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Pioglitazona

Repensando la pioglitazona como agente cardioprotector: una nueva perspectiva

¿Por qué la pioglitazona deber ser considerada un fármaco cardioprotector?

Numerosos estudios han demostrado que la Pioglitazona disminuye el riesgo MACE, de infarto agudo de miocardio y de ACV. Ya en el año 2005 el estudio PROACTIVE demostró una reducción del 16% del compuesto Muerte + IAM no fatal + ACV no fatal (HR 0.84, 95% CI 0.72–0.98). En el año 2017, un metaanálisis que inluyó 12.026 pacientes demostró una reducción de riesgo de MACE del 23% (HR 0.77, IC 0.64–0.93) para pacientes con prediabetes y del 17% (0.83, 0.72–0.97) para pacientes con diabetes. Un nuevo metaanálisis de 26 estudios controlados (N= 19.645) en 2020 confirmó una reducción del riesgo de MACE del 20% (HR 0.80, IC 0.71-0.89) (ver figura 1)

Figura 1. Adaptada de Nesti et al. Cardiovasc Diabetol (2021) 20:109

¿Qué efectos fueron estudiados relacionados con la protección vascular?

La protección cardiovascular observada con pioglitazona se puede deber a diversos mecanismos resumidos en la figura 2.

Figura 2. Adaptada de Nesti et al. Cardiovasc Diabetol (2021) 20:109

¿En qué pacientes debemos contraindicar su uso?

Las evidencias actuales contraindican su uso en pacientes con antecedentes de Insuficiencia cardiaca clase funcional III-IV ya que la pioglitazona podría aumentar el riesgo de internaciones.

MACE: eventos cardiovasculares mayores (mortalidad cardiovascular, infarto no fatal y ACV no fatal)

Trabajo completo publicado en Nesti et al. Cardiovasc Diabetol (2021) 20:109. https://doi.org/10.1186/s12933-021-01294-7

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Hígado graso no alcohólico y esteatohepatitis: Estado del arte sobre la eficacia terapéutica

¿Cuál es la evidencia del tratamiento con pioglitazona en MAFLD?

La prevalencia de MAFLD (enfermedad por hígado graso asociado a enfermedad metabólica) en pacientes con diabetes llega al 57% según algunas publicaciones recientes. La MAFLD puede progresar a cirrosis y a hepatocarcinoma, pero también aumenta el riesgo de enfermedad renal crónica, enfermedad cardiovascular, y otros cánceres. Varios estudios y metaanálisis han demostrado mejorías consistentes con pioglitazona en los scores de esteatosis y en las biopsias (método estándar de oro para diagnóstico). Los beneficios observados con pioglitazona se han podido comprobar en diferentes estadíos de la enfermedad, en la inflamación, en la balonización hepatocitaria e incluso en la etapa de fibrosis (ver figura 1).

Figura 1. Metaanálisis Pioglitazona en fibrosis hepática avanzada.
Adaptado de JAMA Intern Med. doi:10.1001/jamainternmed.2016.9607

Resumen de los beneficios de Pioglitazona en MAFLD

Figura 2. Adaptada de Molecular Metabolism 50, 2021, 101049. https://doi.org/10.1016/j.molmet.2020.101049

¿Con que dosis se evidenciaron resultados positivos en hígado graso?

Se evidenciaron resultados favorables histológicos con las dosis de 30 y 45 mg de pioglitazona. En la actualidad algunos grupos de investigación se encuentran investigando el impacto de 15 mg/día en MAFLD.

Trabajo completo publicado en Molecular Metabolism 50, 2021, 101049. https://doi.org/10.1016/j.molmet.2020.101049

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The forgotten, cost-effective cardioprotective drug for type 2 diabetes

Publicamos esta revisión sobre la evidencia disponible en el uso de pioglitazona como tratamiento en diabetes 2.

Documenta el modo en que el fármaco disminuye los niveles de glucemia y mejora la protección de eventos cardiovasculares a un costo accesible.

El análisis firmado por los especialistas Ralph DeFronzo, Silvio Inzucchi, Steven E Nissen y Muhammad Abdul-Ghani señala los efectos cardioprotectores de la pioglitazona, retrasando los procesos arterioscleróticos y reduciendo eventos cardiovasculares.

Este fármaco, potente sensibilizador de la insulina, mejora y preserva la función de las células beta, llevando a una reducción de la HbA1c. Además ayuda a corregir el síndrome metabólico, y mejora la enfermedad del hígado graso no alcohólico.

Estos beneficios y su bajo costo, lo convierten en una eficaz herramienta en el tratamiento de DT2.

Abstract

Type 2 diabetes individuals are at high risk for macrovascular complications: myocardial infarction, stroke and cardiovascular mortality. Recent cardiovascular outcome trials have demonstrated that agents in two antidiabetic classes (SGLT2 inhibitors and GLP-1 receptor agonists) reduce major adverse cardiovascular events. However, there is strong evidence that an older and now generically available medication, the thiazolidinedione, pioglitazone, can retard the atherosclerotic process (PERISCOPE and Chicago) and reduce cardiovascular events in large randomized prospective cardiovascular outcome trials (IRIS and PROactive). Pioglitazone is a potent insulin sensitizer, preserves beta-cell function, causes durable reduction in HbA1c, corrects multiple components of metabolic syndrome and improves nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adverse effects (weight gain, fluid retention, fractures) must be considered, but are diminished with lower doses and are arguably outweighed by these multiple benefits. With healthcare expenses attributable to diabetes increasing rapidly, this cost-effective drug requires reconsideration in the therapeutic armamentarium for the disease.

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Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

Backgroud

Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease.

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Nonalcoholic Fatty Liver Disease: Current Issues and Novel Treatment Approaches

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world. It is commonly associated with insulin resistance, obesity, dyslipidaemia, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is characterized by steatosis with necroinflammation and eventual fibrosis, which can lead to end-stage liver disease and hepatocellular carcinoma. Its pathogenesis is complex, and involves a state of ‘lipotoxicity’ in which insulin resistance, with increased free fatty acid release from adipose tissue to the liver, play a key role in the onset of a ‘lipotoxic liver disease’ and its progression to NASH. The diagnosis of NASH is challenging, as most affected patients are symptom free and the role of routine screening is not clearly established. A complete medical history is important to rule out other causes of fatty liver disease (alcohol abuse, medications, other). Plasma aminotransferase levels and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for a definitive diagnosis. However, there is an active search for plasma biomarkers and imaging techniques that may non-invasively aid in the diagnosis. The treatment of NASH requires a multifaceted approach. The goal is to reverse obesity-associated lipotoxicity and insulin resistance via lifestyle intervention. Although there is no pharmacological agent approved for the treatment of NAFLD, vitamin E (in patients without T2DM) and the thiazolidinedione pioglitazone (in patients with and without T2DM) have shown the most consistent results in randomized controlled trials. This review concentrates on our current understanding of the disease, with a focus on the existing therapeutic approaches and potential future pharmacological developments for NAFLD and NASH.

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A validated liquid chromatography tandem mass spectrometry method for simultaneous determination of pioglitazone, hydroxypioglitazone, and ketopioglitazone in human plasma and its application to a clinical study

Abstract

A simple and rapid high performance liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of pioglitazone and its active metabolites hydroxypioglitazone and ketopioglitazone in human plasma. Samples were processed by protein precipitation with acetonitrile and selective phospholipid depletion in a 96-well plate format. The method used deuterated internal standards for each analyte. Chromatographic separation was achieved with gradient elution on a Hypersil GOLD C18 column. The mass spectrometer was operated in electrospray positive ion mode with detection by selected reaction monitoring using the transitions m/z 357.1 > 134.0 for pioglitazone, m/z 373.1 > 150.0 for hydroxypioglitazone, and m/z 371.0 > 148.0 for ketopioglitazone. A linear standard curve was established for the range of 10–1800 ng/mL for all three analytes. Intra-run and inter-run precision and accuracy (relative error) were less than 15%, and the mean extraction recoveries of all analytes were more than 87.8%. The validated method is sensitive and selective and was successfully applied to analyze clinical samples obtained from patients with nonalcoholic fatty liver disease taking pioglitazone.

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Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis

Objectives

To evaluate the effect of pioglitazone in people with insulin resistance, pre-diabetes and type 2
diabetes. Design and setting: Systematic review and meta-analysis of randomised, controlled trials.

Data sources:

Literature searches were performed across PubMed, EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials from 1966 to May 2016 to identify randomised, controlled trials with more than 1 year follow-up.

Outcome measures:

Relative risk (RR) with 95% CI was used to evaluate the association between pioglitazone and the risk of major adverse cardiovascular events (MACE: composite of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death) and safety outcomes, after pooling data across trials in a fixed-effects model. Results: Nine trials with 12 026 participants were enrolled in the current meta-analysis. Pioglitazone therapy was associated with a lower risk of MACE in patients with pre-diabetes or insulin resistance (RR 0.77, 95% CI 0.64 to 0.93), and diabetes (RR 0.83, 95% CI 0.72 to 0.97). Risks of heart failure (RR 1.32; CI 1.14 to 1.54), bone fracture (RR 1.52, 95% CI 1.17 to 1.99), oedema (RR, 1.63; CI 1.52 to 1.75) and weight gain (RR 1.60; CI 1.50 to 1.72) increased in pioglitazone group.

Conclusions:

Pioglitazone was associated with reduced risk of MACE in people with insulin resistance, pre-diabetes and diabetes mellitus. However, the risks of heart failure, bone fracture, oedema and weight gain were increased.

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Thiazolidinediones and the Promise of Insulin Sensitization in Type 2 Diabetes

Raymond E. Soccio,1 Eric R. Chen,1 and Mitchell A. Lazar1,

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: lazar@mail.med.upenn.edu
http://dx.doi.org/10.1016/j.cmet.2014.08.005

Abstract

Type 2 diabetes is caused by insulin resistance coupled with an inability to produce enough insulin to control blood glucose, and thiazolidinediones (TZDs) are the only current antidiabetic agents that function primarily by increasing insulin sensitivity. However, despite clear benefits in glycemic control, this class of drugs has recently fallen into disuse due to concerns over side effects and adverse events. Here we review the clinical data and attempt to balance the benefits and risks of TZD therapy. We also examine potential mechanisms of action for the beneficial and harmful effects of TZDs, mainly via agonism of the nuclear receptor PPARg.

Based on critical appraisal of both preclinical and clinical studies, we discuss the prospect of harnessing the insulin sensitizing effects of PPARg for more effective, safe, and potentially personalized treatments of type 2 diabetes.

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Contenido para profesionales de la salud

El material incluido en sección ha sido concebido exclusivamente para los profesionales de la salud con fines informativos, y destinado a orientar sobre el uso adecuado de los medicamentos y a satisfacer sus necesidades de mayor información.

Laboratorios Francelab le sugiere consultar siempre a un profesional de la salud calificado ante cualquier duda sobre una condición médica particular.