Provident Perspective Volume 3, Issue 2

Provident News

Spring has been very busy for Provident! We are pleased to welcome the following staff:

• Julie Acanfora, Research Assistant
• Rose Hanbury, PhD, Medical Writer/Clinical Research Scientist
• Elaine Kendrick, COA, Clinical Research Coordinator
• Rebecca McCall, Research Assistant
• Carol Newman, Executive Assistant
• Mark Peabody, Research Assistant and Laboratory Technician
• Todd Posson, Business Development
• Lisa White, Front Desk
• Linda Derrig, Account Executive

Recent and Upcoming Publications and Presentations

Abstracts/Presentations

Maki KC, Rains TM. Designing a Clinical Trial. Proceedings of the IFT Annual Meeting and Food Expo, 2007, Abstract (in press).

Maki KC. High-viscosity hydroxypropylmethylcellulose (HPMC) – A promising agent for metabolic risk factor management. Proceedings of the Am Chem Soc, 2007, Abstract AGFD3.

Maki KC, Davidson MH, Bays HE, Stein EA, Shalwitz RA, Doyle R. Effects of omega-3-acid ethyl esters on LDL particle size in subjects with hypertriglyceridemia despite statin therapy. Proceedings of the Experimental Biology Meeting, 2007, Abstract # 231.2.

Larsen EK, Maki KC, Lofgren P, Kronmal R. Vitamin E use and congestive heart failure in the cardiovascular health study. Proceedings of the Experimental Biology Meeting, 2007, Abstract # 837.19.

Maki KC, Carson ML, Miller MP, Turowski M, Bell M, Wilder DM, Reeves MS. Glucose tolerance modifies the effects of high-viscosity hydroxpropylmethylcellulose on postprandial glucose and insulin excursions. Proceedings of the Experimental Biology Meeting, 2007, Abstract # 368.6.

Izumi R, Hurt J, Maki KC, Bell M, Zavras A, McCamish M. Clinical predictors of glycosylated hemoglobin responses to thiazolidinedione therapy. Proceedings of the American Heart Association Epidemiology and Prevention Sessions, 2007.

Shalwitz RA, Maki KC, Doyle R. Lipoprotein subfraction responses differentially predict changes in lipoprotein associated phospholipase A2 during prescription Omega-3 therapy. American Heart Association Arteriosclerosis, Thrombosis and Vascular Biology Abstracts #P328, 2007.

Bays H, Maki KC, Doyle R, Stein, EA, Davidson MH, Shalwitz R. Effects of prescription omega-3-acid ethyl esters on glycemic response in subjects with persistent hypertriglyceridemia despite statin therapy. Endocrine Society. 2007.

Davidson MH, Bays H, Stein E, Maki KC, Doyle R, Shalwitz RA. COMBOS – The combination of prescription Omega-3s with simvastatin: a randomized, double-blind, placebo-controlled study to assess the efficacy and safety of prescription Omega-3 (OMACOR®) added to stable statin therapy in hypertriglyceridemic patients. Proceedings of the Midwest Lipid Association 3rd Annual Scientific Forum, 2006

Publications

Davidson MH, Stein EA, Bays H, Maki KC, Doyle R, Shalwitz RA, Ballantyne CM, Ginsberg HN. The lipid and lipoprotein effects of adding prescription Omega-3 fatty acids to a statin in hypertriglyceridemic subjects – The COMBOS Trial. Clin Therapeutics. 2007; (in press).

Maki KC, Carson ML, Miller MP, Turowski M, Wilder D, Reeves MS, Bell M. High-viscosity hydroxypropylmethylcellulose blunts postprandial glucose and insulin responses. Diabetes Care. 2007;30:1039-1043.

Maki KC, Rains TM, Kaden VN, Raneri KR, Davidson MH. Effects of a reduced glycemic load diet on body weight, body composition and cardiovascular risk markers in overweight and obese men and women. Am J Clin Nutr. 2007;85:724.

Deedwania PC, Maki KC, Dicklin MR, Stone NJ, Ballantyne CM, Davidson MH. Application of recent definitions of the metabolic syndrome to survey data from the National Cholesterol Education Program Evaluation Project Utilizing Novel E-technology. J Cardiometabolic Syndrome. 2006;5:295-300.

In the Literature

Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-72.

Comment in: Brown MS, Goldstein JL. Lowering LDL – Not only how low, but how long? Science. 2006;311:1721-3.

Methods: Sequence variations in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) are associated with reduced plasma levels of low-density lipoprotein (LDL) cholesterol. This study compared the incidence of coronary heart disease (CHD) according to the presence or absence of PCSK9 sequence variants over a 15-yr interval (1987 to 2003) in the Atherosclerosis Risk in Communities (ARIC) study. The ARIC study is a prospective study of atherosclerosis in 15,792 individuals, 45-64 years of age.

Results: Approximately one of every 40 black subjects (2.6%) in the ARIC study had a nonsense mutation in PCSK9. Plasma LDL cholesterol level was 28% lower, on average, in these individuals. Not all subjects with a nonsense mutation had low plasma LDL cholesterol, but 81% had a level below the 50th percentile for black subjects. The CHD incidence among black subjects without a nonsense mutation was 9.7%, compared with an incidence of 1.2% (one of 85 participants) among those with a nonsense mutation (P=0.008). The hazard ratio for CHD in carriers vs. non-carriers was 0.11 (95% confidence interval, 0.02 to 0.81; P=0.03), a reduction of 88% in risk.

Nonsense mutations of PCSK9 in white subjects are rare, present in only six of 9537 subjects tested in ARIC. A PCSK9 sequence variation (missense mutation) is more common among white subjects than black subjects. Of the 9524 white subjects examined, 3.2% had a PCSK9 missense mutation that was associated with an average LDL cholesterol level 15% lower than among those without the mutation. Despite its more moderate effect on LDL cholesterol, this variation was associated with a 47% reduction in the rate of coronary events (hazard ratio, 0.50; 95% confidence interval, 0.32 to 0.79; P=0.003).

Risk of carotid atherosclerosis, assessed by measurement of carotid artery intima-media thickness, was compared in carriers and non-carriers of the nonsense and missense mutations of PCSK9. The mean intima-media thickness was slightly but significantly lower among carriers than non-carriers, both in black and white subjects.

Conclusions: The results of this study suggest that nonsense and missense sequence variations in PCSK9 that were associated with lower plasma levels of LDL cholesterol conferred protection against CHD.

Dr. Maki’s Commentary: Although this study is limited by its observational nature, it has extremely important clinical implications. Ecological studies that have compared CHD incidence across countries with differing average levels of cholesterol have suggested that each 1% decrement in LDL cholesterol is associated with a 2-3% lower CHD risk. However, studies of cholesterol-lowering interventions, particularly with statin drugs, have consistently shown reductions of ~1% in CHD event risk for every 1% reduction in LDL cholesterol. One possible explanation for the difference between the predicted and observed effects is that intervention trials have lasted a relatively short time (roughly 5-6 years), which may be an insufficient period for the full benefits of LDL cholesterol reduction to occur.

Cohen et al. have added important new evidence which supports this hypothesis. Individuals who have a sequence variation in the PCSK9 gene have lower LDL cholesterol throughout life. Reductions of 28% and 15% in LDL cholesterol produced by the PCSK9 variations were associated with remarkable reductions of 88% and 47% in CHD incidence in the ARIC study. In other words, risk was reduced by 3.1% for each 1% decrement in LDL-C, which agrees well with results from ecological studies.

As pointed out by Brown and Goldstein (winners of the Nobel Prize for their work on the LDL receptor) in an editorial in Science, the clinical implication is that it is not only the LDL cholesterol level (how low), but also how long it is maintained at that level, that determines risk. From a public health standpoint, we now have safe and effective drugs that are appropriate for use in those at moderate or high risk. However, lifestyle and dietary adjuncts have the potential to reduce LDL cholesterol by 15% or more. For example, if reducing dietary saturated fat (>7% of energy) and cholesterol (>200 mg/d), use of viscous dietary fiber (10 g/d) and consumption of a plant sterol or stanol product (1.5-2.0 g/d) each lower LDL cholesterol by 5-7%, the resulting change in LDL cholesterol would be 15-21%. If maintained over many years, this could potentially cut CHD event risk in half.

I have previously advocated expanded use of dietary interventions for lowering cholesterol. In my experience, the recommendations in the National Cholesterol Education Program guidelines for incorporating viscous fibers and plant sterol/stanol products are widely ignored. The results from the ARIC study underscore the potential of these safe and efficacious interventions for helping to maintain a lower LDL cholesterol level over a longer period. I am hopeful that the food industry and the medical community will take notice and respond.

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