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Fruchart JC, Hermans MP, Fruchart-Najib J, Kodama T. Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα) in the Metabolic Syndrome: Is Pemafibrate Light at the End of the Tunnel? Curr Atheroscler Rep 2021; 23:3. [PMID: 33392801 PMCID: PMC7779417 DOI: 10.1007/s11883-020-00897-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2020] [Indexed: 02/06/2023]
Abstract
Purpose of Review Adoption of poor lifestyles (inactivity and energy-dense diets) has driven the worldwide increase in the metabolic syndrome, type 2 diabetes mellitus and non-alcoholic steatohepatitis (NASH). Of the defining features of the metabolic syndrome, an atherogenic dyslipidaemia characterised by elevated triglycerides (TG) and low plasma concentration of high-density lipoprotein cholesterol is a major driver of risk for atherosclerotic cardiovascular disease. Beyond lifestyle intervention and statins, targeting the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is a therapeutic option. However, current PPARα agonists (fibrates) have limitations, including safety issues and the lack of definitive evidence for cardiovascular benefit. Modulating the ligand structure to enhance binding at the PPARα receptor, with the aim of maximising beneficial effects and minimising adverse effects, underlies the SPPARMα concept. Recent Findings This review discusses the history of SPPARM development, latterly focusing on evidence for the first licensed SPPARMα, pemafibrate. Evidence from animal models of hypertriglyceridaemia or NASH, as well as clinical trials in patients with atherogenic dyslipidaemia, are overviewed. Summary The available data set the scene for therapeutic application of SPPARMα in the metabolic syndrome, and possibly, NASH. The outstanding question, which has so far eluded fibrates in the setting of current evidence-based therapy including statins, is whether treatment with pemafibrate significantly reduces cardiovascular events in patients with atherogenic dyslipidaemia. The PROMINENT study in patients with type 2 diabetes mellitus and this dyslipidaemia is critical to evaluating this.
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Affiliation(s)
- Jean-Charles Fruchart
- Residual Risk Reduction Initiative (R3i) Foundation, Picassoplatz 8, 4010, Basel, Switzerland.
| | - Michel P Hermans
- Division of Endocrinology and Nutrition, Cliniques Universitaires St-Luc and Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Jamila Fruchart-Najib
- Residual Risk Reduction Initiative (R3i) Foundation, Picassoplatz 8, 4010, Basel, Switzerland
| | - Tatsuhiko Kodama
- Laboratory for System Biology and Medicine. Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
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La Fountaine MF, Cirnigliaro CM, Hobson JC, Lombard AT, Specht AF, Dyson-Hudson TA, Bauman WA. Fenofibrate therapy to lower serum triglyceride concentrations in persons with spinal cord injury: A preliminary analysis of its safety profile. J Spinal Cord Med 2020; 43:704-709. [PMID: 30870136 PMCID: PMC7534379 DOI: 10.1080/10790268.2019.1581694] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Context: Fenofibrate is used to treat elevated serum triglyceride (TG) concentrations (e.g. ≥150 mg/dl). The lipoprotein profile of most individuals with spinal cord injury (SCI) would not satisfy conventional criteria to initiate lipid-lowering therapies. Serum TG concentrations of 115 and 137 mg/dl were recently identified as potential intervention thresholds for persons with a SCI proximal to the 4th and below the 5th thoracic vertebrae, respectively. Fenofibrate therapy has not been tested for safety in persons with SCI. Methods: An open-label trial was performed in 15 persons with SCI to determine the safety profile of 4 months of once-daily fenofibrate (145 mg tablet) treatment when initiated using modified intervention thresholds. Fasting blood tests and a review of systems were performed monthly to determine changes in liver and kidney function, as well as overall health status. Results: Fifteen subjects participated and 4 had an adverse event (e.g. 2 with gastrointestinal distress; 2 with elevated liver enzymes). Three subjects discontinued the trial within the first month and one participant remained in the trial with no further adverse events. Two participants were discontinued from fenofibrate after 2 months after not responding to treatment, as per protocol, and 10 participants completed the 4-month trial without experiencing an adverse event. Conclusion: In persons with SCI, 4 months of fenofibrate therapy initiated at lower threshold serum TG concentrations did not result in an increased incidence of adverse events compared to that reported in the general population. Fenofibrate therapy appears to be well tolerated in persons with SCI.
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Affiliation(s)
- Michael F. La Fountaine
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA,Department of Physical Therapy, School of Health and Medical Sciences, Seton Hall University, South Orange, New Jersey, USA,Departments of Medical Sciences and Neurology, Seton Hall-Hackensack Meridian School of Medicine, South Orange, New Jersey, USA,The Institute for Advanced Study of Rehabilitation and Sports Science, School of Health and Medical Sciences, Seton Hall University, South Orange, New Jersey, USA,Correspondence to: Michael F. La Fountaine, National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY10468, USA; Ph: (718) 584-9000, ext. 3121.
| | - Christopher M. Cirnigliaro
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA
| | - Joshua C. Hobson
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA,Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware, USA
| | - Alexander T. Lombard
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA
| | - Adam F. Specht
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA
| | - Trevor A. Dyson-Hudson
- Kessler Foundation, West Orange, New Jersey, USA,Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - William A. Bauman
- Department of Veterans Affairs Rehabilitation Research & Development Service National Center for the Medical, Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA,Departments of Medicine and Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Abstract
As agonists of the peroxisome proliferator-activated receptor α (PPARα), fibrates are established, effective and well-tolerated agents in the management of atherogenic dyslipidaemia. Key actions of fibrates include a reduction in elevated triglyceride levels (by up to 50%) and a rise in high-density lipoprotein cholesterol (HDL-C) concentrations (typically by 5—15%). Fibrates promote a shift from small, dense low-density lipoprotein (LDL) to larger more buoyant particles, which are less susceptible to oxidation and possess higher binding affinity for removal by the non-atherogenic LDL receptor pathway. Thus, fibrates can correct lipid abnormalities commonly observed in patients with type 2 diabetes and metabolic syndrome. Clinical evidence has demonstrated the value of fibrate therapy in secondary and primary prevention settings, as well as in patients with type 2 diabetes. However, FIELD, the largest fibrate study to date in diabetic patients, predominantly in a primary prevention setting, showed a non-significant 11% reduction in the primary end point of coronary heart disease death and non-fatal myocardial infarction with fenofibrate, although total cardiovascular events, corresponding to the secondary end point, were significantly reduced by 11% (p=0.035). It is possible that risk reduction with fenofibrate may have been attenuated by the two-fold greater drop-in use of statin therapy in the placebo group. However, the interesting results of fenofibrate on attenuation of microangiographic symptomatology potentially suggest a new recommendation for fibrate therapy, although further studies are required to validate these findings.
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Affiliation(s)
- M John Chapman
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 551, Dyslipoprotéinemies et Athérosclérose: Génétique, Métabolisme et Thérapeutique, Hôpital de la Pitié, 83, Bd de l'Hôpital — Pavilion B. Delessert, 75651 Paris, Cedex 13, France,
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Abstract
Therapy with both statins and fibrates reduces the risk of coronary events. In the fibrate studies the extent of reduction is disproportionately large in people with features of the metabolic syndrome such as overweight, elevated baseline levels of plasma triglyceride and low baseline high density lipoprotein-cholesterol (HDL-c). In such people, treatment with fibrates results in a 40—50% reduction in coronary heart disease events, much greater than predicted (from the human population studies) by the joint changes in concentrations of HDL-c or low density lipoprotein-cholesterol.
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Affiliation(s)
- Philip Barter
- HRI (The Heart Research Institute), 145 Missenden Road, Camperdown, Sydney, NSW 2050, Australia,
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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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Sando KR, Knight M. Nonstatin therapies for management of dyslipidemia: a review. Clin Ther 2015; 37:2153-79. [PMID: 26412799 DOI: 10.1016/j.clinthera.2015.09.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 08/29/2015] [Accepted: 09/01/2015] [Indexed: 02/08/2023]
Abstract
PURPOSE Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Recently published cholesterol treatment guidelines emphasize the use of statins as the preferred treatment strategy for both primary and secondary prevention of CVD. However, the optimal treatment strategy for patients who cannot tolerate statin therapy or those who need additional lipid-lowering therapy is unclear in light of recent evidence that demonstrates a lack of improved cardiovascular outcomes with combination therapy. The purpose of this review is to summarize and interpret evidence that evaluates nonstatin drug classes in reducing cardiovascular outcomes, to provide recommendations for use of nonstatin therapies in clinical practice, and to review emerging nonstatin therapies for management of dyslipidemia. METHODS Relevant articles were identified through searches of PubMed, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews by using the terms niacin, omega-3 fatty acids (FAs), clofibrate, fibrate, fenofibrate, fenofibric acid, gemfibrozil, cholestyramine, colestipol, colesevelam, ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cardiovascular outcomes. Only English language, human clinical trials, meta-analyses, and systematic reviews were included. Additional references were identified from citations of published articles. FINDINGS Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe-statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome. Long-term effects of emerging nonstatin therapies (CETP and PCSK9 inhibitors) are currently being evaluated in ongoing Phase III trials. IMPLICATIONS Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy. In certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, those with persistent severe elevations in triglycerides, or patients with high cardiovascular risk, some nonstatin therapies may be useful in reducing cardiovascular events. Future research is needed to evaluate the role of nonstatin therapies in those who are unable to tolerate guideline-directed statin doses.
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Affiliation(s)
- Karen R Sando
- College of Pharmacy, Department of Pharmacotherapy & Translational Research, University of Florida, Gainesville, Florida.
| | - Michelle Knight
- College of Pharmacy, Department of Pharmacotherapy & Translational Research, University of Florida, Gainesville, Florida
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Abstract
Cardiovascular disease is more prevalent in type 1 and type 2 diabetes, and continues to be the leading cause of death among adults with diabetes. Although atherosclerotic vascular disease has a multi-factorial etiology, disorders of lipid metabolism play a central role. The coexistence of diabetes with other risk factors, in particular with dyslipidemia, further increases cardiovascular disease risk. A characteristic pattern, termed diabetic dyslipidemia, consists of increased levels of triglycerides, low levels of high density lipoprotein cholesterol, and postprandial lipemia, and is mostly seen in patients with type 2 diabetes or metabolic syndrome. This review summarizes the trends in the prevalence of lipid disorders in diabetes, advances in the mechanisms contributing to diabetic dyslipidemia, and current evidence regarding appropriate therapeutic recommendations.
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Affiliation(s)
- Mamta Jaiswal
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA
| | | | - Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.
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Bajnok L. [HDL, or non-HDL: that is the question. Possibilities of pharmacological treatment in residual dyslipidaemia]. Orv Hetil 2014; 155:62-8. [PMID: 24389322 DOI: 10.1556/oh.2014.29797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Instead of LDL-cholesterol, non-HDL-cholesterol is proposed as a secondary lipid target when triglyceride level is above 2.3 mmol/L. Non-HDL-cholesterol target values are 0.8 mmol/L higher than those for LDL-cholesterol in the same cardiovascular risk category. Currently, the main issue of lipidology is the degree by which the cardiovascular risk can be reduced with the treatment of residual dyslipidemia that exists under statin therapy. In such a role the examined agents have essentially failed despite their more or less profound effect on HDL-cholesterol and/or non-HDL-cholesterol. The largest loser has been the nicotinic acid. The results of cardiovascular, otherwise controversial fish oil studies cannot be considered convincing because of the administered low doses. In a combination with statin (i) ezetimibe may have role if the LDL-cholesterol target cannot be reached with statin monotherapy, or (ii) fibrates, in case of large increase of triglyceride level, or in less severe hypertriglyceridemia if it is associated with considerable decrease in HDL-cholesterol level. Potential further possibilities are: (i) cholesterol ester transfer protein inhibitors that dramatically raise HDL-cholesterol, while reduce LDL-cholesterol, or (ii) proprotein convertase subtilisin/kexin 9 inhibitors that markedly decrease LDL-cholesterol even on the top of statin.
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Affiliation(s)
- László Bajnok
- Pécsi Tudományegyetem, Általános Orvostudományi Kar, Klinikai Központ I. Belgyógyászati Klinika, Hetényi Géza Endokrinológiai és Anyagcsere Osztály Pécs Ifjúság út 13. 7624
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Milwidsky A, Kivity S, Kopel E, Klempfner R, Berkovitch A, Segev S, Sidi Y, Goldenberg I, Maor E. Time dependent changes in high density lipoprotein cholesterol and cardiovascular risk. Int J Cardiol 2014; 173:295-9. [PMID: 24681020 DOI: 10.1016/j.ijcard.2014.03.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 02/18/2014] [Accepted: 03/09/2014] [Indexed: 12/01/2022]
Abstract
BACKGROUND High-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular events. The aim of the current study was to evaluate the correlation between changes in HDL-C and subsequent cardiovascular events. METHODS Study population comprised 13,037 subjects free of cardiovascular disease with a mean follow up of 6 ± 3 years. Low HDL-C was defined as < 40 mg/dl for men and <50mg/dl for women. Participants were divided into three groups based on HDL-C levels at the first and second baseline visits: persistently-low HDL-C (LL); persistently-high HDL-C (HH); and those with high HDL-C in a one visit only: intermittently high HDL-C (LH/HL). The primary endpoint was the first occurrence of a cardiovascular event. RESULTS A total of 529 (4.1%) incident events occurred during follow-up. HDL-C levels increased significantly between the two landmark visits (47.5 ± 12.6 vs. 48.1 ± 12.2, p<0.001). Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was highest among subjects in the LL group (7.6%), and similar among LH/HL and HH groups (3.3% and 4%, respectively; log-rank p=0.001). Multivariate Cox regression analysis, with HDL-C as time-dependent covariate, showed that subjects with persistently low HDL-C during follow up experienced a 51% increased cardiovascular risk compared with subjects with persistently high HDL-C (p=0.026). Subjects with intermittently high HDL-C during follow up experienced similar risk to those with persistently high HDL-C (HR=1.02; p=0.89). CONCLUSIONS Variations in HDL-C levels during follow-up are associated with subsequent cardiovascular risk. Patients who retain low HDL-C levels are at the cardiovascular highest risk.
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Affiliation(s)
- Assi Milwidsky
- Leviev Heart Center, Sheba Medical Center, Israel; Department of Internal Medicine "E", Tel-Aviv Medical Center, Israel
| | - Shaye Kivity
- Department of Internal Medicine C, Sheba Medical Center, Israel; Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Israel; Sackler School of Medicine, Tel-Aviv University, Israel
| | - Eran Kopel
- Leviev Heart Center, Sheba Medical Center, Israel
| | - Robert Klempfner
- Leviev Heart Center, Sheba Medical Center, Israel; Sackler School of Medicine, Tel-Aviv University, Israel
| | | | - Shlomo Segev
- Institute for Medical Screening, Sheba Medical Center, Israel
| | - Yechezkel Sidi
- Department of Internal Medicine C, Sheba Medical Center, Israel; Sackler School of Medicine, Tel-Aviv University, Israel
| | - Ilan Goldenberg
- Leviev Heart Center, Sheba Medical Center, Israel; Sackler School of Medicine, Tel-Aviv University, Israel
| | - Elad Maor
- Leviev Heart Center, Sheba Medical Center, Israel; Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Israel.
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10
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Abstract
The metabolic syndrome (MS), a cluster of metabolic abnormalities with insulin resistance as its central component, is increasing in prevalence and is associated with an increased risk of cardiovascular disease and Type 2 diabetes mellitus (T2DM). Current evidence supports an aggressive intervention approach that comprises lifestyle modification in conjunction with drug treatment of the MS components. Healthier eating and regular exercise greatly reduce waistline and body mass index, lower blood pressure and improve lipid profile. Lifestyle modification has been proven to prevent T2DM development. Nevertheless, appropriate treatment of MS components often requires pharmacologic intervention with insulin-sensitizing agents, such as metformin and thiazolidinediones, while statins and fibrates, or angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are the first-line lipid-modifying or antihypertensive drugs. Only severely obese patients require specific drug treatments. Very often, drug combinations will be necessary to manage multiple risk factors. As we progress in the understanding of the pathophysiology of the MS, new targets for therapies will probably be identified and new treatments will prove to be even more efficacious than those currently available for the management of this life-threatening condition.
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Affiliation(s)
- Cristina Bianchi
- University of Pisa, Department of Endocrinology and Metabolism, Cisanello University Hospital, Pisa, Italy.
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11
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Tsimihodimos V, Mikhailidis DP, Elisaf M. Summarizing the FIELD study: lessons from a ‘negative' trial. Expert Opin Pharmacother 2013; 14:2601-10. [DOI: 10.1517/14656566.2013.850075] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Klop B, Elte JWF, Cabezas MC. Dyslipidemia in obesity: mechanisms and potential targets. Nutrients 2013; 5:1218-40. [PMID: 23584084 PMCID: PMC3705344 DOI: 10.3390/nu5041218] [Citation(s) in RCA: 1009] [Impact Index Per Article: 84.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 02/14/2013] [Accepted: 03/27/2013] [Indexed: 12/13/2022] Open
Abstract
Obesity has become a major worldwide health problem. In every single country in the world, the incidence of obesity is rising continuously and therefore, the associated morbidity, mortality and both medical and economical costs are expected to increase as well. The majority of these complications are related to co-morbid conditions that include coronary artery disease, hypertension, type 2 diabetes mellitus, respiratory disorders and dyslipidemia. Obesity increases cardiovascular risk through risk factors such as increased fasting plasma triglycerides, high LDL cholesterol, low HDL cholesterol, elevated blood glucose and insulin levels and high blood pressure. Novel lipid dependent, metabolic risk factors associated to obesity are the presence of the small dense LDL phenotype, postprandial hyperlipidemia with accumulation of atherogenic remnants and hepatic overproduction of apoB containing lipoproteins. All these lipid abnormalities are typical features of the metabolic syndrome and may be associated to a pro-inflammatory gradient which in part may originate in the adipose tissue itself and directly affect the endothelium. An important link between obesity, the metabolic syndrome and dyslipidemia, seems to be the development of insulin resistance in peripheral tissues leading to an enhanced hepatic flux of fatty acids from dietary sources, intravascular lipolysis and from adipose tissue resistant to the antilipolytic effects of insulin. The current review will focus on these aspects of lipid metabolism in obesity and potential interventions to treat the obesity related dyslipidemia.
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Affiliation(s)
- Boudewijn Klop
- Department of Internal Medicine, Diabetes and Vascular Centre, Sint Franciscus Gasthuis, Rotterdam, P.O. Box 10900, 3004 BA, The Netherlands.
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Puesta al día en el manejo de las dislipidemias. REVISTA MÉDICA CLÍNICA LAS CONDES 2012. [DOI: 10.1016/s0716-8640(12)70368-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Davidson MH, Yannicelli HD. New concepts in dyslipidemia in the metabolic syndrome and diabetes. Metab Syndr Relat Disord 2012; 4:299-314. [PMID: 18370748 DOI: 10.1089/met.2006.4.299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Trials have revealed that cardiovascular risk is not uniform in the population, but is distributed in a "risk pyramid." Diabetic patients with prior cardiovascular disease (CVD) are at greatest risk. Nondiabetic patients with CVD, diabetic patients without CVD, and subjects with the metabolic syndrome form the next three risk categories. The presence of insulin resistance-related metabolic abnormalities is a common denominator in this risk pyramid. Insulin resistance is a core defect in type 2 diabetes and the metabolic syndrome. Because insulin resistance may cause the atherogenic dyslipidemia that is commonly associated with these conditions, therapeutic strategies that combat insulin resistance could substantially reduce cardiovascular risk. Evidence suggests that defects in mitochondrial oxidative phosphorylation (which may be inherited, age related, or lifestyle acquired) may play a critical role in the pathogenesis of insulin resistance. Reduced mitochondrial oxidative phosphorylation can be partially reversed by improved diet, increased exercise, and administration of peroxisome proliferator-activated receptor-alpha agonists (omega-3 fatty acids and fibrates). Statin therapy has demonstrated clinical benefits in insulin-resistant patients but residual cardiovascular risk remains elevated. Fibrates also improve the lipid profile and reduce cardiovascular risk in a variety of insulin-resistant populations. Affected individuals should be targeted for therapeutic lifestyle intervention. Patients with atherogenic dyslipidemia who have developed insulin resistance, the metabolic syndrome, or type 2 diabetes should receive more intensive interventions including, where appropriate, statin-fibrate combination therapy, to comprehensively modify the lipid profile together with aggressive control of blood pressure and glucose to minimize risk in this very high-risk population.
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Affiliation(s)
- Michael H Davidson
- Preventive Cardiology Center, Rush University Medical Center, Chicago, Illinois
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15
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Maki KC, Bays HE, Dicklin MR. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J Clin Lipidol 2012; 6:413-26. [PMID: 23009777 DOI: 10.1016/j.jacl.2012.04.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Revised: 02/21/2012] [Accepted: 04/04/2012] [Indexed: 01/28/2023]
Abstract
A severe elevation in triglycerides (TG; ≥500 mg/dL) increases the risk for pancreatitis. TG levels ≥200 mg/dL are associated with a greater risk of atherosclerotic coronary heart disease (CHD). However, no outcomes trials exist to assess the efficacy of TG lowering for preventing pancreatitis in patients with severe hypertriglyceridemia. Similarly, no completed prospective outcomes trial exists to support or refute a reduction in CHD risk resulting from lipid-altering therapy in patients specifically selected for the presence of hypertriglyceridemia. This review examines the available evidence for the use of statins, omega-3 fatty acids, fibrates, and niacin in the management of hypertriglyceridemic patients. Results from CHD outcomes trials support statins as the first-line lipid-altering drug therapy to reduce CHD in hypercholesterolemic patients, and subgroup analyses suggest statins are efficacious in hypertriglyceridemic patients with fasting TG levels <500 mg/dL. Omega-3 fatty acids and fibrates are reasonable first drug options for patients with TG ≥500 mg/dL and often are used to lower TG levels with the objective of reducing pancreatitis risk, although a statin or niacin may also be reasonable options. Combination lipid drug therapy may be needed to achieve both low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol treatment goals for CHD prevention in patients with elevated TG levels, particularly those with TG ≥500 mg/dL. Additional clinical outcomes data are needed to provide a more evidence-based rationale for clinical lipid management of hypertriglyceridemic patients.
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Affiliation(s)
- Kevin C Maki
- Biofortis Clinical Research, 211 E. Lake Street, Addison, IL 60101, USA.
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16
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Nicholls SJ, Uno K. Peroxisome proliferator-activated receptor (PPAR α/γ) agonists as a potential target to reduce cardiovascular risk in diabetes. Diab Vasc Dis Res 2012; 9:89-94. [PMID: 22407927 DOI: 10.1177/1479164112441477] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The disappointing results of glucose lowering studies have highlighted the ongoing need to develop new therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes. The presence of a range of metabolic abnormalities in diabetic patients presents a number of potential targets for therapeutic intervention. While modulation of peroxisome proliferator activated receptors (PPARs) represents an attractive approach, the results of studies of pharmacological agonists have been variable. The findings of these studies and rationale for development of dual PPAR-α/γ agonists will be reviewed.
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Affiliation(s)
- Stephen J Nicholls
- Cleveland Clinic Coordinating Center for Clinical Research and Department of Cardiovascular Medicine, Cleveland Clinic, OH 44195, USA.
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Ramachandran S, Abbas A, Saraf S, Raju J, Jewkes C, Jones AF. Significant increase in high-density lipoprotein cholesterol with fibrates is associated with low pretreatment high-density lipoprotein cholesterol: findings from an outpatient clinic setting. Metab Syndr Relat Disord 2012; 10:189-94. [PMID: 22283634 DOI: 10.1089/met.2011.0112] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Change in high-density lipoprotein cholesterol (HDL-C) observed in large randomized controlled trials using fibrates has varied. Inconsistent cardiovascular outcomes have also been the common theme of these trials. Subgroup analysis of even the negative trials, however, reveals significant reduction in cardiovascular disease in patients with low HDL-C and high triglycerides. We wished to study HDL-C change following fibrate therapy in our lipid clinic and determine the factors associated with HDL-C change. METHODS Data were collected from case notes of patients started on fibrates (n=248) between 2002 and 2008 in the lipid clinics at Heart of England NHS Foundation Trust. Regression analyses were carried out to determine factors associated with changes in HDL-C. RESULTS Linear regression analysis revealed that HDL-C change was associated with pretreatment HDL-C (P<0.001), diabetes (P=0.004) and treatment duration (P=0.036). Multiple regression analysis with all of the factors in the model suggested that they were independent. Patients with a baseline HDL-C <1.0 mmol/L showed a greater HDL-C increase when compared to patients with a baseline HDL-C ≥1.0 mmol/L; HDL-C <1.0 mmol/L (increase of 0.15 mmol/L, linear regression: c=0.14, 95% confidence interval 0.05-0.30, P<0.001) and HDL-C ≥1.0 (increase of 0.002 mmol/L, linear regression: reference category). A similar relationship between change in HDL-C and baseline HDL-C was observed within groups stratified by patient characteristics (apart from those on concurrent statin therapy and females). CONCLUSIONS Our results may explain the discrepancies observed in some randomized controlled trials whereby subgroup analysis of patients with the metabolic syndrome appeared to show benefit whereas this was absent in the total cohort. Thus, future interventional studies using fibrates should perhaps focus on patients with low HDL-C levels.
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Affiliation(s)
- Sud Ramachandran
- Department of Clinical Biochemistry, Heart of England NHS Foundation Trust, Sutton Coldfield, Birmingham, United Kingdom.
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Abstract
Hypertriglyceridemia is a prevalent risk factor for cardiovascular disease (CVD) and increasingly important in the setting of current obesity and insulin resistance epidemics. High triglyceride (TG) levels are markers for several types of atherogenic lipoproteins. Patients who have hypertriglyceridemia may be at significant risk for CVD even if low-density lipoprotein cholesterol levels are at goal, and therefore warrant treatment that optimizes diet, reduces overweight, and promotes regular exercise. High-risk patients with hypertriglyceridemia, such as those with diabetes, CVD, or metabolic syndrome, may benefit from additional drug treatment aside from a statin to address other lipid abnormalities. In this discussion, we review the role of hypertriglyceridemia and its associated atherogenic lipoproteins in the pathogenesis of atherosclerosis, the relevance of a high TG level as a predictor of CVD, the cardiovascular outcomes from TG-lowering intervention trials, and the current guidelines for treating hypertriglyceridemia.
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Rizzo M, Tomkin GH, Patti AM, Pepe I, Valerio MR, Di Rosa S, Rini GB, Di Fede G. Effects of hypolipidemic and hypoglycemic agents on atherogenic small, dense LDL in Type 2 diabetes. ACTA ACUST UNITED AC 2011. [DOI: 10.2217/clp.11.46] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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PPAR Genomics and Pharmacogenomics: Implications for Cardiovascular Disease. PPAR Res 2011; 2008:374549. [PMID: 18401448 PMCID: PMC2288645 DOI: 10.1155/2008/374549] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Accepted: 12/12/2007] [Indexed: 12/21/2022] Open
Abstract
The peroxisome proliferator-activated receptors (PPARs) consist of three related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease. Numerous pharmacologic studies have assessed the effects of specific PPAR agonists in clinical trials and have provided insight into the clinical effects of these genes while genetic studies have demonstrated clinical associations between PPAR polymorphisms and abnormal cardiovascular phenotypes. With the abundance of data available from these studies as a background, PPAR pharmacogenetics has become a promising and rapidly advancing field. This review focuses on summarizing the current state of understanding of PPAR genetics and pharmacogenetics and the important implications for the individualization of therapy for patients with cardiovascular diseases.
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Reyes-Soffer G, Rondon-Clavo C, Ginsberg HN. Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus. Expert Opin Pharmacother 2011; 12:1429-38. [DOI: 10.1517/14656566.2011.563506] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Florentin M, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Emerging options in the treatment of dyslipidemias: a bright future? Expert Opin Emerg Drugs 2011; 16:247-70. [PMID: 21323473 DOI: 10.1517/14728214.2011.554395] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD). Low-density lipoprotein cholesterol (LDL-C) reduction has been demonstrated to decrease CVD-related morbidity and mortality. However, several patients do not reach LDL-C target levels with the currently available lipid lowering agents, particularly statins. Lipid and non-lipid parameters other than LDL-C may account for the residual CVD risk after adequate LDL-C lowering with statins. AREAS COVERED This review focuses on the efficacy and safety of emerging drugs aiming at high-density lipoprotein cholesterol (HDL-C) elevation (i.e., recombinant or plasma-derived wild-type apolipoprotein (apo) A-I, apo A-I mimetic peptides, reconstituted mutant HDL, partially delipidated HDL and cholesterol ester transfer protein inhibitors), microsomal triglyceride transfer protein inhibitors and antisense oligonucleotides. EXPERT OPINION Several lipid modifying agents in development may potently reduce the residual CVD risk. Ongoing and future studies with clinical outcomes will clarify their efficacy in clinical practice.
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Affiliation(s)
- Matilda Florentin
- University of Ioannina, School of Medicine, Department of Internal Medicine, Ioannina 45110, Greece
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Elam M, Lovato L, Ginsberg H. The ACCORD-Lipid study: implications for treatment of dyslipidemia in Type 2 diabetes mellitus. ACTA ACUST UNITED AC 2011. [PMID: 26207146 DOI: 10.2217/clp.10.84] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with Type 2 diabetes mellitus (T2DM) are at high risk of developing cardiovascular disease (CVD). Treatment of diabetic dyslipidemia, comprised mainly of hypertriglyceridemia, and low HDL-C, with either statin or fibrate monotherapy, is moderately effective at reversing the abnormal lipid levels, but does not completely reverse the risk of CVD. Combination therapy with a statin and fibrate more effectively treats diabetic dyslipidemia; however, neither the impact on CVD risk nor the safety profile of statin-fibrate combined treatment had been tested in a large randomized trial. The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid trial tested the hypothesis that combination therapy with a fibrate and statin would more effectively prevent major CVD events in a high-risk population of patients with T2DM compared with statin monotherapy. In ACCORD-Lipid, over 5000 patients were treated with fenofibrate plus simvastatin versus simvastatin alone. Although combination therapy did not significantly reduce CVD event rates in the ACCORD-Lipid cohort as a whole, a predefined subgroup of participants with the combination of significant hypertriglyceridemia and low HDL-C experienced a 31% lower event rate with combination therapy. Post hoc analyses conducted in similar subsets in previous fibrate monotherapy trials were concordant with these findings in ACCORD-Lipid. Combination therapy was well tolerated and safe, with no detectable increase in myopathy. The implications of the ACCORD-Lipid findings for the treatment of dyslipidemia in patients with T2DM are discussed.
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Affiliation(s)
- Marshall Elam
- Section of Epidemiology, Department of Public Health Sciences, Wake Forest University - School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157-1063, USA
| | - Laura Lovato
- Section of Epidemiology, Department of Public Health Sciences, Wake Forest University - School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157-1063, USA
| | - Henry Ginsberg
- Department of Medicine, College of Physicians & Surgeons of Columbia University, PH-10-305, 630 West 168th Street, New York, NY 10032, USA
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Abstract
PURPOSE OF REVIEW To examine the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid trial, particularly the subgroup analyses. It is important, when a study fails to meet its overall primary endpoint, to ensure that interpretation of the results include analyses of subgroups that might benefit from the treatment tested. The goal of this review, therefore, is to provide insight and advice to physicians and healthcare workers treating patients similar to those enrolled in ACCORD. RECENT FINDINGS The recently published results of ACCORD-Lipid trial will be presented upon the background of previous trials that have tested the ability of fibrates to lower cardiovascular risk. SUMMARY Although ACCORD-Lipid trial did not provide support for the general addition of fenofibrate to statin-treated patients with type 2 diabetes mellitus (T2DM), it added significantly to the results from fibrate monotherapy trials indicative of benefit from such treatment in subgroups of patients who present with significant dyslipidemia. In particular, ACCORD-Lipid trial, in our view, supports the addition of fenofibrate to statin therapy in patients with T2DM and optimal low-density lipoprotein cholesterol levels but persistent, significant hypertriglyceridemia (>200 mg/dl) and low high-density lipoprotein cholesterol levels (<35-40 mg/dl).
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Affiliation(s)
- Marshall Elam
- Departments of Pharmacology and Medicine, University of Tennessee Health Sciences Center-Memphis, Memphis, Tennessee
| | - Laura C. Lovato
- Department of Public Health Sciences, Wake Forest University-School of Medicine, Winston Salem, North Carolina
| | - Henry Ginsberg
- Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA
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Wilke RA. High-density lipoprotein (HDL) cholesterol: leveraging practice-based biobank cohorts to characterize clinical and genetic predictors of treatment outcome. THE PHARMACOGENOMICS JOURNAL 2010; 11:162-73. [PMID: 21151197 DOI: 10.1038/tpj.2010.86] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Over the past decade, large multicenter trials have unequivocally demonstrated that decreasing low-density lipoprotein (LDL) cholesterol can reduce both primary and secondary cardiovascular events in patients at risk. However, even in the context of maximal LDL lowering, there remains considerable residual cardiovascular risk. Some of this risk can be attributed to variability in high-density lipoprotein (HDL) cholesterol. As such, there is tremendous interest in defining determinants of HDL homeostasis. Risk prediction models are being constructed based upon (1) clinical contributors, (2) known molecular determinants and (3) the genetic architecture underlying HDL cholesterol levels. To date, however, no single resource has combined these factors within the context of a practice-based data set. Recently, a number of academic medical centers have begun constructing DNA biobanks linked to secure encrypted versions of their respective electronic medical record. As these biobanks combine resources, the clinical community is in a position to characterize lipid-related treatment outcome on an unprecedented scale.
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Affiliation(s)
- R A Wilke
- Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
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Rizzo M, Berneis K, Koulouris S, Pastromas S, Rini GB, Sakellariou D, Manolis AS. Should we measure routinely oxidised and atherogenic dense low-density lipoproteins in subjects with type 2 diabetes? Int J Clin Pract 2010; 64:1632-42. [PMID: 20831734 DOI: 10.1111/j.1742-1241.2010.02378.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Beyond low-density lipoprotein (LDL)-cholesterol concentrations, in recent years, several clinical studies have shown that both oxidised and small, dense LDL have a strong predictive role for the presence of vascular atherosclerosis. These two lipid parameters seem to have a synergistic impact on cardiovascular risk, with a greater importance in patients at higher-risk, such as those with type-2 diabetes. Increased levels of oxidised and small, dense LDL levels are a feature of diabetic dyslipidaemia, and small, dense LDL have been shown to be a good predictor of future cardiovascular events, at both univariate and multivariate analyses. On the other hand, although the association of oxidised LDL with surrogate markers of atherosclerosis is consistent, the correlation with hard clinical end points seems to be smaller. Yet, measurement of these two lipid parameters has not been widely used in daily practice because of the limited availability of clinical data and methodological problems: lack of availability of easy, cheap and reproducible essays for measurement of oxidised and, particularly, small, dense LDL has reduced their assessment in large clinical end-points trials. However, on the basis of available data, the therapeutic modulation of small, dense LDL is significantly associated with reduced cardiovascular risk, even after adjustment for confounding factors. In conclusion, the routine measurement of oxidised and small, dense LDL in patients with type-2 diabetes cannot be recommended in daily clinical practice so far; yet, their measurement is strongly encouraged to better understand their role on the cardiovascular risk of patients with type-2 diabetes.
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Affiliation(s)
- M Rizzo
- Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy.
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Abstract
PURPOSE New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease. RECENT FINDINGS Endpoint studies have been conducted with fibrates in coronary heart disease (CHD) since 1971 and initial results were contradictory. Fibrates later showed benefits in patients with low HDL-C and low LDL-C. The prominence ascribed to the lipid triad of the metabolic syndrome and the increasing prevalence of diabetes has increased the topicality of fibrates given their main action of converting small dense to light buoyant LDL. The Fenofibrate Intervention in Endpoint Lowering in Diabetes (FIELD) study has carried on the tradition. Fenofibrate therapy in 9795 patients comprising a mixed low-risk primary and a medium-risk secondary prevention cohort resulted in an 11% reduction in coronary events (P = 0.16), a similar but significant reduction in cardiovascular events (P = 0.04; number-needed-to-treat = 70). The benefits were concentrated in primary prevention and on nonfatal myocardial events, and post-hoc greater effects were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-C, as had previously been noted in a trial with bezafibrate. Safety was generally good, including in combination with statins, but old concerns about sudden death, pancreatitis and venous thrombosis returned. Unexpected benefits were seen with fenofibrate for microvascular endpoints including microalbuminuria and retinopathy. SUMMARY Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes, and well tolerated in combination therapy. The benefits of fenofibrate for microvascular disease and its potential role in combination therapy require further confirmation.
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Fruchart JC, Sacks FM, Hermans MP. Implications of the ACCORD lipid study: perspective from the Residual Risk Reduction Initiative (R(3)i). Curr Med Res Opin 2010; 26:1793-7. [PMID: 20482323 DOI: 10.1185/03007995.2010.489341] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Most type 2 diabetes patients remain at high residual risk of cardiovascular events despite best treatment. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial aimed to address this challenge, by evaluating whether intensive control of glycaemia and high blood pressure, or as in ACCORD Lipid, extending lipid treatment with the combination of fenofibrate plus simvastatin, could impact this risk. ACCORD Lipid showed that treatment beyond low-density lipoprotein cholesterol was not appropriate for most type 2 diabetes patients. However, a subgroup analysis did suggest additional benefit in patients with atherogenic dyslipidaemia, the combination of high baseline triglycerides (>or=204 mg/dL or 2.3 mmol/L) and low baseline plasma levels of high-density lipoprotein cholesterol (<or=34 mg/dL or 0.88 mmol/L). This finding is concordant with subgroup analyses from other fibrate trials in patients with high triglycerides and low plasma levels of high-density lipoprotein cholesterol, and consistent with current guideline recommendations. This commentary from the Residual Risk Reduction Initiative (R(3)i), discusses the ACCORD Lipid study results and the next steps to establish the clinical relevance of these findings.
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Abstract
PURPOSE OF REVIEW New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease. RECENT FINDINGS Endpoint studies have been conducted with fibrates in coronary heart disease since 1971 and results have been contradictory. Fibrates have shown benefits in patients with low HDL-cholesterol and low LDL-cholesterol. Fibrates remain topical, given their actions on the lipid triad present in the metabolic syndrome and in diabetes. In the Fenofibrate Intervention in Endpoint Lowering in Diabetes study of mixed primary and secondary prevention cohorts, fenofibrate therapy resulted in an 11% reduction in coronary or cardiovascular events in monotherapy. Despite frequent use, there was little endpoint data on fibrate-statin combination therapy until recently. The Action to Control Cardiovascular Risk in Diabetes trial of fenofibrate added to baseline simvastatin therapy in diabetes showed a nonsignificant 8% reduction in cardiovascular events. The benefits were concentrated in men, and women did slightly worse with fibrate therapy. In post-hoc analysis, slight beneficial effects of fenofibrate were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-cholesterol (<0.88 mmol/l). The safety profile of fibrate-simvastatin combination was good. SUMMARY Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes. They are safe in combination therapy with statins but add little endpoint benefit except possibly in patients with a significant degree of atherogenic dyslipidaemia (high triglycerides and low HDL-cholesterol). The benefits of fibrates on microvascular disease remain to be fully explored.
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Residual Risk Reduction Initiative: výzva ke snížení reziduálního vaskulárního rizika u pacientů s dyslipidemií. COR ET VASA 2010. [DOI: 10.33678/cor.2010.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Joint effect of self-reported sleep problems and three components of the metabolic syndrome on risk of coronary heart disease. J Psychosom Res 2010; 68:149-58. [PMID: 20105697 DOI: 10.1016/j.jpsychores.2009.07.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2009] [Revised: 07/20/2009] [Accepted: 07/21/2009] [Indexed: 11/22/2022]
Abstract
OBJECTIVE This study explored the joint effect of two epidemics, sleep problems and metabolic syndrome (MetS), on the risk of coronary heart disease (CHD). METHODS The study group is part of the Finnish middle-aged men who participated in the first screening for the Helsinki Heart Study (HHS) in 1981-1982. At that time, three components of MetS were measured: body mass index, HDL cholesterol, and blood pressure. Later, in 1986-1988, they were given a psychosocial questionnaire including items on sleep problems. Of the respondents, 2753 formed our study group and were followed up using population-based registers until 1995. The relative risks (RR) of CHD were estimated using Cox's regression models. RESULTS When several sleep problems were present simultaneously, some increased CHD risk was observed. However, when considered jointly with MetS, insomnia or daytime fatigue approximately doubled the CHD risk and the presence of insufficient sleep more than tripled the risk. Among those who had MetS only, the RR was 2.55, and among those with both insufficient sleep and MetS the RR was 9.36 (95% confidence interval: 4.60-19.04; P for interaction 0.09) when compared to those with no insufficient sleep and no components of MetS. CONCLUSION The interaction occurred when all three measured MetS components were present, suggesting that co-occurrence of these two epidemics may predict growing public health problems.
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Jones PH. Fenofibric acid plus statin combination therapy for the treatment of mixed dyslipidemia. ACTA ACUST UNITED AC 2009. [DOI: 10.2217/clp.09.71] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Robinson E, Grieve DJ. Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease. Pharmacol Ther 2009; 122:246-63. [PMID: 19318113 DOI: 10.1016/j.pharmthera.2009.03.003] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Accepted: 03/03/2009] [Indexed: 01/12/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that belong to the nuclear receptor superfamily. Three isoforms of PPAR have been identified, alpha, delta and gamma, which play distinct roles in the regulation of key metabolic processes, such as glucose and lipid redistribution. PPARalpha is expressed predominantly in the liver, kidney and heart, and is primarily involved in fatty acid oxidation. PPARgamma is mainly associated with adipose tissue, where it controls adipocyte differentiation and insulin sensitivity. PPARdelta is abundantly and ubiquitously expressed, but as yet its function has not been clearly defined. Activators of PPARalpha (fibrates) and gamma (thiazolidinediones) have been used clinically for a number of years in the treatment of hyperlipidaemia and to improve insulin sensitivity in diabetes. More recently, PPAR activation has been found to confer additional benefits on endothelial function, inflammation and thrombosis, suggesting that PPAR agonists may be good candidates for the treatment of cardiovascular disease. In this regard, it has been demonstrated that PPAR activators are capable of reducing blood pressure and attenuating the development of atherosclerosis and cardiac hypertrophy. This review will provide a detailed discussion of the current understanding of basic PPAR physiology, with particular reference to the cardiovascular system. It will also examine the evidence supporting the involvement of the different PPAR isoforms in cardiovascular disease and discuss the current and potential future clinical applications of PPAR activators.
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Affiliation(s)
- Emma Robinson
- Centre for Vision and Vascular Science, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 3rd Floor, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL UK
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Toth PP, Zarotsky V, Sullivan JM, Laitinen D. Dyslipidemia treatment of patients with diabetes mellitus in a US managed care plan: a retrospective database analysis. Cardiovasc Diabetol 2009; 8:26. [PMID: 19450274 PMCID: PMC2694778 DOI: 10.1186/1475-2840-8-26] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2009] [Accepted: 05/18/2009] [Indexed: 11/25/2022] Open
Abstract
Background To evaluate real-world pharmacologic treatment of mixed dyslipidemia in patients with diabetes mellitus (DM). Methods All commercial health plan members in a large US managed care database with complete lipid panel results (HDL-C, LDL-C, TG) between 1/1/2006 and 12/31/2006 were identified (N = 529,236). DM patients (N = 53,679) with mixed dyslipidemia were defined as having any 2 suboptimal lipid parameters (N = 28,728). Lipid treatment status 6 months pre- and post-index date was determined using pharmacy claims for any lipid therapy. Results Post-index, 41.1% of DM patients with 2 abnormal lipid parameters and 45.1% with 3 abnormal lipid parameters did not receive lipid-modifying treatment. Post-index treatment rates were 57.4%, 63.6%, and 66.4% for patients with LDL-C, HDL-C, and TG in the most severe quartiles, respectively. Statin monotherapy was the primary lipid-modifying regimen prescribed (54.8% and 47.8% of patients with any 2 and all 3 lipids not at goal, respectively). Less than 30% of treated patients received combination therapy. Conclusion Over 40% of DM patients with mixed dyslipidemia received no lipid-modifying therapy during the follow-up period. Those who were treated were primarily prescribed statin monotherapy. This study suggests that DM patients are not being treated to ADA-suggested targets.
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Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009; 205:1-8. [PMID: 19386311 DOI: 10.1016/j.atherosclerosis.2009.03.008] [Citation(s) in RCA: 178] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Revised: 03/04/2009] [Accepted: 03/06/2009] [Indexed: 10/21/2022]
Abstract
Cardiovascular disease is the leading cause of morbidity and mortality world-wide. The burden of disease is also increasing as a result of the global epidemics of diabetes and obesity. Peroxisome proliferator-activated receptor alpha (PPARalpha), a member of this nuclear receptor family, has emerged as an important player in this scenario, with evidence supporting a central co-ordinated role in the regulation of fatty acid oxidation, lipid and lipoprotein metabolism and inflammatory and vascular responses, all of which would be predicted to reduce atherosclerotic risk. Additionally, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has indicated the possibility of preventive effects in diabetes-related microvascular complications, although the mechanisms of these effects warrant further study. The multimodal pharmacological profile of PPARalpha has prompted development of selective PPAR modulators (SPPARMs) to maximise therapeutic potential. It is anticipated that PPARalpha will continue to have important clinical application in addressing the major challenge of cardiometabolic risk associated with type 2 diabetes, obesity and metabolic syndrome.
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Affiliation(s)
- Jean-Charles Fruchart
- Laboratoire J & K, Inserm UR 545, Université Lille 2, Faculté de Médecine de Lille, Pôle Recherche, Lille Cedex, France.
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Rizzo M, Rizvi AA, Rini GB, Berneis K. The therapeutic modulation of atherogenic dyslipidemia and inflammatory markers in the metabolic syndrome: what is the clinical relevance? Acta Diabetol 2009; 46:1-11. [PMID: 18925358 DOI: 10.1007/s00592-008-0057-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2008] [Accepted: 09/03/2008] [Indexed: 12/29/2022]
Abstract
The metabolic syndrome consists of a constellation of clinical and biochemical risk factors that cluster together and heighten the risk for atherogenesis, cardiovascular diseases, and diabetes. Established risk cardiovascular factors like hypertension, atherogenic dyslipidaemia, and glucose intolerance occur in the setting of insulin resistance and central adiposity, with genetic and environmental influences modulating the ultimate risk. Chronic insults to the endothelium take its toll in the form of silent as well as clinically evident cardiovascular events. The cellular and vascular accompaniments have shed some light into the underlying pathophysiology. Heightened, low-grade inflammatory processes as well as a continuum of vascular insults ranging from early endothelial derangements to advanced atherosclerosis have been examined. In recent years there has been an explosion of basic and clinical knowledge related to the metabolic syndrome. Although dyslipidaemia is considered a traditional risk component for the syndrome, its qualitative aspects, genetically determined subfractions, and variation in proatherogenic tendency have generated renewed interest and debate. New targets within the dyslipidaemic spectrum that have differing clinical relevance are being evaluated. The effect of heredity, lifestyle changes, pharmacotherapeutic agents, and supplements is being investigated. Further research into the impact of dyslipidemia and inflammation as both pathophysiologic risk factors and objects for targeted therapy in the metabolic syndrome should deepen our understanding and unravel answers to the underlying dynamics in this global epidemic.
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Affiliation(s)
- Manfredi Rizzo
- Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy
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Davidson M. A review of the current status of the management of mixed dyslipidemia associated with diabetes mellitus and metabolic syndrome. Am J Cardiol 2008; 102:19L-27L. [PMID: 19084086 DOI: 10.1016/j.amjcard.2008.09.071] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Current treatment guidelines recommend lowering elevated low-density lipoprotein (LDL) cholesterol levels with a statin as the primary lipid-modifying intervention to reduce cardiovascular risk in patients with type 2 diabetes mellitus or metabolic syndrome. However, even with high-dose statin therapy or the combination of statin plus ezetimibe, many patients remain at substantial risk of a cardiovascular event. Increasingly, there is recognition of the importance of treating all components of the atherogenic dyslipidemic profile associated with both conditions, specifically low high-density lipoprotein cholesterol and elevated triglyceride levels, in addition to lowering LDL cholesterol. Both niacin (nicotinic acid) and fibrates are recommended as options for combination with a statin in this setting. Data from ongoing prospective outcomes studies are needed to evaluate the efficacy and safety of these combinations.
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Jones PH. Expert perspective: reducing cardiovascular risk in metabolic syndrome and type 2 diabetes mellitus beyond low-density lipoprotein cholesterol lowering. Am J Cardiol 2008; 102:41L-47L. [PMID: 19084089 DOI: 10.1016/j.amjcard.2008.09.074] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Even with optimal statin therapy, many patients with type 2 diabetes mellitus or metabolic syndrome fail to achieve all lipid targets and remain at high risk of cardiovascular events. Add-on lipid-modifying therapy that is effective in improving the triglyceride and high-density lipoprotein (HDL) cholesterol abnormalities characteristic of these conditions is a recommended approach to reduce this risk. Fibrates or niacin is a logical option, supported by clinical studies showing improved lipid control in combination with a statin. Of the fibrates, fenofibrate may offer microvascular benefits in type 2 diabetes--as demonstrated by the Diabetes Atherosclerosis Intervention Study (DAIS) and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study--as well as a low risk of myopathy when combined with statins compared with gemfibrozil. Although there is good evidence that both agents favorably affect clinical outcome, we need to evaluate their impact against a baseline of statin therapy. We await data from ongoing large-scale studies to evaluate the efficacy and safety of these combinations and to determine the most appropriate option for reducing residual cardiovascular risk in this important patient population.
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Affiliation(s)
- Peter H Jones
- Section of Atherosclerosis and Lipid Research, Baylor College of Medicine, Houston, Texas 77030, USA.
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Isabel Panadero M, González MDC, Herrera E, Bocos C. Modulación del PPARα por agentes farmacológicos y naturales y sus implicaciones metabólicas. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2008. [DOI: 10.1016/s0214-9168(08)75789-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Fruchart JC, Sacks FM, Hermans MP, Assmann G, Brown WV, Ceska R, Chapman MJ, Dodson PM, Fioretto P, Ginsberg HN, Kadowaki T, Lablanche JM, Marx N, Plutzky J, Reiner Z, Rosenson RS, Staels B, Stock JK, Sy R, Wanner C, Zambon A, Zimmet P. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008; 5:319-35. [PMID: 18958843 DOI: 10.3132/dvdr.2008.046] [Citation(s) in RCA: 230] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue. This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3I highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.
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Fibrates and future PPARα agonists in the treatment of cardiovascular disease. ACTA ACUST UNITED AC 2008; 5:542-53. [DOI: 10.1038/ncpcardio1278] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 04/29/2008] [Indexed: 11/09/2022]
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Brinton EA. Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio? Curr Atheroscler Rep 2008; 10:25-32. [PMID: 18366982 DOI: 10.1007/s11883-008-0005-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Statins effectively lower low-density lipoprotein cholesterol levels and the risk of cardiovascular disease (CVD) events, and because of this they have become a standard treatment for dyslipidemia and atheroprevention. Unfortunately, statin monotherapy may fail to normalize high triglycerides and low high-density lipoprotein cholesterol, and it prevents only a minority of CVD events. Further treatment of lipid disorders that remain after statin monotherapy should help reduce the residual CVD risk. Fibrate monotherapy lowers high triglyceride levels, raises low high-density lipoprotein cholesterol, and reduces CVD risk; therefore, fibrates are recommended as an adjunct to statins for treatment of residual dyslipidemia and residual CVD risk. This review provides an update on the benefits and risks of fibrate monotherapy and addresses the benefits and risks of adding fibrates to statins.
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Affiliation(s)
- Eliot A Brinton
- Cardiovascular Genetics, University of Utah School of Medicine, 420 Chipeta Way, Room 1160, Salt Lake City, UT 84108, USA.
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Effects of Modifying Triglycerides and Triglyceride-rich Lipoproteins on Cardiovascular Outcomes. J Cardiovasc Pharmacol 2008; 51:331-51. [DOI: 10.1097/fjc.0b013e318165e2e7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Barter PJ, Rye KA. Is There a Role for Fibrates in the Management of Dyslipidemia in the Metabolic Syndrome? Arterioscler Thromb Vasc Biol 2008; 28:39-46. [PMID: 17717290 DOI: 10.1161/atvbaha.107.148817] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The outcomes of fibrate trials have varied: positive with gemfibrozil in the primary prevention Helsinki Heart Study and the secondary prevention VA-HIT trial; positive with reservations in the primary prevention WHO trial (clofibrate); and mixed with bezafibrate in the secondary prevention BIP study and with fenofibrate in the combined primary and secondary prevention FIELD study. Overall, the mixed results, combined with potential for adverse effects when given in combination with statins, have limited the use of these fibrates as cardioprotective agents. However, post hoc analyses of several of the fibrate studies have shown that people with features of the metabolic syndrome, particularly overweight people with high plasma triglyceride levels and low levels of HDL cholesterol, derive a disproportionately large reduction in cardiovascular events when treated with these agents. Thus, there is a strong case for the use of a fibrate to reduce the cardiovascular risk in overweight people with high triglyceride and low HDL-C. However, it should be noted that such people also have their cardiovascular risk reduced by statin therapy. It remains to be determined whether the combination of a fibrate plus statin reduces the risk beyond that achieved with a statin alone.
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Abstract
BACKGROUND Increasing evidence suggest that the 'quality' rather than only the 'quantity' of low-density lipoprotein (LDL) exerts a great influence on the cardiovascular risk. Small, dense LDL seem to be an important predictor of cardiovascular events and progression of coronary artery disease (CAD) and their predominance has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. DISCUSSION Some studies showed in past years that small, dense LDL are usually elevated in patients at very high cardiovascular risk, such as those with CAD and type 2 diabetes. More recently elevated levels of these particles have been found in other categories of patients at high cardiovascular risk, such as those with non-coronary forms of atherosclerosis (e.g. with carotid artery disease, aortic abdominal aneurysm and peripheral arterial disease) and metabolic diseases (with polycystic ovary syndrome and growth hormone deficiency); notably, in most of them, the predominance of small, dense LDL characterised their type of dyslipidaemia, alone or in combination with elevated triglycerides and reduced high-density lipoproteins cholesterol concentrations. CONCLUSIONS The therapeutical modulation of small, dense LDL have been shown to significantly reduce cardiovascular risk and weight reduction and increased physical activity may constitute first-line therapy. In addition, lipid-lowering drugs are able to favourably alter these particles and fibrates and nicotinic acid seem to be the most effective agents. Promising data are also available with the use of rosuvastatin, the latest statin introduced in the market, and ezetimibe, a cholesterol absorption inhibitor.
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Affiliation(s)
- M Rizzo
- Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy.
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Abstract
The goal of pharmacogenetics is to define the genetic determinants of individual drug responsiveness, and thereby provide personalized treatment to each individual. The peroxisome proliferator-activated receptors (PPARs) are polypeptide products of a set of related genes functioning to regulate several cellular processes that are central to cardiovascular health and disease. Given their pleiotropic roles in lipid and glucose homeostasis, cardiac energy balance and regulation of adipocyte release of circulating inflammatory factors, it is not surprising that PPARs represent an attractive target for clinical investigation and intervention in disease states, such as diabetes, obesity, atherosclerosis, cardiomyopathy, cardiac hypertrophy and heart failure. Research into the manipulation of PPAR function by pharmacologic agents has already resulted in important advances in the treatment of diabetes mellitus and cardiovascular disease. It follows that PPAR pharmacogenetics promises important advances in the personalized treatment of cardiovascular disease.
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Affiliation(s)
- Sharon Cresci
- Washington University School of Medicine, Department of Medicine, Saint Louis, Missouri, 660 South Euclid Avenue, Campus Box 8086 Saint Louis, MO 63110-1093, USA
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Filippatos TD, Gazi IF, Liberopoulos EN, Athyros VG, Elisaf MS, Tselepis AD, Kiortsis DN. The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis 2007; 193:428-37. [PMID: 16911813 DOI: 10.1016/j.atherosclerosis.2006.07.010] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2006] [Revised: 07/07/2006] [Accepted: 07/07/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND Increased concentration of small dense LDL cholesterol (sdLDL-C) and activity of lipoprotein-associated phospholipase A2 (Lp-PLA(2)) are considered as emerging cardiovascular risk factors and are commonly encountered in subjects with metabolic syndrome (MetS). OBJECTIVE The primary endpoint of this study was the effect of orlistat and fenofibrate, alone or in combination, on Lp-PLA(2) activity and LDL phenotype in overweight and obese patients (body mass index>28 kg/m(2)) with MetS. METHODS Patients (n=89) were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg three times daily (O group), micronized fenofibrate 200mg/day (F group) or both (OF group) for 6 months. RESULTS Significant reductions of sdLDL-C levels were observed in all treatment groups. Groups F and OF experienced a greater reduction in sdLDL-C levels (p<0.05) together with a greater increase in LDL particle diameter (p<0.05) compared with group O. Total plasma Lp-PLA(2) activity significantly decreased in all treatment groups. The reduction of Lp-PLA(2) was more pronounced with OF administration compared with each monotherapy (p<0.05). CONCLUSION Orlistat and fenofibrate exhibited favorable effects on Lp-PLA(2) activity and LDL phenotype in overweight and obese patients with MetS. Importantly, combination treatment had a more favorable effect on these risk factors.
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Affiliation(s)
- T D Filippatos
- Department of Internal Medicine, Medical School, University of Ioannina, 45 110 Ioannina, Greece
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Vittone F, Chait A, Morse JS, Fish B, Brown BG, Zhao XQ. Niacin plus Simvastatin Reduces Coronary Stenosis Progression Among Patients with Metabolic Syndrome Despite a Modest Increase in Insulin Resistance: A Subgroup Analysis of the HDL-Atherosclerosis Treatment Study (HATS). J Clin Lipidol 2007; 1:203-210. [PMID: 18591993 DOI: 10.1016/j.jacl.2007.05.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND: Metabolic syndrome, insulin resistance and diabetes are associated with an increased risk of cardiovascular disease. Niacin is known to increase insulin resistance, and have adverse effects on blood glucose levels, but to have beneficial effects on plasma lipids and lipoproteins. We therefore aimed to determine whether intensive lipid therapy with a niacin-containing regimen would have a beneficial effect on cardiovascular disease, despite an expected increase in plasma glucose and insulin resistance in subjects with the metabolic syndrome, insulin resistance or abnormal fasting plasma glucose levels. METHODS: The effect of three years' treatment with niacin plus simvastatin (N+S) on both angiographic and clinical outcomes were analyzed in the 160 subjects with coronary artery disease (CAD) and low levels of high density lipoproteins (HDL) from the HDL-Atherosclerosis Treatment Study (HATS). A subgroup analysis was performed on the basis of: (1) the presence or absence of the metabolic syndrome, (2) higher or lower insulin resistance, and (3) the presence or absence of impaired fasting glucose or diabetes (dysglycemia). Individuals classified as having the MS, increased insulin resistance or dysglycemia would be expected to have increased cardiovascular risk. RESULTS: N+S reduced the change in mean proximal percent stenosis (Δ%S) compared to placebo (PL) in subjects with the metabolic syndrome (Δ%Sprox 0.3 vs 3.0, p=0.003) and in the more insulin resistant group of subjects (Δ%Sprox 0.5 vs 2.7, p=0.001), while subjects with dysglycemia (impaired fasting glucose or diabetes) showed a lesser benefit (Δ%Sprox 1 vs 3.2, p=0.13). These changes occurred despite increased in-treatment fasting glucose levels (3%), fasting insulin (19%) and decreased insulin sensitivity (-10%). Overall primary clinical events were reduced by 60% with N+S compared to PL (p=0.02). A similar reduction of the rate of primary events was seen in patients with metabolic syndrome, insulin resistance, and to a lesser extent in patients with dysglycemia in the N+S group compared to PL. CONCLUSIONS: These data indicate that, in CAD patients with low HDL, treating the atherogenic dyslipidemia with a combination of N+S leads to substantial benefits in terms of stenosis progression and clinical events, independently of whether the patient has the metabolic syndrome or is insulin resistant. Over a 3 year period, the beneficial effect of niacin in combination with simvastatin appears to offset the modest adverse effect of niacin on glucose metabolism and insulin resistance in at higher risk patients, as long as careful attention is paid to glycemic control.
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Affiliation(s)
- Francesca Vittone
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, USA
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Robinson JG, Davidson MH. Investigational drugs targeting HDL-C metabolism and reverse cholesterol transport. ACTA ACUST UNITED AC 2007. [DOI: 10.2217/17460875.2.3.285] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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