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Changes in LDL particle concentrations after treatment with the cholesteryl ester transfer protein inhibitor anacetrapib alone or in combination with atorvastatin.
Krauss, RM, Pinto, CA, Liu, Y, Johnson-Levonas, AO, Dansky, HM
Journal of clinical lipidology. 2015;(1):93-102
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Abstract
OBJECTIVES Our aim was to assess the effects of the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib and atorvastatin, both as monotherapy and in combination, on particle concentrations of low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins in dyslipidemic patients. BACKGROUND Although increases in high-density lipoproteins with CETP inhibition are well-documented, effects on atherogenic lipoprotein particle subclasses in dyslipidemic patients have not been extensively characterized. METHODS Ion mobility was performed on stored plasma samples collected from patients before and after treatment with anacetrapib alone (150 and 300 mg/d) or in combination with atorvastatin (20 mg/d) in a previously conducted 8-week phase IIb study. RESULTS Anacetrapib produced significant placebo-adjusted reductions of total LDL particles and all subfractions except for increases in very small LDL 4a and 4b. Atorvastatin reduced all LDL subfractions except LDL 4b. Results were generally additive for anacetrapib + atorvastatin. For patients treated with anacetrapib, the placebo-adjusted reduction in LDL 3a was attenuated and there was an increase in LDL 3b and 4a for those with low vs high triglyceride (TG) levels. For the atorvastatin alone vs placebo treatment comparison, there were small reductions in LDL 3a, 3b, and 4a for those with low vs high TG levels. CONCLUSIONS Anacetrapib and atorvastatin produced similar reductions from baseline in total LDL particles, but did not have comparable effects on all LDL particle subfractions, and neither drug reduced the smallest LDL 4b particles. The clinical significance of these changes and the differential effects on very small LDL 4a in patients with higher vs lower TG remain to be determined (clinicaltrials.gov, NCT00325455).
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Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies.
Robinson, JG, Colhoun, HM, Bays, HE, Jones, PH, Du, Y, Hanotin, C, Donahue, S
Clinical cardiology. 2014;(10):597-604
Abstract
The phase 3 ODYSSEY OPTIONS studies (OPTIONS I, NCT01730040; OPTIONS II, NCT01730053) are multicenter, multinational, randomized, double-blind, active-comparator, 24-week studies evaluating the efficacy and safety of alirocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, as add-on therapy in ∼ 650 high-cardiovascular (CV)-risk patients whose low-density lipoprotein cholesterol (LDL-C) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV-risk category, high and very high CV risk, respectively, with atorvastatin (20-40 mg/d) or rosuvastatin (10-20 mg/d). Patients are randomized to receive alirocumab 75 mg via a single, subcutaneous, 1-mL injection by prefilled pen every 2 weeks (Q2W) as add-on therapy to atorvastatin (20-40 mg) or rosuvastatin (10-20 mg); or to receive ezetimibe 10 mg/d as add-on therapy to statin; or to receive statin up-titration; or to switch from atorvastatin to rosuvastatin (OPTIONS I only). At week 12, based on week 8 LDL-C levels, the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL-C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk, respectively. The primary efficacy endpoint in both studies is difference in percent change in calculated LDL-C from baseline to week 24 in the alirocumab vs control arms. The studies may provide guidance to inform clinical decision-making when patients with CV risk require additional lipid-lowering therapy to further reduce LDL-C levels. The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL-C reduction required to achieve the desired LDL-C level.
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Differences between rosuvastatin and atorvastatin in lipid-lowering action and effect on glucose metabolism in Japanese hypercholesterolemic patients with concurrent diabetes. Lipid-lowering with highly potent statins in hyperlipidemia with type 2 diabetes patients (LISTEN) study –.
Ogawa, H, Matsui, K, Saito, Y, Sugiyama, S, Jinnouchi, H, Sugawara, M, Masuda, I, Mori, H, Waki, M, Yoshiyama, M, et al
Circulation journal : official journal of the Japanese Circulation Society. 2014;(10):2512-5
Abstract
BACKGROUND Little is known about the differences between standard-dose statins effects on glucose level and lipids in Japanese patients with diabetes mellitus (DM). METHODS AND RESULTS The 1,049 patients were randomly assigned to either the rosuvastatin group or atorvastatin group. There were no significant differences between the 2 groups in the effect on non-high-density lipoprotein cholesterol (non-HDL-C) and HbA1c at 12 months. However, physicians tended to switch to more intensive therapy for DM in the atorvastatin group. CONCLUSIONS Rosuvastatin 5 mg and atorvastatin 10 mg have a similar lowering effect on non-HDL-C, but might be different in terms of adverse effect on glucose levels.
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Comparison of the efficacy of rosuvastatin versus atorvastatin in preventing contrast induced nephropathy in patient with chronic kidney disease undergoing percutaneous coronary intervention.
Liu, Y, Liu, YH, Tan, N, Chen, JY, Zhou, YL, Li, LW, Duan, CY, Chen, PY, Luo, JF, Li, HL, et al
PloS one. 2014;(10):e111124
Abstract
OBJECTIVES We prospectively compared the preventive effects of rosuvastatin and atorvastatin on contrast-induced nephropathy (CIN) in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). METHODS We enrolled 1078 consecutive patients with CKD undergoing elective PCI. Patients in Group 1 (n = 273) received rosuvastatin (10 mg), and those in group 2 (n = 805) received atorvastatin (20 mg). The primary end-point was the development of CIN, defined as an absolute increase in serum creatinine ≥0.5 mg/dL, or an increase ≥25% from baseline within 48-72 h after contrast medium exposure. RESULTS CIN was observed in 58 (5.4%) patients. The incidence of CIN was similar in patients pretreated with either rosuvastatin or atorvastatin (5.9% vs. 5.2%, p = 0.684). The same results were also observed when using other definitions of CIN. Clinical and procedural characteristics did not show significant differences between the two groups (p>0.05). Additionally, there were no significant inter-group differences with respect to in-hospital mortality rates (0.4% vs. 1.5%, p = 0.141), or other in-hospital complications. Multivariate logistic regression analysis revealed that rosuvastatin and atorvastatin demonstrated similar efficacies for preventing CIN, after adjusting for potential confounding risk factors (odds ratio = 1.17, 95% confidence interval, 0.62-2.20, p = 0.623). A Kaplan-Meier survival analysis showed that patients taking either rosuvastatin or atorvastatin had similar incidences of all-cause mortality (9.4% vs. 7.1%, respectively; p = 0.290) and major adverse cardiovascular events (29.32% vs. 23.14%, respectively; p = 0.135) during follow-up. CONCLUSIONS Rosuvastatin and atorvastatin have similar efficacies for preventing CIN in patients with CKD undergoing PCI.
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Paradoxical negative HDL cholesterol response to atorvastatin and simvastatin treatment in Chinese type 2 diabetic patients.
Chang, YH, Lin, KC, Chang, DM, Hsieh, CH, Lee, YJ
The review of diabetic studies : RDS. 2013;(2-3):213-22
Abstract
OBJECTIVES There is extensive but controversial evidence on the diverse effects of statins on the level of high-density lipoprotein cholesterol (HDL-C). Some of these effects may limit the benefits of statins in terms of cardiovascular risk reduction. To identify the conditions for beneficial effects, this study investigated the response to atorvastatin and simvastatin treatment in type 2 diabetic patients with elevated low-density lipoprotein cholesterol (LDL-C). METHODS 2,872 subjects with type 2 diabetes from a disease management program were investigated. Patients with LDL-C ≥130 mg/dl or total cholesterol ≥200 mg/dl were put onto statin therapy by the National Health Insurance system in Taiwan. RESULTS 1,080 patients who completed 1 year of statin treatment were analyzed. There were significant reductions in LDL-C in both the atorvastatin (37.1%) and simvastatin (34.3%) group after one year of treatment compared with baseline levels. Unexpectedly, the majority of diabetic patients who received atorvastatin or simvastatin did not show an increase in HDL-C levels. 59.8% of patients had a significant HDL-C reduction (ΔHDL-C ≤ -3%) after atorvastatin treatment. Multivariate logistic regression analysis showed that the following patients were at higher risk of HDL-C reduction after 12 months: (i) patients in whom statin therapy was initiated aged <65 years and who had a BMI ≥24 kg/m(2), (ii) male patients with a baseline HDL-C >40 mg/dl, and (iii) female patients with a baseline HDL-C >50 mg/dl. However, diabetic patients with severe atherogenic dyslipidemia (LDL-C ≥130, TG ≥204, and HDL-C ≤34 mg/dl) obtained more benefits in terms of HDL-C change after statin therapy. CONCLUSIONS Diabetic patients, except those with severe atherogenic dyslipidemia, are prone to a decrease in serum HDL-C level after statin treatment, particularly after atorvastatin treatment.
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Association between cholesterol synthesis/absorption markers and effects of cholesterol lowering by atorvastatin among patients with high risk of coronary heart disease.
Qi, Y, Liu, J, Ma, C, Wang, W, Liu, X, Wang, M, Lv, Q, Sun, J, Liu, J, Li, Y, et al
Journal of lipid research. 2013;(11):3189-97
Abstract
No indices are currently available to facilitate clinicians to identify patients who need either statin monotherapy or statin-ezetimibe combined treatment. We aimed to investigate whether cholesterol synthesis and absorption markers can predict the cholesterol-lowering response to statin. Total 306 statin-naïve patients with high risk of coronary heart disease (CHD) were treated with atorvastatin 20 mg/day for 1 month. Cholesterol synthesis and absorption markers and LDL cholesterol (LDL-C) levels were measured before and after treatment. Atorvastatin decreased LDL-C by 36.8% (range: decrease of 74.5% to increase of 31.9%). Baseline cholesterol synthesis marker lathosterol and cholesterol absorption marker campesterol codetermined the effect of atorvastatin treatment. The effect of cholesterol lowering by atorvastatin was significantly associated with baseline lathosterol levels but modified bidirectionally by baseline campesterol levels. In patients with the highest baseline campesterol levels, atorvastatin treatment decreased cholesterol absorption by 46.1%, which enhanced the effect of LDL-C lowering. Atorvastatin treatment increased cholesterol absorption by 52.3% in those with the lowest baseline campesterol levels, which attenuated the effect of LDL-C reduction. Especially those with the highest lathosterol but the lowest campesterol levels at baseline had significantly less LDL-C reduction than those with the same baseline lathosterol levels but the highest campesterol levels (27.3% versus 42.4%, P = 0.002). These results suggest that combined patterns of cholesterol synthesis/absorption markers, rather than each single marker, are potential predictors of the LDL-C-lowering effects of atorvastatin in high-risk CHD patients.
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Influence of atorvastatin on serum amyloid A-low density lipoprotein complex in hypercholesterolemic patients.
Kotani, K, Yamada, T, Miyamoto, M, Ishibashi, S, Taniguchi, N, Gugliucci, A
Pharmacological reports : PR. 2012;(1):212-6
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Abstract
The complex of serum amyloid A(SAA) and low-density lipoprotein (LDL), SAA-LDL, is considered a new and unique marker of oxidatively-modified LDL particles, which is associated with atherosclerotic conditions. This study investigated the influence of atorvastatin treatment on circulating SAA-LDL levels among asymptomatic hypercholesterolemic patients. A total of 26 patients (mean age 63 years) received 10 mg/daily atorvastatin during a 12-week treatment period. The levels of LDL cholesterol and SAA-LDL, but not high-sensitivity C-reactive protein and SAA, were significantly reduced after the treatment. Stepwise adjusted regression analyses revealed that changes of SAA-LDL were significantly and positively correlated with those of SAA, while absolute changes were small, which warrants further investigation. The results suggest that atorvastatin may beneficially reduce SAA-LDL, and SAA-LDL may be a sensitive measure for monitoring the efficacy and antioxidant functions of atorvastatin.
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Influence of achieved low-density lipoprotein cholesterol level with atorvastatin therapy on stabilization of coronary plaques: sub-analysis of the TWINS study.
Okada, K, Ueda, Y, Takayama, T, Honye, J, Komatsu, S, Yamaguchi, O, Li, Y, Yajima, J, Takazawa, K, Nanto, S, et al
Circulation journal : official journal of the Japanese Circulation Society. 2012;(5):1197-202
Abstract
BACKGROUND Previously the stabilization of coronary plaque with atorvastatin was demonstrated in the TWINS (evaluaTion With simultaneous angIoscopy and iNtravascular ultraSound) study. The influence of the low-density lipoprotein cholesterol (LDL-C) level on plaque stabilization was analyzed. METHODS AND RESULTS Patients (n=29) with hypercholesterolemia and coronary artery disease (CAD) were analyzed. They received atorvastatin (10-20mg/day) for 80 weeks and were divided into low (< 91 mg/dl) and high (≥ 91 mg/dl) LDL-C groups based on their 80-week LDL-C level. Angioscopy was performed before and after treatment. Yellow coronary plaques were classified into six grades (grades 0 to 5) and mean grade was determined for each patient. The LDL-C levels at week 28 and 80 were reduced in both low LDL-C groups (n=14, 140.3 to 77.9 and 75.9 mg/dl; P<0.001 both groups) and high LDL-C groups (n=15, 151.7 to 93.0 and 99.1mg/dl; P<0.001 both groups). Significant improvement in the mean grade was shown in the low LDL-C groups (1.44 to 1.00 and 1.05; P=0.003 both groups) at week 28 and 80 vs. no significant change in high LDL-C groups (1.43 to 1.23 and 1.28; P=0.032 and P=0.169 respectively). CONCLUSIONS Adequate reduction of LDL-C is important for the stabilization of coronary plaques.
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Study design, rationale, and baseline characteristics: evaluation of fenofibric acid on carotid intima-media thickness in patients with type IIb dyslipidemia with residual risk in addition to atorvastatin therapy (FIRST) trial.
Davidson, M, Rosenson, RS, Maki, KC, Nicholls, SJ, Ballantyne, CM, Setze, C, Carlson, DM, Stolzenbach, J
Cardiovascular drugs and therapy. 2012;(4):349-58
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Abstract
PURPOSE Elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels contribute to cardiovascular disease risk and can be effectively treated with fenofibric acid. A trial is under way to evaluate the effect of once-daily fenofibric acid or placebo on carotid intima-media thickness (CIMT) progression in patients with controlled low-density lipoprotein cholesterol (LDL-C) levels achieved through atorvastatin treatment, but with high TG and low HDL-C levels. METHODS In this multicenter, double-blind study, 682 patients were randomized to once-daily delayed-release capsules of choline fenofibrate 135 mg (fenofibric acid [Trilipix(®); Abbott, North Chicago, IL]) or placebo plus atorvastatin treatment after a 2- to 10-week diet and atorvastatin run-in period. Key inclusion criteria included age ≥45 years; posterior-wall common CIMT ≥0.7 mm on at least one side at baseline; fasting results of TG ≥150 mg/dL, and HDL-C ≤45 mg/dL for men or HDL-C ≤55 mg/dL for women at screening while receiving atorvastatin; controlled LDL-C; and known coronary heart disease (CHD) or a CHD risk equivalent. The primary efficacy variable is the rate of change from baseline through week 104 in the mean posterior-wall intima-media thickness of the common carotid arteries (composite value of left and right sides). CONCLUSIONS This trial is the first to examine the effect of fenofibric acid on CIMT and the first CIMT trial to select patients with controlled LDL-C and elevated TG and low HDL-C as inclusion criteria. Also, this trial will prospectively evaluate the effect of treatment on LDL particles and address shortcomings of previous CIMT trials.
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Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy.
McKenney, JM, Koren, MJ, Kereiakes, DJ, Hanotin, C, Ferrand, AC, Stein, EA
Journal of the American College of Cardiology. 2012;(25):2344-53
Abstract
OBJECTIVES The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 (SAR236553) dosing regimens versus placebo at week 12 in patients with LDL-C ≥100 mg/dl on stable atorvastatin therapy. Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of <100 mg/dl (2.59 mmol/l) and <70 mg/dl (1.81 mmol/l). BACKGROUND Serum proprotein convertase subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein receptors, increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9. METHODS This double-blind, parallel-group, placebo-controlled trial randomized 183 patients with LDL-C ≥100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for ≥6 weeks to: subcutaneous placebo every 2 weeks (Q2W); SAR236553 50, 100, or 150 mg Q2W; or SAR236553 200 or 300 mg every 4 weeks (Q4W), alternating with placebo for a total treatment period of 12 weeks. RESULTS SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration: 40%, 64%, and 72% with 50, 100, and 150 mg Q2W, respectively, and 43% and 48% with 200 and 300 mg Q4W. LDL-C reduction with placebo at week 12 was 5%. SAR236553 also substantially reduced non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). SAR236553 was generally well tolerated. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis. CONCLUSIONS When added to atorvastatin, PCSK9 inhibition with SAR236553 further reduces LDL-C by 40% to 72%. These additional reductions are both dose- and dosing frequency-dependent. (Efficacy and Safety Evaluation of SAR236553 [REGN727] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy; NCT01288443).