A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators.

Oliver, M.F.; Heady, J. A.; Morris, J.N.; Cooper, Jane; Geizerová, H; Gyárfás, I.; Green, K. G.; Strasser, T.; Macfie, W. G.; Scott, E. Marian; Czukas, M.; Duba, J.; Östör, Erika; Grafnetter, D; Hejil, Z.; Písa, Z; Uemura, Kazunori; Lamm, Gudrun; Thorp, John M.

doi:10.1136/hrt.40.10.1069

Cited by 955 publications

(25 citation statements)

References 34 publications

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“…The lipid-lowering effect of PPARα agonists justifies their clinical development for CVD. As the first fibrate, clofibrate was trialed for CVD in the 1960s, the result of which was disappointing because it did not reduce the incidence of fatal heart attacks and angina, and was linked to the increased onset of gallstones and cholecystectomies [81]. A long-term follow-up study revealed that individuals who had previously exposed to clofibrate and stopped had higher mortality compared to the placebo group [82].…”

Section: Cardiovascular Diseases (Cvds)mentioning

confidence: 99%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

167

152

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

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Section: Cardiovascular Diseases (Cvds)mentioning

confidence: 99%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

167

152

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“… 111 Studies have shown that fibrates used to treat hypercholesterolemia also reduce the prevalence of hypertension up to 25%. 112 …”

Section: Risk Factors For Dcmmentioning

confidence: 99%

Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies

Voulgari¹,

Papadogiannis²,

Tentolouris³

2010

VHRM

186

163

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Diabetic cardiomyopathy (DCM), although a distinct clinical entity, is also a part of the diabetic atherosclerosis process. It may be independent of the coexistence of ischemic heart disease, hypertension, or other macrovascular complications. Its pathological substrate is characterized by the presence of myocardial damage, reactive hypertrophy, and intermediary fibrosis, structural and functional changes of the small coronary vessels, disturbance of the management of the metabolic cardiovascular load, and cardiac autonomic neuropathy. These alterations make the diabetic heart susceptible to ischemia and less able to recover from an ischemic attack. Arterial hypertension frequently coexists with and exacerbates cardiac functioning, leading to the premature appearance of heart failure. Classical and newer echocardiographic methods are available for early diagnosis. Currently, there is no specific treatment for DCM; targeting its pathophysiological substrate by effective risk management protects the myocardium from further damage and has a recognized primary role in its prevention. Its pathophysiological substrate is also the objective for the new therapies and alternative remedies.

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“…Some human data on PPAR-α agonist effects are available from fibrate clinical trials and population case–control studies of site-specific cancer ( Bezafibrate Infarction Prevention Study Group 1992 , 2000 ; Canner et al 1986 ; Committee of Principal Investigators 1978 , 1980 , 1984 ; Coronary Drug Research Group 1975 , 1977 ; De Faire et al 1995 ; Diabetes Atherosclerosis Intervention Study Investigators 2001 ; Freeman et al 2006 ; Frick et al 1987 , 1997 ; Huttunen et al 1994 ; Keech et al 2005 , 2006 ; Meade 2001 ; Rubins et al 1993 , 1999 ; Tenkanen et al 2006 ). These studies examined a range of human responses to PPAR-α agonists, which included atherosclerosis, cardiovascular disease, serum biomarkers of fatty acid metabolism, acute toxicity, and, more limitedly, organ-specific chronic toxicity, including cancer.…”

Section: Do Human Epidemiologic Data On Fibrates Offer An Indirect Tementioning

confidence: 99%

“…Past reviews of the PPAR-α activation MOA hypothesis have generally focused on liver cancer response in two fibrate clinical trials, the Helsinki Heart Study ( Frick et al 1987 ; Huttunen et al 1994 ; Tenkanen et al 2006 ) and the World Health Organization’s Cooperative Trial on Primary Prevention of Ischemic Heart Disease ( Committee of Principal Investigators 1978 , 1980 , 1984 ), and have concluded that, although limited, those data did not provide evidence of an increased liver cancer risk from fibrate exposure ( Ashby et al 1994 ; Klaunig et al 2003 ). However, the available studies have low power to detect statistical differences in the risk of liver cancer; an estimated five or fewer liver cancer deaths would have been expected in these studies using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database ( Ries et al 2008 ).…”

Section: Do Human Epidemiologic Data On Fibrates Offer An Indirect Tementioning

confidence: 99%

“…These studies and the other fibrate trials did not examine site-specific causes of mortality or morbidity and did not follow subjects for a sufficient period to adequately consider cancer latency; in addition, placebo subjects were offered fibrate therapy at the end of the clinical trials, making analyses after further follow-up difficult to interpret. For example, the three trials that did assess mortality after a follow-up period > 10 years included liver cancers in a larger category of contiguous sites or in the category of all cancers, introducing disease misclassification and a downward bias for any site-specific treatment-related cancers ( Canner et al 1986 ; Committee of Principal Investigators 1978 , 1980 , 1984 ; Huttunen et al 1994 ; Tenkanen et al 2006 ). In voluntary postmarketing safety reports to the U.S. Food and Drug Administration (FDA), rates of liver adverse event reports for gemfibrozil and fenofibrate (2.6 and 6.9 per 1,000,000 prescriptions, respectively) were similar to those of statins ( Holoshitz et al 2008 ).…”

Section: Do Human Epidemiologic Data On Fibrates Offer An Indirect Tementioning

confidence: 99%

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A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

Guyton

Chiu

Bateson

et al. 2009

Environ Health Perspect

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BackgroundDiverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-α agonists is irrelevant to human carcinogenic risk.Data synthesisHerein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.ConclusionsOur review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.

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A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators.

Cited by 955 publications

References 34 publications

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies

A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

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