Weekly injections of the GLP-1 receptor agonist efpeglenatide led to a 27% lower risk of major adverse cardiovascular events and a 32% lower risk of renal outcomes compared to placebo in a randomized controlled trial of over 4000 patients with type 2 diabetes and high cardiovascular risk. Efpeglenatide significantly reduced HbA1c, blood pressure, weight, and albuminuria. Gastrointestinal side effects were more common with efpeglenatide. The trial demonstrated that efpeglenatide can reduce cardiovascular and renal disease risk in high-risk patients with type 2 diabetes.
Present and Future Impact of Cytogenetics on Acute Myeloid Leukemialarriva
Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In this presentation I cover what cytogenetics are, how they impact patient risk, what therapies to use based on risk, and how genetically targeted agents may be used in the future.
Copyright 2016 American Medical Association. All rights reserv.docxvanesaburnand
Copyright 2016 American Medical Association. All rights reserved.
Effect of Naltrexone-Bupropion on Major Adverse
Cardiovascular Events in Overweight and Obese Patients
With Cardiovascular Risk Factors
A Randomized Clinical Trial
Steven E. Nissen, MD; Kathy E. Wolski, MPH; Lisa Prcela, RN; Thomas Wadden, PhD; John B. Buse, MD, PhD;
George Bakris, MD; Alfonso Perez, MD; Steven R. Smith, MD
IMPORTANCE Few cardiovascular outcomes trials have been conducted for obesity
treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the
cardiovascular safety of obesity agents.
OBJECTIVE To determine whether the combination of naltrexone and bupropion increases
major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke,
or nonfatal myocardial infarction) compared with placebo in overweight and obese patients.
DESIGN, SETTING, AND PARTICIPANTS Randomized, multicenter, placebo-controlled,
double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased
cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public
release of confidential interim data by the sponsor, the academic leadership of the study
recommended termination of the trial and the sponsor agreed.
INTERVENTIONS An Internet-based weight management program was provided to all
participants. Participants were randomized to receive placebo (n=4454) or naltrexone,
32 mg/d, and bupropion, 360 mg/d (n=4456).
MAIN OUTCOMES AND MEASURES Time from randomization to first confirmed occurrence of a
MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after
378 expected events, with a confidential interim analysis after approximately 87 events (25%
interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval.
RESULTS Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years),
54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes,
with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim
analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion–
treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE
occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the
naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were
more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2%
vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001).
CONCLUSIONS AND RELEVANCE Among overweight or obese patients at increased
cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned
events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion
treatment, compared with placebo, did not exceed 2.0. However, because of the
unanticipated ear.
PREDICTIVE MODEL FOR LIKELIHOOD OF DETECTING CHRONIC KIDNEY FAILURE AND DISEA...ijcsitcejournal
Fuzzy logic is highly appropriate and valid basis for developing knowledge-based systems in medicine for different tasks and it has been known to produce highly accurate results. Examples of such tasks include syndrome differentiation, likelihood survival for sickle cell anaemia among paediatric patients, diagnosis and optimal selection of medical treatments and real time monitoring of patients. For this paper, a Fuzzy logic-based system is untaken used to provide a comprehensive simulation of a prediction model for determining the likelihood of detecting Chronic Kidney failure/diseases in humans. The Fuzzy-based system uses a 4-tuple record comprising of the following test taken: Blood Urea Test, Urea Clearance Test, Creatinine Clearance test and Estimated Glomerular Filtrate
ate(eGFR).Understanding of the test was elicited from a private hospital in Ibadan through the help of an experienced and qualified nurse which also follows same test according to National Kidney Foundation. This knowledge was then used in the developing the simulated and rule-base prediction model using MATLAB software. The paper also follows the 3 major stages of Fuzzy logic. The results of fuzzification of variables, inference, model testing and defuzzification of variables was also presented. This in turn simplifies the complication involved in detecting Chronic Kidney failure/disease using Fuzzy logic based model.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology. The aim of the journal is to provide a forum for cardiologists, researchers, physicians, and other health professionals to find most recent advances in the areas of cardiology and cardiovascular diseases.
Austin Journal of Clinical Cardiology accepts original research articles, review articles, case reports, clinical images and rapid communication on all the aspects of cardiology and circulatory system.
Austin Journal of Clinical Cardiology strongly supports the scientific upgradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group also brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology
The Impact of Lymph Node Dissection on Survival in Intermediate- and High-Ris...semualkaira
Aimed to evaluate the therapeutic effect of pelvic lymph node dissection (PLND) on survival and determine the predictors of lymph node involvement (LNI) in patients with intermediate- or high-risk prostate cancer (PCa) treated with Radical Prostatectomy
Present and Future Impact of Cytogenetics on Acute Myeloid Leukemialarriva
Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In this presentation I cover what cytogenetics are, how they impact patient risk, what therapies to use based on risk, and how genetically targeted agents may be used in the future.
Copyright 2016 American Medical Association. All rights reserv.docxvanesaburnand
Copyright 2016 American Medical Association. All rights reserved.
Effect of Naltrexone-Bupropion on Major Adverse
Cardiovascular Events in Overweight and Obese Patients
With Cardiovascular Risk Factors
A Randomized Clinical Trial
Steven E. Nissen, MD; Kathy E. Wolski, MPH; Lisa Prcela, RN; Thomas Wadden, PhD; John B. Buse, MD, PhD;
George Bakris, MD; Alfonso Perez, MD; Steven R. Smith, MD
IMPORTANCE Few cardiovascular outcomes trials have been conducted for obesity
treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the
cardiovascular safety of obesity agents.
OBJECTIVE To determine whether the combination of naltrexone and bupropion increases
major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke,
or nonfatal myocardial infarction) compared with placebo in overweight and obese patients.
DESIGN, SETTING, AND PARTICIPANTS Randomized, multicenter, placebo-controlled,
double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased
cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public
release of confidential interim data by the sponsor, the academic leadership of the study
recommended termination of the trial and the sponsor agreed.
INTERVENTIONS An Internet-based weight management program was provided to all
participants. Participants were randomized to receive placebo (n=4454) or naltrexone,
32 mg/d, and bupropion, 360 mg/d (n=4456).
MAIN OUTCOMES AND MEASURES Time from randomization to first confirmed occurrence of a
MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after
378 expected events, with a confidential interim analysis after approximately 87 events (25%
interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval.
RESULTS Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years),
54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes,
with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim
analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion–
treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE
occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the
naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were
more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2%
vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001).
CONCLUSIONS AND RELEVANCE Among overweight or obese patients at increased
cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned
events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion
treatment, compared with placebo, did not exceed 2.0. However, because of the
unanticipated ear.
PREDICTIVE MODEL FOR LIKELIHOOD OF DETECTING CHRONIC KIDNEY FAILURE AND DISEA...ijcsitcejournal
Fuzzy logic is highly appropriate and valid basis for developing knowledge-based systems in medicine for different tasks and it has been known to produce highly accurate results. Examples of such tasks include syndrome differentiation, likelihood survival for sickle cell anaemia among paediatric patients, diagnosis and optimal selection of medical treatments and real time monitoring of patients. For this paper, a Fuzzy logic-based system is untaken used to provide a comprehensive simulation of a prediction model for determining the likelihood of detecting Chronic Kidney failure/diseases in humans. The Fuzzy-based system uses a 4-tuple record comprising of the following test taken: Blood Urea Test, Urea Clearance Test, Creatinine Clearance test and Estimated Glomerular Filtrate
ate(eGFR).Understanding of the test was elicited from a private hospital in Ibadan through the help of an experienced and qualified nurse which also follows same test according to National Kidney Foundation. This knowledge was then used in the developing the simulated and rule-base prediction model using MATLAB software. The paper also follows the 3 major stages of Fuzzy logic. The results of fuzzification of variables, inference, model testing and defuzzification of variables was also presented. This in turn simplifies the complication involved in detecting Chronic Kidney failure/disease using Fuzzy logic based model.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology. The aim of the journal is to provide a forum for cardiologists, researchers, physicians, and other health professionals to find most recent advances in the areas of cardiology and cardiovascular diseases.
Austin Journal of Clinical Cardiology accepts original research articles, review articles, case reports, clinical images and rapid communication on all the aspects of cardiology and circulatory system.
Austin Journal of Clinical Cardiology strongly supports the scientific upgradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group also brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology
The Impact of Lymph Node Dissection on Survival in Intermediate- and High-Ris...semualkaira
Aimed to evaluate the therapeutic effect of pelvic lymph node dissection (PLND) on survival and determine the predictors of lymph node involvement (LNI) in patients with intermediate- or high-risk prostate cancer (PCa) treated with Radical Prostatectomy
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
- 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
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
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 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
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
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.
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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
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Pharynx and Clinical Correlations BY Dr.Rabia Inam Gandapore.pptx
Literature Evaluation.pptx
1. By Salahadin M.Ali(B.Pharm)
1
Haramaya University Hiwot Fana
Comprehensive Specialized Hospital
Clinical Pharmacy and DIC Unit
Journal club presentation
6/4/2022
3. Outline
Authors and funding source
Background
Objective
Historical context
Hypothesis
Research question
Method
Statistical analysis
Result
Discussions
Strength and weakness
Conclusion
3
4. Authors and funding source
Authors
Hertzel C. Gerstein, M.D., Naveed Sattar, M.D.,
Ph.D., Julio Rosenstock, M.D.,Chinthanie
Ramasundarahettige, M.Sc., Richard Pratley,
M.D.,Renato D. Lopes, M.D., Ph.D., Carolyn S.P.
Lam, M.B., B.S., Ph.D.,Nardev S. Khurmi, M.D.,
Laura Heenan, M.Sc., Stefano Del Prato,
M.D.,Leanne Dyal, M.Sc., and Kelley Branch, M.D.,
Funding source
Sanofi; AMPLITUDE-O ClinicalTrials.gov number,
NCT03496298
4
5. Background
The incidence of adverse cardiovascular events
among persons with diabetes is triple that among
persons without diabetes; the incidence of
adverse renal events is also high among persons
with diabetes. The incidence of adverse
cardiovascular events rises with increasing
duration of diabetes, increasing glycated
hemoglobin level, increasing urinary albumin-to-
creatinine ratio, the presence of kidney
dysfunction, a history of cardiovascular disease,
and the presence of other cardiovascular risk
factors. Similar factors increase the incidence of
adverse renal events.
5
6. Objective
To investigate the effect of an exendin-based
GLP-1 receptor agonist, efpeglenatide, on
cardiovascular and renal outcomes in patients
with type 2 diabetes who are also at high risk for
adverse cardiovascular events
6
7. Historical context
Although the effects of glucagon-like peptide-1
(GLP-1) receptor agonists on cardiovascular and
renal outcomes in persons with cardiovascular
disease have been reported, their effects on
these outcomes when those agents are taken
alone or in combination with a sodium–glucose
cotransporter 2 (SGLT2) inhibitor are unknown,
because these trials included very few persons
who were receiving an SGLT2 inhibitor.
7
8. Hypothesis
Efpeglenatide, a GLP-1 receptor agonist administered
weekly by means of subcutaneous injection, has been
shown to lower glucose levels without causing
hypoglycemia. The drug consists of a modified
exendin-4 molecule conjugated with an IgG4 Fc
fragment. Its mechanism of action is akin to that of
GLP-1 receptor agonists that are structurally similar to
human GLP-1, which have been shown to reduce the
risk of adverse cardiovascular events. This similarity
and an acceptable safety profile suggest that
efpeglenatide may also have cardiovascular and renal
benefits in patients with diabetes and concomitant
cardiovascular disease, kidney disease, or both.
8
10. Method
An international, randomized, placebo-controlled trial
(the AMPLITUDE-O trial) conducted at 344 sites
across 28 countries, it evaluated efpeglenatide in
participants with type 2 diabetes and either a history
of cardiovascular disease or current kidney disease
(defined as an estimated glomerular filtration rate of
25.0 to 59.9 ml per minute per 1.73 m2 of body-
surface area) plus at least one other cardiovascular
risk factor.
Participants were randomly assigned in a 1:1:1 ratio
to receive weekly subcutaneous injections of
efpeglenatide at a dose of 4 or 6 mg or placebo.
Randomization was stratified according to use of
sodium–glucose cotransporter 2 inhibitors.
10
11. Inclusion criteria
Persons with type 2 diabetes mellitus and a
glycated hemoglobin level greater than 7% were
enrolled if they were at least 18 years of age and
had a history of cardiovascular disease (defined
as coronary artery disease, stroke, or peripheral
artery disease) or
If they were at least 50 (if male) or 55 (if female)
years of age and had kidney disease (defined as
an estimated glomerular filtration rate [eGFR] of
25.0 to 59.9 ml per minute per 1.73 m2 of body-
surface area) and at least one additional
cardiovascular risk factor
11
12. Exclusion criteria
gastroparesis, uncontrolled reflux, prolonged
nausea or vomiting,
severe retinal disease,
pancreatitis, or
use of a GLP-1 receptor agonist or a dipeptidyl
peptidase 4 (DPP-4) inhibitor within the previous
3 months.
12
13. Primary outcome
The first occurrence of a major adverse
cardiovascular event (MACE; a composite of
nonfatal myocardial infarction, nonfatal stroke, or
death from cardiovascular or undetermined
causes).
13
14. Secondary outcome
An expanded MACE composite outcome (MACE,
coronary revascularization, or hospitalization for
unstable angina) and a composite renal outcome
(incident macroalbuminuria [defined as a urinary
albumin-to-creatinine ratio of >300, as measured in
milligrams of albumin to grams of creatinine, or >33.9,
as measured in milligrams of albumin to millimoles of
creatinine], plus an increase in the urinary albumin-to-
creatinine ratio of ≥30% from baseline, a sustained
decrease in the eGFR of ≥40% for ≥30 days, renal-
replacement therapy for ≥90 days, or a sustained
eGFR of <15 ml per minute per 1.73 m2 for ≥30
days).
14
15. Cont’d
15
Additional outcomes included the components of
the expanded MACE outcome and composite
renal outcome, death from any cause,
hospitalization for heart failure, glycated
hemoglobin level, vital signs, weight, presence of
antibodies against efpeglenatide, pancreatic
enzyme levels, and other laboratory test results.
16. Statistical analysis
It estimated that a sample size of 4000 participants
followed for up to 3 years (with a primary outcome
event occurring in 330 participants) would provide the
trial with more than 99% power and 90% power to
show noninferiority of efpeglenatide to placebo at
noninferiority margins of 1.8 and 1.3, respectively (as
suggested in a 2008 regulatory guidance16).
It was also assumed that the data from both
efpeglenatide dose groups would be pooled for the
comparison with placebo.
The noninferiority margin represents the upper bound
of the 95% confidence interval of the hazard ratio for
a primary outcome event.
16
17. Cont’d
17
Continuous variables were summarized as mean
values with standard deviations or median values with
interquartile ranges, and categorical variables were
summarized as counts and percentages.
Kaplan–Meier curves were used to display cumulative
risks, and Cox proportional-hazards models adjusted
for geographic region and the randomization
stratification factor were used to estimate the hazard
ratios and 95% confidence intervals for the effect of
efpeglenatide (with data from both dose groups
combined) on the primary and secondary outcomes.
Sample size was calculated with the use of PASS 13
software (NCSS), and all other statistical analyses
were performed with the use of SAS software, version
9.4 (SAS Institute).
18. Result
A total of 5732 patients underwent screening between
May 11, 2018, and April 25, 2019. Eligibility criteria
were met by 4076 participants, who then underwent
randomization — 1359 participants were assigned to
receive the 4-mg dose of efpeglenatide, 1358 to
receive the 6-mg dose of efpeglenatide, and 1359 to
receive placebo.
Follow-up ended on December 10, 2020, after a
median follow-up period of 1.81 years (interquartile
range, 1.69 to 1.98), for a total follow-up of 7395.4
person-years.
At that time, status with respect to the primary
outcome was known for 3941 of the 4076 participants
(96.7%), and the vital status was known for 4073
(99.9%).
The participants assigned to receive efpeglenatide
were exposed to the drug for 88.9% of their maximum
18
19. Cont’d
19
A total of 4076 participants were enrolled; 2717 were
assigned to receive efpeglenatide and 1359 to receive
placebo.
During a median follow-up of 1.81 years, an incident
MACE occurred in 189 participants (7.0%) assigned to
receive efpeglenatide (3.9 events per 100 person-years)
and 125 participants (9.2%) assigned to receive placebo
(5.3 events per 100 person-years) (hazard ratio, 0.73; 95%
confidence interval [CI], 0.58 to 0.92; P<0.001 for
noninferiority; P = 0.007 for superiority).
A composite renal outcome event (a decrease in kidney
function or macroalbuminuria) occurred in 353 participants
(13.0%) assigned to receive efpeglenatide and in 250
participants (18.4%) assigned to receive placebo (hazard
ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001).
Diarrhea, constipation, nausea, vomiting, or bloating
occurred more frequently with efpeglenatide than with
placebo.
20. Cont’d
20
The mean (±SD)age of the participants was 64.5±8.2;
1954 (47.9%) were younger than 65 years of age, and
1344 (33.0%) were female.
A total of 3650 participants (89.6%) had a history of
cardiovascular disease, had1287 (31.6%) an eGFR
of less than 60 ml per minute per 1.73 m2, 888
(21.8%) had both cardiovascular disease and a low
eGFR, and 618 (15.2%) were using an SGLT2
inhibitor at baseline.
During follow-up, 189 of 2717 participants (7.0%)
assigned to receive efpeglenatide and 125 of 1359
participants (9.2%) assigned to receive placebo had
at least one MACE (3.9 vs.5.3 events per 100 person-
years; hazard ratio, 0.73; 95% confidence interval
[CI], 0.58 to 0.92; P<0.001 for noninferiority at both
the 1.8 and1.3 margins and P = 0.007 for superiority).
25. Cont’d
25
The effect of efpeglenatide on least-squares mean
differences in continuous variables (efpeglenatide vs.
placebo) during the follow-up period included a glycated
hemoglobin level that was lower by 1.24% (95% CI, 1.17
to 1.32); a bodymass index (the weight in kilograms
divided by the square of the height in meters) that was
lower by 0.9 (95% CI, 0.8 to 1.0); a body weight that was
lower by 2.6 kg (95% CI, 2.3 to 2.9); systolic and diastolic
blood pressures that were lower by 1.5 mm Hg (95% CI,
0.8 to 2.2) and 0.6 mm Hg (95% CI, 0.2 to 1.0),
respectively; a pulse pressure that was lower by 2.1 mm
Hg (95% CI, 1.4 to 2.7); a heart rate that was higher by 3.9
beats per minute (95% CI, 3.4 to 4.4); a lowdensity
lipoprotein cholesterol level that was lower by 2.7 mg per
deciliter (95% CI, 1.2 to 4.6) (0.07 mmol per liter [95% CI,
0.03 to 0.12]); a urinary albumin-to-creatinine ratio that
was lower by 21% (95% CI, 14 to 28), and a least-squares
29. Discussion
29
In this cardiovascular outcomes trial, weekly
subcutaneous injections of efpeglenatide (4 or 6
mg) for a median of 1.8 years led to a 27% lower
risk of incident MACE and a 32% lower risk of a
composite renal outcome event than placebo
among persons with type 2 diabetes and either a
history of cardiovascular disease or current
kidney disease.
The participants in the two efpeglenatide groups
had gastrointestinal adverse events (as have also
been observed in prior trials of other GLP-1
receptor agonists), but there was no evidence of
retinal, pancreatic, or thyroidrelated events.
30. Cont’d
30
The previously reported salutary effects of GLP-1
receptor agonists on cardiovascular and renal
outcomes were observed in our trial population,
which included more high-risk patients and had a
higher prevalence of kidney disease than seven
previously completed cardiovascular outcomes
trials of GLP-1 receptor agonists.
It observed a high incidence of MACE in the
placebo group (5.3 per 100 person-years), but the
hazard ratio was 27% lower among the
participants assigned to receive efpeglenatide.
31. Cont’d
31
The drug significantly reduced several risk factors
for both cardiovascular and kidney disease,
including glycated hemoglobin level, blood
pressure, body-mass index, lowdensity lipoprotein
cholesterol level, eGFR, and the albumin-to-
creatinine ratio.
The results showed that efpeglenatide reduces
the risk of serious adverse cardiovascular and
renal events among persons with type 2 diabetes
and either a history of cardiovascular disease or
current kidney disease.
32. Strength
32
High adherence and retention, the recruitment of a
high-risk population for the assessment of
cardiovascular and renal outcomes, and the inclusion
of an appreciable number of participants who were
receiving an SGLT2 inhibitor.
It mentioned the dose of efpeglenatide and route of
administration
It mentioned side effects of efpeglenatide
It participated males and 1344 (33.0%) females
It stated hypothesis, limitation and strength
It presented the results clearly
The authors are qualified
It had ethical considerations
33. Weakness
33
short follow-up period, the occurrence of a primary
outcome event in a lower number of participants than
originally planned (314 vs. 330), and selection for
previous cardiovascular or kidney disease,which limit
the power of our trial and its generalizability to lower-
risk persons with type 2 diabetes.
Since it was funded and collected data by sanofi (a
pharmaceutical comapany) it may be biased
Some of the countries included in the study were not
mentioned
Majority of the participants in both efpeglenatide and
placebo were white race totally 3534 (86.7)
34. Conclusion
34
In this trial involving participants with type 2
diabetes who had either a history of
cardiovascular disease or current kidney disease
plus at least one other cardiovascular risk factor,
the risk of cardiovascular events was lower
among those who received weekly subcutaneous
injections of efpeglenatide at a dose of 4 or 6 mg
than among those who received placebo.