Is the evidence from clinical trials for cardiovascular risk or harm for glitazones convincing?

Mannucci, Edoardo; Monami, Matteo

doi:10.1007/s11892-009-0054-1

Cited by 9 publications

(8 citation statements)

References 42 publications

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“…Although its use does not increase overall cardiovascular mortality, previously suspected increased heart failure risk [69] was confirmed [50]. ROS induces cardiac hypertrophy which may occur via PPARγ-independent effects in cardiomyocytes or PPARγ in nonmyocyte cells or may be secondary to blood volume expansion [51,70].…”

Section: Discussionmentioning

confidence: 92%

Rosiglitazone Shows Partial Oncostatic Effect in Rat Mammary Carcinogenesis

Bojková

Kajo²,

Garajová³

et al. 2012

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Peroral antidiabetics from thiazolidinedione (glitazone) group showed oncostatic effects in preclinical models. This study evaluated chemopreventive effects of rosiglitazone in N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. N-methyl-N-nitrosourea was administered in two intraperitoneal doses each per 50 mg/kg b.w. between 40 th and 51 st postnatal days. Rosiglitazone was administered in a diet at a concentration of 10 ppm and 100 ppm, respectively, 9 days before the first carcinogen dose until the termination of the experiment. During the experiment the animals were weekly weighed and palpated for the presence of mammary tumors and estimation of latency period, tumor frequency per group and animal, and tumor volume were recorded. The experiment was terminated 16 weeks after the first carcinogen dose, basic tumor growth parameters and selected metabolic and hormonal variables were evaluated. Chemoprevention with higher rosiglitazone dose decreased tumor frequency per group by 44%, other tumor parameters (incidence, tumor frequency per animal) were decreased insignificantly (at both doses), latency period was not changed. Rosiglitazone administration decreased cumulative tumor volume, more efficiently at lower dose. Glycaemia and insulinaemia decreased after lower rosigitazone dose administration but glycaemia did not exceed normal values. Higher rosiglitazone dose alleviated some metabolic alterations resulting from cancer progression more effectively but induced a prominent cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 92%

Rosiglitazone Shows Partial Oncostatic Effect in Rat Mammary Carcinogenesis

Bojková

Kajo²,

Garajová³

et al. 2012

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“…In spite of the fact that these latter risks of rosiglitazone therapy were not confirmed by other clinical studies [66, 67] restricted access to rosiglitazone was introduced in some countries [16, 17]. …”

Section: Clinical Evidencesmentioning

confidence: 99%

Can the Electrophysiological Action of Rosiglitazone Explain its Cardiac Side Effects?

Szebeni

Szentandrássy

Pacher

et al. 2011

CMC

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Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1–30 μM) shortened AP duration at 90% level of repolarization (APD90) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1–30 μM) caused a significant reduction of APA and maximum velocity of depolarization (Vmax) which was accompanied by lengthening of APD90. In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced Vmax. R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC50 value for this inhibition was 25.2±2.7 μM for the transient outward K+ current (Ito), 72.3±9.3 μM for the rapid delayed rectifier K+ current (IKr), and 82.5±9.4 μM for the L-type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by R up to concentrations of 100 μM. Suppression of Ito, IKr, and ICa has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.

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“…Questions arose regarding some of the methodologies used in the Nissen and Wolski meta-analysis [20]. These included lack of adjudication of cardiovascular events, inclusion of studies with longer observation periods for rosiglitazone compared with the comparator arm (possibly leading to higher event rates), lack of inclusion of studies that were available at the time of publication, and alternative analytical methods that may have changed the overall outcome of the meta-analysis [21].…”

Section: Tzds and Cardiovascular Riskmentioning

confidence: 99%

“…A prespecified main secondary end point was a composite of the usual hard end points of all-cause mortality, MI, or stroke. As reviewed by Mannucci and Monami [20], the PROactive study did not show a difference in the primary end point but did show significant reductions in some of the predefined secondary end points for those subjects taking pioglitazone, including cardiovascular morbidity (excluding need for cardiovascular revascularization) [20]. For those taking pioglitazone with a previous history of an MI, there was a hazard ratio (HR) of 0.72 (95% CI, 0.50-0.99; P= 0.045) for fatal and nonfatal MI (excluding silent MI), and an HR of 0.63 (95% CI, 0.41-0.97; P=0.035) for ACS.…”

Section: Proactive and Pioglitazone Meta-analysesmentioning

confidence: 99%

“…Because of rapid enrollment, the study might not have been long enough to detect a significant difference in the primary outcome between the two groups. Many felt that revascularization or other procedural end points should not have been included in the primary composite end point, given its dependence on clinician decision making rather than less subjective criteria [20].…”

Section: Proactive and Pioglitazone Meta-analysesmentioning

confidence: 99%

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Update on the Safety of Thiazolidinediones

Lieb

McCall

2010

Curr Diab Rep

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Diabetic patients are at increased risk for developing cardiovascular disease, and they constitute a large proportion of the global cardiovascular disease burden. Although multiple drugs exist for treating the hyperglycemia associated with diabetes, few have been shown to reduce cardiovascular risk. Great hope surrounded the arrival of the thiazolidinediones-drugs that favorably affect insulin sensitivity, inflammation, and some aspects of lipid profiles in diabetic patients. However, the cardiovascular effects of these agents are varied, and studies have suggested that they may be associated with increases in ischemic heart disease and heart failure, as well as with an increased risk for bone fracture. The following article provides a summary of important studies that have been published regarding the safety profiles of these agents. Findings from two recently published trials, RECORD and BARI 2D, are emphasized in this paper.

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Is the evidence from clinical trials for cardiovascular risk or harm for glitazones convincing?

Cited by 9 publications

References 42 publications

Rosiglitazone Shows Partial Oncostatic Effect in Rat Mammary Carcinogenesis

Rosiglitazone Shows Partial Oncostatic Effect in Rat Mammary Carcinogenesis

Can the Electrophysiological Action of Rosiglitazone Explain its Cardiac Side Effects?

Update on the Safety of Thiazolidinediones

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