rats15 mg/kg per day po; 21 dInduced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectinRosiglitazone induced cardiac hypertrophy via the mTOR pathway[16]
Reduced heart rate and increased stroke volume
Increased heart glycogen content, myofibrillar protein content and turnover
Reduced glycogen phosphorylase expression and activity
Meta-analysis in T2DM (n = 15 565, control = 12 282)Received rosiglitazone more than 24 wkIncreased the risk of myocardial infarctionRosiglitazone increased in the risk of myocardial infarction and borderline increased in risk of cardiovascular death[11]
Increased cardiovascular death incidence
RECORD study (n = 4447)Received rosiglitazone with mean follow-up time of 3.75 yrIncreased the risk of heart failureRosiglitazone increased risk of heart failure, but did not increase the risk of cardiovascular death or all cause mortality[18]
RECORD study (n = 4447)Received rosiglitazone with mean follow-up time of 5.5 yrIncreased the risk of heart failureRosiglitazone increased risk of heart failure[65]
Suggestion of contraindication for rosiglitazone to be used in patients developing symptomatic heart failure
Case-control analysis of a retrospective cohort study (n = 159 026)Treated with TZDs at least 1 yrIncreased risk of heart failureRosiglitazone was associated with risk of heart failure, acute myocardial infarction, and mortality[19]
Increased mortality
Increased risk of acute myocardial infarction
Retrospective, double-blind, randomized clinical studies with rosiglitazone (n = 14 237)Received rosiglitazone 24-52 wkIncreased heart failure incidenceRosiglitazone increased the risk of heart failure and myocardial infarction[13]
Increased events of myocardial ischemia
A meta-analysis of randomized controlled trials (n = 6421, control = 7870)Received rosiglitazone at least 12 moIncreased risk of myocardial infarction and heart failureRosiglitazone increased risk of myocardial infarction and heart failure, without increased risk of cardiovascular mortality[23]
No increased risk of cardiovascular mortality

Rosiglitazone treatment has been shown to induce apoptotic cell death in cultured vascular smooth muscle cell by increasing caspase 3 activity and the cytoplasmic histone-associated DNA fragmentation via the proapototic extracellular signal-regulated kinase 1/2-independent pathway[17]. Likewise, in an in vivo I/R injury model, it has been demonstrated that rosiglitazone therapy for 8 wk in non-diabetic rats with MI did not reduce either LV infarct size or LV hypertrophy, and increased mortality rate after I/R injury[21]. These findings suggested that rosiglitazone did not have cardioprotective effects in myocardial I/R injury. Furthermore, rosiglitazone treatment has been shown to increase cardiac phosphorylation of the p38MAPK signaling pathway[15], suggesting that rosiglitazone could facilitate cardiomyocyte apoptosis. In addition, rosiglitazone has been shown to be associated with an increased incidence of cardiac hypertrophy due to the increased expression of atrial natriuretic peptide, B-type natriuretic peptide, collagen I and III and fibronectin[16], leading to cardiac hypertrophy. The deterioration in cardiac function was also found in mice and rats when treated with rosiglitazone[12,24].

In a large animal model, which is more similar to a human, a recent study in swine has demonstrated that intravenous administration of rosiglitazone at clinically relevant doses attenuated epicardial monophasic action potential shortening during ischemia, possibly via blockade of cardiac ATP-sensitive potassium channels, and increased the propensity for ventricular fibrillation[20].

Growing evidence from recent clinical trials suggest that rosiglitazone could have serious harmful effects on the cardiovascular system[11,13,14,18,19,22,23,65]. The meta-analysis by Nissen et al[11] was the first report raising concerns about the cardiovascular safety profile of rosiglitazone. In a meta-analysis, Nissen et al[11] demonstrated that T2DM patients who received rosiglitazone treatment had a significantly increased risk of MI, heart failure and cardiovascular mortality. Although the method and statistical analysis used in this study have been criticized[14,52,66], the subsequent meta-analyses showed similar concerns regarding MI and heart failure, but not cardiovascular mortality[23,52,65].

Lipscombe et al[19] also demonstrated that rosiglitazone therapy in patients with T2DM was associated with a significantly increased risk of congestive heart failure, acute MI, and death. Similarly, results from a meta-analysis demonstrated that rosiglitazone treatment for at least 12 mo was associated with a significantly increased risk of MI and heart failure[23]. A retrospective analysis also suggested that rosiglitazone may increase the risk of heart failure[13]. These data from the clinical trials and meta-analysis in recent years strongly indicated that rosiglitazone could have adverse effects on the cardiovascular outcome due to increased risk of MI and heart failure, resulting in increased mortality in patients treated over a long period with rosiglitazone[14,18,22,23]. A meta-analysis demonstrated that patients treated with both rosiglitazone and pioglitazone had a 1.7-fold increase in risk of congestive heart failure with a slightly greater increase in risk with rosiglitazone than with pioglitazone (1.3-fold)[67].

The association between TZDs and heart failure is well recognized as a class effect. An increased plasma volume rather than direct effects on cardiac function is thought to be the mechanism responsible for heart failure[12]. Fluid retention is mediated through increased sodium reabsorption of the renal PPARγ-dependent pathway in the collecting tubules[68].

Unlike the mechanism responsible for heart failure, the mechanism of increased MI risk of rosiglitazone is still controversial. An unfavorable effect of the lipid profile has been proposed, in which rosiglitazone increases low density lipoprotein cholesterol to a greater extent than pioglitazone, and decreases the triglyceride level to a smaller extent than pioglitazone[69].

DISCREPANCY IN FINDINGS FROM ROSIGLITAZONE USE

As summarized in Table 1 for the beneficial effects and Table 2 for the adverse effects of rosiglitazone, these controversial reports are still debated. Although each side for and against the use of rosiglitazone has its own supporting documentation, the growing number of reports of serious adverse cardiovascular effects cannot be taken lightly. It is possible that the controversy on the cardiovascular effects of rosiglitazone could be due to differences in species which could have different drug metabolism, different experimental models, different drug administration methods as well as different time intervals of drug treatment which relates to the effects of the drug. The differences in patients’ clinical characteristics may also contribute to the differences in outcomes, in which older patients with preexisting cardiovascular disease are more likely to have serious cardiovascular events.

Regardless of this controversy, since evidence from clinical reports indicated potential cardiovascular risks of rosiglitazone, the European Medicines Agency suggested that the anti-diabetes drug rosiglitazone (Avandia®) should be suspended from the EU market due to its excessive cardiovascular risk[61,70]. As a result, rosiglitazone has been withdrawn from the EU market[61]. However, rosiglitazone is still available in the US but remains under close monitoring from the US Food and Drug Administration[61-63,71].

CONCLUSION

Rosiglitazone is a potent agent in the treatment of hyperglycemia in patients with T2DM because it is an insulin sensitizer and improves glucose uptake. Despite previous reports on its beneficial effects, growing evidence indicates that rosiglitazone increases cardiovascular risks in patients taking this drug. Although this drug has been withdrawn from the EU market, it is still can be used elsewhere. It is important that future large clinical trials should be done to evaluate the definitive cardiovascular outcome of the drug and the interplay between rosiglitazone and other available anti-hyperglycemic agents. In addition, large meta-analyses are also essential and must be carefully interpreted in order to elucidate the effects of rosiglitazone on cardiovascular risks and outcomes.

Footnotes

Peer reviewer: Antigone Lazou, Professor of Physiology, Lab of Animal Physiology, Sch of Biology,Aristotle University of Thessaloniki, Thessaloniki 54124, Greece

S- Editor Cheng JX L- Editor Cant MR E- Editor Zheng XM

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