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Aktas G, Atak Tel BM, Tel R, Balci B. Treatment of type 2 diabetes patients with heart conditions. Expert Rev Endocrinol Metab 2023; 18:255-265. [PMID: 37078758 DOI: 10.1080/17446651.2023.2204941] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/17/2023] [Indexed: 04/21/2023]
Abstract
INTRODUCTION While type 2 diabetes mellitus (T2DM) increases the risk of cardiac complications, diabetes treatment choices may increase or decrease the rates of cardiac events. In the present review, we comprehensively discussed the treatment options of diabetic subjects with cardiac conditions. AREAS COVERED Current evidence related to diabetes treatment in cardiac situations has been reviewed. Clinical trials and meta-analyses on cardiac safety of anti-diabetic medicines are discussed. Treatment choices with proven benefits and those at least without associated increased cardiac risk were drawn from clinical trials; meta-analyses and cardiac safety studies in the recent medical literature were the basis of the suggestions in the present review. EXPERT OPINION We can suggest that hypoglycemia and extreme hyperglycemia should be avoided in acute ischemic heart conditions. Certain diabetic treatment options, especially sodium-glucose cotransporter-2 (SGLT2) inhibitors, can reduce overall cardiovascular mortality and hospitalization due to heart failure. Therefore, we suggest that physicians should choose SGLT2 inhibitors as the first-line treatment option in diabetic patients with heart failure or those who have a high risk of heart failure development. T2DM increases the risk of atrial fibrillation (AF), and metformin and pioglitazone seem to reduce the risk of AF in diabetic population.
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Affiliation(s)
- Gulali Aktas
- Department of Internal Medicine, Abant Izzet Baysal University Hospital, Bolu, Turkey
| | | | - Ramiz Tel
- Izzet Baysal State Hospital, Department of Emergency, Bolu, Turkey
| | - Buse Balci
- Department of Internal Medicine, Abant Izzet Baysal University Hospital, Bolu, Turkey
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Wu PY, Lai SY, Su YT, Yang KC, Chau YP, Don MJ, Lu KH, Shy HT, Lai SM, Kung HN. β-Lapachone, an NQO1 activator, alleviates diabetic cardiomyopathy by regulating antioxidant ability and mitochondrial function. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 104:154255. [PMID: 35738116 DOI: 10.1016/j.phymed.2022.154255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 05/29/2022] [Accepted: 06/06/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Diabetic cardiomyopathy (DC) is one of the major lethal complications in patients with diabetes mellitus (DM); however, no specific strategy for preventing or treating DC has been identified. PURPOSE This study aimed to investigate the effects of β-lapachone (Lap), a natural compound that increases antioxidant activity in various tissues, on DC and explore the underlying mechanisms. STUDY DESIGN AND METHODS As an in vivo model, C57BL/6 mice were fed with the high-fat diet (HF) for 10 weeks to induce type 2 DM. Mice were fed Lap with the HF or after 5 weeks of HF treatment to investigate the protective effects of Lap against DC. RESULTS In the two in vivo models, Lap decreased heart weight, increased heart function, reduced oxidative stress, and elevated mitochondrial content under the HF. In the in vitro model, palmitic acid (PA) was used to mimic the effects of an HF on the differentiated-cardiomyoblast cell line H9c2. The results demonstrated that Lap reduced PA-induced ROS production by increasing the expression of antioxidant regulators and enzymes, inhibiting inflammation, increasing mitochondrial activity, and thus reducing cell damage. Via the use of specific inhibitors and siRNA, the protective effects of Lap were determined to be mediated mainly by NQO1, Sirt1 and mitochondrial activity. CONCLUSION Heart damage in DM is usually caused by excessive oxidative stress. This study showed that Lap can protect the heart from DC by upregulating antioxidant ability and mitochondrial activity in cardiomyocytes. Lap has the potential to serve as a novel therapeutic agent for both the prevention and treatment of DC.
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Affiliation(s)
- Pei-Yu Wu
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University
| | - Shin-Yu Lai
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University
| | - Yi-Ting Su
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University
| | - Kai-Chien Yang
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University
| | | | | | - Kai-Hsi Lu
- Department of Medical Research and Education, Cheng-Hsin General Hospital
| | - Horng-Tzer Shy
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University
| | - Shu-Mei Lai
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University
| | - Hsiu-Ni Kung
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University.
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Mannucci E, Targher G, Nreu B, Pintaudi B, Candido R, Giaccari A, Gallo M, Monami M. Effects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis 2022; 32:1353-1360. [PMID: 35422359 DOI: 10.1016/j.numecd.2022.03.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/31/2022] [Accepted: 03/04/2022] [Indexed: 10/18/2022]
Abstract
AIM In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect. DATA SYNTHESIS A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively). CONCLUSIONS This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.
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Affiliation(s)
| | - Giovanni Targher
- Endocrinology, Diabetes and Metabolism, University of Verona, Italy
| | - Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Riccardo Candido
- Diabetes Centre District 3, Azienda Sanitaria Universitaria Integrata di Trieste, Via Puccini 48/50, 34100, Trieste, Italy
| | - Andrea Giaccari
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Marco Gallo
- Endocrinology and Metabolic Diseases Unit, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
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Synthesis and biological evaluation of cajanonic acid A derivatives as potential PPARγ antagonists. Bioorg Med Chem Lett 2021; 52:128410. [PMID: 34626784 DOI: 10.1016/j.bmcl.2021.128410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/29/2021] [Accepted: 10/02/2021] [Indexed: 11/23/2022]
Abstract
Four series of cajanonic acid A (CAA) derivatives have been designed and synthesized. The newly prepared compounds have been screened for glucose consumption activity in HepG2 cell lines and PPARγ antagonistic activity in HEK293 cell lines. Compound 26g bearing a tetrahydroisoquinolinone scaffold showed the most potent PPARγ antagonistic and hypoglycemic activities. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 26g was a potent hypoglycemic agent. In addition, the possible binding modes for compound 26g in the PPARγ protein have been investigated in this study.
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Zolty R. Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension. J Exp Pharmacol 2021; 13:817-857. [PMID: 34429666 PMCID: PMC8380049 DOI: 10.2147/jep.s236743] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH.
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Affiliation(s)
- Ronald Zolty
- Pulmonary Hypertension Program, University of Nebraska Medical Center, Lied Transplant Center, Omaha, NE, USA
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Abstract
Diabetes and heart failure (HF) are common diseases, each affecting large segments of the world population. Moreover, prevalence rates for both are expected to rise dramatically over coming decades. The high prevalence rates of both diseases and wellrecognized association of diabetes as a risk factor for HF make it inevitable that both diseases co-exist in a large number of patients, complicating their management and increasing the risk of a poor outcome. Management of diabetes has been shown to impact clinical events in patients with HF and there is emerging evidence that agents used to treat diabetes can reduce HF events, even in non-diabetic patients. In this review we summarize the clinical course and treatment of patients with type 2 diabetes mellitus (T2DM) and HF and review the efficacy and safety of pharmacological agents in patients with T2DM at risk for HF and those with established disease.
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Affiliation(s)
- Jia Shen
- Division of Cardiology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Barry H. Greenberg
- Division of Cardiology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Corresponding author: Barry H. Greenberg https://orcid.org/0000-0002-6605-9385 Division of Cardiology, Department of Medicine, UC San Diego Health Cardiovascular Institute, 9452 Medical Center Drive, La Jolla, CA 92037-7411, USA E-mail:
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Krittayaphong R, Permsuwan U. Cost-utility analysis of add-on dapagliflozin treatment in heart failure with reduced ejection fraction. Int J Cardiol 2020; 322:183-190. [PMID: 32800910 DOI: 10.1016/j.ijcard.2020.08.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/19/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Dapagliflozin is an antidiabetic medication that has been shown to reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF). This study aimed to determine the cost-utility of add-on dapagliflozin treatment for HFrEF. METHODS An analytical decision model was constructed to assess lifetime costs and outcomes from a healthcare system perspective. The cohort comprised HFrEF patients with left ventricular ejection fraction (LVEF) ≤40%, and New York Heart Association (NYHA) class II-IV with an average age of 65 years. Clinical inputs were derived from the results of the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure (DAPA-HF) trial. Risk of non-cardiovascular death data, readmission rate data, and treatment-related cost data were based on Thai population. The outcomes and costs were discounted at 3% annually. A series of sensitivity analyses were also conducted. RESULTS The increased cost of dapagliflozin add-on treatment from 17,442 THB (559 USD) to 54,405 THB (1745 USD) was associated with a QALY gain from 6.33 to 6.92 compared to standard therapy, yielding an ICER of 62,090 THB/QALY (1991 USD/QALY). Sensitivity analyses revealed that the addition of dapagliflozin to the standard treatment demonstrated an 87% cost-effectiveness strategy at a level of willingness to pay (WTP) of 160,000 THB/QALY (5131 USD/QALY). ICER was higher in non-diabetes compared to diabetes (68,304 vs 47,613 THB/QALY or 2191 vs 1527 USD/QALY). CONCLUSIONS Dapagliflozin is a cost-effective add-on therapy for patients with HFrEF at a WTP of 160,000 THB/QALY (5131 USD/QALY).
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Affiliation(s)
- Rungroj Krittayaphong
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Unchalee Permsuwan
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.
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Bhattamisra SK, Shin LY, Saad HIBM, Rao V, Candasamy M, Pandey M, Choudhury H. Interlink Between Insulin Resistance and Neurodegeneration with an Update on Current Therapeutic Approaches. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2020; 19:174-183. [PMID: 32418534 DOI: 10.2174/1871527319666200518102130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/16/2020] [Accepted: 04/27/2020] [Indexed: 02/08/2023]
Abstract
The interlink between diabetes mellitus and neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD) has been identified by several researchers. Patients with Type-2 Diabetes Mellitus (T2DM) are found to be affected with cognitive impairments leading to learning and memory deficit, while patients with Type-1 Diabetes Mellitus (T1DM) showed less severe levels of these impairments in the brain. This review aimed to discuss the connection between insulin with the pathophysiology of neurodegenerative diseases (AD and PD) and the current therapeutic approached mediated through insulin for management of neurodegenerative diseases. An extensive literature search was conducted using keywords "insulin"; "insulin resistance"; "Alzheimer's disease"; "Parkinson's disease" in public domains of Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Studies have shown that impaired insulin signaling contributes to the accumulation of amyloid-β, neurofibrillary tangles, tau proteins and α-synuclein in the brain. Whereas, improvement in insulin signaling slows down the progression of cognitive decline. Various therapeutic approaches for altering the insulin function in the brain have been researched. Besides intranasal insulin, other therapeutics like PPAR-γ agonists, neurotrophins, stem cell therapy and insulin-like growth factor-1 are under investigation. Research has shown that insulin insensitivity in T2DM leads to neurodegeneration through mechanisms involving a variety of extracellular, membrane receptor, and intracellular signaling pathway disruptions. Some therapeutics, such as intranasal administration of insulin and neuroactive substances have shown promise but face problems related to genetic background, accessibility to the brain, and invasiveness of the procedures.
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Affiliation(s)
- Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Lee Yuen Shin
- School of Health Sciences, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | | | - Vikram Rao
- School of Postgraduate Studies, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Mayuren Candasamy
- Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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Wallach JD, Wang K, Zhang AD, Cheng D, Grossetta Nardini HK, Lin H, Bracken MB, Desai M, Krumholz HM, Ross JS. Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses. BMJ 2020; 368:l7078. [PMID: 32024657 PMCID: PMC7190063 DOI: 10.1136/bmj.l7078] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing. DESIGN Systematic review and meta-analysis of randomized controlled trials. DATA SOURCES GlaxoSmithKline's (GSK's) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK's Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Randomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults. DATA EXTRACTION AND SYNTHESIS For analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals. RESULTS 33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK's summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used. CONCLUSIONS The results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety. SYSTEMATIC REVIEW REGISTRATION OSF Home https://osf.io/4yvp2/.
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Affiliation(s)
- Joshua D Wallach
- Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT 06510, USA
- Collaboration for Research Integrity and Transparency, Yale School of Medicine, New Haven, CT, USA
| | - Kun Wang
- Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, CT, USA
| | - Audrey D Zhang
- Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, CT, USA
- New York University School of Medicine, New York, NY, USA
| | - Deanna Cheng
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | | | - Haiqun Lin
- Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
| | - Michael B Bracken
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Mayur Desai
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Harlan M Krumholz
- Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, CT, USA
- Section of Cardiovascular Medicine and the National Clinician Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA
| | - Joseph S Ross
- Collaboration for Research Integrity and Transparency, Yale School of Medicine, New Haven, CT, USA
- Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, CT, USA
- Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA
- Section of General Medicine and the National Clinician Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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Prins KW, Thenappan T, Weir EK, Kalra R, Pritzker M, Archer SL. Repurposing Medications for Treatment of Pulmonary Arterial Hypertension: What's Old Is New Again. J Am Heart Assoc 2020; 8:e011343. [PMID: 30590974 PMCID: PMC6405714 DOI: 10.1161/jaha.118.011343] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Kurt W Prins
- 1 Cardiovascular Division University of Minnesota Medical School Minneapolis MN
| | - Thenappan Thenappan
- 1 Cardiovascular Division University of Minnesota Medical School Minneapolis MN
| | - E Kenneth Weir
- 1 Cardiovascular Division University of Minnesota Medical School Minneapolis MN
| | - Rajat Kalra
- 1 Cardiovascular Division University of Minnesota Medical School Minneapolis MN
| | - Marc Pritzker
- 1 Cardiovascular Division University of Minnesota Medical School Minneapolis MN
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Zhang X, Huang-Fu Z, Lang XY, Chun P, Chi YY, Yuan XY, Wang XG. Pathological and cognitive changes in patients with type 2 diabetes mellitus and comorbid MCI and protective hypoglycemic therapies: a narrative review. Rev Neurosci 2019; 30:757-770. [PMID: 31199776 DOI: 10.1515/revneuro-2018-0083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 01/30/2019] [Indexed: 01/04/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is becoming a significant health issue worldwide. Many studies support the hypothesis that patients with T2DM have a higher-than-expected incidence of mild cognitive impairment (MCI) than individuals without diabetes. Based on the results from recent studies, MCI might be associated with the effects of T2DM on glucose metabolism and brain atrophy. As a narrative review, we will illuminate pathological and cognitive changes in patients with T2DM and comorbid MCI and protective hypoglycemic therapies. The early abnormal signs of cognition must be elucidated, and extensive investigations are needed to develop improved therapies for use in the clinic.
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Affiliation(s)
- Xiao Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian 116000, P.R. China
| | - Zhao Huang-Fu
- The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, P.R. China
| | - Xing-Ying Lang
- Dalian Center for Disease Control and Prevention, Dalian 116021, P.R. China
| | - Pu Chun
- Department of Anatomy, College of Basic Medicine, Dalian Medical University, Dalian 16044, P.R. China
| | - Yan-Yan Chi
- Department of Anatomy, College of Basic Medicine, Dalian Medical University, Dalian 16044, P.R. China
| | - Xiao-Ying Yuan
- Department of Anatomy, College of Basic Medicine, Dalian Medical University, Dalian 16044, P.R. China
| | - Xu-Gang Wang
- Department of Neurology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, P.R. China
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Arsoy D, Salib CG, Trousdale WH, Tibbo ME, Limberg AK, Viste A, Lewallen EA, Reina N, Yaszemski MJ, Berry DJ, van Wijnen AJ, Morrey ME, Sanchez-Sotelo J, Abdel MP. Joint contracture is reduced by intra-articular implantation of rosiglitazone-loaded hydrogels in a rabbit model of arthrofibrosis. J Orthop Res 2018; 36:2949-2955. [PMID: 29901247 PMCID: PMC6347955 DOI: 10.1002/jor.24068] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/03/2018] [Indexed: 02/04/2023]
Abstract
Trauma, surgery, and other inflammatory conditions can lead to debilitating joint contractures. Adjunct pharmacologic modalities may permit clinical prevention and treatment of recalcitrant joint contractures. We investigated the therapeutic potential of rosiglitazone by intra-articular delivery via oligo[poly(ethylene glycol)fumarate] (OPF) hydrogels in an established rabbit model of arthrofibrosis. OPF hydrogels loaded with rosiglitazone were characterized for drug elution properties upon soaking in minimum essential media (MEM) with 10% fetal bovine serum and measurements of drug concentrations via High Performance Liquid Chromatography (HPLC). Drug-loaded scaffolds were surgically implanted into 24 skeletally mature female New Zealand White rabbits that were divided into equal groups receiving OPF hydrogels loaded with rosiglitazone (1.67 mg), or vehicle control (10 µl DMSO). After 8 weeks of joint immobilization, rabbits were allowed unrestricted cage activity for 16 weeks. Contracture angles of rabbit limbs treated with rosiglitazone showed statistically significant improvements in flexion compared to control animals (mean angles, respectively, 64.4° vs. 53.3°, p < 0.03). At time of sacrifice (week 24), animals in the rosiglitazone group continued to exhibit less joint contracture than controls (119.0° vs. 99.5°, p = 0.014). The intra-articular delivery of rosiglitazone using implanted OPF hydrogels decreases flexion contractures in a rabbit model of arthrofibrosis without causing adverse effects (e.g., gross inflammation or arthritis). Statement of Clinical Significance: Post-traumatic joint contractures are common and debilitating, with limited available treatment options. Pharmacologic interventions can potentially prevent and treat such contractures. This study is translational in that a commercially approved medication has been repurposed through a novel delivery device. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2949-2955, 2018.
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Affiliation(s)
- Diren Arsoy
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Christopher G. Salib
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - William H. Trousdale
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Meagan E. Tibbo
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Afton K. Limberg
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Anthony Viste
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Eric A. Lewallen
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Nicolas Reina
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Michael J. Yaszemski
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Daniel J. Berry
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Andre J. van Wijnen
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Mark E. Morrey
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Joaquin Sanchez-Sotelo
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234
| | - Matthew P. Abdel
- Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Phone: (507) 284-2884, Fax: (507) 266-4234,Corresponding author and requests for reprints author (Matthew P. Abdel, M.D.)
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Maciejewski M, Lounkine E, Whitebread S, Farmer P, DuMouchel W, Shoichet BK, Urban L. Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets. eLife 2017; 6. [PMID: 28786378 PMCID: PMC5548487 DOI: 10.7554/elife.25818] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 07/04/2017] [Indexed: 01/06/2023] Open
Abstract
The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms. DOI:http://dx.doi.org/10.7554/eLife.25818.001 New treatments are tested in clinical trials before they are licensed for use in patients, but until the drugs are available for prescribing it’s not always possible to identify every side effect. When the drugs enter the clinic, they might be prescribed to patients with multiple medical conditions, or combined with other treatments. The drugs may also be taken for longer periods of time than tested in trials. It is therefore common for new adverse reactions to emerge after a drug is in widespread use. The FDA Adverse Event Reporting System (FAERS) is a surveillance system used in the United States for reporting drug side effects after new treatments have been licensed. Healthcare professionals and patients can submit reports to the database, logging the adverse drug reactions that they have experienced. FAERS currently contains over 8.5 million entries, and is growing all the time. However, Maciejewski et al. show that the database has several shortcomings that are reducing its usefulness. For instance, on average any given drug will have 16 different names in the system; this makes it challenging to group all of the reported side effects so that trends and patterns can be correctly seen. To address this first problem, Maciejewski et al. grouped together drugs according to their active ingredients, rather than their name. This made it much easier to account for subsequent, and more crucial conflating factors such as multiple reports for the same adverse event and patient, or cases where adverse reactions were confused with the diseases that the drugs are trying to treat. For example, diabetes was listed as a side effect for drugs used to treat diabetes. Building on this cleaned-up dataset, Maciejewski et al. monitored how adverse event signals evolve over time and uncovered biases that were hard to see otherwise. For example, side-effects were reported more often when drugs were in the news. More strikingly, this bias affected not only the drug in question, but also other drugs that acted in the same way or on the same molecular target. The computational method developed by Maciejewski et al. allows the data in FAERS to be combined and corrected, making easier to evaluate the safety of different medicines. The link between adverse side effects and the molecular targets of the drug, via the ingredient’s chemical structure, furthermore makes it possible to analyze such clinical data reliably by using chemical and genetic information. In the future, this method could also help to identify previously unknown side effects and the biological mechanisms behind them. This could help researchers to develop new drugs with improved side effect profiles. DOI:http://dx.doi.org/10.7554/eLife.25818.002
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Affiliation(s)
| | - Eugen Lounkine
- Novartis Institutes for Biomedical Research, Cambridge, United States
| | - Steven Whitebread
- Novartis Institutes for Biomedical Research, Cambridge, United States
| | - Pierre Farmer
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - William DuMouchel
- Oracle Health Sciences, Oracle Health Sciences, Burlington, United States
| | | | - Laszlo Urban
- Novartis Institutes for Biomedical Research, Cambridge, United States
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Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs. THE PHARMACOGENOMICS JOURNAL 2016; 16:399-410. [DOI: 10.1038/tpj.2016.54] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/08/2016] [Accepted: 05/11/2016] [Indexed: 02/06/2023]
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Pladevall M, Riera-Guardia N, Margulis AV, Varas-Lorenzo C, Calingaert B, Perez-Gutthann S. Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. BMC Cardiovasc Disord 2016; 16:14. [PMID: 26769243 PMCID: PMC4714432 DOI: 10.1186/s12872-016-0187-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 01/08/2016] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The results of observational studies evaluating and comparing the cardiovascular safety of glitazones, metformin and sufonylureas are inconsistent.To conduct and evaluate heterogeneity in a meta-analysis of observational studies on the risk of acute myocardial infarction (AMI) or stroke in patients with type 2 diabetes using non-insulin blood glucose-lowering drugs (NIBGLD). METHODS We systematically identified and reviewed studies evaluating NIBGLD in patients with type 2 diabetes indexed in Medline, Embase, or the Cochrane Library that met prespecified criteria. The quality of included studies was assessed with the RTI item bank. Results were combined using fixed- and random-effects models, and the Higgins I(2) statistic was used to evaluate heterogeneity. Sensitivity analyses by study quality were conducted. RESULTS The summary relative risk (sRR) (95% CI) of AMI for rosiglitazone versus pioglitazone was 1.13 (1.04-1.24) [I(2) = 55%]. In the sensitivity analysis, heterogeneity was reduced [I(2) = 16%]. The sRR (95% CI) of stroke for rosiglitazone versus pioglitazone was 1.18 (1.02-1.36) [I(2) = 42%]. There was strong evidence of heterogeneity related to study quality in the comparisons of rosiglitazone versus metformin and rosiglitazone versus sulfonylureas (I (2) ≥ 70%). The sRR (95% CI) of AMI for sulfonylurea versus metformin was 1.24 (1.14-1.34) [I(2) = 41%] and for pioglitazone versus metformin was 1.02 (0.75-1.38) [I(2) = 17%]. Sensitivity analyses decreased heterogeneity in most comparisons. CONCLUSION/INTERPRETATION Sulfonylureas increased the risk of AMI by 24% compared with metformin; an imprecise point estimate indicated no difference in risk of AMI when comparing pioglitazone with metformin. The presence of heterogeneity precluded any conclusions on the other comparisons. The quality assessment was valuable in identifying methodological problems in the individual studies and for analysing potential sources of heterogeneity.
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Affiliation(s)
- Manel Pladevall
- RTI Health Solutions, Trav. Gracia 56 Atico 1 08006, Barcelona, Spain. .,The Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan, USA.
| | | | - Andrea V Margulis
- RTI Health Solutions, Trav. Gracia 56 Atico 1 08006, Barcelona, Spain.
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Youssef J, Badr M. Peroxisome Proliferator-Activated Receptors Features, Functions, and Future. NUCLEAR RECEPTOR RESEARCH 2015. [DOI: 10.11131/2015/101188] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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Peroxisome proliferator-activated receptor (PPAR) gamma in cardiovascular disorders and cardiovascular surgery. J Cardiol 2015; 66:271-8. [DOI: 10.1016/j.jjcc.2015.05.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 05/08/2015] [Accepted: 05/14/2015] [Indexed: 12/28/2022]
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Roughead EE, Chan EW, Choi NK, Kimura M, Kimura T, Kubota K, Lai ECC, Man KKC, Nguyen TA, Ooba N, Park BJ, Sato T, Shin JY, Wang T, Griffiths J, Wong ICK, Yang YHK, Pratt NL. Variation in Association Between Thiazolidinediones and Heart Failure Across Ethnic Groups: Retrospective analysis of Large Healthcare Claims Databases in Six Countries. Drug Saf 2015; 38:823-31. [PMID: 26216600 PMCID: PMC4561996 DOI: 10.1007/s40264-015-0318-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
INTRODUCTION The prevalence of polymorphisms among the metabolising enzymes and pharmacodynamic receptors relevant for the thiazolidinediones differs by ethnic group, a factor that may modify risk of adverse drug events. OBJECTIVE The aim of the study was to determine if the risk of oedema or heart failure associated with the thiazolidinediones varies in populations in Australia, Canada, Hong Kong, Japan, Korea and Taiwan. METHODS Sequence symmetry analyses were undertaken to investigate the risk of peripheral oedema, as measured by incident furosemide dispensing, and risk of hospitalisations for heart failure. Results were pooled, with Australia and Canada representing predominantly Caucasian population and all other countries contributing to Asian population estimates. RESULTS Pooled estimates of risk for furosemide initiation in the Caucasian populations were significantly increased for pioglitazone [adjusted sequence ratio (ASR) 1.47; 95 % confidence interval (CI) 1.14-1.91] and rosiglitazone (ASR 1.65; 95 % CI 1.58-1.72), while in the Asian populations, the pooled risk estimates were lower (ASR 1.11; 95 % CI 0.93-1.32 and ASR 1.21; 95 % CI 1.01-1.45 for pioglitazone and rosiglitazone, respectively). Results for hospitalisation for heart failure showed a similar trend, with elevated risk in the Australian data (ASR 1.88; 95 % CI 1.01-3.5 and ASR 1.25; 95 % CI 0.76-2.05 for pioglitazone and rosiglitazone, respectively), while no increased risk was found in the pooled results for the Asian populations. CONCLUSION The risk of both oedema and heart failure with thiazolidinediones was higher in predominantly Caucasian countries than in the Asian countries assessed. Assessment of adverse events by ethnicity may support safer medicine use.
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Affiliation(s)
- Elizabeth E. Roughead
- />Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
| | - Esther W. Chan
- />Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Nam-Kyong Choi
- />Medical Research Collaborating Centre, Seoul National University College of Medicine/Seoul National University Hospital, Seoul, Korea
| | - Michio Kimura
- />Department of Medical Informatics, Hamamatsu University, School of Medicine, Shizuoka, Japan
| | - Tomomi Kimura
- />Department of Medical Informatics, Hamamatsu University, School of Medicine, Shizuoka, Japan
| | - Kiyoshi Kubota
- />Department of Pharmacoepidemiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Edward Chia-Cheng Lai
- />Institute of Clinical Pharmacy and Pharmaceutical Sciences, Health Outcome Research Centre, National Cheng Kung University, Tainan, Taiwan
| | - Kenneth K. C. Man
- />Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Tuan Anh Nguyen
- />Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
| | - Nobuhiro Ooba
- />Department of Pharmacoepidemiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Byung-Joo Park
- />Department of Preventative Medicine, Seoul National University College of Medicine, Seoul, Korea
- />Korea Institute of Drug Safety and Risk Management, Seoul, Korea
| | - Tsugumichi Sato
- />Department of Pharmacoepidemiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Ju-Young Shin
- />Korea Institute of Drug Safety and Risk Management, Seoul, Korea
| | - TongTong Wang
- />Marketed Health Products Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON Canada
| | - Jenna Griffiths
- />Marketed Health Products Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON Canada
| | - Ian C. K. Wong
- />Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Yea-Huei Kao Yang
- />Institute of Clinical Pharmacy and Pharmaceutical Sciences, Health Outcome Research Centre, National Cheng Kung University, Tainan, Taiwan
| | - Nicole L. Pratt
- />Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
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Böhning D, Mylona K, Kimber A. Meta-analysis of clinical trials with rare events. Biom J 2015; 57:633-48. [DOI: 10.1002/bimj.201400184] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 12/15/2014] [Accepted: 12/16/2014] [Indexed: 12/31/2022]
Affiliation(s)
- Dankmar Böhning
- Southampton Statistical Sciences Research Institute & Mathematical Sciences; University of Southampton; Southampton SO17 1BJ UK
| | - Kalliopi Mylona
- Southampton Statistical Sciences Research Institute & Mathematical Sciences; University of Southampton; Southampton SO17 1BJ UK
| | - Alan Kimber
- Southampton Statistical Sciences Research Institute & Mathematical Sciences; University of Southampton; Southampton SO17 1BJ UK
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Abou Daya K, Abu Daya H, Nasser Eddine M, Nahhas G, Nuwayri-Salti N. Effects of rosiglitazone (PPAR γ agonist) on the myocardium in non-hypertensive diabetic rats (PPAR γ). J Diabetes 2015; 7:85-94. [PMID: 24548695 DOI: 10.1111/1753-0407.12140] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 12/06/2013] [Accepted: 02/13/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND There is ongoing controversy regarding the safety of rosiglitazone and its effects on the myocardium, in some cases causing severe cardiac pathology and even in some instances mortality. In this study we aimed at examining the effects of pharmacologic doses of rosiglitazone on cardiomyocytes in diabetic non-cardiac rats receiving sub-optimal doses of insulin. METHODS Animals were distributed into six groups: normal, diabetic, and diabetic receiving insulin, each subdivided into a control group and an experimental group receiving pharmacologic doses of rosiglitazone. Cardiomyocyte hypertrophy was assessed using heart to body weight index and microscopic examination using the number of cardiomyocytes per quadrant of high power field and intercalated disks in a sector of 100 × field. Fibrosis was assessed using Masson Trichrome staining. A number of sections of each group were stained with periodic acid Shiff and others with Sudan III for glycogen and fat accumulation, respectively. One way ANOVA was used for statistical analysis as appropriate. RESULTS Diffuse cardiomyopathic changes in diabetic control animals were observed consisting of cardiomyocyte hypertrophy, loss of striations and widespread vacuolation. These changes were reduced and even prevented by treatment with insulin and rosiglitazone. Masson staining showed that all rat groups had no more than +1 fibrosis that is equal to what was present in the normal controls. CONCLUSION Rosiglitazone, in combination with even sub-optimal doses of insulin therapy, has protective effects on cardiac muscle in diabetic animals especially those expressed as muscle hypertrophy, muscle cell death, and fibrosis.
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Affiliation(s)
- Khodor Abou Daya
- School of Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Cholerton B, Baker LD, Craft S. Insulin, cognition, and dementia. Eur J Pharmacol 2013; 719:170-179. [PMID: 24070815 DOI: 10.1016/j.ejphar.2013.08.008] [Citation(s) in RCA: 154] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 08/21/2013] [Accepted: 08/26/2013] [Indexed: 01/21/2023]
Abstract
Cognitive disorders of aging represent a serious threat to the social and economic welfare of current society. It is now widely recognized that pathology related to such conditions, particularly Alzheimer's disease, likely begins years or decades prior to the onset of clinical dementia symptoms. This revelation has led researchers to consider candidate mechanisms precipitating the cascade of neuropathological events that eventually lead to clinical Alzheimer's disease. Insulin, a hormone with potent effects in the brain, has recently received a great deal of attention for its potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favorable effects of insulin, is related to multiple chronic conditions known to impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer's disease and other cognitive disorders will continue to rise exponentially. Fortunately, these chronic insulin-related conditions are amenable to pharmacological intervention. As a result, novel therapeutic strategies that focus on increasing insulin sensitivity in the brain may be an important target for protecting or treating cognitive decline. The following review will highlight our current understanding of the role of insulin in brain, potential mechanisms underlying the link between insulin resistance and dementia, and current experimental therapeutic strategies aimed at improving cognitive function via modifying the brain's insulin sensitivity.
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Affiliation(s)
- Brenna Cholerton
- Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Laura D Baker
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, Winston-Salem, NC 27157-1207, USA
| | - Suzanne Craft
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, Winston-Salem, NC 27157-1207, USA.
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The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes. Pharmacogenet Genomics 2013; 23:219-27. [PMID: 23426382 DOI: 10.1097/fpc.0b013e32835f91fc] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPARγ on rosiglitazone's (i) trough steady-state plasma concentration (C(ss,min)), (ii) on glycosylated haemoglobin A1c (HbA1c) and (iii) the risk of developing adverse events, mainly oedema, in patients with type 2 diabetes mellitus (T2D). METHODS The data used in this study were obtained from the South Danish Diabetes Study including 371 T2D patients with a focus on the 187 patients who were treated with rosiglitazone. The study was a placebo-controlled, partly blinded and multicentre clinical trial. The C(ss,min) of rosiglitazone and HbA1c was determined and the genotype of the patients was identified. RESULTS The mean C(ss,min) of rosiglitazone was 21.3 ng/ml (95% confidence interval 18.8; 24.2 ng/ml), with observations ranging from 1 to 296 ng/ml. Carriers of CYP2C8*3 (n=32) (rs10509681 and rs11572080) had a statistically significantly lower mean C(ss,min) than wild types (n=106), and they also had a statistically significantly lower mean absolute difference in HbA1c during rosiglitazone treatment. Finally, the carriers of CYP2C8*3 had a lower odds ratio of developing oedema. CONCLUSION We showed that CYP2C8*3 was associated with lower plasma levels of rosiglitazone and hence a reduced therapeutic response but also a lower risk of developing oedema during treatment with rosiglitazone. Individualized treatment with rosiglitazone on the basis of the CYP2C8 genotype may therefore be possible.
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Kravitz E, Schmeidler J, Beeri MS. Type 2 diabetes and cognitive compromise: potential roles of diabetes-related therapies. Endocrinol Metab Clin North Am 2013; 42:489-501. [PMID: 24011882 PMCID: PMC3767929 DOI: 10.1016/j.ecl.2013.05.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Type 2 diabetes, like dementia, disproportionately affects the elderly. Diabetes has consistently been associated with risk of dementia, mild cognitive impairment, and cognitive decline suggesting that cognitive compromise is a deleterious manifestation of diabetes. This review summarizes observational studies and clinical trials of diabetes medications and their respective associations and effects on cognitive outcomes. Despite biological plausibility, results from most human clinical trials have failed to show any efficacy in treating Alzheimer disease symptomatology and pathology. Clinical trials targeting vascular-related outcomes, diabetic patients, or cognitively normal elderly at risk for dementia, may provide greater cognitive benefits.
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Affiliation(s)
- Efrat Kravitz
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel
| | - James Schmeidler
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY
| | - Michal Schnaider Beeri
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY
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Maria Rotella C, Pala L, Mannucci E. Role of insulin in the type 2 diabetes therapy: past, present and future. Int J Endocrinol Metab 2013; 11:137-44. [PMID: 24348585 PMCID: PMC3860110 DOI: 10.5812/ijem.7551] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 09/26/2012] [Accepted: 09/28/2012] [Indexed: 12/29/2022] Open
Abstract
CONTEXT Since 2006 a relevant number of therapeutical algorithms for the management of type 2 diabetes have been proposed, generating a lively debate in the scientific community, particularly on the ideal timing for introduction of insulin therapy and on which drug should be preferred as add-on therapy in patients failing to metformin. At the moment, there is no real consensus. The aim of the present review is to summarize established knowledge and areas for debate with respect to insulin therapy in type 2 diabetes. EVIDENCE ACQUISITION In type 2 diabetic patients, insulin represents a therapy with a long and well-established history, but, considering the modern insulin therapy, several points must be carefully examined. The role played by the introduction of insulin analogues, the choice of insulin regimens, the ongoing debate on insulin and cancer, the cardiovascular effects of insulin, the role of insulin on β-cell protection and the actual clinical perspective in the treatment of the disease. Nevertheless, still many exciting expectations exist: the new insulin analogues, the technological options, the inhaled and oral insulin and the issue of transplantation. CONCLUSIONS Although insulin is the more potent hypoglicemic agent, the availability of a wider spectrum of therapeutic agents, many of which are better tolerated than insulin, has reduced the field of application for insulin treatment; presently, insulin is used only in those who cannot maintain an adequate glycemic control with other drugs. Furthermore, a lively research activity is currently ongoing, in order to make insulin therapy even safer and simpler for patients.
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Affiliation(s)
- Carlo Maria Rotella
- Obesity Agency, University of Florence Medical School, Careggi Teaching Hospital, Firenze, Italy
| | - Laura Pala
- Endocrinolgy Unit , University of Florence Medical School, Careggi Teaching Hospital, Firenze, Italy
| | - Edoardo Mannucci
- Diabetes Agency, University of Florence Medical School, Careggi Teaching Hospital, Firenze, Italy
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Grunberger G. Will PPAR-γ agonist therapy still have a role in diabetes management in 2013? ACTA ACUST UNITED AC 2013. [DOI: 10.2217/dmt.12.81] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Benz V, Kintscher U, Foryst-Ludwig A. Sex-specific differences in Type 2 Diabetes Mellitus and dyslipidemia therapy: PPAR agonists. Handb Exp Pharmacol 2013:387-410. [PMID: 23027460 DOI: 10.1007/978-3-642-30726-3_18] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The influence of sex on the development of obesity, Type 2 Diabetes Mellitus (T2DM), and dyslipidemia is well documented, although the molecular mechanism underlying those differences reminds elusive. Ligands of peroxisome proliferator-activated receptors (PPARs) are used as oral antidiabetics (PPARgamma agonists: thiazolidinediones, TZDs), or for the treatment of dyslipidemia and cardiovascular diseases, due to their lipid-lowering properties (PPARalpha agonists: fibrates), as PPARs control transcription of a set of genes involved in the regulation of lipid and carbohydrate metabolism. Given a high prevalence of those metabolic disorders, and thus a broad use of PPAR agonists, the present review will discuss distinct aspects of sex-specific differences in antiobesity treatment using those groups of PPAR ligands.
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Affiliation(s)
- Verena Benz
- Charité-Universitätsmedizin Berlin, Berlin, Germany.
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AL-Rasheed NM, AL-Rasheed NM, AL-Amin MA, Hasan IH, AL-Ajmi HN, Attia H, Eissa AA. Effects of Rosiglitazone on Isoproterenol-induced Myocardial Infarction in Rats. INT J PHARMACOL 2012. [DOI: 10.3923/ijp.2013.80.85] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet. Clin Sci (Lond) 2012; 123:259-70. [PMID: 22420611 DOI: 10.1042/cs20110373] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The aim of the present study was to evaluate the effects of ST (rosuvastatin) and GZ (rosiglitazone) on IR (insulin resistance) and on liver as well as adipose tissue in mice fed on an HF (high-fat) diet. Our data show that treatment with ST resulted in a marked improvement in insulin sensitivity characterized by enhanced glucose clearance during the insulin tolerance test and a 70% decrease in the HOMA-IR (homoeostasis model assessment of insulin resistance) index level (P=0.0008). The ST-treated mice exhibited lower gains in BM (body mass; -8%; P<0.01) and visceral fat pad thickness (-60%; P<0.01) compared with the untreated HF group. In comparison with HF-diet-fed mice, HF+ST-treated mice showed a significant reduction in hepatomegaly and liver steatosis (-6%, P<0.05; and -21%, P<0.01 respectively). In HF+ST-treated mice, the hepatic TAG (triacylglycerol) levels were reduced by 58% compared with the HF group (P<0.01). In addition, the expression of SREBP-1c (sterol-regulatory-element-binding protein-1c) was decreased by 50% in the livers of HF+ST-treated mice (P<0.01) relative to the HF-diet-fed mice. The levels of resistin were lower in the HF+ST-treated group compared with the HF group (44% less, P< 0.01). In conclusion, we demonstrated that ST treatment improved insulin sensitivity and decreased liver steatosis in mice fed on an HF diet. Furthermore, ST reduced BM gains, improved the circulating levels of plasma cholesterol and TAG, and reduced hepatic TAG, which was concomitant with lower resistin levels.
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Abstract
INTRODUCTION Thiazolidinediones (TZDs) initially showed great promise as unique receptor-mediated oral therapy for type 2 diabetes, but a host of serious side effects, primarily cardiovascular, have limited their utility. It is crucial at this point to perform a risk-benefit analysis to determine what role TZDs should play in our current treatment of type 2 diabetes and where the future of this class of drugs is headed. AREAS COVERED This review provides a comprehensive overview of the literature from 2000 onward reporting the known side effects of rosiglitazone and pioglitazone, with commentary on the quality of the data available, putative mechanism of each side effect and clinical significance. Finally, a perspective on the future of the TZDs as a class is provided. EXPERT OPINION The current TZDs are first-generation, non-specific activators of peroxisome proliferator-activated receptor (PPAR) gamma, resulting in a wide array of deleterious side effects that currently limit their use. However, the development of highly targeted selective PPAR gamma modulators (SPPARγMs) and dual PPAR gamma/alpha agonists is on the horizon.
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Affiliation(s)
- Jacqueline Kung
- Tufts University, Division of Endocrinology, Diabetes and Metabolism, 800 Washington St #268, Boston, MA 02111, USA.
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Magri CJ, Gatt N, Xuereb RG, Fava S. Peroxisome proliferator-activated receptor-γ and the endothelium: implications in cardiovascular disease. Expert Rev Cardiovasc Ther 2012; 9:1279-94. [PMID: 21985541 DOI: 10.1586/erc.11.140] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Peroxisome proliferator-activated receptors-γ (PPARγs) are ligand-activated transcription factors that play a crucial regulatory role in the transcription of a large number of genes involved in lipid metabolism and inflammation. In addition to physiological ligands, synthetic ligands (the thiazoledinediones) have been developed. In spite of the much publicized adverse cardiovascular effects of one such thiazoledinedione (rosiglitazone), PPARγ activation may have beneficial cardiovascular effects. In this article we review the effects of PPARγ activation on the endothelium with special emphasis on the possible implications in cardiovascular disease. We discuss its possible role in inflammation, vasomotor function, thrombosis, angiogenesis, vascular aging and vascular rhythm. We also briefly review the clinical implications of these lines of research.
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Affiliation(s)
- Caroline Jane Magri
- Department of Cardiac Services, Mater Dei Hospital, Tal-Qroqq, Msida MSD 2090, Malta
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Abstract
This is a review of methods for the meta-analysis of incidence of rare events using summary-level data. It is motivated and illustrated by the dataset used in a published analysis of cardiovascular safety in rosiglitazone trials. This review compares available methods for binary data, considering risk-difference, relative-risk and odds-ratio scales, fixed-effect and random-effects models, and frequentist and Bayesian approaches. Particular issues in this dataset include low incidence rates, the occurrence of studies with no events under one or all treatments, and discrepancy among results achieved using different statistical methodologies. The common method of adding a correction factor to handle zeroes may introduce bias where the incidence of events is small, as in this case. Alternative analyses on the log-odds scale are shown to give similar results, but the choice between them is less important than the potential sources of bias in any meta-analysis arising from limitations in the underlying dataset. It is important to present results carefully, including numerical and graphical summaries on the natural scale of risk when the analysis is on a statistically appropriate scale such as log-odds: the incidence rates should accompany an estimated ratio (of odds or risk) to put the analysis into the proper context. Beyond the statistical methodologies which are the focus of this paper, this dataset highlights the importance of understanding the limitations of the data being combined. Because the rosiglitazone dataset contains clinically heterogeneous trials with low event rates that were not designed or intended to assess cardiovascular outcomes, the findings of any meta-analysis of such trials should be considered hypothesis-generating.
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Affiliation(s)
- Peter W Lane
- Quantitative Sciences, GlaxoSmithKline R&D, Stevenage, UK
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Punthakee Z, Bosch J, Dagenais G, Diaz R, Holman R, Probstfield JL, Ramachandran A, Riddle MC, Rydén LE, Zinman B, Afzal R, Yusuf S, Gerstein HC. Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial. Diabetologia 2012; 55:36-45. [PMID: 22038523 DOI: 10.1007/s00125-011-2357-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 10/06/2011] [Indexed: 11/26/2022]
Abstract
AIMS/OBJECTIVE Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality. METHODS A large multicentre 3 × 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥ 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n = 541), rosiglitazone 4-8 mg/day (n = 399) or pioglitazone 30-45 mg/day (n = 392); 1,221 participants were randomised to placebo (n = 614) or vitamin D 1,000 IU/day (n = 607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis. RESULTS From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups. CONCLUSIONS/INTERPRETATION Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.
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Affiliation(s)
- Z Punthakee
- Population Health Research Institute, McMaster University, 237 Barton St E., Hamilton, ON, Canada, L8L 2X2.
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Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2011; 4:249-63. [PMID: 21765869 PMCID: PMC3131169 DOI: 10.1177/1756283x11403809] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, which includes dyslipidemia, central obesity, hypertension, and insulin resistance. These diseases collectively and individually increase the risk of cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is a subset of NAFLD that can progress to cirrhosis in up to 30% of patients and lead to decompensated liver disease requiring liver transplantation in many patients. Insulin resistance is the pathophysiological hallmark of NASH and addressing insulin resistance is an important aspect of NASH management. Lifestyle modifications with diet and exercise improve insulin sensitivity and are the cornerstone of therapy, but are often difficult to maintain long term. Not surprisingly, insulin-sensitizing agents have been a focus of pharmacologic investigation in NASH. Insulin sensitizers such as the thiazolidinediones, biguanides, glucagon-like peptide-1 receptor agonists, and the dipeptidyl peptidase IV inhibitors, also known as incretins, will be discussed with respect to their mechanism of action and how these drugs might target aspects of NASH pathophysiology. Finally, we will summarize the available clinical data and review both the risks and benefits of insulin sensitizers in the treatment of NASH.
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Affiliation(s)
- Lisa B Van Wagner
- Northwestern University Feinberg School of Medicine, 251 East Huron Street, Galter Pavilion, Suite 3-150, Chicago, IL 60611, USA
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Szentandrássy N, Harmati G, Bárándi L, Simkó J, Horváth B, Magyar J, Bányász T, Lorincz I, Szebeni A, Kecskeméti V, Nánási PP. Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells. Br J Pharmacol 2011; 163:499-509. [PMID: 21232044 PMCID: PMC3101613 DOI: 10.1111/j.1476-5381.2011.01215.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2010] [Revised: 10/21/2010] [Accepted: 10/28/2010] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration-dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts. EXPERIMENTAL APPROACH Standard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts. KEY RESULTS At concentrations ≥10 µM rosiglitazone decreased the amplitude of phase-1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration-dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC(50) value for this inhibition was 25.2 ± 2.7 µM for the transient outward K(+) current (I(to)), 72.3 ± 9.3 µM for the rapid delayed rectifier K(+) current (I(Kr)) and 82.5 ± 9.4 µM for the L-type Ca(2+) current (I(Ca) ) with Hill coefficients close to unity. The inward rectifier K(+) current (I(K1)) was not affected by rosiglitazone up to concentrations of 100 µM. Suppression of I(to), I(Kr), and I(Ca) was confirmed also under action potential voltage clamp conditions. CONCLUSIONS AND IMPLICATIONS Alterations in the densities and kinetic properties of ion currents may carry serious pro-arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients.
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Palee S, Chattipakorn S, Phrommintikul A, Chattipakorn N. PPARγ activator, rosiglitazone: Is it beneficial or harmful to the cardiovascular system? World J Cardiol 2011; 3:144-52. [PMID: 21666815 PMCID: PMC3110903 DOI: 10.4330/wjc.v3.i5.144] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 04/04/2011] [Accepted: 04/11/2011] [Indexed: 02/06/2023] Open
Abstract
Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with type II diabetes. Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity. Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction, inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation, and the protection of myocardial injury during ischemic/reperfusion in different animal models. Previous clinical studies in type II diabetes patients demonstrated that rosiglitazone played an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system. Despite these benefits, inconsistent findings have been reported, and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system, including increased risk of acute myocardial infarction, heart failure and chronic heart failure. As a result, rosiglitazone has been recently withdrawn from EU countries. Nevertheless, the effect of rosiglitazone on ischemic heart disease has not yet been firmly established. Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.
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Affiliation(s)
- Siripong Palee
- Siripong Palee, Nipon Chattipakorn, Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
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Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. EXPERIMENTAL DIABETES RESEARCH 2011; 2011:215764. [PMID: 21584276 PMCID: PMC3092497 DOI: 10.1155/2011/215764] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2010] [Accepted: 02/22/2011] [Indexed: 02/08/2023]
Abstract
Objective. Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists. Design and Methods. MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ≥12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events. Results. Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50–1.08), P = .12 (0.85 (0.50–1.45), P = .55, and 0.69 (0.40–1.22), P = .20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25–0.83), P = .009, and 1.05 (0.63–1.76), P = .84, respectively. Conclusions. To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect.
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Affiliation(s)
- Matthew C Riddle
- Oregon Health & Science University, Division of Endocrinology, Diabetes & Clinical Nutrition L-345, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098, USA.
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Dominguez LJ, Paolisso G, Barbagallo M. Glucose control in the older patient: from intensive, to effective and safe. Aging Clin Exp Res 2010; 22:274-80. [PMID: 19934622 DOI: 10.1007/bf03337724] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Older adults represent an extensive proportion of Type 2 diabetic patients. Managing diabetes in this population is challenging, because complex comorbidity and disability often mean that guidelines are not suitable on an individual basis. Recent evidence has raised animated discussion of the possibility that intensive glucose control may cause more harm than benefit, especially in older adults. The benefit of glycemic control on microvascular diabetic complications has been consistently demonstrated, but the evidence of benefit on macrovascular disease is not uniform in all studies. Glycemic control appears to prevent the development of cardiovascular events, but is less helpful in secondary prevention, when cardio- and cerebro-vascular diseases are established. In addition, treating hyperglycemia in critically ill patients (most of them over 60 years old) with a target close to normal glucose values has been shown to increase morbidity and mortality. It is possible that the attempt to reach euglycemia is not the best goal, in either older non-diabetic critically ill patients or older diabetic adults. The risks associated with hypoglycemia, which induces a counter-regulatory response with prolonged QT interval and cardiac arrhythmias in patients with established cardiovascular disease, should be carefully considered. The reported association of hypoglycemia with dementia and falls should also be examined. In the older adult, prudent, personalized therapy, with less rigid targets for patients at higher risk of hypoglycemia, is essential. The use of agents with a good safety profiles and with the least possibility of causing hypoglycemia is warranted.
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Gerstein HC, Ratner RE, Cannon CP, Serruys PW, García-García HM, van Es GA, Kolatkar NS, Kravitz BG, Miller DM, Huang C, Fitzgerald PJ, Nesto RW. Effect of Rosiglitazone on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. Circulation 2010; 121:1176-87. [PMID: 20194881 DOI: 10.1161/circulationaha.109.881003] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Hertzel C. Gerstein
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Robert E. Ratner
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Christopher P. Cannon
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Patrick W. Serruys
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Héctor M. García-García
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Gerrit-Anne van Es
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Nikheel S. Kolatkar
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Barbara G. Kravitz
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Diane M. Miller
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Chun Huang
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Peter J. Fitzgerald
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
| | - Richard W. Nesto
- From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic,
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Simpson-Haidaris PJ, Pollock SJ, Ramon S, Guo N, Woeller CF, Feldon SE, Phipps RP. Anticancer Role of PPARgamma Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes. PPAR Res 2010; 2010:814609. [PMID: 20204067 PMCID: PMC2829627 DOI: 10.1155/2010/814609] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2009] [Revised: 11/30/2009] [Accepted: 12/16/2009] [Indexed: 12/19/2022] Open
Abstract
The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-gamma agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARgamma agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARgamma agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARgamma and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.
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Affiliation(s)
- P. J. Simpson-Haidaris
- Department of Medicine/Hem-Onc Division, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
- Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
- Department of Pathology and Laboratory Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - S. J. Pollock
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - S. Ramon
- Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - N. Guo
- Department of Opthalmology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - C. F. Woeller
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - S. E. Feldon
- Department of Opthalmology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
| | - R. P. Phipps
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
- Department of Opthalmology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
- The Lung Biology and Disease Program, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
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