Provident Perspective Volume 4, Issue 1

Provident News

Welcome to 2008! Now that most of this very long winter is behind us and spring just ahead of us, Provident would like to extend a warm welcome to the following staff:

• John Marshall, RN – Director of Operations
• MarySue Witchger, RD, CCRA – Project Manager

Announcements

• In addition to our clinic in Bloomington, Indiana, it is Provident’s plan to open a research clinic in the Chicago area this year. John Marshall, with his extensive knowledge of clinical research will be spearheading the project.
• Congratulations to our statistician, WenQing Fan for officially becoming a United States citizen!
• Dr Maki’s continued consulting work as a GLG SCHOLAR for the Gerson Lehrman Group has helped investment firms, corporations and non-profit organizations to better understand products, services, companies, issues, and industries, scoring in the top quintile.
• This quarter we also launched our new website. The website includes information for Sponsors as well as potential study participation. The public will also be able to access current and past issues of The Provident Perspective. Please be sure to visit us.

Recent and Upcoming Publications and Presentations

Abstracts/Presentations

Experimental Biology 2008 - April 5-9th. San Diego, CA. Kevin C. Maki. Lipid effects of prescription omega-3-acid ethyl esters plus simvastatin in subjects with hypertriglyceride. Oral presentation. 147.8.

Experimental Biology 2008 - April 5-9th. San Diego, CA. Lisa M. Sanders, Cyril W. Kendall, Kevin C. Maki, Maria L. Stewart, Joanne L. Slavin and Susan M. Potter. A Novel Maize-based Dietary Fiber is Well Tolerated in Humans. Poster.

Wisconsin Dietetic Association 2008 – April 9th-11th. Appleton, WI. Kevin C. Maki. Weight loss from a guy's point of view. Oral presentation. Thursday, April 10th, 8-9am.

Louisiana Dietetic Association Food & Nutrition Conference and Exposition, 2008 - April 23rd -25th. Bossier City, LA. Kevin C. Maki. Weight loss from a guy’s point of view. Oral presentation. Friday, April 25th, 1-2pm.

Arteriosclerosis Society of Spain 2008 – June 4th-6th. Madrid, Spain. Kevin C. Maki. Strategies and treatments to reach therapeutic objectives in hypertriglyceridemia. Oral presentation. Friday, June 6th, 12pm.

Iowa Dietetic Association 2007 - November 7-9th. Ames IA. Kevin C. Maki. The skinny on glycemic load: weight management of hype? Oral presentation. Wednesday, November 7th, 2-3pm.

Publications

Maki KC, Carson ML, Miller MP, Turowski M, Bell M, Wilder D, Rains TM, Reeves MS. High-viscosity hydroxypropylmethylcellulose lowers postprandial insulin levels. Journal of Nutrition. 2008;138:292-6.

Maki KC, McKenney JM, Reeves MS, Lubin BC, Dicklin MR. Effects of adding prescription omega-3 fatty acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. American Journal of Cardiology. 2008 (In press).

Fan L, Hanbury R, Pandey SC, and Cohen RS. Dose and time effects of estrogen on expression of neuron-specific protein and cyclic AMP response element-binding protein and brain region volume in the medial amygdala of ovariectomized rats. Neuroendocrinology. 2008 (in press).

Books and Book Chapters

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

Maki KC and Mary R. Dicklin. How well do various lipids and lipoprotein measures predict cardiovascular disease morbidity and mortality. In Toth PP, Sica D, (eds). Clinical Challenges in Dyslipidemia Management. Oxford: Clinical Publishing, 2008 (in press).

Toth PP, Maki KC. Practical Lipid Management: London: John Wiley & Sons, (in press). Expected release date July, 2008.

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

In the Literature

Apolipoprotein B and LDL Particle Number in Cardiovascular Risk Assessment

A growing body of evidence supports the view that lipoprotein particle number is more closely related to coronary heart disease (CHD) risk than traditional lipoprotein lipid (cholesterol and triglyceride) measurements. However, from a clinical perspective, it is not yet certain whether measures of lipoprotein particle number such as the concentrations of apolipoprotein (Apo) B and Apo A-I or nuclear magnetic resonance (NMR) measurements of low-density (LDL-P) and high-density (HDL-P) lipoprotein particle concentrations are sufficiently superior to warrant their routine clinical use for risk assessment and/or evaluation of response to lipid therapies.

Van der Steeg et al. (2007) assessed the clinical utility of measuring the Apo B:A-I ratio for the prediction of CHD events. Apparently healthy men and women (45-79 years of age) in the European Prospective Investigation into Cancer and Nutrition – Norfolk were examined in this prospective, nested case-control study. Levels of total-cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, Apo B, and Apo A-I in persons who developed fatal or non-fatal CHD (n = 869) were compared with concentrations of those parameters in individuals without CHD and matched for age, sex, and enrollment period (n = 1511).

The results showed an association between the Apo B:A-I ratio and future CHD events that was independent of traditional lipid values [adjusted odds ratio 1.85; 95% confidence interval (CI) 1.15 to 2.98] and of the Framingham risk score (adjusted odds ratio 1.77; 95% CI 1.31 to 2.39). However, compared with lipid values, including the total-C:HDL-C ratio, the Apo B:A-I ratio was not superior in discriminating between CHD cases and controls [area under the receiver-operating characteristic curve, 0.670 for total-C:HDL-C ratio vs. 0.673 for Apo B:A-I ratio (p = 0.38)]. The Apo B:A-I ratio did add significantly to the Framingham risk score for determining CHD risk [area under the receiver-operating characteristic curve, 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus Apo B:A-I (p < 0.001)], but the degree of improvement was modest.

Ingelsson et al. (2007) recently examined the utility of different lipid measures for CHD prediction in a population-based, prospective cohort. Data from white men and women (mean age = 51 years, 53% women) who attended the fourth examination cycle (1987 to 1991) of the Framingham Offspring Study and were without CHD were examined (n = 3322). The relations of various lipid measures (serum total-C, HDL-C, LDL-C, non-HDL-C, Apo A-I, Apo B, total-C:HDL-C, LDL-C:HDL-C, and Apo B:A-I) to CHD incidence, in multivariate models adjusting for age, systolic blood pressure, antihypertensive treatment, diabetes, and smoking were investigated.

After a median follow-up of 15.0 years, 198 men and 93 women had experienced a first CHD event. The Apo B:A-I ratio predicted CHD [hazard ratio per standard deviation increment (95% CI)] in men [1.39 (1.23-1.58)] and in women [1.40 (1.16-1.67)]. However, the risk was similar to that for the total-C:HDL-C ratio in men [1.39 (1.22-1.58)] and women [1.39 (1.17-1.66)] and for the LDL-C:HDL-C ratio in men [1.35 (1.18-1.54)] and women [1.36 (1.14-1.63)]. In both sexes, models using the Apo B:A-I ratio demonstrated performance characteristics comparable with, but not better than, those for other lipid ratios. The Apo B:A-I ratio did not add predictive power for CHD risk in a model containing all components of the Framingham risk score including total-C:HDL-C (p = 0.12 in men, p = 0.58 in women).

Cromwell et al. (2007) examined an alternative method utilizing LDL-P concentration for prediction of future CVD, also in the Framingham Offspring cohort. Data from white men and women (mean age = 51 years, 53% women) who attended the fourth examination cycle (1987 to 1991) of the Framingham Offspring Study and were without CVD, had serum triglycerides ≤400 mg/dL were examined (n = 3066). CVD included CHD (myocardial infarction or coronary death), as well as new revascularizations, stroke, transient ischemic attack, intermittent claudication and congestive heart failure. Traditional chemical lipid measures of LDL-C and non-HDL-C were compared to LDL-P and VLDL-P as measured by NMR as predictors of incident CVD. Multivariable models adjusted for age, gender (for combined group), systolic and diastolic blood pressure, smoking and lipid medication use were investigated.

After a median follow-up of 14.8 years, 265 men and 166 women experienced a first CVD event. LDL-P strongly predicted CVD in men (p = 0.0005) and in women (p < 0.0001). LDL-P + VLDL-P also predicted CVD in both men (p = 0.0003) and women (p < 0.0001). Comparing extreme quartiles of LDL-C, non-HDL-C and LDL-P values demonstrated that LDL-P produced the greatest discrimination (59 vs. 139 events/1000 person years), non-HDL-C was second best (74 vs. 123 events/1000 person years) and LDL-C was the least predictive (81 vs. 119 events/1000 person years). Hazard ratios for a one standard deviation increment in the three measures were as follows: 1.11 for LDL-C, 1.21 for non-HDL-C and 1.28 for LDL-P.

Dr. Maki’s Commentary:

The results of the three investigations summarized above all suggest that measures of atherogenic lipoprotein particle number, as indicated by Apo B or LDL-P, are slightly better predictors of CHD or CVD event risk than traditional measures such as LDL-C and non-HDL-C. However, the results using these alternative measures are not sufficiently superior to justify their routine use in clinical practice due to the additional expense and complexity associated with their use.

These studies also confirm earlier reports that have shown non-HDL-C to be a stronger predictor of risk than LDL-C, which is not surprising since the correlation between non-HDL-C and Apo B is stronger than the correlation between LDL-C and Apo B. In our upcoming book Practical Lipid Management: Concepts and Controversies (to be published this summer by Wiley), Dr. Peter Toth and I have recommended that the next guideline committee consider replacing the current system of LDL-C goals plus non-HDL-C goals for those with hypertriglyceridemia, with a single set of non-HDL-C goals for everyone. This recommendation is based on data showing that non-HDL-C is a stronger predictor of CHD or CVD risk than LDL-C, and that changes in non-HDL-C induced by lipid altering therapies are more closely associated with changes in CHD risk than changes in LDL-C.

Additional research is needed to assess the degree to which changes in alternative measures of atherogenic (LDL-P and Apo B) and antiatherogenic (HDL-P and Apo AI) lipoproteins induced by various lipid therapies are associated with alterations in event risk. These investigations may have important clinical implications because data from several sources suggest that treatment with the most common class of lipid drug, the statins produces larger reductions in circulating levels of LDL-C and non-HDL-C than in LDL-P or Apo B (see Sniderman 2008 for a review on this topic). Therefore, while these alternative measures may not have sufficiently better predictive value than lipoprotein cholesterol levels to warrant their use for routine risk stratification, they may still prove to be sufficiently superior as indicators of the adequacy of lipid therapies to justify their use for that purpose.

References

1. Berkwits M, Guallar E. Risk factors, risk prediction, and the apolipoprotein B-apolipoprotein A-I ratio. Ann Intern Med. 2007;146:677-679. Editorial accompanying the Van der Steeg paper.
2. Ingelsson E, Schaefer EJ, Contois JH, McNamara JT, Sullivan L, Keyes MJ, Pencina MJ, Schoonmaker C, Wilson PWF, D’Agostino RB, Vasan RS. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298:776-785.
3. Cromwell WC, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan RS, Wilson PWF, D’Agostino RB. LDL particle number and risk of future cardiovascular disease in the Framingham offspring study-implication for LDL management. J Clin Lipidol 2007;1:583-592.
4. Sniderman AD. Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice. J Clin Lipidology 2008;2:36-42.
5. Van der Steeg WA, Boekholdt SM, Stein EA, El-Harcaoul K, Stroes ESG, Sandhu MS, Wareham NJ, Jukema JW, Luben R, Zwinderman AH, Kastelein JJP, Khaw KT. Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. Ann Intern Med. 2007;146:640-648.

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.

Or, contact us directly:

Tia Rains: trains@providentcrc.com, Director of Medical Writing / Principal Scientist