Thiazolidinediones: the Forgotten Diabetes Medications

Lebovitz, Harold E.

doi:10.1007/s11892-019-1270-y

Cited by 264 publications

(207 citation statements)

References 81 publications

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“…PGC1-α, the aforementioned transcription factor known for its role in mitochondrial biogenesis, also functions as a coactivator PPARγ (124). Thiazolidinediones are clinically used anti-diabetic drugs, which increase insulin sensitivity through activation of PPARγ (125). Rosiglitazone, a thiazolidinedione class drug, was shown to attenuate LPS-induced cardiac dysfunction and protect mitochondria leading to improved survival (80).…”

Section: Peroxisome Proliferator-activated Receptor (Ppar) Activatorsmentioning

confidence: 99%

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

et al. 2020

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Critically ill, severely injured and high-risk surgical patients are vulnerable to secondary infections during hospitalization and after hospital discharge. Studies show that the mitochondrial function and oxidative metabolism of monocytes and macrophages are impaired during sepsis. Alternatively, treatment with microbe-derived ligands, such as monophosphoryl lipid A (MPLA), peptidoglycan, or β-glucan, that interact with toll-like receptors and other pattern recognition receptors on leukocytes induces a state of innate immune memory that confers broad-spectrum resistance to infection with common hospital-acquired pathogens. Priming of macrophages with MPLA, CPG oligodeoxynucleotides (CpG ODN), or β-glucan induces a macrophage metabolic phenotype characterized by mitochondrial biogenesis and increased oxidative metabolism in parallel with increased glycolysis, cell size and granularity, augmented phagocytosis, heightened respiratory burst functions, and more effective killing of microbes. The mitochondrion is a bioenergetic organelle that not only contributes to energy supply, biosynthesis, and cellular redox functions but serves as a platform for regulating innate immunological functions such as production of reactive oxygen species (ROS) and regulatory intermediates. This review will define current knowledge of leukocyte metabolic dysfunction during and after sepsis and trauma. We will further discuss therapeutic strategies that target leukocyte mitochondrial function and might have value in preventing or reversing sepsis-and trauma-induced immune dysfunction.

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Section: Peroxisome Proliferator-activated Receptor (Ppar) Activatorsmentioning

confidence: 99%

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

et al. 2020

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“…Pioglitazone belongs to the family of thiazolidinediones (TZDs), i.e. drugs that are commonly used for treating insulin resistance [33]. We know the following facts about insulin resistance: it amplifies inflammation [34], it is associated with several cardiovascular risk factors [35], it is associated with an increase in C-reactive protein, IL-6, and TNF-α [36] and produces a pro-coagulant state with increased fibrinogen and plasminogen activator inhibitor, (PAI-1) [37].…”

Section: Hypothesismentioning

confidence: 99%

Can pioglitazone be potentially useful therapeutically in treating patients with COVID-19?

2020

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic disease (COVID-19) that has spread globally causing more than 30,000 deaths. Despite the immense and ongoing global effort, no efficacious drugs to fight this plague have been identified and patients admitted to the intensive care units (ICU), for respiratory distress, are managed mostly by means of supportive care based on oxygen maintenance. Several authors have reported that the prevalence of hypertension, diabetes, cardiovascular and cerebrovascular diseases comorbidities were indeed frequent among patients with COVID-19, which suggests that these conditions are likely to aggravate and complicate the prognosis. What the aforementioned diseases have in common is a latent chronic inflammatory state that may be associated with the alteration of laboratory parameters that are typical of the metabolic syndrome and insulin resistance. In severe COVID-19 patients laboratory markers of inflammation such as C-reactive protein, IL-6, D-dimer, serum ferritin and lactate dehydrogenase are elevated in many patients; assessed since the 4th-6th day of illness onset, such increases seem to be predictive of an adverse prognosis. Our hypothesis is that drugs belonging to the family of thiazolidinediones (TZD) such as pioglitazone or rosiglitazone, approved for treating the condition of insulin resistance and the accompanying inflammation, could ameliorate the prognosis of those COVID-19 patients with diabetes, hypertension and cardiovascular disorders comorbidities. TZD are PPARγ agonists that act on nuclear receptors, thereby triggering certain transcription factors. TZD were widely used for type-2 diabetes in the first decade of this century and although concerns have been raised for possible side effects associated with long-term treatment, their use has been recently revaluated for their anti-inflammatory properties in numerous medical conditions.

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“…Positive therapeutic benefits from PPAR agonists in general need however to be balanced with their long-term safety and tolerability. Class effects on the increased risk of heart failure, fluid retention/oedema and bone fractures with TZDs were documented [48,49]. Pioglitazone is not widely used because of safety concerns such as risks of cardiac decompensation in patients with pre-existing myocardial dysfunction although overall cardiovascular prognosis improved [50].…”

Section: Clinical Data On Ppar Ligands In Nashmentioning

confidence: 99%

“…Hepatic enzymes ALT, AST and γGT and as well as effect on steatosis on imaging, which are frequently used as surrogate primary parameters of efficacy in proof of concept Phase 2 studies during the early development of different drugs, were not chosen as primary endpoints in NATIVE study as these surrogate endpoints are not always good predictors or representatives of disease activity in NASH [49][50][51]. In the absence of validated markers, only histological assessment through biopsy remains the gold standard for assessment of NAFLD severity and treatment efficacy [56].…”

Section: Choice Of the Primary Endpointmentioning

confidence: 99%

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study

Bédossa

et al. 2020

Contemporary Clinical Trials

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Background Non-alcoholic steatohepatitis (NASH), a multifactorial disease, can progress to hepatic fibrosis and cirrhosis. The Peroxysomal Proliferator-Activated Receptors, PPARα, β/δ and γ, play a central role in the regulation of glucose and lipid metabolism and of the inflammatory and fibrogenic pathways in liver and in other organs that all contribute to NASH pathogenesis. Lanifibranor (IVA337), a panPPAR agonist, by acting on these three different PPAR isotypes, combines pharmacological effects that could address the different components of the disease as demonstrated in preclinical models. Objectives NATIVE study (EudraCT: 2016-001979-70, NCT: NCT03008070) aims to assess the safety and the efficacy of a 24-week treatment with lanifibranor (800 and 1200 mg/day) in adult non-cirrhotic NASH patients. The primary efficacy endpoint is a 2-point reduction in the activity part of the Steatosis Activity Fibrosis (SAF) histological score (combining inflammation and ballooning) without worsening of fibrosis. Design NATIVE is a Phase 2b randomised, placebo-controlled, double-blind, parallel-assignment, dose-range study. Eligible adult patients with a confirmed histological diagnosis of NASH should have a SAF Activity score of 3 or 4 (> 2) and a SAF Steatosis score ≥ 1. There is no specific criterion related to the fibrosis score except that patients with cirrhosis (F4) were excluded. Summary This study will evaluate the efficacy of a 24-week treatment of NASH with lanifibranor based on histological evaluations (SAF score) by biopsy. The number of responders according to the SAF Activity score-based definition from baseline to 24 weeks will be compared between groups and serves as primary endpoint.

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Thiazolidinediones: the Forgotten Diabetes Medications

Cited by 264 publications

References 81 publications

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

Can pioglitazone be potentially useful therapeutically in treating patients with COVID-19?

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study

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