Provident Clinical Research

Volume 5, Issue 4

Provident News

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Announcements

Provident has expanded to include exercise testing capabilities in Addison. Each site now has a metabolic cart, treadmill, cycle ergometer and exercise ECG equipment. Both sites are currently conducting clinical trials to assess the effects of nutritional interventions on exercise performance.

Arianne Orcutt has completed the requirements for a Master's degree in Applied Statistics. Congratulations Arianne!

The Addison site has welcomed two Research Associates, Klaudia Walat, CNA and Steve Schwartz. Welcome Klaudia and Steve!

Provident would like to extend our wishes for a healthy and prosperous new year to all! Happy Holidays.

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Recent and Upcoming Publications and Presentations

Publications

Maki KC, Reeves MS, Farmer M, Griinari M, Berge K, Vik H, Hubacher R, Rains TM. Krill oil supplementation increases plasma concentrations of eicosapentaenoic and docosahexaenoic acids in overweight and obese men and women. Nutr Res. 1009;29:609-615.

Bays HE, McKenney J, Maki KC, Doyle RT, Carter RN, Stein E. Prescription omega-3-acid ethyl esters: effects on non-high-density lipoprotein cholesterol in combined hyperlipidemic patients when combined with escalating doses of atorvastatin. Mayo Clin Proc. 2009. (in press).

Davidson MH, Maki KC, Bays H, Carter R, Ballantyne CM. Effects of prescription omega-3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins Al and Clll, and lipoprotein associated phospholipase A₂ mass in statin-treated subjects with hypertriglyceridemia. J Clin Lipidol. 2009;3:332-340.

Maki KC. Underutilization of dietary adjuncts in dyslipidemia management. Lipid Spin-Practical Pearls. 2009. (in press).

Bays H, Maki KC, Doyle RT, Carter RN, Stein E. The effect of prescription omega-3 fatty acids on body weight after 8 to 16 weeks of treatment for very high triglyceride levels. Postgraduate Medicine. 2009;121:145-150.

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. 2009;104:936-942.

Maki KC, Beiseigel JM, Jonnalagadda SS, Gugger CK, Reeves MS, Farmer MV, Kaden VN, Rains TM. Whole grain ready-to-eat cereal, as part of a dietary program for weight loss, reduces low density lipoprotein particles in statin-treated subjects with hypertriglyceridemia. J Am Diet Assoc. 2010. (in press).

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;28:1-4.

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. 2009;54:196-203.

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In the Literature

Effects of prescription omega-3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A₂ mass in statin-treated subjects with hypertriglyceridemia. J Clin Lipidol. 2009;3:332-340. Davidson MH, Maki KC, Bays H, Carter R, and Ballantyne CM.

Objective and Methods:

Although the effects of both statin and prescription omega-3-acid ethyl esters (P-OM3) monotherapy have been widely studied, less is known about the effects of add-on P-OM3 therapy to stable-dose statin therapy, particularly with regard to the effects on lipoprotein particle concentrations. This study investigated the effects on lipoprotein particles of adding 4 g/d P-OM3 after an 8-week lead-in of simvastatin 40 mg/d in subjects with hypertriglyceridemia. Data from the previously published randomized, double-blind, placebo-controlled combination of prescription omega-3s with simvastatin (COMBOS) trial were analysed.¹ The study sample included 254 predominantly non-Hispanic white (95.7%) men (n=146) and women (n=108) with residual hypertriglyceridemia (200-499 mg/dL) and LDL cholesterol levels no greater than 10% above their National Cholesterol Education Program Third Adult Treatment Panel goals during the diet plus simvastatin run-in. Subjects then either received add-on P-OM3 (n=122) or placebo (n=132) for an additional 8 weeks. Clinical measurements focused on the following laboratory parameters: lipoprotein particle concentrations and sizes (determined via nuclear magnetic resonance spectroscopy²), remnant-like particle cholesterol (RLP-C), apolipoprotein (Apo) CIII, Apo AI, and lipoprotein-associated phospholipase A₂ (Lp-PLA₂).

Results:

Compared to the placebo group, when added to stable-dose simvastatin therapy, P-OM3 reduced mean very-low-density lipoprotein particle (VLDL-P) size and increased low-density lipoprotein particle (LDL-P) size (p< 0.006 for both) without significantly changing high-density-lipoprotein particle (HDL-P) size. Large VLDL-P and intermediate-density-lipoprotein particle (IDL-P) concentrations were lowered (p< 0.01 for both) and the large LDL-P concentration was increased (p< 0.0001) even though total VLDL-P and LDL-P concentrations were not significantly changed by P-OM3. Decreases in medium HDL-P concentration led to a reduction in total HDL-P concentration (p< 0.0001). Shifts in LDL subclasses [reduced levels of intermediate-density lipoprotein (IDL)-P and small low-density lipoprotein (LDL)-P, and increased large LDL-P] resulted in a net increase in mean LDL-P size, even though there was no change in the total LDL-P concentration. There was no significant difference between groups (p=0.2265) in Apo AI levels, although Apo AI decreased in the P-OM3 group (p=0.0083) and decreased slightly (p=0.2148) in the placebo group. Circulating levels of RLP-C, Apo CIII, and Lp-PLA₂ were all significantly lowered (p< 0.0001, p=0.0002, and p=0.0029 respectively) by the addition of P-OM3 treatment. Most subjects in both the P-OM3 (90.0%) and placebo (83.0%) groups were identified as LDL subclass pattern B at baseline. Frequencies of shifts from LDL subclass pattern B to the more favorable pattern A were 19.8% in the P-OM3 group and 3.3% in the placebo group (p=0.0002). On-treatment triglyceride (TG) level was significantly (p=0.0002) predictive of the change in LDL-P size, whereas the change in TG concentration was not (p=0.084).

Conclusions:

These findings suggest that P-OM3, when added to statin therapy, induce changes in lipoprotein particle sizes and concentrations, as well as levels of Apo CIII, RLP-C, and Lp-PLA₂ which may relate to the atherogenic process. Additional research is warranted to assess possible clinical implications of these findings.

Dr. Maki’s Commentary:

This analysis from the COMBOS dataset shows that adding P-OM3 to statin therapy produces changes in lipoprotein particles and composition that may have important clinical implications. The finding that Lp-PLA₂ was significantly lowered in the absence of a reduction in LDL-C is novel and potentially important, since Lp-PLA₂ is a strong predictor of cardiovascular disease (CVD) events^3,4. The main effect on the lipid profile of P-OM3 therapy is to reduce the TG concentration, which likely results from hepatic secretion of fewer VLDL-P and from secretion of VLDL-P that are less TG-rich. The reduction in Apo CIII (which inhibits lipoprotein lipase) and the fact that less delipidation is necessary to convert smaller VLDL particles to LDL particles lead to an enhancement in the rate at which VLDL particles are converted to LDL particles. This may be offset to some degree by increased hepatic uptake of the resulting larger LDL particles. The net result is that LDL-P concentration is unaltered, although shifts do occur in the subclasses of circulating LDL particles (lower IDL, higher large LDL, lower small LDL).

This study also confirms our previous findings indicating that shifts in LDL particle size do not occur in the absence of a change in LDL subclass pattern⁵. The main determinant of LDL subclass pattern is the on-treatment TG concentration because each individual has a threshold value above which he or she will display pattern B (a predominance of small, dense LDL particles) and below which he or she will display pattern A (a predominance of large, buoyant LDL particles). Most people have a threshold between 100 and 250 mg/dL of fasting TG. Accordingly, the TG value can be lowered from 400 to 260 mg/dL without altering LDL-P size. As the on-treatment TG value drops further, more people shift from pattern B to pattern A, thus increasing mean LDL-P size. There is debate about whether smaller, more dense LDL particles are really more atherogenic than larger, more buoyant particles⁶. If smaller LDL particles are more atherogenic, this would be an argument in favor of fasting TG treatment targets, since roughly two-thirds of individuals display pattern A below a TG concentration of 150 mg/dL and roughly 90% display pattern A below a fasting TG concentration of 100 mg/dL. On the other hand, if no strong gradient of atherogenicity exists across apolipoprotein B-containing particles, then measures such as non-HDL-C and apolipoprotein B concentrations should be the focus of therapy without regard to the distribution of subclasses of these lipoproteins in circulation. At present, these questions remain far from resolved and will likely continue to be topics of debate in lipidology for years to come.

Citations:

1. Davidson MH, Stein EA, Bays HE, et al. COMBination of prescription omega-3 with simvastatin (COMBOS) Investigators. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29:1354-1367.

2. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006;113:1556-1563.

3. Packard CJ, O’Reilly DS, Caslake MJ, et al. Lipoprotein-associated phospholipase A₂ as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med. 2000;343:1148-1155.

4. Anderson JL. Lipoprotein-associated phospholipase A₂: an independent predictor of coronary artery disease events in primary and secondary prevention. Am J Cardiol. 2008;101:23F-33F.

5. Davidson MH, Bays HE, Stein E, et al. Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects. Clin Cardiol. 2006;29:268-273.

6. Toth PP and Maki KC. Practical Lipid Management, West Sussex, United Kingdom, Wiley-Blackwell, 2008.

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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, 2010 (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.

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

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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