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Correspondence to: Nipon Chattipakorn, MD, PhD, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. nchattip/at/gmail.com
Telephone: +66-53-945329 Fax: +66-53-945368
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 As a result, rosiglitazone has been recently withdrawn from EU countries.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.
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. The development of T2DM involves 3 metabolic defects that include insulin resistance, alterations in hepatic glucose production and β-cell deficiency. The earliest defect seen in the development of T2DM is insulin resistance. 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. 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. TZDs exert their properties by stimulating a nuclear hormone receptor, the peroxisome proliferator-activated receptor γ (PPARγ). Troglitazone was the first drug developed but was withdrawn from the market due to liver toxicity. Currently, pioglitazone and rosiglitazone are the only compounds that are available for clinical use. 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, 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.
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 Table1.1. 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. Furthermore the accumulation of neutrophils and macrophages and expression of monocyte chemoattractant factor (MCP)-1 in the ischemic heart was diminished by rosiglitazone. 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].
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. 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. 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. 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). Rosiglitazone has been shown to reduce plasma levels of C-reactive protein[5,51,56,58], matrix metalloproteinase-9 and MCP-1 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.
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 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 Table22.
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. 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. 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, 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, 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.
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 was the first report raising concerns about the cardiovascular safety profile of rosiglitazone. In a meta-analysis, Nissen et al 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 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. A retrospective analysis also suggested that rosiglitazone may increase the risk of heart failure. 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).
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. Fluid retention is mediated through increased sodium reabsorption of the renal PPARγ-dependent pathway in the collecting tubules.
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.
As summarized in Table Table11 for the beneficial effects and Table Table22 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. However, rosiglitazone is still available in the US but remains under close monitoring from the US Food and Drug Administration[61-63,71].
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.
Peer reviewer: Antigone Lazou, Professor of Physiology, Lab of Animal Physiology, Sch of Biology,Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Supported by Grants from the Thailand Research Fund RTA 5280006 (NC), BRG (SC), MRG5280169 (AP) and the Commission of Higher Education Thailand (SP, NC)
S- Editor Cheng JX L- Editor Cant MR E- Editor Zheng XM