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Hypercholesterolemia: HELP
Articles by Robert P. Giugliano
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, Robert P. Giugliano wrote the following 16 articles about Hypercholesterolemia.
 
+ Citations + Abstracts
1 Review Does it make sense to combine statins with other lipid-altering agents following AIM-HIGH, SHARP and ACCORD? 2013

Hochholzer, Willibald / Giugliano, Robert P. ·Universitaets-Herzzentrum Freiburg · Bad Krozingen, Suedring 15, 79189, Bad Krozingen, Germany. willibald.hochholzer@herzzentrum.de ·Curr Atheroscler Rep · Pubmed #23242605.

ABSTRACT: Hypercholesterolemia is one of the main risk factors for the development of atherosclerotic diseases. Multiple clinical trials of lipid-lowering agents have demonstrated that lowering cholesterol effectively reduces the risk of cardiovascular events and death. Currently, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") is the most commonly used approach, given their superior efficacy relative to other cholesterol lowering agents. However, not all patients on statin monotherapy achieve target cholesterol levels, and even when cholesterol lowering is successful, significant residual cardiovascular risk remains. There is increasing interest in developing combination cholesterol-modifying therapies that may augment the treatment effect and minimize the side effects of statins. Although there is currently no evidence that any of the potential therapy combinations can improve clinical outcome compared to statin monotherapy alone, results of several large ongoing trials will help to clarify this important field.

2 Review Lipid lowering goals: back to nature? 2010

Hochholzer, Willibald / Giugliano, Robert P. ·TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Ther Adv Cardiovasc Dis · Pubmed #20400493.

ABSTRACT: Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Decades of research have shown that lower cholesterol is better, but how low should we go? The average low-density lipoprotein cholesterol (LDL-C) level in the untreated western population is approximately 130 mg/dl. However, insights from the early phase of life in animals and humans suggest that adult humans were genetically designed for much lower lipids level than is currently considered 'average'. Adult animals in the wild and more primitive contemporary human societies share diets that are low in fats, and have similar very low blood cholesterol levels. Furthermore, extrapolation of data from meta-analyses of large trials suggest that the incidence of cardiovascular events would approach zero if the LDL-C were <60 mg/dl in primary prevention and approximately 30 mg/dl in secondary prevention. Such goals, which are considerably lower than the recommendations in current guidelines, might be attainable with the use of newer more potent lipid-lowering therapies. To date, achieving such low lipid levels appears safe, but the generalizability of these findings to broader populations and the clinical benefit on the reduction of cardiovascular complications remains to be proven.

3 Clinical Trial AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin thErapy-thrombolysis in myocardial infarction 57). 2014

Desai, Nihar R / Giugliano, Robert P / Zhou, Jing / Kohli, Payal / Somaratne, Ransi / Hoffman, Elaine / Liu, Thomas / Scott, Robert / Wasserman, Scott M / Sabatine, Marc S. ·TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Division of Cardiovascular Medicine, University of California at San Francisco, San Francisco, California. · Amgen, Inc., Thousand Oaks, California. · TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: msabatine@partners.org. ·J Am Coll Cardiol · Pubmed #24161333.

ABSTRACT: OBJECTIVES: This study sought to define the ability of AMG 145, a monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), to enable subjects at high risk for major adverse cardiovascular events to achieve National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) parameters for low-density lipoprotein cholesterol (LDL-C) and other lipid goals. BACKGROUND: Many patients at high risk for adverse cardiovascular events are unable to achieve the NCEP-ATP III LDL-C goal of <70 mg/dl, even with high-potency statin therapy. METHODS: In 282 subjects from the LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy-Thrombolysis In Myocardial Infarction 57) trial at high risk according to NCEP-ATP III criteria, we compared the proportion of subjects achieving the NCEP-ATP III recommended LDL-C goal of <70 mg/dl across treatment arms. Other outcomes included the triple goals of LDL-C <70 mg/dl, non-high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and apolipoprotein B (ApoB) <80 mg/dl. RESULTS: During the dosing interval, more than 90% of subjects in both of the top dose groups every 2 weeks and every 4 weeks attained this lipid target over the dosing interval, with similar success rates for the triple lipid goal. CONCLUSIONS: PCSK9 inhibition with AMG 145 enables high-risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing cardiovascular events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications.

4 Clinical Trial AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. 2013

Desai, Nihar R / Kohli, Payal / Giugliano, Robert P / O'Donoghue, Michelle L / Somaratne, Ransi / Zhou, Jing / Hoffman, Elaine B / Huang, Fannie / Rogers, William J / Wasserman, Scott M / Scott, Robert / Sabatine, Marc S. ·TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. ·Circulation · Pubmed #23884353.

ABSTRACT: BACKGROUND: Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a). METHODS AND RESULTS: As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG145 70 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively (P<0.001 for each dose versus placebo). Likewise, AMG145 280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively (P<0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (ρ=0.33, P<0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values. CONCLUSIONS: AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient's atherogenic lipid profile.

5 Clinical Trial Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. 2012

Giugliano, Robert P / Desai, Nihar R / Kohli, Payal / Rogers, William J / Somaratne, Ransi / Huang, Fannie / Liu, Thomas / Mohanavelu, Satishkumar / Hoffman, Elaine B / McDonald, Shannon T / Abrahamsen, Timothy E / Wasserman, Scott M / Scott, Robert / Sabatine, Marc S / Anonymous6100741. ·TIMI Study Group, Brigham and Women's Hospital, Boston, MA, USA. rgiugliano@partners.org ·Lancet · Pubmed #23141813.

ABSTRACT: BACKGROUND: LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin. METHODS: In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730. FINDINGS: 631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening. INTERPRETATION: The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials. FUNDING: Amgen.

6 Clinical Trial Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. 2012

Kohli, Payal / Desai, Nihar R / Giugliano, Robert P / Kim, Jae B / Somaratne, Ransi / Huang, Fannie / Knusel, Beat / McDonald, Shannon / Abrahamsen, Timothy / Wasserman, Scott M / Scott, Robert / Sabatine, Marc S. ·TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. ·Clin Cardiol · Pubmed #22714699.

ABSTRACT: Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60-80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C-lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia.

7 Article Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. 2017

Giugliano, Robert P / Pedersen, Terje R / Park, Jeong-Gun / De Ferrari, Gaetano M / Gaciong, Zbigniew A / Ceska, Richard / Toth, Kalman / Gouni-Berthold, Ioanna / Lopez-Miranda, Jose / Schiele, François / Mach, François / Ott, Brian R / Kanevsky, Estella / Pineda, Armando Lira / Somaratne, Ransi / Wasserman, Scott M / Keech, Anthony C / Sever, Peter S / Sabatine, Marc S / Anonymous7260917. ·TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: rgiugliano@bwh.harvard.edu. · Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway. · TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA. · Department of Molecular Medicine, University of Pavia and Cardiac Intensive Care Unit and Laboratories for Experimental Cardiology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy. · Department of Internal Medicine, Hypertension and Vascular Diseases, The Medical University of Warsaw, Warsaw, Poland. · Center of Preventive Cardiology, 3rd Department Internal Medicine, University General Hospital and 1st Medical Faculty, Prague, Czech Republic. · 1st Department of Medicine, University of Pécs, Pécs, Hungary. · Polyclinic for Endocrinology, Diabetes, and Preventive Medicine, University of Cologne, Cologne, Germany. · Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba, Reina Sofia University Hospital, University of Cordoba, CIBEROBN, Cordoba, Spain. · University Hospital Center Besançon, Besançon, France. · Hopital Cantonal, Hopitaux Universitaires de Geneva, Geneva, Switzerland. · Rhode Island Hospital, Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA. · Amgen, Thousand Oaks, CA, USA. · Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. · International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, UK. ·Lancet · Pubmed #28859947.

ABSTRACT: BACKGROUND: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). METHODS: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. FINDINGS: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. INTERPRETATION: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. FUNDING: Amgen.

8 Article Low-Density Lipoprotein Cholesterol Treatment in the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Era: Getting Back on Target. 2017

Sabatine, Marc S / Giugliano, Robert P. ·TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Deputy Editor. ·JAMA Cardiol · Pubmed #28768310.

ABSTRACT: -- No abstract --

9 Article Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. 2017

Sabatine, Marc S / Giugliano, Robert P / Keech, Anthony C / Honarpour, Narimon / Wiviott, Stephen D / Murphy, Sabina A / Kuder, Julia F / Wang, Huei / Liu, Thomas / Wasserman, Scott M / Sever, Peter S / Pedersen, Terje R / Anonymous7080899. ·From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.) · Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.) · Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.) · International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.) · and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.). ·N Engl J Med · Pubmed #28304224.

ABSTRACT: BACKGROUND: Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS: At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .).

10 Article Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years From the Open-Label OSLER-1 Extension Study. 2017

Koren, Michael J / Sabatine, Marc S / Giugliano, Robert P / Langslet, Gisle / Wiviott, Stephen D / Kassahun, Helina / Ruzza, Andrea / Ma, Yuhui / Somaratne, Ransi / Raal, Frederick J. ·Jacksonville Center for Clinical Research, Jacksonville, Florida. · Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts3Deputy Editor, JAMA Cardiology. · Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Lipid Clinic, Oslo University Hospital, Oslo, Norway. · Amgen Inc, Thousand Oaks, California. · The Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, South Africa. ·JAMA Cardiol · Pubmed #28291870.

ABSTRACT: Importance: The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) evaluated the durability of long-term efficacy and safety during long-term therapy with evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9). Objective: To determine whether LDL-C level reductions with evolocumab persist across different populations. Secondary objectives included assessment of adverse events, antidrug antibodies, and factors contributing to treatment discontinuation. Design, Setting, and Participants: This ongoing, randomized open-label extension trial (OSLER-1) was conducted at 192 sites in 18 countries. A total of 1324 of 1666 patients randomized into 1 of 5 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1255 received 1 or more evolocumab doses. As of August 2016, 812 of 1324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016. Interventions: During year 1, patients were randomized to evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received evolocumab, 420 mg, plus SOC. Main Outcomes and Measures: Lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of evolocumab. Results: At parent study baseline, the mean (SD) age of the population was 57.1 (11.6) years, with 52.9% being women. The median LDL-C level was 133 mg/dL (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% CI, -63% to -60%) vs 2% (95% CI, -5% to -0.2%) with SOC alone (P < .001). At approximately 2, 3, and 4 years of study follow-up, the median LDL-C level was reduced by 59% (95% CI, -60% to -57%), 59% (95% CI, -61% to -58%), and 57% (95% CI, -59% to -55%), respectively, from parent study baseline. For patients receiving statin therapy unchanged from baseline, at week 208, the median LDL-C level reduction was 58%. No neutralizing antibodies to evolocumab were detected. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and, adjusting for duration of evolocumab exposure, 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC). A total of 79% of patients persisted with evolocumab treatment, with a mean exposure duration of 44 months. Conclusions and Relevance: In the longest clinical trial exposure to a PCSK9 inhibitor to date, evolocumab produced sustained reductions in LDL-C levels. The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation. Trial Registration: clinicaltrials.gov Identifier: NCT01439880.

11 Article Association Between Circulating Baseline Proprotein Convertase Subtilisin Kexin Type 9 Levels and Efficacy of Evolocumab. 2017

Desai, Nihar R / Giugliano, Robert P / Wasserman, Scott M / Gibbs, John P / Liu, Thomas / Scott, Rob / Sabatine, Marc S. ·Section of Cardiovascular Medicine, Department of Medicine, Yale School of Medicine, New Haven, Connecticut2Center for Outcomes Research and Evaluation, Yale-New Haven Health Services Corporation, New Haven, Connecticut. · Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Amgen Inc, Thousand Oaks, California. · Amgen Inc, Thousand Oaks, California5currently with AbbVie Inc, North Chicago, Illinois. ·JAMA Cardiol · Pubmed #28122070.

ABSTRACT: Importance: Levels of proprotein convertase subtilisin kexin type 9 (PCSK9) vary markedly across the population and are influenced by genetic and nongenetic factors. Evolocumab is a fully human, monoclonal antibody against PCSK9 that reduces low-density lipoprotein cholesterol (LDL-C) levels by 55% to 75%. Whether the efficacy of evolocumab varies based on an individual's baseline PCSK9 level remains unknown. Objective: To characterize variability in PCSK9 levels and determine whether the LDL-C level reduction achieved with evolocumab differs based on PCSK9 levels. Design, Setting, and Participants: This study included pooled data from 3016 patients from 4 phase 3 randomized clinical trials of evolocumab as part of the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations. Circulating PCSK9 levels were measured at baseline using quantitative enzyme-linked immunosorbent assays and used to stratify patients into quartiles, and LDL-C level was measured at baseline and weeks 10 and 12. In an additional 138 patients enrolled in a pharmacokinetic and pharmacodynamic substudy from 4 phase 2 trials, circulating PCSK9 levels were measured at baseline and then weekly at weeks 8 through 12. Main Outcomes and Measures: Placebo-controlled percentage change in LDL-C level with evolocumab, 140 mg every 2 weeks and 420 mg once monthly, across quartiles of baseline PCSK9 levels. Results: Of the 3016 patients, 1492 (49.5%) were female and 2758 (91.4%) were white. The median baseline circulating PCSK9 level was 323 ng/mL (interquartile range, 258-406 ng/mL). Patients with higher levels of PCSK9 were more likely to be receiving intensive statin therapy (56%, 36%, 25%, and 13% in the fourth through first quartiles; P < .001) and had significantly lower baseline LDL-C level (123 mg/dL, 124 mg/dL, 128 mg/dL, and 137 mg/dL in the fourth through first quartiles; P < .001). After stratifying by statin use, there was no correlation between PCSK9 levels and LDL-C levels (ρ = 0.03 [95% CI, -0.04 to 0.10] for nonstatin users, P = .39, and ρ = 0.03 [95% CI, -0.01 to 0.08] for statin users, P = .12). Across all quartiles of baseline PCSK9 levels, both evolocumab 140 mg every 2 weeks and 420 mg once monthly suppressed circulating PCSK9 levels by 90% to 100% within 1 week of administration. Both evolocumab 140 mg every 2 weeks and 420 mg once monthly were associated with significant reductions in LDL-C levels between 64% and 71% (P < .001), regardless of PCSK9 levels (P for interaction = .76 and .21, respectively). Conclusions and Relevance: Regardless of baseline PCSK9 levels, the doses of evolocumab being studied in a large cardiovascular outcomes trial suppress PCSK9 levels and consistently and substantially reduce LDL-C levels.

12 Article Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. 2015

Sabatine, Marc S / Giugliano, Robert P / Wiviott, Stephen D / Raal, Frederick J / Blom, Dirk J / Robinson, Jennifer / Ballantyne, Christie M / Somaratne, Ransi / Legg, Jason / Wasserman, Scott M / Scott, Robert / Koren, Michael J / Stein, Evan A / Anonymous5760823. ·From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and the Department of Medicine, Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W.) · the Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg (F.J.R.), and the Division of Lipidology, Department of Medicine, University of Cape Town, Cape Town (D.J.B.) - both in South Africa · the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.R.) · the Sections of Cardiovascular Research and Cardiology, Department of Medicine, Baylor College of Medicine, and the Center for Cardiovascular Disease Prevention, Houston Methodist DeBakey Heart and Vascular Center, Houston (C.M.B.) · Amgen, Thousand Oaks, CA (R. Somaratne, J.L., S.M.W., R. Scott) · Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.) · and the Metabolic and Atherosclerosis Research Center, Cincinnati (E.A.S.). ·N Engl J Med · Pubmed #25773607.

ABSTRACT: BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data. METHODS: In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. RESULTS: As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003). CONCLUSIONS: During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.).

13 Article Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. 2014

Koren, Michael J / Giugliano, Robert P / Raal, Frederick J / Sullivan, David / Bolognese, Michael / Langslet, Gisle / Civeira, Fernando / Somaratne, Ransi / Nelson, Patric / Liu, Thomas / Scott, Rob / Wasserman, Scott M / Sabatine, Marc S / Anonymous1710776. ·Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.) · TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (R.P.G., M.S.S.) · Carbohydrate and Lipid Metabolism Research Unit, Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.) · Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia (D.S.) · Bethesda Health Research Center, Bethesda, MD (M.B.) · Lipid Clinic, Oslo University Hospital, Oslo, Norway (G.L.) · Hospital Universitario Miguel Servet, Zaragoza, Spain (F.C.) · and Amgen Inc, Thousand Oaks, CA (R.S., P.N., T.L., R.S., S.M.W.). ·Circulation · Pubmed #24255061.

ABSTRACT: BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. METHODS AND RESULTS: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. CONCLUSION: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT01439880.

14 Article Cholesterol levels and the association of statins with in-hospital mortality of myocardial infarction patients insights from a Chilean registry of myocardial infarction. 2013

Martínez, Gonzalo / Rigotti, Attilio / Acevedo, Mónica / Navarrete, Carlos / Rosales, Juanita / Giugliano, Robert P / Corbalán, Ramón. ·Cardiovascular Division, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. ·Clin Cardiol · Pubmed #23494544.

ABSTRACT: BACKGROUND: Hypercholesterolemia is a strong risk factor for myocardial infarction (MI). There is scarce information regarding lipoprotein levels among patients with MI in Latin America as well as about the association of very early statin therapy during the course of acute MI. HYPOTHESIS: Very early statin prescription might be associated with a reduction on in-hospital mortality in MI patients with nearly normal lipid levels. METHODS: Prospective registry database analysis of MI patients admitted between 2001 and 2007 at a single university hospital from which demographics, treatments, clinical variables, and mortality were assessed. Patients naïve to statin therapy were divided in 2 groups, according to whether they received (group A) or did not receive (group B) statins during the first 24 hours after admission. RESULTS: In the 1465 patients analyzed, mean plasma levels of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C) were 197, 117, and 44 mg/dL, respectively, and 41.8% had HDL-C ≤40 mg/dL. Among statin naïve patients (n = 1272), 67% were classified in group A and 33% in group B. Overall in-hospital mortality was 4.1%: 1.8% in group A and 8.5% in group B. In the multivariate analysis, including propensity score for statin prescription, the odds ratio for in-hospital mortality for group A was 0.971 (95% confidence interval: 0.944-0.999, P = 0.04). CONCLUSIONS: In the Chilean registry of MI patients, low HDL-C was the main lipid disturbance. Very early statin use after MI appears to be associated with a borderline significant and independent reduction of in-hospital mortality.

15 Minor Cognitive Function in a Randomized Trial of Evolocumab. 2017

Giugliano, Robert P / Sabatine, Marc S / Ott, Brian R. ·Brigham and Women’s Hospital, Boston, MA · rgiugliano@bwh.harvard.edu · Warren Alpert Medical School of Brown University, Providence, RI ·N Engl J Med · Pubmed #29141161.

ABSTRACT: -- No abstract --

16 Minor Reply: Adding Ezetimibe to Simvastatin for the Secondary Prevention of Cardiovascular Disease: Is it Useful? 2016

Murphy, Sabina A / Cannon, Christopher P / Blazing, Michael A / Giugliano, Robert P / Tershakovec, Andrew M / Braunwald, Eugene. · ·J Am Coll Cardiol · Pubmed #27339506.

ABSTRACT: -- No abstract --