Evacetrapib

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Stephen J Nicholls - One of the best experts on this subject based on the ideXlab platform.

Jeffrey G. Suico - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetics, pharmacodynamics and drug interactions of Evacetrapib with select statins in healthy Chinese subjects
    International Journal of Pharmacokinetics, 2018
    Co-Authors: Yan Liang, Ellen A Cannady, Ming Dauh Wang, David S. Small, Yimin Cui, Ping Xin, Jian Jun Jin, Xia Zhao, Jeffrey G. Suico
    Abstract:

    Aim: Evaluate steady-state pharmacokinetics and potential interactions between select statins and Evacetrapib. Patients & methods: This open-label, two-part study included 62 healthy native Chinese...

  • Clinical Study A Multidose Study to Examine the Effect of Food on Evacetrapib Exposure at Steady State
    2016
    Co-Authors: David S. Small, Wei Zhang, Jane Royalty, Jeffrey G. Suico
    Abstract:

    Purpose: To determine the effect of a high-fat meal on Evacetrapib exposure at steady state in healthy participants.Methods: This was a randomized, 2-period, 2-sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received Evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day. Plasma samples collected through 24 hours were analyzed for Evacetrapib concentrations and pharmacoki-netic parameter estimates including area under the concentration–time curve during a dosing interval (AUCt), maximum observed concentration (Cmax), and time of Cmax (tmax) were calculated. Pharmacodynamic parameters, including cholesteryl ester transfer protein (CETP) activity, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, were also assessed. Results: A total of 34 males and 6 females, mean age 41.5 years and mean body mass index 26.6 kg/m2, were enrolled. Statistical analysis showed AUCt was 44 % higher (90 % con-fidence interval [CI]: 29%-62%) and Cmax was 51 % higher (90 % CI: 28%-79%) in the fed state than in the fasted state, indicating an effect of food. Consistent with higher Evacetrapib exposure, changes in HDL-C, LDL-C, and CETP activity appeared to be greater in the fed state than in the fasted state. There were no notable changes in total cholesterol or triglycerides following adminis-tration in the fed and fasted states. The 130-mg doses of Evacetrapib were well tolerated with and without food. Conclusion: A high-fat meal increased Evacetrapib mean exposure at steady state by 44 % in healthy participants

  • Impact of Increased Gastric pH on the Pharmacokinetics of Evacetrapib in Healthy Subjects
    Pharmacotherapy, 2016
    Co-Authors: David S. Small, Ellen A Cannady, Ming Dauh Wang, Jane Royalty, Christine Hale, Delyn Downs, Jeffrey G. Suico
    Abstract:

    STUDY OBJECTIVE To examine the effect of increased gastric pH on exposure to Evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease. DESIGN Open-label, two-treatment, two-period, fixed-sequence crossover study. SETTING Clinical research unit. SUBJECTS Thirty-four healthy subjects. INTERVENTION In period 1, subjects received a single oral dose of Evacetrapib 130 mg on day 1, followed by 7 days of analysis for Evacetrapib plasma concentrations. In period 2, subjects received a once/day oral dose of omeprazole 40 mg on days 8-20, with a single oral dose of Evacetrapib 130 mg administered 2 hours after the omeprazole dose on day 14, followed by 7 days of pharmacokinetic sampling. Subjects were discharged on day 21 and returned for a follow-up visit at least 14 days after the last dose of Evacetrapib in period 2. Gastric pH was measured before subjects received each Evacetrapib dose. MEASUREMENTS AND MAIN RESULTS Noncompartmental pharmacokinetic parameters were estimated from plasma concentration-time data and compared between periods 1 and 2. Geometric mean ratios with 90% confidence intervals (CIs) were reported. Safety and tolerability were also assessed. The mean age of the 34 subjects was 40.9 years; mean body mass index was 27.2 kg/m(2) . Omeprazole treatment increased mean gastric pH across all subjects by 2.80 and increased Evacetrapib area under the concentration versus time curve from time zero extrapolated to infinity (AUC0-∞ ) and maximum observed drug concentration (Cmax ) by 15% (90% CI -2 to 35) and 30% (90% CI 3-63), respectively. For both parameters, the upper bound of the 90% CI of the ratio of geometric least-squares means exceeded 1.25 but was less than 2, indicating a weak interaction. To assess the effect of gastric pH on subjects who responded best to omeprazole treatment, the analyses were repeated to include only the 22 subjects whose predose gastric pH was 3.0 or lower in period 1 and 4.0 or higher in period 2. In this subpopulation, mean gastric pH increased by 4.15 during omeprazole treatment, and Evacetrapib AUC0-∞ and Cmax increased by 22% (90% CI 4-42) and 35% (90% CI 1-80), respectively. Despite the small mathematical differences between the analyses, the overall effect in both was a minimal increase in Evacetrapib exposure. Of 35 adverse events reported during the study, 4 (11.4%) were considered to be treatment-related, and most were mild in severity. CONCLUSION The impact of increased gastric pH on Evacetrapib pharmacokinetics would not be expected to be clinically relevant. The magnitude of change in pH did not affect the degree of the interaction.

  • Effect of hepatic or renal impairment on the pharmacokinetics of Evacetrapib
    European Journal of Clinical Pharmacology, 2016
    Co-Authors: David S. Small, Ellen A Cannady, Wei Zhang, Jane Royalty, Demetrio Ortega, Delyn Downs, Jeffrey G. Suico
    Abstract:

    Purpose The aim of this study is to investigate the effect of hepatic or renal impairment on the pharmacokinetics of a single 130-mg Evacetrapib dose. Methods Two open-label, parallel-design studies in males and females with normal hepatic function or Child-Pugh mild, moderate, or severe hepatic impairment, or with normal renal function or severe renal impairment. Non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time data. Evacetrapib safety and tolerability were assessed. Results Pharmacokinetic parameter estimates were comparable between controls and mildly hepatically impaired subjects. Geometric mean area under the concentration-time curve (AUC) was greater, half-life (t_1/2) was longer, and maximum concentration (C_max) was lower in subjects with moderate and severe hepatic impairment than in controls. Apparent clearance (CL/F) did not differ between controls and those with mild hepatic impairment, but CL/F decreased for moderate and severe impairment. Spearman correlation coefficient showed no relationship between CL/F and Child-Pugh score. In the renal study, AUC and t_1/2 were similar between groups, while C_max was 15 % lower in subjects with severe impairment. CL/F in severely renally impaired subjects differed by

  • Effect of hepatic or renal impairment on the pharmacokinetics of Evacetrapib.
    European journal of clinical pharmacology, 2016
    Co-Authors: David S. Small, Ellen A Cannady, Wei Zhang, Jane Royalty, Demetrio Ortega, Delyn Downs, Jeffrey G. Suico
    Abstract:

    Purpose The aim of this study is to investigate the effect of hepatic or renal impairment on the pharmacokinetics of a single 130-mg Evacetrapib dose.

Kathryn A Krueger - One of the best experts on this subject based on the ideXlab platform.

  • Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients
    Journal of clinical lipidology, 2015
    Co-Authors: Stephen J Nicholls, Ming Dauh Wang, Kathryn A Krueger, Giacomo Ruotolo, H. Bryan Brewer, Liping Liu, Mark B. Willey, Mark A. Deeg, Steven E. Nissen
    Abstract:

    Background Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk. Objectives To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor Evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)–containing lipoproteins in mildly hypercholesterolemic patients. Methods VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with Evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials.gov Identifier: NCT01105975). Results Evacetrapib monotherapy resulted in significant placebo-adjusted dose-dependent decreases from baseline in Lp(a) (up to −40% with Evacetrapib 500 mg), total LDL particle (LDL-P) (up to −54%), and small LDL particle (sLDL) (up to −95%) concentrations. Compared to statin alone, coadministration of Evacetrapib and statins also resulted in significant reduction from baseline in Lp(a) (−31%), LDL-P (−22%), and sLDL (−60%) concentrations. The percentage of patients with concentrations above optimal concentrations for LDL-P (>1000 nmol/L) and sLDL (>600 nmol/L) decreased from 88% and 55% at baseline, respectively, to 20% and 12% at week 12, for patients treated with Evacetrapib plus statins. Evacetrapib, alone or with statins, significantly increased LDL-P size. Conclusions Evacetrapib, as monotherapy or with statins, significantly reduces the concentrations of atherogenic apoB-containing lipoproteins, including Lp(a), LDL-P, and sLDL.

  • cyp mediated drug drug interactions with Evacetrapib an investigational cetp inhibitor in vitro prediction and clinical outcome
    British Journal of Clinical Pharmacology, 2015
    Co-Authors: Ellen A Cannady, Ming Dauh Wang, Stuart Friedrich, Jessica Rehmel, Jeffrey G. Suico, Stephen J Nicholls, Kathryn A Krueger
    Abstract:

    Aims Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as ‘add-on’ therapy to statins in patients receiving concomitant medications, so the potential for Evacetrapib to cause clinically important drug–drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated. Methods The DDI potential of Evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic. Results In vitro, Evacetrapib inhibited all of the major CYPs, with inhibition constants (Ki) ranging from 0.57 µm (CYP2C9) to 7.6 µm (CYP2C19). Evacetrapib was a time-dependent inhibitor and inducer of CYP3A. The effects of Evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with Evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, Evacetrapib 100 mg had minimal impact on AUC of co-administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady-state, with no differences in reported hepatic or muscular adverse events. Conclusions Taken together, the extent of CYP-mediated DDI with the potential clinical dose of Evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.

  • Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib.
    Journal of the American College of Cardiology, 2015
    Co-Authors: Stephen J Nicholls, Ming Dauh Wang, Kathryn A Krueger, Giacomo Ruotolo, Steven E. Nissen, H. Bryan Brewer, John P. Kane, Steven J. Adelman, Daniel J. Rader
    Abstract:

    Abstract Background Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited. Objectives This study assessed the impact of Evacetrapib, statins, or combination therapy on CEC. Methods We analyzed samples from 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels who were enrolled in a phase 2 trial of Evacetrapib. Percent changes from baseline in CEC (total, non–ABCA1-, and ABCA1-specific) and HDL subpopulations were evaluated after 12 weeks of treatment with placebo, statin monotherapy, Evacetrapib monotherapy, or Evacetrapib combined with statins. Pre–beta-1 HDL levels were quantified by immunofixation and nondenaturing 2-dimensional gel electrophoresis (2DGE). Results Relative to placebo, Evacetrapib monotherapy increased dose-dependent total and non–ABCA1-specific CEC up to 34% and 47%, respectively. Evacetrapib monotherapy also increased ABCA1-specific CEC up to 26%. Relative to statin monotherapy, Evacetrapib with statins also increased total, non–ABCA1-, and ABCA1-specific CEC by 21%, 27%, and 15%, respectively. In contrast, rosuvastatin and simvastatin significantly reduced total and ABCA1-specific CEC, whereas atorvastatin had no significant effect. Consistent with ABCA1-specific CEC, Evacetrapib monotherapy and Evacetrapib combined with statins significantly increased pre–beta-1 HDL levels as measured by either method. Conclusions Evacetrapib, as monotherapy and combined with statins, not only increased total CEC, but also increased ABCA1-specific CEC and pre–beta-1 HDL. The mechanisms by which potent CETP inhibition increases ABCA1-specific CEC and pre–beta-1 HDL require further study. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975 )

  • abstract 12252 effects of the cholesteryl ester transfer protein inhibitor Evacetrapib administered as monotherapy or in combination with statins on cholesterol efflux and hdl particles in patients with dyslipidemia
    Circulation, 2014
    Co-Authors: Daniel J. Rader, Ming Dauh Wang, Kathryn A Krueger, Giacomo Ruotolo, Steven E. Nissen, Stephen J Nicholls, John P. Kane, Bryan Brewer
    Abstract:

    Objectives: The CETP inhibitor Evacetrapib (EVA) has been shown to substantially increase HDL-C and apoA-I levels as monotherapy and combined with statins. The effects of EVA on cholesterol efflux ...

  • effects of the cholesteryl ester transfer protein inhibitor Evacetrapib on lipoproteins apolipoproteins and 24 h ambulatory blood pressure in healthy adults
    Journal of Pharmacy and Pharmacology, 2014
    Co-Authors: Jeffrey G. Suico, Ellen A Cannady, Ming Dauh Wang, Stuart Friedrich, Giacomo Ruotolo, Christopher S. Konkoy, Kathryn A Krueger
    Abstract:

    Objectives We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of Evacetrapib. Methods Healthy volunteers received multiple daily doses of Evacetrapib (10–600 mg) administered for up to 15 days in a placebo-controlled study. Key findings Mean peak plasma concentrations of Evacetrapib occurred at 4–6 h and terminal half-life ranged 24–44 h. Steady state was achieved at approximately 10 days; all subjects had undetectable levels of Evacetrapib 3 weeks after their last dose. The trough inhibition of cholesteryl ester transfer protein (CETP) activity was 65 and 84% at 100 and 300 mg, respectively. At the highest dose (600 mg), Evacetrapib significantly inhibited CETP activity (91%), increased HDL-C (87%) and apo AI (42%), and decreased LDL-C (29%) and apo B (26%) relative to placebo. For the highest dose tested, levels of Evacetrapib, CETP activity, CETP mass, HDL-C and LDL-C returned to levels at or near baseline after a 2-week washout period. Evacetrapib at the highest dose tested did not produce any significant effect on 24-h ambulatory systolic or diastolic blood pressure. Conclusions Multiple doses of Evacetrapib potently inhibited CETP activity, leading to substantial elevations in HDL-C and lowering of LDL-C. Evacetrapib was devoid of clinically relevant effects on blood pressure and mineralocorticoid levels.

Jeffrey S Riesmeyer - One of the best experts on this subject based on the ideXlab platform.

  • Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease: A Prespecified Secondary Analysis of the ACCELERATE Trial.
    JAMA cardiology, 2020
    Co-Authors: Rishi Puri, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Steven E. Nissen, Venu Menon, Julie St. John, Benoit J. Arsenault, Leslie Cho, Kathy Wolski
    Abstract:

    Importance Although lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease, it remains unclear which patients with established atherosclerotic cardiovascular disease stand to benefit the most from Lp(a) lowering. Whether inflammation can modulate Lp(a)-associated cardiovascular (CV) risk during secondary prevention is unknown. Objective To examine whether Lp(a)-associated CV risk is modulated by systemic inflammation in optimally treated patients at high risk of CV disease. Design, Setting, and Participants A prespecified secondary post hoc analysis of the double-blind, multicenter randomized clinical Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial was conducted between October 1, 2012, and December 31, 2013; the study was terminated October 12, 2015. The study was conducted at 543 academic and community hospitals in 36 countries among 12 092 patients at high risk of CV disease (acute coronary syndrome, stroke, peripheral arterial disease, or type 2 diabetes with coronary artery disease) with measurable Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels during treatment. Statistical analysis for this post hoc analysis was performed from September 26, 2018, to March 28, 2020. Interventions Participants received Evacetrapib, 130 mg/d, or matching placebo. Main Outcomes and Measures The ACCELERATE trial found no significant benefit or harm of Evacetrapib on 30-month major adverse cardiovascular events (CV death, myocardial infarction [MI], stroke, coronary revascularization, or hospitalization for unstable angina). This secondary analysis evaluated rates of CV death, MI, and stroke across levels of Lp(a). Results High-sensitivity C-reactive protein and Lp(a) levels were measured in 10 503 patients (8135 men; 8561 white; 10 134 received concurrent statins; mean [SD] age, 64.6 [9.4] years). In fully adjusted analyses, in patients with hsCRP of 2 mg/L or more but not less than 2 mg/L, increasing quintiles of Lp(a) were significantly associated with greater rates of death, MI, and stroke (P = .006 for interaction). Each unit increase in log Lp(a) levels was associated with a 13% increased risk of CV death, nonfatal MI, or stroke only in those with hsCRP levels of 2 mg/L or more (P = .008 for interaction). There was also a significant stepwise relationship between increasing Lp(a) quintiles and time to first CV death, MI, or stroke (log-rankP  Conclusions and Relevance Elevated Lp(a) levels during treatment are related to CV death, MI, and stroke when hsCRP levels are 2 mg/L or more but not less than 2mg/L. This finding suggests a potential benefit of lowering Lp(a) in patients with residual systemic inflammation despite receipt of optimal medical therapy. Trial Registration ClinicalTrials.gov Identifier:NCT01687998

  • Effect of CETP inhibition with Evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial.
    BMJ open diabetes research & care, 2020
    Co-Authors: Venu Menon, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Anirudh Kumar, Divyang Patel, Julie St. John, Govinda J. Weerakkody, Kathy Wolski, Paul Cremer
    Abstract:

    Background High-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with Evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with Evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial. Methods and results Time to first occurrence of any component of the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina was compared among patients with DM randomized to treatment with Evacetrapib (n=4127) or placebo (n=4109) over a median of 26 months of follow-up. The mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, Evacetrapib resulted in a 131% mean increase in HDL levels and a 32% mean decrease in LDL at 3 months that was sustained during the course of the trial. At 6 months, hemoglobin A1c (HbA1c) levels were lower with Evacetrapib than placebo (7.08% vs 7.15%, p=0.023). Composite event rates were higher in patients with DM than without DM (Kaplan-Meier estimates: 15.2% vs 10.6%, HR 1.46, 95% CI 1.30 to 1.64, p Conclusion Despite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with Evacetrapib on prespecified clinical outcomes in this high-risk population.

  • Genome-Wide Polygenic Score and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study
    Circulation. Genomic and precision medicine, 2020
    Co-Authors: Connor A. Emdin, Jeffrey S Riesmeyer, Stephen J Nicholls, Am Lincoff, Sreekumar G. Pillai, Pallav Bhatnagar, Minxian Wang, Hui Rong Qian, Steven E. Nissen
    Abstract:

    Genome-wide polygenic scores (GPSs) integrate information from many common DNA variants into a single measure of inherited susceptibility, and can identify individuals who are at substantially elev...

  • The Role of Lipoprotein (a) as a Marker of Residual Risk in Patients With Diabetes and Established Cardiovascular Disease on Optimal Medical Therapy: Post Hoc Analysis of ACCELERATE.
    Diabetes care, 2019
    Co-Authors: Nishant P. Shah, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Stephen J Nicholls, Govinda J. Weerakkody, Kathy Wolski, Leslie Cho, Qiuqing Wang, Am Lincoff
    Abstract:

    Despite optimal medical treatment, patients with diabetes and established atherosclerotic disease remain at high risk for recurrent cardiovascular events. Consequently, identification and modification of novel risk factors that mediate residual risk remain an important clinical priority. Lipoprotein (a) [Lp(a)] is an LDL-like particle in which apolipoprotein B is covalently bound by a single disulfide bond to apolipoprotein A, and it has both thrombotic and proinflammatory characteristics (1). There is also a growing body of evidence showing causality of atherosclerotic disease with elevated Lp(a) (1). However, little is known about the predictive role of Lp(a) in patients with diabetes and established cardiovascular disease receiving optimal medical treatment. Thus, given that Lp(a) is an established marker of cardiovascular disease with targeted therapies currently in clinical trials (NCT03070782, ClinicalTrials.gov), we sought to see the impact of elevated Lp(a) in a high-risk secondary prevention cohort of patients with diabetes on optimal medical treatment enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial to identify patients who could potentially benefit from Lp(a)-targeted treatment (2). In our post hoc analysis, participants who met eligibility to enroll in the trial were divided into patients with and without diabetes to assess the impact of Lp(a) tertiles in each group. Baseline Lp(a) levels (in nmol/L) were measured by a central laboratory, using the …

  • Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial.
    Journal of the American Heart Association, 2019
    Co-Authors: Anirudh Kumar, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Am Lincoff, Divyang Patel, Govinda J. Weerakkody, Kathy Wolski, Danielle M. Brennan, Stephen J Nicholls
    Abstract:

    Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off‐target increase in plasma aldosterone. We sought to evaluate the impact of Evacetrapib ...

Giacomo Ruotolo - One of the best experts on this subject based on the ideXlab platform.

  • Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease: A Prespecified Secondary Analysis of the ACCELERATE Trial.
    JAMA cardiology, 2020
    Co-Authors: Rishi Puri, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Steven E. Nissen, Venu Menon, Julie St. John, Benoit J. Arsenault, Leslie Cho, Kathy Wolski
    Abstract:

    Importance Although lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease, it remains unclear which patients with established atherosclerotic cardiovascular disease stand to benefit the most from Lp(a) lowering. Whether inflammation can modulate Lp(a)-associated cardiovascular (CV) risk during secondary prevention is unknown. Objective To examine whether Lp(a)-associated CV risk is modulated by systemic inflammation in optimally treated patients at high risk of CV disease. Design, Setting, and Participants A prespecified secondary post hoc analysis of the double-blind, multicenter randomized clinical Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial was conducted between October 1, 2012, and December 31, 2013; the study was terminated October 12, 2015. The study was conducted at 543 academic and community hospitals in 36 countries among 12 092 patients at high risk of CV disease (acute coronary syndrome, stroke, peripheral arterial disease, or type 2 diabetes with coronary artery disease) with measurable Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels during treatment. Statistical analysis for this post hoc analysis was performed from September 26, 2018, to March 28, 2020. Interventions Participants received Evacetrapib, 130 mg/d, or matching placebo. Main Outcomes and Measures The ACCELERATE trial found no significant benefit or harm of Evacetrapib on 30-month major adverse cardiovascular events (CV death, myocardial infarction [MI], stroke, coronary revascularization, or hospitalization for unstable angina). This secondary analysis evaluated rates of CV death, MI, and stroke across levels of Lp(a). Results High-sensitivity C-reactive protein and Lp(a) levels were measured in 10 503 patients (8135 men; 8561 white; 10 134 received concurrent statins; mean [SD] age, 64.6 [9.4] years). In fully adjusted analyses, in patients with hsCRP of 2 mg/L or more but not less than 2 mg/L, increasing quintiles of Lp(a) were significantly associated with greater rates of death, MI, and stroke (P = .006 for interaction). Each unit increase in log Lp(a) levels was associated with a 13% increased risk of CV death, nonfatal MI, or stroke only in those with hsCRP levels of 2 mg/L or more (P = .008 for interaction). There was also a significant stepwise relationship between increasing Lp(a) quintiles and time to first CV death, MI, or stroke (log-rankP  Conclusions and Relevance Elevated Lp(a) levels during treatment are related to CV death, MI, and stroke when hsCRP levels are 2 mg/L or more but not less than 2mg/L. This finding suggests a potential benefit of lowering Lp(a) in patients with residual systemic inflammation despite receipt of optimal medical therapy. Trial Registration ClinicalTrials.gov Identifier:NCT01687998

  • Effect of CETP inhibition with Evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial.
    BMJ open diabetes research & care, 2020
    Co-Authors: Venu Menon, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Anirudh Kumar, Divyang Patel, Julie St. John, Govinda J. Weerakkody, Kathy Wolski, Paul Cremer
    Abstract:

    Background High-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with Evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with Evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial. Methods and results Time to first occurrence of any component of the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina was compared among patients with DM randomized to treatment with Evacetrapib (n=4127) or placebo (n=4109) over a median of 26 months of follow-up. The mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, Evacetrapib resulted in a 131% mean increase in HDL levels and a 32% mean decrease in LDL at 3 months that was sustained during the course of the trial. At 6 months, hemoglobin A1c (HbA1c) levels were lower with Evacetrapib than placebo (7.08% vs 7.15%, p=0.023). Composite event rates were higher in patients with DM than without DM (Kaplan-Meier estimates: 15.2% vs 10.6%, HR 1.46, 95% CI 1.30 to 1.64, p Conclusion Despite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with Evacetrapib on prespecified clinical outcomes in this high-risk population.

  • The Role of Lipoprotein (a) as a Marker of Residual Risk in Patients With Diabetes and Established Cardiovascular Disease on Optimal Medical Therapy: Post Hoc Analysis of ACCELERATE.
    Diabetes care, 2019
    Co-Authors: Nishant P. Shah, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Stephen J Nicholls, Govinda J. Weerakkody, Kathy Wolski, Leslie Cho, Qiuqing Wang, Am Lincoff
    Abstract:

    Despite optimal medical treatment, patients with diabetes and established atherosclerotic disease remain at high risk for recurrent cardiovascular events. Consequently, identification and modification of novel risk factors that mediate residual risk remain an important clinical priority. Lipoprotein (a) [Lp(a)] is an LDL-like particle in which apolipoprotein B is covalently bound by a single disulfide bond to apolipoprotein A, and it has both thrombotic and proinflammatory characteristics (1). There is also a growing body of evidence showing causality of atherosclerotic disease with elevated Lp(a) (1). However, little is known about the predictive role of Lp(a) in patients with diabetes and established cardiovascular disease receiving optimal medical treatment. Thus, given that Lp(a) is an established marker of cardiovascular disease with targeted therapies currently in clinical trials (NCT03070782, ClinicalTrials.gov), we sought to see the impact of elevated Lp(a) in a high-risk secondary prevention cohort of patients with diabetes on optimal medical treatment enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial to identify patients who could potentially benefit from Lp(a)-targeted treatment (2). In our post hoc analysis, participants who met eligibility to enroll in the trial were divided into patients with and without diabetes to assess the impact of Lp(a) tertiles in each group. Baseline Lp(a) levels (in nmol/L) were measured by a central laboratory, using the …

  • Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial.
    Journal of the American Heart Association, 2019
    Co-Authors: Anirudh Kumar, Jeffrey S Riesmeyer, Ellen Mcerlean, Giacomo Ruotolo, Am Lincoff, Divyang Patel, Govinda J. Weerakkody, Kathy Wolski, Danielle M. Brennan, Stephen J Nicholls
    Abstract:

    Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off‐target increase in plasma aldosterone. We sought to evaluate the impact of Evacetrapib ...

  • abstract 558 cetp inhibitor increases hdl c and cholesterol efflux capacity but reduces subsequent cholesterol esterification and hepatic cell uptake
    Arteriosclerosis Thrombosis and Vascular Biology, 2019
    Co-Authors: Heidi L. Collins, Steven J Nicholls, Jeffrey S Riesmeyer, Giacomo Ruotolo, Debra L. Miller, Daniel J. Rader, Steven Jay Adelman
    Abstract:

    Cholesterol efflux capacity (CEC) has been inversely associated with cardiovascular disease (CVD) in several studies. We have previously shown that the CETP inhibitor Evacetrapib increases CEC, but...

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