Hyperlipidemias: Bays HE

Fox KM, Gandhi SK, Ohsfeldt RL, Blasetto JW, Bays HE. · University of Maryland School of Medicine, Department of Epidemiology & Preventive Medicine, Baltimore, MD, USA. · Curr Med Res Opin. · Pubmed #17655813 No free full text.

Abstract: OBJECTIVE: To compare effectiveness of rosuvastatin (RSV) with other statins on lowering low-density lipoprotein cholesterol (LDL-C) and LDL-C goal attainment among patients with type 1 or type 2 diabetes mellitus. METHODS: A retrospective study using US General Electric Medical Systems (GEMS) database of patients with diabetes mellitus (ICD9 code = 250, prescription for anti-diabetic medication or fasting blood glucose level > or = 126 mg/dL in the 12 months preceding statin therapy) treated across clinical practices in the US, who were newly prescribed statin therapy during August 2003-March 2006, was conducted. Multivariate linear and logistic regression models were used for analyzing prescription data with baseline LDL-C, age, gender, smoking, very high CHD risk, systolic blood pressure, and statin duration as covariates. RESULTS: Of 4754 diabetes mellitus patients, 5% were prescribed RSV, 59% atorvastatin (ATV), 21% simvastatin (SMV), 5% pravastatin (PRV), 2% fluvastatin (FLV), and 7% lovastatin (LOV). RSV patients had significantly higher (p < 0.05) baseline mean LDL-C levels (138 vs. 117-131 mg/dL), lower average starting dose (11.7 vs. 17.0-63.7 mg) and were younger (p < 0.005) than patients on other statins (mean age 61 vs. 63-69 years). Percent LDL-C reduction was significantly greater (p < 0.0001) with RSV (28.4%) compared to ATV (22.5%), SMV (20.1%), PRV (13.7%), FLV (15.8%), and LOV (17.3%). A greater (p < 0.05) proportion of RSV diabetes patients attained LDL-C goal < 100 mg/dL (72.8%) vs. diabetes mellitus patients on other statins (36.8-67.4%). CONCLUSIONS: Rosuvastatin was more effective in lowering LDL-C and achieving LDL-C treatment goals in the diabetes mellitus population as compared to other statins in real-world clinical practice setting. Validating study results in a different diabetes population with dispensed statin prescriptions will help increase generalizability of study findings.

Bays HE, Neff D, Tomassini JE, Tershakovec AM. · Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. · Expert Rev Cardiovasc Ther. · Pubmed #18402536 No free full text.

Abstract: Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol. It appears to exert its effect by blocking intestinal sterol transporters, specifically Niemann-Pick C1-like 1 proteins, thereby inhibiting the intestinal absorption of cholesterol, phytosterols and certain oxysterols. Ezetimibe monotherapy and in combination with statin therapy is primarily indicated for lowering LDL-cholesterol levels. In addition, it may favorably affect other parameters that could potentially further reduce atherosclerotic coronary heart disease risk, such as raising HDL-cholesterol and lowering levels of triglycerides, non-HDL-cholesterol, apolipoprotein B and remnant-like particle cholesterol. Further effects of ezetimibe include a reduction in circulating phytosterols and oxysterols and, when used in combination with statins, a reduction in high-sensitivity C-reactive protein. The clinical significance of the LDL-cholesterol lowering and other effects of ezetimibe is being evaluated in clinical outcome studies.

Bays HE, Tighe AP, Sadovsky R, Davidson MH. · Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. · Expert Rev Cardiovasc Ther. · Pubmed #18327998 No free full text.

Abstract: Hypertriglyceridemia is a risk factor for atherosclerotic coronary heart disease. Very high triglyceride (TG) levels (> or =500 mg/dl [5.65 mmol/l]) increase the risk of pancreatitis. One therapeutic option to lower TG levels is omega-3 fatty acids, which are derived from the oil of fish and other seafood. The American Heart Association has acknowledged that fish oils may decrease dysrhythmias, decrease sudden death, decrease the rate of atherosclerosis and slightly lower blood pressure, and has recommended fish consumption or fish oil supplementation as a therapeutic strategy to reduce cardiovascular disease. A prescription omega-3-acid ethyl esters (P-OM3) preparation has been available in many European nations for at least a decade, and was approved by the US FDA in 2004 to reduce very high TG levels (> or =500 mg/dl [5.65 mmol/l]). Mechanistically, most evidence suggests that omega-3 fatty acids reduce the synthesis and secretion of very-low-density lipoprotein (VLDL) particles, and increase TG removal from VLDL and chylomicron particles through the upregulation of enzymes, such as lipoprotein lipase. Omega-3 fatty acids differ mechanistically from other lipid-altering drugs, which helps to explain why therapies such as P-OM3 have complementary mechanisms of action and, thus, complementary lipid benefits when administered with statins. Additional human studies are needed to define more clearly the cellular and molecular basis for the TG-lowering effects of omega-3 fatty acids and their favorable cardiovascular effects, particularly in patients with hypertriglyceridemia.

Conard SE, Bays HE, Leiter LA, Bird SR, Rubino J, Lowe RS, Tomassini JE, Tershakovec AM. · University of Texas Southwestern Medical School, Dallas, TX, USA. · Am J Cardiol. · Pubmed #19026302 No free full text.

Abstract: The aim of this study was to evaluate the efficacy and safety of ezetimibe 10 mg added to atorvastatin 20 mg compared with doubling atorvastatin to 40 mg in patients with hypercholesterolemia at moderately high risk for coronary heart disease who did not reach low-density lipoprotein (LDL) cholesterol levels <100 mg/dl with atorvastatin 20 mg. In this 6-week, multicenter, double-blind, randomized, parallel-group study, 196 patients treated with atorvastatin 20 mg received atorvastatin 20 mg plus ezetimibe 10 mg or atorvastatin 40 mg for 6 weeks. Adding ezetimibe 10 mg to atorvastatin 20 mg produced significantly greater reductions in LDL cholesterol than increasing atorvastatin to 40 mg (-31% vs -11%, p <0.001). Significantly greater reductions were also seen in non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B (p <0.001). Significantly more patients reached LDL cholesterol levels <100 mg/dl with atorvastatin 20 mg plus ezetimibe compared with atorvastatin 40 mg (84% vs 49%, p <0.001). The 2 treatment groups had comparable results for high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, and high-sensitivity C-reactive protein. The incidences of clinical and laboratory adverse experiences were generally similar between groups. In conclusion, the addition of ezetimibe 10 mg to atorvastatin 20 mg was generally well tolerated and resulted in significantly greater lipid-lowering efficacy compared with doubling atorvastatin to 40 mg in patients with hypercholesterolemia at moderately high risk for coronary heart disease.

McKenney JM, Davidson MH, Saponaro J, Thompson PD, Bays HE. · National Clinical Research Inc., 2809 Emerywood Parkway, Ste. 140, Richmond, VA 23294, USA. · J Cardiovasc Pharmacol. · Pubmed #16220065 No free full text.

Abstract: This multicenter, 8-week, single-step titration, open-label study sought to assess the percentage of subjects who achieved their National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III low-density lipoprotein (LDL)-cholesterol target when assigned a starting dose of atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg) selected using an algorithm based on their 10-year CHD risk and the magnitude of LDL-cholesterol lowering necessary to reach goal. Following an 8-week washout period, 1298 subjects, categorized as low, medium, or high risk, were assigned to 4 weeks of treatment with a starting dose of atorvastatin selected by the algorithm. At week 4, subjects who did not achieve goal (15.8%) were titrated to the next-higher dose. The primary endpoint was the percentage of subjects in each risk group who achieved LDL-cholesterol goal at week 8. At 8 weeks, 84.8% of subjects (low risk 92.9%; moderate risk 84.0%; high risk 81.1%) achieved LDL-cholesterol target. The majority of patients (84.2%) achieved their lipid target through the use of the algorithm-based starting dose (10-80 mg) without the need for titration. No patient had elevations in creatine phosphokinase >10 times the upper limit of normal. Elevations in alanine aminotransaminase or aspartate aminotransaminase were observed in <1% of study subjects and were unrelated to dose. Selecting the starting dose of atorvastatin using a treatment algorithm achieves NCEP ATP III LDL-cholesterol goals in the majority of patients and minimizes the need for dose titration.

Deedwania PC, Hunninghake DB, Bays HE, Jones PH, Cain VA, Blasetto JW, Anonymous00354. · VA Central California Health Care System and University of California-San Francisco, Fresno, California, USA. · Am J Cardiol. · Pubmed #15670545 No free full text.

Abstract: The metabolic syndrome (MS) is a constellation of coronary risk factors. Atherogenic dyslipidemia is an important factor in cardiovascular risk in these patients, and treatment of atherogenic dyslipidemia has been identified as an important goal of therapy in patients with MS. This post hoc analysis of data from a 6-week, randomized, open-label, parallel-group, comparative trial (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin [STELLAR]) assessed the effects of rosuvastatin 10, 20, and 40 mg, atorvastatin 10, 20, 40, and 80 mg, simvastatin 10, 20, 40, and 80 mg, and pravastatin 10, 20, and 40 mg on plasma lipids in hypercholesterolemic patients (low-density lipoprotein cholesterol >/=160 and <250 mg/dl; triglycerides <400 mg/dl) who had >/=3 of the 5 National Cholesterol Education Program Adult Treatment Panel III criteria for MS (body mass index >30 kg/m(2) substituted for waist circumference). Of 2,268 patients, 811 met criteria for MS. Percent reductions in low-density lipoprotein cholesterol ranged from 20% in the pravastatin 10-mg group to 55% in the rosuvastatin 40-mg group. In patients with MS, triglyceride reductions were 22% to 34% with rosuvastatin, 23% to 33% with atorvastatin, 15% to 23% with simvastatin, and 12% to 15% with pravastatin. High-density lipoprotein cholesterol increased by 8% to 11% with rosuvastatin, 5% to 9% with atorvastatin, 8% to 10% with simvastatin, and 3% to 7% with pravastatin. Rosuvastatin, atorvastatin, simvastatin, and pravastatin treatment had favorable effects in hypercholesterolemic patients on the atherogenic dyslipidemia associated with MS. Rosuvastatin had the most favorable effect on the atherogenic lipid profile of MS overall.

Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, Johnson-Levonas AO, Sapre A, Donahue SR, Anonymous00402. · Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. · Clin Ther. · Pubmed #15639688 No free full text.

Abstract: OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia. METHODS: This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study After a 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides [TG], < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP]. RESULTS: There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of -44.8% to -602%, non-high-density lipoprotein cholesterol of -40.5% to -55.7%, and TG of -22.5% to -30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels > or =3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creature kinase levels > or =10 times ULN (0.0% for EZE/SIMVA and 02% for SIMVA; P = NS). CONCLUSION: The EZE/SIMVA tablet was a highly effective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia.

Hunninghake DB, Stein EA, Bays HE, Rader DJ, Chitra RR, Simonson SG, Schneck DW. · Heart Disease Prevention Clinic, University of Minnesota, Minneapolis, Minnesota 55455, USA. · Coron Artery Dis. · Pubmed #15024300 No free full text.

Abstract: BACKGROUND: We examined the effects of rosuvastatin treatment on triglyceride levels and lipid measures in a parallel-group multicenter trial (4522IL/0035) in patients with hypertriglyceridemia (Fredrickson Type IIb or IV). METHODS: After a 6-week dietary lead-in period while on a National Cholesterol Education Program step I diet, 156 patients with fasting triglyceride levels >/= 300 and < 800 mg/dl were randomized to 6 weeks of double-blinded treatment: once-daily rosuvastatin of 5, 10, 20, 40 or 80 mg or placebo. The primary end point was mean percentage change from baseline in total serum triglyceride levels at week 6 as determined by analysis of variance. RESULTS: Rosuvastatin at all doses produced significant mean reductions in triglycerides compared with placebo (-18 to -40 compared with +2.9%, P </= 0.001); median reductions in triglycerides with rosuvastatin at 5-80 mg ranged from -21 to -46%. All doses of rosuvastatin significantly reduced levels of atherogenic lipoprotein and apolipoproteins over placebo, including low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, apolipoprotein B and apolipoprotein C-III. Statistically significant increases in high-density lipoprotein cholesterol were observed with rosuvastatin doses > 5 mg. The occurrence of adverse events was generally low and not dose related, although some adverse events occurred more frequently in the rosuvastatin 80 mg group. CONCLUSIONS: Rosuvastatin reduced triglyceride levels and improved the overall atherogenic and atheroprotective lipid profiles in hypertriglyceridemic patients.

Bays HE, McKenney JM, Dujovne CA, Schrott HG, Zema MJ, Nyberg J, MacDougall DE, Anonymous00253. · Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky 40213, USA. · Am J Cardiol. · Pubmed #12943873 No free full text.

Abstract: This study evaluated the efficacy and tolerability of gemcabene, a new lipid-altering agent, in a double-blind, randomized, dose-response study of 161 patients with high-density lipoprotein (HDL) cholesterol of <35 mg/dl and serum triglyceride (TG) levels of either >/=200 (n = 94) or <200 mg/dl (n = 67). After a 6-week, placebo, dietary lead-in period, patients were administered either 150, 300, 600, or 900 mg of gemcabene or placebo once daily for 12 weeks. In the TG >/=200 mg/dl stratum, gemcabene significantly increased serum HDL cholesterol by 18% with corresponding significant increases of 6% in both apolipoprotein A-I and A-II levels at the 150-mg dose. HDL cholesterol levels also increased 12% at the 300-mg dose; however, this did not reach statistical significance. Also, in the TG >/=200 mg/dl stratum, serum TG levels were significantly reduced by 27% and 39% at the 150- and 300-mg doses of gemcabene, respectively. No significant differences were found in serum HDL cholesterol or TG levels in the TG >/=200 mg/dl groups that received 600 or 900 mg of gemcabene, or in TG <200 mg/dl groups administered any dose of gemcabene. However, at these higher 600- and 900-mg doses, gemcabene significantly reduced serum low-density lipoprotein (LDL) cholesterol levels by 15% to 25%, respectively, in both TG strata, with proportionate decreases in the levels of apolipoprotein B. Gemcabene was well tolerated with a frequency of adverse events similar to that of placebo. In conclusion, at the lower doses, gemcabene significantly increased HDL cholesterol and reduced TG serum levels in patients with low HDL cholesterol and TG >/=200 mg/dl. At the higher doses, gemcabene significantly reduced LDL cholesterol levels in all patients with low HDL cholesterol.

Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW, Anonymous00313. · Baylor College of Medicine, 6565 Fannin Avenue, A-601, Houston, TX 77030, USA. · Am J Cardiol. · Pubmed #12860216 No free full text.

Abstract: The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol > or =160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.

Rosenson RS, Bays HE. · Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. · Am J Cardiol. · Pubmed #12667578 No free full text.

This publication has no abstract.

Bays HE, Dujovne CA, McGovern ME, White TE, Kashyap ML, Hutcheson AG, Crouse JR, Anonymous00125. · Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky 40213, USA. · Am J Cardiol. · Pubmed #12633795 No free full text.

Abstract: This study compared the relative efficacy of a once-daily niacin extended-release (ER)/lovastatin fixed-dose combination with standard doses of atorvastatin or simvastatin, with a special emphasis on relative starting doses. Subjects (n = 315) with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol blood levels (defined as LDL cholesterol blood levels > or =160 mg/dl without coronary artery disease, or > or =130 mg/dl if coronary artery disease was present, and HDL cholesterol <45 mg/dl in men and <50 mg/dl in women) were randomized to atorvastatin, simvastatin, or niacin ER/lovastatin for 16 weeks. The primary efficacy variables were the mean percent change in LDL cholesterol and HDL cholesterol levels from baseline. After 8 weeks, the starting dose niacin ER/lovastatin 1,000/40 mg and the 10-mg starting dose atorvastatin both lowered mean LDL cholesterol by 38%. After 12 weeks, niacin ER/lovastatin 1,000/40 mg lowered LDL cholesterol by 42% versus 34% with the 20-mg starting dose of simvastatin (p <0.001). Niacin ER/lovastatin increased HDL cholesterol significantly more than atorvastatin or simvastatin at all compared doses (p <0.001). Niacin ER/lovastatin also provided significant improvements in triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B, and HDL subfractions. A total of 6% of study subjects receiving niacin ER/lovastatin withdrew because of flushing. No significant differences were seen among study groups in discontinuance due to elevated liver enzymes. No drug-induced myopathy was observed. Niacin ER/lovastatin was comparable to atorvastatin 10 mg and more effective than simvastatin 20 mg in reducing LDL cholesterol, was more effective in increasing HDL cholesterol than either atorvastatin or simvastatin, and provided greater global improvements in non-HDL cholesterol, triglycerides, and lipoprotein(a).

Brown WV, Bays HE, Hassman DR, McKenney J, Chitra R, Hutchinson H, Miller E, Anonymous00358. · Emory University School of Medicine, Atlanta, Ga 30322, USA. · Am Heart J. · Pubmed #12486428 No free full text.

Abstract: OBJECTIVE: The primary objective of this trial was to compare the efficacy of rosuvastatin with that of pravastatin and simvastatin for lowering low-density lipoprotein cholesterol (LDL-C) levels. METHODS: In this randomized, double-blind, multicenter trial, lipid levels were measured in 477 patients (baseline LDL-C > or =160 and <250 mg/dL) who received fixed doses of 5 mg of rosuvastatin, 10 mg of rosuvastatin, 20 mg of pravastatin, or 20 mg of simvastatin for 12 weeks. For an additional 40 weeks, individual daily doses were sequentially doubled to a maximum of 80 mg of rosuvastatin, 40 mg of pravastatin, and 80 mg of simvastatin, according to investigator discretion and if National Cholesterol Education Program Adult Treatment Panel II (ATP II) LDL-C goals were not achieved. RESULTS: At 12 weeks, percent LDL-C reductions after both 5-mg and 10-mg rosuvastatin treatment, which were 39.1% and 47.4%, respectively, were significantly different (P <.05) from LDL-C reductions after 20-mg pravastatin (26.5%) and 20-mg simvastatin (34.6%) treatment. After 52 weeks, more rosuvastatin-treated patients remained at their starting dose than did simvastatin or pravastatin patients. After dose titration, 88% and 87.5% of the rosuvastatin 5-mg and 10-mg groups, respectively, achieved their ATP II LDL-C goals, compared with 60% for pravastatin and 72.5% for simvastatin. All study treatments were well tolerated. CONCLUSION: Rosuvastatin reduced LDL-C levels more than pravastatin or simvastatin in patients with hypercholesterolemia in a 52-week dose-titration study.

Gagné C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, Cho M, Musliner TA, Gumbiner B, Anonymous00089. · Chul du Chuq, Ste-Foy, Quebec, Canada. · Am J Cardiol. · Pubmed #12423708 No free full text.

Abstract: Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients with primary hypercholesterolemia was evaluated in a randomized, double-blind, placebo-controlled study. The study group included 769 adults (aged > or =18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for > or =6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of -25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides -14.0%) compared with LDL cholesterol -3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides -2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.

Bays HE, Stein EA, Shah AK, Maccubbin DL, Mitchel YB, Mercuri M. · L-MARC Research Center, Louisville, Kentucky , USA. · Am J Cardiol. · Pubmed #12398959 No free full text.

Abstract: This study examined the effects of simvastatin on C-reactive protein (CRP) and other inflammatory markers in study subjects with significant elevations in triglyceride (TG) blood levels. CRP, vascular cellular adhesion molecule (VCAM), serum amyloid A (SAA), and interleukin 6 (IL-6) were measured in archived plasma samples from 2 multicenter, randomized, double-blind, placebo-controlled studies designed to examine the lipid-altering efficacy of simvastatin in study subjects with elevated TGs. In the first study, 130 study subjects with mixed hyperlipidemia (low-density lipoprotein [LDL] cholesterol > or =130 mg/dl; TGs 300 to 700 mg/dl) received placebo or simvastatin 40 or 80 mg once daily for three 6-week periods in a complete-block crossover design. In the second study, 195 study subjects with hypertriglyceridemia (TGs 300 to 900 mg/dl) received daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. Significant but weak correlations were observed between baseline CRP values and baseline levels of LDL cholesterol and high-density lipoprotein (HDL) cholesterol, but not with TGs. CRP was also correlated with body mass index and fasting levels of glucose and insulin. Treatment with simvastatin 20, 40, and 80 mg led to significant reductions in CRP plasma levels versus placebo (p <0.05). Although CRP change was weakly correlated with changes in LDL cholesterol, TGs, and HDL cholesterol, results of regression analyses showed that only baseline CRP and treatment allocation were significant predictors of CRP response after 6 weeks of study drug administration. Simvastatin had no effect on VCAM, SAA, or IL-6. In summary, simvastatin significantly reduced CRP in patients with mixed hyperlipidemia and hypertriglyceridemia.

Kashyap ML, McGovern ME, Berra K, Guyton JR, Kwiterovich PO, Harper WL, Toth PD, Favrot LK, Kerzner B, Nash SD, Bays HE, Simmons PD. · Veterans Affairs Healthcare System, Long Beach, California 90822, USA. · Am J Cardiol. · Pubmed #11897208 No free full text.

Abstract: Combination therapy is increasingly recommended for patients with multiple lipid disorders, especially those at high risk for coronary events. We investigated the long-term safety and effectiveness of a new drug formulation containing once-daily extended-release niacin and lovastatin. A total of 814 men and women (mean age 59 years) with dyslipidemia were enrolled in a 52-week multicenter, open-label study. We used 4 escalating doses (niacin/lovastatin in milligrams): 500/10 for the first month, 1,000/20 for the second, 1,500/30 for the third, and 2,000/40 for the fourth month through week 52. Dose-dependent effects were observed for all major lipid parameters. At week 16, mean low-density lipoprotein (LDL) cholesterol and triglycerides were reduced by 47% and 41%, respectively; mean high-density lipoprotein (HDL) cholesterol was increased by 30% (all p <0.001). LDL/HDL cholesterol and total/HDL cholesterol ratios were also decreased by 58% and 48%, respectively. These effects persisted through week 52, except for the mean increase in HDL cholesterol, which had increased to 41% at 1 year. Lipoprotein (a) and C-reactive protein also decreased in a dose-related manner (by 25% and 24%, respectively, on 2,000/40 mg; p <0.01 vs baseline). Treatment was generally well tolerated. The most common adverse event was flushing, which caused 10% of patients to withdraw. Other adverse events included gastrointestinal upset, pruritus, rash, and headache. Drug-induced myopathy did not occur in any patient. The incidence of elevated liver enzymes to >3 times the upper limit of normal was 0.5%. Once-daily niacin/lovastatin exhibits substantial effects on multiple lipid risk factors and represents a significant new treatment option in the management of dyslipidemia.

Bays HE, Moore PB, Drehobl MA, Rosenblatt S, Toth PD, Dujovne CA, Knopp RH, Lipka LJ, Lebeaut AP, Yang B, Mellars LE, Cuffie-Jackson C, Veltri EP, Anonymous00103. · Louisville Metabolic and Atherosclerosis Research Center Louisville, Kentucky, USA. · Clin Ther. · Pubmed #11558859 No free full text.

Abstract: BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. Conclusions: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Maccubbin D, Bays HE, Olsson AG, Elinoff V, Elis A, Mitchel Y, Sirah W, Betteridge A, Reyes R, Yu Q, Kuznetsova O, Sisk CM, Pasternak RC, Paolini JF. · Merck Research Laboratories, Rahway, NJ 07065, USA. · Int J Clin Pract. · Pubmed #19166443 No free full text.

Abstract: BACKGROUND: Improving lipids beyond low-density lipoprotein cholesterol (LDL-C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into a fixed-dose tablet. METHODS AND RESULTS: Dyslipidaemic patients were randomised to ERN/LRPT 1 g (n = 800), ERN 1 g (n = 543) or placebo (n = 270) for 4 weeks. Doses were doubled (2 tablets/day; i.e. 2 g for active treatments) for 20 weeks. ERN/LRPT 2 g produced significant changes vs. placebo in LDL-C (-18.4%), high-density lipoprotein cholesterol (HDL-C; 20.0%), LDL-C:HDL-C (-31.2%), non-HDL-C (-19.8%), triglycerides (TG; -25.8%), apolipoprotein (Apo) B (-18.8%), Apo A-I (6.9%), total cholesterol (TC; -8.5%), TC:HDL-C (-23.1%) and lipoprotein(a) (-20.8%) across weeks 12-24. ERN/LRPT produced significantly less flushing than ERN during initiation (week 1) and maintenance (weeks 2-24) for all prespecified flushing end-points (incidence, intensity and discontinuation because of flushing). Except for flushing, ERN/LRPT had a safety/tolerability profile comparable with ERN. CONCLUSION: Extended-release niacin/LRPT 2 g produced significant, durable improvements in multiple lipid/lipoprotein parameters. The improved tolerability of ERN/LRPT supports a simplified 1 g-->2 g dosing regimen of niacin, a therapy proven to reduce cardiovascular risk.

Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitz RA, Ballantyne CM, Ginsberg HN, Anonymous00174. · Radiant Research, 515 North State Street, Suite 2700, Chicago, IL 60610, USA. · Clin Ther. · Pubmed #17825687 No free full text.

Abstract: BACKGROUND: Patients with elevated serum triglyceride (TG) levels often have elevations in non-high-density lipoprotein cholesterol (non-HDL-C) levels as well. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) has identified non-HDL-C as a secondary therapeutic target in these patients, but treatment goals may not be reached with statin monotherapy alone. OBJECTIVE: This study evaluated the effects on non-HDL-C and other variables of adding prescription omega-3-acid ethyl esters (P-OM3; Lovaza, formerly Omacor [Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey]) to stable statin therapy in patients with persistent hypertriglyceridemia. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adults who had received > or = 8 weeks of stable statin therapy and had mean fasting TG levels > or = 200 and < 500 mg/dL and mean low-density lipoprotein cholesterol levels < or = 10% above their NCEP ATP III goal. The study regimen consisted of an initial 8 weeks of open-label simvastatin 40 mg/d and dietary counseling, followed by 8 weeks of randomized treatment with double-blind P-OM3 4 g/d plus simvastatin 40 mg/d or placebo plus simvastatin 40 mg/d. The main outcome measure was the percent change in non-HDL-C from baseline to the end of treatment. RESULTS: The evaluable population included 254 patients, of whom 57.5% (146) were male and 95.7% (243) were white. The mean (SD) age of the population was 59.8 (10.4) years, and the mean weight was 92.0 (19.6) kg. At the end of treatment, the median percent change in non-HDL-C was significantly greater with P-OM3 plus simvastatin compared with placebo plus simvastatin (-9.0% vs -2.2%, respectively; P < 0.001). P-OM3 plus simvastatin was associated with significant reductions in TG (29.5% vs 6.3%) and very-low-density lipoprotein cholesterol (27.5% vs 7.2%), a significant increase in high-density lipoprotein cholesterol (HDL-C) (3.4% vs -1.2%), and a significant reduction in the total cholesterol:HDL-C ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo). Adverse events (AEs) reported by > or= 1% of patients in the P-OM3 group that occurred with a higher frequency than in the group that received simvastatin alone were nasopharyngitis (4 [3.3%]), upper respiratory tract infection (4 [3.3%]), diarrhea (3 [2.5%]), and dyspepsia (3 [2.5%]). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treatment related. CONCLUSION: In these adult, mainly white patients with persistent hypertriglyceridemia, P-OM3 plus simvastatin and dietary counseling improved non-HDL-C and other lipid and lipoprotein parameters to a greater extent than simvastatin alone.

Davidson MH, Bays HE, Stein E, Maki KC, Shalwitz RA, Doyle R, Anonymous00221. · Department of Cardiology, Rush University Medical College, 60610, USA. · Clin Cardiol. · Pubmed #16796078 No free full text.

Abstract: BACKGROUND: The metabolic syndrome (MS) is often accompanied by atherogenic dyslipidemia, which is characterized by elevated triglycerides (TG), reduced high-density lipoprotein cholesterol (HDL-C), and elevated numbers of small, dense low-density lipoprotein (LDL) particles. HYPOTHESIS: It was hypothesized that a threshold exists for the circulating TG level needed to produce changes in LDL subclass distribution. METHODS: Hypertriglyceridemic (TG > or =300 and <1000 mg/dl) subjects with the MS were randomly assigned to placebo (n=50) or 130 mg/day of micronized fenofibrate-coated microgranules (n=96) for 8 weeks. RESULTS: In the overall analysis, fenofibrate treatment resulted in significant (p < 0.05) changes versus placebo in TG (-36.6%), non-HDL-C (-7.5%), very low-density lipoprotein-C (-32.7%), LDL-C (15.0%), HDL-C (14.0%), remnant lipoprotein-C (-35.1%), apolipoprotein B (-6.0%), apolipoprotein A-I (5.3%), and apolipoprotein C-III--29.7%). Changes in LDL particle diameter in the fenofibrate group were significantly inversely associated with the TG level achieved on treatment (p = 0.019). When individually matched for percent change in TG, subjects with on-treatment TG < 200 mg/dl, in contrast to those with on-treatment values > or =200 mg/dl, had significantly different median responses (p < 0.05) in LDL size (0.79 vs. -0.06 nm) and cholesterol carried by small (-35 vs. 21 mg/dl) and large (31 vs. 11 mg/dl) particles. CONCLUSION: These data support the view that a threshold exists below which the TG level must be lowered to produce shifts in LDL particle size.

McKenney JM, Farnier M, Lo KW, Bays HE, Perevozkaya I, Carlson G, Davies MJ, Mitchel YB, Gumbiner B. · National Clinical Research Inc., Richmond, Virginia 23294, USA. · J Am Coll Cardiol. · Pubmed #16630994 No free full text.

Abstract: OBJECTIVES: This study sought to determine the long-term safety and efficacy of co-administered fenofibrate (FENO) and ezetimibe (EZE) in patients with mixed hyperlipidemia. BACKGROUND: Both EZE and FENO offer complementary benefits to the lipid profile of patients with mixed hyperlipidemia. METHODS: After completing the 12-week randomized, double-blind base study that compared EZE 10 mg, FENO 160 mg, FENO 160 mg plus EZE 10 mg, and placebo in patients with mixed hyperlipidemia, patients continued into a double-blind, 48-week extension phase. Those patients in the FENO plus EZE and FENO groups continued on their respective base study treatment, and patients in the EZE and placebo groups were switched to FENO plus EZE and FENO, respectively. RESULTS: Of the 587 patients who completed the base study, 576 continued into the extension study (n = 340 in FENO plus EZE and n = 236 in FENO). The FENO plus EZE produced significantly greater reductions in low-density lipoprotein-cholesterol compared with FENO (-22% vs. -9%, respectively; p < 0.001). There were also significantly greater improvements in triglycerides, high-density lipoprotein cholesterol (HDL-C), total cholesterol, non-HDL-C, and apolipoprotein B with FENO plus EZE compared with FENO. Changes in apolipoprotein A-I and high-sensitivity C-reactive protein were similar between groups. Overall, FENO plus EZE was well tolerated during the extension study. The proportion of patients with consecutive elevations of alanine aminotransferase/aspartate aminotransferase > or =3 times upper limit of normal were similar between the FENO plus EZE (1.2%) and FENO (1.7%) groups. No cases of creatine phosphokinase elevations > or =10 times upper limit of normal or myopathy were observed in either group. CONCLUSIONS: Long-term, 48-week co-administration of FENO plus EZE was well tolerated and more efficacious than FENO in patients with mixed hyperlipidemia.

Bays HE, Davidson M, Jones MR, Abby SL. · Louisville Metabolic and Atherosclerosis Research Center Incorporated, Louisville, Kentucky, USA. · Am J Cardiol. · Pubmed #16616026 No free full text.

Abstract: Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with an increased risk of atherosclerotic coronary heart disease (CHD). The addition of the bile acid sequestrants, such as colesevelam hydrochloride (HCl), to statins further reduces low-density lipoprotein (LDL) cholesterol levels. However, the effects of approved cholesterol-lowering bile acid sequestrants on hs-CRP have not previously been reported. Three randomized, double-blind, placebo-controlled, parallel, 6-week clinical trials of similar design investigated the efficacy of adding colesevelam HCl to stable simvastatin, atorvastatin, or pravastatin treatment in 204 patients with primary hypercholesterolemia. The primary end point was the mean percent change in the LDL cholesterol levels. Secondary end points included the effects on other lipid parameters and hs-CRP levels. A pooled analysis showed that adding colesevelam HCl to statin therapy significantly lowered LDL cholesterol levels (21 mg/dl or 16% mean reduction from baseline, p = 0.0013, and 11 mg/dl or 9% mean reduction compared with placebo, p = 0.0003). Four times as many patients receiving colesevelam HCl plus a statin achieved a LDL cholesterol target of <100 mg/dl compared with patients receiving a statin plus placebo (39% vs 10%, respectively, p <0.0001). The incidence of mild gastrointestinal adverse effects was slightly higher in the colesevelam HCl plus statin group than in the placebo plus statin group. Finally, the differences in the change in hs-CRP levels with colesevelam HCl plus statin therapy were significant compared with the changes with placebo plus statin (median change -23%, p = 0.0069). In conclusion, this is the first report suggesting that an approved cholesterol-lowering bile acid sequestrant, specifically colesevelam HCl, decreases hs-CRP levels when added to statin therapy.

Bays HE, McGovern ME. · Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY 40213, USA. · Prev Cardiol. · Pubmed #14605511 No free full text.

Abstract: Standard lipoprotein measurements may not adequately reflect the increased atherogenic risk found in patients with abnormalities in lipoprotein particle size and subfraction distribution such as disproportionate amounts of small, dense low-density lipoprotein particles, small high-density lipoprotein particles, or large very-low-density lipoprotein particles. Measurement or anticipation of patients most susceptible to lipoprotein subfraction abnormalities may influence therapeutic choices for the optimal management of dyslipidemia. Previously, the ADvicor Vs. Other Cholesterol-modulating Agents Trial Evaluation demonstrated that niacin extended release/lovastatin provided greater global improvement in lipid parameters such as low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, lipoprotein (a), apolipoprotein B, and apolipoprotein A-I blood levels compared with atorvastatin and simvastatin monotherapies. In this report, niacin extended release/lovastatin was also more effective than atorvastatin and simvastatin monotherapies in reducing small, dense low-density lipoprotein particles and improving low-density lipoprotein phenotype pattern at relative starting doses, and was more effective in increasing the proportion of high-density lipoprotein in the potentially cardioprotective 2b subclass at all doses.