Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses

Wallach, John R.; Wang, Kun; Zhang, Audrey D; Cheng, Deanna; Nardini, Holly K. Grossetta; Lin, Haiqun; Bracken, Michael B.; Desai, Mayur M.; Krumholz, Harlan M.; Ross, Joseph S.

doi:10.1136/bmj.l7078

Cited by 66 publications

(38 citation statements)

References 63 publications

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“…The initial results with rosiglitazone were promising [39, 46], but later clinical trials with larger numbers of patients and a longer duration achieved very poor results [16, 41, 42]. Moreover, its use as rosiglitazone was withdrawn from the market due to increased cardiovascular risk [61].…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic Drugs in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review

Muñoz-Jiménez

Zaarkti

García-Arnés

et al. 2020

Dement Geriatr Cogn Disord

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Introduction: Considering that Alzheimer’s disease (AD) and diabetes mellitus share pathophysiological features and AD remains with no cure, antidiabetic drugs like intranasal insulin, glitazones, metformin, and liraglutide are being tested as a potential treatment. Objective: The aim of this systematic review was to assess the efficacy of antidiabetic drugs in patients with AD, mild cognitive impairment (MCI), or subjective cognitive complaints (SCCs). Cognition was studied as the primary outcome and modulation of AD biomarkers, and imaging was also assessed as a secondary outcome. Methods: We conducted a search in the electronic databases PubMed/MEDLINE, EMBASE, and Scopus seeking clinical trials evaluating the effect on cognition of antidiabetic drugs in patients with AD, MCI, or SCCs. Results: A total of 23 articles were found eligible. Intranasal regular insulin improved verbal memory in most studies, especially in apoE4− patients, but results in other cognitive domains were unclear. Detemir improved cognition after 2 months of treatment, but it did not after 4 months. Pioglitazone improved cognition in diabetic patients with AD or MCI in 3 clinical trials, but it is controversial as 2 other studies did not show effect. Metformin and liraglutide showed promising results, but further research is needed as just 2 clinical trials involved each of these drugs. Almost all drugs tested were shown to modulate AD biomarkers and imaging. Conclusions: Intranasal insulin, pioglitazone, metformin, and liraglutide are promising drugs that could be useful in the treatment of AD. However, many questions remain to be answered in future studies, so no particular antidiabetic drug can currently be recommended to treat AD.

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Section: Discussionmentioning

confidence: 99%

Antidiabetic Drugs in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review

Muñoz-Jiménez

Zaarkti

García-Arnés

et al. 2020

Dement Geriatr Cogn Disord

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“…Several of the enrichments recapitulate important known biology. For example, among cardiometabolic traits, high-density lipoprotein (HDL) and triglyceride levels were enriched for dexamethasone (P=2.10 x 10 -3 and P=6.53 x 10 -3 ), a corticosteroid known to induce dyslipidemia 31,32 , and cardiovascular disease was enriched for rosiglitazone (P=6.44 x 10 -3 ), an antidiabetic drug shown to increase risk of cardiovascular disease 33 . In addition, these enrichments were often manifested through a single specific relevant cell line.…”

Section: Prioritizing Complex Disease-relevant Environmental Perturbamentioning

confidence: 99%

An integrated approach to identify environmental modulators of genetic risk factors for complex traits

Balliu

Orive

Gloudemans

et al. 2021

Preprint

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Complex traits and diseases can be influenced by both genetics and environment. However, given the large number of environmental stimuli and power challenges for gene-by-environment testing, it remains a critical challenge to identify and prioritize specific disease-relevant environmental exposures. We propose a novel framework for leveraging signals from transcriptional responses to environmental perturbations to identify disease-relevant perturbations that can modulate genetic risk for complex traits and inform the functions of genetic variants associated with complex traits. We perturbed human skeletal muscle, fat, and liver relevant cell lines with 21 perturbations affecting insulin resistance, glucose homeostasis, and metabolic regulation in humans and identified thousands of environmentally responsive genes. By combining these data with GWAS from 31 distinct polygenic traits, we show that heritability of multiple traits is enriched in regions surrounding genes responsive to specific perturbations and, further, that environmentally responsive genes are enriched for associations with specific diseases and phenotypes from the GWAS catalogue. Overall, we demonstrate the advantages of large-scale characterization of transcriptional changes in diversely stimulated and pathologically relevant cells to identify disease-relevant perturbations.

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“…The thiazolidinedione rosiglitazione was approved for use in type-2 diabetes mellitus patients in 1999 by the U.S. Food and Drug Administration (FDA), and in 2000 by the European Medicines Agency (EMA). However, after doubts arose about the cardiovascular safety of the drug, both agencies revised their approvals, with the EMA fully withdrawing it in 2010 [ 58 , 59 ]. Various hypotheses exist on the nature of rosiglitazone cardiotoxicity.…”

Section: Mitochondrial Dysfunction and Cardiovascular Disordersmentioning

confidence: 99%

Mitochondrial Dysfunction and Heart Disease: Critical Appraisal of an Overlooked Association

Bisaccia

Ricci

Gallina

et al. 2021

IJMS

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The myocardium is among the most energy-consuming tissues in the body, burning from 6 to 30 kg of ATP per day within the mitochondria, the so-called powerhouse of the cardiomyocyte. Although mitochondrial genetic disorders account for a small portion of cardiomyopathies, mitochondrial dysfunction is commonly involved in a broad spectrum of heart diseases, and it has been implicated in the development of heart failure via maladaptive circuits producing and perpetuating mitochondrial stress and energy starvation. In this bench-to-bedside review, we aimed to (i) describe the key functions of the mitochondria within the myocardium, including their role in ischemia/reperfusion injury and intracellular calcium homeostasis; (ii) examine the contribution of mitochondrial dysfunction to multiple cardiac disease phenotypes and their transition to heart failure; and (iii) discuss the rationale and current evidence for targeting mitochondrial function for the treatment of heart failure, including via sodium-glucose cotransporter 2 inhibitors.

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Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses

Cited by 66 publications

References 63 publications

Antidiabetic Drugs in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review

Antidiabetic Drugs in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review

An integrated approach to identify environmental modulators of genetic risk factors for complex traits

Mitochondrial Dysfunction and Heart Disease: Critical Appraisal of an Overlooked Association

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