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Prakash Y, Bhatt DL, Malick WA. Emerging agents targeting triglycerides. Curr Opin Lipidol 2025; 36:119-129. [PMID: 39964788 DOI: 10.1097/mol.0000000000000979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
PURPOSE OF REVIEW Hypertriglyceridemia (HTG), which arises from defects in triglyceride-rich lipoprotein (TRL) metabolism, is associated with increased morbidity and mortality from pancreatitis and atherosclerotic cardiovascular disease. Traditional therapies, including fibrates and omega-3 fatty acids, have shown limited efficacy in controlling triglyceride (TG) levels and cardiovascular risk. This review explores the role of emerging therapies that target TG and TRL metabolism via novel biochemical pathways. RECENT FINDINGS Apolipoprotein C-III inhibitors appear most effective for patients with variants of severe HTG, particularly multifactorial and familial chylomicronemia syndromes, by enhancing TRL metabolism through both lipoprotein lipase-dependent and independent mechanisms. Angiopoeitin-like proteins 3 and 4 inhibitors appear most useful for mixed hyperlipidemia, with favorable effects across the entire spectrum of apoB-containing atherogenic lipoproteins. For patients with HTG and concomitant complications of insulin resistance, including metabolic associated steatotic liver disease and type 2 diabetes mellitus, fibroblast growth factor-21 analogs may provide significant benefit. SUMMARY HTG is a diverse condition. Apolipoprotein C-III inhibitors, angiopoeitin-like proteins 3 and 4 inhibitors, and fibroblast growth factor-21 analogs represent significant advancements in the treatment of HTG, offering new hope for effectively managing this condition across its full spectrum of disease.
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Affiliation(s)
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Waqas A Malick
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Maiti R, Mohanty RR, Dey A, Maji S, Padhan M, Mishra A. Effect of Virgin Coconut Oil (VCO) on Cardiometabolic Parameters in Patients with Dyslipidemia: A Randomized, Add-on Placebo-Controlled Clinical Trial. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2024; 43:244-251. [PMID: 37708389 DOI: 10.1080/27697061.2023.2256816] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/28/2023] [Accepted: 09/04/2023] [Indexed: 09/16/2023]
Abstract
OBJECTIVE Statin monotherapy for dyslipidemia is limited by adverse effects and limited effectiveness in certain subgroups like metabolic syndrome. Add-on therapy with an agent with a known safety profile may improve clinical outcomes, and virgin coconut oil (VCO) may be the candidate agent for improving the cardiometabolic profile. The present study was conducted to evaluate the effect of add-on VCO with atorvastatin in dyslipidemia in adults. METHODS A randomized, double-blind clinical trial was conducted on 150 patients with dyslipidemia who were randomized into control and test groups. The control group received atorvastatin monotherapy, whereas the test group received add-on VCO with atorvastatin for 8 weeks. At baseline, demographic, clinical, and biochemical parameters were assessed and repeated after 8 weeks of therapy. The main outcome measures were lipid profile, cardiovascular risk indices, 10-year cardiovascular risk, body fat compositions, and thiobarbituric acid reactive substances (TBARS). RESULTS The increase in HDL in the test group was significantly greater than in the control group (MD: 2.76; 95%CI: 2.43-3.08; p < 0.001). The changes in the atherogenic index (p = 0.003), coronary risk index (p < 0.001), cardiovascular risk index (p = 0.001), and TBARS (p < 0.001) were significantly greater in the test group. The decrease in LDL, total cholesterol and lipoprotein(a), were significantly higher in the control group. There were no significant differences between the groups with respect to the changes in triglyceride, VLDL, and 10-year cardiovascular risk. CONCLUSIONS Add-on VCO (1000 mg/day) with atorvastatin (10 mg/day) can achieve a better clinical outcome in patients with dyslipidemia by increasing HDL and improving oxidative stress cardiovascular risk indices.
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Affiliation(s)
- Rituparna Maiti
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
| | - Rashmi Ranjan Mohanty
- Department of General Medicine, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, Odisha, India
| | - Anupam Dey
- Department of General Medicine, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, Odisha, India
| | - Shampa Maji
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
| | - Milan Padhan
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
| | - Archana Mishra
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
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Sherratt SCR, Mason RP, Libby P, Steg PG, Bhatt DL. Do patients benefit from omega-3 fatty acids? Cardiovasc Res 2024; 119:2884-2901. [PMID: 38252923 PMCID: PMC10874279 DOI: 10.1093/cvr/cvad188] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 08/11/2023] [Accepted: 09/26/2023] [Indexed: 01/24/2024] Open
Abstract
Omega-3 fatty acids (O3FAs) possess beneficial properties for cardiovascular (CV) health and elevated O3FA levels are associated with lower incident risk for CV disease (CVD.) Yet, treatment of at-risk patients with various O3FA formulations has produced disparate results in large, well-controlled and well-conducted clinical trials. Prescription formulations and fish oil supplements containing low-dose mixtures of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have routinely failed to prevent CV events in primary and secondary prevention settings when added to contemporary care, as shown most recently in the STRENGTH and OMEMI trials. However, as observed in JELIS, REDUCE-IT, and RESPECT-EPA, EPA-only formulations significantly reduce CVD events in high-risk patients. The CV mechanism of action of EPA, while certainly multifaceted, does not depend solely on reductions of circulating lipids, including triglycerides (TG) and LDL, and event reduction appears related to achieved EPA levels suggesting that the particular chemical and biological properties of EPA, as compared to DHA and other O3FAs, may contribute to its distinct clinical efficacy. In vitro and in vivo studies have shown different effects of EPA compared with DHA alone or EPA/DHA combination treatments, on atherosclerotic plaque morphology, LDL and membrane oxidation, cholesterol distribution, membrane lipid dynamics, glucose homeostasis, endothelial function, and downstream lipid metabolite function. These findings indicate that prescription-grade, EPA-only formulations provide greater benefit than other O3FAs formulations tested. This review summarizes the clinical findings associated with various O3FA formulations, their efficacy in treating CV disease, and their underlying mechanisms of action.
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Affiliation(s)
- Samuel C R Sherratt
- Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
- Elucida Research LLC, Beverly, MA, USA
| | - R Preston Mason
- Elucida Research LLC, Beverly, MA, USA
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Peter Libby
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Ph Gabriel Steg
- Université Paris-Cité, INSERM_UMR1148/LVTS, FACT (French Alliance for Cardiovascular Trials), Assistance Publique–Hôpitaux de Paris, Hôpital Bichat, Paris, France
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, NewYork 10029-5674, NY, USA
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MIAO CY, YE XF, ZHANG W, SHENG CS, HUANG QF, WANG JG. Serum triglycerides concentration in relation to total and cardiovascular mortality in an elderly Chinese population. J Geriatr Cardiol 2022; 19:603-609. [PMID: 36339465 PMCID: PMC9630003 DOI: 10.11909/j.issn.1671-5411.2022.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023] Open
Abstract
OBJECTIVE To investigate serum triglycerides in relation to all-cause, cardiovascular, and non-cardiovascular mortality in an elderly Chinese population. METHODS The study participants (n = 3565) were elderly (≥ 60 years) community dwellers living in a suburban town of Shanghai. Hypertriglyceridemia was defined as a serum triglycerides concentration ≥ 2.30 mmol/L (definite) and ≥ 1.70 mmol/L (borderline), respectively. RESULTS The prevalence of definite and borderline hypertriglyceridemia at baseline was 7.5% and 29.5%, respectively. It was higher in women (n = 1982, 9.0% and 33.8%, respectively) than men (n = 1583, 6.2% and 27.9%, respectively), in obese and overweight participants (n = 1566, 10.5% and 36.4%, respectively) than normal weight participants (n = 1999, 5.6% and 27.1%, respectively), and in diabetic participants (n = 177, 11.9% and 39.0%, respectively) than non-diabetic participants (n = 3388, 7.5% and 30.8%, respectively). During a median of 7.9 years follow-up, all-cause, cardiovascular and non-cardiovascular deaths occurred in 529, 216 and 313 participants, respectively. In analyses according to the quintile distributions of serum triglycerides concentration, the sex- and age-standardized mortality rate was lowest in the middle quintile for all-cause, cardiovascular and non-cardiovascular mortality (18.6, 7.8 and 11.9 per 1000 person-years, respectively, versus 21.5, 10.5 and 12.7 per 1000 person-years, respectively, in the two lower quintiles and 21.7, 9.5 and 14.0 per 1000 person-years, respectively, in the two higher quintiles). The fully adjusted hazard ratios (95% CI) for the middle quintile versus the combined two lower with two higher quintiles were 0.85 (95% CI: 0.67-1.07, P = 0.17), 0.81 (95% CI: 0.54-1.19, P = 0.28) and 0.87 (95% CI: 0.64-1.17, P = 0.35) for all-cause, cardiovascular and non-cardiovascular mortality, respectively. CONCLUSIONS Our study showed high prevalence of hypertriglyceridemia, especially when defined as borderline and in obese and overweight participants, and mildly but non-significantly elevated risks of cardiovascular mortality relative to the middle level of serum triglycerides.
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Affiliation(s)
- Chao-Ying MIAO
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Fei YE
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei ZHANG
- Department of Cardiovascular Medicine, the Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang-Sheng SHENG
- Department of Cardiovascular Medicine, the Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi-Fang HUANG
- Department of Cardiovascular Medicine, the Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ji-Guang WANG
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Cardiovascular Medicine, the Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Sherratt SCR, Libby P, Bhatt DL, Mason RP. A biological rationale for the disparate effects of omega-3 fatty acids on cardiovascular disease outcomes. Prostaglandins Leukot Essent Fatty Acids 2022; 182:102450. [PMID: 35690002 DOI: 10.1016/j.plefa.2022.102450] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/09/2022] [Accepted: 05/19/2022] [Indexed: 12/29/2022]
Abstract
The omega-3 fatty acids (n3-FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) rapidly incorporate into cell membranes where they modulate signal transduction pathways, lipid raft formation, and cholesterol distribution. Membrane n3-FAs also form specialized pro-resolving mediators and other intracellular oxylipins that modulate inflammatory pathways, including T-cell differentiation and gene expression. Cardiovascular (CV) trials have shown that EPA, administered as icosapent ethyl (IPE), reduces composite CV events, along with plaque volume, in statin-treated, high-risk patients. Mixed EPA/DHA regimens have not shown these benefits, perhaps as the result of differences in formulation, dosage, or potential counter-regulatory actions of DHA. Indeed, EPA and DHA have distinct, tissue-specific effects on membrane structural organization and cell function. This review summarizes: (1) results of clinical outcome and imaging trials using n3-FA formulations; (2) membrane interactions of n3-FAs; (3) effects of n3-FAs on membrane oxidative stress and cholesterol crystalline domain formation during hyperglycemia; (4) n3-FA effects on endothelial function; (5) role of n3-FA-generated metabolites in inflammation; and (6) ongoing and future clinical investigations exploring treatment targets for n3-FAs, including COVID-19.
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Affiliation(s)
- Samuel C R Sherratt
- Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH 03823, USA; Elucida Research LLC, Beverly, MA 01915-0091, USA
| | - Peter Libby
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-6110, USA
| | - Deepak L Bhatt
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-6110, USA
| | - R Preston Mason
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-6110, USA; Elucida Research LLC, Beverly, MA 01915-0091, USA.
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Ginsberg HN, Hounslow NJ, Senko Y, Suganami H, Bogdanski P, Ceska R, Kalina A, Libis RA, Supryadkina TV, Hovingh GK. Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy. Diabetes Care 2022; 45:898-908. [PMID: 35238894 DOI: 10.2337/dc21-1288] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 12/29/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12. RESULTS Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations. CONCLUSIONS Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.
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Affiliation(s)
- Henry N Ginsberg
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | | | | | | | - Pawel Bogdanski
- Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Richard Ceska
- Department of Internal Medicine, Charles University and University General Hospital, Prague, Czech Republic
| | - Akos Kalina
- Hungarian Defense Forces Medical Centre, Budapest, Hungary
| | | | | | - G Kees Hovingh
- Department of Vascular Medicine, Amsterdam UMC, Amsterdam, the Netherlands
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Petersen KS, Kris-Etherton PM, McCabe GP, Raman G, Miller JW, Maki KC. Perspective: Planning and Conducting Statistical Analyses for Human Nutrition Randomized Controlled Trials: Ensuring Data Quality and Integrity. Adv Nutr 2021; 12:1610-1624. [PMID: 33957665 PMCID: PMC8483948 DOI: 10.1093/advances/nmab045] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/02/2021] [Accepted: 03/17/2021] [Indexed: 12/29/2022] Open
Abstract
Appropriate planning, execution, and reporting of statistical methods and results is critical for research transparency, validity, and reproducibility. This paper provides an overview of best practices for developing a statistical analysis plan a priori, conducting statistical analyses, and reporting statistical methods and results for human nutrition randomized controlled trials (RCTs). Readers are referred to the other NURISH (NUtrition inteRventIon reSearcH) publications for detailed information about the preparation and conduct of human nutrition RCTs. Collectively, the NURISH series outlines best practices for conducting human nutrition research.
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Affiliation(s)
| | - Penny M Kris-Etherton
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - George P McCabe
- Department of Statistics, Purdue University, West Lafayette, IN, USA
| | - Gowri Raman
- Institute for Clinical Research and Health Policy Studies, Center for Clinical Evidence Synthesis (CCES),Tufts Medical Center, Boston, MA, USA
| | - Joshua W Miller
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Kevin C Maki
- Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN, USA
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Is multiple sclerosis a risk factor for atherosclerosis? J Neuroradiol 2021; 48:99-103. [DOI: 10.1016/j.neurad.2019.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/17/2019] [Accepted: 10/17/2019] [Indexed: 11/20/2022]
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Qi YY, Yan L, Wang ZM, Wang X, Meng H, Li WB, Chen DC, Li M, Liu J, An ST. Comparative efficacy of pharmacological agents on reducing the risk of major adverse cardiovascular events in the hypertriglyceridemia population: a network meta-analysis. Diabetol Metab Syndr 2021; 13:15. [PMID: 33514420 PMCID: PMC7845128 DOI: 10.1186/s13098-021-00626-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hypertriglyceridemia (HTG) is considered an independent risk factor for major adverse cardiovascular events (MACE). METHODS This study analyzed the effects of various agents on MACE risk reduction in HTG (serum triglyceride ≥ 150 mg/dl) populations by performing a network meta-analysis. We performed a frequentist network meta-analysis to conduct direct and indirect comparisons of interventions. PubMed, EMBASE, and the Cochrane library were searched for trials until Jul 6, 2020. Randomized controlled trials that reported MACE associated with agents in entire HTG populations or in subgroups were included. The primary outcome was MACE. RESULTS Of the 2005 articles screened, 21 trials including 56,471 patients were included in the analysis. The network meta-analysis results for MACE risk based on frequency data showed that eicosapentaenoic acid (EPA) (OR: 1.32; 95% CI 1.19-1.46), gemfibrozil (OR: 1.53; 95% CI 1.20-1.95), niacin plus clofibrate (OR: 2.00; 95% CI 1.23-3.25), pravastatin (OR: 1.32; 95% CI 1.15-1.52), simvastatin (OR: 2.38; 95% CI 1.55-3.66), and atorvastatin (OR: 0.55; 95% CI 0.37-0.82) significantly reduced the risk of MACE compared to the control conditions. In the subgroup analysis of HTG patients with triglycerides ≥ 200 mg/dL, bezafibrate (OR: 0.56; 95% CI 0.33-0.94), EPA (OR: 0.72; 95% CI 0.62-0.82), and pravastatin (OR: 1.33; 95% CI 1.01-1.75) significantly reduced the MACE risk. CONCLUSIONS Simvastatin had a clear advantage in reducing the risk of MACE in the entire HTG population analyzed in this meta-analysis. EPA, but not omega-3 fatty acid, was considered an effective HTG intervention. Among fibrates, gemfibrozil was most effective, though bezafibrate may significantly reduce the risk of MACE in populations with triglyceride levels of 200-300 mg/dL. Trial registration retrospectively registered in PROSPERO (CRD42020213705).
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Affiliation(s)
- Yan-Yan Qi
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Li Yan
- Department of Cardiology, Hongxing hospital, Hami, 839000, China
| | - Zhong-Min Wang
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Xi Wang
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Hua Meng
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Wen-Bo Li
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Dong-Chang Chen
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Meng Li
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Jun Liu
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China
| | - Song-Tao An
- Department of Cardiology, People's Hospital of Zhengzhou University No, 7, Weiwu Road, Zhengzhou, 450003, China.
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O'Connell TD, Mason RP, Budoff MJ, Navar AM, Shearer GC. Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites. Eur Heart J Suppl 2020; 22:J3-J20. [PMID: 33061864 PMCID: PMC7537803 DOI: 10.1093/eurheartj/suaa115] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Patients with well-controlled low-density lipoprotein cholesterol levels, but persistent high triglycerides, remain at increased risk for cardiovascular events as evidenced by multiple genetic and epidemiologic studies, as well as recent clinical outcome trials. While many trials of low-dose ω3-polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have shown mixed results to reduce cardiovascular events, recent trials with high-dose ω3-PUFAs have reignited interest in ω3-PUFAs, particularly EPA, in cardiovascular disease (CVD). REDUCE-IT demonstrated that high-dose EPA (4 g/day icosapent-ethyl) reduced a composite of clinical events by 25% in statin-treated patients with established CVD or diabetes and other cardiovascular risk factors. Outcome trials in similar statin-treated patients using DHA-containing high-dose ω3 formulations have not yet shown the benefits of EPA alone. However, there are data to show that high-dose ω3-PUFAs in patients with acute myocardial infarction had reduced left ventricular remodelling, non-infarct myocardial fibrosis, and systemic inflammation. ω3-polyunsaturated fatty acids, along with their metabolites, such as oxylipins and other lipid mediators, have complex effects on the cardiovascular system. Together they target free fatty acid receptors and peroxisome proliferator-activated receptors in various tissues to modulate inflammation and lipid metabolism. Here, we review these multifactorial mechanisms of ω3-PUFAs in view of recent clinical findings. These findings indicate physico-chemical and biological diversity among ω3-PUFAs that influence tissue distributions as well as disparate effects on membrane organization, rates of lipid oxidation, as well as various receptor-mediated signal transduction pathways and effects on gene expression.
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Affiliation(s)
- Timothy D O'Connell
- Department of Integrative Biology and Physiology, University of Minnesota, 3-141 CCRB, 2231 6th Street SE, Minneapolis, MN 55414, USA
| | - Richard Preston Mason
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Matthew J Budoff
- Cardiovascular Division, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Ann Marie Navar
- Cardiovascular Division, Duke Clinical Research Institute, Duke University, Durham, NC, USA
| | - Gregory C Shearer
- Department of Nutritional Sciences, The Pennsylvania State University, 110 Chandlee Laboratory, University Park, PA 16802, USA
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Willeit P, Tschiderer L, Allara E, Reuber K, Seekircher L, Gao L, Liao X, Lonn E, Gerstein HC, Yusuf S, Brouwers FP, Asselbergs FW, van Gilst W, Anderssen SA, Grobbee DE, Kastelein JJP, Visseren FLJ, Ntaios G, Hatzitolios AI, Savopoulos C, Nieuwkerk PT, Stroes E, Walters M, Higgins P, Dawson J, Gresele P, Guglielmini G, Migliacci R, Ezhov M, Safarova M, Balakhonova T, Sato E, Amaha M, Nakamura T, Kapellas K, Jamieson LM, Skilton M, Blumenthal JA, Hinderliter A, Sherwood A, Smith PJ, van Agtmael MA, Reiss P, van Vonderen MGA, Kiechl S, Klingenschmid G, Sitzer M, Stehouwer CDA, Uthoff H, Zou ZY, Cunha AR, Neves MF, Witham MD, Park HW, Lee MS, Bae JH, Bernal E, Wachtell K, Kjeldsen SE, Olsen MH, Preiss D, Sattar N, Beishuizen E, Huisman MV, Espeland MA, Schmidt C, Agewall S, Ok E, Aşçi G, de Groot E, Grooteman MPC, Blankestijn PJ, Bots ML, Sweeting MJ, Thompson SG, Lorenz MW. Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients. Circulation 2020; 142:621-642. [PMID: 32546049 PMCID: PMC7115957 DOI: 10.1161/circulationaha.120.046361] [Citation(s) in RCA: 295] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.
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Affiliation(s)
- Peter Willeit
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Lena Tschiderer
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Elias Allara
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK
| | - Kathrin Reuber
- Department of Neurology, Goethe University, Frankfurt am Main, Germany
| | - Lisa Seekircher
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Lu Gao
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Ximing Liao
- Department of Neurology, Goethe University, Frankfurt am Main, Germany
| | - Eva Lonn
- Department of Medicine and Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Hamilton General Hospital, Hamilton, Ontario, Canada
| | - Hertzel C. Gerstein
- Department of Medicine and Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Hamilton General Hospital, Hamilton, Ontario, Canada
| | - Salim Yusuf
- Department of Medicine and Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Hamilton General Hospital, Hamilton, Ontario, Canada
| | - Frank P. Brouwers
- Department of Cardiology, Haga Teaching Hospital, the Hague, the Netherlands
| | - Folkert W. Asselbergs
- Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Wiek van Gilst
- Department of Experimental Cardiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Sigmund A. Anderssen
- Department of Sports Medicine, Norwegian School of Sports Sciences, Oslo, Norway
| | - Diederick E. Grobbee
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - John J. P. Kastelein
- Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Frank L. J. Visseren
- Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - George Ntaios
- Department of Medicine, University of Thessaly, Larissa, Greece
| | - Apostolos I. Hatzitolios
- 1st Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christos Savopoulos
- 1st Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pythia T. Nieuwkerk
- Department of Medical Psychology, Amsterdam UMC- Location AMC, Amsterdam, the Netherlands
| | - Erik Stroes
- Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Matthew Walters
- School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK
| | - Peter Higgins
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Jesse Dawson
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Paolo Gresele
- Division of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Giuseppe Guglielmini
- Division of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Rino Migliacci
- Division of Internal Medicine, Cortona Hospital, Cortona, Italy
| | - Marat Ezhov
- Laboratory of Lipid Disorders, National Medical Research Center of Cardiology, Moscow, Russia
| | - Maya Safarova
- Atherosclerosis Department, National Medical Research Center of Cardiology, Moscow, Russia
| | - Tatyana Balakhonova
- Ultrasound Vascular Laboratory, National Medical Research Center of Cardiology, Moscow, Russia
| | - Eiichi Sato
- Division of Nephrology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Mayuko Amaha
- Division of Nephrology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Tsukasa Nakamura
- Division of Nephrology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Kostas Kapellas
- Australian Research Centre for Population Oral Health, University of Adelaide, Adelaide, SA, Australia
| | - Lisa M. Jamieson
- Australian Research Centre for Population Oral Health, University of Adelaide, Adelaide, SA, Australia
| | - Michael Skilton
- Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Sydney, NSW, Australia
| | - James A. Blumenthal
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - Alan Hinderliter
- Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Andrew Sherwood
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - Patrick J. Smith
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - Michiel A. van Agtmael
- Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands
| | - Peter Reiss
- Department of Global Health, Amsterdam UMC- Location AMC, Amsterdam, the Netherlands
- Amsterdam Institute for Global Health and Development, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Stefan Kiechl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- VASCage GmbH, Research Centre on Vascular Ageing and Stroke, Innsbruck, Austria
| | | | - Matthias Sitzer
- Department of Neurology, Goethe University, Frankfurt am Main, Germany
- Department of Neurology, Klinikum Herford, Herford, Germany
| | - Coen D. A. Stehouwer
- Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Heiko Uthoff
- Department of Angiology, University Hospital Basel, Basel, Switzerland
| | - Zhi-Yong Zou
- Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China
| | - Ana R. Cunha
- Department of Clinical Medicine, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mario F. Neves
- Department of Clinical Medicine, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Miles D. Witham
- AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle-upon-Tyne Hospitals Trust, Newcastle, UK
| | - Hyun-Woong Park
- Department of Internal Medicine, Gyeongsang National University Hospital, Daejeon, South Korea
| | - Moo-Sik Lee
- Department of Internal Medicine, Gyeongsang National University Hospital, Daejeon, South Korea
- Department of Preventive Medicine, Konyang University, Jinju, South Korea
| | - Jang-Ho Bae
- Heart Center, Konyang University Hospital, Daejeon, South Korea
- Department of Cardiology, Konyang University College of Medicine, Daejeon, South Korea
| | - Enrique Bernal
- Infectious Diseases Unit, Reina Sofia Hospital, Murcia, Spain
| | | | | | - Michael H. Olsen
- Department of Internal Medicine, Holbaek Hospital, University of Southern Denmark, Odense, Denmark
| | - David Preiss
- MRC Population Health Research Unit, Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Naveed Sattar
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Edith Beishuizen
- Department of Internal Medicine, HMC+ (Bronovo), the Hague, the Netherlands
| | - Menno V. Huisman
- Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
| | - Mark A. Espeland
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Caroline Schmidt
- Wallenberg Laboratory for Cardiovascular Research, University of Gothenburg, Gothenburg, Sweden
| | - Stefan Agewall
- Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - Ercan Ok
- Nephrology Department, Ege University School of Medicine, Bornova-Izmir, Turkey
| | - Gülay Aşçi
- Nephrology Department, Ege University School of Medicine, Bornova-Izmir, Turkey
| | - Eric de Groot
- Imagelabonline & Cardiovascular, Eindhoven and Lunteren, the Netherlands
| | | | - Peter J. Blankestijn
- Department of Nephrology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Michiel L. Bots
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Michael J. Sweeting
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Simon G. Thompson
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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Mason RP, Libby P, Bhatt DL. Emerging Mechanisms of Cardiovascular Protection for the Omega-3 Fatty Acid Eicosapentaenoic Acid. Arterioscler Thromb Vasc Biol 2020; 40:1135-1147. [PMID: 32212849 PMCID: PMC7176343 DOI: 10.1161/atvbaha.119.313286] [Citation(s) in RCA: 255] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 03/03/2020] [Indexed: 02/07/2023]
Abstract
Patients with well-controlled LDL (low-density lipoprotein) levels still have residual cardiovascular risk associated with elevated triglycerides. Epidemiological studies have shown that elevated fasting triglyceride levels associate independently with incident cardiovascular events, and abundant recent human genetic data support the causality of TGRLs (triglyceride-rich lipoproteins) in atherothrombosis. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower blood triglyceride concentrations but likely exert additional atheroprotective properties at higher doses. Omega-3 fatty acids modulate T-cell differentiation and give rise to various prostaglandins and specialized proresolving lipid mediators that promote resolution of tissue injury and inflammation. The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) with an EPA-only formulation lowered a composite of cardiovascular events by 25% in patients with established cardiovascular disease or diabetes mellitus and other cardiovascular risk factors. This clinical benefit likely arises from multiple molecular mechanisms discussed in this review. Indeed, human plaques readily incorporate EPA, which may render them less likely to trigger clinical events. EPA and DHA differ in their effects on membrane structure, rates of lipid oxidation, inflammatory biomarkers, and endothelial function as well as tissue distributions. Trials that have evaluated DHA-containing high-dose omega-3 fatty acids have thus far not shown the benefits of EPA alone demonstrated in REDUCE-IT. This review will consider the mechanistic evidence that helps to understand the potential mechanisms of benefit of EPA.
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Affiliation(s)
- R. Preston Mason
- From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (R.P.M., P.L., D.L.B.)
- Elucida Research LLC, Beverly, MA (R.P.M.)
| | - Peter Libby
- From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (R.P.M., P.L., D.L.B.)
| | - Deepak L. Bhatt
- From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (R.P.M., P.L., D.L.B.)
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Ascaso JF, Millán J, Hernández-Mijares A, Blasco M, Brea Á, Díaz Á, Pedro-Botet J, Pintó X. Atherogenic Dyslipidaemia 2019. Consensus document of the Atherogenic Dyslipidaemia Group of the Spanish Arteriosclerosis Society. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2020; 32:120-125. [PMID: 32291195 DOI: 10.1016/j.arteri.2019.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 11/27/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Juan F Ascaso
- Universitat de Valencia, CIBERDEM, INCLIVA, Valencia, España.
| | - Jesús Millán
- Unidad de Lípidos, Servicio de Medicina Interna, Hospital General Universitario Gregorio Marañón; Facultad de Medicina Universidad Complutense, Madrid, España
| | | | - Mariano Blasco
- Centro de Salud Delicias Sur, Área Sanitaria III, Zaragoza, España
| | - Ángel Brea
- Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, España
| | - Ángel Díaz
- Centro de Salud de Bembibre, Universidad de León, León, España
| | - Juan Pedro-Botet
- Unidad de Lípidos y Riesgo Vascular, Servicio Endocrinología y Nutrición, Hospital del Mar; Universitat Autònoma de Barcelona, Barcelona, España
| | - Xavier Pintó
- Servicio de Medicina Interna, Hospital de Bellvitge, CIBERobn, Fipec; Universidad de Barcelona; IBIDELL, Barcelona, España
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14
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Sherratt SCR, Juliano RA, Mason RP. Eicosapentaenoic acid (EPA) has optimal chain length and degree of unsaturation to inhibit oxidation of small dense LDL and membrane cholesterol domains as compared to related fatty acids in vitro. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183254. [PMID: 32135144 DOI: 10.1016/j.bbamem.2020.183254] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 02/14/2020] [Accepted: 02/29/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND Oxidation of small dense low-density lipoprotein (sdLDL) and membranes is causally related to atherosclerosis. The omega-3 fatty acid (FA) eicosapentaenoic acid (EPA, 20:5, ω-3) significantly reduced oxidized LDL in patients with hypertriglyceridemia by unknown mechanisms. We compared EPA effects to related FAs of varying chain length and unsaturation on oxidation of sdLDL and model membranes, and on cholesterol crystal domains. We compared EPA to the FAs: stearic (SA, 18:0), oleic (OA, 18:1, ω-9), linoleic (LA, 18:2, ω-6), alpha-linolenic (ALA, 18:3, ω-3), eicosanoic (EA, 20:0), eicosatrienoic (ETE, 20:3, ω-3), arachidonic (AA, 20:4, ω-6), docosapentaenoic (DPA, 22:5, ω-3), and docosahexaenoic (DHA, 22:6, ω-3). METHODS Human sdLDL or model membranes of cholesterol and 1,2-Dilinoleoyl-sn-glycero-3-phosphocholine [18:2(cis)PC or DLPC] were preincubated with FAs followed by copper-induced oxidation. Malondialdehyde (MDA) or lipid hydroperoxides (LOOH) levels measured oxidation; small-angle X-ray diffraction assessed cholesterol domain formation. RESULTS After 40 min, EPA reduced MDA levels 70% compared to vehicle (p < 0.001). Lesser inhibition was observed with DHA, DPA, ETE, and ALA (33%, 34%, 32%, and 16%, respectively; all p < 0.001 versus vehicle). Similar relative FA effects were observed in model membranes where EPA more substantially inhibited cholesterol crystal domain formation. CONCLUSION We observed relationships between hydrocarbon length and unsaturation with antioxidant activity and membrane cholesterol domain formation. EPA had the most favorable molecular structure, likely contributing to membrane stability, improved lipoprotein clearance, and reduced inflammation. GENERAL SIGNIFICANCE Insight is provided into FA hydrocarbon length and unsaturation relationships with antioxidant activity in lipoproteins and membranes, and cholesterol crystal domains formation.
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Affiliation(s)
| | | | - R Preston Mason
- Elucida Research LLC, Beverly, MA 01915-0091, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-6110, USA.
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Masuda D, Miyata Y, Matsui S, Yamashita S. Omega-3 fatty acid ethyl esters improve low-density lipoprotein subclasses without increasing low-density lipoprotein-cholesterol levels: A phase 4, randomized study. Atherosclerosis 2020; 292:163-170. [DOI: 10.1016/j.atherosclerosis.2019.11.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/07/2019] [Accepted: 11/13/2019] [Indexed: 10/25/2022]
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Abstract
PURPOSE OF REVIEW To describe lipid abnormalities in diabetes, when they occur and the evidence base for lipid management with established and new drugs to prevent diabetes complications. We also discuss how to manage statin intolerance. RECENT FINDINGS Statins remain first-line therapy in patients with diabetes, though newer therapies to reduce LDL-C have emerged, including ezetimibe as an add-on therapy to statins, and injectable PCSK9 inhibitors, both of which are safe and effective in diabetes. Emerging evidence suggests a need to consider lipid-lowering therapies more often in younger patients with both type 1 and type 2 diabetes. Statins remain the cornerstone of lipid management in diabetes but other options are increasing. There is also now evidence for better managing apparent statin intolerance. Notably, younger patients lose the most life years from their diabetes, an observation that future guidelines need to consider.
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Affiliation(s)
- Anne Sillars
- The Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, 126 University Place, Glasgow, G12 8TA UK
| | - Naveed Sattar
- The Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, 126 University Place, Glasgow, G12 8TA UK
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Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα): Pooled Analysis of Phase 2 and 3 Studies in Dyslipidemic Patients with or without Statin Combination. Int J Mol Sci 2019; 20:ijms20225537. [PMID: 31698825 PMCID: PMC6888510 DOI: 10.3390/ijms20225537] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/01/2019] [Accepted: 11/02/2019] [Indexed: 02/06/2023] Open
Abstract
Hypertriglyceridemia has emerged as an independent risk factor for cardiovascular events, despite low-density lipoprotein-cholesterol (LDL-C) well-controlled with statins. We pooled data from the first 12 weeks of six randomized double-blind placebo-controlled studies of pemafibrate in Japan and investigated its efficacy and safety with and without statins, particularly focusing on patients with renal dysfunction. Subjects were 1253 patients (677 in the "with-statin" group and 576 in the "without-statin" group). At Week 12 (last observation carried forward), triglyceride (TG) was significantly reduced at all pemafibrate doses (0.1, 0.2, and 0.4 mg/day), both with and without statin, compared to placebo (p < 0.001 vs. placebo for all groups). In the "with-statin" group, the estimated percent change from baseline was -2.0% for placebo and -45.1%, -48.5%, and -50.0%, respectively, for the pemafibrate groups. Findings for both groups showed significant decreases in TG-rich lipoproteins and atherogenic lipid parameters compared to placebo. The incidence of adverse events was similar between the pemafibrate and placebo groups and was also similar for patients with and without renal dysfunction in the "with-statin" group. Pemafibrate lowered TG and improved atherogenic dyslipidemia without a significant increase in adverse events in comparison to the placebo, even among "with-statin" patients who had renal dysfunction.
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Davidson MH. Triglyceride-rich lipoprotein cholesterol (TRL-C): the ugly stepsister of LDL-C. Eur Heart J 2019; 39:620-622. [PMID: 29342252 DOI: 10.1093/eurheartj/ehx741] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Michael H Davidson
- Professor, Director of the Lipid Clinic, The University of Chicago Pritzker School of Medicine, 150 E. Huron Chicago, IL 600611, USA
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Araki E, Yamashita S, Arai H, Yokote K, Satoh J, Inoguchi T, Nakamura J, Maegawa H, Yoshioka N, Tanizawa Y, Watada H, Suganami H, Ishibashi S. Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52-week data from the PROVIDE study. Diabetes Obes Metab 2019; 21:1737-1744. [PMID: 30830727 PMCID: PMC6617746 DOI: 10.1111/dom.13686] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/25/2019] [Accepted: 02/28/2019] [Indexed: 01/03/2023]
Abstract
The aim of this study was to evaluate the efficacy and safety of pemafibrate in people with type 2 diabetes and hypertriglyceridaemia over a 52-week period. Participants were randomly assigned to receive treatment with placebo or pemafibrate at a dose of 0.2 or 0.4 mg/d for 24 weeks (treatment period 1). The main results from treatment period 1 have been reported previously. The assigned treatment was continued up to week 52, except that the placebo was changed to pemafibrate 0.2 mg/d after week 24 (treatment period 2). The percentage changes in fasting serum triglyceride (TG) levels at week 52 (last observation carried forward) were -48.2%, -42.3%, and -46.4% in the placebo/pemafibrate 0.2 mg/d (n = 57), pemafibrate 0.2 mg/d (n = 54), and pemafibrate 0.4 mg/d (n = 55) groups, respectively. Levels of TG, non-HDL cholesterol and total cholesterol stably decreased, whereas levels of HDL cholesterol increased with pemafibrate treatments over 52 weeks. Pemafibrate was well tolerated throughout the study period. The present study is the first to show that pemafibrate treatment substantially ameliorated lipid abnormalities and was well tolerated for 52 weeks in people with type 2 diabetes and hypertriglyceridaemia.
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Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Shizuya Yamashita
- Department of Community Medicine and Department of Cardiovascular MedicineOsaka University Graduate School of MedicineOsakaJapan
- Rinku General Medical CentreOsakaJapan
| | - Hidenori Arai
- National Centre for Geriatrics and GerontologyAichiJapan
| | - Koutaro Yokote
- Department of Diabetes, Metabolism and EndocrinologyChiba University HospitalChibaJapan
- Department of Endocrinology, Haematology and GerontologyChiba University Graduate School of MedicineChibaJapan
| | - Jo Satoh
- Tohoku Medical and Pharmaceutical University Wakabayashi HospitalMiyagiJapan
| | | | - Jiro Nakamura
- Division of Diabetes, Department of Internal MedicineAichi Medical UniversityAichiJapan
| | - Hiroshi Maegawa
- Department of MedicineShiga University of Medical ScienceShigaJapan
| | - Narihito Yoshioka
- Division of Diabetes and Endocrinology, Department of MedicineSapporo Medical Centre, NTT East CorporationHokkaidoJapan
| | - Yukio Tanizawa
- Division of Endocrinology, Metabolism, Haematological Science and TherapeuticsYamaguchi University Graduate School of MedicineYamaguchiJapan
| | - Hirotaka Watada
- Department of Metabolism and EndocrinologyJuntendo University Graduate School of MedicineTokyoJapan
| | | | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of MedicineJichi Medical UniversityTochigiJapan
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Chaiyasothi T, Nathisuwan S, Dilokthornsakul P, Vathesatogkit P, Thakkinstian A, Reid C, Wongcharoen W, Chaiyakunapruk N. Effects of Non-statin Lipid-Modifying Agents on Cardiovascular Morbidity and Mortality Among Statin-Treated Patients: A Systematic Review and Network Meta-Analysis. Front Pharmacol 2019; 10:547. [PMID: 31191304 PMCID: PMC6540916 DOI: 10.3389/fphar.2019.00547] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 05/01/2019] [Indexed: 11/13/2022] Open
Abstract
Background: Currently, there is a lack of information on the comparative efficacy and safety of non-statin lipid-lowering agents (NST) in cardiovascular (CV) disease risk reduction when added to background statin therapy (ST). This study determine the relative treatment effects of NST on fatal and non-fatal CV events among statin-treated patients. Methods: A network meta-analysis based on a systematic review of randomized controlled trials (RCTs) comparing non-statin lipid-modifying agents among statin-treated patients was performed. PubMed, EMBASE, CENTRAL, and Clinicaltrial.gov were searched up to April 10, 2018. The primary outcomes were CV and all-cause mortalities. Secondary CV outcomes were coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), any stroke, and coronary revascularization. Risks of discontinuations were secondary safety outcomes. Results: Sixty-seven RCTs including 259,429 participants with eight interventions were analyzed. No intervention had significant effects on the primary outcomes (CV mortality and all-cause mortality). For secondary endpoints, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK) plus statin (PCSK/ST) significantly reduced the risk of non-fatal MI (RR 0.82, 95% CI 0.72–0.93, p = 0.003), stroke (RR 0.74, 95% CI 0.65–0.85, p < 0.001), coronary revascularization (RR 0.84, 95% CI 0.75–0.94, p = 0.003) compared to ST. Combinations of ST and all NST except PCSK and ezetimibe showed higher rate of discontinuation due to adverse events compared to ST. Conclusions: None of NST significantly reduced CV or all-cause death when added to ST. PCSKs and to a lesser extent, ezetimibe may help reduce cardiovascular events with acceptable tolerability profile among broad range of patients.
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Affiliation(s)
- Thanaputt Chaiyasothi
- Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.,Department of Clinical Pharmacy, Faculty of Pharmacy, Srinakharinwirot University, Nakhon Nayok, Thailand
| | - Surakit Nathisuwan
- Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Piyameth Dilokthornsakul
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Center of Pharmaceutical Outcomes Research, Naresuan University, Phitsanulok, Thailand
| | - Prin Vathesatogkit
- Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ammarin Thakkinstian
- Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Christopher Reid
- School of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.,School of Public Health, Curtin University, Perth, WA, Australia
| | - Wanwarang Wongcharoen
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nathorn Chaiyakunapruk
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Center of Pharmaceutical Outcomes Research, Naresuan University, Phitsanulok, Thailand.,School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.,School of Pharmacy, University of Wisconsin, Madison, WI, United States.,Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes, Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway, Malaysia
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21
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Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol 2019; 18:38. [PMID: 30898163 PMCID: PMC6429757 DOI: 10.1186/s12933-019-0845-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/13/2019] [Indexed: 12/27/2022] Open
Abstract
Background Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the efficacy and safety of pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia. Methods A search was performed using the MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov databases. We decided to employ RCTs to evaluate the effects of pemafibrate on lipid and glucose metabolism-related parameters in patients with dyslipidemia. For statistical analysis, standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) were calculated using the random effect model. Results Our search yielded seven RCTs (with a total of 1623 patients) that satisfied the eligibility criteria of this study; hence, those studies were incorporated into this meta-analysis. The triglyceride concentration significantly decreased in the pemafibrate group (SMD, − 1.38; 95% CI, − 1.63 to − 1.12; P < 0.001) than in the placebo group, with a reduction effect similar to that exhibited by fenofibrate. Compared with the placebo group, the pemafibrate group also showed improvements in high-density and non-high-density lipoprotein cholesterol levels as well as in homeostasis model assessment for insulin resistance. Furthermore, the pemafibrate group showed a significant decrease in hepatobiliary enzyme activity compared with the placebo and fenofibrate groups; and, total adverse events (AEs) were significantly lower in the pemafibrate group than in the fenofibrate group (OR, 0.60; 95% CI, 0.49–0.73; P < 0.001). In contrast, the low-density lipoprotein cholesterol level was significantly higher in the pemafibrate group than in the placebo (P = 0.006) and fenofibrate (P < 0.001) groups. Conclusions The lipid profile significantly improved in the pemafibrate group than in the placebo group. In addition to the pemafibrate group having an improved lipid profile, which was comparable with that of the fenofibrate group, the AEs were significantly lower than in the fenofibrate group and an improvement in hepatobiliary enzyme activity was also recognized. However, we believe that actual clinical data as well as long-term efficacy and safety need to be investigated in the future. Electronic supplementary material The online version of this article (10.1186/s12933-019-0845-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Satoshi Ida
- Department of Diabetes and Metabolism, Ise Red Cross Hospital, 1-471-2, Funae, 1-Chome, Ise-shi, Mie, 516-8512, Japan.
| | - Ryutaro Kaneko
- Department of Diabetes and Metabolism, Ise Red Cross Hospital, 1-471-2, Funae, 1-Chome, Ise-shi, Mie, 516-8512, Japan
| | - Kazuya Murata
- Department of Diabetes and Metabolism, Ise Red Cross Hospital, 1-471-2, Funae, 1-Chome, Ise-shi, Mie, 516-8512, Japan
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22
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Guan J, Zhao M, He C, Li X, Li Y, Sun J, Wang W, Cui YL, Zhang Q, Li BY, Qiao GF. Anti-Hypertensive Action of Fenofibrate via UCP2 Upregulation Mediated by PPAR Activation in Baroreflex Afferent Pathway. Neurosci Bull 2019; 35:15-24. [PMID: 30173356 PMCID: PMC6357279 DOI: 10.1007/s12264-018-0271-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/29/2018] [Indexed: 12/31/2022] Open
Abstract
Fenofibrate, an agonist for peroxisome proliferator-activated receptor alpha (PPAR-α), lowers blood pressure, but whether this action is mediated via baroreflex afferents has not been elucidated. In this study, the distribution of PPAR-α and PPAR-γ was assessed in the nodose ganglion (NG) and the nucleus of the solitary tract (NTS). Hypertension induced by drinking high fructose (HFD) was reduced, along with complete restoration of impaired baroreceptor sensitivity, by chronic treatment with fenofibrate. The molecular data also showed that both PPAR-α and PPAR-γ were dramatically up-regulated in the NG and NTS of the HFD group. Expression of the downstream signaling molecule of PPAR-α, the mitochondrial uncoupling protein 2 (UCP2), was up-regulated in the baroreflex afferent pathway under similar experimental conditions, along with amelioration of reduced superoxide dismutase activity and increased superoxide in HFD rats. These results suggest that chronic treatment with fenofibrate plays a crucial role in the neural control of blood pressure by improving baroreflex afferent function due at least partially to PPAR-mediated up-regulation of UCP2 expression and reduction of oxidative stress.
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Affiliation(s)
- Jian Guan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Miao Zhao
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Chao He
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xue Li
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Ying Li
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Jie Sun
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Wei Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Ya-Li Cui
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Qing Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Bai-Yan Li
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
| | - Guo-Fen Qiao
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
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Preston Mason R. New Insights into Mechanisms of Action for Omega-3 Fatty Acids in Atherothrombotic Cardiovascular Disease. Curr Atheroscler Rep 2019; 21:2. [PMID: 30637567 PMCID: PMC6330561 DOI: 10.1007/s11883-019-0762-1] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Treatment of hypercholesterolemia with statins results in significant reductions in cardiovascular risk; however, individuals with well-controlled low-density lipoprotein cholesterol (LDL-C) levels, but persistent high triglycerides (TG), remain at increased risk. Genetic and epidemiologic studies have shown that elevated fasting TG levels are associated with incident cardiovascular events. At effective doses, omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower TG levels but may have additional atheroprotective properties compared to other TG-lowering therapies such as niacin and fibrates. The purpose of this review is to evaluate mechanisms related to the potential benefits of omega-3 fatty acids in atherothrombotic disease. RECENT FINDINGS Large randomized clinical trials are currently under way to test the cardiovascular benefits of omega-3 fatty acids at a pharmacologic dosage (4 g/day). A large randomized trial with a prescription EPA-only formulation was shown to reduce a composite of cardiovascular events by 25% in statin-treated patients with established cardiovascular disease or diabetes and other CV risk factors. EPA and DHA have distinct tissue distributions as well as disparate effects on membrane structure and lipid dynamics, rates of lipid oxidation, and signal transduction pathways. Compared to other TG-lowering therapies, EPA has been found to inhibit cholesterol crystal formation, inflammation, and oxidative modification of atherogenic lipoprotein particles. The anti-inflammatory and endothelial benefits of EPA are enhanced in combination with a statin. Omega-3 fatty acids like EPA only at a pharmacologic dose reduce fasting TG and interfere with mechanisms of atherosclerosis that results in reduced cardiovascular events. Additional mechanistic trials will provide further insights into their role in reducing cardiovascular risk in subjects with well-managed LDL-C but elevated TG levels.
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Affiliation(s)
- R Preston Mason
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
- Elucida Research LLC, Beverly, MA, 01915, USA.
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24
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Pradhan AD, Paynter NP, Everett BM, Glynn RJ, Amarenco P, Elam M, Ginsberg H, Hiatt WR, Ishibashi S, Koenig W, Nordestgaard BG, Fruchart JC, Libby P, Ridker PM. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018; 206:80-93. [PMID: 30342298 DOI: 10.1016/j.ahj.2018.09.011] [Citation(s) in RCA: 241] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 09/24/2018] [Indexed: 10/28/2022]
Abstract
Observational, genetic, and experimental data indicate that triglyceride rich lipoproteins (TRLs) likely participate causally in atherothrombosis. Yet, robust clinical trial evidence that triglyceride (TG) lowering therapy reduces cardiovascular events remains elusive. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α), pemafibrate, will be used to target residual cardiovascular risk remaining after treatment to reduce low-density lipoprotein cholesterol (LDL-C) in individuals with the dyslipidemia of type 2 diabetes mellitus (T2). The PROMINENT study will randomly allocate approximately 10,000 participants with T2D, mild-to-moderate hypertriglyceridemia (TG: 200-499 mg/dl; 2.26-5.64 mmol/l) and low high-density lipoprotein cholesterol levels (HDL-C: ≤40 mg/dl; 1.03 mmol/l) to either pemafibrate (0.2 mg twice daily) or matching placebo with an average expected follow-up period of 3.75 years (total treatment phase 5 years; 24 countries). At study entry, participants must be receiving either moderate-to-high intensity statin therapy or meet specified LDL-C criteria. The study population will be one-third primary and two-thirds secondary prevention (established cardiovascular disease). The primary endpoint is a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina requiring urgent coronary revascularization, and cardiovascular death. This event-driven study will complete when 1092 adjudicated primary endpoints have accrued with at least 200 occurring in women. Statistical power is at least 90% to detect an 18% reduction in the primary endpoint. Pre-specified secondary and tertiary endpoints include all-cause mortality, hospitalization for heart failure, new or worsening peripheral artery disease, new or worsening diabetic retinopathy and nephropathy, and change in biomarkers including select lipid and non-lipid biomarkers, inflammatory and glycemic parameters.
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25
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Woo Y, Shin JS, Shim CY, Kim JS, Kim BK, Park S, Chang HJ, Hong GR, Ko YG, Kang SM, Choi D, Ha JW, Hong MK, Jang Y, Lee SH. Effect of fenofibrate in 1113 patients at low-density lipoprotein cholesterol goal but high triglyceride levels: Real-world results and factors associated with triglyceride reduction. PLoS One 2018; 13:e0205006. [PMID: 30286170 PMCID: PMC6171908 DOI: 10.1371/journal.pone.0205006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 09/18/2018] [Indexed: 01/01/2023] Open
Abstract
Fibrates are used in patients with dyslipidemia and high cardiovascular risk. However, information regarding drug response to fibrate has been highly limited. We investigated treatment results and factors associated with triglyceride reduction after fenofibrate therapy using large-scale real-world data. Patients with one or more cardiovascular risk factors, at low-density lipoprotein-cholesterol goal but with triglyceride level ≥150 mg/dL, and undergoing treatment with fenofibrate 135–160 mg for the first time were included in this retrospective observational study. The outcome variable was the percentage changes of TG levels. The achievement rate of triglyceride <150 mg/dL was additionally analyzed. Factors associated with treatment results were also analyzed. Among 2546 patients who were initially screened, 1113 patients were enrolled (median age: 61 years; male: 71%). After median follow-up of 4 months, the median change in triglyceride was -60%, and 49% of the patients reached triglyceride <150 mg/dL. After adjusting for confounding variables, female sex, non-diabetic status, coronary artery disease, lower baseline triglyceride, and no statin use were identified to be independently associated with achievement of triglyceride <150 mg/dL. Among them, female sex, non-diabetic status, and coronary artery disease were also related to median or greater percentage reduction of triglyceride. In conclusion, only half of the study patients reached triglyceride levels <150 mg/dL after real-world fenofibrate therapy. This study indicates that more attention is needed on some subgroups to obtain optimal triglyceride levels when treating with fenofibrate.
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Affiliation(s)
- Yeongmin Woo
- Division of Cardiology, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Jeong-soo Shin
- Department of Biostatistics and Computing, Yonsei University College of Medicine, Seoul, Korea
| | - Chi-Young Shim
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jung-Sun Kim
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Byeong-Keuk Kim
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Sungha Park
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyuk-Jae Chang
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Geu-Ru Hong
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Young-Guk Ko
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Seok-Min Kang
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Donghoon Choi
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jong-Won Ha
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Myeong-Ki Hong
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Yangsoo Jang
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Sang-Hak Lee
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
- * E-mail:
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26
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Mason RP, Dawoud H, Jacob RF, Sherratt SCR, Malinski T. Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin. Biomed Pharmacother 2018; 103:1231-1237. [PMID: 29864903 DOI: 10.1016/j.biopha.2018.04.118] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 04/04/2018] [Accepted: 04/16/2018] [Indexed: 11/27/2022] Open
Abstract
The endothelium exerts many vasoprotective effects that are largely mediated by release of nitric oxide (NO). Endothelial dysfunction represents an early but reversible step in atherosclerosis and is characterized by a reduction in the bioavailability of NO. Previous studies have shown that eicosapentaenoic acid (EPA), an omega-3 fatty acid (O3FA), and statins individually improve endothelial cell function, but their effects in combination have not been tested. Through a series of in vitro experiments, this study evaluated the effects of a combined treatment of EPA and the active metabolite of atorvastatin (ATM) on endothelial cell function under conditions of oxidative stress. Specifically, the comparative and time-dependent effects of these agents on endothelial dysfunction were examined by measuring the levels of NO and peroxynitrite (ONOO-) released from human umbilical vein endothelial cells (HUVECs). The data suggest that combined treatment with EPA and ATM is beneficial to endothelial function and was unique to EPA and ATM since similar improvements could not be recapitulated by substituting another O3FA docosahexaenoic acid (DHA) or other TG-lowering agents such as fenofibrate, niacin, or gemfibrozil. Comparable beneficial effects were observed when HUVECs were pretreated with EPA and ATM before exposure to oxidative stress. Interestingly, the kinetics of EPA-based protection of endothelial function in response to oxidation were found to be significantly different than those of DHA. Lastly, the beneficial effects on endothelial function generated by combined treatment of EPA and ATM were reproduced when this study was expanded to an ex vivo model utilizing rat glomerular endothelial cells. Taken together, these findings suggest that a combined treatment of EPA and ATM can inhibit endothelial dysfunction that occurs in response to conditions such as hyperglycemia, oxidative stress, and dyslipidemia.
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Affiliation(s)
- R Preston Mason
- Elucida Research LLC, Beverly, MA, 01915, United States; Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
| | - Hazem Dawoud
- Nanomedical Research Laboratory, Ohio University, Athens, OH, 45701, United States
| | | | | | - Tadeusz Malinski
- Nanomedical Research Laboratory, Ohio University, Athens, OH, 45701, United States
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Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S. Efficacy and Safety of Pemafibrate Versus Fenofibrate in Patients with High Triglyceride and Low HDL Cholesterol Levels: A Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial. J Atheroscler Thromb 2018; 25:521-538. [PMID: 29628483 PMCID: PMC6005227 DOI: 10.5551/jat.44412] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Aim: To verify the superiority of pemafibrate over placebo and the non-inferiority of pemafibrate to the maximum dose of fenofibrate for determining the percent change in fasting serum triglyceride (TG) levels and to investigate safety by assessing the incidence of adverse events (AEs) and adverse drug reactions (ADRs). Methods: This phase III, placebo/active drug-controlled, randomized, double-blind, parallel group comparison study enrolled patients with high TG and low high-density lipoprotein cholesterol levels. Patients were randomly assigned to receive placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, or 0.4 mg/day; or fenofibrate 100 mg/day or 200 mg/day for 12 weeks. Results: Among 526 randomized patients, 489 completed the study, with drop-out rates of 0%, 6.7%, 5.5%, 5.9%, 8.2%, and 10.7% in the placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, and 0.4 mg/day; and fenofibrate 100 mg/day and 200 mg/day groups. The study showed the non-inferiority of pemafibrate 0.4 mg/day and 0.2 mg/day to fenofibrate 200 mg/day as well the non-inferiority and superiority of all pemafibrate doses to fenofibrate 100 mg/day for reducing TG levels. No dose-dependent increase in the incidence of AEs or ADRs was observed among the pemafibrate dose groups. The incidence of AEs and ADRs for all pemafibrate doses was similar to that for placebo and fenofibrate 100 mg/day and significantly lower than that for fenofibrate 200 mg/day (P < 0.05). Conclusions: The favorable safety profile of pemafibrate, with fewer adverse effects on kidney/liverrelated laboratory tests and fewer AEs/ADRs, including those leading to treatment discontinuation, over fenofibrate 200 mg/day may justify the use of this novel and potent treatment option for reducing TG levels in a broader range of patients.
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Affiliation(s)
| | - Shizuya Yamashita
- Department of Community Medicine and Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine.,Rinku General Medical Center
| | - Koutaro Yokote
- Department of Diabetes, Metabolism and Endocrinology, Chiba University Graduate School of Medicine.,Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine
| | - Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University
| | | | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University
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28
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Sherratt SCR, Mason RP. Eicosapentaenoic acid inhibits oxidation of high density lipoprotein particles in a manner distinct from docosahexaenoic acid. Biochem Biophys Res Commun 2018; 496:335-338. [PMID: 29331380 DOI: 10.1016/j.bbrc.2018.01.062] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 01/09/2018] [Indexed: 10/18/2022]
Abstract
The omega-3 fatty acid eicosapentaenoic acid (EPA) reduces oxidation of ApoB-containing particles in vitro and in patients with hypertriglyceridemia. EPA may produce these effects through a potent antioxidant mechanism, which may facilitate LDL clearance and slow plaque progression. We hypothesize that EPA antioxidant effects may extend to ApoA-containing particles like HDL, potentially preserving certain atheroprotective functions. HDL was isolated from human plasma and incubated at 37 °C in the absence (vehicle) or presence of EPA and/or DHA; 5.0 or 10.0 μM each. Samples were then subjected to copper-induced oxidation (10 μM). HDL oxidation was inhibited similarly by EPA and DHA up to 1 h. EPA (10 μM) maintained significant HDL oxidation inhibition of 89% (0.622 ± 0.066 μM MDA; p < .001) at 4 h, with continued inhibition of 64% at 14 h, vs. vehicle (5.65 ± 0.06 to 2.01 ± 0.10 μM MDA; p < .001). Conversely, DHA (10 μM) antioxidant benefit was lost by 4 h. At a lower concentration (5 μM), EPA antioxidant activity remained at 81% (5.53 ± 0.15 to 1.03 ± 0.10 μM MDA; p < .001) at 6 h, while DHA lost all antioxidant activity by 4 h. The antioxidant activity of EPA was preserved when combined with an equimolar concentration of DHA (5 μM each). EPA pretreatment prevented HDL oxidation in a dose-dependent manner that was preserved over time. These results suggest unique lipophilic and electron stabilization properties for EPA as compared to DHA with respect to inhibition of HDL oxidation. These antioxidant effects of EPA may enhance certain atheroprotective functions for HDL.
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Affiliation(s)
| | - R Preston Mason
- Elucida Research LLC, Beverly, MA 01915-0091, USA; Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-6110, USA.
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Millan J, Pintó X, Brea A, Blasco M, Hernández-Mijares A, Ascaso J, Diaz A, Mantilla T, Pedro-Botet J. Fibrates in the secondary prevention of cardiovascular disease (infarction and stroke). Results of a systematic review and meta-analysis of the Cochrane collaboration. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2018; 30:30-35. [PMID: 29395493 DOI: 10.1016/j.arteri.2017.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 11/16/2017] [Indexed: 06/07/2023]
Abstract
Fibrates are a group of drugs that are known mainly for reducing triglycerides, increasing high density lipoproteins (HDL), and reducing the fraction of small, dense LDL particles. The results of a Cochrane Collaboration study have recently been published on their efficacy and safety in the secondary prevention of severe cardiovascular accidents, including coronary and cerebrovascular disease. The study included randomised clinical trials in which the fibrate was compared with placebo or with no treatment. Clinical trials comparing two different fibrates were excluded. The clinical trials evaluated included a total of 16,112 patients (13 trials). The meta-analysis (including all the trials with fibrates) showed evidence of a protective effect of the fibrates compared with placebo as regards a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin (hazard ration of 0.88, with a 95% confidence interval of 0.83 to 0.94; in 16,064 individuals included in 12 studies). Thus, the results showed, with a moderate level of evidence, that fibrates could be effective in secondary prevention considering a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin.
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Affiliation(s)
- Jesus Millan
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis.
| | - Xavier Pintó
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis
| | - Angel Brea
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis
| | - Mariano Blasco
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis
| | | | - Juan Ascaso
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis
| | - Angel Diaz
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis
| | - Teresa Mantilla
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis
| | - Juan Pedro-Botet
- Grupo de trabajo de Dislipemia Aterogénica, Sociedad Española de Arteriosclerosis
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Kim CH, Han KA, Yu J, Lee SH, Jeon HK, Kim SH, Kim SY, Han KH, Won K, Kim DB, Lee KJ, Min K, Byun DW, Lim SW, Ahn CW, Kim S, Hong YJ, Sung J, Hur SH, Hong SJ, Lim HS, Park IB, Kim IJ, Lee H, Kim HS. Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized, Double-blind, and Placebo-controlled Trial. Clin Ther 2018; 40:83-94. [DOI: 10.1016/j.clinthera.2017.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 11/09/2017] [Accepted: 11/14/2017] [Indexed: 12/20/2022]
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Copple T, Ciffone NA. Managing hypertriglyceridemia: What can we learn from cardiovascular outcomes trials? Nurse Pract 2017; 42 Suppl 12:3-9. [PMID: 29176336 DOI: 10.1097/01.npr.0000526627.04268.80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Cardiovascular (CV) risk remains in some patients who are treated with statins. Evidence supports a role for triglycerides (TGs) in CV disease. TG-lowering agent outcomes studies have been inconsistent, but eicosapentaenoic acid significantly reduced coronary events in hypercholesterolemic patients who were treated with statins. Ongoing outcomes studies will clarify the role of TG-lowering treatments in CV risk reduction.
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Affiliation(s)
- Tina Copple
- Tina Copple is a Senior Nurse Practitioner at the Diabetes & Glandular Disease Clinic, San Antonio, Tex. Nicole A. Ciffone is an Adult Nurse Practitioner, Clinical Lipid Specialist, and Founder of the Arizona Center for Advanced Lipidology, Tucson, Ariz
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Peng J, Luo F, Ruan G, Peng R, Li X. Hypertriglyceridemia and atherosclerosis. Lipids Health Dis 2017; 16:233. [PMID: 29212549 PMCID: PMC5719571 DOI: 10.1186/s12944-017-0625-0] [Citation(s) in RCA: 162] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 11/27/2017] [Indexed: 11/12/2022] Open
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and it has been confirmed that increased low density lipoprotein cholesterol (LDL-C) is an independent risk factor for atherosclerosis. Recently, the increasing evidence has showed that hypertriglyceridemia is associated with incremental ASCVD risk. But the proatherogenic mechanism of triglyceride (TG) remains unclear. Therefore, this article focuses on the clinical studies and proatherogenic mechanism related to hypertriglyceridemia, in order to provide reference for the prevention and treatment of ASCVD.
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Affiliation(s)
- Jia Peng
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China
| | - Fei Luo
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China
| | - Guiyun Ruan
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China
| | - Ran Peng
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China
| | - Xiangping Li
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China.
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Abstract
INTRODUCTION Significant advancements in the treatment of hypercholesterolemia have recently been achieved. However, a considerable level of residual cardiovascular risk still affects patients' outcomes. Atherogenic dyslipidemia is one of the major constituents of residual risk. Fibrates, PPAR alpha agonists, which modify lipid profile and have numerous pleiotropic effects, seem to be drugs of choice in patients with atherogenic dyslipidemia. These drugs are effective both in monotherapy and combined therapy with statins. Areas covered: A review of clinical trials and experimental studies on fibrates and their use in the treatment of lipid disorders has been performed. Expert commentary: Fibrates are an effective and safe group of drugs to treat patients with atherogenic dyslipidemia. In this particular population of patients, they improve cardiovascular outcomes. Benefits of fibrate treatment extend beyond the impact of lipid profile. Significant improvements in carbohydrate metabolism, adipokines levels, thrombosis and inflammation were also noted.
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Affiliation(s)
- Bogusław Okopień
- a Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice , Medical University of Silesia , Katowice , Poland
| | - Lukasz Buldak
- a Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice , Medical University of Silesia , Katowice , Poland
| | - Aleksandra Bołdys
- a Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice , Medical University of Silesia , Katowice , Poland
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Eicosapentaenoic Acid Inhibits Oxidation of ApoB-containing Lipoprotein Particles of Different Size In Vitro When Administered Alone or in Combination With Atorvastatin Active Metabolite Compared With Other Triglyceride-lowering Agents. J Cardiovasc Pharmacol 2017; 68:33-40. [PMID: 26945158 PMCID: PMC4936437 DOI: 10.1097/fjc.0000000000000379] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Eicosapentaenoic acid (EPA) is a triglyceride-lowering agent that reduces circulating levels of the apolipoprotein B (apoB)-containing lipoprotein particles small dense low-density lipoprotein (sdLDL), very–low-density lipoprotein (VLDL), and oxidized low-density lipoprotein (LDL). These benefits may result from the direct antioxidant effects of EPA. To investigate this potential mechanism, these particles were isolated from human plasma, preincubated with EPA in the absence or presence of atorvastatin (active) metabolite, and subjected to copper-initiated oxidation. Lipid oxidation was measured as a function of thiobarbituric acid reactive substances formation. EPA inhibited sdLDL (IC50 ∼2.0 μM) and LDL oxidation (IC50 ∼2.5 μM) in a dose-dependent manner. Greater antioxidant potency was observed for EPA in VLDL. EPA inhibition was enhanced when combined with atorvastatin metabolite at low equimolar concentrations. Other triglyceride-lowering agents (fenofibrate, niacin, and gemfibrozil) and vitamin E did not significantly affect sdLDL, LDL, or VLDL oxidation compared with vehicle-treated controls. Docosahexaenoic acid was also found to inhibit oxidation in these particles but over a shorter time period than EPA. These data support recent clinical findings and suggest that EPA has direct antioxidant benefits in various apoB-containing subfractions that are more pronounced than those of other triglyceride-lowering agents and docosahexaenoic acid.
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Steinbuch J, van Dijk AC, Schreuder F, Truijman M, Hendrikse J, Nederkoorn PJ, van der Lugt A, Hermeling E, Hoeks A, Mess WH. Definition of common carotid wall thickness affects risk classification in relation to degree of internal carotid artery stenosis: the Plaque At RISK (PARISK) study. Cardiovasc Ultrasound 2017; 15:9. [PMID: 28376791 PMCID: PMC5379498 DOI: 10.1186/s12947-017-0097-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 02/23/2017] [Indexed: 01/27/2023] Open
Abstract
Background Mean or maximal intima-media thickness (IMT) is commonly used as surrogate endpoint in intervention studies. However, the effect of normalization by surrounding or median IMT or by diameter is unknown. In addition, it is unclear whether IMT inhomogeneity is a useful predictor beyond common wall parameters like maximal wall thickness, either absolute or normalized to IMT or lumen size. We investigated the interrelationship of common carotid artery (CCA) thickness parameters and their association with the ipsilateral internal carotid artery (ICA) stenosis degree. Methods CCA thickness parameters were extracted by edge detection applied to ultrasound B-mode recordings of 240 patients. Degree of ICA stenosis was determined from CT angiography. Results Normalization of maximal CCA wall thickness to median IMT leads to large variations. Higher CCA thickness parameter values are associated with a higher degree of ipsilateral ICA stenosis (p < 0.001), though IMT inhomogeneity does not provide extra information. When the ratio of wall thickness and diameter instead of absolute maximal wall thickness is used as risk marker for having moderate ipsilateral ICA stenosis (>50%), 55 arteries (15%) are reclassified to another risk category. Conclusions It is more reasonable to normalize maximal wall thickness to end-diastolic diameter rather than to IMT, affecting risk classification and suggesting modification of the Mannheim criteria. Trial registration Clinical trials.gov NCT01208025.
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Affiliation(s)
- J Steinbuch
- Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - A C van Dijk
- Radiology, Erasmus Medical Center, Rotterdam, The Netherlands.,Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Fhbm Schreuder
- Radiology, Maastricht University Medical Center, Maastricht, The Netherlands.,Clinical Neurophysiology, Maastricht University Medical Center, PO Box 5800, 6202, Maastricht, AZ, The Netherlands.,Neurology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Mtb Truijman
- Radiology, Maastricht University Medical Center, Maastricht, The Netherlands.,Clinical Neurophysiology, Maastricht University Medical Center, PO Box 5800, 6202, Maastricht, AZ, The Netherlands.,Neurology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - J Hendrikse
- Radiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - P J Nederkoorn
- Neurology, Academic Medical Center, Amsterdam, The Netherlands
| | - A van der Lugt
- Radiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - E Hermeling
- Radiology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Apg Hoeks
- Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - W H Mess
- Clinical Neurophysiology, Maastricht University Medical Center, PO Box 5800, 6202, Maastricht, AZ, The Netherlands.
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Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S. Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Atherosclerosis 2017; 261:144-152. [PMID: 28410749 DOI: 10.1016/j.atherosclerosis.2017.03.032] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 03/15/2017] [Accepted: 03/23/2017] [Indexed: 01/19/2023]
Abstract
BACKGROUND AND AIMS Substantial residual cardiovascular risks remain despite intensive statin treatment. Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins. K-877 (pemafibrate) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good safety profile as a monotherapy. The aim of these studies was to evaluate the efficacy and safety of K-877 add-on therapy to treat residual hypertriglyceridaemia during statin treatment. METHODS The objectives were investigated in two, multicentre, randomised, double-blind, placebo-controlled, parallel group comparison clinical trials: (A) K-877 0.1, 0.2, and 0.4 mg/day in combination with pitavastatin for 12 weeks in 188 patients, (B) K-877 0.2 (fixed dose) and 0.2 (0.4) (conditional up-titration) mg/day in combination with any statin for 24 weeks in 423 patients. RESULTS In both studies, we found a robust reduction in fasting triglyceride levels by approximately 50% in all combination therapy groups, which was significant compared to the statin-monotherapy (placebo) groups (p < 0.001). High-performance liquid chromatography analysis for lipoprotein subfractions revealed that atherogenic lipoprotein profiles were ameliorated by K-877 add-on therapy, i.e. small low-density lipoproteins decreased whereas larger ones increased, and larger high-density lipoproteins decreased whereas smaller ones increased. The incidence rates of adverse events and adverse drug reactions in K-877 combination therapy groups were comparable to those in statin-monotherapy groups without any noteworthy event in both studies. CONCLUSIONS These results strongly support the favourable benefit-to-risk ratio of K-877 add-on therapy in combination with statin treatment.
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Affiliation(s)
- Hidenori Arai
- National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
| | - Shizuya Yamashita
- Department of Community Medicine and Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Rinku General Medical Center, Izumisano, Osaka, Japan
| | - Koutaro Yokote
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
| | - Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
| | - Hideki Suganami
- Clinical Data Science Department, Kowa Company, Ltd., Chuo-ku, Tokyo, Japan
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
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38
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Gonzalez L, Helkin A, Gahtan V. Dyslipidemia Part 2: Review of Dyslipidemia Treatment in Patients With Noncoronary Vascular Disease. Vasc Endovascular Surg 2016; 50:119-35. [PMID: 26983668 DOI: 10.1177/1538574416628655] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Dyslipidemia is one of the major modifiable risk factors associated with atherosclerotic cardiovascular disease. Appropriate modification of lipid profiles reduces the progression of atherosclerosis in vessel walls across all vascular beds. The management of dyslipidemia has evolved over the last several decades, especially since the discovery of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins. Statin use in atherosclerotic heart disease is well described in observational and prospective placebo-controlled studies, citing both lipid-lowering and pleiotropic effects. However, the effect of statins and other lipid-lowering agents on noncoronary arterial beds (the aorta, arteries to the extremities, renal, and carotid arteries) is less understood. This article is part 2 of a 2-part review, with part 1 having focused on lipid metabolism and the downstream effects of lipids on the development of atherosclerosis. The current review (part 2) will discuss trials, retrospective reviews, and observational cohort studies regarding the use of statins and/or other lipid-lowering drugs for primary and secondary prevention of peripheral noncoronary atherosclerotic disease.
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Affiliation(s)
- Lorena Gonzalez
- Department of Veterans Affairs Healthcare Network Upstate New York at Syracuse, Syracuse, NY, USA Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Alex Helkin
- Department of Veterans Affairs Healthcare Network Upstate New York at Syracuse, Syracuse, NY, USA Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Vivian Gahtan
- Department of Veterans Affairs Healthcare Network Upstate New York at Syracuse, Syracuse, NY, USA Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
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Abstract
PURPOSE OF REVIEW This article focuses on the potential role by which a complex mixture of omega-3 fatty acids (OM3-FAs) may beneficially modify cardiovascular risk by modifying the cholesterol composition of atherogenic lipoproteins. This hypothesis is being tested in the STRENGTH trial, which is enrolling 13 000 patients on statins at high cardiovascular risk with hypertriglyceridemia and low HDL cholesterol (HDL-C) treated with an OM3-carboxylic acid. RECENT FINDINGS Complex mixtures of OM3-FAs containing predominately eicosapentanoic acid and docosahexanoic acid in combination with statins lowers non-HDL by reducing triglyceride-rich lipoprotein cholesterol (TRL-C) while shifting small LDL cholesterol (LDL-C) to large LDL-C. Recent genomic and epidemiological studies have implicated TRL-C and small LDL-C as causal for cardiovascular disease. Therefore OM3-FAs containing both eicosapentanoic acid and docosahexanoic acid in combination with statins may beneficially modify the high residual risk for patients with hypertriglyceridemia and low HDL-C. SUMMARY Although outcome trials are underway, subgroup analyses of data from previous randomized controlled trials are suggestive of a reduction in coronary artery disease and atherosclerotic cardiovascular disease event rates with triglyceride and TRL-C lowering therapies, particularly if accompanied by low HDL-C. Although the limitations of such data are acknowledged, clinicians must make treatment decisions while awaiting more definitive results from well-designed large-scale randomized controlled trials.
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Affiliation(s)
- Michael H Davidson
- Department of Medicine, Section of Cardiology, The University of Chicago, Chicago, Illinois, USA
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40
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Jakob T, Nordmann AJ, Schandelmaier S, Ferreira‐González I, Briel M, Cochrane Heart Group. Fibrates for primary prevention of cardiovascular disease events. Cochrane Database Syst Rev 2016; 11:CD009753. [PMID: 27849333 PMCID: PMC6464497 DOI: 10.1002/14651858.cd009753.pub2] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Fibrates are effective for modifying atherogenic dyslipidaemia, and particularly for lowering serum triglycerides. However, evidence that fibrates reduce mortality and morbidity associated with cardiovascular disease (CVD), or overall mortality and morbidity, in the primary prevention of CVD is lacking. OBJECTIVES This Cochrane Review and meta-analysis aimed to evaluate the clinical benefits and harms of fibrates versus placebo or usual care or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone for the primary prevention of cardiovascular disease (CVD) morbidity and mortality. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCO), and Web of Science (all from inception to 19 May 2016). We searched four clinical trial registers (last searched on 3 August 2016) with the help of an experienced professional librarian. We searched the databases to identify randomised controlled trials (RCTs) evaluating the clinical effects of fibrate therapy in the primary prevention of CVD events. We did not impose any language restrictions. SELECTION CRITERIA We aimed to include all RCTs comparing the effects of fibrate monotherapy versus placebo or usual care, or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone. Included studies had a follow-up of at least six months for the primary prevention of CVD events. We excluded trials with clofibrate, because it was withdrawn from the market in 2002. DATA COLLECTION AND ANALYSIS Two review authors independently screened titles and abstracts for potential study inclusion. Two review authors independently retrieved the full-text papers and extracted data. Disagreements were resolved by consensus. We calculated risk ratios (RRs) and accompanying 95% confidence intervals (CIs) for aggregate data on primary and secondary outcomes. We tested for heterogeneity with the Cochrane Q-test and used the I2 statistic to measure inconsistency of treatment effects across studies. Using the GRADE approach, we assessed the quality of the evidence and used the GRADE profiler software (GRADEpro GDT) to import data from Review Manager 5 to create 'Summary of findings' tables. MAIN RESULTS We identified six eligible trials including 16,135 individuals. The mean age of trial populations varied across trials; between 47.3 and 62.3 years. Four trials included individuals with diabetes mellitus type 2 only. The mean treatment duration and follow-up of participants across trials was 4.8 years. We judged the risks of selection and performance bias to be low; risks of detection bias, attrition bias, and reporting bias were unclear. Reporting of adverse effects by included trials was very limited; that is why we used discontinuation of therapy due to adverse effects as a proxy for adverse effects. Patients treated with fibrates had a reduced risk for the combined primary outcome of CVD death, non-fatal myocardial infarction, or non-fatal stroke compared to patients on placebo (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74 to 0.96; participants = 16,135; studies = 6; moderate-quality of evidence). For secondary outcomes we found RRs for fibrate therapy compared with placebo of 0.79 for combined coronary heart disease death or non-fatal myocardial infarction (95% CI 0.68 to 0.92; participants = 16,135; studies = 6; moderate-quality of evidence); 1.01 for overall mortality (95% CI 0.81 to 1.26; participants = 8471; studies = 5; low-quality of evidence); 1.01 for non-CVD mortality (95% CI 0.76 to 1.35; participants = 8471; studies = 5; low-quality of evidence); and 1.38 for discontinuation of therapy due to adverse effects (95% CI 0.71 to 2.68; participants = 4805; studies = 3; I2 = 74%; very low-quality of evidence). Data on quality of life were not available from any trial. Trials that evaluated fibrates in the background of statins (2 studies) showed no benefits in preventing cardiovascular events. AUTHORS' CONCLUSIONS Moderate-quality evidence suggests that fibrates lower the risk for cardiovascular and coronary events in primary prevention, but the absolute treatment effects in the primary prevention setting are modest (absolute risk reductions < 1%). There is low-quality evidence that fibrates have no effect on overall or non-CVD mortality. Very low-quality evidence suggests that fibrates are not associated with increased risk for adverse effects.
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Affiliation(s)
- Tobias Jakob
- University of BaselBasel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical ResearchBaselSwitzerland
| | - Alain J Nordmann
- University of BaselBasel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical ResearchBaselSwitzerland
| | - Stefan Schandelmaier
- University of BaselBasel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical ResearchBaselSwitzerland
| | - Ignacio Ferreira‐González
- Vall d'Hebron HospitalCardiology Department, Epidemiology UnitPasseig Vall d'Hebron 119‐129BarcelonaBarcelonaSpain08035
| | - Matthias Briel
- University of BaselBasel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical ResearchBaselSwitzerland
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Triglycerides and Triglyceride-Rich Lipoproteins in the Causal Pathway of Cardiovascular Disease. Am J Cardiol 2016; 118:138-45. [PMID: 27184174 DOI: 10.1016/j.amjcard.2016.04.004] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 04/06/2016] [Accepted: 04/06/2016] [Indexed: 12/20/2022]
Abstract
Epidemiologic and clinical studies suggest that elevated triglyceride levels are a biomarker of cardiovascular (CV) risk. Consistent with these findings, recent genetic evidence from mutational analyses, genome-wide association studies, and Mendelian randomization studies provide robust evidence that triglycerides and triglyceride-rich lipoproteins are in the causal pathway for atherosclerotic CV disease, indicating that they may play a pathogenic role, much like low-density lipoprotein cholesterol (LDL-C). Although statins are the cornerstone of dyslipidemia management, high triglyceride levels may persist in some patients despite statin therapy. Several triglyceride-lowering agents are available, including fibrates, niacin, and omega-3 fatty acids, of which prescription omega-3 fatty acids have the best tolerability and safety profile. In clinical studies, omega-3 fatty acids have been shown to reduce triglyceride levels, but products containing both eicosapentaenoic acid and docosahexaenoic acid may increase LDL-C levels. Icosapent ethyl, a high-purity eicosapentaenoic acid-only product, does not raise LDL-C levels and also reduces triglyceride, non-high-density lipoprotein cholesterol, and triglyceride-rich lipoprotein levels. In conclusion, omega-3 fatty acids are currently being evaluated in large CV outcome studies in statin-treated patients; these studies should help to elucidate the causative role of triglycerides in atherosclerotic CV disease.
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Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol 2016; 10:905-914. [DOI: 10.1016/j.jacl.2016.03.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/22/2016] [Accepted: 03/14/2016] [Indexed: 11/30/2022]
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Tajuddin N, Shaikh A, Hassan A. Prescription omega-3 fatty acid products: considerations for patients with diabetes mellitus. Diabetes Metab Syndr Obes 2016; 9:109-18. [PMID: 27143943 PMCID: PMC4846047 DOI: 10.2147/dmso.s97036] [Citation(s) in RCA: 11] [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] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) and metabolic syndrome contribute to hypertriglyceridemia, which may increase residual risk of cardiovascular disease in patients with elevated triglyceride (TG) levels despite optimal low-density lipoprotein cholesterol (LDL-C) levels with statin therapy. Prescription products containing the long-chain omega-3 fatty acids (OM3FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are an effective strategy for reducing TG levels. This article provides an overview of prescription OM3FAs, including relevant clinical data in patients with T2DM and/or metabolic syndrome. Prescription OM3FAs contain either combinations of DHA and EPA (omega-3-acid ethyl esters, omega-3-carboxylic acids, omega-3-acid ethyl esters A) or EPA alone (icosapent ethyl). These products are well tolerated and can be used safely with statins. Randomized controlled trials have demonstrated that all prescription OM3FAs produce statistically significant reductions in TG levels compared with placebo; however, differential effects on LDL-C levels have been reported. Products containing DHA may increase LDL-C levels, whereas the EPA-only product did not increase LDL-C levels compared with placebo. Because increases in LDL-C levels may be unwanted in patients with T2DM and/or dyslipidemia, the EPA-only product should not be replaced with products containing DHA. Available data on the effects of OM3FAs in patients with diabetes and/or metabolic syndrome support that these products can be used safely in patients with T2DM and have beneficial effects on atherogenic parameters; in particular, the EPA-only prescription product significantly reduced TG, non-high-density lipoprotein cholesterol, Apo B, remnant lipoprotein cholesterol, and high-sensitivity CRP levels without increasing LDL-C levels compared with placebo. Ongoing studies of the effects of prescription OM3FAs on cardiovascular outcomes will help determine whether these products will emerge as effective add-on options to statin therapy for reduction of residual cardiovascular disease risk.
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Affiliation(s)
- Nadeem Tajuddin
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Ali Shaikh
- Clinic of Endocrinology, Houston, TX, USA
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Switching statin-treated patients from fenofibrate to the prescription omega-3 therapy icosapent ethyl: a retrospective case series. DRUGS & THERAPY PERSPECTIVES 2016; 32:162-169. [PMID: 27065746 PMCID: PMC4801984 DOI: 10.1007/s40267-016-0288-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Introduction Patients receiving statin therapy for dyslipidaemia often require treatment with an additional agent to control triglyceride levels. Options for add-on therapy include fibrates and omega-3 fatty acids. This case series describes the effects of switching add-on therapy from fenofibrate to icosapent ethyl (the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on patient lipid profiles. Methods This was a retrospective analysis of patient records from a private medical practice in western New York. Statin-treated patients with dyslipidaemia who had been treated with fenofibrate and later switched to icosapent ethyl were selected for analysis. Lipid profiles before and after the switch to icosapent ethyl were compared. Results The records of five patients were analysed. All patients had hypertension and were overweight, male, and at high cardiovascular risk. After the switch to icosapent ethyl (treatment duration 3.9–5.8 months), triglyceride levels decreased in four patients, and low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and total cholesterol levels decreased in all patients. High-density lipoprotein levels increased in four patients. Icosapent ethyl was well tolerated. Conclusions Switching from fenofibrate to icosapent ethyl as add-on to a statin therapy due to clinical need may provide an option for patients to maintain or improve lipid parameters.
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Shipman KE, Strange RC, Ramachandran S. Use of fibrates in the metabolic syndrome: A review. World J Diabetes 2016; 7:74-88. [PMID: 26981181 PMCID: PMC4781903 DOI: 10.4239/wjd.v7.i5.74] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 10/30/2015] [Accepted: 01/21/2016] [Indexed: 02/06/2023] Open
Abstract
The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years. Their role appeared clear at the start of this century. The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit, especially in patients with atherogenic dyslipidaemia. However, this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention, Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials. In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful. We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials. The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins. Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future. We also present other features of fibrate treatment we have observed in our clinical practice; changes in creatinine, liver function tests and the paradoxical high density lipoprotein reduction. Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.
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Wang D, Liu B, Tao W, Hao Z, Liu M, Cochrane Heart Group. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev 2015; 2015:CD009580. [PMID: 26497361 PMCID: PMC6494578 DOI: 10.1002/14651858.cd009580.pub2] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Fibrates are a class of drugs characterised by mainly lowering high triglyceride, raising high-density lipoprotein (HDL) cholesterol, and lowering the small dense fraction of low-density lipoprotein (LDL) cholesterol. Their efficacy for secondary prevention of serious vascular events is unclear, and to date no systematic review focusing on secondary prevention has been undertaken. OBJECTIVES To assess the efficacy and safety of fibrates for the prevention of serious vascular events in people with previous cardiovascular disease (CVD), including coronary heart disease and stroke. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2014) on the Cochrane Library, MEDLINE (OVID, 1946 to October week 1 2014), EMBASE (OVID, 1980 to 2014 week 41), the China Biological Medicine Database (CBM) (1978 to 2014), the Chinese National Knowledge Infrastructure (CNKI) (1979 to 2014), Chinese Science and Technique Journals Database (VIP) (1989 to 2014). We also searched other resources, such as ongoing trials registers and databases of conference abstracts, to identify further published, unpublished, and ongoing studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) in which a fibrate (for example gemfibrozil, fenofibrate) was compared with placebo or no treatment. We excluded RCTs with only laboratory outcomes. We also excluded trials comparing two different fibrates without a placebo or no-treatment control. DATA COLLECTION AND ANALYSIS Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted the data. We contacted authors of trials for missing data. MAIN RESULTS We included 13 trials involving a total of 16,112 participants. Eleven trials recruited participants with history of coronary heart disease, two trials recruited participants with history of stroke, and one trial recruited participants with a mix of people with CVD. We judged overall risk of bias to be moderate. The meta-analysis (including all fibrate trials) showed evidence for a protective effect of fibrates primarily compared to placebo for the primary composite outcome of non-fatal stroke, non-fatal myocardial infarction (MI), and vascular death (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.94; participants = 16,064; studies = 12; I(2) = 45%, fixed effect). Fibrates were moderately effective for preventing MI occurrence (RR 0.86, 95% CI 0.80 to 0.93; participants = 13,942; studies = 10; I(2) = 24%, fixed effect). Fibrates were not effective against all-cause mortality (RR 0.98, 95% CI 0.91 to 1.06; participants = 13,653; studies = 10; I(2) = 23%), death from vascular causes (RR 0.95, 95% CI 0.86 to 1.05; participants = 13,653; studies = 10; I(2) = 11%, fixed effect), and stroke events (RR 1.03, 95% CI 0.91 to 1.16; participants = 11,719; studies = 6; I(2) = 11%, fixed effect). Excluding clofibrate trials, as the use of clofibrate was discontinued in 2012 due to safety concerns, the remaining class of fibrates were no longer effective in preventing the primary composite outcome (RR 0.90, 95% CI 0.79 to 1.03; participants = 10,320; studies = 7; I(2) = 50%, random effects). However, without clofibrate data, fibrates remained effective in preventing MI (RR 0.85, 95% CI 0.76 to 0.94; participants = 8304; studies = 6; I(2) = 47%, fixed effect). There was no increase in adverse events with fibrates compared to control. Subgroup analyses showed the benefit of fibrates on the primary composite outcome to be consistent irrespective of age, gender, and diabetes mellitus. AUTHORS' CONCLUSIONS Moderate evidence showed that the fibrate class can be effective in the secondary prevention of composite outcome of non-fatal stroke, non-fatal MI, and vascular death. However, this beneficial effect relies on the inclusion of clofibrate data, a drug that was discontinued in 2002 due to its unacceptably large adverse effects. Further trials of the use of fibrates in populations with previous stroke and also against a background treatment with statins (standard of care) are required.
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Affiliation(s)
- Deren Wang
- West China Hospital, Sichuan UniversityDepartment of NeurologyNo. 37, Guo Xue XiangChengduSichuanChina610041
| | - Bian Liu
- West China Hospital, Sichuan UniversityDepartment of NeurologyNo. 37, Guo Xue XiangChengduSichuanChina610041
| | - Wendan Tao
- West China Hospital, Sichuan UniversityDepartment of NeurologyNo. 37, Guo Xue XiangChengduSichuanChina610041
| | - Zilong Hao
- West China Hospital, Sichuan UniversityDepartment of NeurologyNo. 37, Guo Xue XiangChengduSichuanChina610041
| | - Ming Liu
- West China Hospital, Sichuan UniversityDepartment of NeurologyNo. 37, Guo Xue XiangChengduSichuanChina610041
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Baroncini LAV, de Castro Sylvestre L, Filho RP. Carotid intima-media thickness and carotid plaque represent different adaptive responses to traditional cardiovascular risk factors. IJC HEART & VASCULATURE 2015; 9:48-51. [PMID: 28785705 PMCID: PMC5497319 DOI: 10.1016/j.ijcha.2015.08.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 07/30/2015] [Accepted: 08/06/2015] [Indexed: 11/26/2022]
Abstract
Aim To assess the effects of each traditional cardiovascular risk factor (hypertension, diabetes mellitus, dyslipidemia, and smoking), including the presence of coronary artery disease (CAD), on carotid intima-media thickness (CIMT) and to assess the degree of carotid plaque occurrence. Methods A total of 553 outpatients (216 men and 337 women; mean age 67.06 ± 12.44 years) who underwent a carotid artery ultrasound were screened for carotid plaque and CIMT measurements. Results The CIMT medians were higher in males (P < .001) and in patients with hypertension (P < .001). A linear increase occurred in mean CIMT of 0.0059 mm for each year of increase in age. The presence of plaque indicated a tendency to correlate with CIMT (P = .067). The presence of hypertension associated with diabetes (P = .0061; estimated difference 0.0494 mm) or dyslipidemia (P = .0016; estimated difference 0.0472 mm) or CAD (P = .0043; estimated difference 0.0527 mm) increased the mean CIMT measurements. The probability of plaque occurrence in carotid arteries is influenced by the age (P < .001) and is higher in patients with dyslipidemia (P = .008) and CAD (P < .001). Conclusions Hypertension is the strongest cardiovascular risk factor that increases CIMT, followed by age and male sex. Age and dyslipidemia increase the probability of carotid plaque. Increased CIMT and plaque could be present in the same patient caused by different risk factors and with independent effects on the artery wall and different clinical prognoses.
Hypertension alone or with diabetes, dyslipidemia or CAD increases CIMT, but not the probability of carotid plaque. There is no current evidence to suggest that CIMT may progress to atherosclerotic plaque. Increased CIMT and plaque have different clinical prognoses in the same patient.
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Affiliation(s)
- Liz Andréa Villela Baroncini
- Pontifícia Universidade Católica do Paraná, Medical School, Health Sciences Postgraduate Program, Rua Imaculada Conceição 1155 - Bloco CCBS, CEP: 80215-901 Curitiba, Brazil
| | - Lucimary de Castro Sylvestre
- Pontifícia Universidade Católica do Paraná, Medical School, Health Sciences Postgraduate Program, Rua Imaculada Conceição 1155 - Bloco CCBS, CEP: 80215-901 Curitiba, Brazil
| | - Roberto Pecoits Filho
- Pontifícia Universidade Católica do Paraná, Medical School, Health Sciences Postgraduate Program, Rua Imaculada Conceição 1155 - Bloco CCBS, CEP: 80215-901 Curitiba, Brazil
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Abstract
Atherosclerosis is a chronic inflammatory disease with deposition of excessive cholesterol in the arterial intima. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that can activate or inhibit the expression of many target genes by forming a heterodimer complex with the retinoid X receptor. Activation of PPARα plays an important role in the metabolism of multiple lipids, including high-density lipoprotein, cholesterol, low-density lipoprotein, triglyceride, phospholipid, bile acids, and fatty acids. Increased PPARα activity also mitigates atherosclerosis by blocking macrophage foam cell formation, vascular inflammation, vascular smooth muscle cell proliferation and migration, plaque instability, and thrombogenicity. Clinical use of synthetic PPARα agonist fibrate improved dyslipidemia and attenuated atherosclerosis-related disease risk. This review summarizes PPARα in lipid and lipoprotein metabolism and atherosclerosis, and also highlights its potential therapeutic benefits.
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Kühnast S, Fiocco M, van der Hoorn JWA, Princen HMG, Jukema JW. Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raising: A systematic review and meta-analysis of relevant preclinical studies and clinical trials. Eur J Pharmacol 2015; 763:48-63. [PMID: 25989133 DOI: 10.1016/j.ejphar.2015.03.089] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 01/27/2015] [Accepted: 03/05/2015] [Indexed: 12/25/2022]
Abstract
Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials. Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area (R(2)=0.258, P=0.045; R(2)=0.760, P<0.001), but not for HDL-C (R(2)=0.030, P=0.556). In clinical trials, non-fatal myocardial infarction risk was significantly less in the treatment group with pooled odd ratios of 0.87 [0.81; 0.94] for all trials and 0.85 [0.78; 0.93] after excluding some trials due to off-target adverse events, whereas all-cause mortality was not affected (OR 1.05 [0.99-1.10]). Meta-regression analyses revealed a trend towards an association between between-group differences in absolute change from baseline in LDL-C and non-fatal myocardial infarction (P=0.066), whereas no correlation was found for HDL-C (P=0.955). We conclude that the protective role of lowering LDL-C and non-HDL-C is well-established. The contribution of raising HDL-C on inhibition of atherosclerosis and the prevention of cardiovascular disease remains undefined and may be dependent on the mode of action of HDL-C-modification. Nonetheless, treatment strategies aimed at improving HDL function and raising apolipoprotein A-I may be worth exploring.
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Affiliation(s)
- Susan Kühnast
- TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands; Department of Cardiology, LUMC, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands
| | - Marta Fiocco
- Department of Medical Statistics and Bioinformatics, LUMC, Leiden, The Netherlands; Mathematical Institute, Leiden University, Leiden, The Netherlands
| | - José W A van der Hoorn
- TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands; Department of Cardiology, LUMC, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands
| | - Hans M G Princen
- TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
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Gaarder M, Seierstad T. Measurements of carotid intima media thickness in non-invasive high-frequency ultrasound images: the effect of dynamic range setting. Cardiovasc Ultrasound 2015; 13:5. [PMID: 25628215 PMCID: PMC4328984 DOI: 10.1186/1476-7120-13-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 01/22/2015] [Indexed: 12/22/2022] Open
Abstract
Background Carotid intima media thickness (CIMT) measured with ultrasound (US) is widely used as biomarker for arteriosclerosis and as surrogate endpoint in interventional studies to assess efficacy of drug therapies. Strict US protocols are necessary to ensure reproducibility. The range of US signal intensities used for image formation, the dynamic range (DR), is rarely reported in studies and little is known about its effect on CIMT measurements in humans. The purpose of this study was to quantify the impact of DR on measurements of CIMT. Methods US was used to examine 313 carotid arteries in participants from two different clinical studies. For each artery, images with DR of 40, 55, 70 and 85 dB were captured from the same frozen US frame. Mean CIMT (CIMTmean), maximum CIMT (CIMTmax) and standard deviation of CIMT (CIMTsd) were obtained for all images. CIMT for different DRs were compared using student t-test. Results CIMTmean for 40, 55, 70 and 85 dB were 0.529, 0.564, 0.590 and 0.605 mm respectively. For CIMTmax the corresponding values were 0.626, 0.667, 0.698, and 0.716 mm. CIMTmean and CIMTmax increased significantly for increasing DR steps (p < 0.01). The relative change in CIMTmean and CIMTmax were largest between 40 and 55 dB (6.7% and 7.0%) and smallest between 70 and 85 dB (2.6% and 2.7%) indicating a declining dependency for increasing DR. Conclusions DR significantly changes CIMT measurements and the changes are most prominent for lower DRs. The effect of changing DR is larger in human arteries than in phantoms. Reporting the DR will therefore increase the validity of CIMT data.
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Affiliation(s)
- Mario Gaarder
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, P,O, Box 4950, Nydalen 0424, Oslo, Norway.
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