Provident Perspective Volume 4, Issue 2

Provident News

Provident continues to grow and proudly welcomes our newest staff members.

• Andrea Lawless, MD, Clinical Research Investigator
• Mano Patri, MD, Clinical Research Investigator
• Mickey Rubin, PhD, Clinical Research Scientist
• Adrienne Scherschel, Recruitment Specialist

Congratulations and welcome to Provident!

Announcements

Provident Clinical Research opening a new site this summer:

Our Chicago-area clinic is currently under renovation and we anticipate an opening date of July 1st, 2008 followed by a grand opening later this summer. Located in Addison, Illinois, the clinic is conveniently located within an ethnically diverse community and will participate in both nutrition and pharmaceutical research trials. The clinic will occupy approximately 3600 square feet including 4 exam rooms, a laboratory, private office space and a large nurses' station.

Recent and Upcoming Publications and Presentations

Abstracts/Presentations

Experimental Biology 2008 - April 5-9th. San Diego, CA. Kevin C. Maki, McKenney J, Lubin BC and Reeves MS. Lipid effects of prescription omega-3-acid ethyl esters plus simvastatin in subjects with hypertriglyceridemia. 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.

Louisiana Dietetic Association Food and 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.

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.

National Lipid Association 2008 - Maki KC, McKenney JM, Reeves MS, Lubin BC, Dicklin MR. Effects of prescription omega-3 acid ethyl esters plus simvastatin on lipids and lipoprotein particles in mixed dyslipidemia. Journal of Clinical Lipidology. May/June, poster #221.

America Dietetic Association 2008 - Maki KC, Carson ML, Reeves MS, Herther DC, Anderson WHK, Miller MP, Dicklin MR. Effects of hydroxypropylmethylcellulose on fasting lipids in men and women with primary hypercholesterolemia receiving statin therapy. Tuesday (9:45 am-11:15 am) October 28th. Oral presentation (session 112).

American Academy Neurology 2008 - April 12th-19th. Chicago, IL. Evaluating parkinson's disease patients at home: utility of self-videotaping for objective motor, dyskinesia and on/off assessments. Hinson V, Goetz CK, Leurgans S, Blasucci LM, Zimmerman JL, Fan W, Nguyen T, Hsu A. Poster #P02.017.

American Academy Neurology 2008 - April 12th-19th. Chicago, IL. Screening for cognitive impairment in multiple sclerosis (MS): evaluation of the HIV dementia scale (HDS). Barton B, Fan W, Leurgans S, Smith C, Bartt R. Poster #P04.160.

American Academy Neurology 2008 - April 12th-19th. Chicago, IL. Subjective assessments do not adequately evaluate excessive daytime sleepiness in parkinson's disease. Comella CL, Itin I, Park M, Stevens S, Jaglin J, Fan W. Poster # P05.152.

American Academy Neurology 2008 - April 12th-19th. Chicago, IL. Risk factors for falls in huntington's disease (HD). Barton BR, Watson N, Fan W, Jaglin JA, Leurgans S, Shannon K. Poster #P08.018.

American Academy Neurology 2008 - April 12th-19th. Chicago, IL. Montreal cognitive assessment (MoCA) as a screening tool for cognitive dysfunction in huntington's disease (HD). Videnovic A, Bernard B, Fan W, Jaglin J, Leurgans S, Shannon K. Poster #P08.019.

American Academy Neurology 2008 - April 12th-19th. Chicago, IL. Bilayer formulation of carbidopa/levodopa (IPX054) 50/200 mg given twice daily is comparable to standard carbidopa/levodopa 25/100 mg given four times daily in stable parkinson's disease (PD) Patients. Hinson V, Goetz C, Leurgans S, Fan W, Hsu A. Poster #S55.004.

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, 2008 (in press).

Publications

Maki KC, Curry LL, Carakostas MC, Tarka SM, Reeves MS, Farmer MV, McKenney JM, Toth PD, Schwartz SL, Lubin BC, Dicklin MR, Boileau AC, Bisognano JD. The hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure. Food and Chemical Toxicology, 2008 (in press, epub ahead of publication).

Maki KC, Curry LL, Reeves MS, Toth PD, McKenney JM, Farmer MV, Schwartz SL, Lubin BC, Boileau AC, Dicklin MR, Carakostas MC, Tarka SM. Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus. Food and Chemical Toxicology, 2008 (in press, epub ahead of publication).

Voss AC, Maki KC, Carvey TW, Hustead DS, Alish C, Fix B, Mustad VA. Effect of two carbohydrate-modified tube-Feeding formulas on metabolic responses in patients with type 2 diabetes. Nutrition, 2008 (in press).

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, epub ahead of publication).

Books and Book Chapters

Toth PP, Maki KC. Practical Lipid Management: London: John Wiley & Sons, (in press). Expected release date July, 2008. 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 Therapeutic Lipidology edited by Drs. Michael Davidson, Peter Toth and Kevin C. Maki, is available for purchase at Amazon.com

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, 2nd ed. 2008 (in press).

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, 2008 (in press).

In the Literature

Not long before this book was scheduled to go to press, results from the ENHANCE trial were released, producing a firestorm of debate among scientists and clinicians (1-3). The controversy centers on the appropriateness of assuming that new agents that effectively lower low-density lipoprotein cholesterol (LDL-C) will reduce cardiovascular events in the absence of data from cardiovascular event trials. The prevailing view during the prior decade has been that the evidence showing benefits of LDL-C reduction through a variety of interventions (statin drugs, bile acid sequestrants, niacin, ileal bypass surgery, dietary intervention) was strong enough to warrant the view that the most important consideration was reaching treatment targets (i.e., how low you go) and not the type of therapy used to achieve those goals (i.e., how you get there).

Two types of compounds that lower LDL-C had previously failed to show benefits in clinical event trials: conjugated equine estrogens (with or without medroxyprogesterone acetate) and torcetrapib (a cholesteryl ester transfer protein inhibitor). However, these drugs also had identifiable off-target effects that might be reasonably expected to offset the benefits of LDL-C reductions. Conjugated estrogens also raise triglycerides and C-reactive protein (CRP), increase thrombogenicity and activate metalloproteinases that may destabilize atherosclerotic plaques (4-6). Torcetrapib increases blood pressure, as well as serum aldosterone and bicarbonate levels and reduces circulating potassium (7).

In contrast, ezetimibe, the agent studied in ENHANCE, is minimally absorbed systemically and exerts its effects on the lipid profile through reducing intestinal absorption of cholesterol by binding the Nieman-Pick C1-like-1 protein in the intestinal wall. In addition to lowering LDL-C, ezetimibe reduces apolipoprotein (Apo) B, triglycerides and CRP. No off-target effects have been identified that would be expected to offset its favorable effects on the lipid profile.

In the ENHANCE trial 720 patients with heterozygous familial hypercholesterolemia were randomly assigned to receive 80 mg/d of simvastatin plus either ezetimibe 10 mg/d or placebo (3) for two years. The primary outcome variable was the change from baseline in intima-media thickness of the carotid artery (CIMT), a surrogate marker for progression of atherosclerosis. Despite significantly lower levels (all p < 0.01) of LDL-C (141 vs. 193 mg/dL), Apo B (135 vs. 169 mg/dL), triglycerides (108 vs. 120 mg/dL) and CRP (0.9 vs. 1.2 mg/L) during treatment, the group receiving ezetimibe showed a mean change in CIMT that was no different from that in the group receiving placebo (0.0111 vs. 0.0058 mm, respectively in the ezetimibe and placebo groups, respectively, p = 0.29).

The lack of benefit of ezetimibe on CIMT was surprising since other trials have found that more aggressive treatment of hypercholesterolemia results in slowed progression or even regression of CIMT (8-11). For example, the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial studied a group of 325 subjects with heterozygous familial hypercholesterolemia (8). The results showed that more aggressive lowering of LDL-C with 80 mg/d of atorvastatin produced regression of CIMT (-0.031 mm), while the group that received less aggressive statin therapy (40 mg/d of simvastatin) showed progression of 0.036 mm (p = 0.0001 for the comparison between groups).

Given that other studies using the same methods of measurement have shown benefits of more aggressive LDL-C therapy, at least two potential explanations exist for the lack of benefit associated with ezetimibe treatment during the ENHANCE trial:

Ezetimibe may not be antiatherogenic, despite its ability to lower LDL-C, atherogenic lipoprotein particles and CRP. The participants in the ENHANCE trial may have had a lower than expected risk of progression, limiting the ability of the study to demonstrate a benefit.

Regarding the first issue, ezetimibe could have as yet unidentified off-target adverse effects. While this cannot be entirely ruled out, the fact that it is minimally absorbed reduces the likelihood that this is the explanation. Alternatively, ezetimibe may fail to provide some benefit that is obtained with the use of other agents. Ezetimibe does not generally raise HDL-C and in some studies has failed to improve endothelial function (12, 13). However, a recent meta-regression study conducted by Robinson et al. (14) showed that the relationship between LDL-C lowering and the reduction in risk of coronary heart disease over five years of treatment was not dependent on the type of treatment that induced the LDL-C reduction. Thus, lowering LDL-C through the use of dietary intervention (5 studies), bile acid sequestrants (3 studies), ileal bypass (1 study) and statin therapy (10 studies) produced similar reductions in risk for a given reduction in LDL-C, arguing against a large influence of effects beyond those of reducing LDL-C and atherogenic lipoproteins. Data from imaging studies suggest that changes in both atherogenic (LDL-C) and antiatherogenic (HDL-C) lipoprotein cholesterol levels predict changes in atheroma volume (15). Nevertheless, due to the generally greater effect of drug therapy on LDL-C, the influence of changes in LDL-C is quantitatively larger. Therefore, while it is possible that the lack of some benefit beyond the reduction in LDL-C and atherogenic lipoproteins accounts for the failure to demonstrate a benefit of treatment with ezetimibe, this also appears to be unlikely given the available evidence.

In the authors' view, the more likely explanation for the lack of difference in progression between treatments in the ENHANCE trial is the low baseline CIMT values in both treatment groups. In the ASAP trial, initial CIMT value was the strongest predictor of the degree of progression, with higher baseline CIMT associated with greater progression (9). The subjects in the ENHANCE and ASAP trials were of similar age with the same underlying condition (familial hypercholesterolemia). Table 1 shows selected characteristics for the subjects assigned to the simvastatin monotherapy arms in the two studies. Before and during treatment the subjects in the two trials receiving simvastatin monotherapy had similar levels of LDL-C. However, the baseline CIMT in the ASAP trial was 31% larger (0.92 vs. 0.70 mm). In fact, the baseline CIMT among ENHANCE trial participants was similar to the mean value among subjects without CHD in the Atherosclerosis Risk in Communities study (0.72 mm, 16). CIMT progression over 2 years among subjects in the ASAP trial receiving simvastatin monotherapy was six times that for subjects in ENHANCE trial receiving simvastatin monotherapy (0.0360 vs. 0.0058 mm). Thus, despite receiving the same drug and having similar levels of LDL-C at baseline and during treatment, subjects in the simvastatin monotherapy arm in the ENHANCE trial had much lower baseline CIMT and only a fraction of the CIMT progression that was observed in the simvastatin monotherapy arm in the ASAP trial. The fact that the comparator arm in the ENHANCE trial showed essentially no CIMT progression suggests that the ability of an additional therapy to show incremental benefit may have been limited. This is analogous to conducting a cardiovascular event trial in children. No matter how effective the lipid alteration, one would not expect to find a difference between treatments in events since the event rate would be too low in both groups to demonstrate a benefit.

What might account for these different responses in the comparator arms of these two studies? One potential explanation is that usual care for management of familial hypercholesterolemia changed during the time between the ASAP and ENHANCE trials. Most ENHANCE trial participants had their lipid therapy stopped temporarily prior to the baseline lipid measurements. Subjects who participated in the ENHANCE trial were likely to have been treated more aggressively before entering the study because standards of care changed over the several years before recruitment began, favoring more aggressive therapy. Aggressive management of lipids and other risk factors over a period of several years before entering the trial may have produced changes in the carotid artery wall, rendering it less likely to respond to additional therapy. In fact, over the two year extension to the ASAP trial, subjects who continued on 80 mg/d of atorvastatin had little additional change in CIMT (0.005 mm/year or 0.010 mm over two years). This is nearly identical to the degree of progression observed in the simvastatin plus ezetimibe group in the ENHANCE trial (0.011 mm). Thus, the failure to observe a difference between treatments in the ENHANCE trial may have been a case of an inability to "make healthy arteries healthier".

The panel convened to discuss the clinical implications of the ENHANCE trial at the American College of Cardiology meeting, as well as the two editorials in the New England Journal of Medicine that accompanied the ENHANCE paper recommended that, in light of the failure to show a benefit of adding ezetimibe to simvastatin in the ENHANCE trial, ezetimibe should be reserved for use in patients who cannot tolerate other drug classes or who cannot achieve their treatment targets with statins plus niacin, fibrates or bile acid sequestrants. At the American College of Cardiology meeting, there was no meaningful debate about the validity of the results or the design of the study. Many physicians in attendance disagreed with both the content and tone of the discussants' presentation. Press coverage also appeared heavily weighted toward the extraordinarily negative opinions of a few physicians. The press even managed to call the entire "LDL hypothesis" into question, resulting inconsiderable confusion among patients, many of whom discontinued their therapy based on newspaper and television reports. This constitutes a profound disservice to patients. Physicians also began to withdraw patients from ezetimibe therapy out of fear that continuing the drug would leave them exposed to litigation.

Ezetimibe accounted for more than 15% of the total prescriptions for lipid therapy in the U.S. in 2006 (17). Therefore, moving it to the "back of the line" would have substantial implications for lipid management. Ezetimibe has been popular because of its favorable safety and side effect profiles, as well as its efficacy for lowering LDL-C, particularly as an adjunct to a statin. Its use significantly increases the number of high and very high risk patients able to attain their LDL-C goals (18-23).

The authors of this book disagree with the conclusion that ezetimibe should be moved to the back of the line as a treatment for dyslipidemia. We are of the opinion that the atherogenicity of Apo B-containing lipoproteins has been well enough established that, in the absence of a compelling reason to believe that off-target adverse effects may be at work, the demonstrated effects on atherogenic lipoproteins are sufficient to tip the odds in favor of a presumed net benefit. Achieving the newer optional treatment targets for LDL-C and non-HDL-C is difficult without combination therapy in many patients. For most, statin therapy will be the first line of drug therapy. Of the available treatment options, we only have direct evidence of benefit with addition to a statin for niacin (24). The combination niacin and simvastatin has been shown to be effective for reducing the progression of coronary atherosclerosis and CIMT (25, 26). No large scale outcome trials have been completed for combinations of lipid drug therapies.

The recently published Stop Atherosclerosis in Native Diabetics Study (SANDS) illustrated the difficulty of achieving more aggressive treatment goals. In this trial (27), 499 Native American subjects with type 2 diabetes (but free of clinical CHD), were assigned to receive standard care for lipids and blood pressure (LDL-C goal < 100 mg/dL and systolic blood pressure goal < 130 mm Hg) or aggressive treatment (LDL-C goal < 70 mg/dL and systolic blood pressure goal < 115 mm Hg) for three years. The surrogate markers of CIMT and left ventricular mass were the main outcome variables. Among patients unable to reach their LDL-C target in this trial, ezetimibe was added. Aggressive LDL-C and blood pressure reduction resulted in significant improvements in CIMT and left ventricular mass. Mean on-treatment levels of LDL-C (72 mg/dL) and systolic blood pressure (117 mm Hg) in the aggressive treatment arm indicate that fewer than half of subjects were able to achieve and maintain the treatment goals, even in the setting of a clinical trial. The authors believe that the net impact of a recommendation to move ezetimibe to the back of the line as a lipid treatment will likely result in fewer patients reaching their treatment targets. While we feel that the best evidence to guide clinical decisions arises from randomized clinical event trials, such data for ezetimibe will not be available before 2011 at the earliest (from the ongoing IMPROVE-IT or Improved Reduction of Outcomes: VYTORIN Efficacy International Trial) and no such data are available for combinations of statin therapy with any other lipid altering drug. In the meantime, for the reasons cited above, our view is that the ENHANCE trial does not raise sufficient doubts about the likelihood of benefit with ezetimibe to warrant any change in clinical practice*. This is consistent with a position statement released by the National Lipid Association released in January of 2008 (28).

*The authors wish to disclose that both have received support in the form of research grants and/or consulting fees/honoraria from the manufacturers of ezetimibe (Merck/Schering Plough).

References

1. Brown BG, Taylor AJ. Does ENHANCE diminish confidence in lowering LDL or in ezetimibe. N Engl J Med 2008;358:1504-1506.
2. Drazen JM, Jarcho JA, Morissey S, Curfman GD. Cholesterol lowering and ezetimibe. N Engl J Med 358:1507-1508.
3. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-1443.
4. Luyer MDP, Khosla S, Owen WG, Miller VM. Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammation in postmenopausal women. J Clin Endocrinol Metab 2001;86:3629-3634.
5. Koh KK, Shin M-S, Sakuma I, et al. Effects of conventional or lower doses of hormone replacement therapy in postmenopausal women. Arterioscler Thromb Vasc Biol 2004;24:1516-1521.
6. Lewandowski KC, Komorowski J, Mikhalidis DP, et al. Effects of hormone replacement therapy type and route of administration on plasma matrix metalloproteinases and their tissue inhibitors in postmenopausal women. J Clin Endocrinol Metab 2006;91:3123-3130.
7. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-2122.
8. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomized, double-blind trial. Lancet 2001;357:577-581.
9. Van Wissen S, Smilde TJ, Trip MD, Stalenhoef AFH, Kastelein JJP. Long-term safety and efficacy of high-dose atorvastatin treatment in patients with familial hypercholesterolemia. Am J Cardiol 2005;95:264-266.
10. Nissen SE, Nicholls SJ, Sipahi I, et al: ATSERIOD Investigators. Effect of very-high intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-1565.
11. Crouse JR III, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: The METEROR Trial. JAMA 2007;297:1344-1353.
12. Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005;111:2356-2363.
13. Fichtischerer S, Schmidt-Lucke C, Bojunga S, et al. Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD; clinical evidence for ÔpleiotropicÕ functions of statin therapy. Eur Heart J 2006;27:1182-1190.
14. Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005;46:1855-1862.
15. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499-508.
16. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: The Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997;146:483-494.
17. Jackevicius CA, Tu JV, Ross JS, Ko DT, Krumholz HM. Use of ezetimibe in the United States and Canada. N Engl J Med 2008;358:1819-1828.
18. Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003;24:729-741.
19. Abate N, Catapano AL, Ballantyne CM, Davidson MH, et al. Effect of ezetimibe/simvastain versus atorvastatin or rosuvastatin on modifying lipid profiles in patients with diabetes, metabolic syndrome, or neither: Results of two subgroup analyses. J Clin Lipidol 2008;2:91-105.
20. Davidson MH, Ballantyne CM, Kerzner B, et al. Effectiveness of ezetimibe added to ongoing statin therapy in modifying lipid profiles and low-density lipoprotein cholesterol goal attainment in patients of different races and ethnicities: a substudy of the Ezetimibe add-on to statin for effectiveness trial. Mayo Clin Proc 2006;81:1177-85.
21. Denke M, Pearson T, McBride P, et al. Ezetimibe added to ongoing statin therapy improves LDL-C goal attainment and lipid profile in patients with diabetes or metabolic syndrome. Diab Vasc Dis Res 2006;3:93-102.
22. Guyton JR, Goldberg RB, Mazzone T, et al. Lipoprotein and apolipoprotein ratios in the VYTAL trial of ezetimibe/simvastatin compared with atorvastatin in type 2 diabetes. J Clin Lipidol 2008;2:19-24.
23. Pearson TA, Denke MA, McBride PE, et al. Effectiveness of ezetimibe added to ongoing statin therapy in modifying lipid profiles and low-density lipoprotein cholesterol goal attainment in patients of different races and ethnicities: a substudy of the ezetimibe add-on to statin for effectiveness trial. Mayo Clin Proc 2006;81:1177-85.
24. Ballantyne CM, Davidson MH, McKenney J, et al. Comparison of the safety and efficacy of a combination tablet niacin extended release and simvastatin vs. simvastatin monotherapy in patients with increased non-HDL cholesterol (from the SEACOAST I Study). Am J Cardiol 2008;101:1428-1436.
25. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness. ARBITER 3. Curr Med Res Opin 2006;22:2243-2250.
26. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-3517.
27. Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: The SANDS randomized trial. JAMA 2008;299:1678-1689.
28. National Lipid Association Statement on ENHANCE study findings: Premature judgment unwarranted. Accessed 5/19/08 at http://www.lipid.org/press/index.php.

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