This phase 3 clinical trial evaluated the safety and efficacy of evolocumab, a monoclonal antibody that inhibits PCSK9, in over 900 patients with hyperlipidemia over 52 weeks. Patients received evolocumab or placebo injections monthly in addition to background lipid-lowering therapy. The primary outcome was the percent change in LDL cholesterol from baseline to week 52. Evolocumab reduced LDL cholesterol by 57% on average compared to placebo and over 80% of patients achieved an LDL cholesterol level under 70 mg/dL. More adverse events occurred in the evolocumab group, including myalgia and elevated creatine kinase. The study demonstrated evolocumab significantly lowered LDL cholesterol over 52 weeks when added to standard lipid-lower
New Treatments for Severe HypercholesteremiaAllina Health
By Thomas Knickelbine, MD. New medication options for people with familial hypercholesteremia and statin intolerance: how they work, effectiveness, case examples and ongoing research. "We're getting to the point where we can offer just about anyone tools or treatments that will help reduce their risk of a cardiovascular event."
L. berarducci new cholesterol management guidelinesAlysia Smith
Dr. Laurence Berarducci, MD, FACC presents on "New Cholesterol Management Guidelines" at the March 4 -6, 2016 Cardiac and Thoracic Surgery Associates, Cardiovascular Summit at The Westin Riverfront Resort and Spa.
Evolocumab is a monoclonal antibody and it inhibits Proprotein Convertase Subtilisin/kexin type 9 (PCSK9) to reduce LDL cholesterol in the bloodstream.
An introduction to PCSK-9 inhibitors: a new therapeutic class of drugs approved by US FDA in July 2015 to treat Heterozygous familial hypercholesterolemia (HeFH) and its superiority over gold standard statins in treatment. Does it have potential to become a blockbuster and emulate Lipitor's success?
New Treatments for Severe HypercholesteremiaAllina Health
By Thomas Knickelbine, MD. New medication options for people with familial hypercholesteremia and statin intolerance: how they work, effectiveness, case examples and ongoing research. "We're getting to the point where we can offer just about anyone tools or treatments that will help reduce their risk of a cardiovascular event."
L. berarducci new cholesterol management guidelinesAlysia Smith
Dr. Laurence Berarducci, MD, FACC presents on "New Cholesterol Management Guidelines" at the March 4 -6, 2016 Cardiac and Thoracic Surgery Associates, Cardiovascular Summit at The Westin Riverfront Resort and Spa.
Evolocumab is a monoclonal antibody and it inhibits Proprotein Convertase Subtilisin/kexin type 9 (PCSK9) to reduce LDL cholesterol in the bloodstream.
An introduction to PCSK-9 inhibitors: a new therapeutic class of drugs approved by US FDA in July 2015 to treat Heterozygous familial hypercholesterolemia (HeFH) and its superiority over gold standard statins in treatment. Does it have potential to become a blockbuster and emulate Lipitor's success?
iPCSK9 Una nueva era en riesgo cardiovascular
17 de Mayo de 2014, 17:00h
http://iPCSK9.secardiologia.es
iPCSK9 Nuevo paradigma. Dislipemia en Cardiología: ¿Cuál es el futuro?
Dr. José Luis López-Sendón Hentschel
Jefe de Servicio de Cardiología. Hospital Universitario La Paz (Madrid)
Statins are highly effective LDL-c lowering agents that actually reduce clinical cardiovascular events. The 2013 ACC/AHA guidelines on the management of blood cholesterol recommend high-intensity statin therapy in individuals with high cardiovascular risk as assessed by the 10-year atherosclerotic cardiovascular disease risk calculator. However, a significant number of individuals do not tolerate or respond adequately to statins, and continue to have residual risk in spite of high intensity statin therapy.
There are some exciting developments in the field of lipidology. This decade has been labeled “The PCSK9 decade”. A new class of monoclonal antibodies directed against the PCSK9 glycoproteins appears very promising in further lowering LDL cholesterol and thereby cardiovascular risk. Evolocumab and alirucomab are novel PCSK9 inhibitors that can be given subcutaneously once or twice in a month, and have the potential to reduce LDL-cholesterol to very low levels without any major adverse effects.
Other classes of drugs like Apo-B antisense oligonucleotides (mipomersen), CETP inhibitors (especially anacetrapib), microsomal transfer protein inhibitors (lomitapide) also hold some promise. The future of lipid lowering therapy looks reassuring with these new developments.
Shashikiran Umakanth presented this at the Egyptian Association of Endocrinology, Diabetes & Atherosclerosis (EAEDA) 2014 conference at Alexandria, Egypt. This conference was help in association with Endocrine Society, USA and the European Association for the Study of Diabetes (EASD).
Nueva diana hipolipemiante: terapia anti-PCSK9
02/06/2016 18:30h Casa del Corazón, Madrid
http://antipcsk9.secardiologia.es
#antiPCSK9
Resultados de la inhibición de PCSK9: superando los límites
Dr. José Luis Zamorano Gómez, Hospital Universitario Ramón y Cajal (Madrid)
@cardioXXI
High density lipoprotein cholesterol (HDL-c), often termed “good cholesterol”, is one of the major targets of cardiovascular risk reduction. Constant attempts have been made over the past 3 decades to increase their level in the blood in an attempt to reduce cardiovascular risk. In spite of these efforts, raising HDL-c still remains an enigma.
While several methods are known to raise HDL-c, they are not as dramatic as reduction of low density lipoprotein cholesterol (LDL-c). Statins, fibrates, niacin and cholesteryl-ester transfer protein (CETP) inhibitors are useful in increasing HDL-c. However, it was recently demonstrated that raising HDL-c using these pharmacological means did not have any significant effect on reducing clinical cardiovascular events. The 2013 ACC/AHA guidelines on managing blood cholesterol did not give much importance to HDL-c management too.
An important question is the method with which HDL-c is tested. Is HDL-cholesterol more important or HDL lipoprotein particle number? Are HDL-based therapies dead? Are there newer ongoing techniques that raise HDL cholesterol as well as reduce cardiovascular risk?
Shashikiran Umakanth presented this at the Egyptian Association of Endocrinology, Diabetes & Atherosclerosis (EAEDA) 2014 conference at Alexandria, Egypt. This conference was help in association with Endocrine Society, USA and the European Association for the Study of Diabetes (EASD).
iPCSK9 Una nueva era en riesgo cardiovascular
17 de Mayo de 2014, 17:00h
http://iPCSK9.secardiologia.es
iPCSK9 Nuevo paradigma. Dislipemia en Cardiología: ¿Cuál es el futuro?
Dr. José Luis López-Sendón Hentschel
Jefe de Servicio de Cardiología. Hospital Universitario La Paz (Madrid)
Statins are highly effective LDL-c lowering agents that actually reduce clinical cardiovascular events. The 2013 ACC/AHA guidelines on the management of blood cholesterol recommend high-intensity statin therapy in individuals with high cardiovascular risk as assessed by the 10-year atherosclerotic cardiovascular disease risk calculator. However, a significant number of individuals do not tolerate or respond adequately to statins, and continue to have residual risk in spite of high intensity statin therapy.
There are some exciting developments in the field of lipidology. This decade has been labeled “The PCSK9 decade”. A new class of monoclonal antibodies directed against the PCSK9 glycoproteins appears very promising in further lowering LDL cholesterol and thereby cardiovascular risk. Evolocumab and alirucomab are novel PCSK9 inhibitors that can be given subcutaneously once or twice in a month, and have the potential to reduce LDL-cholesterol to very low levels without any major adverse effects.
Other classes of drugs like Apo-B antisense oligonucleotides (mipomersen), CETP inhibitors (especially anacetrapib), microsomal transfer protein inhibitors (lomitapide) also hold some promise. The future of lipid lowering therapy looks reassuring with these new developments.
Shashikiran Umakanth presented this at the Egyptian Association of Endocrinology, Diabetes & Atherosclerosis (EAEDA) 2014 conference at Alexandria, Egypt. This conference was help in association with Endocrine Society, USA and the European Association for the Study of Diabetes (EASD).
Nueva diana hipolipemiante: terapia anti-PCSK9
02/06/2016 18:30h Casa del Corazón, Madrid
http://antipcsk9.secardiologia.es
#antiPCSK9
Resultados de la inhibición de PCSK9: superando los límites
Dr. José Luis Zamorano Gómez, Hospital Universitario Ramón y Cajal (Madrid)
@cardioXXI
High density lipoprotein cholesterol (HDL-c), often termed “good cholesterol”, is one of the major targets of cardiovascular risk reduction. Constant attempts have been made over the past 3 decades to increase their level in the blood in an attempt to reduce cardiovascular risk. In spite of these efforts, raising HDL-c still remains an enigma.
While several methods are known to raise HDL-c, they are not as dramatic as reduction of low density lipoprotein cholesterol (LDL-c). Statins, fibrates, niacin and cholesteryl-ester transfer protein (CETP) inhibitors are useful in increasing HDL-c. However, it was recently demonstrated that raising HDL-c using these pharmacological means did not have any significant effect on reducing clinical cardiovascular events. The 2013 ACC/AHA guidelines on managing blood cholesterol did not give much importance to HDL-c management too.
An important question is the method with which HDL-c is tested. Is HDL-cholesterol more important or HDL lipoprotein particle number? Are HDL-based therapies dead? Are there newer ongoing techniques that raise HDL cholesterol as well as reduce cardiovascular risk?
Shashikiran Umakanth presented this at the Egyptian Association of Endocrinology, Diabetes & Atherosclerosis (EAEDA) 2014 conference at Alexandria, Egypt. This conference was help in association with Endocrine Society, USA and the European Association for the Study of Diabetes (EASD).
New class of therapeutic agents called soluble guanylate cyclase (sGC) stimulators.
Impairment of NO synthesis and signaling through the NO-sGC–cGMP pathway is involved in the pathogenesis of pulmonary hypertension.
Dual mode of action,
Directly stimulating sGC independently of NO, and
Increasing the sensitivity of sGC to NO.
vasorelaxation , antiproliferative and antifibrotic effects
Semaglutide brings breakthroughs in weight management for type 2 diabetes bio...DoriaFang
On March 2, "The Lancet" published an important study of semaglutide in patients with type 2 diabetes. In the STEP-2 trial, medication once a week can help overweight or obese type 2 diabetic patients lose an average of nearly 10 kg in weight, and more than a quarter of the patients lose more than 15%, which is much higher than the existing drugs in diabetic patients. At the same time, this also significantly improves overall health conditions including blood sugar, blood pressure, and blood lipids.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
3. Evolocumab, a monoclonal antibody that inhibits
proprotein convertase subtilisin/ kexin type 9
(PCSK9), significantly reduced low-density lipoprotein
(LDL) cholesterol levels in phase 2 studies. This was a
phase 3 trial to evaluate the safety and efficacy of 52
weeks of treatment with evolocumab.
4. Proprotein convertase subtilisin/kexin type 9 (PCSK9),
a serine protease that is produced predominantly in
the liver.
PCSK9 is a protein that targets LDL receptors for
degradation and thereby reduces the liver's ability to
remove LDL-C, or "bad" cholesterol, from the blood.
.
In previous short-term (8-to-12-week), placebo-
controlled, phase 2 trials, PCSK9 inhibitors have been
shown to significantly reduce LDL cholesterol levels.
5. Evolocumab was compared with placebo in patients
with hyperlipidemia who received the study drug for
52 weeks after a run-in period of 4 to 12 weeks of
background lipid- lowering therapy.
6.
7. This study was conducted at 88 centers in nine
countries .
Of the 2120 patients who were screened, 905
underwent randomiza- tion, 901 received at least one
dose of a study drug, and 800 (88.4%) completed 52
weeks of treatment
Patients were eligible for enrollment in the trial if they
were adults 18 to 75 years of age with an LDL
cholesterol level of 75 mg per dl or higher and a fasting
triglyceride level of 400 mg per deciliter.
8. Exclusion criteria were heart failure, recent
myocardial infarction, recent or planned revascu-
larization procedure, uncontrolled hypertension,
hyperthyroidism or hypothyroidism, moderate- to-
severe renal dysfunction, and active liver disease or
hepatic dysfunction.
9. Patients who met eligibility criteria and, after re- ceiving a
6-ml test placebo injection, agreed to undergo a regimen of
monthly subcutaneous injections for a year entered a run-
in period of 4 to 12 weeks, during which open-label
background lipid-lowering therapy was administered
On the basis of the screening LDL cholesterol level,
previous use of statin therapy, and cardiovascular risk (as
determined by the ATP-III guidelines), we assigned all
patients to one of four lipid-lowering regimens:
diet alone
diet with 10 mg of atorvastatin daily,
diet with 80 mg of atorvastatin daily,
diet with 80 mg of atorvastatin plus 10 mg of ezetimibe
daily.
10. At the conclusion of the first 4 weeks of the run-in
period, eligibility for randomization was based on a
fasting LDL cholesterol level of 75 mg per deciliter or
higher, as determined by the central laboratory
Among patients who met that criterion were
, those with coronary heart disease (or a coronary heart
disease risk equivalent) who had an LDL cholesterol
level of less than 100 mg/dl
and those without coronary heart disease (or a coronary
heart disease risk equivalent) who had an LDL
cholesterol level of less than 130 mg/dl were eligible for
randomization.
11. Among patients in whom the lipid-lowering goal had
not been reached, therapy was increased to the next
level for an additional 4 weeks; the process was
repeated a month later if the goal had still not been
reached.
Patients with an LDL cholesterol level of less than 75
mg per deciliter were excluded, except for those who
were receiving 80 mg of atorvastatin plus 10 mg of
ezetimibe daily.
These patients were allowed to discontinue ezetimibe
and to participate in the study if the ATP-III goal was
maintained after 4 weeks on the regimen of 80 mg of
atorvastatin daily.
12. After randomization, no changes to the as- signed
background lipid-lowering therapy were permitted.
Patients were assigned in a 2:1 ratio(600 in the
evolocumab group and 300 in the placebo group) to
receive either 6 ml (420 mg) of evolocumab or placebo,
administered subcutaneously every 4 weeks for 48
weeks.
Final administration of a study drug occurred at week
48
13. The primary efficacy end point was the percent change
from baseline in the LDL cholesterol level at week 52
in patients receiving evolocumab, as compared with
the change in those receiving placebo.
The primary efficacy end point was also assessed
separately for each of the background- therapy groups.
Secondary efficacy end points included the absolute
change from baseline in the LDL cholesterol level at
week 52, the percent change from baseline in the LDL
cholesterol at week 12, and the percentage of patients
with an LDL cholesterol level of less than 70 mg per
deci- liter (1.81 mmol per liter) at week 52.
14. Additional secondary end points included the percent
change from baseline at week 52 in levels of total
choles- terol, high-density lipoprotein (HDL)
cholesterol, non-HDL cholesterol, very-low-density
lipoprotein (VLDL) cholesterol, and apolipoprotein B,
the ra- tio of total cholesterol to HDL cholesterol, the
ratio of apolipoprotein B to apolipoprotein A1, and the
levels of lipoprotein(a) and triglycerides.
Anti-evolocumab anti- bodies were assayed at baseline
and at weeks 12, 24, 36, and 52,
15.
16. The study was conducted from January 2012 through
November 2013.
As would be antici- pated, the prevalence of
cardiovascular disease and of cardiovascular risk
factors was higher in the groups receiving more
intensive background lipid-lowering therapy
The mean baseline levels of unbound (free) PCSK9
were lowest in the diet-alone group and increased
progressively with the intensity of lipid-lowering
therapy, as would be expected with statin treatment
17. EFFICACY END POINTS
At 52 weeks, the least-squares mean (±SE) reduction in
LDL cholesterol from baseline in the evolocumab group,
taking into account the change in the placebo group, was
57.0±2.1% at week 52 (Table 2) and 57.5±1.6% at week 12.
In the analysis according to background-therapy group,
the reduction in LDL cholesterol in the evolocumab
group, was
1. 55.7±4.2% in the diet-alone group,
2. 61.6±2.6% in the group receiving 10 mg of atorvastatin,
3. 56.8±5.3% in the group receiving 80 mg of atorvastatin,
and
4. 48.5±5.2% in the group receiving 80 mg of atorvastatin plus
10 mg of ezetimibe
18. The level of LDL cholesterol was reduced below 70 mg
per deciliter in 82.3% of patients in the evolocumab
group, as compared with 6.4% of those in the placebo
group
Evolocumab treatment, as compared with placebo, also
resulted in significant least-squares mean percent
reductions from baseline in levels of apolipoprotein B,
non-HDL cholesterol, lipoprotein(a), and triglycerides.
No meaningful changes were seen in levels of high-
sensitivity C-reactive protein
19. In the evolocumab group, mean reductions from
baseline in unbound PCSK9 levels were consistently
around 90% regardless of background therapy, but
those at 4 weeks after drug administration were greater
in the diet- alone group and the group receiving 10 mg
of atorvastatin than in the two groups receiving 80 mg
of atorvastatin.
20. Similar in the evolocumab group and the placebo
group, with 448 of 599 pa- tients (74.8%) and 224 of
302 patients (74.2%), respectively, having an adverse
event.
The most common adverse events in the evolocumab
group were nasopharyngitis, upper respiratory tract in-
fection, influenza, and back pain
Serious adverse events occurred in 33 patients (5.5%)
in the evolocumab group and 13 patients (4.3%) in the
placebo group
21. Adverse events leading to the discontinuation of a
study drug occurred in 13 patients in the evolocumab
group and 3 patients in the placebo group
Elevations of creatine kinase levels to more than five
times the upper limit of the normal range occurred in 7
patients (1.2%) in the evolocumab group and 1 patient
(0.3%) in the placebo group,
Myalgia reported by 24 patients (4.0%) and 9 patients
(3.0%), respectively
elevations of aminotransferase levels to more than
three times the upper limit of the normal range
occurred in 5 patients (0.8%) and 3 patients (1.0%),
respectively
22. Evolocumab treat- ment did not have an adverse effect
on glycemic measures
No anti-evolocumab neutralizing antibodies were
detected in any pa- tient
23.
24.
25. With 420 mg of evolocumab every 4 weeks for 52
weeks resulted in a relative reduction in LDL
cholesterol levels of 57%, taking into account the
change in the pl cebo group.
This result was consistent with the effects that were
observed with the same evolocumab regimen in the 12-
week phase 2 trials.
No decrement in the efficacy of evolocumab from
week 12 to week 52.
26. Percent reductions in LDL cholesterol in the evolocumab
group, taking into account the change in the placebo group,
differed slightly according to background therapy, ranging
from 48.5% in the group receiving atorvastatin plus
ezetimibe to 61.6% in the group receiving 10 mg of
atorvastatin.
the study also provide some insights into the magnitude
and duration of PCSK9 inhibition with antibodies as a
function of background lipid-lowering therapy.
unbound PCSK9 was measured at 1 week and at 4 weeks
after the administration of evolocumab.
The differences in unbound PCSK9 among background-
therapy groups at 1 week were minimal, despite
substantial differences in baseline levels, indicating that
virtually all PCSK9 is antibody-bound initially.
27. Not only were baseline levels of PCSK9 higher among
patients receiving highdose atorvastatin than other
groups, but there also was a more rapid increase in
PCSK9 levels 4 weeks after the administration of each
dose of evolocumab in these patients, suggesting that
the rate of PCSK9 production is increased in patients
receiving intensive statin therapy.
Thus, it may be that patients who have already been
treated with high-dose statins or combination lipid-
lowering therapy may have slightly less capacity to
further up-regulate LDL-receptor activity with
PCSK9 inhibition or may require higher doses of
antibody.
28. In this study, this target of LDL cholesterol level of less
than 70 mg per deciliter was achieved in more than
80% of patients with the use of 420 mg of evolocumab
every 4 weeks.
In addition there were significant reductions in the
levels of other atherogenic, apolipoprotein B–
containing lipoproteins, including lipoprotein(a), and
modest but significant increases in levels of HDL
cholesterol and apolipoprotein A1.
More patients in the evolocumab group than in the
placebo group were reported to have serious adverse
events during treatment and drug discontinuation.
29.
30. There were more reports of myalgia and elevated
creatine kinase levels among patients receiving
evolocumab.
In conclusion, among patients at risk for a wide
range of coronary diseases who were receiving
guideline-recommended background lipid-
lowering therapy, the monoclonal PCSK9 anti-
body evolocumab reduced LDL cholesterol levels
by 57%, as compared with placebo, at 52 weeks.