Robert H. Eckel, MD, Division of Endocrinology, Metabolism, and Diabetes, Division of Cardiology, University of Colorado Anschutz Medical Campus speaks about Review Article - Cardiovascular effects of omega-3 fatty acids: Hope or hype?
After a clinical trial (REDUCE-IT) revealed excellent outcomes with icosapent ethyl (IPE) in patients undergoing maximally tolerated statin treatment, omega-3 fatty acids have emerged as a novel alternative for reducing the residual risk of cardiovascular disease (CVD) in the statin era. Another experiment (STRENGTH) that employed a high dose of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combination failed. These findings pose clinically significant issues when taken together. Are the effects of omega-3 fatty acids neutral, helpful, or perhaps detrimental in individuals on statin therapy? Different kinds of omega-3 fatty acids (just EPA or EPA + DHA), dosages (greater vs. lower dose) of omega-3 fatty acids, or comparators (corn oil or mineral oil), as well as the underlying severity of the CVD risk or usage of statins, might explain the present conflicting results. In addition to these topics, we will examine the biological and clinical consequences of various kinds of omega-3 fatty acids, as well as how to assess the findings of historical and current clinical research and provide practical recommendations for patient treatment.
Hertzel C. Gerstein, MD, MSc, FRCPC, professor and population health institute chair in diabetes research at McMaster University and Hamilton Health Sciences speaks about AMPLITUDE-O: Efpeglenatide reduces CV events, CKD progression in high-risk type 2 diabetes. American Diabetes Association Scientific Sessions.
Data demonstrate that a new GLP-1 receptor agonist decreased cardiovascular event risk by 27% and renal disease progression by 32% in high-risk people with type 2 diabetes, with or without prior SGLT2 inhibitor treatment, when compared to placebo.
The AMPLITUDE-O trial found that weekly efpeglenatide, an investigational exendin-4-based GLP-1 receptor agonist, was safe for high-risk patients and had CV and renal benefits comparable to other human-based GLP-1 receptor agonists in the class, according to data presented at the American Diabetes Association Scientific Sessions and simultaneously published in The New England Journal of Medicine, according to Hertzel. According to him, the study was also the first major CV outcomes trial to evaluate the use of a GLP-1 receptor agonist in a population on background SGLT2 inhibitor treatment, which accounted for 15% of the trial participants.
GLP-1 effects in nonhumans
Four GLP-1 receptor agonists with human GLP-1-like structures have been demonstrated to lower the incidence of cardiovascular events in individuals with type 2 diabetes. The impact of efpeglenatide, an exendin-4-based GLP-1 receptor agonist, on cardiovascular and renal outcomes in high-risk people with type 2 diabetes remains unknown.
Gerstein and colleagues looked at data from 4,076 people with type 2 diabetes, a history of CVD or renal disease, and at least one CV risk factor (mean age, 65 years; 33 percent women; 87 percent white), who were recruited from 344 locations in 28 countries. The average duration of diabetes was 15.4 years, and 90 percent of the participants had previous CVD, with 32 percent having a glomerular filtration rate of less than 60 mL/min/1.73 m2. Researchers randomly allocated patients to receive weekly subcutaneous efpeglenatide 4 mg or 6 mg (n = 2,717) or placebo (n = 1,359), with SGLT2 inhibitor usage (n = 618) stratifying randomization.
The main outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unexplained causes as the first major adverse CV event.
During a median follow-up of 1.81 years, major adverse CV events occurred in 189 participants (7%) who were given efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) who were given placebo (5.3 events per 100 person-years), for an HR of 0.73 (95 percent CI, 0.58-0.92; P =.0069 for superiority). The HR for efpeglenatide vs. placebo for the secondary expanded outcome of significant adverse CV events, coronary revascularization, or unstable angina was 0.79. (95 percent CI, 0.65-0.96).
C. Michael Gibson, MD, CEO non-profit Baim / PERFUSE Research Institute, Harvard Professor, Cardiologist BIDMC, Founder & Chairman WikiDoc.org speaks about ACC 2021 Abstract - 1063-07 - Association Of Cholesterol Efflux Capacity With Adverse Cardiovascular Outcomes - A Meta Analysis
The principal process by which macrophages remove cholesterol from atherosclerotic plaque is reverse cholesterol transport. A systematic literature review and meta-analysis were done to investigate the relationship between cholesterol efflux capacity (CEC), a measure of high-density lipoprotein (HDL) function, and poor cardiovascular (CV) events.
A literature study was conducted to gather papers that looked at the link between CEC and CV outcomes. Adverse CV events, a composite of incident atherosclerotic CV disease (acute coronary syndrome, stroke/transient ischemic attack, revascularization, or new atherosclerotic plaque), or all-cause death, were the main outcomes.
The following are the outcomes:
Twenty investigations yielded a total of 25,132 individuals. High CEC levels were linked with a 37 percent decreased risk of the main outcome when compared to low CEC levels (RR=0.63; 95 percent CI, 0.52-0.76; P0.00001; Figure A). A 20 percent decreased risk of unfavorable CV events was related with every SD rise in CEC (HR=0.80; 95 percent CI, 0.66-0.97; P=0.02). After controlling for CV risk factors, medicines, and HDL concentration, the link remained significant (HR=0.76; 95 percent CI, 0.63-0.91; P=0.004). There was a 5% risk decrease in unfavorable CV events for every 0.1 unit rise in CEC (RR=0.95; 95 percent CI, 0.91-0.99; Figure B).
Higher CEC is linked to less negative CV outcomes. These findings call for more research on CEC as a possible therapeutic target in order to enhance clinical outcomes.
A. Michael Lincoff, MD, Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University speaks about Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design.
CVD is a leading cause of morbidity and mortality in the United States. While it is widely accepted that obesity is a major risk factor for CVD, successful, long-term weight loss therapies and the effects of weight loss on lowering cardiovascular risk have remained elusive. Instead, drugs for managing lipids, hyperglycemia, blood pressure, heart disease, inflammation, and/or thrombosis have made progress in lowering CVD risk. Obesity has been linked to many of these problems, implying that sustained, successful weight loss may have a separate cardiovascular gain. GLP-1 receptor agonists (RAs) help people with diabetes lose weight, boost their glycemia, and reduce cardiovascular events. They can also have other cardioprotective effects. At a dosage of 2.4 mg subcutaneously (s.c.) once weekly, the GLP-1 RA semaglutide is in phase 3 trials as an obesity treatment. SELECT (Semaglutide Impact on Cardiac Disease and Stroke in Patients with Overweight or Obesity) is a randomized, double-blind, parallel-group study to see whether semaglutide 2.4 mg subcutaneously once weekly is better than placebo at preventing significant adverse cardiovascular events in patients with proven CVD and overweight or obesity but no diabetes when added to standard of care. SELECT is the first cardiovascular outcomes study to measure an antiobesity medication's superiority in reducing significant adverse cardiovascular conditions in this population. As a result, SELECT has the ability to advance novel approaches to lowering CVD risk while also addressing obesity.
Design and care of the overall sample
SELECT (NCT03574597, www.clinicaltrials.gov) is a randomized, double-blind, parallel-group, placebo-controlled study that compares semaglutide to placebo as an alternative to the standard of care for the prevention of major adverse cardiovascular events (MACE) in patients with existing CVD who are overweight or obese. Novo Nordisk is the main sponsor of the trial. Every participating center's institutional review board and ethics committee approved the trial protocol. Before any trial-related operation, all patients gave written informed consent.
Figure 1 portrays a high-level overview of SELECT's core design elements. Once-weekly subcutaneous (sc) semaglutide 2.4 mg or placebo is given to patients in a 1:1 ratio. Patients are started on a once-weekly dose of 0.24 mg, which is increased every four weeks (to doses of 0.5, 1.0, 1.7, and 2.4 mg/wk) before they hit the target dose of 2.4 mg after 16 weeks. To minimize the possibility of side effects, the procedure is versatile, allowing for prolonged escalation and treatment pauses if appropriate. The investigators will receive ongoing support from a Global Exert Panel, which is made up of local experts with experience in CVOTs and GLP-1RA use, and there will be a strong emphasis on educating and encouraging them during the trial. Since the most common side effects are gastrointestinal (nausea, vomiting, diarrhea, and constipation), manuals for clinicians and patients have been established and distributed. Overall, trial behavior places a heavy emphasis on maximizing trial product exposure. The management of cardiovascular risk factors is emphasized in the SELECT trial to ensure that patients meet international recommendations for quality of care. Investigators are given guidelines in the form of a standard-of-care document that is revised on a regular basis.
The patient is in touch with the investigator every 13th week during the trial to ensure retention and compliance, as well as to optimize care. During the first months of the study, site visits are more frequent to help the patient during the dose-escalation phase. Detailed tracking and recording of treatment pauses, missed visits, and possible loss of follow-up is done during the study. To ensure a high retention rate and ongoing support for investigators and patients involved in Pick, a number of mitigation steps have been introduced.
Numbers of people
Around 17,500 volunteers will be enrolled in the study from over 750 locations around the world, including locations on all six continents (Africa, Asia, Oceania, Europe, and North and South America). The first patient was randomized in November 2018, and the trial is planned to last 5 years, despite being event-driven. Patients must be at least 45 years old, have a BMI of 27 kg/m2, and have a history of CVD. Prior myocardial infarction (MI), prior ischemic or hemorrhagic stroke, symptomatic peripheral arterial disease (PAD) with an ankle-brachial index of less than 0.85 at rest, prior peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease are all examples of proven CVD. Patients with hemoglobin A1c (HbA1c) ≥48 mmol/mol (6.5%); with a history of type 1 or type 2 diabetes; or who had suffered MI, stroke, hospitalization for unstable angina pectoris, or a transient ischemic attack within 60 days of screening are excluded. The full eligibility requirements can be found in Table I. Patients who acquire diabetes during the study are held in the study and given concomitant diabetes medication (excluding other GLP-1 RAs) at the investigator's discretion.
Prof. Dr. John J.P. Kastelein of the Department of Vascular Medicine, Amsterdam UMC, and the University of Amsterdam speaks about New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4.
Novel, emerging low-density lipoprotein cholesterol (LDL-C)–lowering therapies are under development for the prevention of cardiovascular disease, adding to the base of statins, ezetimibe, and proprotein convertase subtilisin–kexin type 9 inhibitors (PCSK9i). Inclisiran, a PCSK9-inhibiting small interfering RNA molecule that only needs to be dosed twice a year, has the ability to help address existing obstacles to lipid-lowering therapy persistence and adherence. Patients with statin intolerance can benefit from bempedoic acid, which lowers LDL-C upstream from statins. In patients with homozygous familial hypercholesterolemia, angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering without the significant side effects seen with lomitapide and mipomersen, and may minimize the need for apheresis. Finally, with the production of obicetrapib, CETP inhibitors may still be effective. From primary prevention and secondary prevention to null-null homozygous hereditary hypercholesterolemia patients, these novel agents provide clinicians the resources they need to effectively lower LDL-C across the entire spectrum of LDL-C–induced elevations of cardiovascular danger.
Aspects to Consider
• Despite existing methods, atherosclerotic cardiovascular disease continues to be a major problem.
• Low-density lipoprotein cholesterol (LDL-C) is a significant cause of atherosclerotic cardiovascular disease.
• The most commonly used pharmacological agents for reducing LDL-C are statins, ezetimibe, and PCSK9 inhibitor monoclonal antibodies.
• Inclisiran, bempedoic acid, ANGPTL3, and CETP inhibitors, all of which are still in production, have the potential to reduce residual LDL-C risk.
According to a recent study, regardless of the procedure used to increase ketone bodies' presence in the heart, they could have therapeutic benefits for patients with cardiovascular disease (CVD).
The authors examined the current body of experimental and clinical research on the potential function of ketone bodies in improving CVD and discovered that increasing circulating ketone levels can provide protective benefits in patients with the disease.
A ketogenic diet, which consists of a very low carbohydrate and high-fat intake, is a common way to induce ketosis; however, exogenous ketones could be a viable and superior alternative to the diet for increasing circulating ketone bodies, according to the researchers.
The study was published in the Journal of the American College of Cardiology on February 23.
This realization prompted Westenbrink and colleagues to conduct a clinical trial to examine the impact of exogenous ketones on exercise efficiency in patients with heart failure.
The aim of this review was to "summarize the existing literature from animal and human studies, in the hopes of facilitating more research into the benefits of ketones as therapeutic agents in CVD."
Beyond Fuel Efficiency
The authors have looked at the processes of ketone metabolism, such as ketogenesis and ketolysis, as well as cardiac metabolism in both healthy and diseased hearts.
The reactions that lead to the formation of the ketone bodies acetoacetate (AcAc), -hydroxybutyrate (OHB), and acetone are known as ketogenesis.
Fasting causes a reduction in the insulin-to-glucagon ratio, which mobilizes fatty acids, which the liver then converts into ketone bodies. They are then moved to peripheral tissues, where they go through a process known as "terminal oxidation."
The heart appears to "reprogram metabolism to increased dependence on ketone bodies as a fuel source" as heart failure progresses, according to the authors, with increased circulating ketone concentrations and cardiac ketone consumption.