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Provident Perspective Volume 2, Issue 1 Provident NewsProvident is proud to welcome new team members to our staff:
New Books to be Published Next YearDr. Maki has been contracted to produce two books that are scheduled for publication in 2007. The first is a book that he is co-editing with Drs. Michael Davidson and Peter Toth called Therapeutic Lipidology. This book is intended to serve as a study guide for individuals who are preparing to take their board examination in Lipidology. The second book is called Practical Lipid Management: Concepts and Controversies, which he is co-authoring with Dr. Peter Toth. This is intended to be a concise, user friendly guide for primary care physicians on the management of lipid disorders and discussions of topics about which expert opinion is divided or rapidly evolving. Recent and Upcoming Publications and PresentationsPublicationsDavidson MH, Bays HE, Stein E, Maki KC, Shalwitz RA, Doyle R. Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects. Clin Cardiol. 2006 (in press). Ansell BJ, Fonarow GC, Maki KC, Dicklin MR, Bell M, Davidson MH. Reduced treatment success in lipid management among women with coronary heart disease or risk equivalents: results of a national survey. Am Heart J. 2006;(in press). Maki KC, Galant R, Davidson MH. Non-high-density lipoprotein cholesterol: the forgotten therapeutic target. Am J Cardiol. 2005;96(Suppl 9A):59-64. Davidson MH, Dittakavi V, Bandari A, Davidson DJ, Maki KC, Subbaiah P. Colesevelam HCl decreases atherosclerosis and may activate reverse cholesterol transport in cholesterol-fed rabbits. Journal of Applied Research. 2006;(in press). Clark LT, Maki KC, Galant R, Maron DJ; Pearson TA; Davidson MH. Ethnic differences in achievement of cholesterol treatment goals: results from the National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II. J Gen Intern Med. 2006; (in press). Maki KC, Davidson MH, Dicklin MR. A comparison of Canadian and United States’ guidelines for lipid management using data from the National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II. Can J Cardiol. 2006; (in press). Maki KC. Maximizing the role of non-drug interventions in lipid management. Nutrition and the MD. 2006; (in press). Upcoming PresentationsJune 1, 2006. Kevin C. Maki. The Metabolic Syndrome: A Tangled Web of Risk Factors for Coronary Heart Disease and Diabetes Mellitus. Montana Dietetic Association. In the LiteratureKeech A, Simes, RJ, Barter P, Best J, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomized controlled trial. Lancet. 2005 Nov 26;366(9500):1849-1861. Methods: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational, randomized, controlled trial of 9795 subjects between the ages of 50-75 who had been diagnosed with type 2 diabetes mellitus and were not on a lipid-lowering drug at study entry. Subjects were randomly assigned to placebo or fenofibrate 200 mg/day. Data were collected over a 5-year average follow-up period. The primary outcome was coronary events [coronary heart disease (CHD) death and non-fatal myocardial infarction (MI)]. Secondary outcomes included major cardiovascular disease (CVD) events (CHD events, total stroke and other CVD death combined) and total CVD events (major CVD events plus coronary and carotid revascularization, CHD death, total CVD deaths, hemorrhagic and non-hemorrhagic stroke, coronary and peripheral revascularization procedures, cause-specific non-coronary heart disease mortality and total mortality). Results: Fenofibrate was associated with a non-significant 11% relative reduction in the primary outcome. This was found to correspond to a significant 24% relative risk reduction in non-fatal MI, with a non-significant increase in fatal CHD. Total CVD events decreased by 11% in the fenofibrate group, which was mainly due to a decrease in non-fatal MI long with a significant 21% reduction in coronary revascularization. There were no significant differences in other secondary outcomes. The rate of progression to albuminuria was significantly reduced in the fenofibrate group (p = 0.002). Of note, 17% of the placebo group and 8% of the treatment group started a non-study lipid-lowering agent, a statin in 93% of cases, during the study period. Once an adjustment was made for use of additional drug therapy, fenofibrate was found to have lowered the risk of CHD events by 19% (p = 0.01) and total CVD events by 15% (p = 0.004). Conclusion: The results of the FIELD study do not support a recommendation for increased fenofibrate use in patients with diabetes mellitus. It also did not provide supporting evidence for a benefit of fenofibrate therapy in patients already at the target LDL-C goal. Dr. Maki’s Commentary: The FIELD study enrolled subjects with type 2 diabetes mellitus. However, in clinical practice, fibrates are generally used as first-line therapy only in patients with hypertriglyceridemia, with or without diabetes. The mean baseline triglyceride level was 172 mg/dL (median = 153 mg/dL). This suggests that only about one-third of the subjects would have qualified for drug therapy for elevated triglycerides (³200 mg/dL) under the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines. The benefits of fibrate therapy are most evident in subjects with triglycerides ³200 mg/dL. In the Bezafibrate Infarction Prevention study, the effect of bezafibrate on the primary outcome was not significant in the overall study population (-7.3%), but was highly significant in the subset of 25% with triglycerides ³200 mg/dL (-39.5%). Similar findings were reported for the Helsinki Heart Study and the Veterans Affairs HDL Intervention Trial, which both showed significantly greater risk reductions in subgroups with higher triglycerides. In addition to the relatively low mean triglyceride level in the study sample, the mean baseline total cholesterol concentration was <200 mg/dL (195 mg/dL), the mean HDL cholesterol concentration was >40 mg/dL (43 mg/dL) and the mean body mass index was <30 kg/m2 (29.8 kg/m2). As expected, based on the lower risk profile of these subjects compared to a typical sample with type 2 diabetes in the United States, the CHD event rate (myocardial infarction or cardiovascular disease death) was only ~1.2% per year in the placebo group. The NCEP ATP III report has specified a CHD event rate of ~2% per year (20% 10-year risk) as a coronary heart disease equivalent and suggested that average event rates in subjects with diabetes mellitus will be at or above this level. Unbalanced Use of Additional Lipid-altering Drugs Differences were present in the use of lipid-altering therapies being added to study drug/placebo between the groups. Among patients with pre-existing cardiovascular disease, this occurred in 23% of subjects in the placebo group vs. 14% in the fenofibrate group. Among those without pre-existing cardiovascular disease, the corresponding frequencies were 16% vs. 7%. There was also a clear indication that additional therapy was more likely to be added in subjects with more severe baseline lipid abnormalities. Thus, the highest-risk subsets of the study sample, based on pre-existing cardiovascular disease and/or greater lipid abnormalities, were more likely to receive additional lipid therapy. Given these differences, the most appropriate analysis, in my view, is the one in which additional lipid therapy is included in the model as a time-dependent covariate. After this adjustment, fenofibrate lowered the risk of CHD events by 19% (p = 0.01) and total cardiovascular disease events by 15% (p = 0.004). In my opinion, the analysis wherein subjects’ data were censored at the time that new lipid therapy was started is of little value because the highest risk subjects in both groups, and those in the placebo group in particular, were more likely to receive additional therapy, clearly biasing the results against fenofibrate. Failure to Maintain Lipid Differences Throughout the Trial Largely as a result of the preferential addition of lipid-altering therapies in the placebo group, the lipid effects of fenofibrate vs. placebo that were present at 4 months were not maintained throughout the trial. For example, the difference between groups for total cholesterol declined from -11.4% at 4 months to -6.9% at study close. Corresponding values for LDL cholesterol were from -12.0% to -5.8% and for triglycerides from -28.6% to -21.9%, respectively. When evaluating a lipid-altering intervention, clear separations between the groups must be maintained throughout the treatment period for the results of the trial to be fully interpretable. That was not the case for the FIELD study. Two previous large-scale trials that failed to maintain such separation also showed equivocal results: MRFIT and ALLHAT. Bottom Line Because of the problems cited above, I believe that the FIELD study has not significantly advanced our understanding of the influence of fenofibrate on cardiovascular risk. The failure of the FIELD study to demonstrate significant risk reduction for the primary outcome variable appears more related to the issues cited above than a failure of the drug per se. However, the increases in cardiovascular mortality and pulmonary embolism remain disturbing. The increase in pancreatitis is also of concern, although it appears that few subjects would have been considered to be at risk of hypertriglyceridemia-associated pancreatitis, making the clinical relevance of this finding questionable. About ProvidentProvident has a team of research professionals with extensive experience in the design and conduct of clinical trials to evaluate pharmaceuticals, medical and functional foods, dietary supplements and medical devices. For more information, visit our web site: http://www.providentcrc.com. Or, contact us directly: Tia Rains: trains@providentcrc.com, Director of Medical Writing / Principal Scientist |
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