Thiazolidinediones in Type 2 Diabetes: A Cardiology Perspective

Khanderia, Ujjaini; Pop‐Busui, Rodica; Eagle, Kim A.

doi:10.1345/aph.1k666

Cited by 41 publications

(23 citation statements)

References 60 publications

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“…However, large-scale clinical studies also have suggested that TZDs increase risks of heart failure (HF) in patients with T2D (Robinson, 2008;Zinn et al, 2008). Furthermore, clinical studies and meta-analyses of rosiglitazone (RGZ) clinical trials failed to establish clear cardiovascular benefits and in fact raised concerns that RGZ may increase cardiovascular events risk, especially cardiac death (Robinson 2008), although this matter is still subject to controversy (Lago et al, 2007;Nissen and Wolski, 2007;Khanderia et al, 2008). In addition, it has been well documented that treatment with TZDs (e.g., RGZ) is associated with fluid retention, edema, and exacerbation of heart failure, probably due to renal mechanism (Staels, 2005;Yang and Soodvilai, 2008).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Wang

Liu²,

Zhan³

et al. 2010

J Pharmacol Exp Ther

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Peroxisome proliferator-activated receptor (PPAR)-␥ modulators, a class of antidiabetic drugs, have been associated with cardiovascular risks in type 2 diabetes in humans. The objective of this study was to explore possible cardiovascular risk biomarkers associated with PPAR-␥ in rodents that could provide an alert for risk to humans. Normal, myocardial infarction-induced heart failure (HF) or Zucker diabetic fatty (ZDF) rats were used. Rats (n ϭ 5-6) were treated with either vehicle or rosiglitazone (RGZ; 3 or 45 mg/kg/day p.o.) for 4 weeks. Biomarkers for potential cardiovascular risks were assessed, including 1) ultrasound for cardiac structure and function; 2) neuroendocrine and hormonal plasma biomarkers of cardiovascular risk; 3) pharmacogenomic profiling of cardiac and renal tissue by targeted tissue low-density gene array representing ion channels and transporters, and components of the renin-angiotensin-aldosterone system; and 4) immunohistochemistry for cardiac fibrosis, hypertrophy, and inflammation (macrophages and tumor necrosis factor-␣). HF was confirmed by increase in cardiac brain natriuretic peptide expression (p Ͻ 0.01) and echocardiography. Adequate exposure of RGZ was confirmed by pharmacokinetics (plasma drug levels) and the pharmacodynamic biomarker adiponectin. In normal or HF rats, RGZ had no negative effects on any of the biomarkers investigated. Similarly, RGZ had no significant effects on gene expression except for the increase in interleukin-6 mRNA expression in the heart and decrease in epithelial sodium channel ␤ in the kidney. In contrast, echocardiography showed improved cardiac structure and function after RGZ in ZDF rats. Taken together, this study suggests a limited predictive power of these preclinical models in respect to observed clinical adverse effects associated with RGZ.

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Section: Introductionmentioning

confidence: 99%

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Wang

Liu²,

Zhan³

et al. 2010

J Pharmacol Exp Ther

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“…While metformin has also been shown to prevent weight gain and improve blood glucose levels in hypertensive patients who received combination therapy of calcium antagonist (nitrendipine) and beta-blocker (atenolol) [94], in combination with drugs blocking the rennin-angiotensin system (ACEI or ARB), metformin may be associated with lactic acidosis and acute renal failure in patients with reduced renal function [95]. Whilst thiazolidinedione drugs (TZDs) may prove useful in the metabolic syndrome, or type 2 diabetes, a large concern has been expressed over the cardiovascular risks associated with rosiglitazone and pioglitazone [96]. Hsiao et al [97] performed retrospective cohort study of 473,483 newly diagnosed patients with type 2 diabetes in order to evaluate the associations between oral antihyperglycemics (TZDs including rosiglitazone and pioglitazone, sulfonylureas, and metformin) with myocardial infarction, congestive heart failure, angina pectoris, stroke and transient ischemic attack.…”

Section: Pharmacological Treatments For the Metabolic Syndrome As A Pmentioning

confidence: 99%

Treatments for Hypertension in Type 2 Diabetes-Non-Pharmacological and Pharmacological Measurements

Masuo

2011

Recent Advances in the Pathogenesis, Prevention and Management of Type 2 Diabetes and Its Complications

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“…This effect is thought to be mediated via the PI3K signaling pathway in skeletal muscle (4,17,24). However, there have been discussions about the therapeutic effects of the currently available TZDs in the management of type 2 diabetes (21). The major concern of the TZD PPAR␥ agonists is that they have problems in fluid retention and weight gain and the increased risk of congestive heart failure (21,33,39).…”

mentioning

confidence: 99%

“…However, there have been discussions about the therapeutic effects of the currently available TZDs in the management of type 2 diabetes (21). The major concern of the TZD PPAR␥ agonists is that they have problems in fluid retention and weight gain and the increased risk of congestive heart failure (21,33,39). Additionally, TZD treatment has been shown to decrease bone mineral density in type 2 diabetic humans and animals (16,21,27,40).…”

mentioning

confidence: 99%

“…The major concern of the TZD PPAR␥ agonists is that they have problems in fluid retention and weight gain and the increased risk of congestive heart failure (21,33,39). Additionally, TZD treatment has been shown to decrease bone mineral density in type 2 diabetic humans and animals (16,21,27,40). Moreover, increased numbers of peripheral fractures were seen in patients with type 2 diabetes treated with pioglitazone or rosiglitazone (16,39).…”

mentioning

confidence: 99%

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Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice

Lee

Choi

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Lee DH, Huang H, Choi K, Mantzoros C, Kim YB. Selective PPAR␥ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice. Am J Physiol Endocrinol Metab 302: E552-E560, 2012. First published January 3, 2012; doi:10.1152/ajpendo.00569.2011.-INT131 is a potent nonthiazolidinedione (TZD)-selective peroxisome proliferator-activated receptor-␥ modulator being developed for the treatment of type 2 diabetes. In preclinical studies and a phase II clinical trial, INT131 has been shown to lower glucose levels and ameliorate insulin resistance without typical TZD side effects. To determine whether the insulinsensitizing action of INT131 is mediated by effects on insulinmediated glucose homeostasis and insulin signaling, high-fat dietinduced obese (DIO) insulin-resistant mice treated with INT131 were studied. INT131's effects on bone density were also investigated. Treatment with INT131 enhanced systemic insulin sensitivity, as revealed by lower insulin levels in the fasted state and an increase in the area above the curve during an insulin tolerance test. These effects were independent of changes in adiposity. Insulin-stimulated PI3K activity in skeletal muscle and adipose tissue of DIO mice was significantly reduced ϳ50 -65%, but this was restored completely by INT131 therapy. The INT131 effects on PI3K activity are most likely due to increased IRS-1 tyrosine phosphorylation. Concurrently, insulin-mediated Akt phosphorylation also increased after INT131 treatment in DIO mice. Importantly, INT131 therapy caused a significant increase in bone mineral density without alteration in circulating osteocalcin in these mice. These data suggest that a newly developed insulin-sensitizing agent, INT131, normalizes obesity-related defects in insulin action on PI3K signaling in insulin target tissues by a mechanism involved in glycemic control. If these data are confirmed in humans, INT131 could be used for treating type 2 diabetes without loss in bone mass.

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Thiazolidinediones in Type 2 Diabetes: A Cardiology Perspective

Cited by 41 publications

References 60 publications

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Treatments for Hypertension in Type 2 Diabetes-Non-Pharmacological and Pharmacological Measurements

Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice

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