Podcasts about Dapagliflozin

Dapagliflozin in Patients Undergoing Transcatheter Aortic Valve Implantation

The FiltrateJoel TopfAC GomezSophia AmbrusoNayan AroraSpecial Guest Charles Edelstein, MD, PhD Professor, Medicine-Renal Med Diseases/HypertensionExtra-Special GuestMichelle Rheault, MD Professor of Pediatrics, University of MinnesotaEditing bySimon and Joel TopfThe Kidney Connection written and performed by by Tim YauShow NotesKDIGO ADPKD Guidelines:WebsiteGuideline PDFExecutive Summary PDFNephJC coverageConsortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP)Hy's Law (Wikipedia) has three components:ALT or AST by 3-fold or greater above the upper limit of normalAnd total serum bilirubin of greater than 2× the upper limit of normal, without findings of cholestasis (defined as serum alkaline phosphatase activity less than 2× the upper limit of normal)And no other reason can be found to explain the combination of increased aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of causing the observed injuryMeeting this definition yields a very high risk of fulminant kidney failure (76% in one series)Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database (PubMed) Two of 957 patients on tolvaptan met Hy's law criteria. None had fulminant kidney failure.Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial (PubMed) Patients had a baseline urine volume on tolvaptan of 6.9 L/24 h. Urine volume decreased to 5.1 L/24 h with hydrochlorothiazide and to 5.4 L/24 h on metformin.TEMPO 3:4 Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (NEJM)Reprise Trial Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease ( NEJM | NephJC )Unified ultrasonographic diagnostic criteria for polycystic kidney disease by Edelstein in JASN (PubMed)Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies (PubMed)Charles' draft choice Recommendation 4.1.1.1: We recommend initiating tolvaptan treatment in adults with ADPKD with an estimated glomerular filtration rate (eGFR) ‡25 ml/min per 1.73 m2 who are at risk for rapidly progressive disease (1B).Sophia's draft choice Recommendation 1.4.2.1: We recommend employing the Mayo Imaging Classi cation (MIC) to predict future decline in kidney function and the timing of kidney failure (1B).Progression to kidney failure in ADPKD: the PROPKD score underestimates the risk assessed by the Mayo imaging classification (Frontiers of Science)AC's draft choice Recommendation 9.2.1: We recommend targeting BP to ≤ 50th percentile for age, sex, and height or ≤ 110/70 mm Hg in adolescents in the setting of ADPKD and high BP (1D).HALT-PKD Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease (NEJM)Nayan's draft choice Recommendation 6.1.2: We recommend screening for ICA in people with ADPKD and a personal history of SAH or a positive family history of ICA, SAH, or unexplained sudden death in those eligible for treatment and who have a reasonable life expectancy (1D).Screening for Intracranial Aneurysms in Patients with Autosomal Dominant Polycystic Kidney Disease (CJASN)Surgical Clipping Versus Endovascular Coiling in the Management of Intracranial Aneurysms (PubMed) Clipping is associated with a higher rate of occlusion of the aneurysm and lower rates of residual and recurrent aneurysms, whereas coiling is associated with lower morbidity and mortality and a better postoperative course.Joel's editorial pick Recommendation 6.1.1: We recommend informing adults with ADPKD about the increased risk for intracranial aneurysms (ICAs) and subarachnoid hemorrhage (1C).Joel's first draft pick The bring out your dead pick:Recommendation 4.3.1: We recommend not using mammalian target of rapamycin (mTOR) inhibitors to slow kidney disease progression in people with ADPKD (1C).Recommendation 4.4.1: We suggest not using statins specfiically to slow kidney disease progression in people with ADPKD (2D).Recommendation 4.5.1: We recommend not using metformin specifically to slow the rate of disease progression in people with ADPKD who do not have diabetes (1B).Recommendation 4.6.1: We suggest that somatostatin analogues should not be prescribed for the sole purpose of decreasing eGFR decline in people with ADPKD (2B).Perfect match: mTOR inhibitors and tuberous sclerosis complex (Orphanet Journal of Rare Diseases)Navitor Pharmaceuticals Announces Janssen Has Acquired Anakuria Therapeutics, Inc. (BioSpace) This is press release about acquiring the mTor1 inhibitor.Joel's second draft pick Recommendation 4.2.1.1: We suggest adapting water intake, spread throughout the day, to achieve at least 2–3 liters of water intake per day in people with ADPKD and an eGFR ≥ 30 ml/min per 1.73 m2 without contraindications to excreting a solute load (2D).Nayan's bonus draft Practice Point 4.7.1: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) should not be used to slow eGFR decline in people with ADPKD.Open-Label, Randomized, Controlled, Crossover Trial on the Effect of Dapagliflozin in Patients With ADPKD Receiving Tolvaptan (KIReports)SMART Trial of GLP-1ra in non-diabetics: Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial (PubMed)Tubular SecretionsNayan: Landman on Paramount Plus (IMDB)Sophia: PassNayan: steps in with The Pitt on HBO (Wikipedia)Charles: The White Lotus, Yellowstone 1923, Poirot (IMDB)AC: The PittMichael Crichton's Estate Sends The Pitt to the Courtroom (Vulture)Joel: I Must Betray you by Ruta Sepetys (Amazon)

Program notes:0:33 TAVR outcomes improved1:33 Dapagliflozin 2:33 Looked at comorbidities3:00 Tolebrutinib for relapsing MS4:00 Annualized relapse rate5:00 Works in the CNS6:00 First endpoint wasn't proven6:20 Invasive group A strep7:20 Become more resistant to antibiotics8:01 Not a single type of group A strep8:25 Hearing loss and heart failure9:25 Psychological distress mediiates10:25 With hearing aids, you would think it would go down11:20 Everything looks associated12:03 End

Trials from the 2025 American College of Cardiology scientific sessions, including the WARRIOR, PROTECT TAVI, DAPATAVI, and SOUL are reviewed by John Mandrola, MD This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I Thank you Comments II WARRIOR Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD Keep Fighting INOCA After Neutral WARRIOR Trial https://www.medscape.com/viewarticle/keep-fighting-inoca-after-neutral-warrior-trial-2025a10007uf III Cerebral Embolic Protection in TAVI PROTECT TAVI https://www.nejm.org/doi/full/10.1056/NEJMoa2415120 PROTECTED TAVR https://www.nejm.org/doi/full/10.1056/NEJMoa2204961 Instrumental Variables in Randomized Trials https://evidence.nejm.org/doi/10.1056/EVIDctw2400204 IV  DAPATAVI SGLT2 Inhibitors Progressing to New Standard After TAVI https://www.medscape.com/viewarticle/sglt2-inhibitors-progressing-new-standard-after-tavi-2025a100081y Dapagliflozin in Patients Undergoing Transcatheter Aortic-Valve Implantation https://www.nejm.org/doi/full/10.1056/NEJMoa2500366 V SOUL Study of Oral Semaglutide and CV outcomes in Diabetes Oral GLP-1 Receptor Agonist Reduces CV Risk https://www.medscape.com/viewarticle/oral-glp-1-receptor-antagonist-reduces-cv-risk-2025a10007kr Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes https://www.nejm.org/doi/full/10.1056/NEJMoa2501006 You may also like: The Bob Harrington Show with the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Send us a textEpisode 112 - Top Papers from the 2025 American College of Cardiology (ACC) SessionWelcome back Rounds Table Listeners! We are back today with a special Rapid Fire Podcast! This week, Drs. Mike and John Fralick discuss top papers from the 2025 American College of Cardiology (ACC) Annual Scientific Session. Hot off the presses, here we go!Extended Reduced-Dose Apixaban for Cancer-Associated Venous Thromboembolism (0:00 - 5:55)Dapagliflozin in Patients Undergoing Transcatheter Aortic-Valve Implantation (DapaTAVI) (5:56 - 9:51)Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes (9:52 - 14:04)Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE) (14:05 - 18:36)The Good Stuff:The Studio TV series on Apple (18:37 - 19:11)Cardiology Trial Files (19:12 - 20:40)Questions? Comments? Feedback? We'd love to hear from you! @roundstable @InternAtWork @MedicinePodsSupport the show

Send us a textWelcome back Rounds Table Listeners! We are back today with a special Rapid Fire Podcast! This week, Drs. Mike and John Fralick discuss top papers from the 2025  American College of Cardiology (ACC) Annual Scientific Session. Hot off the presses, here we go!Extended Reduced-Dose Apixaban for Cancer-Associated Venous Thromboembolism (0:00 - 5:55)Dapagliflozin in Patients Undergoing Transcatheter Aortic-Valve Implantation (DapaTAVI) (5:56 - 9:51)Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes (9:52 - 14:04)Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE) (14:05 - 18:36)The Good Stuff:The Studio TV series on Apple (18:37 - 19:11)Cardiology Trial Files (19:12 - 20:40)Questions? Comments? Feedback? We'd love to hear from you! @roundstable @InternAtWork @MedicinePods

In this special episode on Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) our host, Dr. Neil Skolnik will lead a case-based discussion on HFpEF, presenting challenges and integration of emerging evidence into clinical practice. This special episode is supported by an independent educational grant from Roche. Presented by: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health Susan Kuchera, M.D. - Clinical Assistant Professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University and Program Director of the Family Medicine Residency at Jefferson Health Abington. Muthu Vaduganathan M.D. - Cardiologist and Co-Director, Center for Cardiometabolic Implementation Science at Brigham and Women's Hospital and Harvard Medical School; Associate Editor of the Journal of the American College of Cardiology.   Selected references referred to the in the Podcast: Heart Failure: An Underappreciated Complication of Diabetes. A Consensus Report of the American Diabetes Association.  Diabetes Care 2022  2023 American College of Cardiology Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction (HFpEF). Journal of the American College of Cardiology 2023 Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction. JAMA Cardiology 2022;7(12):1259-1263    

Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association's four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 25 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update   discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. Welcome to diabetes core update where every month we go over the most important articles to come out in the field of diabetes. Articles that are important for practicing clinicians to understand to stay up with the rapid changes in the field.  This issue will review: 1.     Dapagliflozin plus calorie restriction for remission of type 2 diabetes 2.     Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity 3.     Effectiveness of Empagliflozin vs Dapagliflozin for Kidney Outcomes in Type 2 Diabetes 4.     Tirzepatide Associated With Reduced Albuminuria in Participants With Type 2 Diabetes 5.     Use of SGLT2i Versus DPP-4i as an Add-On Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery)   For more information about each of ADA's science and medical journals, please visit Diabetesjournals.org. Hosts: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Chair-Department of Family Medicine, Abington Jefferson Health

It's In the News.. a look at the top headlines and stories in the diabetes community. This week's top stories: Dexcom updates investors on its 15-day sensor, TrialNet marks a big anniversary, Beta Bionics goes public, NFL fans support Mark Andrews and much more! Find out more about Moms' Night Out  Please visit our Sponsors & Partners - they help make the show possible! Learn more about Gvoke Glucagon Gvoke HypoPen® (glucagon injection): Glucagon Injection For Very Low Blood Sugar (gvokeglucagon.com) Omnipod - Simplify Life Learn about Dexcom  Edgepark Medical Supplies Check out VIVI Cap to protect your insulin from extreme temperatures Learn more about AG1 from Athletic Greens  Drive research that matters through the T1D Exchange The best way to keep up with Stacey and the show is by signing up for our weekly newsletter: Sign up for our newsletter here Here's where to find us: Facebook (Group) Facebook (Page) Instagram Twitter Check out Stacey's books! Learn more about everything at our home page www.diabetes-connections.com  Reach out with questions or comments: info@diabetes-connections.com Episode transcription with links: Hello and welcome to Diabetes Connections In the News! I'm Stacey Simms and every other Friday I bring you a short episode with the top diabetes stories and headlines happening now. XX Couple of quick updates from the JP Morgan Healthcare Conference. Dexcom's CEO Kevin Sayer expects to launch a 15-day sensor in the second half of the year. That's in front of the FDA right now. Competitor Abbott currently has 15-day sensors with its Freestyle Libre 2 Plus and Freestyle Libre 3 Plus devices, which the FDA cleared in 2023. Sayer also talked about expanded insurance coverage for the G7, to include more people with type 2. They haven't pursued that with Stelo, the OTC version of their sensors. The company has begun work on a next-generation CGM. Sayer said the sensor will be smaller, less expensive and include better electronics. Dexcom is also studying new sensor probes, one of which can support multiple analytes, such as measuring lactate or ketones in addition to insulin.   https://www.medtechdive.com/news/dexcom-ceo-stelo-otc-strategy-jp-morgan/737424/ XX TrialNet reaches a big milestone – more than a quarter million people have learned their risk of developing T1D through screening. TrialNet screening is available to family members of those diagnosed with T1D. Having a family history of the disease places individuals at a 15 times greater risk than those with no family members with T1D. Over the course of VUMC's 18 years participating in the program, the community of T1D patients has become increasingly more engaged with research efforts. More than ever, there is an eagerness to give back to others by participating in clinical trials that could help revolutionize care for those diagnosed with or at risk of developing T1D. In such trials, TrialNet typically takes drugs already shown to be effective in treating other autoimmune diseases and seeks to determine their efficacy in treating, delaying or preventing T1D.   Spencer Mannahan, a 10-year-old patient at Monroe Carell Jr. Children's Hospital at Vanderbilt, is participating in a TrialNet study that is looking to determine whether a treatment regimen using both rituximab and abatacept can preserve insulin production in patients newly diagnosed with T1D. Russell, one of the PIs for the study (Protocol TN-25), also treated Spencer's father, Zach, when he was diagnosed with T1D as a child. She enrolled in a different TrialNet study (Protocol TN-31) examining the effect of abrocitinib and ritlecitinib on insulin production in newly diagnosed individuals. While the possibility exists that her insulin production could be preserved, O'Neal joined the study because it presented an opportunity to make a positive impact on future patients.     These clinical trials support TrialNet's goal of a future without T1D. Research is underway on new methods of blocking the advance of T1D in patients with diabetes-related antibodies. One study will investigate whether T cells that have been activated against insulin can be specifically targeted, rather than issuing a treatment that targets all the body's T cells (thus rendering the patient immunocompromised).   TrialNet, the largest clinical trial network assembled to change the course of Type 1 diabetes, is funded by the National Institutes of Health through grant number NCT00097292.   For more information about screening for Type 1 diabetes risk if it runs in your family, contact info@trialnet.org, visit www.trialnet.org, or contact the Vanderbilt Type 1 Diabetes TrialNet Program at 615-936-8638. https://news.vumc.org/2025/01/22/milestone-in-vumc-affiliated-diabetes-screening-and-research-program-underscores-impact-of-clinical-trials/   XX Another study links air pollution to type 2 diabetes. This is from Wayne State University, and established a robust association between exposure to benzene, a prevalent airborne volatile organic compound, and insulin resistance in humans across all ages. “In this study, we exposed mice to benzene to see how it affects their blood glucose levels and energy expenditure,” she explained. “Our research revealed that within seven days of exposure, they developed high blood glucose insulin levels.” https://today.wayne.edu/medicine/news/2025/01/23/study-links-air-pollution-exposure-to-type-2-diabetes-susceptibility-65321 XX Adults with overweight or obesity and type 2 diabetes who are given the sodium glucose cotransporter 2 (SGLT-2) inhibitor drug dapagliflozin alongside moderate calorie restriction achieve much higher rates of remission compared with calorie restriction alone. The researchers say this study provides a practical strategy to achieve remission for patients with early type 2 diabetes. As well as helping to lower blood sugar levels, SGLT-2 inhibitors can also lead to weight loss, but their effect alongside calorie restriction on diabetes remission has not yet been investigated in a randomised controlled trial.   To address this, researchers carried out a trial involving 328 patients with type 2 diabetes of less than six years' duration at 16 centres in mainland China from 12 June 2020 to 31 January 2023.   Participants were aged 20-70 years with a body mass index (BMI) greater than 25 and were not taking any anti-diabetic medication other than metformin. https://www.news-medical.net/news/20250123/Dapagliflozin-and-calorie-restriction-show-higher-remission-rates-in-type-2-diabetes.aspx XX Beta Bionics has set the terms for its plan to go public, with a goal of raising at least $114 million to support its artificial pancreas system for people with Type 1 diabetes. That's as we're recroding, it's likely they will have begun trading on the NASDAQ by now.. the ticker is BBNX. Beta Bionics' iLet system was first cleared by the FDA for people ages six and up with Type 1 diabetes in May 2023. The Fierce Medtech Fierce 15 winner has since expanded its blood sugar sensor compatibility to include Abbott's FreeStyle Libre and Dexcom's G6 and G7 platforms. The company also said it plans to pursue new clinical studies and an FDA clearance that would enable the iLet's use among people with Type 2 diabetes. The ultmite goal is to have a dual-chambered pump with both insulin and glucagon.. but I didn't find anything about that in the articles about this IPO.. I followed up with Beta Bionics and they told me that the dual chambered pump is still very much the goal. Not sure why most of the publications left that out.. but good to hear. https://www.fiercebiotech.com/medtech/artificial-pancreas-maker-beta-bionics-aims-raise-120m-nasdaq-ipo XX Large new study estimates the size of the current US population with type 1 diabetes and project growth over the next ten years. They say about 2 million live with type 1.. about 1.79 million adults and 290-thousand children. Growth in the ten years is predicted to be about 10% https://jheor.org/article/124604 XX The American Diabetes Association® (ADA) teams up with Xeris Pharmaceuticals® makers of Gvoke – ready to use emergency glucagon. It is estimated that up to 46% of people with type 1 diabetes and 21% of those with type 2 diabetes using insulin experience at least one severe hypoglycemia event each year.2 The ADA, with support from Xeris, seeks to rectify the low rates of appropriate glucagon prescriptions by developing education materials and training resources for health care professionals and people living with diabetes, as well as through a national awareness campaign to educate people on who is at risk for severe hypoglycemia and should have glucagon, preferably ready-to-use, as a safety net. https://www.prnewswire.com/news-releases/the-american-diabetes-association-and-xeris-pharmaceuticals-announce-national-collaboration-to-provide-life-saving-hypoglycemia-education-and-awareness-302355703.html XX XX Wearing a CGM makes pharmacy students better at counseling patients. New study randomly assigned students to wear a CGM during lab sessions.. those who did had a higher average counseling score during the encounter with a patient and a higher overall confidence score. There was also a statistically significant positive correlation between average confidence and average empathy, and empathy and counseling performance. https://www.drugtopics.com/view/hands-on-cgm-training-helps-student-pharmacists-prepare-for-career XX Mark Andrews Bills Mafia Baltimore Ravens tight end Mark Andrews received a host of negative attention after flubbing a potential game-tying two-point conversion in Sunday night's loss to the Buffalo Bills.   In the face of the online rage, Bills Mafia is again showing some support.   Bills fan Nicholas Howard kicked off a GoFundMe to back Breakthrough T1D, a global Type 1 diabetes research organization that Andrews has supported.   "As many of you know, Ravens TE wasn't able to catch the game-tying 2-point conversion and upset Ravens fans," Howard wrote. "On top of that, the TE has been receiving death threats and nasty comments after his performance last night. We want Bills Mafia to donate to Marks charity for [Type 1] diabetes."   As of Wednesday morning, the fund raised more than $50,000 for the charity.   Related Links Lamar Jackson, Ravens bemoan missed opportunities in loss to Bills, defend Mark Andrews Ravens WR Zay Flowers: Missing 2024 playoff run due to injury 'took a little toll on me' Biggest winners and losers from Sunday's Divisional Round NFL playoff games The Ravens thanked Bills fans for supporting Andrews.     "Shout out to Bills Mafia for showing support to our guy Mark Andrews and donating to the [BreakthroughT1D] organization, which works towards curing and improving the lives of those dealing with Type 1 diabetes," the club posted.   Andrews was diagnosed with Type 1 diabetes as a child, an autoimmune disease for which there is currently no cure. He's one of several NFL players diagnosed with Type 1 -- Kansas City Chiefs tight end Noah Gray is another.   "Breakthrough T1D [formerly JDRF] greatly appreciates the generosity of the Buffalo Bills community and the many fans who were compelled to donate after Sunday's game," the organization said in a statement to ESPN's Alaina Getzenberg. "These donations will support research and advocacy on behalf of the 1.6 million Americans who, like Mark Andrews, live with type 1 diabetes."   It's not the first time that Bills fans have donated to the cause of a non-Buffalo player. Back in January 2018, Buffalo fans famously donated to the charity of former Cincinnati Bengals quarterback Andy Dalton after his win over Baltimore helped Buffalo make its first playoff appearance in nearly two decades. Over and over again, Bills Mafia has shown it will support a good cause when some spew hate. https://www.nfl.com/news/bills-fans-supporting-ravens-te-mark-andrews-after-drop-by-donating-to-type-1-diabetes-research

Welcome to the 44th episode of my drug pronunciation series. As we go through the alphabet from A-Z, we're on the letter “D” for dapagliflozin.    In this episode, I break down dapagliflozin (generic name) and Farxiga (brand name) into syllables, tell you which syllables to emphasize, and share my sources.  The written pronunciations are helpful.  Find them below

Join our scientific team in the discussion of the 3 most clinically impactful papers of the month, the crème de la crème of our weekly top picks. This month we're discussing:   Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging. A Systematic Review and Meta-Analysis https://jamanetwork.com/journals/jama/article-abstract/2823869   The Effect of Dapagliflozin on Accelerometer-Based Measures of Physical Activity in Patients with Heart Failure: An Analysis of the DETERMINE Trials https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.124.012349   Islet-after-kidney Transplantation versus Kidney Alone in Kidney Transplant Recipients with Type 1 Diabetes (KAIAK): a Population-based Target Trial Emulation in France https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00241-9/abstract   Scientific team: Ricardo Ladeiras Lopes, Mário Santos and João Sérgio Neves Discover Medical Portfolio App weekly top picks - the latest and most relevant papers, curated by our team of experts! https://linktr.ee/medicalportfolioapp

CardioNerds Drs. Jason Feinman, Gurleen Kaur, and Rick Ferraro discuss the implementation of SGLT inhibitors in clinical practice with Dr. Alison Bailey. Notes were drafted by Dr. Jason Feinman. In this episode, we discuss the implementation of SGLTi in clinical practice scenarios, including for individuals with heart failure regardless of ejection fraction, those with chronic kidney disease, and those with diabetes mellitus. The group also discusses important side effects to monitor for, as well as how to counsel patients when prescribing these medications. This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals. CardioNerds Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - Clinical Implementation of SGLT Inhibitors For patients with heart failure with reduced ejection fraction, SGLT inhibitors reduce the composite outcome of cardiovascular death or heart failure hospitalization by 25%. SGLT inhibitors can be safely started in patients with an eGFR as low as 20. There are ongoing trials investigating the safety of these medications in individuals with eGFR lower than 20 or those who are receiving dialysis. An eGFR decrease of 3-5 ml/min on average is expected after starting an SGLTi, but this will stabilize over time and provides protective effects of renal dysfunction in the long run. Early data that suggested an association between SGLTi and bacterial UTI development hasn't panned out in the long run, but there is an association between SGLTi and the development of either genital mycotic infections or yeast infections. Perineal hygiene is important to prevent the development of either. A patient-centered, shared decision-making approach should guide the choice of agents for individuals with type 2 diabetes mellitus. In certain patients, it may be reasonable to choose an SGLTi as the first-line agent. Show notes - Clinical Implementation of SGLT Inhibitors What is the data supporting the use of SGLTi in HFpEF? The EMPEROR-Preserved and DELIVER trials investigated the impact of empagliflozin and dapagliflozin, respectively, on cardiovascular outcomes in patients with mildly reduced or preserved ejection fraction. The SOLOIST-WHF trial investigated a combined SGLT1/2 inhibitor, sotagliflozin, in patients with recently worsening heart failure, irrespective of ejection.SGLTi have been demonstrated to reduce the risk of cardiovascular death or worsening heart failure, including heart failure hospitalization, in these individuals. A meta-analysis of the EMPEROR-Preserved and DELIVER trials demonstrated a hazard ratio of 0.80 for cardiovascular death or first hospitalization for heart failure for empagliflozin or dapagliflozin over placebo in the setting of HFpEF. What is the data supporting the use of SGLTi in HFrEF? In addition to the SOLOIST-WHF trial that was previously discussed, the EMPEROR-HF and DAPA-HF investigated the impact of SGLTi medications in patients with HFrEF. In patients with HFrEF, SGLTi medications have been demonstrated to reduce the risk of either cardiovascular death or heart failure hospitalization. Dapagliflozin and empagliflozin had a pooled risk reduction of all-cause death of 13%, a pooled risk reduction of cardiovascular death of 14%, and a 26% reduction in the combination of CV death or first hospitalization for heart failure. What is the expected impact of SGLTi on renal function? Dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, and canagliflozin have all been studied for their impact on renal dysfunction in individuals both with and without diabetes. In the CANVAS trial,

In this CCO Nephrology podcast episode, hear from nephrologists Pietro Canetta, MD, MS, and Andy Bomback, MD, PhD, experts in clinical management and research on glomerular diseases as they discuss key updates in managing IgAN. Faculty highlight the importance of a comprehensive supportive care regimen to protect patients' kidneys and prevent progression of disease. In addition, they review the merits and place in therapy of novel and emerging therapies.  Topics include:Supportive care as the foundation of IgAN managementPlace in therapy for new and emerging agentsTargeted-release formulation of budesonideEndothelin receptor antagonists (eg, sparsentan)Factor B inhibitors (eg, iptacopan)The role of clinical trial involvementLearn more about IgA nephropathy with educational activities and resources here:  CME-certified text module with animated pathophysiology video and patient voice audio clipClinicalThought commentariesResources on IgAN from the American Kidney Fund

Editor's Summary by Mary McGrae McDermott, MD, Deputy Editor of JAMA, the Journal of the American Medical Association, for the August 6, 2024, issue.

With Guillaume Baudry, University Hospital of Brabois, Nancy - France, and Marco Metra, University of Brescia - Italy. In this episode of the HFA Cardiotalk podcast, Guillaume Baudry interviews Marco Metra, the lead author of the recent HFA clinical consensus statement on worsening heart failure. They delve into the definition of worsening heart failure, its prognosis, prevention strategies, and both acute and long-term management of this condition. Related scientific paper: Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the Heart Failure Association of the European Society of Cardiology Risk of readmission and death after hospitalization for worsening heart failure: Role of post-discharge follow-up visits in a real-world study from the Grand Est Region of France Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction   This 2024 HFA CardioTalk podcast serie is supported by Novartis in the form of an educational grant. The discussion has not been influenced in any way by its sponsor. 

Skyrizi has been approved for ulcerative colitis; New pneumococcal vaccine approved; An indictment may impact as much as 50,000 patients who need ADHD meds; Results announced for Moderna's next-gen COVID-19 vaccine; Farxiga approval expanded.

The Filtrate:Joel TopfSwapnil HiremathJosh WaitzmanNayan AroraSophia AmbrusoWith Special Guest:Brendon Neuen Super smart guy and clinical trialistVlado Perkovic Lead author of FLOW and friend of NephJCEditor Joel TopfShow NotesThe manuscript (NEJM): Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 DiabetesThe acronym FLOW from the title: evaluate renal Function with semagLutide Once Weekly (Twitter)Joel wrote a blog post prior to the FLOW publication to try to set the table: Peeking Inside Schrödinger's BoxBrendon's Neuen's tweet about total versus chronic slope (X | Twitter)Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity (Science Direct)Semaglutide and Diabetic Retinopathy Risk in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials (PubMed)The Efficacy and Safety of the Combination Therapy With GLP-1 Receptor Agonists and SGLT-2 Inhibitors in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis (Frontiers in Pharmacology)Statistical considerations for testing multiple endpoints in group sequential or adaptive clinical trials (PubMed)Proteinuria Thresholds Are Irrational: A Call for Proteinuria Indexing (Nephron Clinical Practice)Frank Harrel on why the NNT sucks (data methods)Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells (PubMed)Switching Between Glucagon-Like Peptide-1 Receptor Agonists: Rationale and Practical Guidance (PubMed)Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial (PubMed)Doctors are like the pyromaniac fireman (PBFluids)Suggest topics for NephMadness (Twitter)Design of the COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint study (CONFIDENCE) (PubMed)Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and Their Combination in Patients with Chronic Kidney Disease: A Randomized Crossover Clinical Trial (PubMed)Spitzer's involvement in revolutionizing nephrology is part of this lecture I did at the University of Nebraska Diabetes Symposium. (Dropbox: Start on slide 29)Spitzer Resigns, Citing Personal Failings (New York Times)Tubular Secretions Swap: Dumb Money on NetFlix (Wikipedia)Josh: Hiking Zion National Park (National Park Service)Sophia: Lost in Space 2018 TV series on NetFlix (Wikipedia)Nayan: Pelican Hill resort (Website)Joel: BodkinNephJC Summer Book Club: Covenant of Water by Abraham Verghese (Amazon)

Join our scientific team in the discussion of the 3 most clinically impactful papers of the month, the crème de la crème of our weekly top picks. This month we're discussing: Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction DOI: 10.1056/NEJMoa2401479 Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT): a multicentre, open-label, randomised controlled trial DOI: 10.1016/S0140-6736(24)00413-6 Familial aggregation and heritability of childhood-onset and adult-onset type 1 diabetes: a Swedish register-based cohort study. DOI:10.1016/S2213-8587(24)00068-8 Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER DOI: 10.1002/ejhf.3184 Scientific team: Ricardo Ladeiras Lopes, Mário Santos and João Sérgio Neves Discover Medical Portfolio App weekly top picks - the latest and most relevant papers, curated by our team of experts! ⁠⁠⁠⁠⁠⁠⁠https://linktr.ee/medicalportfolioapp

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

DAPA-MI - A Registry-Based Randomized Trial of Dapagliflozin in Patients With Acute Myocardial Infarction Without Diabetes (AHA 2023)

Welcome to the latest episode of Cardiology Digest, where we dive into the pressing questions of today's medical research. Here's a glimpse of what's to come:   STUDY #1: Have you ever wondered about the optimal timing for introducing DOACs (direct-acting oral anticoagulants) after strokes due to atrial fibrillation? This New England Journal of Medicine study dives into the potential advantages of early DOAC introduction. You might be surprised at the rates of symptomatic intracranial hemorrhage. But remember, patient profiles vary—for example, what works for those with mild neurologic deficits might not hold true for everyone. Fischer, U, Koga, M, Strbian, D, et al. 2023. Early versus later anticoagulation for stroke with atrial fibrillation. N Engl J Med. 26: 2411–2421. (https://doi.org/10.1056/NEJMoa2303048)   STUDY #2: Next, we'll take a look at the curious case of rising hematocrit in certain chronic kidney disease patients who have anemia and were treated with SGLT-2 inhibitors. Did they have a genuine improvement in anemia or was it merely an illusion? SGLT-2 inhibitors are the focal point, and we'll dissect their multifaceted effects that may be at play here.  Koshino, A, Schechter, M, Chertow, GM, et al. 2023. Dapagliflozin and anemia in patients with chronic kidney disease. NEJM Evid.  6. (https://doi.org/10.1056/EVIDoa2300049)   STUDY #3: Hospitalization due to COVID-19 has presented a conundrum regarding post-discharge thromboprophylaxis. With the pandemic making such profound impacts on global health, it's crucial to address these concerns. See how new findings align with prior observational studies, and where rivaroxaban fits into all of this. Wang, TY,  Wahed, AS, Morris, A, et al. 2023. Effect of thromboprophylaxis on clinical outcomes after COVID-19 hospitalization. Ann Intern Med. 4: 515–523. (https://doi.org/10.7326/M22-3350)   STUDY #4: Cholesterol management remains pivotal in cardiac care. But the question our fourth study poses is this: do age differences impact the effectiveness of statins, particularly in lowering LDL cholesterol? A dive into this study could reshape perceptions on dosage recommendations for certain patient demographics. Corn, G, Melbye, M, Hlatky, MA, et al. 2023. Association between age and low-density lipoprotein cholesterol response to statins: A Danish nationwide cohort study. Ann Intern Med. 8: 1017–1026. (https://doi.org/10.7326/M22-2643)   So, arm yourself with your favorite beverage and comfy earphones, and join us in uncovering the gems these studies hold. The revelations might just change the way you see these medications and treatments!

Welcome back Rounds Table Listeners! We are back today with our Classic Rapid Fire Podcast! This week, Drs. Mike and John Fralick discuss two recent papers exploring the role of semaglutide in patients with obesity without diabetes and the clinical implications of the decline in glomerular filtration rate after starting dapagliflozin in patients with heart ...The post Episode 75 – Semaglutide in Obesity without Diabetes and Dapagliflozin in Heart Failure appeared first on Healthy Debate.

Welcome back Rounds Table Listeners! We are back today with our Classic Rapid Fire Podcast! This week, Drs. Mike and John Fralick discuss two recent papers exploring the role of semaglutide in patients with obesity without diabetes and the clinical implications of the decline in glomerular filtration rate after starting dapagliflozin in patients with heart ... The post Episode 75 – Semaglutide in Obesity without Diabetes and Dapagliflozin in Heart Failure first appeared on Healthy Debate. The post Episode 75 – Semaglutide in Obesity without Diabetes and Dapagliflozin in Heart Failure appeared first on Healthy Debate.

AHA23 Congress Coverage: Dapagliflozin in MI without DM or HF (DAPA MI)

Join Drs Matthew Sparks and Kirk Campbell as they dive into the murky waters of focal segmental glomerular sclerosis. How do you diagnose? How do you treat? Tune in to find out. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/991604). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Chronic Kidney Disease (CKD) https://emedicine.medscape.com/article/238798-overview Focal Segmental Glomerulosclerosis https://emedicine.medscape.com/article/245915-overview Membranoproliferative Glomerulonephritis https://emedicine.medscape.com/article/240056-overview Membranous Glomerulonephritis https://emedicine.medscape.com/article/239799-overview Collapsing Focal Segmental Glomerulosclerosis in Viral Infections https://pubmed.ncbi.nlm.nih.gov/35095882/ Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis https://pubmed.ncbi.nlm.nih.gov/36644367/ Glomerular Diseases (GD) https://kdigo.org/guidelines/gd/ A Review of Podocyte Biology https://pubmed.ncbi.nlm.nih.gov/29852492/ APOL1 Nephropathy: From Genetics to Clinical Applications https://pubmed.ncbi.nlm.nih.gov/32616495/ A Study to Test BI 764198 in People With a Type of Kidney Disease Called Primary Focal Segmental Glomerulosclerosis https://classic.clinicaltrials.gov/ct2/show/NCT05213624 Efficacy and Safety of ACE Inhibitor and Angiotensin Receptor Blocker Therapies in Primary Focal Segmental Glomerulosclerosis Treatment: A Systematic Review and Meta-Analysis https://pubmed.ncbi.nlm.nih.gov/35518835/ Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors https://www.ncbi.nlm.nih.gov/books/NBK576405/ Calcineurin Inhibitors in the Treatment of Primary Focal Segmental Glomerulosclerosis: A Protocol of Systematic Review and Meta-Analysis of Randomized Controlled Trials https://pubmed.ncbi.nlm.nih.gov/33530282/ Effect of Dapagliflozin on Clinical Outcomes in Patients With Chronic Kidney Disease, With and Without Cardiovascular Disease https://pubmed.ncbi.nlm.nih.gov/33186054/ IgA Nephropathy https://emedicine.medscape.com/article/239927-overview Impact of Diabetes on the Effects of Sodium Glucose Co-Transporter-2 Inhibitors on Kidney Outcomes: Collaborative Meta-Analysis of Large Placebo-Controlled Trials https://pubmed.ncbi.nlm.nih.gov/36351458/ African Trypanosomiasis (Sleeping Sickness) https://emedicine.medscape.com/article/228613-overview Lupus Nephritis https://emedicine.medscape.com/article/330369-overview Inaxaplin for Proteinuric Kidney Disease in Persons With Two APOL1 Variants https://pubmed.ncbi.nlm.nih.gov/36920755/ Phase 2/3 Adaptive Study of VX-147 in Adults and Adolescents With APOL1-Mediated Proteinuric Kidney Disease https://classic.clinicaltrials.gov/ct2/show/NCT05312879 Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development https://pubmed.ncbi.nlm.nih.gov/32604776/ Janus Kinase-STAT Inhibition to Reduce APOL1 Associated Kidney Disease (JUSTICE) https://classic.clinicaltrials.gov/ct2/show/NCT05237388 APOL1 Long-Term Kidney Transplantation Outcomes Network (APOLLO) (APOLLO) https://classic.clinicaltrials.gov/ct2/show/NCT03615235 Nephrotic Syndrome Study Network (NEPTUNE) https://repository.niddk.nih.gov/studies/neptune/

Commentary by Dr. Valentin Fuster

Join experts Drs Matt Sparks and Dawn Caster as they discuss the complexities around the management of lupus nephritis. What tools do we have now? What is on the horizon? Tune in to find out. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/991602). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Novel Aspects in the Pathophysiology and Diagnosis of Glomerular Diseases https://pubmed.ncbi.nlm.nih.gov/36535746/ Derivation and Validation of the Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus https://pubmed.ncbi.nlm.nih.gov/22553077 EULAR/ACR Classification Criteria for SLE https://pubmed.ncbi.nlm.nih.gov/31779843/ Sensitivity and Specificity of ANA and Anti-dsDNA in the Diagnosis of Systemic Lupus Erythematosus: A Comparison Using Control Sera Obtained From Healthy Individuals and Patients With Multiple Medical Problems https://pubmed.ncbi.nlm.nih.gov/24383972/ Podocyte Foot Process Effacement Precedes Albuminuria and Glomerular Hypertrophy in CD2-Associated Protein Deficient Mice https://pubmed.ncbi.nlm.nih.gov/34568396/  KDIGO 2023 Clinical Practice Guideline for the Management of Lupus Nephritis https://kdigo.org/wp-content/uploads/2023/03/KDIGO-2023-Lupus-Nephritis-Guideline_Public-Review_9-Mar-2023.pdf Management of Lupus Nephritis: A Systematic Literature Review Informing the 2019 Update of the Joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) Recommendations https://pubmed.ncbi.nlm.nih.gov/32699043/ Nonrenal Disease Activity Following Mycophenolate Mofetil or Intravenous Cyclophosphamide as Induction Treatment for Lupus Nephritis: Findings in a Multicenter, Prospective, Randomized, Open-Label, Parallel-Group Clinical Trial https://pubmed.ncbi.nlm.nih.gov/20039429/ Immunosuppressive Therapy in Lupus Nephritis: The Euro-Lupus Nephritis Trial, a Randomized Trial of Low-Dose Vs High-Dose Intravenous Cyclophosphamide https://pubmed.ncbi.nlm.nih.gov/12209517/ Voclosporin: A Novel Calcineurin Inhibitor for the Treatment of Lupus Nephritis https://pubmed.ncbi.nlm.nih.gov/35168373 Safety and Efficacy of Belimumab in Patients With Lupus Nephritis: Open-Label Extension of BLISS-LN Study https://pubmed.ncbi.nlm.nih.gov/36302567/ Anti-CD19 CAR T Cell Therapy for Refractory Systemic Lupus Erythematosus https://pubmed.ncbi.nlm.nih.gov/36109639/ Dapagliflozin in People With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/37257897/ Empagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/36331190/

Commentary by Dr. Valentin Fuster

Interviewees: Associate Professor Jasper Brugts, Erasmus University Medical Centre of Rotterdam, The Netherlands; Professor John Cleland and Doctor Ross Campbell, University of Glasgow, United Kingdom of Great Britain & Northern Ireland; Doctor Jeroen Dauw AZ Saint-Lucas, Ghent, Belgium and Interviewers: Doctor Antonio Cannata, King's College London, United Kingdom of Great Britain & Northern Ireland; Doctor Jozine Ter Maaten, University Medical Centre Groningen, The Netherlands; Doctor Sotiria Liori, Attikon University Hospital, Athens, Greece; Doctor Francesca Musella, Royal Brompton Hospital, London, United Kingdom of Great Britain & Northern Ireland. This podcast discusses the results of four late breaking clinical trials presented at the Heart Failure congress 2023 in Prague, Czech. First, dr. Brugts shares the results of the MONITOR-HF trial, an open-label, randomized trial showing that haemodynamic monitoring using a cardioMEMS device, significantly improved quality of life and reduced heart failure hospitalizations in patients with moderate-to-severe heart failure. This trial was simultaneously published in the Lancet (Remote haemodynamic monitoring of pulmonary artery pressures in patients with chronic heart failure (MONITOR-HF): a randomised clinical trial - The Lancet). Second, dr. Cleland walks us through a population study from the greater Glasgow area that found that use of loop diuretics in patients without a diagnosis of heart failure was associated with poor outcomes. He consequently discusses possible explanations and clinical consequences. Third, dr. Campbell shares the results of the DAPA-RESIST trial, that found that in patients with diuretic resistance, dapagliflozin was not superior to metolazone at relieving congestion (Dapagliflozin versus metolazone in heart failure resistant to loop diuretics | European Heart Journal | Oxford Academic (oup.com)). Fourth, dr. Dauw discusses the results of the ENACT-HF trial where a strategy of natriuresis guided therapy as recommended by the HF guidelines, in an open label, sequential roll-out (first 10 patients standard of care, followed by 10-30 patients in the natriuresis arm), was shown to improve natriuresis and reduced length of hospital stay. No effect on change in congestion score or in-hospital mortality was observed. The podcast is concluded with a brief discussion of some HFA Young highlights at the congress. 

Two new papers on left atrial appendage occlusion, the promise of DNA, statins in the elderly, and SGLT2 inhibitors are the topics John Mandrola, MD, discusses in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. Listener Feedback - When to Start a Statin Is a Preference-Sensitive Decision https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.117.029808 II. Left Atrial Appendage Closure LAA Closure Outcomes Improve With CCTA: Swiss-Apero Subanalysis https://www.medscape.com/viewarticle/991623 - Impact of Preprocedural Computed Tomography on Left Atrial Appendage Closure Success: A Swiss-Apero Trial Subanalysis https://doi.org/10.1016/j.jcin.2023.02.027 - Outcomes of percutaneous left atrial appendage occlusion device implantation in atrial fibrillation patients based on underlying stroke risk https://doi.org/10.1093/europace/euad049 III. Polygenic Risk Scores - Predictive Accuracy of a Polygenic Risk Score Compared With a Clinical Risk Score for Incident Coronary Heart Disease https://jamanetwork.com/journals/jama/fullarticle/2761086 - Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program https://jamanetwork.com/journals/jamacardiology/article-abstract/2804439 - Validity of polygenic risk scores: are we measuring what we think we are? https://doi.org/10.1093/hmg/ddz205 IV. Statins in Older Patients High Cholesterol in Seniors: Use Statins for Primary Prevention? https://www.medscape.com/viewarticle/991801 V. SGLT2 Inhibitors FDA Expands Use of Dapagliflozin to Broader Range of HF https://www.medscape.com/viewarticle/991736 - Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction https://www.nejm.org/doi/full/10.1056/NEJMoa2206286 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Episode 138: SGLT-2 Inhibitors in heart failureFuture doctor Enuka explains the use of sodium-glucose-linked cotransporter-2 inhibitors (SGLT-2 inhibitors) in heart failure. Dr. Arreaza adds his experience with these medications and emphasizes their role as an effective treatment for type 2 diabetes.  Written by  Princess Enuka, MSIV, Ross University School of Medicine. Editing by Hector Arreaza, MD.You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.Intro:Heart failure is a major medical condition that affects millions of people worldwide. It is one of the leading causes of hospitalization and death in developed countries. Recently, SGLT2 inhibitors have emerged as a promising treatment option for heart failure. Today, we will discuss their benefits, their effectiveness, and their adverse effects.SGLT2 inhibitors, also known as sodium-glucose-linked cotransporter-2 inhibitors, are a relatively novel class of drugs that have shown promise in heart failure treatment. This transporter reabsorbs glucose from the glomerular filtrate back into the bloodstream. Under normal circumstances, SGLT-2 reabsorbs 100% of the filtered glucose unless it is saturated (as in hyperglycemia) or blocked by medications. SGLT2 inhibitors increase the amount of glucose excreted in the urine, which leads to blood glucose reduction. Examples include empagliflozin, dapagliflozin, and canagliflozin.SGLT-2 inhibitors have become a first-line therapy for diabetes mellitus. I heard before that it was used in Europe for T1DM, but it seems like they are no longer used, according to my most recent review of articles. SGLT2 inhibitors are not approved by the FDA for use in type 1 diabetes due to the risk of DKA. Princess, besides the benefits in diabetes, what else did you find in your review?Benefits/Efficacy:SGLT2 inhibitors have additional benefits beyond their glucose-lowering effects. One of the benefits of SGLT2 inhibitors is their ability to increase myocardial energy production, alleviate systemic microvascular dysfunction, and improve systemic endothelial function. Natriuresis and glucosuria mediated by SGLT2 inhibitors have been shown to lower cardiac pre-load and reduce pulmonary congestion and systemic edema, which is beneficial for heart failure management.Studies have shown that these drugs can also improve cardiovascular outcomes in patients with heart failure with a reduced ejection fraction. Some studies:The EMPEROR-Reduced trial demonstrated that empagliflozin, brand name Jardiance®, reduced the risk of cardiovascular death and hospitalization for heart failure in patients with reduced ejection fraction by 25% compared to placebo. Several clinical trials have also shown that this result is significant whether patients have type 2 diabetes or not. Also, in a multicenter, double-blind, randomized, placebo-controlled trial in patients with heart failure, treatment with dapagliflozin, brand name Farxiga®, improved heart failure-related symptoms and physical limitations after only 12 weeks of treatment. Patients treated with dapagliflozin had a significant, clinically meaningful improvement in the 6-minute walking test distance. The magnitude of these benefits was statistically and clinically significant, spanning all subgroups categorized. This included patients with and without type 2 diabetes and those with an ejection fraction above or below 60%.Anecdote:During a previous clinical rotation, I had a patient taking Jardiance for heart failure. He also had a history of chronic kidney disease and managed his condition well with medications and regular follow-ups. Interestingly, he was prescribed Jardiance®, which I initially believed was solely for diabetes management. When I asked him about it, he explained that his cardiologist prescribed Jardiance specifically for his heart. At the time, I did not understand the rationale behind prescribing Jardiance®, especially since the patient did not have type 2 diabetes. But after researching the medication, I figured that his cardiologist had chosen Jardiance® due to its demonstrated benefits in reducing the risk of cardiovascular death and hospitalization for heart failure. Although initially considered to be only glucose-lowering agents, the effects of SGLT2 inhibitors have expanded far beyond that. Their use has expanded to include heart failure and chronic kidney disease, even in patients without diabetes. It is, therefore, essential that cardiologists, diabetologists, nephrologists, and primary care physicians are familiar with this drug class.Adverse effects:It is worthwhile to note that SGLT2 inhibitors are not typically used as first-line treatment for heart failure, and not all patients with heart failure are appropriate candidates for these medications. SGLT2 inhibitors are generally well-tolerated, but they can cause adverse effects. Genital and urinary tract infections and euglycemic diabetic ketoacidosis are the most common side effects experienced by patients. The incidence of these adverse effects is generally low and can be managed with appropriate monitoring and treatment. In addition, SGLT2 inhibitors can also cause dehydration, electrolyte imbalances, hypotension, and acute kidney injury (AKI). These imbalances are more common in elderly patients or those with renal impairment, like the patient I discussed earlier. Genital yeast infections: Diabetes is also a risk factor for genital yeast infections because glucose in the urine is used as a substrate by microorganisms to grow in the GU tract. UTI and genital yeast infections are prevented by staying well hydrated while taking these meds. Increased intake of water will dilute the urine and decrease the concentration of glucose in urine. UTI/genital yeast infections are treated as usual, and the SGLT-2 can be resumed after infections are treated. In case of recurrence, the clinician may consider discontinuation of medication based on a case-by-case assessment. Patients using SGLT2 inhibitors for treatment should have regular follow-ups with their physicians for the early detection of adverse effects. Bladder cancer: It is not clear if chronic glucosuria is tumorigenic since there are no long-term data. In clinical trials, 10 cases of bladder cancer were diagnosed among dapagliflozin users, five of which occurred only in the first six months of treatment. The FDA has recommended postmarketing surveillance studies. Dapagliflozin is not recommended in patients with active bladder cancer. Bone fractures and limb amputation: One trial (CANVAS) demonstrated an increased incidence of bone fractures and limb amputations among users of canagliflozin, but another trial (CREDENCE) did not demonstrate such an increased incidence of bone fractures or limb amputations. This increased risk has not been proven with empagliflozin. Summary: SGLT2 inhibitors have shown promise in heart failure treatment, particularly in patients with a reduced ejection fraction. Even though the specific mechanism of action through which they work on the cardiovascular system is currently unknown, they have been shown to reduce the risk of hospitalization for heart failure and cardiovascular death in several clinical trials. These medications lower blood glucose levels and have other beneficial effects on the cardiovascular system that make them good options for the management of heart failure.____________________Conclusion: Now we conclude episode number 138, “SGLT-2 inhibitors in heart failure.” Princess explained that SGLT-2 inhibitors have many benefits that go beyond their glucose-lowering properties. Recently, the use of SGLT-2 inhibitors has been extended to include heart failure with reduced ejection fraction and chronic kidney disease, even in patients without diabetes. Dr. Arreaza also explained that FDA has not approved the use of SGLT-2 inhibitors for the treatment of type 1 diabetes because of the reported increased risk of diabetic ketoacidosis or DKA. There is ongoing research about additional uses of SGLT-2 inhibitors, and we are looking forward to hearing more about these medications in the future.This week we thank Hector Arreaza and Princess Enuka. Audio editing by Adrianne Silva.Even without trying, every night, you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you. Send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _________________Links:Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424. https://pubmed.ncbi.nlm.nih.gov/32865377/Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255-323. https://pubmed.ncbi.nlm.nih.gov/31497854/Heerspink HJL, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752-772. https://pubmed.ncbi.nlm.nih.gov/27470878/Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(4):422-434. https://pubmed.ncbi.nlm.nih.gov/32000955/Nassif, M. E., et al. (2020). The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: A multicenter randomized trial. Nature Medicine, 27(11), 1954-1960. https://doi.org/10.1038/s41591-021-01536-xRoyalty-free music used for this episode: "Tempting Tango." Downloaded on October 13, 2022, from https://www.videvo.net/

⁠DozeNews PRIME⁠⁠⁠⁠: as melhores e mais didáticas revisões de cardiologia direto na sua caixa de entrada! Assine agora e tenha acesso à todo material já produzido! - ⁠⁠⁠⁠https://dozeporoito.substack.com Continuamos com o sarrafo alto!  A parceria Doze Por Oito Cardiologia e o 81º Curso Intensivo do Dante Pazzanese continua e, dessa vez, Rapha Rossi e William Batah contam com o retorno de nossa querida convidada e especialista em disfunção ventricular, Dra. Carolina Casadei para debater as principais nuances do uso das duas novas principais medicações no tratamento da insuficiência cardíaca: os INRAs e I-SGLT2. Esse episódio tem apoio do Insituto Dante Pazzanese de Cardiologia ⏱️ Minutagem: (00:00) Apresentação (02:20) Quem são e quando usar os INRAs? (08:30) Como iniciar o INRA? (12:50) Quando nao usar os INRAs (17:15) Qual o papel dos INRAs na ICFEP (20:00) Porque usar os I-SGLT2 (27:00) Como funcionam os I-SGLT2 e quando usar? (33:00) Dapagifozina na ICFEP (37:20) Cuidados ao usar I-SGLT2 (42:00) Considerações finais Referências: McMurray JJ, et al ; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015. Packer M,et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28. PMID: 32865377. Solomon SD, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021 Jul;23(7):1217-1225. doi: 10.1002/ejhf.2249. Epub 2021 Jun 9. PMID: 34051124; PMCID: PMC8361994.

This week, please join author Milind Desai and Associate Editor Mark Link as they discuss the article "Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.  Dr. Carolyn Lam: Oh, Greg. Today's feature paper is just so, so important. It's the long-term follow up or the longer term follow up of the VALOR-HCM trial. And this, if I can remind you, examined the effect of mavacampten on the need for septal reduction therapy in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy. So we're going to hear the results through 32 weeks, but not until we discuss the other papers in today's issue. And I'd like to go first. I'd like to tell you about a paper that really provides the foundation for deciphering chamber selective gene transcription. So in this study from Dr. William Pu of Boston Children's Hospital and colleagues, authors mapped the chromatin features of atrial and ventricular cardiomyocytes and nominated candidate chamber selective enhancers based on differential features. The candidate enhancers were tested in vivo using adeno associated virus delivered massively parallel reporter assay leading to identification of 229 chamber selective enhancers. They then characterized chromatin features of these chamber selective enhancers and used dense mutagenesis to identify their essential features. Altogether the study suggested that estrogen-related receptor promoted ventricular chamber selective enhancer activity. They validated this prediction by showing that estrogen-related receptor inactivation led to loss of ventricular cardiomyocyte identity. So in aggregate, the studies yielded a rich resource of chamber selective chromatin features and chamber selective enhancers, and began to unravel the molecular basis for chamber selective transcriptional programs. Dr. Greg Hundley: Wow. So Carolyn, estrogen-related receptor promotion and then inactivation and finding really very interested preclinical results. So tell us now what are the clinical implications of this very nice study.  Dr. Carolyn Lam: Wow. I mean, there are just so many implications. It can facilitate functional interpretation of genetic associations between variants and cardiac disease. Of course, it opens the doors to potential gene therapies and regenerative medicine and finally, identification of transcription regulators of the chamber identity really yield important mechanistic insights into the pathogenesis of important diseases like atrial fibrillation and cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn, beautifully summarized. Well, my next paper pertains to COVID vaccines. So Carolyn, as we have seen SARS-CoV-2 targeted mRNA vaccines are a life-saving medical advancement developed to combat, of course, the COVID-19 pandemic. But in rare cases, some individuals can develop myocarditis following these mRNA vaccinations. Cases of adolescents and young adults developing post vaccine myocarditis have been reported globally, although the underlying immuno profiles of these individuals, they really haven't been described in detail. So these authors led by Dr. Lael Yonker from Massachusetts General Hospital, performed extensive system serology SARS-CoV-2 specific T-cell analysis and cytokine and SARS-CoV-2 antigen profiling on blood samples collected from adolescents and young adults either developed myocarditis or were asymptomatic following SARS-CoV-2 targeted mRNA vaccination.  Dr. Carolyn Lam: Wow. Wow. Important question. Everyone's interested in the results. So what did they find? Dr. Greg Hundley: Right, Carolyn. So 16 cases with post vaccine myocarditis and 45 asymptomatic vaccinated controls were enrolled with extensive antibodies profiling, including assessment for autoantibodies or antibodies against the human relevant virome. And Carolyn, they found that T-cell responses were essentially indistinguishable from controls despite a modest increase in cytokine production. Notably, markedly elevated levels of full length spike protein unbound by antibodies were detected in the plasma of individuals with post vaccine myocarditis, a finding that was absent. It was absent in the asymptomatic vaccinated controls. So Carolyn, in conclusion, immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals that developed myocarditis versus individuals that did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post mRNA vaccine myocarditis. Now while this finding does not alter the risk benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes, it may provide some insight into the potential underlying etiology associated with post mRNA vaccine-induced myocarditis. Carolyn, this is accompanied by a wonderful editorial by Dr. Biykem Bozkurt indicating that these results raise a question as to why the circulating spike protein levels remain elevated despite adequate levels and functionality of the anti-spike antibodies. Well, Carolyn, we do have some other articles in the issue and from the mailbag we have a research letter from Professor Cho entitled PERM1 Protects the Heart From Pressure Overload Induced Dysfunction by Promoting Oxidative Metabolism. Also, there's a new drugs and devices piece from Professor Kabatano entitled Pharmacology and Clinical Development of Factor XI inhibitors. And then Tracy Hansen has a wonderful cardiology news summary regarding articles entitled The Study Reveals Rapid Intestinal Adaptations after Switching to High Fat Diet From Cell Research. Another article entitled New Insights into Immunotherapy Related Myocarditis from Nature. And finally, an article entitled Scientist Identified Genetic Variants Linked to Longevity published in the Journal of Science.  Dr. Carolyn Lam: Wow. Interesting. There's also an exchange of letters between Drs. Monzo and Shah regarding the article, “Metabolomic Profiling of Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction.” That is a Perspective piece by Dr. Davenport on contrast induced acute kidney injury and cardiovascular imaging, danger or distraction? Wow. What a beautiful issue. Thank you so much, Greg. Let's go to our feature discussion, shall we? Dr. Greg Hundley: Absolutely. Welcome, listeners, to this feature discussion on March 14th. And we have with us today Dr. Milind Desai from Cleveland Clinic in Cleveland, Ohio, and our own associate editor, Dr. Mark Link from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen, Milind, we'll begin with you and bringing to us this study of mavacampten. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address? Dr. Milind Desai: Thank you to the editorial staff, Dr. Hundley and the editorial staff at Circulation. So yes, mavacampten, as we know, is a novel first in class cardiac myocin inhibitor that was developed in the context of managing patients with hypertrophic obstructive cardiomyopathy. So the preliminary early stage studies have shown that it helped significantly in reducing outflow tract gradients as well as improved symptoms. But we wanted to take the conversation a bit further. In highly symptomatic patients, the current standard of care treatment is septal reduction therapy, which requires an experienced center and an experienced set of providers. So what we wanted to see was in such patients that are referred for septal reduction therapy, what does mavacampten do versus placebo? So does it reduce the need for septal reduction therapy? We divided the study into three parts. The first part was the placebo controlled 16 week study. The second part was we wanted to see what happens when the placebo arm crossed over to mavacampten and the mavacampten arm continued long-term. And that was the genesis of the study that we are discussing today. Dr. Greg Hundley: Very nice. So we've got a planned study, patients with hypertrophic cardiomyopathy, they ordinarily, because of guideline related therapeutic recommendations would undergo septal reduction therapy, but before that you're going to randomize patients to mavacampten versus a placebo. So we've sort of described a little bit the study design, and let's clarify specifically perhaps the study population and how many patients did you enroll? Dr. Milind Desai: Yes. In the original study, we enrolled 112 patients, 56 to mavacampten and 56 to placebo. After week 16, four patients, two of which underwent SRT and two withdrew consent. So essentially for the 32 week analysis, we had 108 patients, 56 in the mavacampten group and 52 in the placebo group that crossed over to mavacampten. So 108 patients. Dr. Greg Hundley: Very nice. So Milind, what were your study results? Dr. Milind Desai: Yes. What we found was at week 16, we have previously demonstrated that the group that got randomized mavacampten had a significant reduction in outflow tract radius, both resting and Valsalva, as well as biomarkers. And at week 16, what we found was 82% patients from the original group did not meet criteria for septal reduction therapy. So a hundred percent to begin with, 82%, that was at week 16. What we wanted to see, is the effect continued longer lasting and what happens to the placebo group that crossed over? So essentially what we found was at week 32, 89% of the total population no longer met criteria for septal reduction therapy. In addition to that, the mavacampten group continued to have reduced outflow tract gradients, continued improvement in Kansas City Score as well as biomarkers. But more importantly, the similar findings were demonstrated in the placebo arm that cross over to the mavacampten where, again, a significant proportion continued to show improvement in outflow tract gradient, Kansas City Score, as well as biomarker. The important point here in this study was at week 32, 95% patients chose to remain on medical therapy as opposed to going for SRT. Remember, a hundred percent patients were referred at the outset to undergo SRT. Dr. Greg Hundley: And Milind, did you notice any differences in your study results based on the age of the patients or based on their sex? Dr. Milind Desai: No, actually, we did not. This had a beneficial effect across gender, age, all the other variables. In fact, this is one of the strengths of the study because almost 50% patients that were randomized were women. So this was well represented across different genders. Dr. Greg Hundley: And then you mentioned a marked reduction in the gradient across the left ventricular outflow tract. What about the patient's symptomatology? Did you notice differences there? Dr. Milind Desai: There were significant improvement in patient symptomatology. More than 70% patients had a improvement in one NYHA class, 30% or thereabouts had a significant improvement in two NYHA class compared to placebo. So yes, there was a significant improvement in their functional capacity. Dr. Greg Hundley: And then last question, hypertrophic cardiomyopathy. Were most of these patients, was this concentric? Was this asymmetric septal hypertrophy? What was the breakdown, if you will, of the morphology of the left ventricles? Dr. Milind Desai: The vast majority of the patients had asymmetric septal hypertrophy, the characteristic with dynamic outflow tract gradient. There were some patients, but the vast majority of them were asymmetric septal hypertrophy. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn to our associate editor, Dr. Mark Link. Mark, this really sounds striking, randomized clinical trial, patients needing septal reduction therapy. They're randomized. The group randomized to mavacampten has marked reductions in left ventricular outflow tract gradient, symptomatology, and so much so that they no longer met the criteria for septal reduction therapy. I know you have a lot of papers come across your desk. Can you help us put what seemingly are exciting results into the context of other studies pertaining to mavacampten as well as treatment for patients with symptomatic hypertrophic cardiomyopathy? Dr. Mark Link: Yeah. There are very few randomized studies in patients with hypertrophic cardiomyopathy, probably only two that I know of. And mavacampten is a very exciting new drug that's a novel drug, a novel mechanism and has the potential to really improve life for our patients with hypertrophic cardiomyopathy. So this is a longer term study of mavacampten that's ever been published. So yeah, it was very exciting for us to look at this data to see how the patients did and we were very, very pleased to publish this paper. Dr. Greg Hundley: Very nice. So maybe, Milind, turn this back to you. What do you think are some of the next studies that'll be performed really in this arena of research? Dr. Milind Desai: Yes. Obviously, as Mark pointed out, this was one of the longest term studies, but we need to do a lot longer. So long term extension studies are ongoing. We should be evaluating one year outcomes in this specific population as well as longer, number one. Number two, I think in the grand scheme of things, this is a brand new class. So overall it is obviously now FDA approved and post-marketing survey and analysis should help us see a signal in terms of outcomes, mortality, et cetera. In your sister journal Circulation Imaging, we have simultaneously also published that mavacampten is causing a significant improvement in the structural changes like diastolic dysfunction, like LV mass, LA volume index. So we need to see how that plays out. Another important piece is about 30% patients have non-obstructive hypertrophic cardiomyopathy and there's no real treatment for this group and there's no outflow tract obstruction to cure in this. So we have just recently launched and started to randomize ODYSSEY HCM trial, which is checking the role of mavacampten versus placebo in non-obstructive HCM group. And I am fortunate. So it's a multi-centered trial that is being led out of Cleveland Clinic. So more data in that exciting field. But overall, this entire field of hypertrophic cardiomyopathies is exploding with multiple randomized controlled trials. There's another drug that is being tested in phase three trials, cardiac myocin inhibition. So that story also remains to see how that plays out. So a lot of stuff that is happening in this space. And then now there's gene therapy emerging. Dr. Greg Hundley: Right. And Milind, since you have quite extensive experience here, for our listeners, what side effect profiles have you observed in some of these patients? And if someone is considering working with placing a patient on this therapy, what are some of the considerations that they should be thinking about? Dr. Milind Desai: So that's a very important question. So the drug, as you are aware, was approved by the FDA under the REMS or Risk Evaluation Mitigation Strategy program. So the fundamental thing is both the patient and the physician have to sign up for the REMS program. The biggest issue that FDA wants us to be careful about is this is a cardiac myosin inhibitor. So it means we have to be very careful about over inhibition of the cardiac myosin and a drop in ejection fraction and its downstream ramifications including heart failure. The other aspect is drug-drug interaction because of its pathway of metabolism. So these are the two key things we have to be on the careful about. Now you asked my clinical experience. So we have been prescribing this for almost six, seven months, and we have dozens of patients on this using the REMS strategy, careful echocardiographic monitoring and clinical decision making. So far, we have been very successfully able to navigate these patients without any major adverse events. And the vast majority of the patients, true to form as we have shown in the clinical trial, are doing very, very well in terms of their symptoms, their need for SRT, as well as their markers, including outflow tract gradient. Dr. Greg Hundley: Very nice. And Mark, turning to you from the perspective of an electrophysiologist, what potential future studies do you see forming in this space? Dr. Mark Link: Yeah, very similar to Milind. And I think the long term efficacy and safety really has to be looked at. There's a signal for potential harm in that the EF can drop, and Milind mentioned that too, that we have to learn how to deal with that. The way to prescribe it now, you have to be in a special program. You have to be trained, you have to agree to get echoes every three months, I believe it is, essentially for the rest of their life. So we need to see what happens long term with these drugs and we need to know how to dose them and how to do it safely. Dr. Greg Hundley: Very nice. So for our listeners, really a class of drugs that is emerging and at this time only under really strictly supervise protocols. Well, from the perspective of our listeners, we want to thank Dr. Milind Desai and our own associate editor, Dr. Mark Link, for bringing us this informative new early randomized trial study results indicating that in severely symptomatic patients with obstructive hypertrophic cardiomyopathy, 32 weeks of mavacampten treatment showed sustained reduction in the proportion proceeding to septal reduction therapy. Well, on behalf of Petter, Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association's four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 25 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. This issue will review: 1.     Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study  2.     An Examination of Whether Diabetes Control and Treatments Are Associated With Change in Frailty Index Across 8 Years   3.     Diabetes Obesity and Metabolism. =Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity  4.     Glucagon Prescribing and Costs Among U.S. Adults With Diabetes, 2011–2021  5.     Two-Year Follow-up From the T1GER Study: Continued Off-Therapy Metabolic Improvements in Children and Young Adults With New-Onset T1D Treated With Golimumab and Characterization of Responders    6.     Youth-onset type 2 diabetes: the epidemiology of an awakening epidemic   For more information about each of ADA's science and medical journals, please visit www.diabetesjournals.org. Presented by: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis? Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion. Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address? Dr. Carolyn Lam: Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine. And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan. However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials. Dr. Greg Hundley: Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find? Dr. Carolyn Lam: In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure. Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña. Dr. Greg Hundley: Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis. So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition. And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage. So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression. Dr. Carolyn Lam: Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex. They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models. So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression. Dr. Carolyn Lam: Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension. So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence. Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development. As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age. So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results. Dr. Greg Hundley: Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models? Dr. Carolyn Lam: Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension. The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration." So lots of translational implications of this paper. Dr. Greg Hundley: Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe. Dr. Carolyn Lam: Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants." There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea." In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature. Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity. There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study. Dr. Greg Hundley: Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion? Dr. Carolyn Lam: Let's go. Thanks. Dr. Greg Hundley: Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen. Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Amil Shah: Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today. So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality. Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes. Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation. Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction. And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals. But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults. And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease. To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life. Dr. Greg Hundley: So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population? Dr. Amil Shah: Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota. Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age. We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally. And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion. Dr. Greg Hundley: Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results? Dr. Amil Shah: So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair. And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort. And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes. Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest. Dr. Greg Hundley: Now, did you find similar results for men and for women? Dr. Amil Shah: So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar. Dr. Greg Hundley: And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions? Dr. Amil Shah: Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages. So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly. So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings. For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that. Dr. Greg Hundley: Very nice. Well, thank you so much, Amil. And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper? Dr. Ntobeko Ntusi: Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle. And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms. We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex. And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution. The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease. And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations. So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg. Dr. Greg Hundley: Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research? Dr. Amil Shah: So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life. And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in. I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients. Dr. Greg Hundley: Very nice. Ntobeko, do you have anything to add? Dr. Ntobeko Ntusi: Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward. The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease. Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time. And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events. Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Drug and non-drug therapies for HFpEF, the search for AF, and exercise as medicine are the topics John Mandrola, MD, discusses in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. SGLT2 Inhibitors in HFpEF Dapagliflozin Gets Expanded Heart Failure Indication in Europe https://www.medscape.com/viewarticle/988034 Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction https://www.nejm.org/doi/full/10.1056/NEJMoa2206286 II. HFpEF and Heart Rate Accelerated Pacing a Possible Strategy for Preserved-EF Heart Failure? https://www.medscape.com/viewarticle/987815 III. Stroke and AF STROKE AF at 3 Years: High AF Rate After Atherosclerotic Stroke https://www.medscape.com/viewarticle/988076 Effect of Long-term Continuous Cardiac Monitoring vs Usual Care on Detection of Atrial Fibrillation in Patients With Stroke Attributed to Large- or Small-Vessel Disease https://jamanetwork.com/journals/jama/fullarticle/2780490 Cryptogenic Stroke and Underlying Atrial Fibrillation https://www.nejm.org/doi/full/10.1056/nejmoa1313600 Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT https://pubmed.ncbi.nlm.nih.gov/28329139/ Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke https://www.nejm.org/doi/full/10.1056/NEJMoa2101897 IV. Exercise as Medicine Trending Clinical Topic: Exercise Prescription https://reference.medscape.com/viewarticle/985373 Effect of Moderate and Vigorous Aerobic Exercise on Incident Diabetes in Adults With Obesityhttps://pubmed.ncbi.nlm.nih.gov/36716009/ Features Could a Breakthrough in Heart Failure With Preserved Ejection Fraction Just Take a Change of Pace? https://www.medscape.com/viewarticle/988088 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Commentary by Dr. Valentin Fuster

The NACE Journal Club with Dr. Neil Skolnik, is a new series of episodes that provide review and analysis of recently published journal articles important to the practice of primary care medicine. In this episode Dr. Skolnik and guests review the following publications:1. The protective effect of exercise against Covid infection and hospitalization in individuals vaccinated against covid, Association between regular physical activity and the protective effect of vaccination against SARS-CoV-2 in a South African case–control study. Collie S, et al. Br J Sports Med2022;0:1–7. doi:10.1136/bjsports-2022-105734Guest: Connie Jiang, MD is chief resident in the family medicine residency at Jefferson-Abington Health, Abington Hospital, Abington, PA2. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. Solomon, et.al. N Engl J Med 2022; 387:1089-1098DOI: 10.1056/NEJMoa2206286Guest: Orly Vardeny, Pharm.D is a BPS Board Certified clinical pharmacist with current research that focuses on novel therapies in the treatment of heart failure and the impact of influenza vaccination on heart disease. She has over 10 years of experience researching the effects of medications on cardiovascular conditions. Dr. Varney is a Core Investigator at the Center for Care Delivery and Outcomes Research, United States Department of Veterans Affairs, Associate Professor of Medicine, University of Minnesota Medical School, and Adjunct Faculty, University of Minnesota College of Pharmacy.3. Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Adults With Anxiety Disorders: A Randomized Clinical Trial. Hoge EA, et al, JAMA Psychiatry. 2023 Jan 1;80(1):13-21. doi: 10.1001/jamapsychiatry.2022.3679.Guest: Bridget Smith, MD is a second-year resident in the family medicine residency at Jefferson Health – Abington, Abington Hospital, Abington, PA 4. Empagliflozin in Patients with Chronic Kidney Disease. The EMPA-KIDNEY Collaborative Group, N Engl J Med 2023; 388:117-127DOI: 10.1056/NEJMoa2204233Guest: Katie McKormick, MD  is a second year resident in the family medicine residency at Jefferson Health – Abington, Abington Hospital, Abington, PAMedical Director and Host: Neil Skolnik, MD, is an academic family physician who sees patients and teaches residents and medical students as professor of Family and Community Medicine at the Sidney Kimmel Medical College, Thomas Jefferson University and Associate Director, Family Medicine Residency Program at Abington Jefferson Health in Pennsylvania. Dr. Skolnik graduated from Emory University School of Medicine in Atlanta, Georgia, and did his residency training at Thomas Jefferson University Hospital in Philadelphia.Please visit http://naceonline.com to engage in more live and on demand CME/CE content.

Various SGLT-2s have been shown to improve cardiovascular outcomes in the presence and absence of diabetes. A recent study evaluated the effect of dapagliflozin in mildly reduced or preserved ejection fraction. Join host, Geoff Wall, as he discusses how SGLT-2s may be a real GameChanger in heart failure with expert, Troy Lynn Lewis.The GameChangerThe data showcasing the benefits of SGLT-2s in patients with heart failure with or without diabetes continues to grow. Dapagliflozin may be another treatment option for persons with heart failure.Are you a CEimpact Member? Members get exclusive access to new courses and CE for this podcast. Over 62 hours of new CE each year + access to hundreds more on demand. Go to www.CEimpact.com to become a member today! Show Segments00:00 - Introductions01:55 - The DELIVER Study14:10 - GameChanger: DELIVER Discussion20:44 - Connecting to Practice: Patient Considerations26:11 - Closing RemarksHostGeoff Wall, PharmD, BCPS, FCCP, CGPProfessor of Pharmacy Practice, Drake UniversityInternal Medicine/Critical Care, UnityPoint HealthGuestTroy Lynn Lewis, PharmD, BC-ADMAssistant Professor, Pharmacy PracticeWilkes UniversityReferences and ResourcesDapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection FractionRedeem your CPE or CME hereCPE (Pharmacist) CME (Physician) Get a membership & earn CE for GameChangers Podcast episodes (30 mins/episode)Pharmacists: Get a membershipPrescribers: Get a membershipCE InformationLearning ObjectivesUpon successful completion of this knowledge-based activity, participants should be able to:1. Describe the role of SGLT-2s in heart failure management2. Discuss the results of the DELIVER trial0.05 CEU/0.5 HrUAN: 0107-0000-22-414-H01-PInitial release date: 11/14/2022Expiration date: 11/14/2023Additional CPE and CME details can be found here.Follow CEimpact on Social Media:LinkedInInstagramDownload the CEimpact App for Free Continuing Education + so much more!

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

This week, please join authors Hanna-Kaisa Nordenswan and Jukka Lehtonen, as well as Associate Editor Mark Link as they discuss the article "Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor in Circulation from Akershus University Hospital, and University of Oslo, Norway. Dr. Carolyn Lam: Oh, I am so excited about our feature paper today. It is about a condition that may not be as commonly encountered, but this paper can change clinical practice. It's about cardiac sarcoidosis and the indications for an ICD. Listen up. Very important stuff and discussion coming right up. But first, let's grab coffees and discuss the other papers in today's issues. Shall we? Dr. Greg Hundley: Right. So Carolyn, Peder, how about I go first? And so, both of you... we start with a really interesting, very practical study. It's somewhat unclear whether replacing an oral glucose tolerance test with just a hemoglobin A1C measurement for diagnosing diabetes is justified. And so these authors led by Adam Tabák, from University College of London in the United Kingdom, aimed to assess proportion of oral glucose tolerance tests, diagnosed diabetes cases that can be confirmed with hemoglobin A1C measures. And to examine whether individuals with oral glucose tolerance test diagnoses, but non-diagnostic hemoglobin and A1C are at higher risk of macro and microvascular disease. So the study included 5,773 men and women from the population based Whitehall II prospective of cohort study in the United Kingdom. New oral glucose tolerance tests, diabetes cases diagnosed in clinical examinations between the years of 2002 and 2004. And again, in 2007 and 2009 were assessed for hemoglobin A1C confirmation of a value greater than 6.5% in these. And then again, so in those years, and then again, in subsequent clinical examinations in the periods of 2012 to 2013 and 2015 to 2016, now all participants were followed for major cardiovascular events via linkage to electronic health records until the year of 2017. And for incident chronic kidney disease by an estimated glomerular filtration blade of less than 60 mLs per minute per meter squared, until the last clinical examination. Dr. Peder Myhre: Thank you, Greg. That is such an important study with direct clinical implications. And I'm so curious to know what did they find? Dr. Greg Hundley: Right, Peder. Right, Carolyn. Carolyn's in the background, it's like a mind meld with Peder. She's going to keep pounding me with these same questions. Okay. So in this population based cohort study, with five yearly repeated oral glucose tolerance tests and hemoglobin A1C measurements, only 59.3% of the oral glucose tolerance tests diagnosed diabetes cases were confirmed by hemoglobin A1C at the same or a subsequent examination during 4.1 years of follow up. Incident oral glucose tolerance test diagnosed diabetes cases with hemoglobin A1C confirmation, and preexisting diabetes cases had similarly increased risks of cardiovascular disease and chronic kidney disease. While notably unconfirmed oral glucose tolerance test cases had a similar risk as the diabetes free population. Dr. Peder Myhre: Wow. That is really remarkable, Greg. Thank you for that summary. But can you please just give us, from this complicated paper, can you just give us some take-home points for the listeners. Dr. Greg Hundley: Right, Peder. So first, in this study, people with oral glucose tolerance tests diagnosed diabetes without diagnostic hemoglobin A1C have a risk of cardiovascular disease and chronic kidney disease, similar to the diabetes free population. And therefore, replacement of oral glucose tolerance tests with hemoglobin A1C based diagnoses appears justified. Second, there seems to be no need to consider oral glucose tolerance testing when hemoglobin A1C and fasting glucose levels are apparently inconclusive. Fasting glucose tests are needed only in exceptional circumstances where hemoglobin A1C results are felt to be unreliable. And then, finally, these findings lend confidence to widespread use of hemoglobin A1C for diagnosing diabetes in the vast majority of clinical settings. Dr. Peder Myhre: Wow. Greg, thank you so much. This was so helpful. Well, I'm going to move on to the second original research article. And that is from the DAPA-HF trial, that I know Carolyn has been quizzing you throughout the years about. So I'm not going to quiz you, but I'm just going to ask you. Did you know that SGLT-2 inhibitors increase hematocrit and that it has been identified as one of the key mediators of the clinical benefits on this class of drugs. Dr. Greg Hundley: So Peder, they're really interesting. And the second week of this you're popping out with these quizzes. I didn't do this to Carolyn. It was like a couple months. So anyway, but- Dr. Carolyn Lam: Way to go, Peder. Way to go. Dr. Greg Hundley: Yeah. Well, the good news is, I can just say yes. I did know that. Dr. Peder Myhre: That's nice. And in this paper, we're going to learn even more. Because the authors are taking this further by looking into the iron metabolism and assessing iron deficiency in the DAPA-HF trial. So just to remind you, although, you are familiar with it at this point, Greg, and of course, Carolyn, the DAPA-HF trial was large RCT testing efficacy and safety of the SGLT-2 inhibitor compared to placebo in patients with heart failure and a reduced ejection fraction. And in this post talk analysis, the authors examine the prevalence and consequences of iron deficiency and the effect of dapagliflozin on markers of iron metabolism. They also analyze the effect dapagliflozin on outcomes according to iron status at baseline. Dr. Greg Hundley: Oh, wow, Peder. So what did they find? Dr. Peder Myhre: So in total, 44% of patients in DAPA-HF were defined as iron deficient. And that was defined as having less than 100 nanogram per milliliter of ferritin or a key set of less than 20% and a ferritin level between 100 and 299 nanogram per milliliter. So the rate of the primary outcome was higher in patients with iron deficiency compared to those without. That was 16 versus 10 per 100% years. And the effect of dapagliflozin on the primary outcome was consistent in iron deficient compared to iron replace patients with a fever interaction of 4.59. And similar findings were observed for cardiovascular death, heart failure hospitalizations and all-cause mortality. And finally, and very importantly, ferritin, T cell, and hepcidin were reduced with dapagliflozin versus placebo. So the authors conclude that iron deficiency was common in DAPA-HF. And associated with worse outcomes. Dapagliflozin, appeared to increase iron utilization, but improved outcomes, irrespective of iron status at baseline. Dr. Greg Hundley: Very nice, Peder. Wow. Just another important piece of information that we're learning about SGLT-2 inhibition. Well, Peder, my next paper comes from the world of preclinical science and it's from a group of authors led by Dr. Osamu Takeuchi from Kyoto University. Primary pulmonary arterial hypertension, Peder, is often characterized by obliterative pulmonary vascular remodeling, resulting in right heart failure. And although, the pathogenesis of pulmonary arterial hypertension is not fully understood. Inflammatory responses and cytokines have been shown to be associated with pulmonary arterial hypertension, particularly with connective tissue disease. So in this sense, Regnase-1 and RNAs, which regulates mRNAs in coding genes related to immune reactions was investigated in relationship to the pathogenesis of pulmonary hypertension. Dr. Peder Myhre: Wow, Greg. Pulmonary arterial, a hypertension and mRNA degradation of IL-6. So what did they find, Greg? Dr. Greg Hundley: Right, Peder. So these investigators examined the expression levels of Z3H12A in coding Regnase-1, in peripheral blood mononuclear cells from pulmonary hypertension patients classified under various types of pulmonary hypertension, searching for an association between the ZC3H12A expression and the clinical features associated with pulmonary hypertension. They then generated mice lacking Regnase-1 and myeloid cells, including alveolar macrophages and examined right ventricular systolic pressures, and histologic changes in the lung. They found that Regnase-1 maintains lung innate immune homeostasis via the control of IL-6 and PDGF in alveolar macrophages, thereby, suppressing the development of pulmonary arterial hypertension in mice. And furthermore, the decreased expression of Regnase-1 in various types of pulmonary hypertension implied its involvement in pulmonary hypertension pathogenesis. And then, therefore, may serve as a disease biomarker as well as a therapeutic target for pulmonary hypertension. Very, very interesting work from the world of preclinical science. So how about we jump and see what else is in the mail bag? Dr. Peder Myhre: So we have From the Literature by Dr. Tracy Hampton, and this time we get three summaries from preclinical science papers published on their journals. First, there is a summary of a paper suggesting that circadian and pluripotency networks control longevity related genes, and that was published in cell metabolism. There is also a summary from a paper on the varied responses to a high fat diet using mouse models published in high science. And finally, there is a summary related to Brugada syndrome and how gene therapy is a potential future therapy. And that was published in scientific translational medicine. So Greg, what did you have in the mail bag? Dr. Greg Hundley: Sure. Well, Peder, I've got a research letter from Professor Fang entitled “Mitochondrial Stress Induces HRIEIF2A Pathway that's Protective for Cardiomyopathy.” Dr. Peder Myhre: And finally, we have clinical implications of basic research from Dr. Garry and colleagues entitled “Cardiac Xenotransplantation, the Clinical Impact of Science and Discovery.” So let's move on the future discussion, Carolyn. Dr. Carolyn Lam: Absolutely. Thank you for excellent summary, Greg and Peder. Now, let's go the feature discussion on cardiac sarcoidosis. Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Wow. Today's feature discussion is on a rare, but very important topic. And it's that of cardiac sarcoidosis. And you have to listen up because today's paper could actually change practice. So I'm very pleased and grateful to have the authors of this paper. The corresponding author, Dr. Hanna-Kaisa Nordenswan and coauthor, Dr. Jukka Lehtonen both from Helsinki University Hospital. As well as our associate editor, Dr. Mark Link, from UT Southwestern to discuss this very important paper. Hannah-Kaisa if you don't mind, could you start by just telling us about your paper and what you found? Dr. Hanna-Kaisa Nordenswan: Thank you so much for inviting us to the podcast. So cardiac sarcoidosis predisposes to sudden cardiac death. But how well the current guidelines for implantable cardioverter-defibrillators in CS issued by the Heart Rhythm Society in 2014 and the American College of Cardiology, American Heart Association and Heart Rhythm Society, consortium guidelines from 2017, discriminate high from low risk of sudden cardiac death is unknown. And this is what we wanted to examine. So our study is a nationwide study, including 398 patients with cardiac sarcoidosis. All patients had clinical cardiac manifestations and a histological diagnosis of sarcoidosis. The histological diagnosis was myocardial in nearly one half of the population. So patients with and without class 1 to 2A indications for an implantable cardioverting-defibrillator at presentation were identified from this population. The occurrence of fatal or aborted sudden cardiac death and sustained ventricular tachycardias in follow-up were recorded. We also noted ICD indications emerging first on, follow up. Dr. Carolyn Lam: Great. What did you find? Dr. Hanna-Kaisa Nordenswan: So, first of all, we found that by the current ICD guidelines, 85 to 100% of our patients had at least one strong to modest class 1 to 2a indication for an early ICD implementation. And we also found a 10%, five-year cumulative incidence of sudden cardiac death in our population of cardiac sarcoidosis patients. Further, we found that patients without an early indication for an ICD by the Heart Rhythm Society guidelines had nearly 5% cumulative risk of sudden cardiac death at five years. These patients further had a 53% cumulative risk of either developing an indication or suffering from a life-threatening ventricular arrhythmia at five years follow up. Finally, we also found that a diagnosis of cardiac sarcoidosis based on myocardial histology, IE definite CS. So definite cardiac sarcoidosis predicted twice higher combined five-year risk of sudden cardiac death and life-threatening ventricular arrhythmia than diagnosis based on extra cardiac histology, IE probable cardiac sarcoidosis. Dr. Carolyn Lam: Wow. Thank you so much, Hannah-Kaisa and congratulations on such impactful findings. 398 patients and if I read correctly, a cohort spanning 30 years. Jukka, could you tell us a little bit more on how these patients were identified? And I think this is important too, because it speaks to the generalizability of your findings. Dr. Jukka Lehtonen: Exactly. Yeah. So we have a very proactive approach to cardiac sarcoidosis. So basically, if I give you an example, so we screen all patients less than 60 years of age with MRI. And if the MRI shows that there's any signs of myocardial damage, we do endomyocardial biopsy. And then, if we do biopsy, once take 10 samples from the right ventricular septum. If that comes out negative, as it very often comes, then we do a PET study. And if there's an extra cardiac signal, then we do biopsy that side. So usually, it's lymph nodes very often. And that gives us a probable cardiac sarcoidosis. So probable cardiac sarcoidosis is the terminology that's used in Heart Rhythm Society, 2014 guidelines. It has the same prognosis, basically, the definite cardiac sarcoidosis that's based on endomyocardial biopsy. So if the PET shows no signal outside the heart, we usually repeat the biopsy either right or left side, depending where there's most signal. And we can do that up to three times. So we have a very proactive approach. And that explains why we have so many patients. So because you may end up taking 30 biopsy samples and you have one sample that's positive. So that explains why 5.3 million people can have such a huge number of sarcoid patients. We don't think that we are special. We just think that we are very active in biopsy area. And I know that this is something that differs in different places, and the different centers in the US have very different policies, and in Europe as well. So why I think this explains why we have such a large population and why they're all biopsy verified cases. Dr. Carolyn Lam: Thank you so much, Mark. I know that as editors we spotted immediately what a precious, valuable cohort in data we were looking at. Could you frame that for us? Take us behind the scenes a little bit on what you thought when this paper first crossed your desk. Dr. Mark Link: Yeah. This was a paper that caught our interest right away for a number of reasons. One, is the large number of sarcoid patients, nearly 400, that's one of the largest series that's ever been published. And two, is the systematic way in which sarcoid was approached. And what we found fascinating is that once you had a diagnosis of cardiac sarcoid, be it either probable or actual, there was a high risk of having ventricular arrhythmias. And this is something that in the guidelines, it's not so clear, because it's clear if the EF's less than 35%, you should get an ICD. But if your EF's greater than 35% by current guidelines, that's not a class 1 indication. So we thought this paper had the possibility to move guidelines and that perhaps we should think about an ICD and any patient that has diagnosis of cardiac sarcoid. Dr. Carolyn Lam: Wow. That's a brave postulation though. Exactly, as I said at the beginning, I think it may be practice changing. What do you think about that? Jukka and Hannah? Dr. Jukka Lehtonen: I think that's exactly what we have noticed that we have, most of the cardiac sarcoid patients are less than 50 years of age. So I think, the average age is 49 or something. And they're mostly females, so 70% are females. So it's pretty unique cardiac disease, that's more common in females than in males. And I think this population is benefiting tremendously from the ICD therapy, so that's something that we can see. It's not based on randomized data, it's follow up data, but these patients have lots of ICD events, events treated by an ICD. So we think that this is a major problem. Our previous papers have shown that the mortality in sarcoidosis is 90% is ventricle arrhythmia. So this conclusion fits with that previous findings as well. Dr. Carolyn Lam: Wow. Hannah has this impacted your personal clinical practice? I mean, do you now therefore think any patient, especially, if they've got confirmed cardiac sarcoidosis biopsy proven. Are you going to just, no matter what, regardless, anything else be more likely to put an ICD? Dr. Hanna-Kaisa Nordenswan: Yeah. Based on this study, we think that all cardiac sarcoidosis patients presenting with clinical cardiac manifestations and with histologically proven cardiac sarcoidosis should be considered for an ICD implantation. But with patients, with having non-definite cardiac sarcoidosis and without class 1 to 2A indications for an ICD in these patients, probably, the pros and cons of an ICD should be carefully discussed. Well, if an ICD is not implanted, at least repeated risk appraisal is needed regularly during follow up. Dr. Carolyn Lam: That's great comments. Mark, what do you think is going to be needed as future steps to get it to change practice? Or do you think this is it? Because, I mean, this is... the issue is, it's not easy to say let's just do a trial in cardiac sarcoidosis, right? Where are we going to find those patients and so on. What do you think, Mark? Dr. Mark Link: Yeah. That's a very good question. Because this isn't randomized trial data, and the strength of evidence is best with randomized trial data. And will we get a randomized trial in sarcoid? I doubt it. I really doubt it. So we're going to be left with registry data. And so where I would see this going is other registries coming out, showing their data. I think we do need confirmatory data from another large registry or two, and that's going to change practice, but are we there yet? I don't know. I don't know. Based on the lack of randomized trial data. Dr. Carolyn Lam: Thanks. If I could then for the last questions, if I could give it to the authors, what are your plans for next steps, if any. Maybe, Jukka, do you want to start first? Dr. Jukka Lehtonen: Well, I think cardiac sarcoidosis has lots of open questions. It has only open questions. I think the direction we are going is to go to the drug trial. So whether treatment of the inflammation by different agents would provide benefit in terms of arrhythmias and heart failure. So there's an idea that take patients with, for example, that's something that we haven't finalized yet, but take patients with normal ejection fraction, randomized them to cortisone and no cortisone and see how they do. Because we don't really know whether even corticosteroids actually make a huge difference. I think we have more than 200 cardiac sarcoid patients under follow up in our hospital. And I can see that there are patients that have very good prognosis and no events whatsoever over many years or even decade. And then we have other patients that have lots of events, arrhythmias and develop heart failure. So I think we need trials that help us to distinguish those patients and also trials that help us select right medications for each group. Dr. Carolyn Lam: Thank you, Hannah? Dr. Hanna-Kaisa Nordenswan: Based on this particular study, we think that also the next study should preferably be a larger multicenter study that would focus on the prognostic factors in cardiac sarcoidosis. Perhaps, a risk score could be developed by using more detailed information of the presenting manifestations and ventricular function and imaging findings, cardiac magnetic resonance and positron emission tomography. Dr. Mark Link: Yeah. And we at the editorial staff thought this was important enough paper to have an editorial, to comment on its usefulness and way forward in dealing with cardiac sarcoid patients. And this editorial is written by Rick Patton and will accompany the printed issue. Dr. Carolyn Lam: Thanks. And so, you heard it, everyone pick up that editorial, pick up that paper. This is an important topic, and so grateful that it was published with us. Thank you once again to the authors. Thank you once again, Mark, for managing this paper. So lovely. And thank you, audience for joining us today from Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism." Dr. Carolyn Lam: Welcome to Circulation On Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health Richmond, Virginia. Dr. Carolyn Lam: In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg? Dr. Greg Hundley: You bet, Carolyn. Well, how about if I go first? Dr. Carolyn Lam: Please. Dr. Greg Hundley: Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4. Dr. Carolyn Lam: Nice. Okay. Important question, what did they find? Dr. Greg Hundley: Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women. Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome. Dr. Carolyn Lam: Oh, you are right. A lot of interesting data here. What's a take home message? Dr. Greg Hundley: Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step. Dr. Carolyn Lam: Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis. Dr. Greg Hundley: Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find? Dr. Carolyn Lam: Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC. Dr. Greg Hundley: Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight? Dr. Carolyn Lam: Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth? Dr. Greg Hundley: Yeah. Remember seven dwarfs, Sleepy. Dr. Carolyn Lam: Sleep. Dr. Greg Hundley: Very good. Great job, Carolyn. Dr. Carolyn Lam: Thank you. Dr. Greg Hundley: Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018. Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression. Dr. Carolyn Lam: Okay, Greg. What did they find? Dr. Greg Hundley: Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years. Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group. Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large. Dr. Carolyn Lam: Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility. Dr. Greg Hundley: Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion? Dr. Carolyn Lam: Yes, let's go Greg. Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found. Dr. Senthil Selvaraj: Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites. To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment. The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity. Dr. Carolyn Lam: Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati? Dr. Svati Shah: Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself. To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn. Dr. Carolyn Lam: Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically? Dr. Manuel Mayr: Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress. Dr. Carolyn Lam: Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that? Dr. Senthil Selvaraj: I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space. The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet. Dr. Svati Shah: Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do. Dr. Carolyn Lam: And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps? Dr. Manuel Mayr: Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis. Dr. Senthil Selvaraj: That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process. Dr. Carolyn Lam: Anything to add, Svati? Dr. Svati Shah: No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also. Dr. Carolyn Lam: Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view? Dr. Manuel Mayr: Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure. Dr. Carolyn Lam: Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

A second ESC review covering REVIVED, the DANCAVAS CV screening trial, DELIVER on dapagliflozin in HF with mildly reduced EF, and the INVICTUS trial of rivaroxaban in rheumatic heart disease. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I REVIVED BCIS - PCI Fails to Beat OMT in Ischemic Cardiomyopathy: REVIVED-BCIS2 https://www.medscape.com/viewarticle/979853 - Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction https://www.nejm.org/doi/full/10.1056/NEJMoa2206606 - Coronary-Artery Bypass Surgery in Patients with Left Ventricular Dysfunction https://www.nejm.org/doi/full/10.1056/nejmoa1100356 II DANCAVAS - DANCAVAS Misses Primary Endpoint but Hints at Benefit from Comprehensive CV Screening https://www.medscape.com/viewarticle/979854 - Five-Year Outcomes of the Danish Cardiovascular Screening (DANCAVAS) Trial https://www.nejm.org/doi/full/10.1056/NEJMoa2208681 - Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure https://www.nejm.org/doi/full/10.1056/NEJMoa1608029 III DELIVER Trial - Dapagliflozin's HFpEF Benefit Recasts Heart Failure Treatment: DELIVER https://www.medscape.com/viewarticle/979855 - Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction https://www.nejm.org/doi/full/10.1056/NEJMoa2206286 - Empagliflozin in Heart Failure with a Preserved Ejection Fraction https://www.nejm.org/doi/full/10.1056/NEJMoa2107038 - SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials https://doi.org/10.1016/S0140-6736(22)01429-5 IV Rheumatic Heart Disease - Rivaroxaban Outmatched by VKAs for AF in Rheumatic Heart Disease https://www.medscape.com/viewarticle/979861 - Rivaroxaban in Rheumatic Heart Disease–Associated Atrial Fibrillation https://www.nejm.org/doi/full/10.1056/NEJMoa2209051 - Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve https://www.nejm.org/doi/full/10.1056/NEJMoa2029603 - Outcomes of Direct Oral Anticoagulants in Patients With Mitral Stenosis https://www.jacc.org/doi/full/10.1016/j.jacc.2018.12.047 Features: - Do SGLT2 Inhibitors DELIVER in All Patients With Heart Failure? https://www.medscape.com/viewarticle/979852 - PCI Fails in Stable Disease Again: REVIVED-BCIS https://www.medscape.com/viewarticle/979862 - DANCAVAS: Might Cardiovascular Screening Extend Men's Lives? https://www.medscape.com/viewarticle/979632 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

This week on Pharm5: Farxiga (dapagliflozin) for HFpEF Updated boosters for COVID-19 Xenpozyme (olipudase alfa) for rare ASMD New York Times on “growing chains, falling wages” Phase III olokizumab vs. adalimumab for RA Connect with us! Listen to our podcast: Pharm5 Watch us on TikTok: @LizHearnPharmD Follow us on Twitter: @LizHearnPharmD References Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. New England Journal of Medicine. August 2022. doi:10.1056/nejmoa2206286 FDA Approves Treatment for Wider Range of Patients with Heart Failure https://bit.ly/3B20I8N. Published February 24, 2022. Accessed February 24, 2022. Coronavirus (COVID-19) update: FDA authorizes Moderna, Pfizer-BioNTech bivalent COVID-19 vaccines for use as a booster dose. U.S. Food and Drug Administration. https://bit.ly/3cDuyHd. Accessed August 31, 2022. Scheiber N. How pharmacy work stopped being so great. The New York Times. https://www.nytimes.com/2022/08/20/business/economy/pharmacists-job-inflation.html. Published August 20, 2022. Accessed September 1, 2022. FDA approves first treatment for acid sphingomyelinase deficiency, a rare genetic disease. U.S. Food and Drug Administration. https://bit.ly/3AziPS5. Accessed August 31, 2022. Dunleavy K. Sanofi's rare disease drug XENPOZYME scores FDA approval after nods in Japan and Europe. Fierce Pharma. https://bit.ly/3B3kz7F. Published August 31, 2022. Accessed August 31, 2022. Smolen JS, Feist E, Fatenejad S, et al. Olokizumab versus placebo or adalimumab in rheumatoid arthritis. New England Journal of Medicine. 2022;387(8):715-726. doi:10.1056/nejmoa2201302

This week, please join authors John McMurray and David Cherney, editorialist Kausik Umanath, as well as Associate Editors Ian Neeland and Brendan Everett as they discuss the original research articles "Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF" and "Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition" and editorial ""Dip" in eGFR: Stay the Course With SGLT-2 Inhibition." Dr. Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, it's the season of double features. Except this time, we're having a forum discussion of two related articles and an editorial that discusses both. What is it on? SGLT2 inhibitors. In the first paper, an analysis from the DAPA-HF trial, looking specifically at that initial dip in GFR that follows initiation of dapagliflozin in patients with HFrEF. Then we will discuss further, in a mechanistic way, the renal and vascular effects of combining SGLT2 inhibition on top of ACE inhibition. Lots and lots of good learning and insights, but let's go on first to the other papers in today's issue. Shall we? Dr. Greg Hundley: You bet, Carolyn, and I'm going to grab a cup of coffee. Carolyn, in this issue, wow, so many exciting original articles. In fact, there are two more articles that were going to pair together, both clinical and pertaining to TAVR procedures. In the first one, it was a group of authors led by Dr. Duk-Woo Park from the Asan Medical Center at the University of Ulsan College of Medicine. They conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy or DAPT, aspirin plus clopidogrel, in patients who had undergone successful TAVR and did not have an indication for anticoagulation. Now in this study, Carolyn, the primary endpoint was an incidence of leaflet thrombosis on four-dimensional computed tomography, CT, performed at six months after the TAVR procedure. Key secondary endpoints were the number and volume of new cerebral lesions on brain magnetic resonance imaging or MRI and the serial changes of neurological and neurocognitive function between six months and that time immediately post the TAVR procedure. Dr. Carolyn Lam: Oh, interesting. What did they find? Dr. Greg Hundley: Right, Carolyn. In patients without an indication for long-term anticoagulation after successful TAVR, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effect on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the two groups. Now because the study was underpowered, the results should be considered really as hypothesis generating, but do highlight the need for further research. Dr. Greg Hundley: Carolyn, there's a second paper pertaining to transcatheter aortic valve prosthesis. It's led by a group directed by Dr. Paul Sorajja from the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. Carolyn, these authors prospectively examined 565 patients with cardiac CT screening for HALT, or what we would define as hypoattenuating leaflet thickening, at 30 days following balloon-expandable and self-expanding TAVR. Now, deformation of the TAVR prosthesis, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the post-procedural CT. For descriptive purposes, an index of prosthesis deformation was calculated, with values greater than 1 representing relative midsegment underexpansion. A time-to-event model was also performed to evaluate the association of HALT with the clinical outcomes. Dr. Carolyn Lam: Oh, interesting. What did they find? Dr. Greg Hundley: Right, Carolyn. Nonuniform expansion of TAVR prosthesis resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume was related to the occurrence of HALT in patients who underwent TAVR. What's the take home here, Carolyn? These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes in these patients. Now, Carolyn, both of these articles are accompanied by an editorial from Dr. Raj Makkar from the Smidt Heart Institute at Cedars-Sinai's Medical Center. It's a very lovely piece entitled Missing Pieces of the TAVR Subclinical Leaflet Thrombosis Puzzle. Well, how about we check what else is in this issue? My goodness, this was a packed issue. First, Carolyn, there are three letters to the editor from Professors Ennezat, Dweck, and then a response from Dr. Banovic pertaining to a follow-up from a previously published study, the AVATAR study, in evaluating valve replacement in asymptomatic aortic stenosis. There's also a Perspective piece from Dr. Wells entitled “Treatment of Chronic Hypertension in Pregnancy: Is It Time For A Change?” There's a Global Rounds piece from Professor Berwanger entitled “Cardiovascular Care in Brazil: Current Status, Challenges, and Opportunities.” Then there's also a Research Letter from Professor Eikelboom entitled “Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis.” Dr. Carolyn Lam: There's another Research letter by Dr. Borlaug on longitudinal evolution of cardiac dysfunction in heart failure with normal natriuretic peptide levels. There's also a beautiful Cardiology News piece by Bridget Kuehn on the post-COVID return to play guidelines and how they're evolving. Well, that was a great summary of today's issue. Let's hop on to our feature forum. Shall we? Dr. Greg Hundley: You bet, Carolyn. Can't wait. Dr. Carolyn Lam: Today's feature discussion is actually a forum because we have two feature papers in today's issue. They all surround the cardiorenal interaction, should I say, of the SGLT2 inhibitors. For the first paper, discussing that initial decline or that dip in the GFR following initiation of dapagliflozin would be Dr. John McMurray, who's the corresponding author of this paper from DAPA-HF. Dr. John McMurray's from the University of Glasgow. Now next, we have also the corresponding author of another paper, really going into the mechanistic insights of the renal and vascular effects of combined SGLT2 and ACE inhibition. Dr. David Cherney is from Toronto General Hospital, University of Toronto. Dr. Carolyn Lam: We have the editorial list of these two wonderful papers, Dr. Kausik Umanath from Henry Ford Health in Michigan. Finally, our beloved associate editors, Dr. Ian Neeland from Case Western Reserve and Dr. Brendan Everett from Brigham and Women's Hospital, Harvard Medical School. Thank you, gentlemen. Now with all of that, what an exciting forum we have in front of us. Could I start by asking, of course, the respective authors to talk a little bit about your papers? I think a good place to start would be with Dr. McMurray. John, please. Dr. John McMurray: Thanks, Carolyn. I think our paper had three key messages. The early dip in eGFR that we saw was, on average, very small in patients with heart failure, about 3 mLs/min or about 5%. Very few patients had a large reduction in the eGFR. It was around 3%. Dapagliflozin-treated patients had a 30% or greater decline compared to about 1% of placebo patients. Finally, very few of those patients had a decline in the eGFR below a critical threshold, which for cardiologists might be around 20 mLs/min. We saw that in only five patients; that's 0.2% of the dapagliflozin-treated patients. Second message was that that early decline partially reverses. The nadir in our study was about 14 days. But by 60 days, on average, eGFR had increased again. Hold your nerve if you see an early decline in eGFR.   Dr. John McMurray: Maybe the most important message was that that decline in the eGFR is not associated with worse cardiovascular or renal outcomes. In fact, if anything, the opposite. If you look at the patients in the dapagliflozin group with a 10% or greater decline in eGFR, then compare it to patients who didn't have that decline, these individuals were about 27% less likely to experience the primary composite outcome of worsening heart failure and cardiovascular death. If you look at the placebo group, we saw exactly the opposite. Amongst those who had a greater than 10% decline in eGFR compared to those who didn't, those people with the early decline in eGFR were 45% more likely to experience the primary composite endpoint. The same is true for other cardiovascular outcomes for worsening kidney function. In the dapagliflozin group, decline in eGFR was not associated with more adverse events, not associated with more treatment discontinuation. That small decline in the eGFR is not a bad prognostic sign. If anything, it might be the opposite. Dr. Carolyn Lam: Thank you so much. That was really clear. David, are you going to tell us why this decline occurs? Dr. David Cherney: Yeah. Perhaps the paper that we published gives some insights into the mechanisms that are responsible for some of those changes in GFR that are thought to be acute hemodynamic effects. In the between trial, which is the trial that we published examining the effect of ACE inhibition followed by SGLT2 inhibition in patients with type 1 diabetes, we also saw that there was an expected effect of adding SGLT2 inhibition on top of an ACE inhibitor in people with uncomplicated type 1 diabetes. This acute dip in GFR was seen in this cohort of patients. We included only 30 patients in this small mechanistic study. At the same time, along with that dip in GFR, we also saw an increase in measures of proximal natriuresis. That proximal sodium loss is linked with changes in sodium handling in the kidney, which then causes changes in both probably afferent and efferent tone, which causes this dip in GFR primarily through natriuresis in this phenomenon called tubuloglomerular feedback. That was one major observation that gives insight into what we see in larger trials around the dip in GFR. Dr. David Cherney: In our mechanistic study, we also saw an additive effect on blood pressure. Blood pressure went down further with the addition of empagliflozin on top of an ACE inhibitor. In terms of the mechanisms that are responsible for the reduction in blood pressure, natriuresis certainly may be in part responsible, but we also saw a novel observation whereby there was a reduction in peripheral vascular resistance using noninvasive measures. There are likely several mechanisms that are responsible for the reduction in blood pressure. Then finally, we also saw reductions in markers of oxidative stress, which may also account for some of the effects that we see in blood pressure, as well as potentially some of the anti-inflammatory and anti-fibrotic effects that we see at least in experimental models that may have some clinical translatability to humans as well around the clinical benefits. I think the blood pressure, the renal hemodynamic effects, and some of the neurohormonal mechanisms are the major observations that we saw that may in part explain some of the really nice changes that were seen in Dr. McMurray's study. Dr. Carolyn Lam: Right. Thanks, David. But these were patients with type 1 diabetes and no heart failure. John, do you have any reflections or questions about how that may apply? By the way, what a beautiful study. Thank you, David. Dr. David Cherney: Pleasure. Thank you. Dr. John McMurray: Yes, David. I really enjoyed your study. In fact, I think, Carolyn, it does shed some insights perhaps to what's going on. As David pointed out, the reduction in peripheral arterial resistance, reduction in blood pressure, that may play some role in that early dip in eGFR as well as autoregulation in the kidney. Then the other interesting thing is that the distal nephron seems to adapt to that effect in the proximal tubule. Again, that may account for some of that recovery in eGFR, that reversal in the early dip that I spoke about, and which I think is very clinically important because, of course, physicians should make sure that they recheck eGFR if they see that early dip. Because they may find that few weeks later that that dip is much smaller and of much less concern. Dr. Carolyn Lam: Thank you, John. In fact, you're saying, stay the course, right- Dr. John McMurray: I have. Dr. Carolyn Lam: ... with the SGLT2 inhibitors. I'm actually stealing the words of the title of the editorial, a beautiful editorial by Kausik. I love that. Stay the course. Kausik, please, could you frame both papers and then with an important clinical take home message for our audience? Dr. Kausik Umanath: Sure. I think the analysis by John and his group was really relevant with the large sample size. What's impressive? Similar to a lot of these other SGLT2 studies that have come out, both in heart failure and in kidney disease progression and so on, it's remarkable how the other analysis, like the analysis of EMPA-REG and CREDENCE and so on, of similar dips. All show more or less the same magnitude, the same relative proportions of this GFR trajectory. I think the mechanistic study only highlights that though it's working with a slightly different population of type 1 patients and much earlier in their course in terms of where their GFRs are. Dr. Kausik Umanath: The other piece is that ultimately we need to understand this dip and know to monitor for it and so on. But I think the general clinician should really understand that a dip of greater than 10% really occurs in less than half the population that takes these agents. That dip, if it occurs, certainly doesn't do any harm. That said, if they see a bigger dip in the 30% range, monitor more closely and consider making sure that there aren't any other renal issues out there for that patient because they are a much smaller proportion of patients in these large trials that generate that level of dip. They should be monitored. Dr. Kausik Umanath: The other thought that we had, and thinking through this in a practical sense, is because you expect this dip, many of our cardiologists or even the nephrologists when we titrate these drugs, they're on a suite of other drugs. It's probably best to not adjust their Lasix or their loop diuretic, or their RAAS inhibitor at the same time as you're adjusting the SGLT2 inhibitor or starting it because then you may just introduce more noise into the GFR changes that you see over the next several weeks. It may be a sequential piece or at least holding those other agents constant while this gets titrated and introduced is a prudent course of action, so you don't misattribute changes. Dr. Carolyn Lam: Thanks so much. What clinically relevant points. In fact, that point about the diuretic especially applies in our heart failure world. You see the dip. Well, first, make sure the patient's not overdiuresed. Remember, there's more that the patient's taking. Thank you. That was a really great point. Brendan and Ian, I have to get you guys to share your views and questions right now. But before that, can I take a pause with you and just say, aren't you just so proud to be AEs of Circulation when we see papers like these and we just realize how incredible the data are and the clinical implications are? I just really had to say that. All right. But with that, please, what are your thoughts, Brendan? Dr. Brendan Everett: Yeah, sure. Thank you, Carolyn. Hats off to all three of our authors today for doing some amazing science. Thank you for sending it to Circulation. I think, in particular, I handled David's paper. I'm not a nephrologist and I'm probably the furthest thing from a nephrologist. Had to do my best to try and understand these concepts that I'm not sure I ever even was exposed to in medical school many years ago. I think it shows the breadth of the interest in our readership. The fact that these changes in eGFR have become a primary focus for our cardiovascular patients and that the clinical implications are really important. I guess my question, David, is... In your paper, you talked a little bit about this hypothesis of hyperfiltration and the role that hyperfiltration plays in setting patients with diabetes up for kidney disease. Is that playing a role in John's observation or not? Again, as a non-nephrologist, I have trouble connecting the dots in terms of that hypothesis and John's observation of the clinical benefit for patients that have a reduction in eGFR as opposed to no change. Dr. David Cherney: Yeah. It's a great question. It's very difficult to know with certainty in a human cohort because we can't measure the critical parameter, which is intraglomerular pressure, which we think these changes in GFR are a surrogate for. But if we go along with that train of thought, along reductions in glomerular hypertension, it very much makes sense that the patients who dip are those who have the... They're taking their medication, number one. Number two, they respond physiologically in the way that you expect them to, which is that their GFR dips at least transiently and then goes back up again through some of the compensatory mechanisms that John mentioned earlier. As was mentioned not only in this paper, but also in previous analyses from CREDENCE and previous analyses from VERTIS CV and others have shown that indeed that dip in GFR is linked with longer term renal benefits, at least. That is reflected in a reduction in the loss of kidney function over time. Dr. David Cherney: The patients who are on an SGLT2 inhibitor and those who dip by around 10% or less, those patients tend to do the best over time in terms of preserving GFR, not losing kidney function compared to patients who are on an SGLT2 inhibitor but do not dip, or those patients who actually have an increase in GFR. That is consistent with this idea that there may be a reduction in glomerular pressure, which is protective over the long term. That ties back into your question around hyperfiltration that this may indeed be due to a reduction in glomerular pressure, which is linked with risk over the long term. Dr. Carolyn Lam: Ian? Dr. Ian Neeland: I wanted to echo Brendan's comments about the excellent science. When I read these papers, it really speaks to the existential struggle that cardiologists have between kidney function and these medications that we know have cardiovascular benefits. How do we manage that practically? It's so clinically relevant, both the observation that John's paper made about the dip in the DAPA-HF trial as well as, David, your mechanistic insights. Dr. Ian Neeland: I wanted to ask John potentially about the most fascinating aspect to me of this paper was that patients with a dip of 10% or more actually ended up doing better in terms of cardiovascular outcomes, specifically hospital heart failure and hospitalizations than people on placebo with a greater than 10% dip. It speaks to the fact that... Is the physiology going on here different between those individuals whose GFR went down on placebo versus those who are on SGLT2 inhibitors? All the mechanistic insight that David's paper had in terms of blood pressure and intraglomerular pressure, how does that feedback and speak to why heart failure is strongly linked to this mechanism? We see this not just with SGLT2 inhibitors, but there are other medications now coming out showing that there's a relationship between this dip in GFR and heart failure. Can you speak to why this heart failure-kidney connection is so important and becoming greater and greater in terms of our understanding? Dr. John McMurray: Well, thank you for asking me the hardest question and one that I truly don't think I have a good answer to. I think it's obvious to all of us that the kidney is central in heart failure and perhaps cardiologists have neglected that fact, focusing more on the other organ. But by definition, almost the fluid retention that characterizes heart failure in terms of signs, and probably is the primary cause of symptoms, that clearly is a renally-mediated phenomenon. The kidney must be central to all of this. I think David right. I think the decline in eGFR that you see with this drug is simply a marker that the drug is having its physiological effect or effects. Whatever those are, they're beneficial. Clearly, patients who have an eGFR decline on placebo are different and they reflect, again, the patients that we see all the time. As our patients with heart failure deteriorate, one of the things that we commonly see, in fact becomes one of the biggest problems that we have to deal with, is that their kidney function declines. As their symptoms get worse, as their cardiac function gets worse, their kidney function also declines. Dr. John McMurray: I think you're seeing two contrasting effects here. One is the background change in eGFR, which is the placebo patients, and we've always known that that's a bad thing. Then we're seeing that early within 14 days marker of the pharmacological or physiological action of the drug. I hope you don't ask me how SGLT2 inhibitors work in heart failure. That's the other most difficult question I can think of, but I think this is just a marker of the fact that they are working. Dr. David Cherney: Yeah. Just to add to that briefly, there is this difficulty in sorting out the mechanisms that are relevant around the acute effects in the kidney that the dip in GFR reflects natriuresis that could keep patients out of heart failure; that the reduction in glomerular pressure reduces albuminuria. Albuminuria reduction is linked with kidney protection. It's linked with heart failure and ASCVD protection. Then there's also this concept of if you dip and then you stay stable afterwards, your GFR stays stable afterwards, those patients with stable kidney function that's not declining, the dippers in other words, those patients are probably able to maintain salt and water homeostasis better than someone who's declining more rapidly. All these things probably tie together in order to reflect, of course, there's a renal protective effect, but that some of those mechanisms may also tie into the heart failure mechanisms that John was mentioning. Dr. John McMurray: But, David, it's hard to imagine if we don't protect the kidney, we won't protect patients with heart failure given how fundamental, as I said, the kidney is, and how fundamentally important worsening kidney function is. Not only because it is a marker of things going badly, but also because it often results in discontinuation or reduction in dose of other life-saving treatments. To Kausik's point, it was very important about the risk of changing background life-saving disease modifying therapy. Actually, we didn't see that in DAPA-HF, which was very intriguing. There was no reduction in use of renin-angiotensin system blockers or mineralocorticoid receptor antagonists. Dr. Carolyn Lam: Thank you so much, gentlemen. Unfortunately, we are running out of time, but I would really like to ask one last question to the guests, if possible. Where do you think the field is heading? What next? What's the next most important thing we need to know? David, do you want to start? Then John, then Kausik. Dr. David Cherney: I think one of the aspects that we need to know in the future is where else can we extend these therapies into novel indications and extend the boundaries of where we currently work with these therapies. People with type 1 diabetes, for example, with either heart failure or with significant kidney disease, patients with kidney transplantation, is there a renal or cardiovascular protective effect? Then another high risk cohorts who have not been included in trials, those on immunosuppressants, for example, who were excluded from the trials. I think those are some of the areas that we need to extend into now that we understand how these therapies work in even very sick patients and that we also know that they likely have at least some benefit through suppressing inflammation, and possibly reducing infectious risks. That would provide a rationale for extending into some of these new areas. I think that's certainly, hopefully on the horizon for us. Dr. Carolyn Lam: John? Dr. John McMurray: Carolyn, obviously I think looking at post myocardial infarction population, that's an obvious place to go. There are a couple of trials there. I suppose the trial that I would love to see, and which I think would address the core question that we've been discussing today, which is: Is this all about the effect in the kidney and how important is the diuretic and natriuretic action of these drugs in heart failure? I think the key study that would address this would be doing a study in patients on dialysis. Because in those patients we could, I think, separate the issue of natriuresis, diuresis, and maybe even the dip in EGR that we've been talking about. If these drugs prove to be effective in end-stage kidney disease, patients on dialysis, that would be really fascinating. Dr. Carolyn Lam: Kausik? Dr. Kausik Umanath: That is a very interesting point. I don't know that we know necessarily outcomes, but I think from working with the DAPA-CKD, we do have a little bit of the safety data because we did continue it. I was the US MLI for that study and we did continue the SGLT2 passed into renal failure. There is a little bit of safety data there. But I don't think once you've declared an outcome, you're not collecting outcomes data after that point. That's a very interesting area to look into. Dr. Kausik Umanath: I also think the other place where this field's heading is trying to better tier and layer the multitude of agents. I think we've been waiting for about 20 to 30 years, at least in the kidney field, for something new to affect the progression of kidney disease after the ACE/ARB trials and so on. This one we've got SGLT2 inhibitors. We've got the new MRA, finerenone, and so on, which also have very beneficial cardiovascular effects. The question becomes: How do we layer these therapies? Which sequence to go in? Some of the others that are in pipeline as well that are out there that have very beneficial cardiovascular effects that may indeed also help kidney function and diabetes control, which do you go with first and so on? Dr. Carolyn Lam: Wow! Thank you so much. We really could go on forever on this topic, but it has been tremendous. Thank you once again. On behalf of Brendan, Ian, Greg, thank you so much for joining us today in the audience. You've been listening to Circulation On the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Obstructive hypertrophic cardiomyopathy and mavacamten, SGLT2 inhibitors, the triple whammy, espresso, and clinician burnout are the topics John Mandrola, MD, covers in today's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I – Mavacamten - FDA Clears Mavacamten (Camzyos) for Obstructive Hypertrophic Cardiomyopathy https://www.medscape.com/viewarticle/972945 - Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial https://doi.org/10.1016/S0140-6736(20)31792-X - FDA approves new drug to improve heart function in adults with rare heart condition https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-drug-improve-heart-function-adults-rare-heart-condition II – Dapagliflozin in HFpEF - Positive Topline Results for Dapagliflozin in HFpEF: DELIVER https://www.medscape.com/viewarticle/973490 - Empagliflozin in Heart Failure with a Preserved Ejection Fraction https://www.nejm.org/doi/full/10.1056/NEJMoa2107038 III – Triple Whammy for AKI - Mixing BP Meds With NSAID May Be 'Triple Whammy' for Kidneys https://www.medscape.com/viewarticle/973885 IV – Espresso - Espresso Coffee Associated With Increased Total Cholesterol https://www.medscape.com/viewarticle/973819 - Association between espresso coffee and serum total cholesterol: the Tromsø Study 2015–2016 https://openheart.bmj.com/content/9/1/e001946 - Is everything we eat associated with cancer? A systematic cookbook review https://pubmed.ncbi.nlm.nih.gov/23193004/ - Enough With the Coffee Research and Other Distractions https://www.medscape.com/viewarticle/883709 V – Clinician Burnout - Administrative Hassle Hacks: Strategies to Curb Physician Stress https://www.medscape.com/viewarticle/973597 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

How does dapagliflozin affect kidney outcomes in patients hospitalized with COVID-19? Find out about this and more in today's PV Roundup podcast.

Impact of Dapagliflozin on the survival of HFrEF patients