Volume 5, Issue 2

Provident News

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Announcements

Provident and Cognitive Drug Research (CDR) are entering into a strategic alliance to provide comprehensive clinical trials services for evaluating the cognitive effects of functional foods, food additives, consumer health products, and dietary supplements . The alliance will allow Provident to become an official “Center of Excellence” for studies that use the CDR test battery, improving efficiencies and reducing costs to our sponsors.

Both Provident research sites have been very busy, for which we are very thankful (during a recession no less)! Kudos to the staff who are working so diligently to maintain our high standards during this busy period.

Arianne Orcutt has successfully completed her comprehensive examinations toward a Master’s Degree in Applied Statistics. Congratulations Arianne! Arianne is also transitioning to the role of Biostatistician at Provident.

Mitch Silverman has received a promotion to a new role as Data Manager. We are grateful to Mitch for wearing many hats as we work through these transitions!

Dr. Matthew S. Reeves has passed his board re-certification exam in Family Practice Medicine. Congratulations!

Kristina Tuz has joined the Addison team as a Research Assistant. Welcome Kristina.

Adam Niess and his wife Anne are expecting their first child in October. They will also be moving out east in July as Adam prepares to attend the Reformed Presbyterian Theological Seminary. Many changes are on the horizon for this couple and we wish them the best!

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Recent and Upcoming Publications and Presentations

Publications

Maki KC, Carson ML, Anderson WHK, Geohas J, Reeves MS, Farmer MV, Turowski M, Miller M, Kaden VN, Dicklin MR, Rains TM.  Lipid altering effects of different formulations of hydroxymethylcellulose. J Clin Lipidol.  (in press).

Maki KC, Dicklin MR, Lawless A, Reeves MS.  Omega-3 fatty acids for the treatment of elevated triglycerides.  Clinical Lipidology.  (in press).

Roth EM, Bays HE, Forker AD, Maki KC, Carter R, Doyle RT, Stein EA. Prescription omega-3 fatty acids as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects. J Cardiovasc Pharmacol. (in press).

Maki KC, McKenney JM, Farmer MV, Reeves MS, Dicklin MR.  Indices of insulin sensitivity and secretion from a standard liquid meal test in subjects with type 2 diabetes, impaired or normal fasting glucose.  Nutrition J. (in press).  

Davidson MH, Maki KC, Dicklin MR, Feinstein SB, Witchger MS, Bell M, McGuire DK, Provost JC, Liker H, Aviram M.  Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease.  Am J Cardiol. (in press).

Maki KC, Lubin BC, Reeves MS, Dicklin MR, Harris WS. Prescription omega-3 acid ethyl esters plus simvastatin 20 and 80 mg: effects in mixed dyslipidemia.  J Clin Lipidol. 2009;3:33-38.

Maki KC, Mustad V, Dicklin MR, Geohas J. Postprandial metabolism with 1,3-diglyceride oil vs. equivalent intakes of long-chain and medium-chain triglyceride oils. Nutrition. 2009;25:627-33.  

Rains TM, Anderson B, Maki KC.  Green Tea Catechins and Abdominal Fat Loss.  SCAN’s Pulse: A Publication for Sports, Cardiovascular, and Wellness Nutritionists from the Sports, Cardiovascular and Wellness Nutrition Practice Group within the American Dietetic Association 2009 (in press).  

 

 

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Abstracts/Presentations

National Lipid Association Annual Scientific Session.   Maki KC, Rubin MR, Wong LG, McManus JF, Jensen CD, Marshall JW, Lawless A.  Serum 25-hydroxyvitamin D is an independent predictor of high density lipoprotein cholesterol and metabolic syndrome in men and women.  May, 2009.  

National Lipid Association Annual Scientific Session.  Maki KC.   Epidemiology and Statistics: Masters in Lipidology Advanced Training & Board Review Course.  May, 2009.  

XV International Symposium on Atherosclerosis.   Bays HE, Maki KC, McKenney J, Doyle RT, Stein E.  Long-term efficacy of prescription omega-3 fatty acids co-administered with simvastatin in hypertriglyceridemic patients.  June, 2009.

Arteriosclerosis, Thrombosis and Vascular Biology Annual Conference.   Maki KC, Bays, HE, McKenney J, Doyle RT, Carter RN, Stein E.  Effects of prescription omega-3 fatty acids co-administered with escalating doses of atorvastatin on lipoprotein particle sizes and concentration in hypertriglyceridemic patients.  May, 2009.  Poster #504.  

American Diabetes Association: 69th Scientific Sessions.  Bays HE, Maki KC, Carter RN, Doyle RT, Stein E. Effect of prescription omega-3 fatty acids on body weight in patients with very high triglyceride levels.  June, 2009. (submitted).  

Experimental Biolology 2009.   Maki KC, Sanders, L, Reeves MS, Kaden VN, Cartwright Y.  Resistant starch improves laxation in healthy adults.  April, 2009.  Abstract #334.

Experimental Biology 2009.   Maki KC, Beiseigel JM, Jannalagadda SS, Reeves MS, Farmer MV.  Ready-to-eat oat cereal, as part of a reduced energy diet, reduces low-density lipoprotein cholesterol and waist circumference in overweight and obese adults.  April, 2009.  Abstract #3983.  

Experimental Biology 2009.   Maki KC, Curry LL, McKenney JM, Farmer MV, Reeves MS, Dicklin MR, Gerich JE, Zinman B.  Glycemic and blood pressure responses to acute doses of rebaudioside A, a steviol glycoside, in subjects with normal glucose tolerance or type 2 diabetes mellitus.  April, 2009.  Abstract #1779.  

Experimental Biology 2009.   Maki KC, McKenney JM, Farmer MV, Reeves MS, Dicklin MR.  Indices of insulin sensitivity and secretion from a standard liquid meal test in subjects with type 2 diabetes, impaired and normal fasting glucose.  April, 2009.  Abstract #348.  

American Diabetes Association: 69th Scientific Sessions.  Bays HE, Maki KC, Carter RN, Doyle RT, Stein E.  Effects of prescription omega-3 fatty acids on body weight in patients with very high triglyceride levels.  June, 2009.

American Heart Association: 49th Cardiovascular Disease Epidemiology and Prevention Conference.   Maki KC, Davidson MH, Doyle RT, Ballantyne CM.  Effect of prescription omega-3 fatty acids on non-HDL cholesterol (stratified by baseline LDL cholesterol level) in statin treated patients with hypertriglyceridemia.  March, 2009.  Poster #230.

American Heart Association: 49th Cardiovascular Disease Epidemiology and Prevention Conference.   Davidson MH, Maki KC, Feinstein S, Bell M. Triglyceride/high-density lipoprotein cholesterol ratio is the strongest predictor of carotid intima-media thickness progression.  March, 2009.  Poster #250.

 

 

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In the Literature

Effects of Fenofibrate Treatment on Cardiovascular Disease Risk in 9,795 Individuals with Type 2 Diabetes and Various Components of the Metabolic Syndrome: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care  2009;32:493-498.  

Methods:  The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a randomized, double-blind clinical trial designed to assess the long-term (~ 5 yr of follow up) effect of fenofibrate (n = 4,895) compared with placebo (n = 4,900) on cardiovascular events in a cohort of subjects with type 2 diabetes (1).  The analyses described in this article explored whether cardiovascular disease (CVD) event rates differed in these subjects according to the presence of the metabolic syndrome.  The value of utilizing an elevated triglyceride (TG) level (200 mg/dL [≥2.3 mmol/L]) alone or in combination with low plasma high-density lipoprotein cholesterol (HDL-C), as indicators of marked hypertriglyceridemia or marked dyslipidemia, respectively, was also examined.  

 

The prevalence of the metabolic syndrome and its features was determined according to the modified National Cholesterol Education Program (NCEP) Third Adult Treatment Panel (ATP III) definition (2).  Metabolic syndrome was present when type 2 diabetes plus at least two of the following additional features were found:  blood pressure ≥130/85 mm Hg; HDL-C <40 mg/dL (<1.03 mmol/L) in men and <50 mg/dL (<1.29 mmol/L) in women; TG ≥150 mg/dL (≥1.7 mmol/L); and waist circumference >102 cm (men) and >88 cm (women).  CVD event rates were measured in men (62.7%) and women (37.3%) without prior CVD (n = 7664) and with CVD (n = 2131), according to the presence of metabolic syndrome and any of its features.  A determination of the independent contributions of metabolic syndrome and its features to CVD rates and the effects of fenofibrate was performed using Cox proportional models adjusted for age, sex, CVD status, and baseline glycosylated hemoglobin levels.  The effect of fenofibrate according to baseline HDL-C and TG levels was also determined.   

 

Results:  More than 80% of the participants met the criteria for metabolic syndrome.  The prevalence rates for features of the metabolic syndrome were as follows: increased blood pressure (84%), increased waist circumference (68%), reduced HDL-C (59%), and raised TG (52%).  All metabolic syndrome features were more prevalent in women than in men.  Marked hypertriglyceridemia and marked dyslipidemia occurred in 26% and 21%, respectively, of subjects with metabolic syndrome. 

 

The 5-yr placebo group CVD event rate was 14.5% and 11.3% in those with and without metabolic syndrome, respectively (P < 0.0001).  The CVD event rates for subjects with any particular features of the metabolic syndrome were similar to those of the overall population, but each additional feature of the metabolic syndrome (in addition to established diabetes) resulted in a cumulatively higher risk of CVD events.  The presence of each metabolic syndrome feature compared with its absence, other than increased waist circumference, increased the absolute risk of CVD events over 5 yr by 3%.  Marked dyslipidemia was associated with the highest risk of CVD risk (17.8% over 5 yr).  In the overall population, among those with the metabolic syndrome, and in those with any particular feature of the metabolic syndrome, men had twice the risk for CVD vs. women.  Among subjects with metabolic syndrome or any of its features, those with prior CVD had a higher risk for CVD events than those with no prior CVD. 

 

Fenofibrate reduced the 5-yr CVD risk in subjects with metabolic syndrome from 14.5 to 13.1%, an 11% proportional risk reduction.  Fenofibrate reduced CVD risk in those who did not have metabolic syndrome from 11.3 to 9.7%, a 12% proportional reduction.  The treatment effects were similar among individuals with and without any particular feature of the metabolic syndrome.  However, the treatment effect appeared to be greater in women than men (18% vs. 7% CVD risk reduction in metabolic syndrome group) and in primary vs. secondary prevention (17% vs. 1% reduction in metabolic syndrome group).  In all of these subgroups, the effects of fenofibrate were larger when marked hypertriglyceridemia or marked dyslipidemia was present.  Treatment with fenofibrate in subjects with TG ≥200 mg/dL (≥2.3 mmol/L) was associated with a 23% CVD risk reduction (HR 0.77 [95% CI 0.63-0.94], P = 0.010) compared with a 6% CVD risk reduction in the absence of elevated TG (HR 0.94 [95% CI 0.83-1.07], P = 0.344).  Fenofibrate significantly reduced total CVD events by 11% (P = 0.035), and the effect of fenofibrate among individuals with metabolic syndrome was close to being independently significant (P = 0.052).  In terms of their associations with CVD risk, HDL-C concentration, systolic blood pressure, and TG level each made independent significant contributions to CVD risk, whereas waist circumference did not. 

 

Conclusions:  The clustering of risk factors making up the metabolic syndrome is useful in predicting the incidence of diabetes, and in identifying higher CVD risk in individuals with type 2 diabetes.  Fenofibrate provides greater CVD risk reduction when features of the metabolic syndrome are present.  Subjects with diabetes and marked hypertriglyceridemia or marked dyslipidemia are at highest CVD risk, and gain the greatest benefits of fenofibrate.  

 

Dr. Maki’s Commentary:  This analysis from FIELD adds information about an important subgroup for which data were not presented in the initial paper.  Results from previous fibrate trials (the Helsinki Heart Study, the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial and the Bezafibrate Infarction Prevention study) have suggested that the benefits associated with fibrate therapy were larger in those with TG ≥200 mg/dL than for those with lower TG concentrations, for whom little or no benefit was evident (3).  The original FIELD paper provided an analysis of results for subjects with TG < or ≥150 mg/dL, but did not provide data on outcomes for the subgroup with higher TG.  This new analysis suggests that the same pattern that was evident in previous trials was also present in FIELD.  Given the high and growing prevalence of hypertriglyceridemia in the US population, it is astonishing that no large-scale outcome trial has been completed to evaluate lipid treatment options in patients selected specifically for the presence of hypertriglyceridemia.  Such information is urgently needed to guide therapy in this large and growing subset of individuals who are known to have increased risk for cardiovascular events (4,5).  

 

Citations:

 

1.  Keech A, Simes RJ, Barter P, 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;366:1849-1861.

2.  Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol and Adults: Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adult (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

3.  Maki KC. Fibrates for treatment of the metabolic syndrome. Curr Atheroscler Rep 2004;6:45-51.

4.  Lloyd-Jones Dm, O’Donnell CJ, D’Agostino RB, et al. Applicability of cholesterol-lowering primary prevention trials to a general population. Arch Intern Med 2001;161:949-954.

5.  Hopkins PN, Heiss G, Ellison RC, et al. Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia : A case control comparison from the National Heart, Lung, and Blood Institute Family Heart Study. Circulation 2003;108:519-523.

 

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Books and Book Chapters

 
  • Maki KC, Rubin M. Cardiovascular Epidemiology and Characterization of Atherosclerotic Disease Risk Factors.  In: Toth PP, Cannon CP (eds).  Comprehensive Cardiovascular Care in the Primary Care Setting, Humana Press, 2009 (in press).

 

                     

 

 

  • Toth PP, Maki KC. Practical Lipid Management: London: John Wiley & Sons.  Practical Lipid Management: Concepts and Controversies, is a text on the clinical management of dyslipidemias. As its title suggests, the book provides a straightforward and practical approach to the identification and treatment of abnormalities in lipid metabolism. The target audience consists of family physicians, internists, nurse practitioners, physician assistants, cardiologists, endocrinologists and allied health professionals involved in the care of patients with lipid disorders.  The book is available for purchase at Amazon.com.

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  • The book Therapeutic Lipidology edited by Drs. Michael Davidson, Peter Toth and Kevin Maki is available for purchase at Amazon.com.

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  • Maki KC. High-viscosity hydroxypropylmethylcellulose (HV-HPMC) a promising agent for metabolic risk factor management. ACS Press, 2008 (in press).

 

 

 

                      

 

 

  • Maki KC, Matsuo N, Dicklin MR. Clinical studies evaluating the benefits of diacylglycerol for managing excess adiposity. In: Katsuragi Y, Yasukawa T, Matsuo N, Flickinger BD, Tokimitusu I, and Matlock MG. (eds) Chapter 10. Diacylglycerol Oil, AOCS Press, 2nd ed. 2008.

     

  • Maki, KC and Dicklin M. How well do various lipids and lipoprotein measures predict cardiovascular disease morbidity and mortality. In: Toth PP, Sica D. (eds). Clinical Challenges in Lipid Disorders. Oxford: Clinical Publishing. June, 2008.

     

  • Huth PJ, Rains TM, Yang Yifan, Philips SM. Current and emerging role of whey protein on muscle accretion. In: Onwulata CI and Huth PJ. (eds) Chapter 13. Whey Processing, Functionality and Health Benefits. Wiley-Blackwell. 2008.

 

 

About Provident

Provident 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.

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