Hypercholesterolemia: 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, Goldberg RB. · Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY 40213, USA. · Am J Ther. · Pubmed #18090882 No free full text.

Abstract: Over 30 years ago, bile acid sequestrants (BAS) were among the first drugs approved to lower cholesterol levels. For over 10 years, BAS have been known to reduce glucose levels. Most importantly, BAS have been shown in outcomes studies to reduce cardiovascular events. Because they are true nonsystemic agents, BAS are generally safe and not associated with serious systemic adverse experiences. Despite their proven atherosclerotic coronary heart disease (CHD) benefits, and irrespective of their favorable effects on major CHD risk factors (hypercholesterolemia and hyperglycemia), BAS are not among the more frequently used drug treatments for hypercholesterolemia, even in patients with type 2 diabetes mellitus. Recent "high-profile" findings of investigational and approved lipid-altering and antidiabetes drug therapies illustrate that drug-induced improvements in lipid and glucose levels do not always reduce CHD risk. It may therefore be time to reconsider the clinical use of BAS. This review focuses on the recent lessons learned, and the potential mechanisms involved in efficacy and safety issues raised with torcetrapib and rosiglitazone with analogies related to the use of BAS therapy. Known and proposed mechanisms of how BAS may improve lipid and glucose levels are discussed, which are effects that may help explain how BAS reduce CHD risk. Improved tolerability of newer BAS (eg, colesevelam hydrochloride) and a "new" appreciation of the historic benefits of these "old" therapeutic agents may lead to an increased treatment role for these drugs, particularly in hypercholesterolemic patients with type 2 diabetes mellitus.

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.

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.

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.

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, 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.

Bays HE, Maccubbin D, Meehan AG, Kuznetsova O, Mitchel YB, Paolini JF. · Louisville Metabolic and Atherosclerosis Research Center Inc., Louisville, Kentucky, USA. · Clin Ther. · Pubmed #19243712 No free full text.

Abstract: BACKGROUND: Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D(2) receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear. OBJECTIVE: The aim of this analysis was to examine the blood pressure effects of ERN and ERN/LRPT. Methods: This was a post hoc analysis of a 24-week, worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel, Phase III, previously published study of dyslipidemic patients, which examined the effect of ERN and ERN/LRPT on systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: A total of 1613 men and women, aged 21 to 85 years, with primary hypercholesterolemia or mixed dyslipidemia (66% on statins), were included in the original analysis. ERN alone, or in combination with LRPT, was associated with significant reductions in SBP and DBP at 24 weeks from baseline. The placebo-adjusted mean changes from baseline at week 24 in SBP were -2.2 and -3.1 mm Hg for the ERN and ERN/LRPT groups, respectively (P < 0.05 and P < 0.001). Similar changes in DBP were observed; -2.7 and -2.5 mm Hg in the ERN and ERN/ LRPT groups, respectively (both, P < 0.001). CONCLUSION: This post hoc analysis of a 24-week trial found that ERN alone, or in combination with LRPT, was associated with significant placebo-adjusted reductions from baseline in blood pressure in these hyperlipidemic hypertensive or normotensive subjects.

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.

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.