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In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipidtrial, published on-line in the New England Journal of Medicine,(1) the groupwith atherogenic dyslipidemia had 70 percent more cardiovascular events(cardiovascular death, heart attacks and strokes) than patients without. Infact, the risk associated with atherogenic dyslipidemia was comparable tothat in people with previous cardiovascular disease (17.3 percent versus 18.1percent).
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Professor Jean-Charles Fruchart, President of the Residual Risk ReductionInitiative (R3i), an independent Swiss academic foundation, said: 'For thelast two years, the R3i has focused on the hypothesis that residualcardiovascular risk in statin-treated patients is associated with atherogenicdyslipidemia.(2,3) ACCORD Lipid confirms both the hypothesis and the value ofadding fenofibrate to a statin to reduce this high residual cardiovascularrisk. This is consistent with current guidelines from the American DiabetesAssociation(4) and the National Cholesterol Education Program Adult TreatmentPanel III.(5)'
The benefit of fenofibrate was only seen in the pre-specified group ofdiabetic patients with atherogenic dyslipidemia and not in the total studypopulation. 'While patients with atherogenic dyslipidemia only represented 17percent of the ACCORD Lipid population, in clinical practice the size of theproblem is significantly greater. We are now quantifying this in theR3i-funded REsiduAl risk Lipids and Standard Therapies (REALIST) study whichis being conducted at Harvard Medical School and over 20 well-known academiccenters worldwide,' said Professor Frank Sacks of Harvard Medical School,Boston, USA and Vice-President of the R3i.
In ACCORD Lipid, fenofibrate also reduced micro- and macro-albuminuria,markers of diabetic renal disease. This is consistent with results fromearlier clinical trials.(6,7) 'Diabetic nephropathy is a major managementissue. Therefore it is important knowledge that fenofibrate provides benefitto these patients,' said Professor Michel Hermans of Cliniques UniversitairesSaint-Luc, Brussels, Belgium and General Secretary of the R3i.
The study also confirmed that adding fenofibrate to simvastatin did notresult in any excess risk of myopathy (muscle problems), venous thrombosis orpancreatitis. In fact, there were fewer all-cause and cardiovascular deathsin fenofibrate-treated patients than in patients treated with simvastatinalone.
R3i leads new research into atherogenic dyslipidemia in type 2 diabetes
Atherogenic dyslipidemia is common and the prevalence is markedlyincreasing as a result of the global epidemic of type 2 diabetes, obesity andmetabolic syndrome.(8) So, in the U.S. about half of the high- risk patientsbeginning statin therapy may require additional treatment to lower theirtriglycerides and/or to raise their HDL-C.(9)
The R3i is responding to this critically important clinical problem.'Given the magnitude of the global epidemic of type 2 diabetes - especiallyin developing regions - targeting atherogenic dyslipidemia is crucial. As theonly independent global research foundation focusing on this issue, the R3iis urgently developing recommendations for evidence-based strategies toreduce residual vascular risk. Currently, we are conducting the firstworld-wide epidemiological study, REALIST, to establish the prevalence ofatherogenic dyslipidemia and consequent residual risk of cardiovascularevents. Now, as a result of ACCORD Lipid, we will also initiate ameta-analysis of the atherogenic dyslipidemic subgroups of patients (high TGand/or low HDL-C) in previous fibrate studies,' said Professor Fruchart.
Notes to Editors
About ACCORD
The ACCORD study was sponsored by the National Heart, Lung, and BloodInstitute (NHLBI), part of the National Institutes of Health (NIH) in theU.S, and was conducted across the U.S. and Canada. The key question addressedin the ACCORD Lipid treatment arm was whether the combination of fenofibrateplus simvastatin, i.e. targeting elevated TG and low HDL-C in addition toLDL-C, was more effective in reducing cardiovascular events than statintherapy alone in a cohort of 5,518 high-risk patients with controlled type 2diabetes mellitus at target for LDL-C. Fenofibrate was chosen becausesubgroup analyses from previous trials had shown added benefits in patientswith type 2 diabetes, or in those with abdominal obesity characteristic ofthe metabolic syndrome.(10-14) No other clinical trial had previously testedthis strategy.
However, the population treated was broader than that recommended bycurrent guidelines for fenofibrate. More than 80 percent of patients did nothave sufficiently elevated TG and low HDL-C warranting treatment according tocurrent clinical practice.
ACCORD Lipid established that extending fenofibrate treatment to thisbroader population did not significantly benefit any of the primary orsecondary cardiovascular outcomes in the total study population. However, thestudy did show a substantial reduction in cardiovascular events withfenofibrate-simvastatin treatment in patients with atherogenic dyslipidemia,with event rates decreasing from 17.3 percent in the simvastatin monotherapygroup to 12.4 percent with combination treatment over 4.7 years. This resultsupports current guidelines and common clinical practice.
More information on the R3i is available from:
The R3i website: http://www.r3i.org
References
1. The ACCORD Study Group. Effects of combination lipid therapy in type 2diabetes mellitus. N Eng JMed 2010. DOI:10.1056/NEJMoa1001282.
2. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk ReductionInitiative: a call to action to reduce residual vascular risk indyslipidaemic patients. Diab Vasc Dis Res 2008;5:319-35.
3. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk ReductionInitiative: a call to action to reduce residual vascular risk in dyslipidemicpatients. Am J Cardiol 2008;102(10 Suppl):1K-34K.
4. American Diabetes Association. Standards of medical care indiabetes-2008. Diabetes Care 2008; 31(suppl 1): S12-S54. [Updated 2009:Executive Summary: Standards of Medical Care in Diabetes-2009. Diabetes Care2009;32 (suppl 1):S6-S12.]
5. National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III). Third Report of the National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation, and Treatmentof High Blood Cholesterol in Adults (Adult Treatment Panel III). Finalreport. Circulation 2002;106:3143-421.
6. Keech A, Simes RJ, Barter P et al. The FIELD study investigators.Effect of long-term fenofibrate therapy on cardiovascular events in 9795people with type 2 diabetes mellitus (the FIELD study): randomised controlledtrial. Lancet 2005;366:1849-61.
7. Ansquer JC, Foucher C, Rattier S et al. Fenofibrate reducesprogression to microalbuminuria over 3 years in a placebo-controlled study intype 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study(DIAS). Am J Kidney Dis 2005;45: 485-93.
8. International Diabetes Federation. E-Atlas available athttp://www.diabetesatlas.org/. [Accessed 12 March 2010].
9. Nichols GA, Ambegaonkar BM, Sazonov V et al. Frequency of obtainingNational Cholesterol Education Program Adult Treatment Panel III goals forall major serum lipoproteins after initiation of lipid altering therapy. Am JCardiol 2009;104:1689-94.
10. Scott R, O'Brien R, Fulcher G et al. The effects of fenofibratetreatment on cardiovascular disease risk in 9795 people with type 2 diabetesand various components of the metabolic syndrome: the FIELD study. DiabetesCare 2009;32:493-8.
11. Manninen V, Tenkanen L, Koskinen P et al. Joint effects of serumtriglyceride and LDL cholesterol and HDL cholesterol concentrations oncoronary heart disease risk in the Helsinki Heart Study. Implications fortreatment. Circulation 1992;85:37-45.
12. Rubins HB, Robins SJ, Collins D et al. Diabetes, plasma insulin, andcardiovascular disease. Subgroup analysis from the Department of VeteransAffairs High-density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med2002;162:2597-2604.
13. Tenkanen L, Mantarri M, Manninen V. Some coronary risk factorsrelated to the insulin resistance syndrome and treatment with gemfibrozil:experience from the Helsinki Heart Study. Circulation 1995; 92: 1779-85.
14. Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyko V, Behar S.Bezafibrate for the secondary prevention of myocardial infarction in patientswith metabolic syndrome. Arch Intern Med 2005; 165: 1154-60.
SOURCE Residual Risk Reduction initiative (R3i)
