Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage

Abstract

Aims/hypothesisThe mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy.MethodsWe conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (<2.5 or ≥2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume.ResultsThirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (ΔTERalb: rosiglitazone +2.43 ± 0.45%/h, placebo −0.11 ± 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation.Conclusions/interpretationRosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention.Trial registrationClinicalTrials.gov NCT00422955FundingGlaxoSmithKline

Preserved Response to Diuretics in Rosiglitazone-Treated Subjects With Insulin Resistance: A Randomized Double-Blind Placebo-Controlled Crossover Study

“…Within our study population, we could not detect such an influence. However, in actual clinical practice, subjects may have additional problems (e.g., autonomic neuropathy) in addition to their original metabolic disease, which may influence water and sodium homeostasis 26 . This makes us careful with the extrapolation of our results to the clinic.…”

Edema macular por tratamiento con rosiglitazona en diabetes mellitus

“…Las glitazonas (tiazolidinedionas) son antidiabéticos orales frecuentemente utilizados en el tratamiento de la diabetes tipo 2 y del ovario poliquístico; así en 2003 se estimó su facturación en 5 billones de dólares [1][2][3] . Incluyen dos fárma-cos la pioglitazona y la rosiglitazona.…”

“…La rosiglitazona actúa aumentando en los tejidos diana la sensibilidad a la insulina, así como disminuyendo la gluconeogénesis hepática 1 . Se calcula que hasta el 15% de los pacientes desarrollan retención de fluidos especialmente si se asocian con insulina, y algunos de ellos presentan alteraciones visuales secundarias a edema macular [1][2][3] . En el edema macular se produce un aumento de la permeabilidad de los vasos retinianos.…”

“…El 15% de los diabéticos tipo 2 tratados con insulina desarrollará edema macular frente al 4% de los que sólo toman antidiabéticos orales. Generalmente la retención de líquidos por glitazonas es refractaria al tratamiento con diuréticos y se piensa que es secundaria a una alteración en el transporte iónico a nivel intestinal y renal, incrementando el volumen plasmático, la activación simpática y aumentando la permeablidad endotelial a través de un incremento plasmático del VEGF [1][2][3][4] .…”

Efectos de los ácidos grasos omega 3 y otros suplementos alimenticios en procesos patológicos relacionados con la tercera edad

“…los PUFA n-3 de cadena larga) sin bloquear una vía concreta, lo que podría presentar efectos secundarios graves, como ha sido el caso de los inhibidores específicos de COX-2, rofecoxib, celecoxib, parecoxib, etoricoxib y valdecoxib, que se han retirado del mercado o se ha restringido mucho su uso o el de la Rosiglitazona, un agonista específico de PPAR-gamma (84)(85)(86)(87), que como en el caso anterior, ha sido prohibido o restringido su uso, debido a sus efectos secundarios. Además, se ha demostrado recientemente, los efectos aditivos o sinérgicos de estos productos cuando actúan por diferentes vías, como son los agonistas de los dos componentes del heterodímero PPAR-gamma -RXR (46,88).…”