Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis?

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-gamma may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-gamma agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-gamma-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-gamma-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.     

Selective peroxisome proliferator-activated receptor-γ modulation to reduce cardiovascular risk in patients with insulin resistance

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone improve glucose homeostasis through activation of peroxisome proliferator-activated receptor (PPAR)-γ. Their use, however, has been limited due to adverse effects that include body weight gain and edema leading to congestive heart failure. Selective PPAR-γ modulators (SPPARMs) are second generation PPAR-γ ligands designed to improve insulin sensitivity with minimal undesirable effects associated with first generation PPAR-γ agonists. INT131 is one of the first SPPARMs to reach human trials. Early phase human studies with INT131 look promising with changes in plasma lipids and glucose being equal or better than what is seen with rosiglitazone and pioglitazone treatment but without evidence of edema. This profile of improved glucose homeostasis, improved plasma lipids, and reduced inflammation in the absence of edema would be expected to reduce cardiovascular risk in patients with Type 2 diabetes mellitus. Recent patents of novel approaches for the use of PPAR-γ related compounds with the potential for this improved risk-benefit ratio are discussed.     

选择性PPARγ调节剂治疗二型糖尿病的分子机制研究进展

第一类胰岛素增敏剂——过氧化物酶体增殖体激活受体γ(PPARγ)激动剂噻唑烷二酮类药物(TZDs)曾在二型糖尿病(T2DM)治疗中具有不可替代的作用。但由于TZDs类药物存在增重、水肿、骨折、充血性心力衰竭等严重副作用,保留TZDs类药物的胰岛素增敏效果而无其副作用的选择性PPARγ调节剂(SPPARγM)是新型胰岛素增敏剂的发展方向。现有实验主要对SPPARγM候选分子影响PPARγ受体构象改变、受体磷酸化、受体对共调节因子的选择性募集和PPARγ下游靶基因选择性开启等几个层次的分子作用机制作了初步探讨。该文综述了SPPARγM治疗二型糖尿病的分子机制研究进展。     

Pharmacokinetics, efficacy and safety of aleglitazar for the treatment of type 2 diabetes with high cardiovascular risk

INTRODUCTION: In preliminary clinical studies, aleglitazar, a new dual PPAR-α-γ agonist, has been demonstrated to improve hyperglycemia and dyslipidemia in patients with type 2 diabetes mellitus. This review will provide up-to-date information on the clinical safety and efficacy of aleglitazar, which is currently under Phase III clinical investigation for reduction of cardiovascular events in patients with type 2 diabetes and recent acute coronary syndrome. AREAS COVERED: A PubMed literature search (January 1950 to February 2011) was conducted using the following search terms: aleglitazar, PPAR, PPAR α agonist, PPAR γ agonist and PPAR α/γ agonist. Additional articles were gathered using reference lists from sources obtained from the original literature search. This review summarizes available information pertaining to pharmacodynamics, pharmacokinetics, clinical studies and safety/tolerability of aleglitazar. The effects of this new drug are compared and contrasted with those of fibrates (PPAR-α agonists), thiazolidinediones (PPAR-γ agonists) and other dual PPAR-α-γ agonists. EXPERT OPINION: Preliminary evidence from clinical studies with aleglitazar is promising, with reported improvements in glycemia, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein B and blood pressure. However, PPAR-α- and -γ-associated side effects have been observed and additional large-scale, long-term clinical studies are necessary to better understand the clinical implications of these effects.     

过氧化物酶体增生物激活受体γ激动剂致水肿机制及预防的研究进展

过氧化物酶体增生物激活受体γ（peroxisome proliferator-activated receptor gamma,PPAR-γ）激动剂主要包括噻唑烷二酮类（thiazolidinediones,TZDs）和非噻唑烷二酮类新型PPAR-γ激动剂。噻唑烷二酮类药物常用的有曲格列酮、吡咯列酮及罗格列酮。PPAR-γ激动剂的常见不良反应之一为水肿,并可加重或引致充血性心力衰竭。水肿发生率为3%～28.9%;PPAR-γ激动剂和其他口服降血糖药或胰岛素合用可增加水肿发生率。PPAR-γ引起水肿的机制涉及水钠潴留、血管扩张以及血管通透性增加等因素,特别是分布于远端肾小管和集合管的水、钠转运蛋白调节异常对水钠潴留的发生起重要作用。PPAR-γ激动剂引起的水肿一般较轻,停药后可消退。糖尿病合并中、重度充血性心力衰竭患者[NYHA（New York Heart Association）Ⅲ或Ⅳ级]避免用PPAR-γ激动剂,合并轻度充血性心力衰竭患者（NYHAI至Ⅱ级）应慎用,尽可能用最小剂量,必需时,剂量应逐渐增加,可联合应用利尿剂,并应严密监测患者体重和水肿的发生情况。预防治疗水肿的方法包括应用新的选择性PPAR-γ调节剂、蛋白激酶C-β或上皮细胞钠通道的特异性抑制剂及PPAR-γ拮抗剂。     

Dual acting and pan-PPAR activators as potential anti-diabetic therapies

The thiazolidinedione PPAR-γ activator drugs rosiglitazone and pioglitazone suppress insulin resistance in type 2 diabetic patients. They lock lipids into adipose tissue triglyceride stores, thereby preventing lipid metabolites from causing insulin resistance in liver and skeletal muscle and β-cell failure. They also reduce the secretion of inflammatory cytokines such as TNFα and increase the plasma level of adiponectin, which increases insulin sensitivity in liver and skeletal muscle. However, they have only a modest effect on dyslipidaemia, and they increase fat mass and plasma volume. Fibrate PPAR-α activator drugs decrease plasma triglycerides and increase HDL-cholesterol levels. PPAR-δ activators increase the capacity for fat oxidation in skeletal muscle.Clinical experience with bezafibrate, which activates PPAR-δ and -α, and studies on the PPAR-α/δ activator tetradecylthioacetic acid, the PPAR-δ activator GW501516, and combinations of the PPAR-α activator fenofibrate with rosiglitazone or pioglitazone have encouraged attempts to develop single molecules that activate two or all three PPARs. Most effort has focussed on dual PPAR-α/γ activators. These reduce both hyperglycaemia and dyslipidaemia, but their development has been terminated by issues such as increased weight gain, oedema, plasma creatinine and myocardial infarction or stroke. In addition, the FDA has stated that many PPAR ligands submitted to it have caused increased numbers of tumours in carcinogenicity studies.Rather than aiming for full potent agonists, it may be best to identify subtype-selective partial agonists or compounds that selectively activate PPAR signalling pathways and use these in combination. Nutrients or modified lipids that are low-affinity agonists may also have potential.     

Effects of telmisartan and valsartan on insulin sensitivity in obese diabetic mice

Telmisartan and valsartan have angiotensin II receptor blocking activity. Because telmisartan has also an agonistic action for peroxisome proliferators-activator receptor (PPAR)-γ, it is speculated that an effect of telmisartan on insulin sensitivity is different from that of valsartan, which lacks of PPAR-γ agonistic activity. To address the issue, effects of telmisartan and valsartan on insulin sensitivity, adipocytokines and PPAR-γ target genes were evaluated in obese diabetic mice. KK-A^y mice were treated with telmisartan (5 mg/kg) and valsartan (15 mg/kg), once daily for 3 weeks. Insulin tolerance test was performed on day14, and plasma adiponectin concentration and mRNA expression levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in adipose tissues were measured on day 21. Time-course of plasma glucose level after the injection of insulin in mice with telmisartan was not significantly different from that of animals with valsartan. In addition, PPAR-γ antagonist did not diminished the improvement of insulin sensitivity by telmisartan. Telmisartan and valsartan elevated plasma adiponectin concentration and suppressed the mRNA expressions of TNF-α and IL-6 in adipose tissues. These variables of the telmisartan- and valsartan-treated groups did not significantly differ. Influence of telmisartan on the PPAR-γ target genes (ap2 and fatty acid synthase) mRNA expressions was not detected in adipose tissues under the present condition. These data suggest that the effect of telmisartan on insulin sensitivity is similar to that of valsartan, and a role of PPAR-γ-mediated stimuli is small in the telmisartan-induced improvement of insulin sensitivity.     

PPAR- γ agonist in treatment of diabetes: cardiovascular safety considerations

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.     

Current status of viral gene therapy for brain tumours

There is genetic evidence that reducing the activity of peroxisome proliferation receptor-γ (PPAR-γ) may increase insulin sensitivity. SR-202 is a selective antagonist at PPAR-γ, which inhibits the adipocyte differentiation normally seen with the PPAR-γ agonist rosiglitazone. SR-202 also reduces the ability of young mice to put on weight and accumulate fat. The levels of circulating TNF-α correlates with body fat stores and/or hyperinsulinaemia. SR-202- treated wild-type mice have reduced TNF-α levels. When wild-type mice are fed a high-fat diet, the plasma levels of TNF-α are raised, and SR-202 treatment protects against this rise. Feeding mice with a high-fat diet induced insulin resistance measured as increased plasma levels of glucose, insulin and free fatty acids, and SR-202 protected against these changes. The ob/ob mouse is diabetic at 8 weeks and plasma glucose and insulin levels continue to rise over the next 3 weeks, and treatment with SR-202 prevents these increases. The development of PPAR-γ antagonists should continue as the results to date suggest that they have clinical potential for the treatment of diabetes Type 2 and obesity.     

Lycium barbarum (Goji Berry) extracts and its taurine component inhibit PPAR-γ-dependent gene transcription in human retinal pigment epithelial cells: Possible implications for diabetic retinopathy treatment

The peroxisome proliferator activated receptor-γ (PPAR-γ) is involved in the pathogenesis of diabetic retinopathy. Diabetic retinopathy is a preventable microvascular diabetic complication that damages human retinal pigment epithelial cells. Taurine is abundant in the fruit of Lycium barbarum (Goji Berry), and is reportedly beneficial for diabetic retinopathy. However, the mechanism of its action is unknown. Hence, we have investigated the mechanism of action of an extract from L. barbarum on a model of diabetic retinopathy, the retinal ARPE-19 cell line, and identified the receptor function of taurine, an active component of L. barbarum (Goji Berry) extract, which is potentially responsible for the protective effect on diabetic retinopathy. We demonstrate for the first time that L. barbarum extract and its taurine component dose-dependently enhance PPAR-γ luciferase activity in HEK293 cell line transfected with PPAR-γ reporter gene. This activity was significantly decreased by a selective PPAR-γ antagonist GW9662. Moreover, L. barbarum extract and taurine dose-dependently enhanced the expression of PPAR-γ mRNA and protein. In an inflammation model where ARPE-19 cells were exposed to high glucose L. barbarum extract and taurine down-regulated the mRNA of pro-inflammatory mediators encoding MMP-9, fibronectin and the protein expression of COX-2 and iNOS proteins. The predicted binding mode of taurine in the PPAR-γ ligand binding site mimics key electrostatic interactions seen with known PPAR-γ agonists. We conclude that PPAR-γ activation by L. barbarum extract is associated with its taurine content and may explain at least in part its use in diabetic retinopathy progression.     

Thiazolidinediones: potential as therapeutics for psoriasis and perhaps other hyperproliferative skin disease

The thiazolidinediones constitute a family of synthetic compounds that act as high-affinity ligands for persoxisome proliferator-activated receptor-γ (PPAR-γ), a member of the nuclear hormone receptor family. Although originally developed to facilitate glucose control in patients with Type 2 diabetes, a number of studies showed that these agents effectively inhibited epithelial cell proliferation and tissue inflammation. Many of the initial cell growth inhibition studies were conducted with malignant epithelial cells from various sites; however, in addition to malignant epithelial cells, other studies showed that rapidly proliferating epidermal keratinoctyes in culture were also sensitive to the growth-inhibiting action of these moieties. Additional studies subsequently demonstrated that some patients with plaque psoriasis responded to treatment with one or another member of the thiazolidinedione family. Due to the potential therapeutic benefit of these compounds in diseases such as psoriasis, studies have been conducted to elucidate mechanisms by which growth inhibition is achieved. Interference with a number of growth-influencing signalling pathways has been demonstrated. Of interest, some of the growth-inhibiting effects are seen under conditions in which PPAR-γ activation may not be responsible for the activity. Based on therapeutic potential, additional ongoing studies are aimed at developing novel thiazolidinediones that may have better efficacy than the currently available agents. Other studies are aimed at identifying optimal ways to use these agents in the treatment of hyperplastic skin diseases such as psoriasis.     

Therapeutic approaches to insulin resistance

Insulin resistance is now acknowledged to be a significant predictor of cardiovascular morbidity and mortality as well as the primary defect in Type 2 diabetes. Such pathologies are set to pose an ever greater socio-economic burden in developed and developing nations, especially in the light of evidence that insulin resistance may be acquired through the (Western) diet. Given the recognition of the central role of insulin resistance in the progression of syndrome X and diabetes, improving insulin sensitivity has become a major clinical focus. The traditional ‘first line of defence’ approach to restoring glycaemic control in diabetes involving dietary and exercise regimens, may now be supplemented with insulin-sensitising pharmacotherapy. This therapeutic modality, which was clinically pioneered with the biguanide metformin, is also today provided by the thiazolidinedione (TZD) class of anti-hyperglycaemic agent, exemplified by rosiglitazone and pioglitazone. More TZD derivatives are to be expected, along with novel, non-TZD ligands of their common therapeutic target: the peroxisome proliferator-activated receptor-γ (PPARγ). In addition, the role of PPARα activation in the regulation of insulin sensitivity is gaining attention. There is also the theoretical prospect at least of creating a therapeutic synergy by co-administering retinoid X receptor (RXR) agonists or so-called rexinoids with these PPAR ligands. Furthermore, interest has been registered in a nutraceutical approach to insulin resistance concerning supranutritional levels of chromium and biotin. While TZDs are currently only licensed for use in established Type 2 diabetes, such insulin-sensitising interventions have the potential to delay or prevent both cardiovascular and diabetic disease progression in insulin resistant individuals.     

The potential of antidiabetic thiazolidinediones for anticancer therapy

The thiazolidinediones (TZDs) are a class of synthetic compounds for treatment of insulin-resistant Type 2 diabetes mellitus. TZDs are known activators of the peroxisome proliferator-activated receptor-γ (PPAR-γ), and exert their antidiabetic action largely through this nuclear receptor family. Moreover, increasing experimental evidences of PPAR-γ-independent effects are accumulating. Apart from the established metabolic actions, TZD treatment exerts additional biological effect such as control of cell growth, differentiation, motility and programmed cell death. In this context, considerable interest has focused on TZDs as potential chemopreventive agents in oncology; however, despite encouraging observation on the potential anticancer effect of these drugs in several in vitro experimental models, controversial results have been obtained with animal models and in pilot clinical trials. This review summarises the molecular mechanisms of the antineoplastic actions of TZDs and the relevance of these findings in human pathology and therapy.     

Thiazolidinediones in the treatment of Type 2 diabetes

In the last few years there has been an explosion of research that has improved our understanding of the pathogenesis of Type 2 diabetes mellitus (DM-2) and has led to the development of new oral antidiabetic drugs. Thiazolidinediones (TZDs) are the newest of these antidiabetic agents. TZDs are insulin sensitisers that depend on the presence of insulin for their action. They target insulin resistance, which is thought to play a central role in DM-2 and the associated metabolic syndrome characterised by central obesity, hypertension, dyslipidemia and hypercoagulability, all leading to increased cardiovascular morbidity and mortality. As a result, TZDs have the potential to improve other conditions associated with the metabolic syndrome, in addition to their glycaemic action. TZDs act by activating peroxisome proliferator-activated receptor (PPAR) γ, a nuclear receptor implicated not only in lipid and glucose metabolism but other physiological functions as well. TZDs may have wide clinical applications beyond DM-2, as they can potentially be used to treat other conditions associated with insulin resistance and PPAR-γ receptors, such as impaired glucose tolerance, polycystic ovarian syndrome and HIV lipodystrophy.     

Thiazolidinediones: effects on insulin resistance and the cardiovascular system

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) primarily in adipose tissue. PPAR-gamma receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR-alpha/gamma agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured.     

Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson’s disease

Introduction: Current treatment of Parkinson’s disease (PD) is limited to symptomatic dopaminergic therapy, while no interventions have been shown to slow down disease progression.

Areas covered: The following article highlights a group of PPAR-γ agonists called thiazolidinediones (TZDs), which are currently being tested for a putative disease-modifying benefit in PD, using pioglitazone as a prototypic compound. PPAR-γ is highly expressed in neurons of the substantia nigra and CNS immune cells. Preclinical data in rodent and primate support an effect of TZDs in preventing and/or arresting neurodegeneration and development of motor symptoms. Although no data on the neuroprotective effect of TZDs is currently available, a clinical trial is ongoing where the primary objective is to assess pioglitazone’s impact on the progression of PD. The trial is also evaluating the drug’s safety concerns.

Expert opinion: The efficacy data from clinical trials must be carefully weighed against the safety concerns. However, given the solid preclinical data, and since the safety data are not yet fully conclusive and limited to the diabetic population, PPAR-γ research in PD can continue with caution. Ideally, drug discovery and development efforts will lead to the identification of new compounds with reduced risk of peripheral side effects.     

Saroglitazar for the treatment of dyslipidemia in diabetic patients

Introduction: Diabetes and dyslipidemia are commonly associated modifiable risk factors for cardiovascular diseases. Majority of patients with diabetes also suffer from dyslipidemia (diabetic dyslipidemia). Diabetic dyslipidemia is more atherogenic as it is commonly associated with high triglyceride (TG) levels, high proportion of small dense low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol (HDL-C) level (atherogenic dyslipidemia). Currently used pharmacotherapies for the management of diabetes and dyslipidemia like thiazolidinediones (PPAR-γ agonist; for insulin resistance) and fibrates (PPAR-α agonist; for hypertriglyceridemia) have many limitations and side effects. Saroglitazar, a dual PPAR-α/γ agonists, is an emerging therapeutic option with its dual benefit on glycemic and lipid parameters.

Areas covered: This paper reviews the clinical development of saroglitazar for the management of diabetic dyslipidemia. The efficacy and safety profile of saroglitazar is reviewed in context to currently available therapy like pioglitazone for diabetes and fibrates for hypertriglyceridemia. In addition, this paper also reviews the association between diabetes and dyslipidemia and the role of TG in reducing cardiovascular events.

Expert opinion: Saroglitazar, a dual PPAR-α/γ agonist, is a potential therapeutic option for the management of diabetic dyslipidemia. It has dual benefit of significant improvement in glycemic parameters (glycated hemoglobin and fasting blood glucose) and significant improvement in dyslipidemia (TGs, apolipoprotein B, non-HDL-C). The results of Phase III clinical trials indicate that saroglitazar is devoid of conventional side effects of fibrates and pioglitazone. Future clinical trials of saroglitazar will further establish its place in the management of diabetes, dyslipidemia and associated cardiovascular risk.     

PPAR-γ signaling pathway in placental development and function: A potential therapeutic target in the treatment of gestational diseases

Background: PPAR-γ is a target for the treatment of metabolic disorders, as Pioglitazone and Rosiglitazone are already used against type 2 diabetes. Pleiotropic functions, such as antiproliferative and anti-inflammatory effects against several pathological states, including cardiovascular disease and cancer, are currently being explored in clinical studies. Objective: Evidence indicates that PPAR-γ is expressed in the placenta, playing a crucial role in placental development and function, while PPAR-γ ligands appear to modulate fetal membrane signals. Thus, in the last few years, the pivotal role of PPAR-γ in placental biology has been the focus of extensive research, as diabetes appears to be the most common metabolic dysfunction in pregnancy. Methods: We aim to present data concerning the expression of PPAR-γ in animal and human placenta, underlining its significance in normal placental development and several gestational diseases. The effects of PPAR-γ ligands as modulators of placental biology in normal and certain pathological conditions are also discussed. Results/conclusion: Current research provides substantial evidence that PPAR-γ plays a pivotal role in placental biology and may reveal new perspectives in the treatment of gestational diseases.     

The safety of thiazolidinediones

INTRODUCTION: The prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions. Many new therapies have emerged, including thiazolidinediones (TZDs), selective agonists of PPAR-γ, now used as both primary and add-on therapies. Given that T2DM is a lifetime disease, there is a need for assurance that new drugs are both safe and effective. Recent concern about the cardiovascular safety of one of the new drugs, rosiglitazone, is the stimulus for this review. AREAS COVERED: The safety of pioglitazone and rosiglitazone under the headings of liver safety, cardiovascular safety, fluid retention, weight gain and bone fractures is reviewed based on a PubMed search of the years 1997 through June 2010. This review also describes the magnitude of the risks of the TZDs and provides a recommendation on the use of TZDs. EXPERT OPINION: Liver safety is no longer an issue with the TZDs. There are no significant differences between rosiglitazone and pioglitazone in fluid retention, weight gain and bone fractures. However, pioglitazone tends to be cardioprotective while rosiglitazone is cardiotoxic. There is no current justification for prescribing rosiglitazone.