Podcasts about Canagliflozin

Drs Carol H. Wysham and Liana K. Billings discuss how to incorporate SGLT2 inhibitors and GLP-1 receptor agonists into the management of patients with type 2 diabetes and chronic kidney disease. Relevant disclosures can be found with the episode show notes on Medscape https://www.medscape.com/viewarticle/1002049. The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Type 2 Diabetes Mellitus https://emedicine.medscape.com/article/117853-overview Chronic Kidney Disease (CKD) https://emedicine.medscape.com/article/238798-overview Global, Regional, and National Burden of Chronic Kidney Disease Due to Diabetes Mellitus Type 2 From 1990 to 2021, With Projections to 2036: A Systematic Analysis for the Global Burden of Disease Study 2021 https://pubmed.ncbi.nlm.nih.gov/40034386/ Advantages, Limitations, and Clinical Considerations in Using Cystatin C to Estimate GFR https://pubmed.ncbi.nlm.nih.gov/36514729/ New Creatinine- and Cystatin C-Based Equations to Estimate GFR Without Race https://pubmed.ncbi.nlm.nih.gov/34554658/ Effects of Semaglutide on Chronic Kidney Disease in Patients With Type 2 Diabetes https://pubmed.ncbi.nlm.nih.gov/38785209/ Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy https://pubmed.ncbi.nlm.nih.gov/30990260/ Dapagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/32970396/ Empagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/36331190/ Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 https://pubmed.ncbi.nlm.nih.gov/39651975/ CKD Early Identification & Intervention Toolkit https://kdigo.org/wp-content/uploads/2019/01/ISN_KDIGO_EarlyScreeningBooklet_WEB_updatedOct11.pdf Combination Therapy as a New Standard of Care in Diabetic and Non-Diabetic Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/39907542/ Living With Chronic Kidney Disease and Type 2 Diabetes Mellitus: The Patient and Clinician Perspective https://pubmed.ncbi.nlm.nih.gov/36282450/

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this special episode of The Drive, Peter introduces a brand-new roundtable format. Joined by three renowned experts in longevity science—Steven Austad, Richard Miller, and Matt Kaeberlein—the group explores the rapidly evolving field of geroscience. Together, they dive deep into topics like the relationship between healthspan and lifespan, evaluating interventions like rapamycin and senolytics, the role of epigenetic changes in aging, and whether GLP-1 receptor agonists hold geroprotective potential. They also tackle major challenges in funding and public acceptance of longevity research including how geroprotective interventions might be tested in humans. Packed with nuanced debate, humor, and groundbreaking insights, this episode is a must-listen for anyone fascinated by the science of aging. We discuss: The recent rise in public interest in longevity, misconceptions, and the link between healthspan and lifespan [3:45]; Redefining healthspan, the US healthcare paradox, and separating longevity science from commercial hype [12:30]; The need to redirect medical research from disease-specific models to aging-focused approaches [21:30]; Proactive healthcare: rethinking health, disease, and the role of aging [30:00]; Biologic age versus chronologic age, and the limitations and potential of epigenetic clocks [35:00]; The utility and drawbacks of the “hallmarks of aging” as a framework for research and funding [49:30]; The role of epigenetic changes in aging and the challenges of proving causality [56:45]; The translational challenges of moving aging research from preclinical studies to human applications [1:03:45]; Distinguishing between a biomarker of aging and aging rate indicators [1:17:15]; The difficulties of translating longevity research in mice to humans, and the difficulties of testing interventions in humans [1:21:15]; Exercise, aging, and healthspan: does exercise slow aging? [1:35:45]; Are GLP-1 receptor agonists geroprotective beyond caloric restriction effects? [1:41:00]; The role of senescent cells in aging, challenges with reproducibility in studies, and differing views on the value of current research approaches [1:46:15]; How funding challenges and leadership in NIH and other institutes impact the advancement of aging-related research [2:00:15]; Metformin: geroprotective potential, mechanisms, and unanswered questions [2:02:30]; Canagliflozin and rapamycin as geroprotective molecules: mechanisms, dosing strategies, and longevity potential [2:10:45]; Resveratrol and NAD precursors—a lack of evidence for anti-aging effects [2:22:45]; The potential of parabiosis and plasmapheresis to slow aging, the challenges in translating mouse studies to humans, and possible design for human studies [2:29:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Dr. Hiddo J.L. Heerspink summarizes the findings of his study, "Glycemic Control and Effects of Canagliflozin in Reducing Albuminuria and eGFR," on behalf of his colleagues.

Dr. Hiddo J.L. Heerspink summarizes the findings of his study, "Glycemic Control and Effects of Canagliflozin in Reducing Albuminuria and eGFR," on behalf of his colleagues.

Drs Sparks and Neuen discuss the proper use of SGLT2 inhibitors to prevent chronic kidney disease, including how to start them and monitor them and their possible side effects. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/971884). The topics and discussions are planned, produced, and reviewed independently of advertiser. This podcast is intended only for US healthcare professionals. Resources SGLT2 Inhibitors in Primary Care: 'All Hands on Deck' for Improving Heart Failure Outcomes https://www.medscape.com/viewarticle/965473 Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes https://www.nejm.org/doi/full/10.1056/nejmoa1611925 Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy https://www.nejm.org/doi/full/10.1056/nejmoa1811744 CKD Epidemiology Collaboration CKD-EPI Consortium https://www.tuftsmedicalcenter.org/research-clinical-trials/institutes-centers-labs/chronic-kidney-disease-epidemiology-collaboration/overview Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes https://www.nejm.org/doi/full/10.1056/NEJMoa2025845 Net Effects of Sodium-Glucose Co-Transporter-2 Inhibition in Different Patient Groups: A Meta-Analysis of Large Placebo-Controlled Randomized Trials https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00443-0/fulltext EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) https://www.empakidney.org/ FDA Removes Boxed Warning About Risk of Leg and Foot Amputations for the Diabetes Medicine Canagliflozin (Invokana, Invokamet, Invokamet XR) https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin

CastSusan ThanabalasingamDana LarsenMythri ShankarSandy SureshReferencesNeal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine. 2017 Aug 17;377(7):644–57.Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine. 2019 Jun 13;380(24):2295–306.Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine. 2020 Oct 8;383(15):1436–46.Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart. 2021 Jul 1;107(13):1032–8.Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015 Nov 26;373(22):2117–28.ScriptContributors: Susan Thalabalasingam, Mythri Shankar, Dana Larsen, Sandhya SureshHost (Susan):Hey everyone! Welcome to our episode of 2 truths and a lie, an NSMC podcast.Let's go over the ground rules.One at a time each member of our elite education panel will state two truths and one lie about Nephrology.This episode will focus specifically on SGLT2 inhibitors. The other panelist will then discuss which statement they think is The Lie.Our presenter will then educate us all on which statement is incorrect and why.So let's warm up our lie detectors.Let's meet our four players for today.I'm your host Susan Thanabalasingam and I'm a first year internal medicine resident at Queen's University in Kingston, Ontario, Canada. I'm really excited to be your host today and to have an amazing discussion with these wonderful women today! Our second panelist is Dr. Mythri Shankar from India. Hi Dr. Mythri, can you please introduce yourself?Mythri: Hello everyone. I am Dr. Mythri Shankar, Assistant Professor in Nephrology from Institute of Nephro-urology, Bengaluru, India.I am also the Associate Program Director of the NSMC. Glad to be here and I have no conflicts of interest to declare.Our third Panelist Dr. Dana Larsen from the United States of America! Hi Dr. Larsen, can you please introduce yourself? Dana: Hi all! I am Dana Larsen, a second year nephrology fellow at University of California, San Francisco and so grateful to get to be on this podcast with this great group today. I have no conflicts of interest in today's topics. Our fourth Panelist is Dr. Sandhya Suresh from India. Hi Dr. Suresh, can you please introduce yourself?Sandhya: Hi to all my fellow members of the 4th Pod, the Distal convoluted Pod and also… Hi to everyone listening to this podcast. I am Dr. Sandhya Suresh and I'm an early career nephrologist working in a medical college in Southern India. My only declaration here is that I am a flozinator who is continually amazed by everything that the SGLT inhibitors can do. Susan: Great, so let me start, I'll give you 3 statements. My statements all focus on the use of SGLT2i in the non-diabetic CKD setting, which is a cohort that merits special attention when discussing the benefits of SGLT2i use (Susan)SGLT-2 inhibitors are nephroprotective in diabetic and non-diabetic CKD (TRUE)SGLT2 inhibitors decrease proteinuria in non-diabetic CKD (TRUE)SGLT2 inhibitors are indicated for all etiologies of non-diabetic CKD (FALSE) Explanation for 1 → Statement 1 is TRUE. SGLT-2 inhibitors are in fact nephroprotective in BOTH diabetic and non-diabetic CKD. The CREDENCE trial was the first to specifically examine kidney outcomes in patients with diabetic, proteinuric CKD, and it demonstrated significant decrease in risk for kidney failure and cardiovascular events in patients treated with canagliflozin (Perkovic et al, 2019). As the effects were independent of glucose lowering effects, further studies have been conducted in the non-diabetic CKD setting. DAPA-CKD included patients with both diabetic and non-diabetic CKD and found that the use of dapagliflozin was associated with decreased risk of >= 50% decline in eGFR, ESKD or death from renal or cardiovascular causes (Heerspink et al, 2020). Explanation for 2 → Statement 2 is ALSO TRUE. We do in fact have compelling data that proteinuria is reduced with the use of SGLT2i in non-diabetic kidney disease. Pre-specified analyses from the DAPA-CKD trial demonstrated that dapagliflozin significantly reduced proteinuria in both diabetic and non-diabetic CKD, although the effect was larger in the diabetic subset. Because clinical outcomes were similar with dapagliflozin initiation between diabetic and non-diabetic patients, despite this difference in effect size on proteinuria, it has been postulated that the observed nephroprotection may not actually be related to reduction in proteinuria. Explanation for 3 → Statement 3 was the FALSE statement. In DAPA-CKD, included etiologies of non diabetic CKD were FSGS, minimal change disease, chronic pyelonephritis, chronic interstitial nephritis and hypertensive, IgA, membranous, and obstructive nephropathies. However, patients with lupus nephritis, polycystic kidney disease and vasculitis were excluded. The results of EMPA-Kidney are highly anticipated, in part as it includes a larger number of participants without diabetes, in particular those with glomerular disease, which will hopefully give us more answers about whether these patients will also benefit from SGLT2i initiation. EMPA-Kidney does however also exclude patients with PKD (The EMPA-KIDNEY Collaborative Group, 2022). That was fun, I can't wait to hear more from the rest of our panelists. Moving on to Dr. Mythri now, can you please give us your 2 truths and a lie?Mythri:SGLT2i are the initial therapy for T2DM (FALSE)SGLT2i are beneficial in heart failure with reduced ejection fraction as it reduces both preload and afterload (TRUE)SGLT2i are analogs of Phlorizin (TRUE)Explanation for 1. SGLT2i are not the initial therapy. Initial therapy consists of lifestyle modifications, diet and exercise (American diabetes association guidelines 2021).Explanation for 2. SGLT2 inhibitors promote osmotic diuresis and natriuresis in patients with and without diabetes, and thus may reduce preload. SGLT2 inhibitors may also have vascular effects (including improving endothelial function) that promote vasodilation and thus may also reduce afterload. It has also been postulated that SGLT2 inhibitors may improve myocardial metabolism and thus improve cardiac efficiency. SGLT2 inhibitors promote osmotic diuresis and natriuresis in patients with and without diabetes, and thus may reduce preload (Joshi et al, 2021).Explanation for 3:A natural compound, phlorizin, was isolated from apple trees in the early 1800s and for decades played an important role in diabetes and renal physiology research. The compound is poorly absorbed from the gastrointestinal tract and inhibits both SGLT1 (primarily found in the gastrointestinal tract) and SGLT2. Analogs of phlorizin have been developed that circumvent these two problems. These are the current SGLT2i (Atanasov et al, 2016).Susan: That was great Dr. Mythri, thank you, I feel like I learned so much! Moving on to Dr. Dana, can you give us your 2 truths and a lie?Dana:Awesome, thank you Susan! Alright, please identify the lie from among these statements all concerning potential SGLT2 side effects:SGLT2 inhibitors definitively increase the risk of vulvovaginal candidiasis and may increase the risk of urinary tract infections. (TRUE)SGLT2 inhibitors do not definitively increase risk of bladder cancers. (TRUE)SGLT2 inhibitors definitively increase risk for limb amputations. (FALSE)Do you think you have the answer!?! Let's take a closer look…My first statement, SGLT2 inhibitors definitely increase the risk of urinary tract infections and vulvovaginal candidiasis is TRUE. Multiple studies on SGLT2 inhibitors including a 2018 canagliflozin RCT and a 2013 dapagliflozin RCT have shown 2-4 fold increase in vulvovaginal candidiasis in 10-15% of patients on SGLT2 inhibitors compared with placebo (Neal et al, 2017). A 2019 meta-analysis of over 100 RCTs with SGLT2s compared with other anti-diabetic agents or placebo did NOT show an increase in risk of UTIs for SGLT2s as a group, though there was a signal for increased risk of UTIs specifically for dapagliflozin, mechanistically it is unclear why this would be the case (Donnan et al, 2019). At this time, where there is definitive increased risk of vulvovaginal candidiasis, increased risk of UTI is likely not something you need to counsel your patients on.Alright, moving on, our second statement, SGLT2 inhibitors do not definitely increase risk of bladder cancers is also TRUE. While few cases of bladder cancers have been diagnosed in patients taking dapagliflozin, half of these occurred within the first 6 months, which is thought to be too soon for tumorigenesis promotion by dapagliflozin itself. EMPA-REG trial did not find increased incidence of bladder cancer once event rates that occured within the first 6mo of drug therapy were removed (Kohler et al, 2017). Currently, the FDA recommends ongoing postmarketing surveillance And finally, moving on to our final statement which must be FALSE given the name of the game, the statement says SGLT2 inhibitors definitively increase risk for limb amputations. While the CANVAS program found that in the over 10,000 combined patients from their two major trials there was an increased risk of amputations 6.3 vs 3.4 per 1000 participants with hazard ratio 1.97, these amputations were primarily at the level of the toe or metatarsal, not the limb (Neal et al, 2017). Furthermore, there is ongoing discussion over true risk of amputation attributed to SGLT2 inhibitors as post hoc analysis of empa-reg and CREDENCE, the renal outcomes trial for canagliflozin, no association for increased risk of lower extremity amputation was found (Perkovic et al, 2019). While further investigation into the topic is warranted, we can rest assured that this is our FALSE statement on side effects of SGLT2-inhibitors. Susan: Wow Dana, thanks so much for those very important lessons on SGLT2i side effects, I certainly have a lot of take home points from your discussion! Perfect, now we'll move on to Dr. Sandhya. Please join me in welcoming her to give us our final set of 2 truths and a lie today.Sandhya:Thank you Susan. So here, I will be focussing my 2 truths and a lie on the cardioprotective effects of SGLT2 inhibitors. Without further ado, here are my 3 statements:Statement 1: Increased ketone body production is postulated as one of the mechanisms for the cardioprotective effects of SGLT2 inhibitors (TRUE)Statement 2: Glucose lowering effect and cardiovascular benefits both decline at lower GFRs (FALSE)Statement 3: Sotagliflozin in a combined SGLT2 and SGLT1 inhibitor which has demonstrated cardioprotective benefits (TRUE)Explanations for the above statements: Let me go through the explanation for each statement one by one.Statement 1 is true. The cardioprotective effects of SGLT2 inhibitors may be multifactorial. While they target the traditional cardiovascular risk factors through their glycosuric and natriuretic effects, it is also postulated that SGLT2 inhibitors improve the cardiac metabolism and bioenergetics. 90-95% of cardiac energy is derived from mitochondrial oxidative metabolism for which the predominant fuel is free fatty acids. In a diabetic heart, the metabolic flexibility in terms of substrate utilization is impaired and the myocardium becomes more dependent on free fatty acids as fuel leading to build up of free fatty acid intermediates which lead to lipotoxicity and myocardial dysfunction. SGLT2 inhibitors produce a starvation simulation with reduced insulin and higher glucagon levels which promotes lipolysis and ketogenesis. They also reduce the excretion of ketone bodies by reducing the GFR. These ketone bodies like beta hydroxybutyrate serve as an alternate super fuel for myocardial cells producing ATP more efficiently and help to preserve the mitochondrial integrity and these factors lead to improved cardiac efficiency (Joshi et al, 2021).Now coming to statement 2. The glucose lowering effect of SGLT2 inhibitors does decrease with declining GFRs because the magnitude of glucose excretion and consequently the HbA1c reduction is dependent on the filtered glucose load. This filtered glucose load is high in diabetic patients with normal GFR and reduced in patients with renal impairment thereby leading to reduction in the glucose lowering effect of SGLT2 inhibitors (Kelly et al, 2018). Conversely, the cardioprotective effects of this class of drugs seems to be remarkably preserved at lower GFRs as has been demonstrated in several trials. For example, in the EMPAREG OUTCOME trial, analysis of a subgroup of patients with prevalent kidney disease was done which included type 2 diabetic patients with established cardiovascular disease and an estimated GFR between 30-60 . There was significant reduction in the cardiovascular and all-cause mortality as well as hospitalization for heart failure in this subgroup and this effect was consistent across different categories of GFR (Wanner et al, 2017). So statement 2 is false.So by that logic statement 3 has to be a truth. We often talk about the 4 traditional flozins so I just wanted to throw in a statement about this new subclass within this class of agents. Sotagliflozin is an SGLT2 inhibitor which also inhibits the intestinal SGLT1 transporters. It was originally targeted for use in patients with type 1 diabetes mellitus with the hope that SGLT1 inhibition in the intestine could reduce postprandial hyperglycemia and improve overall glycemic control in these patients. Studies have also shown excellent efficacy for this purpose. However they also showed a higher incidence of Diabetic ketoacidosis episodes. 2 cardiovascular trials were conducted, both of which unfortunately, ended early as they lost funding sometime during the COVID pandemic. The SCORED trial included CKD patients and the SOLOIST-WHF trial included patients who had recently recovered from an episode of decompensated heart failure. I won't go into the strengths and limitations of these trials but they did show benefit in terms of cardiovascular endpoints in the sotagliflozin group compared to placebo (Bhatt et al, 2021; Bhat et al, 2021). The drug isn't commercially available as of now and is not FDA approved yet but it remains as a novel agent within the SGLT2i landscape.Susan (Conclusion by host):Amazing, thank you so much Dr. Sandhya! That was an enlightening discussion on cardioprotection with SGLT2i use. And this has been so much fun! I hope you've all found our conversation really helpful and informative - I certainly know that I have learned a lot from my colleagues today. I can't thank them enough for sharing their time and expertise with us. Be sure to tune in next time for more FOAMed nephrology education.

Canagliflozin is an SGLT2 inhibitor. I discuss the pharmacology, dosing, adverse effects, and drug interactions of this medication. Canagliflozin reduces blood sugar, by facilitating its exit through the urine. This can increase the risk of genitourinary infections. A diuresis type effect can happen due to canagliflozin and this effect may be exacerbated by the use of thiazide and loop diuretics. Hyperkalemia has been reported with the use of canagliflozin; the risk for this is increased with the use of medications like ACE inhibitors, ARBs, and aldosterone antagonists.

Dr. Richard Miller runs one of the labs for the Interventions Testing Program or the ITP, which is largely considered the gold standard for testing longevity drugs. This was one of the best conversations I've had on longevity supplements that affect lifespan and those that might me subject to mere hype. Dr. Miller is rigorous in his approach and states the data clearly. He also has opinions on lifespan vs. healthspan that are unique from those of most others and worth paying attention to. I genuinely walked away having learned so much from this conversation and feeling more awakened, and I hope it is useful to you too in parsing the data out there on longevity supplements. In today's episode, you will learn: - The 4 winning drugs that increase lifespan in mice as tested by the ITP: Rapamycin, Acarbose, 17-alpha estradiol, Canagliflozin - 3 other drugs that produce small lifespan benefits: NDGA, Glycine, Captopril - Drug combinations: Rapamycin + Acarbose, Rapamycin + Metformin - Drugs that show no lifespan increase in mice in the ITP: Resveratrol, Nicotinamide-Riboside (NR), Fisetin, Curcumin, MCT Oil, Green tea extract, Fish Oil + more - Richard's thoughts on lifespan vs. healthspan All platforms / Episode Show Notes / Timestamps: https://livelongerworld.substack.com/p/rmiller Find the previous podcast episodes & subscribe to be notified: https://www.livelongerworld.com/podcast Sign up for Premium Subscriber Summarized Show Notes: https://www.livelongerworld.com/premium Support on Patreon: https://www.patreon.com/livelongerworld One-Time support: https://www.paypal.com/paypalme/livelongerworld RICHARD MILLER LINKS: Website: http://www.richmillerlab.com/ Photography: https://richardmiller.zenfolio.com/ Interventions Testing Program: https://www.nia.nih.gov/research/dab/interventions-testing-program-itp LIVE LONGER WORLD LINKS: Website: https://www.livelongerworld.com/ Twitter: https://twitter.com/livelongerworld Newsletter: https://livelongerworld.substack.com/ Instagram: https://www.instagram.com/longevityfuture/ Patreon: https://www.patreon.com/livelongerworld YouTube: https://www.youtube.com/c/LiveLongerWorld Premium Subscriber: https://www.livelongerworld.com/premium TIMESTAMPS: 0:55 Richard Miller Intro 1:51 Richard Miller Wildlife photography 3:30 ITP - the gold standard for testing longevity drugs & winning drugs 10:51 Rapamycin, Rapamycin + Acarbose 18:48 Rapamycin + Acarbose Dosing Schedule 20:15 Combination of drugs, Rapamycin + Metformin 21:56 17-Alpha Estradiol 25:45 Canagaflozin 31:34 Does Richard take the 4 winning drugs? 32:46 3 Drugs that have small lifespan effects & promising 36:30 GPLD-1 & shared mechanisms in longevity drugs 44:04 Resveratrol in ITP 46:27 NR, NMN 52:34 Curcumin, Green Tea Extract, MCT Oil 54:54 Fisetin & Senolytics 56:12 Why most published research findings are false 1:00:03 Healthspan biomarkers at the ITP 1:02:38 Can you have healthspan without lifespan? 1:07:37 Fish Oil, Spermidine, Sulforophane 1:12:13 Unpublished data Richard is excited about 1:17:47 Flying Pigs & Aubrey De Grey 1:20:00 Exponential rise in aging research Episode Show Notes: https://livelongerworld.substack.com/p/rmiller Thanks for listening & if you enjoy the episode, let's spread the message on longevity. You can leave a review on Apple podcasts, subscribe and share the podcast. Aging is universal. Let's unite in this fight.

Huge improvements in treatments for type 2 diabetes are outlined in recent diabetes guidelines. Get the upshot on best evidence from leading experts Drs Silvio Inzucchi and Rita Kalyani. Relevant disclosures can be found with the episode show notes on Medscape.com (https://www.medscape.com/viewarticle/963267). The topics and discussions are planned, produced, and reviewed independently of our advertiser. This podcast is intended only for US healthcare professionals. Resources Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022 https://diabetesjournals.org/care/article/45/Supplement_1/S125/138908/9-Pharmacologic-Approaches-to-Glycemic-Treatment Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes https://www.fda.gov/media/71297/download Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes https://www.nejm.org/doi/full/10.1056/nejmoa1504720 Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes https://www.nejm.org/doi/full/10.1056/nejmoa1603827 Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups: Results From the Randomized CREDENCE Trial https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.042007 Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): A Double-Blind, Randomised Placebo-Controlled Trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31149-3/fulltext Semaglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes https://www.nejm.org/doi/full/10.1056/NEJMoa1607141 SGLT2 Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-analysis of the EMPEROR-Reduced and DAPA-HF Trials https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31824-9/fulltext The SGLT2 Inhibitor Dapagliflozin in Heart Failure With Preserved Ejection Fraction: A Multicenter Randomized Trial https://www.nature.com/articles/s41591-021-01536-x A Research Study to Find Out How Semaglutide Works in the Kidneys Compared to Placebo, in People With Type 2 Diabetes and Chronic Kidney Disease (the REMODEL Trial) (REMODEL) https://clinicaltrials.gov/ct2/show/NCT04865770

Commentary by Dr. Valentin Fuster

The findings of CREDENCE Trial

CHIEF HF Trial was recently presented at the AHA 2021 meeting. It tested an #SGLT2Inhibitor #CANAGLIFLOZIN in #HEARTFAILURE. CHIEF HF Trial or CANAGLIFLOZIN in HEART FAILURE which was recently presented at AHA 2021 is yet to be published. If you were searching about CHIEF HF Trial or role of CANAGLIFLOZIN in HEART FAILURE you can find it in this video. The authors first presented its results in AHA 2021.

Written By: Dr. Samantha Pomroy Expert Review By: Dr Karin Winston - Paediatric Endocrinologist Chris Cochrane and Caleb Dusdal review the first two objective of the CCFP Key Topic of Diabetes. Lots of definitions, screening guidelines, numbers, and a review of the lifestyle and pharmacologic options available to you to help your patient.

Manal Abdelmalek, Ian Rowe and first-timer Ken Cusi join Louise Campbell and Roger Green to review a thought-provoking, assumption-challenging Day Three of #ILC2021.Most of the presentations the panel covered focused on medications, the core ideas and discussions spoke to changes in thinking. One theme that ran through the discussion was about multi-disciplinary care...and not only because Fatty Liver Endocrinologist Ken Cusi was on the panel. Another was to think about drugs for NASH holistically. In all, this podcast takes the broad view and the long view on treating Fatty Liver diseases, and should provoke new thoughts and ideas in you the listener.

Drs. Meg Jardine and Carinna Hockham discuss the findings from their study "Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria," on behalf of their colleagues.

Drive with Dr. Peter Attia Podcast Notes Introduction Interventions Testing Program developed the gold standard protocol of using mice to testing lifespan drugs“I don’t really care what causes aging. What I care about is what can postpone all the different aspects of aging. Once you rephrase the question you are well on the way to designing experimental paradigms which address the serious question.” – Dr. Richard MillerA good lifespan drug will extend life in the oldest animals in the treatment group compared to the oldest animals in the control groupA big surprise is that rapamycin and acarbose have positive lifespan effects even when administered late in life Most longevity drugs have differential effects in males and femalesRegulation of glucose in males seems to be a potential driver in increasing lifespan and healthspan in mice models Positive impact on longevity: 17-alpha estradiol (in males only), acarbose, rapamycin, canagliflozin (SGLT-2 inhibitor)Read the full notes @ podcastnotes.org Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan. He is one of the architects of the NIA-funded Interventions Testing Programs (ITPs) animal study test protocol. In this episode, Rich goes through the results of the long list of molecules tested by the ITP—including rapamycin, metformin, nicotinamide riboside, an SGLT-2 inhibitor called canagliflozin, and more. Many of the discussed outcomes have had surprising outcomes—both positive and negative findings. We discuss: Rich’s interest in aging, and how Hayflick’s hypothesis skewed aging research (3:45); Dispelling the myth that aging can’t be slowed (15:00); The Interventions Testing Program—A scientific framework for testing whether drugs extend lifespan in mice (29:00); Testing aspirin in the first ITP cohort (38:45); Rapamycin: results from ITP studies, dosing considerations, and what it tells us about early- vs. late-life interventions (44:45); Acarbose as a potential longevity agent by virtue of its ability to block peak glucose levels (1:07:15); Resveratrol: why it received so much attention as a longevity agent, and the takeaways from the negative results of the ITP study (1:15:45); The value in negative findings: ITP studies of green tea extract, methylene blue, curcumin, and more (1:24:15); 17α-Estradiol: lifespan effects in male mice, and sex-specific effects of different interventions (1:27:00); Testing ursolic acid and hydrogen sulfide: rationale and preliminary results (1:33:15); Canagliflozin (an SGLT2 inhibitor): exploring the impressive lifespan results in male mice (1:35:45); The failure of metformin: reconciling negative results of the ITP with data in human studies (1:42:30); Nicotinamide riboside: insights from the negative results of the ITP study (1:48:45); The three most important takeaways from the ITP studies (1:55:30); Philosophies on studying the aging process: best model organisms, when to start interventions, which questions to ask, and more (1:59:30); Seven reasons why pigs can't fly (2:08:00); and More. Learn more: https://peterattiamd.com/   Show notes page for this episode: https://peterattiamd.com/RichardMiller    Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/   Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/   Connect with Peter on Facebook | Twitter | Instagram.

Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan. He is one of the architects of the NIA-funded Interventions Testing Programs (ITPs) animal study test protocol. In this episode, Rich goes through the results of the long list of molecules tested by the ITP—including rapamycin, metformin, nicotinamide riboside, an SGLT-2 inhibitor called canagliflozin, and more. Many of the discussed outcomes have had surprising outcomes—both positive and negative findings. We discuss: Rich’s interest in aging, and how Hayflick’s hypothesis skewed aging research (3:45); Dispelling the myth that aging can’t be slowed (15:00); The Interventions Testing Program—A scientific framework for testing whether drugs extend lifespan in mice (29:00); Testing aspirin in the first ITP cohort (38:45); Rapamycin: results from ITP studies, dosing considerations, and what it tells us about early- vs. late-life interventions (44:45); Acarbose as a potential longevity agent by virtue of its ability to block peak glucose levels (1:07:15); Resveratrol: why it received so much attention as a longevity agent, and the takeaways from the negative results of the ITP study (1:15:45); The value in negative findings: ITP studies of green tea extract, methylene blue, curcumin, and more (1:24:15); 17α-Estradiol: lifespan effects in male mice, and sex-specific effects of different interventions (1:27:00); Testing ursolic acid and hydrogen sulfide: rationale and preliminary results (1:33:15); Canagliflozin (an SGLT2 inhibitor): exploring the impressive lifespan results in male mice (1:35:45); The failure of metformin: reconciling negative results of the ITP with data in human studies (1:42:30); Nicotinamide riboside: insights from the negative results of the ITP study (1:48:45); The three most important takeaways from the ITP studies (1:55:30); Philosophies on studying the aging process: best model organisms, when to start interventions, which questions to ask, and more (1:59:30); Seven reasons why pigs can't fly (2:08:00); and More. Learn more: https://peterattiamd.com/   Show notes page for this episode: https://peterattiamd.com/RichardMiller    Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/   Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/   Connect with Peter on Facebook | Twitter | Instagram.

Show notes at pharmacyjoe.com/episode570. In this episode, I ll discuss the possibility of euglycemic DKA occurring after stopping canagliflozin. The post 570: Euglycemic Diabetic Ketoacidosis After Stopping Canagliflozin appeared first on Pharmacy Joe.

Patients with diabetes are 10 times more likely to experience lower limb amputations than the general population and amputations have very significant morbidity, mortality, and financial implications. While common risk factors for amputation in patients with diabetes include poor glycemic control, diabetic peripheral neuropathy, or peripheral arterial disease, canagliflozin use was implicated in the CANVAS and CANVAS-R trials. However, the CANVAS Program trials were not specifically designed to evaluate the risk of lower-extremity amputations.  Clearly, we need more information about the magnitude of risk when canagliflozin is used widely in a general population and who is at most risk. Guest Authors:  Julie Dally, PharmD, BCPS, BCACP and Amanda Schartel, PharmD, BCACP Music by Good Talk

Commentary by Dr. Valentin Fuster

FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)

Dr. George Bakris, of the University of Chicago, discusses the impact of canagliflozin approval and how it impacts the current treatment of diabetic kidney disease. 

Listen to the journal review on canagliflozin and cardiovascular and renal events in type 2 diabetes.

Seit der Entwicklung von ACE-Hemmern und AT-1-Rezeptor-Antagonisten, die einen nephoprotektiven Effekt aufweisen, gab es keine relevanten Fortschritte in der medikamentösen Nephroprotektion bei Typ-2-Diabetikern. Die CREDENCE-Studie konnte nun protokollgerecht frühzeitig beendet werden, da die Ergebnisse so überzeugend waren - bahnt sich hier eine Revolution an?

In this podcast, George Bakris, MD, from the University of Chicago, talks about the renal outcomes from the Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial. More at: www.consultant360.com/cardiology.

Listen to CANVAS investigators Carol Wysham and Lori Berard discussing the efficacy and safety findings of the trials. Find more on Medicine Matters diabetes This content was originally published on Medicine Matters diabetes (https://diabetes.medicinematters.com) on August 8, 2017.

Andrew Frankel, Consultant Physician and Nephrologist at Imperial College Healthcare NHS Trust, tells medwireNews about the rationale and key findings of the CREDENCE trial, and discusses the potential benefits of SGLT2 inhibitors beyond type 2 diabetes. Find more on Medicine Matters diabetes This content was originally published on Medicine Matters diabetes (https://diabetes.medicinematters.com) on April 17, 2019.

Editorial board member John Wilding discusses the lessons for healthcare professionals from the SGLT2 inhibitor cardiovascular outcome trials about the benefits and drawbacks of the medication class. Find more on Medicine Matters diabetes This content was originally published on Medicine Matters diabetes (https://diabetes.medicinematters.com) on September 8, 2017.

Kieran Quinn, general internist and palliative care physician in Toronto, is joined by Emily Hughes, the producer of the show and soon-to-be Internal Medicine resident at the University of Toronto on this week’s episode of The Rounds Table! Together they are covering canagliflozin and renal outcomes, and quality of life among patients with atrial fibrillation receiving ... The post REPLAY: Sugar and Spice – Canagliflozin and Renal Outcomes and Quality of Life in Atrial Fibrillation appeared first on Healthy Debate.

Kieran Quinn, general internist and palliative care physician in Toronto, is joined by Emily Hughes, the producer of the show and soon-to-be Internal Medicine resident at the University of Toronto on this week's episode of The Rounds Table! Together they are covering canagliflozin and renal outcomes, and quality of life among patients with atrial fibrillation receiving ...The post REPLAY: Sugar and Spice – Canagliflozin and Renal Outcomes and Quality of Life in Atrial Fibrillation appeared first on Healthy Debate.

Kieran Quinn, general internist and palliative care physician in Toronto, is joined by Emily Hughes, the producer of the show and soon-to-be Internal Medicine resident at the University of Toronto on this week’s episode of The Rounds Table! Together they are covering canagliflozin and renal outcomes, and quality of life among patients with atrial fibrillation receiving ... The post Sugar and Spice: Canagliflozin and Renal Outcomes and Quality of Life in Atrial Fibrillation appeared first on Healthy Debate.

Kieran Quinn, general internist and palliative care physician in Toronto, is joined by Emily Hughes, the producer of the show and soon-to-be Internal Medicine resident at the University of Toronto on this week's episode of The Rounds Table! Together they are covering canagliflozin and renal outcomes, and quality of life among patients with atrial fibrillation receiving ...The post Sugar and Spice: Canagliflozin and Renal Outcomes and Quality of Life in Atrial Fibrillation appeared first on Healthy Debate.

This is a discussion on the recent CREDENCE trial for canagliflozin in diabetics with nephropathy.  

Kevin Fernando, GP Partner at the North Berwick Health Centre near Edinburgh, UK, talks to medwireNews about the importance of the CREDENCE trial from a primary care perspective. Find more on Medicine Matters diabetes This content was originally published on Medicine Matters diabetes (https://diabetes.medicinematters.com) on April 17, 2019.

Lead investigator Vlado Perkovic talks about the main findings from the CREDENCE trial – demonstrating that canagliflozin is associated with a reduced risk for kidney failure and cardiovascular events in people with type 2 diabetes and chronic kidney disease – and discusses how these results will impact clinical practice. Find more on Medicine Matters diabetes This content was originally published on Medicine Matters diabetes (https://diabetes.medicinematters.com) on April 15, 2019.

This week in clinical cardiology. PCI reduces mortality after STEMI in older adults. Canagliflozin lowers kidney failure risk in T2D: CREDENCE. Poor response to statins hikes risk of cardiovascular events. Low LDL cholesterol may increase women’s risk of hemorrhagic stroke  

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. Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction. However, what are its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease? Well, stay tuned to find out, as we will be discussing the results of the UK Harp III Trial, right after these summaries.                                                 The first original paper this week reveals that inhibition of a long non-coding RNA may serve as a novel molecular therapy for aortic aneurysms. First author, Dr Li, corresponding author, Dr Maegdefessel from Technical University Munich, and colleagues, identified the long non-coding RNA H-19 with functional relevance in experimental aortic aneurysm progression in two mirroring models, a novel genetically mutated mini-pig model, as well as end-stage human disease. They found that H-19 mediated expression levels of the transcription factor hypoxia inducible factor 1-Alpha. Which, in the chronic hypoxic environment of an aneurysm, triggers apoptosis in aortic smooth muscle cells. This study, therefore, introduces inhibition of H-19 as a novel molecular therapy to limit smooth muscle cell death in progressing aortic aneurysms.                                                 The next study provides insights into molecular mechanisms underlying heart failure progression in chronic pressure overload. Co-first author, Dr Chiang and Alsina, co-corresponding authors, Dr Heck, from Utrecht University, and Dr Wehrens, from Baylor College of Medicine, and their colleagues developed a novel and unbiased way to comprehensively study protein phosphatase 1 or PP1 interactors in a mouse model of progressive heart failure induced by elevated afterload. This so-called PP1 interaction enabled simultaneous interrogation of multiple pathways relevant to heart failure pathogenesis. They found nine specific PP1 interactors that were strongly associated with heart failure progression. Among these, the PP1 regulatory subunit 7 was shown to play a central role by regulating the PP1 interaction, and by acting as a competitive molecular sponge of PP1.                                                 In clinical trials of direct oral anticoagulants for atrial fibrillation, patients with end stage kidney disease on dialysis were excluded. Today's study answers the question, "What are the outcomes with Apixaban in dialysis dependent end stage kidney disease patients with atrial fibrillation?"                                                 Co-corresponding authors Dr Siontis and Dr Saran from University of Michigan and their colleagues performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System from 2010-2015. All eligible patients were those with end stage kidney disease and atrial fibrillation undergoing dialysis who had initiated treatment with an oral anticoagulant.                                                 In prognostic score-matched analysis, Apixaban was associated with lower rates of major bleeding compared with Warfarin, whereas there was no difference in stroke or systemic embolism. Patients on standard dose of Apixaban of 5 mg had a lower rate of stroke and death compared to those on reduced dose Apixaban of 2.5mg. Thus, Apixaban may be associated with superior safety and comparable effectiveness outcomes as Warfarin in dialysis patients with atrial fibrillation. However, these findings require confirmation in a randomized trial setting.                                                 Does Canagliflozin have benefits in people with chronic kidney disease, including those with an Estimated Glomerular Filtration Rate, or EGFR, between 30 and 45, in whom the drug is currently not approved? First author Dr Neuen, corresponding author Dr Perkovic from the George Institute of Global Health, and their colleagues performed a secondary analysis of the CANVAS Program to describe outcomes in participants with and without chronic kidney disease, as well as according to baseline kidney function as measure by EGFR.                                                 They found that the effect of Canagliflozin on HbA1c was progressively attenuated at lower EGFR levels, but blood pressure and body weight reductions were comparable. The reduction in risk of major adverse cardiovascular events, hospitalization for heart failure and progression of kidney disease appeared similar across different levels of kidney function, down to an EGFR of 30. Safety outcomes were also mostly consistent, but the risk of hypoglycemia may increase as EGFR declines.                                                 That wraps it up for our summaries, now for our feature discussion.                                                 Cubitalis-valsartan improves outcomes in patients with heart failure with reduced ejection fraction, and we know that from the Paradigm trial, but what about its effects on kidney function and cardiac biomarkers in people with chronic kidney disease?                                                 Well, this week's feature paper provides important randomized trial data addressing this question. To discuss it, we have none other than the first and corresponding author, Dr Richard Haynes from University of Oxford, as well as our editorialist for the paper, Braden Manns and Matthew James, both from University of Calgary and in addition, we have Dr Justin Ezekowitz, associate editor who manages paper, and Justin is from University of Alberta.                                                 Welcome gentlemen, we have a full house. Richard, could you start by sharing about your trial and your findings? Dr Richard Haynes:          So, the trial was called UK Harp-III, and it was really a pilot trial, just to work to investigate the effects of Cubitalis-valsartan on patients with chronic kidney disease, and in particular to see what it did for their kidney function in the short term, and also what it did to other measures of interest like their blood pressure and cardiac biomarkers.                                                 It was a randomized control trial double blind, among just over 400 people with chronic kidney disease, and we compared Cubitalis-valsartan with Irbesartan, which is standard of care for most of these patients. Our primary outcome was really to look at the effects of these drugs on kidney function when it was being precisely measured in hospitals. We found, actually, that Cubitalis-valsartan had very similar effects to Irbesartan on kidney function. So, there was no real difference in kidney function at any point in the trial between patients who were allocated the Cubitalis-valsartan or those allocated Irbesartan. Dr Carolyn Lam:                Richard, the way you described it I'm sure you're prepared for this question so why Irbesartan as the control versus Valsartan? Dr Richard Haynes:          That's a very good question and a question asked quite often. There were six of one and half a dozen of the other. We could have chosen Valsartan. The difficulty with that is that Valsartan doesn't have a license indication for the treatment of chronic kidney disease so if we found a difference people might have said we just chosen an inferior comparator, so we chose Irbesartan because that does have an indication for the treatment of proteinuria kidney disease and obviously that leaves us open for the question about how different Valsartan and Irbesartan are. My opinion is they might be subtly different, but I don't think the difference is big enough to really impact these results in any meaningful way. Dr Carolyn Lam:                Indeed, and I know Braden and Matthew you have thought about it a lot. Congratulations on the beautiful editorial. I love the way you set the context in the heart failure world where perhaps we have noted something different with regards to kidney function. Would either of you like to start the ball rolling with discussing that? Matthew James:              Sure, this is Matthew James. So really the Paradigm Heart Failure Trial is a very important place to start in thinking about the effect of these medications on kidney function. That was a very large trial that did report changes in estimated Glomerular Filtration Rate and did show a small but statistically significant change in kidney function between the Sacubitril-valsartan arm and the control arm. There are many potential mechanisms for that, but it is important to realize that there were limitations in the population specifically around chronic kidney disease due to the level of kidney function that the patients were enrolled in to the study. So, some of the patients with more advanced chronic kidney disease wouldn't have been included in the Paradigm Heart Failure Trial so this trial is actually giving us more information about patients with kidney disease who we would expect to be at higher risk of seeing progressive loss of kidney function or progression of their kidney disease. Dr Carolyn Lam:                Thanks for setting that up and just to clarify for the audience here so in Paradigm EGFR went down to 30 right, and here in UK Harp we are talking about measured GFR down to 20. Am I right? Dr Richard Haynes:          Eligibility was actually determined by the EGFR, the estimated GFR.                                                 Yeah it went down to 20, up to 60. We also had a much more proteinuria in the patients in Paradigm. Dr Carolyn Lam:                Right, and do you have a take Richard on why the results seem different from at least the secondary analysis that Milton Packer wrote about on its effects on kidney function in Paradigm? Dr Richard Haynes:          I do have a take. I'm really interested to hear what Braden and Matthew thought. My take was that probably when you've got heart failure one of the major determinants of how well your kidneys work is actually how well your heart is working. That is probably one of the major determinants in that setting and because we know Sacubitril-valsartan has such beneficial effects on cardiac function in people with heart failure perhaps it's not surprising that it then is protected by kidney function a little bit better than people given Enalapril in Paradigm. However, in UK Harp III, we had a group of patients whose kidney had very definite kidney disease and probably the determinants of kidney progression quite different and having any impact on their heart function probably wouldn't really be noticed because the effect of their kidney disease would outweigh that. Perhaps, Sacubitril-valsartan doesn't have any beneficial effects on the kidney itself. As far as we can tell, from what is a relatively small and a relatively short trial. Dr Carolyn Lam:                Justin, I mean you come from the heart failure world too just like me. What was your take? Dr Justin Ezekowitz:        I think there are a number of features here we should take a step back and think about. Number one is as Richard outlined there is a lot more proteinuria here than would typically be seen in a heart failure related population. So, the comparator between the two groups, while similar in overlap while co-manage these patients is somewhat different in terms of what the result we are looking for. So, you know, it brings to mind that what we look at in the secondary analysis in for example Paradigm, is simple EGFR creatinine changes versus here we are looking at a much more sophisticated measure of GFR plus also looking at a comparator that is known to reduce proteinuria and I would say stabilize or not change or prevent their progression of renal disease in the larger trials in the renal population. So, it's a slightly different population, a slightly different comparator as well. The importance in the choice of comparators becomes really important when we are looking for this specific effect.                                                 Now, to Richard's point, which he opened with, which is talking about this as a pilot project to a larger outcome trial, it is hard to know whether or not the effects that Richard and his team on the NT-proBNP, troponin, and other effects would play out in the larger cardiovascular outcomes trial that would be potentially different results than simply a GFR change or proteinuria change. I would be interested in Richard's thoughts on that and Matt and Braden's as well. Matthew James:              Maybe we can also get add another question to Richard which this was a really well-done study and you talked about it being relatively small and certainly by heart standards this was a relatively small pilot study with a limited duration of follow up. By kidney standards, this is a fairly this would be a usual sized clinical trial and so getting all these patients in the trial was a wonderful result to start with and while the study wasn't directly looking at safety of these medications, there is some I think assurance we have some tolerability data at least with this medication and the challenge as Richard would well know in managing patients with chronic kidney disease once they developed more advanced chronic kidney disease GFR is less than 30 is often difficult to use medications because of side effects, high potassium, and things. The most challenging types of patients we see are patients with lower levels of kidney function and with low ejection fractions. So at least this paper provides some hope that we've got a medication that is reasonably well tolerated in that population.                                                 I think that when Richard talks about this being a pilot study where a lot of patients, in fact patients with chronic kidney disease are much more likely to die from heart disease than they are to develop end stage renal disease. For many types of patients that is true at least. So, we are often thinking about what medications could be used to improve cardiovascular outcomes. So, in that sense, again given that the majority of the structural heart disease is not necessarily reduced heart function but is left ventricular hypertrophy I'm sure, and perhaps Richard has some comments as to the next study that might be considered given this medication seemed tolerable. It didn't have the effects that were perhaps hoped on progression although in the Paradigm sub study there was only a difference of 0.5 ml per minute and they were powered to detect 3 ml per minute in this study but actually the immediate hemodynamic drop was about 3 ml per minute and then kidney function was relatively stable thereafter. So hard to imagine this study would have showed a difference in kidney function now in retrospect but potentially this opens up some additional studies to look at cardiovascular outcomes in patients with chronic kidney disease who don't have reduced ejection fraction. Dr Richard Haynes:          I think that's a really good point. I think it would be fascinating to see the results of the Paradigm Trial with Sacubitril-valsartan in patients with heart failure and preserved ejection fraction. Nevertheless, I think this trial does raise the hypothesis that this might be a drug that could improve regardless of whether it has any effect on the kidney or not. It could be possibly be used for improving cardiac outcomes but I just don't think the trial that we've done is enough to justify that at the moment. I think it's a good indicator that it may well work, but I think before anybody could recommend that with much enthusiasm I think it would require a large outcomes trial but focusing quite rightly on cardiovascular outcomes in people with chronic kidney disease which as Matthew said is actually the major burden of disease in those patients. Dr Justin Ezekowitz         I think the question remains though is if as a pilot trial at that time as a longer-term trial would there be any difference because the mechanism of action of Sacubitril is different from that of Irbesartan and that was also shown in the nice table you have in the supplemental file which talks about the Sacubrital lapse concentration going up with the lower GFR's. So, there is the potential for those small subgroups where the GFR is lower they may have a substantial benefit over a longer period of time, not measured necessarily by GFR but measured by clinical outcomes. I think that is where the balance of getting the pilot trial versus a longer follow-up clinical outcomes trial is really important to get.                                                 I may actually just state one other thing or two. First, it's really important to investigate or initiate a trial and this is one of critical parts of why we do clinical trials. Medicine tests the effects initially a pilot and then hopefully a larger trial.                                                 The second is the importance of randomization here. We all think that the shiny new medications are important but getting randomization in trials like this done are really advanced knowledge, so we know what to do with the medication if we are faced with it or if we want to make an important choice for a patient that we can really make a point for the patient that we will base it on the best scientific knowledge.                                                 The third point that I would just come back to something else that we have not talked about yet is this overall is a neutral trial. There are no major effects that were seen but the importance of getting a neutral trial done and published is really critical as this advances the field potentially, so others can now decide what to do and perhaps launch larger trials with cardiovascular outcomes or decide to do a different comparator or different other tasks forward. So, this one we emphasize it is critically important to get these types of trials done and then published. Dr Carolyn Lam:                You know Justin, I couldn't have said it better and completely echo your words. We are so proud to be publishing your paper Richard and that beautiful editorial in circulation. So, I'm just going to wrap up then because in the absence of better data at the moment what is the main take home message of this trial for patients with CKD right now and their care providers. I would love to start with Braden because you wrote about it in the editorial as well. What do you think of the take home messages? Braden Manns:                 Well again I think that we often struggle when peoples GFRs are in the 20 to 30 range with identifying a medication that's tolerable particularly in the context of people with reduced ejection fraction. I must say personally I would now be comfortable using this medication in patients with reduced ejection fraction who remain symptomatic who have GFRs in the 20 to 30 range. Those patients aren't that common but feel comfortable now using that type of medication there despite the fact that most patients weren't necessarily enrolled in the Paradigm study. A much larger population though of patients with structural heart disease but not reduced ejection fraction who have chronic kidney disease. It is not clear to me where this medication fits in the armamentarium. As Justin says it certainly wouldn't use this in preference to an ace inhibitor or an angiotensin receptor blocker at this point. So, it's hard to know where it fits without some larger studies looking at cardiac outcomes. Matthew James:              I agree with Braden. I think we are already seeing this medication now enter practice here in Canada. There is this overlap in population between the patients with kidney disease and impaired left ventricular ejection fraction, so this is actually very helpful for us when we see these patients in practice around the appropriateness of continuing these medications in this patient population. Dr Justin Ezekowitz:        So, I think it's critically important to remember the take home message here is to do proper clinical trials and then do again the large trial because without that would not really advance in knowledge. There could be a huge value to a newer medication or potentially the old ones are still just as good as we if we continue them safely. Dr Richard Haynes:          I'd like to echo what everybody said already really. I mean I think what Justin just said trial is the key. We can't get away from the need for randomized control trials. I'm pleased that we've managed to deliver this one. In terms of a clinical take home message I think if I was a patient with kidney disease and heart failure, especially with reduced ejection fraction, I hope that I would feel a bit more comfortable to take this drug now knowing is it going to benefit me from a cardiovascular point of view it doesn't seem it is going to do my kidneys any harm either. So, hopefully it will reassure more patients that they can yield the benefits of a trial this drug has. Dr Carolyn Lam:                Great stuff! Thank you so much gentlemen. This has been such an enlightening conversation.                                                 Thank you very much to audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Short on time but hungry for knowledge? Curbsiders’ Journal Club gives you the speedy article analysis you crave. We provide brief summaries of recent research and news items in the field of internal medicine, so you can save time and stay on top of the literature. On this episode, we were joined by Kashlak Memorial’s very own Chair of Medicine, Dr. Robert Centor AKA @medrants on Twitter or “Uncle Bob” to the Curbsider Crew. This month’s topics include: estimating atherosclerotic cardiovascular disease risk, whether CT pulmonary angiography (CTPA) effectively rules out pulmonary embolism, discharging low risk patients with pulmonary embolism from the ED, metformin and risk of acidosis in patients with CKD, treating opioid use disorder after a nonfatal overdose, Canagliflozin and renal protection in type 2 diabetes, screening for diabetes among patients below age 40, and the association between nose-picking and staphylococcus. ACP members can claim free CME-MOC at acponline.com/curbsiders (goes live 0900 EST on podcast release date). Join our mailing list to receive a PDF copy of our show notes every Monday! And hey, while you’re here, consider rating us on iTunes and leaving a review. The Curbsiders thank you! Thoughts on the Journal Club series? Article or guest nominations? Compliments or complaints? You can reach us at thecurbsiders@gmail.com. We are also on Facebook, Instagram, and Twitter: @thecurbsiders.   Credits: Written by: Christopher J Chiu MD, Sarah Phoebe Roberts MPH Producers: Christopher J Chiu MD, Sarah Phoebe Roberts MPH Editor: Matthew Watto MD Hosts: Christopher J Chiu MD, Stuart Brigham MD, Paul Williams MD, and Matthew Watto MD Guest: Robert Centor MD Time stamps: 00:00 Disclaimer and Intro to Curbsiders Journal Club 04:00 Dr. Centor's Pick of the Week 06:10 Clinical Implications of the Revised Pooled Cohort Equations 12:10 Negative Predictive Value in CTPA for VTE 18:34 Can low risk patients with PE be discharged from the ED? 23:03 Is Metformin associated with Lactic Acidosis in those with low eGFR? 28:45 How do medications for opioid use disorder affect mortality after non-fatal overdose? 36:44 Canagliflozin and Renal Protection 43:00 Performance of USPSTF screening criteria for diabetes 46:08 Stuart on Nose picking 50:00 Chiu Bites: Infectious ties and physical attire 53:50 Outro Tags: atherosclerotic, cardiovascular, disease, risk, CT, pulmonary, angiography, CTPA, embolism, ED, metformin, acidosis, CKD, treatment, opioid, use, disorder, oud, mat, overdose, canagliflozin, renal, diabetes, screening, nose-picking, staphylococcus, ACP, CME, MOC, assistant, care, doctor, education, family, FOAM, FOAMim, FOAMed, health, hospitalist, hospital, internal, internist, meded, medical, medicine, nurse, practitioner, professional, primary, physician, resident, student

Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2016 Jan;101(1):157-66

It's diabetes week on The Rounds Table. Mike Fralick and Kieran Quinn are back with the latest evidence in another Rapid Fire episode: four articles covered instead of the usual two. Canagliflozin has an impressive cardiovascular benefit profile for patients with a high burden of cardiovascular disease, based on data from randomized control trials. Mike ... The post Sugar Coating Diabetes Meds? Oral Antiglycemics and Diabetes Management, Rapid Fire appeared first on Healthy Debate.

It's diabetes week on The Rounds Table. Mike Fralick and Kieran Quinn are back with the latest evidence in another Rapid Fire episode: four articles covered instead of the usual two. Canagliflozin has an impressive cardiovascular benefit profile for patients with a high burden of cardiovascular disease, based on data from randomized control trials. Mike ...The post Sugar Coating Diabetes Meds? Oral Antiglycemics and Diabetes Management, Rapid Fire appeared first on Healthy Debate.

Dr. Carolyn Lam:               Hello from the American Heart Association meeting in Anaheim. I'm Dr. Carolyn Lam, associate editor from Circulation at National Heart Centre in Duke National University of Singapore and I'm so pleased to be here with the Circulation team led by editor in chief Dr. Joe Hill, as well as with Dr. Laura Mauri, senior editor from Brigham and Women's Hospital, and Dr. Dharam Kumbhani, associate editor from UT Southwestern. Boy, we've got lots to discuss. I mean, I want to just first start with congratulating you, Joe. We have got quite a number of simultaneous publications here at the AHA. Dr. Joseph Hill:                  I appreciate that, Carolyn. Don't congratulate me. We have a team that is a privilege to work with. One of the initiatives that we launched right from the start was a desire to foster and shine a bright light on emerging science at the major meetings around the world. Often, that involves simultaneous publication.                                                 I'm proud to say that we have 11 simultaneous publications, a record for us here at AHA. Most of them are clinical trials. A few are clinical science, and two of them are young investigators who are competing in the various different competitions. We reached out to them a few weeks ago and offered them the opportunity to submit to us, of course with no guarantees, and our standard remains the same, but we promised that we would provide them with an external peer review. Two of them made it through the process and they will be simultaneously published with their presentations here in Anaheim. Dr. Carolyn Lam:               Wow, well you heard it. A record 11 simultaneous publications. We've got a lot to talk about. Let me just maybe group the topics a little bit. Let's start with talking about peripheral artery disease. I think there are at least three papers around that area, and then we'll talk about coronary artery disease, and almost focusing more on implementation science, papers, there are two there, and then of course we have to talk about heart failure. Dharam, could you start? Tell us about the FOURIER PAD trial. Dr. Dharam Kumbhani:  Yeah. It's very exciting to have clinical trials in the PAD realm. FOURIER PAD is certainly really well done sub-study of the FOURIER trial. As you remember, this was a landmark trial, which compared a PCSK9 inhibitor Evolocumab in two doses, two placebo. The overall trial was done in about 27,000 patients who were followed for a median of 2.2 years. In this trial, Marc Bonaca and investigators, they looked at the PAD subset, which were about 13% of the total cohort. Now, they specifically set out to look at how patients with PAD, during this trial and very gratifyingly, they also specifically assessed how patients with PAD did as far as limb events, not just cardiovascular events.                                                 At the outset, not surprisingly, patients with PAD had a higher risk of cardiovascular events by, I think it was about 60% higher for the primary end point compared with patients who did not have PAD. There was really no, in fact, modification by PAD in that the benefit of Evolocumab that we saw in the overall trial was preserved among the patients with PAD as well as those without PAD. However, because patients with PAD had higher event rates, the absolute risk reductions were higher in patients with PAD.                                                 Then, these investigators looked specifically at the incidents of major adverse limb events, which is a composite of acute limb ischemia, urgent revasc, and major amputations. What they show is that in the overall cohort, there is a 42% reduction in the risk of these major adverse limb events with Evolocumab compared with placebo. Obviously, the effect is significantly higher in patients with PAD. Although the benefit wasn't noted in the PAD subset specifically, the overall p-value for interaction was negative.                                                 One of the really exciting things about this paper is that just like investigators have shown a monotonic reduction in cardiovascular event rates with LDL reduction, similarly, the investigators show a reduction in limb events, which is dose related and the same way in a monotonic fashion with Evolocumab. I think this is really exciting and I think this will be a very important paper for the field. Dr. Carolyn Lam:               Yeah. Dharam, that was beautifully summarized but once you start talking about the peripheral artery disease and this lack of interaction on effects and so on, I think of the CANVAS trial results that were reported at this meeting too. If I could maybe briefly summarize what the authors did in this circumstance, they looked at the more than 10,000 patients in the CANVAS trial who were randomized into Canagliflozin versus placebo in diabetic patients but this time they looked at whether or not there was a difference in effect with the primary prevention cohort versus the secondary prevention.                                                 Primary prevention meaning those adults who had diabetes and risk factors but no established cardiovascular disease and the secondary prevention were those with peripheral artery disease, for example, and other established cardiovascular disease. The same thing, a lack of interaction, which I think is really important because it was the same sort of idea that the overall risk of cardiovascular events was lower in the primary prevention group. Looking at them as a subgroup alone, you didn't get the p-value that crossed the limit because the power was less in a lower risk group, but the lack of statistical interaction really gives us additional information, I think, that Canagliflozin and maybe the SGLT2s in general may be effective for primary prevention in diabetic patients. What do you think? Dr. Dharam Kumbhani:  Yeah. I mean, I think certainly, very interesting findings along those lines. As you pointed out, the event rates are much lower in the primary prevention cohort. All the confidence intervals overlap one, but because all the p-values for interaction for the three-point maze, the four-point maze, et cetera, one would say that there really isn't a difference between the primary and the secondary prevention subgroups. You would potentially have the same benefit in that subgroup as well. Dr. Carolyn Lam:               Fortunately or unfortunately, in that same study, they looked at the risk of amputations and there was a lack of interaction too for that meaning there was a higher risk of amputations with Canagliflozin versus placebo. That of course is a really hot topic now, isn't it? I just wanted to point out though, when you look at it in the primary prevention group, there are only 33 events. What do you think? It spells caution but further look needs to be done? Yeah. Contrast that with the EMPA-REG outcome PAD analysis. You want to tell us about it? Dr. Dharam Kumbhani:  Yeah. Once the Canagliflozin CANVAS findings came out showing a high rate of amputations with Canagliflozin, the Empagliflozin, the EMPA-REG outcome's investigators went back and looked at the PAD subset in EMPA-REG outcomes. This was about 20% of the total cohort. I will say that unlike FOURIER, which we just discussed, the ascertainment of amputations was not prospectively defined for this trial and it was really obtained from the CRF forms.                                                 However, having said that, it did not appear that amputation rates were higher with Empagliflozin. They did not break it down by the different doses but one assumes that the benefit is consistent between the two doses that they study. One would imagine the PAD patients would have a higher rate overall, which it was, but even in that group, it was about 6% over three years and there was really no difference between the patients who received Empagliflozin versus those who got placebo. Dr. Carolyn Lam:               That EMPA-REG outcome paper, I mean, interestingly, it was a research letter. Joe, you've been watching this whole field unfold right now and our journal has published so many good papers, including CVD REAL, all in this space. Could you comment on that a little bit and the research letter concept and the fact that we're publishing so many of these interesting papers in this topic? Dr. Joseph Hill:                  Well, Carolyn, as you inferred, this field is evolving very rapidly. Now, the interface between metabolic disease and diabetes and heart disease is blurring. Some of these diabetic drugs are really emerging as heart failure drugs, it looks like and so there's a great deal of interest in exploring that and trying to find underlying mechanisms. It's an incredibly exciting time. In parallel with that, we are publishing research letters now for papers where, again, our bar starts with validity. Our bar doesn't change but if it's a story that can be communicated with really one multi-paneled figure and an 800word text, then that is a nice bite-size piece of information that we can get out to our readership. We're publishing one or two a week now. Overall, it appears to be well received and I think it's an effective vehicle for conveying certain types of our content. Dr. Carolyn Lam:               Frankly, it's such a delight to read, isn't it? It's hard to write. I think the shorter, the harder to write but this just goes to show how equally important they are. Dr. Joseph Hill:                  Absolutely. Dr. Carolyn Lam:               That we're discussing it here. Well, let's go on to the next topic then, coronary artery disease. Regionalization of the care. I'll say that again, regionalization of the care. Would you like to comment on the two papers that are simultaneously being published? One would be the ACCELERATOR-2 trial. That's in the U.S. Then, a second from New Zealand, the ICare-ACS trial. Slightly different but- Dr. Joseph Hill:                  Well, that's exactly right. Often, we know what to do but we don't do what we know we need to do in medicine. The implementation of what we already know is an area of hot research and is an area that's evolving rapidly. These two studies, ACCELERATOR-2 here in the United States, focused on regionalization of the interface between EMS systems and EDs, how to get patients identified in the hospital to their device, whether it's a stent or a balloon pump or whatever it is. The first medical contact to device was the metric and by implementing what we already know, the AHA mission lifeline principles, these investigators were able to optimize this regionalization, so there wasn't so much variability across these 12 metropolitan regions. As a consequence, the time to first medical contact to device was shortened, and there was in fact a striking, maybe even surprising, mortality benefit. Dr. Carolyn Lam:               Exactly. That was striking to me too. Dr. Joseph Hill:                  From the street to the lab, another paper from New Zealand that you referred to called ICare-ACS focused on doing a better job in the emergency department with serial ECGs and serial high sensitivity troponins, risk stratification algorithms and they found that, again, by developing these clinical pathways within the ED, they were able to shorten the length of stay in the ED and the length of stay in the hospital. Dr. Carolyn Lam:               Yeah. I thought those were amazing and then also from different parts of the world, really strong public health messages as well. Laura, you take care of these ACS patients right on there. What did you think of these papers? Dr. Laura Mauri:                No, I agree. I think that we've, in the past, focused on science and focused on clinical trials but ultimately, none of that matters if we don't deliver the healthcare to the patient. I think this is just a growing field and I'm glad that we're emphasizing it in circulation. Dr. Carolyn Lam:               Absolutely. If we would now go to another area that is really increasing in prevalence throughout the world. Heart failure, and of course, heart failure with preserved ejection fraction. Dr. Joseph Hill:                  Your favorite topic. Dr. Carolyn Lam:               Congratulations, Laura on the paper that you're presenting, that is being presented at this meeting, the REDUCE LAP trial. Could you tell us a little bit more about that? Dr. Laura Mauri:                Sure. Yes, as you know, it's a really challenging field, heart failure with preserved ejection fraction. There aren't a lot of therapies that we have. We really don't have great medical therapy. This study actually looks at a medical device to treat patients. It really is a feasibility study, so it's a relatively small trial, just over 90 patients but it's randomized. We know in the device arena, as in all trials, how important randomization is but also blinding. This was actually a sham-controlled blinded trial really designed to look at this interatrial shunt device in patients who have an elevated wedge pressure.                                                 The REDUCE LAP stands for reduce left atrial pressure. That was the primary endpoint, was pulmonary capillary wedge pressure. This was not only looked at the safety, which showed that the device placement was very safe, but at the same time also looked at the proof of concept that by placing the shunt device, there was actually a reduction in wedge pressure over a period of exercise. It needs to be followed on. It's certainly just the first phase of trials but a pretty good standard with the sham control. Dr. Carolyn Lam:               Yeah, well, congratulations again. I mean, this follows … There was a previous publication of the single arm trial and now, this is the first randomized sham-controlled, and the results are consistent. It's a very difficult trial to carry out. HFpEF patients are notoriously difficult to recruit. Could you tell us a little bit about what it was like successfully completing this trial? Dr. Laura Mauri:                Yeah. Well, we had very enthusiastic centers and principal investigators, Ted Feldman and Sanjiv Shah. I think what it really required in this early phase was sites that were committed to characterizing the exercise physiology. The next stage of rolling this out to a broader number of sites and a larger number of patients to see if there's a clinical effect will really be more focused on the clinical endpoints and quality of life because ultimately that's the goal, is to improve symptoms in these patients. Dr. Carolyn Lam:               What I love about the design and the whole concept, it's so simple and elegant. We almost sometimes forget that HFpEF is heart failure, which means that by definition, there's raised filling pressures. It's hemodynamic at the end and this is just a simple concept of offloading the left atrium. That's so beautiful but it does come with some questions. Every time you mention this to someone, they go, “What about, I don't know, Eisenmenger's syndrome developing later?” The right side, volume overload, pulmonary hypertension, what about atrial fibrillation down the line? How about the safety parts of it? Dr. Laura Mauri:                Right, so the procedural safety was excellent but then I think you raise really important questions and these patients are still in follow-up but looking at the report here at this meeting, there was no pulmonary hypertension in excess in the shunt treated arm. The patient selection was towards patients who had higher wedge compared with right atrial pressure and among those patients, there was no evidence of RV overload. At least at this stage things look good to go on to the next step. Dr. Carolyn Lam:               That's wonderful and exciting. We definitely need a therapy for HFpEF. Joe, would you like to highlight any other trial? We have 11. We've discussed six. Dr. Joseph Hill:                  Tonight at the editorial board meeting, we will be saluting these two young investigators who are presenting their work in this competition and simultaneously publishing their work. We've invited these young investigators and their mentor and they will present a short talk to the editorial board dinner. It's an effort to salute and recognize these early career investigators, to congratulate them on outstanding work. We're pleased and privileged to publish it, so I'm particularly excited about that. Dr. Carolyn Lam:               Wow, Joe. That is great. Thank you. I didn't know that was happening either. That's fabulous. Dharam or Laura, any other highlights that you may want to mention in this meeting? Dr. Laura Mauri:                I think that it's just been a wonderful kickoff to the meeting. We've covered, I think, many of the really important trials so it's really exciting to be able to see the work in print. Dr. Carolyn Lam:               That's great, and to discuss it as well. Dr. Dharam Kumbhani:  Yeah, I agree. This is really exciting and hopefully, we can keep growing from strength to strength every year. Dr. Carolyn Lam:               Yep. You heard it right here everyone. We are going to grow from strength to strength under your leadership and with this great team, so thank you very much for joining us today.  

While good glycemic control has been shown to prevent microvascular complications (e.g. retinopathy, nephropathy, neuropathy), only a few anti-diabetic agents have been shown to reduce macrovascular complications (e.g. cardiovascular events. Empagliflozin, a sodium glucose transporter-2 (SGLT2) inhibitor, not only reduced the risk of CV events but also all-cause mortality in the EMPA-REG OUTCOME study.  Based on this data, the SGLT2 inhibitors were given favorable second-line treatment status in the most recent AACE/ACE clinical practice guidelines. But do all SGLT2 inhibitors confer the same benefits… and risks? The Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) trial assessed the cardiovascular and renal benefits from long-term canagliflozin use.  The results are both reassuring and unexpected. Guest Author:  Sean Lasota, Pharm.D. Music by Good Talk

Commentary by Dr. Valentin Fuster

It's not only run of the mill DKA, starvation and alcoholic ketoacidosis that can cause a metabolic acidosis with elevated ketones. Euglycemic DKA can be caused by the newer diabetes medications sodium-glucose co-transporter 2 inhibitors like Canagliflozin; and it's important to recognize this tricky diagnosis early and initiate treatment for DKA despite a normal serum glucose level... The post Best Case Ever 58 Euglycemic DKA appeared first on Emergency Medicine Cases.

Listen to an audio podcast of the May 16, 2017, FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR).

Based on new data from two large clinical trials, the FDA concluded that the type 2 diabetes medicine canagliflozin (brand names Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. The FDA is requiring new warnings, including their most prominent Boxed Warning, be added to the canagliflozin drug labels to describe this risk. Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, below and above the knee, also occurred. Some patients had more than one amputation, some involving both limbs. Report side effects involving canagliflozin and other medicines to the FDA MedWatch program at fda.gov/medwatch. A link to the full communication detailing specific information for health care professionals and the complete Data Summary can be found at fda.gov/DrugSafetyCommunications. If you have drug questions, contact the FDA at druginfo@fda.hhs.gov. Released 5/16/2017

Based on new data from two large clinical trials, the FDA concluded that the type 2 diabetes medicine canagliflozin (brand names Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. The FDA is requiring new warnings, including their most prominent Boxed Warning, be added to the canagliflozin drug labels to describe this risk. Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, below and above the knee, also occurred. Some patients had more than one amputation, some involving both limbs. Report side effects involving canagliflozin and other medicines to the FDA MedWatch program at fda.gov/medwatch. A link to the full communication detailing specific information for health care professionals and the complete Data Summary can be found at fda.gov/DrugSafetyCommunications. If you have drug questions, contact the FDA at druginfo@fda.hhs.gov. Released 5/16/2017

Based on new data from two large clinical trials, the FDA concluded that the type 2 diabetes medicine canagliflozin (brand names Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. The FDA is requiring new warnings, including their most prominent Boxed Warning, be added to the canagliflozin drug labels to describe this risk. Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, below and above the knee, also occurred. Some patients had more than one amputation, some involving both limbs. Report side effects involving canagliflozin and other medicines to the FDA MedWatch program at fda.gov/medwatch. A link to the full communication detailing specific information for health care professionals and the complete Data Summary can be found at fda.gov/DrugSafetyCommunications. If you have drug questions, contact the FDA at druginfo@fda.hhs.gov. Released 5/16/2017

FDA Drug Safety Podcast: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate

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