174 results on '"Arnott, C."'
Search Results
2. Chronic Breathlessness Management in Primary Care: Current Gaps and Practical Solutions
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Sunjaya, A.P., primary, Martin, A., additional, Arnott, C., additional, Marks, G.B., additional, and Jenkins, C.R., additional
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- 2023
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3. Acceptability and Feasibility of a Chronic Breathlessness Clinical Algorithm in Australian Primary Care
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Sunjaya, A.P., primary, Martin, A., additional, Arnott, C., additional, Di Tanna, G.L., additional, Gianacas, C., additional, Marks, G.B., additional, and Jenkins, C.R., additional
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- 2023
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4. Sex disaggregated analysis of risk factors for adverse outcomes in hypertrophic cardiomyopathy
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Butters, A, primary, Arnott, C, additional, Sweeting, J, additional, Claggett, B, additional, Atherton, J, additional, Semsarian, C, additional, Lakdawala, N K, additional, Ho, C Y, additional, and Ingles, J, additional
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- 2022
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5. Multidisciplinary perspectives on the role of primary care in managing chronic breathlessness
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Sunjaya, A P, primary, Martin, A, additional, Arnott, C, additional, and Jenkins, C, additional
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- 2022
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6. Value-adding to the Victorian FLOWS Methodology
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Hydrology and Water Resources Symposium (32nd : 2009 : Newcastle, Australia), Turner, M, Wealands, A, Arnott, C, Roach, S, van Rensburg, J, and Hughes, C
- Published
- 2009
7. Colchicine in Cardiovascular Disease: In-Depth Review
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Deftereos, S.G. Beerkens, F.J. Shah, B. Giannopoulos, G. Vrachatis, D.A. Giotaki, S.G. Siasos, G. Nicolas, J. Arnott, C. Patel, S. Parsons, M. Tardif, J.-C. Kovacic, J.C. Dangas, G.D.
- Abstract
Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular outcomes. For years, colchicine has been used as a safe and well-tolerated agent in diseases such as gout and familial Mediterranean fever. The widely available therapeutic has several anti-inflammatory effects, however, that have proven effective in a broad spectrum of cardiovascular diseases as well. It is considered standard-of-care therapy for pericarditis, and several clinical trials have evaluated its role in postoperative and postablation atrial fibrillation, postpericardiotomy syndrome, coronary artery disease, percutaneous coronary interventions, and cerebrovascular disease. We aim to summarize colchicine's pharmacodynamics and the mechanism behind its anti-inflammatory effect, outline thus far accumulated evidence on treatment with colchicine in cardiovascular disease, and present ongoing randomized clinical trials. We also emphasize real-world clinical implications that should be considered on the basis of the merits and limitations of completed trials. Altogether, colchicine's simplicity, low cost, and effectiveness may provide an important addition to other standard cardiovascular therapies. Ongoing studies will address complementary questions pertaining to the use of low-dose colchicine for the treatment of cardiovascular disease.
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- 2022
8. Sex Disaggregated Analysis of Risk Factors for Adverse Outcomes in Hypertrophic Cardiomyopathy
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Butters, A., primary, Arnott, C., additional, Sweeting, J., additional, Claggett, B., additional, Ashley, E., additional, Parikh, V., additional, Colan, S., additional, Day, S., additional, Owens, A., additional, Helms, A., additional, Saberi, S., additional, Jacoby, D., additional, Michels, M., additional, Olivotto, I., additional, Pereira, A., additional, Rossano, J., additional, Wittekind, S., additional, Ware, J., additional, Atherton, J., additional, Semsarian, C., additional, Lakdawala, N., additional, Ho, C., additional, and Ingles, J., additional
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- 2022
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9. Effects of canagliflozin on hyperkalaemia and serum potassium in people with diabetes and chronic kidney disease: insights from the CREDENCE trial
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Neuen, B L, primary, Oshima, M, additional, Perkovic, V, additional, Arnott, C, additional, Bakris, G, additional, Cannon, C P, additional, Charytan, D M, additional, Jardine, M, additional, Levin, A, additional, Neal, B, additional, Pollock, C, additional, Wheeler, D C, additional, Mahaffey, K W, additional, and Heerspink, H J L, additional
- Published
- 2021
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10. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial
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Neuen B, Oshima M, Perkovic V, Agarwal R, Arnott C, Bakris G, Cannon C, Charytan D, Edwards R, Gorriz J, Jardine M, Levin A, Neal B, De Nicola L, Pollock C, Rosenthal N, Wheeler D, Mahaffey K, and Heerspink H
- Abstract
AIMS: Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium?glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. METHODS AND RESULTS: The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium =6.0 and
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- 2021
11. Canagliflozin and Cardiovascular Outcomes in Patients With and Without Peripheral Artery Disease At Baseline: Data from the CANVAS Program and CREDENCE Trials
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Yu, J., primary, Barraclough, J., additional, Neal, B., additional, Figtree, G., additional, and Arnott, C., additional
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- 2021
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12. The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: analysis of the CREDENCE trial
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de Zeeuw, D., Arnott, C., Li, J. -W., Cannon, C. P., Neuen, B. L., Heerspink, H. J. L., Neal, B., Charytan, D. M., Bakris, G., Chang, T. -H., Rosenthal, N., Zinman, B., Perkovic, V., Jardine, M. J., Mahaffey, K. W., Groningen Kidney Center (GKC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
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Endocrinology & Metabolism ,Science & Technology ,1114 Paediatrics and Reproductive Medicine ,1103 Clinical Sciences ,Life Sciences & Biomedicine ,1117 Public Health and Health Services - Published
- 2020
13. Blood pressure postpartum (BP2) RCT protocol: Follow-up and lifestyle behaviour change strategies in the first 12 months after hypertensive pregnancy
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Henry A, Arnott C, Makris A, Davis G, Hennessy A, Beech A, Pettit F, Se Homer C, Craig ME, Roberts L, Hyett J, Chambers G, Fitzgerald O, Gow M, Mann L, Challis D, Gale M, Ruhotas A, Kirwin E, Denney-Wilson E, and Brown M
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1114 Paediatrics and Reproductive Medicine - Abstract
OBJECTIVES:Women who had hypertensive disorders of pregnancy (HDP) are twice as likely to experience maternal cardiovascular disease later in life. The primary aim of this study (BP2) is to compare outcomes of 3 different management strategies, including lifestyle behaviour change (LBC), in the first 12 months postpartum in women who had HDP in their preceding pregnancy. Secondary aims include assessing the effects on other cardiometabolic parameters. STUDY DESIGN:Three-arm multicentre randomised trial in metropolitan Australian hospitals, (registration: ACTRN12618002004246) target sample size 480. Participants are randomised to one of three groups: 1) Optimised usual care: information package and family doctor follow-up 6 months postpartum 2) Brief intervention: information package as per group 1, plus assessment and brief LBC counselling at a specialised clinic with an obstetric physician and dietitian 6 months postpartum 3) Extended intervention: as per group 2 plus enrolment into a 6 month telephone-based LBC program from 6 to 12 months postpartum. All women have an outcome assessment at 12 months. MAIN OUTCOME MEASURES:Primary outcomes: (a) BP change or (b) weight change and/or waist circumference change. SECONDARY OUTCOMES:maternal health-related quality of life, engagement and retention in LBC program, biochemical markers, vascular function testing, infant weight trajectory, incremental cost-effectiveness ratios. The study is powered to detect a 4 mmHg difference in systolic BP between groups, or a 4 kg weight loss difference/2cm waist circumference change. CONCLUSIONS:BP2 will provide evidence regarding the feasibility and effectiveness of postpartum LBC interventions and structured clinical follow-up in improving cardiovascular health markers after HDP.
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- 2020
14. Elastic Chest Compression Reduced Hyperinflation in People with Chronic Obstructive Pulmonary Disease
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Chapman, D.G., primary, Arnott, C., additional, Puranik, R., additional, Prael, G., additional, Patel, K., additional, Tonga, K.O., additional, Milne, S., additional, Zimmermann, S.C., additional, Munoz, P.A., additional, Lake, C.D., additional, Kaminsky, D.A., additional, Lau, E., additional, and King, G.G., additional
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- 2020
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15. Departure time and route choice for the morning commute
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Arnott, C., de Palma, A., and Lindsey, R.
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Traffic congestion -- Models ,Origin and destination traffic surveys -- Models ,Traffic flow -- Models ,Business ,Transportation industry - Published
- 1990
16. The Impact of Sewage Discharge in a Marine Embayment: A Stable Isotope Reconnaissance
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Waldron, S., Tatner, P., Jack, I., and Arnott, C.
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- 2001
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17. Selective Pulmonary Vasodilator Therapy and Improved Survival in Eisenmenger Syndrome: The ANZ CHD-PAH Registry
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Arnott, C., primary, Strange, G., additional, O’Donnell, C., additional, Bullock, A., additional, Radford, D., additional, Grigg, L., additional, and Celermajer, D., additional
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- 2017
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18. Detailed Quantification of Right Atrial Function Using 4D-flow MRI
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Callaghan, F., primary, Arnott, C., additional, Figtree, G., additional, Celermajer, D., additional, and Grieve, S., additional
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- 2016
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19. Exercise Cardiac Magnetic Resonance Imaging: Assessing Real-Time Biventricular Contractile Reserve
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Arnott, C., primary, Celermajer, D., additional, and Puranik, R., additional
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- 2016
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20. Subtle increases in heart size persist into adulthood in growth restricted babies- the cardiovascular risk in young Finns study
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Arnott, C., primary, Skilton, M., additional, Ruohonen, S., additional, Juonala, M., additional, Viikari, J., additional, Kahonen, M., additional, Lehtimaki, T., additional, Laitinen, T., additional, Celermajer, D., additional, and Raitakari, O., additional
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- 2015
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21. Outcomes in pulmonary arterial hypertension patients with systemic right ventricular pressure
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Arnott, C., primary, Boehm, C., additional, Lau, E., additional, and Celermajer, D., additional
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- 2015
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22. Early Australian Experience With AbsorbTM Bioresorbable Scaffold Technology in “Real-World” Coronary Disease
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Arnott, C., primary, Pitney, M., additional, Ooi, S., additional, and Jepson, N., additional
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- 2013
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23. Naphthenate Scale Formation – Examination of Molecular Controls in Idealised Systems
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Dyer, S. J., additional, Graham, G. M., additional, and Arnott, C., additional
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- 2003
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24. Dual-antenna phased-array UWB transceiver in 0.18/spl mu/m CMOS.
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Lo, S., Sever, I., Ssu-Pin Ma, Jang, P., Zou, A., Arnott, C., Ghatak, K., Schwartz, A., Huynh, L., and Nguyen, T.
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- 2006
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25. Erratum to “Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis”
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Moore, R.J., primary, Owens, D.M., additional, Stamp, G., additional, Arnott, C., additional, Burke, F., additional, East, N., additional, Holdsworth, H., additional, Turner, L., additional, Rollins, B., additional, Pasparakis, M., additional, Kollias, G., additional, and Balkwill, F., additional
- Published
- 1999
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26. Role of ERK1/ERK2 and p70^S^6^K pathway in insulin signalling of protein synthesis
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Sale, E. M., Atkinson, P. P., Arnott, C. H., Chad, J. E., and Sale, G. J.
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- 1999
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27. Use of an antisense strategy to dissect the signaling role of protein-tyrosine phosphatase alpha.
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Arnott, C H, Sale, E M, Miller, J, and Sale, G J
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The protein-tyrosine phosphatase PTPalpha has been proposed to play an important role in controlling the dephosphorylation of a number of key signaling proteins and in regulating insulin signaling. To examine the potential cellular functions and physiological substrates of PTPalpha, a potent phosphorothioate oligonucleotide-based antisense strategy was developed that specifically depleted endogenous PTPalpha from 3T3-L1 adipocytes. The antisense probe, alphaAS1, achieved PTPalpha depletion levels normally of >/=85% and which varied up to levels where PTPalpha was not detected at all. Elimination of PTPalpha by 85% inhibited c-Src activity by 80%. Abolishing PTPalpha to levels undetected did not alter the tyrosine dephosphorylation of the insulin receptor or insulin receptor substrate proteins. Moreover, the ability of insulin to activate ERK2 or to stimulate DNA synthesis was not altered by alphaAS1. It is concluded that endogenous PTPalpha is a key regulator of c-Src activity in 3T3-L1 adipocytes and that PTPalpha is not required for the dephosphorylation of the insulin receptor or the insulin receptor substrate proteins or for the regulation of several downstream insulin signaling events in 3T3-L1 adipocytes. Finally, the development of the antisense probe, alphaAS1, provides an important molecular tool of general applicability for further dissecting the roles and precise targets of endogenous PTPalpha.
- Published
- 1999
28. Medical Ethics
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Arnott, C. D.
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n/a
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- 1856
29. ON WHAT IS COMMONLY CALLED "RIGIDITY OF THE OS UTERI."
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ARNOTT, C, primary
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- 1860
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30. Risk of Cardiovascular Disease in Female Cancer Survivors: A Population Cohort Study Using Linked Australian Health Datasets.
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Houston, L., Fletcher, R., Gianacas, C., and Arnott, C.
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CANCER survivors , *CARDIOVASCULAR diseases risk factors , *CARDIOVASCULAR diseases , *COHORT analysis , *FEMALES - Published
- 2024
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31. Safety and Tolerability of Regular Oral Colchicine—A Systematic Review and Meta-Analysis of Randomised Placebo-Controlled Trials.
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Tucker, B., Houston, L., Tucker, W., Keech, A., Arnott, C., and Patel, S.
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COLCHICINE , *SAFETY - Published
- 2024
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32. Geographic and racial variability in kidney, cardiovascular and safety outcomes with canagliflozin: A secondary analysis of the CREDENCE randomized trial.
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Cardoza K, Kang A, Smyth B, Yi TW, Pollock C, Agarwal R, Bakris G, Charytan DM, de Zeeuw D, Wheeler DC, Zhang H, Cannon CP, Perkovic V, Arnott C, Levin A, and Mahaffey KW
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- Humans, Male, Female, Middle Aged, Aged, Diabetic Nephropathies, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic ethnology, Hospitalization statistics & numerical data, Kidney Failure, Chronic complications, Kidney Failure, Chronic ethnology, Europe epidemiology, Treatment Outcome, North America epidemiology, Proportional Hazards Models, Canagliflozin therapeutic use, Canagliflozin adverse effects, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 ethnology, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Sodium-Glucose Transporter 2 Inhibitors adverse effects, Cardiovascular Diseases epidemiology, Cardiovascular Diseases mortality, Cardiovascular Diseases prevention & control
- Abstract
Aim: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups., Materials and Methods: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end-stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes. Secondary outcomes included: (i) cardiovascular death or heart failure (HF) hospitalization; (ii) cardiovascular death, myocardial infarction (MI) or stroke; (iii) HF hospitalization; (iv) doubling of the SCr level, ESKD or kidney death; (v) cardiovascular death; (vi) all-cause death; and (vii) cardiovascular death, MI, stroke, or hospitalization for HF or for unstable angina., Results: The 4401 patients were divided into six geographic region subgroups: North America (n = 1182, 27%), Central and South America (n = 941, 21%), Eastern Europe (n = 947, 21%), Western Europe (n = 421, 10%), Asia (n = 749, 17%) and Other (n = 161, 4%). The analyses included four racial groups: White (n = 2931, 67%), Black or African American (n = 224, 5%), Asian (n = 877, 20%) and Other (n = 369, 8%). Canagliflozin reduced the relative risk of the primary composite outcome in the overall trial by 30% (hazard ratio 0.70, 95% confidence interval 0.59-0.82; P = 0.00001). Across geographic regions and racial groups, canagliflozin consistently reduced the primary composite endpoint without evidence of heterogeneity (interaction P values of 0.39 and 0.91, respectively) or significant safety outcome differences., Conclusions: Canagliflozin reduces the risk of kidney and cardiovascular events similarly across geographic regions and racial groups., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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33. Bidirectional Relationship Between Kidney Disease Progression and Cardiovascular Events in Type 2 Diabetes.
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Neuen BL, Ostrominski JW, Claggett B, Beldhuis IE, Chatur S, McCausland FR, Badve SV, Arnott C, Heerspink HJL, Jun M, Falster M, de Oliveira Costa J, Pollock C, Jardine MJ, Mahaffey KW, Perkovic V, Solomon SD, and Vaduganathan M
- Abstract
Competing Interests: Funding Support and Author Disclosures Dr Neuen has received fees for travel support, advisory boards, and scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, the Limbic, Janssen, Medscape, Novo Nordisk, and Travere Therapeutics; and has served on clinical trial committees for studies sponsored by AstraZeneca, Bayer, and CSL Behring, with all honoraria paid to The George Institute for Global Health. Dr Ostrominski has received research funding from the National Institutes of Health (grant 5T32HL007604-39). Dr Claggett as received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket. Dr McCausland has received research funding from National Institutes of Health, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon paid directly to his institution; and has received consulting fees from GlaxoSmithKline and Zydus Therapeutics. Dr Badve has received consulting fees from Bayer, AstraZeneca, GlaxoSmithKline, and Vifor Pharma; has received speaker fees from Bayer, AstraZeneca, Pfizer, and Vifor Pharma (all honoraria paid to his institution); and has received nonfinancial research support from Bayer. Dr Arnott has received honoraria from AstraZeneca, Novo Nordisk, and Amgen. Dr Heerspink has received grants or contracts from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Novo Nordisk, Novartis, and Travere Therapeutics; and has received payment or honoraria for speaking from AstraZeneca and Novo Nordisk. Dr Jun has been responsible for research projects that have received unrestricted research funding from Boehringer Ingelheim and Eli Lilly Alliance. Dr Pollock serves as an Advisory Board member for AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Vifor Pharma; and has received speaker fees for AstraZeneca, Janssen-Cilag, Novartis, Otsuka, and Vifor Pharma. Dr Jardine is supported by an National Health and Medical Research Council investigator grant; has been responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and Merck Sharp & Dohme; and has received fees for advisory, steering committee, scientific presentations, or a combination of these from Akebia, Amgen, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, Chinook, CSL, Janssen, Medscape, Merck Sharp & Dohme, Occuryx, Roche, and Vifor with any consultancy, honoraria, or travel support paid to her institution. Dr Mahaffey has received research support from Afferent, Amgen, Apple, AstraZeneca, Cardiva Medical, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, National Institutes of Health, Novartis, Sanofi, St Jude, and Tenax; and has served as a consultant (speaker fees for CME events only) for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi Tanabe, Myokardia, the National Institutes for Health, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and the University of California-San Francisco. Dr Perkovic serves as a board director for St Vincent’s Health Australia, Victor Chang Cardiac Research Institute, and Mindgardens; and has received honoraria for steering committee roles, scientific presentations, advisory board attendance, or a combination of these from Abbvie, Amgen, AstraZeneca, Bayer, Baxter, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pharmalink, Pfizer, Reata, Travere, Relypsa, Roche, Sanofi, Servier, and Tricida. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Bristol Myers Squibb, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Published
- 2024
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34. Machine learning for prediction of chronic kidney disease progression: Validation of the Klinrisk model in the CANVAS Program and CREDENCE trial.
- Author
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Tangri N, Ferguson TW, Bamforth RJ, Leon SJ, Arnott C, Mahaffey KW, Kotwal S, Heerspink HJL, Perkovic V, Fletcher RA, and Neuen BL
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- Humans, Male, Female, Middle Aged, Aged, Diabetic Nephropathies diagnosis, Diabetic Nephropathies physiopathology, Diabetic Nephropathies urine, Risk Assessment methods, Machine Learning, Disease Progression, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic physiopathology, Renal Insufficiency, Chronic urine, Diabetes Mellitus, Type 2 complications, Glomerular Filtration Rate
- Abstract
Aim: To validate the Klinrisk machine learning model for prediction of chronic kidney disease (CKD) progression in patients with type 2 diabetes in the pooled CANVAS/CREDENCE trials., Materials and Methods: We externally validated the Klinrisk model for prediction of CKD progression, defined as 40% or higher decline in estimated glomerular filtration rate (eGFR) or kidney failure. Model performance was assessed for prediction up to 3 years with the area under the receiver operating characteristic curve (AUC), Brier scores and calibration plots of observed and predicted risks. We compared performance of the model with standard of care using eGFR (G1-G4) and urine albumin-creatinine ratio (A1-A3) Kidney Disease Improving Global Outcomes (KDIGO) heatmap categories., Results: The Klinrisk model achieved an AUC of 0.81 (95% confidence interval [CI] 0.78-0.83) at 1 year, and 0.88 (95% CI 0.86-0.89) at 3 years. The Brier scores were 0.020 (0.018-0.022) and 0.056 (0.052-0.059) at 1 and 3 years, respectively. Compared with the KDIGO heatmap, the Klinrisk model had improved performance at every interval (P < .01)., Conclusions: The Klinrisk machine learning model, using routinely collected laboratory data, was highly accurate in its prediction of CKD progression in the CANVAS/CREDENCE trials. Integration of the model in electronic medical records or laboratory information systems can facilitate risk-based care., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
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- 2024
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35. An overview of the CANVAS Program and CREDENCE trial: The primary outcomes and key clinical implications for those managing patients with type 2 diabetes.
- Author
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Chen AX, Fletcher R, Neuen BL, Neal B, and Arnott C
- Abstract
Aims: To provide an overview of the primary outcomes and key clinical implications of the CANVAS Program and CREDENCE trial, which were event-driven, double-blind randomized controlled trials that established the efficacy and safety of canagliflozin in those with type 2 diabetes (T2D) and high cardiovascular risk (CV) or albuminuric chronic kidney disease (CKD)., Methods and Results: The CANVAS programme (CANVAS and CANVAS-R trials) randomized 10 142 people with T2D and high CV risk to canagliflozin or placebo and followed them for a median of 126 weeks. The primary efficacy outcome was met, with canagliflozin treatment associated with a 14% reduction in major adverse CV events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.75 to 0.97; p < 0.001) as compared to placebo. The CREDENCE trial randomized 4401 individuals with T2D and albuminuric CKD to canagliflozin or placebo and followed them for 109 weeks. The CREDENCE trial also met its primary endpoint; canagliflozin treatment was associated with a 30% reduction in the composite of kidney failure, sustained doubling of serum creatinine level, or death from kidney or CV causes (HR 0.70, 95% CI 0.59 to 0.82; p < 0.001). Substantial reductions in hospitalization for heart failure (CANVAS: HR 0.67, 95% CI 0.52 to 0.87; CREDENCE: HR 0.61, 95% CI 0.47 to 0.80) and other key CV and kidney outcomes were also identified. Relative clinical benefits were consistent across subgroups defined by baseline age, sex, kidney function and history of CV disease but absolute benefits were greatest in those at highest baseline risk. Total serious adverse events were less common with canagliflozin treatment. Concerns about amputation and fracture risk observed in the CANVAS Program were not seen in CREDENCE and appear to have been spurious chance findings., Conclusion: Canagliflozin reduced important CV, kidney and mortality outcomes in those with T2D and high CV risk or CKD across diverse patient groups, with a good safety profile. Taken together with the other sodium-glucose cotransporter-2 inhibitor CV and renal outcomes trials, these landmark findings have changed the treatment landscape for patients worldwide., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
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- 2024
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36. Prediction of new-onset heart failure in patients with type 2 diabetes derived from ALTITUDE and CANVAS.
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Said F, Arnott C, Voors AA, Heerspink HJL, and Ter Maaten JM
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- Humans, Female, Middle Aged, Male, Aged, Canagliflozin therapeutic use, Amides therapeutic use, Troponin T blood, Albuminuria, Body Mass Index, Biomarkers blood, Risk Factors, Risk Assessment, Fumarates, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 blood, Heart Failure epidemiology, Peptide Fragments blood, Natriuretic Peptide, Brain blood, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
Aim: To create and validate a prediction model to identify patients with type 2 diabetes (T2D) at high risk of new-onset heart failure (HF), including those treated with a sodium-glucose cotransporter-2 (SGLT2) inhibitor., Methods: A prediction model was developed from the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), a trial in T2D patients with albuminuria or cardiovascular disease. We included 5081 patients with baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) measurement and no history of HF. The model was developed using Cox regression and validated externally in the placebo arm of the Canagliflozin Cardiovascular Assessment Study (CANVAS), which included 996 participants with T2D and established cardiovascular disease or high cardiovascular risk, and in patients treated with canagliflozin., Results: ALTITUDE participants (mean age 64 ± 9.8 years) had a median serum NT-proBNP level of 157 (25th-75th percentile 70-359) pg/mL. Higher NT-proBNP level, troponin T (TnT) level and body mass index (BMI) emerged as significant and independent predictors of new-onset HF in both cohorts. The model further contained urinary albumin-to-creatinine ratio, glycated haemoglobin, age, haematocrit, and use of calcium channel blockers. A prediction model including these variables had a C-statistic of 0.828 (95% confidence interval [CI] 0.801-0.855) in ALTITUDE and 0.800 (95% CI 0.720-0.880) in CANVAS. The C-statistic of this model increased to 0.847 (95% CI 0.792-0.902) in patients after 1 year of canagliflozin treatment., Conclusion: In patients with T2D, higher NT-proBNP level, TnT level and BMI are independent and externally validated predictors of new-onset HF, including patients using an SGLT2 inhibitor. This newly developed model may identify patients at high risk of new-onset HF, contributing to early recognition and possibly prevention., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
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- 2024
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37. Effects of canagliflozin on total heart failure events across the kidney function spectrum: Participant-level pooled analysis from the CANVAS Program and CREDENCE trial.
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Vaduganathan M, Cannon CP, Jardine MJ, Heerspink HJL, Arnott C, Neuen BL, Sarraju A, Gogate J, Seufert J, Neal B, Perkovic V, Mahaffey KW, and Kosiborod MN
- Abstract
Aims: People with type 2 diabetes (T2D) face high risks of heart failure (HF) hospitalizations that are often recurrent, especially as kidney function declines. We examined the effects of canagliflozin on total HF events by baseline kidney function in patients with T2D at high cardiovascular risk and/or with chronic kidney disease., Methods and Results: Leveraging pooled participant-level data from the CANVAS programme (n = 10 142) and CREDENCE trial (n = 4401), first and total HF hospitalizations were examined. Cox proportional hazards models were built for the time to first HF hospitalization, and proportional means models based on cumulative mean functions were used for recurrent HF hospitalizations. Treatment effects were evaluated overall as well as within baseline estimated glomerular filtration rate (eGFR) strata (<45, 45-60, and >60 ml/min/1.73 m
2 ). HF hospitalizations were independently and blindly adjudicated. Among 14 540 participants with available baseline eGFR values, 672 HF hospitalizations occurred over a median follow-up of 2.5 years. Among participants who experienced a HF hospitalization, 357 had a single event (201 in placebo-treated patients and 156 in canagliflozin-treated patients), 77 had 2 events, and 39 had >2 events. Canagliflozin reduced risk of first HF hospitalization (hazard ratio 0.58, 95% confidence interval [CI] 0.48-0.70) consistently across baseline eGFR strata (pinteraction = 0.84). Canagliflozin reduced total HF hospitalizations overall (mean event ratio 0.63, 95% CI 0.54-0.73) and across eGFR subgroups (pinteraction = 0.51). Canagliflozin also reduced cardiovascular death and total HF hospitalizations (mean event ratio 0.72, 95% CI 0.65-0.80) and across eGFR subgroups (pinteraction = 0.82). The absolute risk reductions were numerically larger, and numbers needed to treat were smaller when evaluating total events versus first events alone. These observed HF benefits were highly consistent across the range of eGFR, with larger absolute benefits in participants who had worse kidney function at baseline., Conclusions: In individuals with T2D at high cardiovascular risk and/or with chronic kidney disease, canagliflozin reduced the total burden of HF hospitalizations, with consistent benefits observed across the kidney function spectrum., Clinical Trial Registration: ClinicalTrials.gov Identifier: CANVAS (NCT01032629), CANVAS-R (NCT01989754), CREDENCE (NCT02065791)., (© 2024 European Society of Cardiology.)- Published
- 2024
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38. Secondary Analysis of the Salt Substitute and Stroke Study (SSaSS): Effects of Potassium-Enriched Salt on Cardiac Outcomes.
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Yu J, Arnott C, Li Q, Di Tanna GL, Tian M, Huang L, Yin X, Zhang X, Pearson SA, Labarthe DR, Elliott P, Yan LL, Zhou B, Wu Y, and Neal B
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- Adult, Humans, Arrhythmias, Cardiac, Death, Sudden, Potassium, Acute Coronary Syndrome, Heart Failure, Stroke prevention & control
- Abstract
Background: The SSaSS (Salt Substitute and Stroke Study) has shown that use of a potassium-enriched salt lowers the risk of stroke, total cardiovascular events, and premature death. The effects on cause-specific cardiac outcomes are reported here., Methods: SSaSS was an unblinded, cluster-randomised trial assessing the effects of potassium-enriched salt compared with regular salt among 20 995 Chinese adults with established stroke and older age and uncontrolled hypertension. Post hoc efficacy analyses were performed using an intention-to-treat method and a hierarchical Poisson regression model adjusting for clustering to obtain rate ratios and 95% CIs. We assessed acute coronary syndrome, heart failure, arrhythmia, and sudden death., Results: Over a mean 4.74 years follow-up, there were 695 acute coronary syndrome events, 454 heart failure events, 230 arrhythmia events, and 1133 sudden deaths recorded. The rates of events were lower in potassium-enriched salt group for all outcomes but CIs were wide for most: acute coronary syndrome (6.32 versus 7.65 events per 1000 person-years; rate ratio, 0.80 [95% CI, 0.65-0.99]); heart failure (9.14 versus 11.32 events per 1000 person-years; rate ratio, 0.88 [95% CI, 0.60-1.28]); arrhythmia (4.43 versus 6.20 events per 1000 person-years; rate ratio, 0.59 [95% CI, 0.35-0.98]); and sudden death (11.01 versus 11.76 events per 1000 person-years; rate ratio, 0.94 [95% CI, 0.82-1.07]; all P >0.05 with adjustment for multiple comparisons)., Conclusions: These results suggest that use of potassium-enriched salt is more likely to prevent than cause cardiac disease but the post hoc nature of these analyses precludes definitive conclusions., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02092090., Competing Interests: Disclosures The Salt Substitute and Stroke Study was funded by grants APP1164206 and APP1049417 from the National Health and Medical Research Council of Australia. Salt substitute was donated by Jiangsu Sinokone Technology Co Ltd for years 3 and 4 of the trial. The other authors report no conflicts.
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- 2024
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39. Knowledge, attitudes, and behaviors related to dietary salt intake and the acceptability of salt substitute among the Australian culturally and linguistically diverse community: An online survey.
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Yu J, Houston L, Gianacas C, Lee V, Fletcher RA, Chen AX, and Arnott C
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- Humans, Australia epidemiology, Cross-Sectional Studies, Female, Male, Adult, Middle Aged, Surveys and Questionnaires, Hypertension ethnology, Hypertension epidemiology, Aged, Cultural Diversity, Language, Young Adult, Health Knowledge, Attitudes, Practice, Sodium Chloride, Dietary administration & dosage, Sodium Chloride, Dietary adverse effects
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The Australian culturally and linguistically diverse (CALD) communities may be at higher risk of salt intake than recommended given the use of a combination of discretionary sources and exposure to processed foods within a western country. This survey aimed to understand the knowledge, attitudes, and behaviors toward dietary salt and the acceptability of salt substitutes in the CALD communities. An online cross-sectional survey was conducted among adults who self-reported being a part of a CALD community, which was defined as non-Indigenous cultural groups in Australia having cultural or linguistic connections with their overseas place of birth, ancestry or ethnic origin, religion, preferred language or language spoken at home. A total of 218 respondents opened the survey link. A total of 196 completed the entire survey. The majority of respondents (162, 83%) were aware that high salt intake causes serious health problems. Altogether 134 (69%) respondents were aware that there is a recommended amount for daily salt consumption although only 59 (44%) knew precise recommendations as <5 g salt per day. Around one quarter of the respondents rarely or never looked for ‟low in salt'' or ‟reduced salt'' messages on food labels when shopping. Over half specified they always or often added salt during cooking or preparing foods in the household. Almost 4 in 5 CALD respondents were willing to reduce their salt intake for health and 3 in 4 were open to trying a salt substitute. Further research into the utility of a salt substitute intervention in the Australian CALD community is warranted., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)
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- 2024
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40. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cause-Specific Cardiovascular Death in Patients with CKD: A Meta-Analysis of CKD Progression Trials.
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Fletcher RA, Herrington WG, Agarwal R, Mayne KJ, Arnott C, Jardine MJ, Mahaffey KW, Perkovic V, Staplin N, Wheeler DC, Chertow GM, Heerspink HJL, and Neuen BL
- Abstract
Clinical Trial registry name and registration number: ClinicalTrials.gov Identifiers: NCT02065791 (CREDENCE), NCT03036150 (DAPA-CKD), NCT03594110 (EMPA-KIDNEY)., (Copyright © 2024 by the American Society of Nephrology.)
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- 2024
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41. Effects of no mask, a surgical mask and a fabric buff on peripheral oxygenation saturation during moderate intensity exercise: a randomised cross-over study.
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Janse van Rensburg DC, Jansen van Rensburg A, Botha T, Elliott K, Ramagole D, Pillay L, Hendricks S, Eyden D, Arnott C, and Stevens DJ
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Background: Mask-wearing caused significant reductions in coronavirus disease 2019 (COVID-19) transmission. We aimed to determine whether face mask-wearing during exercise caused reductions in peripheral oxygen saturation (SpO
2 ) and whether it affected secondary physiological measures [end-tidal carbon dioxide (EtCO2 ), respiratory rate (RR), heart rate (HR), expired breath temperature (EBT)]. Subjective measurements included ratings of perceived exertion (RPE), ratings of perceived breathlessness (RPB), and symptomology., Methods: A randomised cross-over trial examined no mask (NM), surgical mask (SM) and a buff mask (BM). Thirty participants (30-45 years) cycled at 60% power output for 30 min in three exercise sessions, 24 h apart, within 6 days. Each session recorded all measures at resting baseline (T0), 9 min (T1), 18 min (T2), and 27 min (T3). Dependent statistical tests determined significant differences between masks and time-points., Results: SpO2 decreased for SM and BM between T0 compared to T1, T2 and T3 (all P<0.005). BM caused significant reductions at T1 and T2 compared to NM (P<0.001 and P=0.018). Significant changes in EtCO2 and EBT occurred throughout exercise and between exercise stages for all mask conditions (P<0.001). As expected for moderate intensity exercise, RR and HR were significantly higher during exercise compared to T0 (P<0.001). RPB significantly increased for each condition at each time point (P<0.001). RPE was not significant between mask conditions at any exercise stage., Conclusions: SM and BM caused a mild but sustained reduction in SpO2 at commencement of exercise, which did not worsen throughout short (<30 min) moderate intensity exercise. Level of perception was similar, suggesting healthy people can wear masks during moderate exercise and activities of daily living., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1178/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)- Published
- 2024
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42. Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria.
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Neuen BL, Heerspink HJL, Vart P, Claggett BL, Fletcher RA, Arnott C, de Oliveira Costa J, Falster MO, Pearson SA, Mahaffey KW, Neal B, Agarwal R, Bakris G, Perkovic V, Solomon SD, and Vaduganathan M
- Subjects
- Humans, Middle Aged, Canagliflozin therapeutic use, Glucagon-Like Peptide-1 Receptor Agonists, Albuminuria drug therapy, Kidney, Glucagon-Like Peptide 1 pharmacology, Glucagon-Like Peptide 1 therapeutic use, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Sodium-Glucose Transporter 2 Inhibitors adverse effects, Diabetic Nephropathies drug therapy, Diabetic Nephropathies etiology, Cardiovascular Diseases, Renal Insufficiency, Chronic
- Abstract
Background: Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known., Methods: We used data from 2 SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), 2 ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney, and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE., Results: Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% CI, 0.55-0.76) for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI, 3.0-5.7), with a number needed to treat of 23 (95% CI, 18-33). For a 50-year-old patient commencing combination therapy, estimated major adverse cardiovascular event-free survival was 21.1 years compared with 17.9 years for conventional care (3.2 years gained [95% CI, 2.1-4.3]). There were also projected gains in survival free from hospitalized heart failure (3.2 years [95% CI, 2.4-4.0]), chronic kidney disease progression (5.5 years [95% CI, 4.0-6.7]), cardiovascular death (2.2 years [95% CI, 1.2-3.0]), and all-cause death (2.4 years [95% CI, 1.4-3.4]). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for major adverse cardiovascular events (2.4 years [95% CI, 1.1-3.5]), chronic kidney disease progression (4.5 years [95% CI, 2.8-5.9]), and all-cause death (1.8 years [95% CI, 0.7-2.8])., Conclusions: In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival., Competing Interests: Disclosures Dr Neuen has received fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Alexion, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, Janssen, the limbic, and Medscape, with all honoraria paid to The George Institute for Global Health. Dr Heerspink is a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli-Lilly, Gilead, Janssen, Merck, Novo Nordisk, ProKidney, Travere Therapeutics, and Vifor Fresenius. He has received research support from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk. Dr Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, and Intellia, Rocket. Dr Arnott has received honoraria from AstraZeneca, Novo Nordisk, and Amgen. Dr Pearson is a member of the Drug Utilisation Sub-Committee of the Australian Pharmaceutical Benefits Advisory Committee. The views expressed in this article do not represent those of the committee. Dr Mahaffey has received research support from Afferent, Amgen, Apple Inc, AstraZeneca, Cardiva Medical Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, National Institutes of Health, Novartis, Sanofi, St. Jude, and Tenax, and has served as a consultant (speaker fees for continuing medical education events only) for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi Tanabe, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and University of California, San Francisco. Dr Neal has held research grants for large-scale cardiovascular outcome trials of sodium glucose co-transporter 2 from Janssen, and his institution has received consultancy, honoraria, and travel support for contributions he has made to advisory boards or the continuing medical education programs of Janssen. Dr Agarwal has received consultancy fees from Vifor, Boehringer Ingelheim, Eli Lilly, Akebia, Reata, Diamedica, Bayer, Chinook, and Vertex. Dr Bakris reports research funding, paid to the University of Chicago Medicine, from Bayer, Novo Nordisk, and Vascular Dynamics; has acted as a consultant and received personal fees from for Alnylam, Merck, and Relypsa; is an editor of the American Journal of Nephrology, Nephrology and Hypertension, and section editor of UpToDate; and is an associate editor of Diabetes Care and Hypertension Research. Dr Perkovic serves as a board director for St. Vincent’s Health Australia, George Clinical, and several medical research institutes. He has received honoraria for steering committee roles, scientific presentations, and advisory board attendance from Abbvie, Amgen, Astra Zeneca, Bayer, Baxter, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pharmalink, Pfizer, Reata, Travere, Relypsa, Roche, Sanofi, Servier, and Tricida. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. All other authors report no relevant disclosures.
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- 2024
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43. Primary and Secondary Cardiovascular and Kidney Prevention With Canagliflozin: Insights From the CANVAS Program and CREDENCE Trial.
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Sharma A, Razaghizad A, Joury A, Levin A, Bajaj HS, Mancini GBJ, Wong NC, Slee A, Ang FG, Rapattoni W, Neuen BL, Arnott C, Perkovic V, and Mahaffey KW
- Subjects
- Humans, Female, Canagliflozin therapeutic use, Canagliflozin pharmacology, Treatment Outcome, Kidney, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 drug therapy, Sodium-Glucose Transporter 2 Inhibitors adverse effects, Cardiovascular Diseases epidemiology, Cardiovascular Diseases prevention & control, Cardiovascular Diseases drug therapy, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic epidemiology
- Abstract
Background: This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention)., Methods and Results: This was a pooled participant-level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. The CANVAS Program included participants with type 2 diabetes at elevated cardiovascular risk, whereas the CREDENCE trial included participants with type 2 diabetes and albuminuric chronic kidney disease. Hazard ratios (HRs) with interaction terms were obtained from Cox regression models to estimate relative risk reduction with canagliflozin versus placebo across the primary and secondary prevention groups. We analyzed 5616 (38.9%) and 8804 (61.1%) individuals in the primary and secondary prevention subgroups, respectively. Primary versus secondary prevention participants were on average younger (62.2 versus 63.8 years of age) and more often women (42% versus 31%). Canagliflozin reduced the risk of major adverse cardiovascular events (HR, 0.84 [95% CI, 0.76-0.94]) consistently across primary and secondary prevention subgroups ( P
interaction =0.86). Similarly, no treatment effect heterogeneity was observed with canagliflozin for hospitalization for heart failure, cardiovascular death, end-stage kidney disease, or all-cause mortality (all Pinteraction >0.5)., Conclusions: Canagliflozin reduced cardiovascular and kidney outcomes with no statistical evidence of heterogeneity for the treatment effect across the primary and secondary prevention subgroups in the CANVAS Program and CREDENCE trial. Although studies on the optimal implementation of canagliflozin within these populations are warranted, these results reinforce canagliflozin's role in cardiorenal prevention and treatment in individuals with type 2 diabetes., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.- Published
- 2024
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44. The Effect of Weight Loss Through Lifestyle Interventions in Patients With Heart Failure With Preserved Ejection Fraction-A Systematic Review and Meta-Analysis of Randomised Controlled Trials.
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Lee VYJ, Houston L, Perkovic A, Barraclough JY, Sweeting A, Yu J, Fletcher RA, and Arnott C
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- Adult, Humans, Quality of Life, Stroke Volume physiology, Life Style, Body Weight, Weight Loss, Randomized Controlled Trials as Topic, Heart Failure
- Abstract
Background: Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of heart failure cases and is associated with significant morbidity and health system burden. To date, there have been limited treatment options proven to improve outcomes in these patients, with sodium glucose co-transporter 2 (SGLT2) inhibitors the first class of drug to demonstrate significant clinical benefits, including reductions in heart failure hospitalisation. Obesity is associated with all forms of heart failure and has been linked with worse clinical outcomes. Numerous reviews support the benefits of weight loss in heart failure, more specifically in patients with heart failure with reduced ejection fraction. However, the evidence in HFpEF patients is less clear. With limited pharmacotherapy options and growing support for weight loss in patients with HFpEF, this systematic review and meta-analysis aims to examine the effects of lifestyle interventions on weight loss and other health outcomes in patients with HFpEF., Methods: Web of Science, Embase, Scopus, and PubMed databases were searched to identify relevant studies up to February 2023. Included studies were randomised controlled trials (with a duration of four weeks or more) of lifestyle interventions conducted in adults with HFpEF that reported weight loss. Outcomes of interest were body weight, body mass index (BMI), blood pressure (systolic and diastolic), aerobic capacity (6-minute walk distance), New York Heart Association (NYHA) Functional Classification, self-reported health quality of life (Minnesota Living with Heart Failure Questionnaire; MLHFQ), and N-terminal pro B-Type Natriuretic Peptide (NT-proBNP) levels. Review Manager software was used to conduct random effect meta-analyses, forest plots were generated for each outcome, and between-study heterogeneity was estimated using the I
2 test statistic. Risk-of-bias assessment used the Cochrane risk-of-bias tool, and the certainty of the evidence was assessed using GRADE., Results: From 2,282 records identified, six studies with a total of 375 participants, between three to six months in duration, were included in this systematic review and meta-analysis. Lifestyle interventions consisted of diet only, exercise only, combination of diet and exercise, and education and exercise. Over a mean follow-up of 4.5 months, pooled effects of the interventions were associated with a reduction in body weight of >5kg (weight mean difference (WMD): -5.30 kg; 95% CI: -8.72 to -1.87; p=0.002), and a reduction in resting systolic (WMD: -2.98 mmHg; 95% CI: -4.20 to -1.76; p<0.001) and diastolic blood pressure (WMD: -4.51 mmHg; 95% CI: -8.39 to -0.64; p=0.02) compared with those who received usual care. Interventions also improved 6-minute walk distance (WMD: 43.63 m; 95% CI: 22.28 to 64.97; p<0.001), NYHA class (WMD: -0.54; 95% CI: -0.75 to -0.33; p<0.001), and MLHFQ score (WMD: -17.77; 95% CL: -19.00 to -16.53; p<0.001)., Conclusion: In patients with HFpEF, lifestyle intervention was associated with a significant reduction in body weight and had favourable effects on blood pressure, aerobic capacity, NYHA class, and health-related quality of life. Further research is needed in this population to examine the feasibility and durability of weight loss interventions and to examine the potential impact on hard clinical endpoints., Competing Interests: Conflict of Interest No conflict of interest to declare for VL, LH, JY, and AS. JB is supported by an NSW Health EMCR Grant for income. AS has received NHMRC and MRFF grant support. RF is supported by a PhD studentship from the Health Data Research UK–The Alan Turing InstituteWellcome Trust programme in Health Data Science. CA has received NHMRC, MRFF, and NSW Health grant support. CA has received honoraria from Astra Zeneca, Novo Nordisk, and Amgen. These fundings have no role in the production of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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45. Timing of statistical benefit of canagliflozin in patients with type 2 diabetes for cardiovascular and heart failure outcomes: Insights from the CANVAS Program and CREDENCE trial.
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Sharma A, Marques P, Neuen BL, Fletcher RA, Slee A, Rapattoni W, Ang FG, Arnott C, Levin A, Verma S, Perkovic V, and Mahaffey KW
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- Humans, Canagliflozin therapeutic use, Clinical Trials as Topic, Cardiovascular Diseases epidemiology, Cardiovascular Diseases prevention & control, Cardiovascular System, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Heart Failure drug therapy, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
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- 2024
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46. Treatment effect of canagliflozin for patients on therapy for heart failure: Pooled analysis of the CANVAS program and CREDENCE trial.
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Jain SS, Yu J, Arnott C, Neal B, Perkovic V, Neuen BL, Jardine M, and Mahaffey KW
- Subjects
- Humans, Canagliflozin therapeutic use, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 epidemiology, Cardiovascular Diseases, Heart Failure diagnosis, Heart Failure drug therapy, Heart Failure chemically induced, Myocardial Infarction drug therapy
- Abstract
Background: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that has been shown to reduce cardiovascular events in diabetic patients with and without heart failure (HF). Whether the clinical benefits and safety profile of canagliflozin are different in those on a beta blocker and an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (BB + RAASi) is unknown., Methods: We pooled participants with HF at baseline from the CANVAS Program and CREDENCE trial and assessed major adverse cardiovascular events and its components; hospitalization for heart failure (HHF); HHF or CV death; all-cause mortality; a renal composite; and a combined renal and CV composite., Results: Of 14,543 participants, 2113 had HF at baseline, and 1280 were on BB + RAASi. In those with a history of HF, participants on BB + RAASi therapy were more likely to have coronary atherosclerotic disease (82 vs 72%, p < 0.001), history of myocardial infarction (42 vs 29%, p < 0.001), higher mean body mass index (34 vs 32 kg/m
2 , p < 0.001), and lower mean estimated glomerular filtration rate (67 vs 70 mL/min/1.73 m2 , p < 0.01). They were also more likely to be on insulin, a statin, antithrombotic agent, and a diuretic (all p < 0.001). In unadjusted analysis and when adjusted for selected baseline factors, there was no heterogeneity in canagliflozin treatment effect except for HHF/CV death in those on baseline BB + RAASi vs. those not on baseline BB + RAASi (Pheterogeneity = 0.02)., Conclusion: Canagliflozin mostly improved CV and kidney outcomes in participants with a history of HF irrespective of use of BB + RAASi at baseline, with possible greater benefit on HHF/CV death in participants on BB + RAASi., Competing Interests: Declaration of Competing Interest S.S. Jain has no financial disclosures. J. Yu has no financial disclosures. C. Arnott is supported by a Medical Research Future Fund Priority Investigator Grant and NSW Health EMCR Grant. She has received honoraria from AstraZeneca and Amgen B. Neal has received grants for CANVAS and CREDENCE, advisory board, honoraria, travel reimbursement all from Janssen and all paid to his institution. He has received research support from the Australian National Health and Medical Research Council Principal Research Fellowship and from Janssen, and has served on advisory boards and/or has had involvement in continuing medical education programs for Janssen, with any consultancy, honoraria, or travel support paid to his institution. He also notes institutional relationships with AbbVie, Actelion and Janssen. V. Perkovic B. Neuen has received fees for advisory boards, steering committee roles and travel support from AstraZeneca, Bayer and Janssen, with all honoraria paid to his employer. M. Jardine is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro and MSD. She has received advisory, steering committee and/or speaker fees from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Medical, Chinook, CSL, Janssen, Medscape, MSD, Roche and Vifor; with any consultancy, honoraria or travel support are paid to her institution. K.W. Mahaffey's financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey., (Copyright © 2023. Published by Elsevier B.V.)- Published
- 2024
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47. A life-course approach to tackling noncommunicable diseases in women.
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Carcel C, Haupt S, Arnott C, Yap ML, Henry A, Hirst JE, Woodward M, and Norton R
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- Female, Humans, Cardiovascular Diseases epidemiology, Cardiovascular Diseases prevention & control, Women's Health, Neoplasms epidemiology, Neoplasms prevention & control, Noncommunicable Diseases epidemiology, Noncommunicable Diseases prevention & control
- Abstract
Women's health has been critically underserved by a failure to look beyond women's sexual and reproductive systems to adequately consider their broader health needs. In almost every country in the world, noncommunicable diseases are the leading causes of death for women. Among these, cardiovascular disease (including heart disease and stroke) and cancer are the major causes of mortality. Risks for these conditions exist at each stage of women's lives, but recognition of the unique needs of women for the prevention and management of noncommunicable diseases is relatively recent and still emerging. Once they are diagnosed, treatments for these diseases are often costly and noncurative. Therefore, we call for a strategic, innovative life-course approach to identifying disease triggers and instigating cost-effective measures to minimize exposure in a timely manner. Prohibitive barriers to implementing this holistic approach to women's health exist in both the social arena and the medical arena. Recognizing these impediments and implementing practical approaches to surmounting them is a rational approach to advancing health equity for women, with ultimate benefits for society as a whole., (© 2024. Springer Nature America, Inc.)
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- 2024
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48. Autoantibodies to Erythropoietin Receptor and Clinical Outcomes in Patients With Type 2 Diabetes and CKD: A Post Hoc Analysis of CREDENCE Trial.
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Koshino A, Neuen BL, Oshima M, Toyama T, Hara A, Arnott C, Neal B, Jardine M, Badve SV, Mahaffey KW, Pollock C, Hansen MK, Wada T, and Heerspink HJL
- Abstract
Introduction: Autoantibodies to erythropoietin receptor (anti-EPOR antibodies) have been identified in patients with various kidney diseases. However, data in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) is limited. We assessed the prevalence of anti-EPOR antibodies and their association with clinical outcomes in this population., Methods: The CREDENCE randomized patients with T2D and CKD to canagliflozin or placebo. Serum anti-EPOR antibodies, the exposure of interest, were measured using enzyme-linked immunosorbent assay. The primary outcome was doubling of serum creatinine, end-stage kidney disease, or death from kidney or cardiovascular (CV) causes. Secondary outcomes included CV and all-cause mortality. Multivariable Cox-regression models estimated associations between anti-EPOR antibodies and outcomes. The effects of canagliflozin on hemoglobin and hematocrit, stratified by the presence of anti-EPOR antibodies were assessed with a repeated measures mixed effects model., Results: Of 2600 participants with available biosamples, 191 (7.3%) were positive for anti-EPOR antibodies. Higher baseline anti-EPOR antibodies were associated with increased risk of primary outcome (hazard ratio [HR] per 1-SD increase = 1.12, 95% confidence interval [CI] = 1.01-1.24, P = 0.04), with CV death (HR = 1.27, 95% CI = 1.08-1.48, P < 0.01) and all-cause mortality (HR = 1.26, 95% CI = 1.11-1.43, P < 0.01). During follow-up, canagliflozin, compared to placebo, increased hemoglobin and hematocrit by 7.0 g/l (95% CI = 6.2-7.9) and 2.4% (2.2-2.7), respectively. These effects were consistent across patients with and without anti-EPOR antibodies ( P -interaction = 0.24 and 0.36, respectively)., Conclusion: In patients with T2D and CKD, anti-EPOR antibodies were associated with the composite kidney and CV outcome, as well as CV and all-cause mortality. Canagliflozin increased hemoglobin and hematocrit regardless of anti-EPOR antibodies., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)
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- 2023
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49. The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial.
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Yu J, Sweeting AN, Gianacas C, Houston L, Lee V, Fletcher RA, Perkovic V, Li Q, Neuen BL, Berwanger O, Heerspink HJL, de Zeeuw D, and Arnott C
- Subjects
- Adult, Humans, Canagliflozin adverse effects, Body Mass Index, Albuminuria drug therapy, Body Weight, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 chemically induced, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Cardiovascular Diseases epidemiology, Cardiovascular Diseases prevention & control, Cardiovascular Diseases chemically induced, Myocardial Infarction drug therapy
- Abstract
Aim: To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population-specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial., Methods: Individual participant data were pooled and analysed in subgroups according to population-specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed-effect models were used., Results: A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (P
heterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95)., Conclusions: The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population-specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial., (© 2023 John Wiley & Sons Ltd.)- Published
- 2023
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50. Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials.
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Fletcher RA, Jongs N, Chertow GM, McMurray JJV, Arnott C, Jardine MJ, Mahaffey KW, Perkovic V, Rockenschaub P, Rossing P, Correa-Rotter R, Toto RD, Vaduganathan M, Wheeler DC, Heerspink HJL, and Neuen BL
- Subjects
- Humans, Renin-Angiotensin System, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Angiotensin-Converting Enzyme Inhibitors pharmacology, Angiotensin Receptor Antagonists therapeutic use, Angiotensin Receptor Antagonists pharmacology, Creatinine, Double-Blind Method, Albumins pharmacology, Randomized Controlled Trials as Topic, Sodium-Glucose Transporter 2 Inhibitors pharmacology, Diabetes Mellitus, Type 2 drug therapy, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic drug therapy, Renal Insufficiency, Chronic chemically induced
- Abstract
Significance Statement: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD., Background: Strategies to enable persistent use of renin-angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated., Methods: We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups., Results: During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials ( P -heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P -heterogeneity = 0.009)., Conclusions: In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade., Clinical Trial Registry Name and Registration Number: ClinicalTrials.gov, NCT02065791 and NCT03036150 ., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_11_21_JASN0000000000000248.mp3., (Copyright © 2023 by the American Society of Nephrology.)
- Published
- 2023
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