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Significant advances have been made in artificial intelligence technology in recent years. Many health care applications have been investigated to assist clinicians and the technology is close to being integrated into routine clinical practice. The high prevalence of cardiac disease in Australia places overwhelming demands on the existing health care system, challenging its capacity to provide quality patient care. Artificial intelligence has emerged as a promising solution. This discussion paper provides an Australian perspective on the current state of artificial intelligence in cardiology, including the benefits and challenges of implementation. This paper highlights some current artificial intelligence applications in cardiology, while also detailing challenges such as data privacy, ethical considerations, and integration within existing health infrastructures. Overall, this paper aims to provide insights into the potential benefits of artificial intelligence in cardiology, while also acknowledging the barriers that need to be addressed to ensure safe and effective implementation into an Australian health system. [ABSTRACT FROM AUTHOR]

Aim: In the CANVAS Program and CREDENCE trials, the sodium glucose co‐transporter 2 inhibitor canagliflozin reduced the risk of cardiovascular and kidney events in patients with type 2 diabetes. The current study analysed a pooled population to ascertain the kidney protection provided by canagliflozin across the full spectrum of kidney parameters. Methods: This post‐hoc pooled analysis of the CANVAS Program (N = 10 142) and CREDENCE trial (N = 4401), assessed the risk of the primary kidney composite (doubling of serum creatinine, end‐stage kidney disease, renal death), in all patients and subgroups defined by baseline estimated glomerular filtration rate (<30, 30 to <45, 45 to <60 and ≥60 ml/min/1.73 m2), albuminuria [<30, 30‐300, >300 mg/g (<3.39, 3.39‐33.9, >33.9 mg/mmol)] and 2012 Kidney Disease: Improving Global Outcomes (KDIGO) classification of chronic kidney disease (low/moderate, high and very high risk). Results: In the overall population, the risk for the primary kidney composite outcome was 37% lower in the canagliflozin group versus placebo (HR: 0.63; 95% CI: 0.53, 0.77; p <.001). There was no evidence of heterogeneity in the kidney protective effects of canagliflozin across a range of kidney risks when stratified by baseline estimated glomerular filtration rate, albuminuria or KDIGO risk category (all pinteraction >.05). A statistically significant risk reduction of the primary kidney composite outcome was sustained by approximately 18 months after randomization. Conclusions: These results emphasize a critical role of canagliflozin in kidney protection across a broad spectrum of participants with type 2 diabetes with varying levels of kidney function. [ABSTRACT FROM AUTHOR]

Aims: To assess whether the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin affects risk of non‐genital skin and soft tissue infections (SSTIs). Materials and methods: We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator‐reported adverse events were assessed by two blinded authors following predetermined criteria for non‐genital SSTIs. Risks of non‐genital SSTIs, overall and within prespecified subgroups, and risk of non‐genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non‐genital SSTIs were assessed using multivariable Cox regression models. Results: Overall, 903 of 14 531 participants (6%) experienced non‐genital SSTIs over a median follow‐up of 26 months. No difference was observed in non‐genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person‐years vs. 23.9 events/1000 person‐years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85‐1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non‐genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94‐1.19 [P = 0.32] and HR 1.18, 95% CI 0.88‐1.60 [P = 0.27], respectively). Baseline factors independently associated with non‐genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. Conclusions: Canagliflozin did not affect risk of non‐genital SSTIs or non‐genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor‐mediated change in skin microenvironment is unlikely to have meaningful clinical consequences. [ABSTRACT FROM AUTHOR]

Similarly, Barraclough et al. showed that canagliflozin consistently decreased the risk of major CV and kidney outcomes in patients with T2D, regardless of PAD status at baseline. The MACE benefit with canagliflozin in individuals with T2D, CKD and PAD translates into an ARR of -26.0 events/1000 patients over 2.5 years versus placebo. [Extracted from the article]

In addition, generalizability of the results may be limited to individuals with previous CV events, high CV risk or nephropathy, similar to the patients enrolled in the CANVAS programme and CREDENCE trial. This post-hoc analysis assessed the effects of canagliflozin versus placebo on CV and kidney outcomes in patients with T2DM and high CV risk, and/or chronic kidney disease according to baseline treatment target achievement and risk factors. Keywords: canagliflozin; cardiovascular disease; diabetic nephropathy; type 2 diabetes EN canagliflozin cardiovascular disease diabetic nephropathy type 2 diabetes 2038 2042 5 06/06/23 20230701 NES 230701 BACKGROUND Management of type 2 diabetes mellitus (T2DM), a progressive metabolic disorder associated with substantial cardiovascular (CV) and kidney complications, includes risk factor optimization of glucose, blood pressure (BP) and lipids. [Extracted from the article]

Cardiovascular diseases (CVD), including coronary artery disease (CAD), continue to be the leading cause of global mortality among women. While traditional CVD/CAD prevention tools play a significant role in reducing morbidity and mortality among both men and women, current tools for preventing CVD/CAD rely on traditional risk factor-based algorithms that often underestimate CVD/CAD risk in women compared with men. In recent years, some studies have suggested that breast arterial calcifications (BAC), which are benign calcifications seen in mammograms, may be linked to CVD/CAD. Considering that millions of women older than 40 years undergo annual screening mammography for breast cancer as a regular activity, innovative risk prediction factors for CVD/CAD involving mammographic data could offer a gender-specific and convenient solution. Such factors that may be independent of, or complementary to, current risk models without extra cost or radiation exposure are worthy of detailed investigation. This review aims to discuss relevant studies examining the association between BAC and CVD/CAD and highlights some of the issues related to previous studies' design such as sample size, population types, method of assessing BAC and CVD/CAD, definition of cardiovascular events, and other confounding factors. The work may also offer insights for future CVD risk prediction research directions using routine mammograms and radiomic features other than BAC such as breast density and macrocalcifications. [ABSTRACT FROM AUTHOR]

Background: Sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of kidney and heart failure events independent of glycemic effects. We assessed whether initiation of the SGLT2 inhibitor canagliflozin guided by multivariable predicted risk based on clinical characteristics and novel biomarkers is more efficient to prevent clinical outcomes compared to a strategy guided by HbA1c or urinary-albumin-creatinine ratio (UACR) alone. Methods: We performed a post-hoc analysis of the CANVAS trial including 3713 patients with available biomarker measurements. We compared the number of composite kidney (defined as a sustained 40% decline in eGFR, chronic dialysis, kidney transplantation, or kidney death) and composite heart failure outcomes (defined as heart failure hospitalization or cardiovascular (CV) death) prevented per 1000 patients treated for 5 years when canagliflozin was initiated in patients according to HbA1c ≥ 7.5%, UACR, or multivariable risk models consisting of: (1) clinical characteristics, or (2) clinical characteristics and novel biomarkers. Differences in the rates of events prevented between strategies were tested by Chi2-statistic. Results: After a median follow-up of 6.1 years, 144 kidney events were recorded. The final clinical model included age, previous history of CV disease, systolic blood pressure, UACR, hemoglobin, body weight, albumin, estimated glomerular filtration rate, and randomized treatment assignment. The combined biomarkers model included all clinical characteristics, tumor necrosis factor receptor-1, kidney injury molecule-1, matrix metallopeptidase-7 and interleukin-6. Treating all patients with HbA1c ≥ 7.5% (n = 2809) would prevent 33.0 (95% CI 18.8 to 43.3) kidney events at a rate of 9.6 (95% CI 5.5 to 12.6) events prevented per 1000 patients treated for 5 years. The corresponding rates were 5.8 (95% CI 3.4 to 7.9), 16.6 (95% CI 9.5 to 22.0) (P < 0.001 versus HbA1c or UACR approach), and 17.5 (95% CI 10.0 to 23.0) (P < 0.001 versus HbA1c or UACR approach; P = 0.54 versus clinical model). Findings were similar for the heart failure outcome. Conclusion: Initiation of canagliflozin based on an estimated risk-based approach prevented more kidney and heart failure outcomes compared to a strategy based on HbA1c or UACR alone. There was no apparent gain from adding novel biomarkers to the clinical risk model. These findings support the use of risk-based assessment using clinical markers to guide initiation of SGLT2 inhibitors in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Hypertensive disorders of pregnancy have longer-term implications, increasing women's lifetime cardiovascular disease risk. The Blood Pressure Postpartum study is a multi-centre randomised three-arm trial of interventions, ranging in intensity and including education and lifestyle coaching, to support women to maintain or adopt healthy eating and physical activity during the first postpartum year. This qualitative sub-study nested within the main trial aimed to investigate whether and how women adopted healthy behaviours after a pregnancy complicated by a hypertensive disorder.Methods: Semi-structured telephone interviews were recorded, transcribed and analysed thematically, following Braun and Clarke principles. They explored behaviour change among new mothers following their hypertensive pregnancy, and the intervention's effect on their capacity and motivation to pursue healthy lifestyles.Results: Thirty-four women from all three trial arms participated at 10-12 months postpartum. The three main themes were 1) Awareness of cardiovascular risk: some did not acknowledge the health risks, whereas others embraced this information. 2) Sources of motivation: while the majority were motivated to make a concerted effort to adapt their health behaviour, motivation often centred on their baby and family rather than their own needs. 3) Sustaining behaviour change with a new baby: women in the more intensive intervention arm demonstrated increased recognition of the importance of reducing cardiovascular health risks, with greater motivation and guidance to change their health behaviour. There was minimal evidence of crossover amongst groups, with women largely accepting their randomised level of intervention and not seeking additional help when randomised to minimal intervention.Conclusions: Among women participating in an early post-hypertensive disorders of pregnancy randomised controlled trial aimed at improving their cardiovascular disease risk profile, the majority recognised the future health risks and appeared motivated to improve their lifestyle, particularly women in the highest-intensity intervention group. This highlights the importance of structured support to assist women embrace healthy lifestyles especially during the challenges of new parenthood.Trial Registration: The Blood Pressure Postpartum study was prospectively registered as a clinical trial with the Australian New Zealand Clinical Trials Registry (anzctr.org.au) on 13 December 2018 (registration number: ACTRN12618002004246). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Large-scale outcome trials of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have identified consistent effects on major adverse cardiovascular events, heart failure, and progression of kidney disease. However, the magnitude of effects on cardiovascular and all-cause death appeared to vary between some of the studies. We explored the impact of differences in trial methodologies, participant characteristics, types of deaths, follow-up duration, effects on intermediate markers of risk, and drug selectivity for SGLT2 on the magnitude of the protective effect against fatal events achieved in the 4 trials. The trial populations differed substantively in the proportions with baseline atherosclerotic cardiovascular disease history (99.2% in EMPA-REG OUTCOME to 40.6% in DECLARE-TIMI 58), and macroalbuminuria (88.0% in CREDENCE to 7.6% in the CANVAS Program). Meta-regression analyses identified no clear effect of these (both P > 0.09) or other participant characteristics on mortality benefits (all P > 0.55). Other differences between the trials (duration, selectivity of the SGLT2 inhibitor, or effects on intermediate markers of risk) also did not explain the heterogeneity in effects on mortality observed (all P > 0.30). No clear explanation for the statistical evidence of heterogeneity in effects of SGLT2 inhibition on fatal outcomes between the trials could be identified. While the analyses had limited statistical power, these results raise the possibility that the observed variations in treatment effects on fatal outcomes between trials may be at least partly due to chance. • Heterogeneity in mortality was observed in large-scale trials of SGLT2 inhibitors. • Meta-regression analyses found no explanation for variations in fatal outcomes. • Variations in SGLT2 inhibitor effects on fatal outcomes may be partly due to chance. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death in Australian women, as well as men, with clear disparities in treatment and outcomes between the sexes. Moreover, disease pathophysiology differs between the sexes, with women more likely to suffer from microvascular coronary disease, endothelial dysfunction and heart failure with preserved ejection fraction, as compared to men, who are more likely to experience macrovascular disease or heart failure with reduced ejection fraction. Evidence suggests that both traditional and novel cardiovascular risk factors are often under-recognised and under-treated in women. Certain 'traditional' risk factors, including diabetes mellitus and smoking, may also portend a greater risk of cardiovascular disease in women than men. Furthermore, a number of female-specific risk factors have been identified as increasing the risk of cardiovascular disease in women, including pre-term delivery, pre-eclampsia, gestational diabetes, and polycystic ovary syndrome. Currently, these factors are not included in primary prevention risk stratification tools, nor are they routinely considered in a cardiovascular assessment at a clinical level. This represents a missed opportunity, as early identification may allow for risk factor modification and possible amelioration of the disease burden. This review explores the role of traditional, sex-specific and novel risk factors for cardiovascular disease in women, in addition to pathophysiological differences between the sexes, and contributing societal and behavioural factors. These differences argue strongly for a 'precision medicine' approach to cardiovascular disease that includes sex as a key component. [ABSTRACT FROM AUTHOR]

Background: Despite improvements in diagnostic and therapeutic interventions to combat cardiovascular disease (CVD) in recent decades, there are significant ongoing access gaps and sex disparities in prevention that have not been adequately quantified in China.Methods: A representative, cross-sectional, community-based survey of adults (aged ≥45 years) was conducted in 7 geographic regions of China between 2014 and 2016. Logistic regression models were used to determine sex differences in primary and secondary CVD prevention, and any interaction by age, education level, and area of residence. Data are presented as adjusted odds ratios (ORs) and 95% CIs.Results: Of 47 841 participants (61.3% women), 5454 (57.2% women) had established CVD and 9532 (70.5% women) had a high estimated 10-year CVD risk (≥10%). Only 48.5% and 48.6% of women and 39.3% and 59.8% of men were on any kind of blood pressure (BP)-lowering medication, lipid-lowering medication, or antiplatelet therapy for primary and secondary prevention, respectively. Women with established CVD were significantly less likely than men to receive BP-lowering medications (OR, 0.79 [95% CI, 0.65-0.95]), lipid-lowering medications (OR, 0.69 [95% CI, 0.56-0.84]), antiplatelets (OR, 0.53 [95% CI, 0.45-0.62]), or any CVD prevention medication (OR, 0.62 [95% CI, 0.52-0.73]). Women with established CVD, however, had better BP control (OR, 1.31 [95% CI, 1.14-1.50]) but less well-controlled low-density lipoprotein cholesterol (OR, 0.66 [95% CI, 0.57-0.76]), and were less likely to smoke (OR, 13.89 [95% CI, 11.24-17.15]) and achieve physical activity targets (OR, 1.92 [95% CI, 1.61-2.29]). Conversely, women with high CVD risk were less likely than men to have their BP, low-density lipoprotein cholesterol, and bodyweight controlled (OR, 0.46 [95% CI, 0.38-0.55]; OR, 0.60 [95% CI, 0.52-0.69]; OR, 0.55 [95% CI, 0.48-0.63], respectively), despite a higher use of BP-lowering medications (OR, 1.21 [95% CI, 1.01-1.45]). Younger patients (<65 years) with established CVD were less likely to be taking CVD preventive medications, but there were no sex differences by area of residence or education level.Conclusions: Large and variable gaps in primary and secondary CVD prevention exist in China, particularly for women. Effective CVD prevention requires an improved overall nationwide strategy and a special emphasis on women with established CVD, who have the greatest disparity and the most to benefit. [ABSTRACT FROM AUTHOR]

'Food is medicine' strategies aim to integrate food-based nutrition interventions into healthcare systems and are of growing interest to healthcare providers and policy makers. 'Medically Tailored Meals' (MTM) is one such intervention, which involves the 'prescription' by healthcare providers of subsidized, pre-prepared meals for individuals to prevent or manage chronic conditions, combined with nutrition education. This study will test the efficacy of an MTM program in Australia among participants with type 2 diabetes (T2D) and hyperglycemia, who experience difficulties accessing and eating nutritious food. This study will be a two-arm parallel trial (goal n = 212) with individuals randomized in a 1:1 ratio to a MTM intervention group or a control group (106 per arm). Over 26 weeks, the intervention group will be prescribed 20 MTM per fortnight and up to 3 sessions with an accredited dietitian. Controls will continue with their usual care. The primary outcome is glycated hemoglobin (HbA1c, %) and secondary outcomes include differences in blood pressure, blood lipids and weight, all measured at 26 weeks. Process and economic data will be analyzed to assess the feasibility, acceptability, scalability, and cost-effectiveness of the intervention. Recruitment commenced in the first quarter of 2023, with analyses and results anticipated to be available by March 2025. Few randomized controlled trials have assessed the impact of MTM on clinical outcomes. This Australian-first trial will generate robust data to inform the case for sustained, large-scale implementation of MTM to improve the management of T2D among vulnerable populations. ANZCTR: ACTRN12622000852752. Protocol version: Version 1.1, July 2023. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Our aim was to assess sex differences in the efficacy of angiotensin receptor blockers (i.e. losartan and irbesartan) on kidney and cardiovascular outcomes in individuals with type 2 diabetes and diabetic kidney disease., Methods: Data from the Angiotensin II Antagonist Losartan Study (RENAAL) and Irbesartan type II Diabetic Nephropathy Trial (IDNT) were used. The kidney outcome was time to first event of end-stage kidney disease or doubling of serum creatinine. The cardiovascular outcome was time to first event of a composite of stroke, myocardial infarction, cardiovascular death or hospitalisation for heart failure. Sex differences were assessed by a sex × treatment interaction term in Cox proportional hazards models., Results: Included were 1737 male participants and 924 female participants. The beneficial effect of angiotensin receptor blockers on the kidney outcome was similar between male and female participants (HR in male participants 0.72 [95% CI 0.59, 0.86] vs HR in female participants 0.86 [95% CI 0.69, 1.06]; sex × treatment interaction HR 1.19 [95% CI 0.89, 1.59]). For the cardiovascular outcome, angiotensin receptor blockers lowered the risk in male but not in female participants (HR in male participants 0.81 [95% CI 0.69, 0.95] vs HR in female participants 1.11 [95% CI 0.88, 1.40]; sex × treatment interaction HR 1.37 [95% CI 1.03, 1.82])., Conclusions/interpretation: This study in individuals with type 2 diabetes and diabetic kidney disease suggests that the beneficial effects of angiotensin receptor blockers are similar in male and female participants for the kidney outcome but not for the cardiovascular outcome. More attention to sex differences in angiotensin receptor blockers' efficacy and underlying mechanisms of differences in response is needed., Trial Registration: ClinialTrials.gov NCT00308347., Competing Interests: Data availability statement: The data used for this study are available upon reasonable request to the corresponding author. Funding: This study was conducted in the context of the BEAt-DKD project. This project received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115974. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and JDRF. Any dissemination of results reflects only the authors’ view; the JU is not responsible for any use that may be made of the information this study contains. Funding was also obtained from European Union’s HORIZON Research and Innovation Actions (HORIZON-HLTH-2022-TOOL-11-01 - Tools and technologies for a healthy society) undertaking under grant agreement no. 101095146. The views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. SAEP is supported by a Vidi Fellowship from the Dutch Organisation for Health Research and Development (ZonMW) (09150172010050). HJLH is supported by Vidi grant from the Netherlands Organisation for Scientific Research (917.15.306). Authors’ relationships and activities: DHvR has acted as a consultant and received honoraria from Boehringer Ingelheim and Lilly, Merck, Bayer and AstraZeneca and has received research operating funds from Boehringer Ingelheim-Lilly Diabetes Alliance, AstraZeneca and Merck. CA has received honoraria from Astra Zeneca, Novo Nordisk and Amgen. AAV has acted as a consultant for AnaCardio, Bayer, BMS, Boehringer Ingelheim, Corteria, Cytokinetics, Eli Lilly, Merck, Novartis, Novo Nordisk and Roche Diagnostics. HJLH is a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, DImerix, Eli Lilly, Fresenius, Gilead, Janssen, NovoNordisk, Novartis and Travere Therapeutics. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: STdV and MJP contributed to the analyses, to the interpretation of the data and writing of the manuscript. SCT conducted the analyses. SCT, SAEP, DHvR, CA, AAV, PGMM and PD contributed to the interpretation of the data and writing of the manuscript. HJLH provided the data and contributed to the interpretation of the data and writing of the manuscript. All authors read and approved the manuscript. HJLH is responsible for the integrity of the work as a whole., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Insulin is a mainstay treatment for diabetes, but its use is associated with weight gain and hypoglycaemia. Data on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on insulin use in people with chronic kidney disease (CKD) is limited., Methods: We conducted a post-hoc analysis of the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. Effects of canagliflozin versus placebo on insulin use (initiation, dose intensification, reduction and discontinuation) in people with CKD and type 2 diabetes were evaluated using Cox regression models. The primary outcome was insulin initiation or >25% insulin dose intensification (in those not receiving and receiving insulin at baseline, respectively). Effects on kidney, cardiovascular and safety outcomes by baseline insulin use were also assessed., Results: Among 4401 participants, 2884 (65.5%) were receiving insulin at baseline; these participants were more likely to have lower estimated glomerular filtration rate, higher albuminuria and longer duration of diabetes (all P<0.001). Over a median on-treatment period of 2.0 years, canagliflozin reduced the need for insulin initiation or >25% dose intensification by 19% compared to placebo (HR 0.81, 95% CI 0.71-0.93), irrespective of baseline kidney function or albuminuria (both P-interaction>0.10). Sustained insulin dose reductions of >50% were achieved more frequently with canagliflozin than placebo (HR 1.49, 95% CI 1.15-1.91), although no difference in insulin discontinuation was observed between treatment arms. Effects of canagliflozin on kidney, cardiovascular and safety outcomes were consistent regardless of baseline insulin use (all P-interaction>0.05)., Conclusions: In CKD and type 2 diabetes, canagliflozin reduces insulin use with consistent effects regardless of baseline kidney function. This supports the use of canagliflozin in people with CKD, not only for end organ protection, but also to improve glycaemic control and reduce exposure to insulin and its associated adverse effects., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Peripheral arterial disease (PAD) is characterised by atherosclerotic stenosis or occlusion of arteries that leads to reduced blood flow to the limbs. PAD is associated with a very high rate of cardiovascular morbidity and mortality making the health and economic burden of PAD substantial. Despite high-quality evidence and international guidelines recommending conservative medical management of risk factors, and exercise and lifestyle interventions, surgical revascularisation (open or endovascular) remains the main treatment for PAD. Alarmingly, up to one-third of patients do not receive best medical therapy after revascularisation surgery despite evidence supporting this treatment reduces cardiovascular events. Due to the considerable health burden that PAD presents, this manuscript aims to identify gaps in care and clinical research in PAD across Australia and proposes potential collaborative solutions. In Australia, there is significant disparity in care between rural/regional and metropolitan communities. These gaps are exacerbated by inequitable access to services across Australia, particularly for First Nation Australians, culturally and linguistically diverse groups and those living in regional and remote areas. This review identifies unmet needs for patients with PAD that are multifaceted, spanning from improved understanding of disease mechanisms, diagnostic tools for risk stratification and personalised therapy, to a paucity of medical and rehabilitation therapies for symptoms or prevention of cardiovascular complications. Furthermore, there are opportunities for national and international registries to optimise clinical trial quality and outcomes. Strategies should be applied to improve implementation of optimal medical therapy in PAD which will improve quality of life, reduce health care costs, and prevent secondary complications, limb loss, and mortality across Australia's diverse population., Competing Interests: Declaration of Competing Interests There are no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry., Methods: Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for females and males to find the sex-specific hazard ratio (HR)., Results: After a mean follow-up of 6.4 years, females had a higher risk of heart failure (HR, 1.51 [95% CI, 1.21-1.88]; P =0.0003) but a lower risk of atrial fibrillation (HR, 0.74 [95% CI, 0.59-0.93]; P <0.0001) and ventricular arrhythmia (HR, 0.60 [95% CI, 0.38-0.94]; P =0.027) than males. No sex difference was observed for death ( P =0.84). Sarcomere-positive males had higher heart failure (HR, 1.34 [95% CI, 1.06-1.69]) and death risks (HR, 1.48 [95% CI, 1.08-2.04]) not seen in females (HR, 0.85 [95% CI, 0.66-1.08] versus HR, 0.86 [95% CI, 0.71-1.21]). MYBPC3 variants lowered heart failure risk in females (HR, 0.56 [95% CI, 0.41-0.77]) but not in males (HR, 1.29 [95% CI, 0.99-1.67]). A sex difference appeared in moderate (4% to <6%) versus low risk (<4%) European Society of Cardiology hypertrophic cardiomyopathy risk score, with females at moderate risk more prone to ventricular arrhythmia (HR, 3.57 [95% CI, 1.70-7.49]), unobserved in males (HR, 1.13 [95% CI, 0.63-2.03])., Conclusions: We found that clinical and genetic factors contributing to adverse outcomes in hypertrophic cardiomyopathy affect females and males differently. Thus, research to inform sex-specific management of hypertrophic cardiomyopathy could improve outcomes for both sexes., Competing Interests: J.I. receives research grant support from Bristol Myers Squibb. J.R. is a consultant for Bayer, Merk, Bristol Myers Squibb, and Cytokinetics. C.A. has received honoraria from Astra Zeneca and Amgen. N.K.L. is a consultant for Bristol Myers Squibb, Cytokinetics, Pfizer, Tenaya, and Sarepta and receives grant support from Pfizer. C.Y.H. is a consultant for Bristol Myers Squibb, Cytokinetics, and Viz.ai and receives research support from Bristol Myers Squibb, Cytokinetics, and Pfizer. D.A. is a consultant for Rocket Pharmaceuticals. V.N.P. receives research funding from BioMarin and consults for Nuevocor and Viz.ai. S.M.D. is a consultant for Tenaya and Lexeo. S.S. is a consultant for Bristol Myers Squibb and Cytokinetics. M.M.is a consultant for Bristol Myers Squibb and Cytokinetics. J.S.W receives research support from Bristol Myers Squibb, and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics. A.S.H. is a consultant or receives research funding from Tenaya and Lexeo. All other authors report no conflicts.

Aims: The sodium-glucose cotransporter 2 inhibitor canagliflozin reduces the risk of heart failure (HF) hospitalization or cardiovascular death and chronic kidney disease (CKD) progression among patients with type 2 diabetes at high cardiovascular risk or with CKD. Patients with type 2 diabetes commonly have coexisting HF or CKD that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized., Methods and Results: In this participant-level pooled analysis of the CREDENCE and CANVAS trials (not including CANVAS-R), 1454/8731 (16.7%) patients were treated with loop diuretics at baseline. Over a median on-treatment follow-up of 2.2 years, 1264 patients (14.5%) required oral loop diuretic intensification, of whom 981 (77.6%) required initiation of oral loop diuretics and 283 (22.4%) required oral loop diuretic dose increase. Patients requiring oral loop diuretic intensification experienced rates of subsequent HF hospitalization, CKD progression and mortality that were 29.5-, 5.0-, and 3.5-fold higher, respectively, than those not requiring oral loop diuretic intensification. Treatment with canagliflozin reduced the need for oral loop diuretic intensification by 41% (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.53-0.66) including both new diuretic initiation (HR 0.65; 95% CI 0.57-0.74) and diuretic dose increase (HR 0.42; 95% CI 0.33-0.54). Inclusion of oral diuretic intensification in an expanded HF composite outcome inclusive of cardiovascular death and HF hospitalization approximately double the number of events, with similar observed treatment effect (HR 0.64; 95% CI 0.58-0.70)., Conclusion: Among high-risk patients with type 2 diabetes, new oral loop diuretic intensification was frequent and portended adverse prognostic significance. Treatment with canagliflozin significantly reduced the need for loop diuretic intensification., Clinical Trial Registration: CANVAS (Canagliflozin Cardiovascular Assessment Study), ClinicalTrials.gov NCT01032629; CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), ClinicalTrials.gov NCT02065791., (© 2025 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been proven to prevent decline in kidney function and failure. Whether SGLT2i affect the risk of contrast-associated acute kidney injury (CA-AKI) remains uncertain., Methods: Use of SGLT2i was assessed in consecutive diabetics undergoing coronary angiography (CA) or percutaneous coronary intervention (PCI) from January 2020 to May 2023 at a tertiary hospital in Chongqing, China. Propensity-matched analysis was used to adjust for baseline variables. CA-AKI was defined by the Acute Kidney Injury Network (AKIN) as creatinine increase ≥ 0.3 mg/dl (26.4 μmol/l), or a percentage increase in the serum creatinine level of ≥ 50%., Results: A total of 604 new users of SGLT2i, and 298 chronic users of SGLT2i were matched with non-users. New use of SGLT2i was not associated with an increased incidence of AKIN-defined CA-AKI (OR 1.60; 95% CI 0.97-2.63; p = 0.065), in-hospital new-onset dialysis (OR 0.50; 95% CI 0.09-2.73; p = 0.422), or death (OR 0.55; 95% CI 0.18-1.66; p = 0.289). However, it was associated with a minor (> 25%) creatinine elevation (OR 1.55; 95% CI 1.04-2.30; p = 0.030), a 0.3 mg/dl increase in creatinine (OR 1.66; 95% CI 1.01-2.75; p = 0.048), and CMSC-defined CA-AKI (OR 1.51; 95% CI 1.02-2.24; p = 0.039). By 90 days, there was no evidence creatinine elevation differed between the two groups (p = 0.590). Chronic use of SGLT2i was not associated with AKIN-defined CA-AKI (OR, 0.92; 95% CI 0.41-2.05; p = 0.838)., Conclusions: New use of SGLT2i during CA or PCI was not associated with an AKIN-defined CA-AKI, and it did not translate into new-onset dialysis or death during hospital stay. Chronic usage of SGLT2i did not affect creatinine. Further randomized clinical trials are warranted to confirm this finding., Competing Interests: Declarations. Ethics approval and consent to participate: The Institutional Review Board of the Xinqiao Hospital approved the research protocol. The study was performed in accordance with Declaration of Helsinki. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The health-care sector is responsible for 5·2% of global emissions, however, little data exist regarding the environmental impact of disease management strategies. SGLT2 inhibitors are now widely used to reduce the risk of hospital admission and kidney failure in people with type 2 diabetes and chronic kidney disease. This study aimed to estimate the impact of SGLT2 inhibitors on greenhouse gas emissions using data from the CREDENCE trial., Methods: For this modelling analysis, we used data from the randomised, double-blind, placebo-controlled, CREDENCE trial, which compared the effect of canagliflozin versus placebo on kidney and cardiovascular outcomes in patients with type 2 diabetes and albuminuric chronic kidney disease. For this secondary analysis, we included all participants randomly assigned to canagliflozin or placebo at baseline in the CREDENCE trial. Data on greenhouse gas emissions resulting from hospital inpatient days, maintenance dialysis therapy, and SGLT2 inhibitor tablet production were derived from published reports and used to model greenhouse gas emissions from total number of hospital inpatient days, total number of days of maintenance dialysis therapy, and from SGLT2 inhibitor treatment over the course of the CREDENCE trial. We compared greenhouse gas emission estimates for participants in the canagliflozin group and placebo group of the CREDENCE trial. We used bootstrapping analyses to calculate uncertainty estimates and permutation tests to generate p values for the difference in number of days on dialysis and inpatient bed days between treatment groups., Findings: 4401 participants who were randomly assigned to the canagliflozin (n=2202) or placebo group (n=2199) were included in the secondary analyses. During a median follow-up of 2·62 years (IQR 0·02 to 4·53), SGLT2 inhibitor production for 2202 participants resulted in greenhouse gas emissions of 63 tonnes of CO 2 equivalent (CO 2 e; 95% CI 62 to 64). The total number of inpatient bed days was 17 002 days in the placebo group versus 13 672 days in the canagliflozin group; the 3330 fewer inpatient days (95% CI 1037 to 5686; p=0·042) with SGLT2 inhibitor treatment equated to a reduction of approximately 126 tonnes of CO 2 e (95% CI 39 to 216). Participants in the placebo group required 24 877 days of maintenance dialysis compared with 16 605 days in the treatment group; 8272 fewer days of dialysis ( -168 to 16 755; p=0·16), equated to a reduction of 161 tonnes of CO 2 e (-3 to 327). Overall, mean greenhouse gas emissions per-participant-year were reduced from 196 kg of CO 2 e per-participant-year to 157 kg of CO 2 e per-participant-year., Interpretation: The addition of an SGLT2 inhibitor to routine therapy for people with type 2 diabetes and chronic kidney disease has the potential to reduce greenhouse gas emissions through the prevention of hospital admissions and need for dialysis., Funding: None., Competing Interests: Declaration of interests BT was in receipt of a Scientia Scholarship from University of New South Wales; has stock ownership in Ellen Medical Devices; and has received consultancy fees for Scientific Leadership with George Clinical. RAF acknowledges receipt of studentship awards from the Health Data Research UK-The Alan Turing Institute Wellcome PhD Programme in Health Data Science (grant number 218529/Z/19/Z). FA is chair of the Sustainable Healthcare Coalition. KM has a leadership role in the Sustainable Healthcare Coalition. FM has received an MRFF grant for COVID-19 related infections disease research and received royalties or licences for Medihood (a portable, protective hood for patient care); has patents issued for Medihood (the McMonty) and ReResp (a reusable N95 mask); and is the College of Intensive Care Medicine Sustainability Committee lead. KAB has received consulting fees from AstraZeneca. JK is an honorary professorial fellow at The George Institute for Global Health; has received fees for travel support, advisory boards, scientific presentations, consultancy, and steering committee roles from The Med Tech Actuator, Organ Transport, and Baymatob; and has stock ownership in Johnson & Johnson and Ellen Medical Devices. BLN is supported by an Australian National Health and Medical Research Council Emerging Leader Investigator Grant (number 2026621) and a Ramaciotti Foundation Health Investment Grant (number 2023HIG69); and has received fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Alexion, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, Janssen, the Limbic, Medscape, Novo Nordisk, and Travere Therapeutics, with all honoraria paid to The George Institute for Global Health. CA has received honoraria or sat on advisory boards for AstraZeneca and Novo Nordisk; and is supported by a Medical Research Futures Fund Investigator Grant. BN, MO, and SM declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Chronic breathlessness is a frequent diagnostic challenge in primary care. Our aim is to evaluate the feasibility of a stepwise breathlessness diagnostic algorithm for primary care., Method: This mixed-methods study included: (1) a general practitioner (GP) nominal group technique study; (2) focus groups on GPs' views on the algorithm; and (3) analysis of algorithm alignment against patterns of diagnostic referrals and diagnoses of breathlessness presentations (2014-19) from the MedicineInsight primary care electronic health record (EHR) dataset of 1,961,264 patients (405 general practice sites)., Results: All the tests in our algorithm, except for echocardiography, were ranked in the top 10 tests used by most GPs for patients presenting with chronic breathlessness. Themes from the focus group include similarity with current practice and test accessibility. Analysis of EHR diagnostic referrals revealed that all tests in the algorithm are regularly utilised and covered the major tests needed for breathlessness diagnoses recorded., Discussion: The results of the three studies support the acceptability and feasibility of the clinical algorithm in primary care.

Background: Heart failure is common, complex, and often associated with coexisting chronic medical conditions and a high mortality. We aimed to assess the epidemiology of people admitted to hospital with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), including the period covering the COVID-19 pandemic, which was previously not well characterised., Methods: In this retrospective, cohort study, we used whole-population electronic health records with 57 million individuals in England to identify patients hospitalised with heart failure as the primary diagnosis in any consultant episode of an in-patient admission to a National Health Service (NHS) hospital. We excluded individuals with less than 1 year of medical history records in primary or secondary care; admissions to NHS hospitals for which less than 10% of heart failure cases were linkable to the National Heart Failure Audit (NHFA); individuals younger than 18 years at the time of the heart failure hospitalisation; and patients who died in hospital during the index heart failure admission. For patients with new onset heart failure, we assessed incidence rates of 30-day and 1-year all-cause and cause-specific (cardiovascular, non-cardiovascular, and heart failure-related) emergency rehospitalisation and mortality after discharge, and dispensed guideline-recommended medical therapy (GRMT). Follow-up occurred from the index admission to the earliest occurrence of the event of interest, death, or end of data coverage. We estimated adjusted hazard ratios (HRs) to compare HFrEF with HFpEF. We computed population-attributable fractions to quantify the percentage of outcomes attributable to coexisting chronic medical conditions., Findings: Among 233 320 patients identified who survived the index heart failure admission across 335 NHS hospitals between Jan 1, 2019, and Dec 31, 2022, 101 320 (43·4%) had HFrEF, 71 910 (30·8%) had HFpEF, and 60 090 (25·8%) had an unknown classification. In patients with new onset heart failure, there were reductions in all-cause 30-day (-5·2% [95% CI -7·7 to -2·6] in 2019-22) and 1-year rehospitalisation rates (-3·9% [-6·6 to -1·2]). Declining 30-day rehospitalisation rates affected patients with HFpEF (-4·8% [-9·2 to -0·2]) and HFrEF (-6·2% [-10·5 to -1·6]), although 1-year rates were not statistically significant for patients with HFpEF (-2·2% [-6·6 to 2·3] vs -5·7% [-10·6 to -0·5] for HFrEF). There were no temporal trends in incidence rates of 30-day or 1-year mortality after discharge. The rates of all-cause (HR 1·20 [1·18-1·22]) and cause-specific rehospitalisation were uniformly higher in those with HFpEF than those with HFrEF. Patients with HFpEF also had higher rates of 1-year all-cause mortality after discharge (HR 1·07 [1·05-1·09]), driven by excess risk of non-cardiovascular death (HR 1·25 [1·21-1·29]). Rates of rehospitalisation and mortality were highest in patients with coexisting chronic kidney disease, chronic obstructive pulmonary disease, dementia, and liver disease. Chronic kidney disease contributed to 6·5% (5·6-7·4) of rehospitalisations within 1 year for HFrEF and 5·0% (4·1-5·9) of rehospitalisations for HFpEF, double that of any other coexisting condition. There was swift implementation of newer GRMT, but markedly lower dispensing of these medications in patients with coexisting chronic kidney disease., Interpretation: Rates of rehospitalisation in patients with heart failure in England have decreased during 2019-22. Further population health improvements could be reached through enhanced implementation of GRMT, particularly in patients with coexisting chronic kidney disease, who, despite being at high risk, remain undertreated., Funding: Wellcome Trust, Health Data Research UK, British Heart Foundation Data Science Centre., Competing Interests: Declaration of interests RAF received studentship awards from the Health Data Research UK-The Alan Turing Institute Wellcome Trust PhD Programme in Health Data Science (grant 218529/Z/19/Z). PR received a grant from the Dr Johannes and Hertha Tuba Foundation. BLN reports fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Alexion, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, Janssen, Limbic, Medscape, Novo Nordisk, and Travere Therapeutics with all honoraria paid to the George Institute for Global Health. CT received a studentship from the University College London UK Research and Innovation Centre for doctoral training in AI-enabled healthcare (EP/S021612/1), Medical Research Council Clinical Top-Up, and a studentship from the National Institute for Health and Care Research (NIHR) Biomedical Research Centre at University College London Hospital NHS Trust. NC received a personal fellowship from the Research Foundation Flanders and a research grant from the European Society of Cardiology. ER is funded by Forte Swedish Research Council for Health, Working Life And Welfare (2022–00882) individual postdoctoral fellowship, and Vetenskapsrådet Swedish Research Council (grant 2023–01982). SD received research funding from GlaxoSmithKline, AstraZeneca, Bayer, and BenevolentAI. CS is a director of the British Heart Foundation Data Science Centre and a chief scientist and deputy director at Health Data Research UK; has codeveloped National Health Service (NHS) England Secure Data Environment; and leads the CVD-COVID UK/COVID-IMPACT Consortium. SEP has a leadership role for the European Association of Cardiovascular Imaging, received consulting fees from Circle Cardiovascular Imaging, and holds an advisory role for the PROTEUS trial (NCT05028179). GMC served on the board of directors of Satellite Healthcare; served as chair or cochair of trial steering committees for Akebia, AstraZeneca, CSL Behring, Sanifit, and Vertex; served as an advisor for Applaud, CloudCath, Durect, Eliaz Therapeutics, Miromatrix, Outset, Physiowave, Renibus, and Unicycive; and served on data safety monitoring boards for Bayer, Mineralys, and ReCor. KK acted as a consultant or speaker and receiving grants for investigator-initiated studies from AstraZeneca, Abbott, Amgen, Bayer, Daiichi-Sankyo, Embecta, Nestle Health Science, Novartis, Novo Nordisk, Roche, Servier, Sanofi-Aventis, Lilly, MSD, Boehringer Ingelheim, Oramed Pharmaceuticals, and Applied Therapeutics; and was a chair of the scientific advisory group for Emergencies Ethnicity Subgroup. JS has direct or indirect stock ownership in Anagram Kommunikation, Sence Research, Symptoms Europe, and MinForskning; and professional services to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, and WeMind. CA received grants from the National Health Medical Research Council (Medical Research Futures Fund) and NSW Health; and honoraria from AstraZeneca, Novo Nordisk, and Amgen. JGFC reports receipt of personal honoraria for lectures and advisory boards from Pharmacosmos, Vifor, AstraZeneca, Amgen, Bayer, Novartis, and Servier; has received research grants through The University of Glasgow from Pharmacosmos and Vifor; and received funding from the British Heart Foundation Center of Research Excellence (RE/18/6134217). JD reports grants, personal fees, and non-financial support from MSD and Novartis; grants from Pfizer and AstraZeneca; and is part of the International Cardiovascular and Metabolic Advisory Board for Novartis, Steering Committee of UK Biobank, MRC International Advisory Group, MRC High Throughput Science Omics Panel, Scientific Advisory Committee for Sanofi, International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis, AstraZeneca Genomics Advisory Board, Scientific Advisory Board of Nightingale Health, Access Board of Our Future Health, and Scientific Advisory Committee of Leducq Foundation. JJVM received payments through Glasgow University for work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal; personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, JB Pharma, Lupin Pharma, Medscape (Heart.org), ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners. MV received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter, 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 AstraZeneca, Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. AMW received funding from the British Heart Foundation Data Science Centre (HDRUK2023.0239) and NIHR (NIHR303137). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Hypothesis: Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post-hoc analysis of the CREDENCE trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency., Methods: We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT < 20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively., Results: Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared to placebo, increased TIBC by 2.1% (95%CI 0.4-3.8; p = 0.014) and decreased ferritin by 11.5% (95%CI 7.1-15.7; p < 0.001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2-8.5; p < 0.001) and 6.7 g/L (95% CI 5.2- 8.2; p < 0.001) in patients with and without iron deficiency, respectively (p-interaction = 0.38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (HR 0.70, 95%CI 0.56-0.87) was consistent regardless of iron deficiency (p-interaction 0.83), as were effects on other cardiovascular and mortality outcomes (all p-interactions ≥ 0.10)., Conclusions: Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with T2D and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

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.)

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.

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.)

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 P interaction >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.

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.)

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.)

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&#95;11&#95;21&#95;JASN0000000000000248.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background Sodium glucose cotransporter-2 inhibitors reduce systolic blood pressure (SBP), but whether they affect SBP variability is unknown. There also remains uncertainty regarding the prognostic value of SBP variability for different clinical outcomes. Methods and Results Using individual participant data from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, we assessed the effect of canagliflozin on SBP variability in people with type 2 diabetes across 4 study visits over 1.5 years as measured by standard deviation, coefficient of variation, and variability independent of the mean. We used multivariable Cox regression models to estimate associations of SBP variability with cardiovascular, kidney, and mortality outcomes. In 11 551 trial participants, canagliflozin modestly lowered the standard deviation of SBP variability (-0.25 mm Hg [95% CI, -0.44 to -0.06]), but there was no effect on coefficient of variation (0.02% [95% CI, -0.12 to 0.16]) or variability independent of the mean (0.08 U [95% CI, -0.11 to 0.26]) when adjusting for correlation with mean SBP. Each 1 standard deviation increase in standard deviation of SBP variability was independently associated with higher risk of hospitalization for heart failure (hazard ratio [HR], 1.19 [95% CI, 1.02-1.38]) and all-cause mortality (HR, 1.12 [95% CI, 1.01-1.25]), with consistent results observed for coefficient of variation and variability independent of the mean. Increases in SBP variability were not associated with kidney outcomes. Conclusions In people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease, higher visit-to-visit SBP variability is independently associated with risks of hospitalization for heart failure and all-cause mortality. Canagliflozin has little to no effect on SBP variability, independent of its established SBP-lowering effect. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.

Introduction: This study aims to explore the perspectives of patients and carers with chronic breathlessness on current provision of care, care expectations, and self-management needs to develop relevant health services and resources to improve clinical outcomes., Methods: In-depth semistructured interviews were conducted on patients living with chronic breathlessness and carers., Results: Thirteen patients (cardiac, respiratory, and noncardiorespiratory) and two carers were interviewed (mean age 57 years, 47% female, median duration with breathlessness 5 years). Four main themes were identified: (1) living with breathlessness, (2) diagnosis delays, misdiagnosis, and knowledge gaps, (3) beyond curing disease: symptom relief and improving quality of life, and (4) self-management and limited support for it., Conclusion: Breathlessness has a high personal impact but remains a neglected condition in Australia. Patients suffer from lack of personal, community, and provider awareness, discontinuity of care, and too few clinical and self-management options., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study., Study Design: Secondary analysis of a randomized controlled trial., Setting & Participants: Participants in the CREDENCE trial., Intervention: Participants were randomly assigned to receive canagliflozin 100mg/d or placebo., Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and≥70 years) and sex in the intention-to-treat population using Cox regression models., Results: The mean age of the cohort was 63.0±9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages<60, 60-69, and≥70 years, respectively; P=0.3for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P=0.8for interaction). No differences in safety outcomes by age group or sex were observed., Limitations: This was a post hoc analysis with multiple comparisons., Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants., Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical., Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain., Research Design and Methods: We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components., Results: HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m 2 , overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control., Conclusions: The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22., Competing Interests: Competing interests: DMC has personal fees or fees paid by Janssen Pharmaceuticals to the Baim Institute for work on the CREDENCE trial steering committee. He has received consulting fees from Amgen, CSL Behring, Eli Lilly, Fresenius, Gilead, Medtronic/Covidien, Merck, Novo Nordisk, Zoll, AstraZeneca, GlaxoSmithKline, PLC Medical, and Allena Pharmaceuticals, and has received research support from Medtronic and Amgen. KWM’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. MJJ is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; is responsible for research projects that have received unrestricted funding from Amgen, Baxter, CSL, Eli Lilly, Gambro, and MSD; has served on advisory boards sponsored by Akebia, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim (BI), MSD, and Vifor; serves on steering committee for trials sponsored by CSL and Janssen; serves on a steering committee for an investigator-initiated trial with funding support from Dimerix, spoken at scientific meetings sponsored by Janssen, Amgen, Roche, and Vifor; with any consultancy, honoraria, or travel support paid to her institution. CPC reports in calendar years 2020–2022: Research Grants from: Amgen, Better Therapeutics, BI, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer. Consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, Sanofi. He serves on the Data and Safety Monitoring Boards for the Veteran’s Administration, Applied Therapeutics, and Novo Nordisk. BN has received research grants and consulting fees from Janssen, all paid to his institution. HJLH has received honoraria for participation in steering committees or advisory boards from AstraZeneca, BI, Bayer, CSL Behring, Chinook, Gilead, Goldfinch, Janssen, Merck, Mitsubishi Tanabe, Mundipharma; Novartis, Novo Nordisk, and Travere Pharmaceuticals. His institution received research grants from AstraZeneca, AbbVie, Janssen, BI, and Novo Nordisk. RA was a member of the CREDENCE study steering committee and chair of its adjudication committee; is a member of the steering committees of FIDELIO/FIGARO (Bayer); INNOVATE/PROTECT (Akebia); AMBER (Relypsa/Vifor), and chairs a data safety monitoring board (Chinook). He also serves as a consultant for AstraZeneca, Bayer, BI, DiaMedica, Janssen, Merck, Reata, Relypsa, and Sanofi. GLB works for The University of Chicago Medicine. He is a consultant for Merck, Bayer, Vascular Dynamics, KBP Biosciences, Ionis, Alnylam, and AstraZeneca. He has research support and is on the steering committee of trials for Bayer and Vascular Dynamics. He is the editor of the American Journal of Nephrology. DdZ: advisory boards and/or speaker fees for Bayer, BI, Fresenius, Mitsubishi-Tanabe, Travere Pharmaceuticals; steering committees and/or speaker for AbbVie and Janssen; data safety and monitoring committees for Bayer. Honoraria paid to institution and consultant/speaker. AL serves as a scientific advisor to BI, AstraZeneca, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); is on the data safety and monitoring board for NIDDK, Kidney Precision Medicine, University of Washington Kidney Research Institute Scientific Advisory Committee; and is funded by the Canadian Institute of Health Research and Kidney Foundation of Canada. She has received fees for time as CREDENCE National Coordinator from Janssen, directed to her academic team. CP has received honoraria for serving on advisory boards and as a speaker for Merck Sharp & Dohme, AstraZeneca, and BI/Eli Lilly. HZ has received fees for CREDENCE steering committee roles and travel support from Janssen. BZ has received honoraria for serving on advisory boards for BI, Novo Nordisk, Sanofi, and Eli Lilly. NR had has nothing to disclose. KR is the recipient of research funding from the NHMRC and MRFF and has received honoraria from Elsevier and PLOS for commissioned reviews. JY has nothing to disclose. CA is supported by a NSW Health EMCR Grant and a NHMRC/MRFF Priority Investigator Grant. She is an employee of the George Institute. She has received honoraria from AstraZeneca and Amgen. DCW has an ongoing consultancy contract with AstraZeneca and over the last 2 years has received payments for consultancy, speaking, or educational activities from Amgen, Astellas, Bayer, BI, GlaxoSmithKline, Gilead, Janssen, Merck Sharp & Dohme, Tricida, Vifor, and Zydus., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To investigate the extent to which improvements in multiple cardiovascular risk markers are associated with a lower risk of cardiovascular and kidney outcomes in patients with type 2 diabetes and high cardiovascular risk participating in the CANVAS programme., Materials and Methods: Clinically relevant improvements in cardiovascular risk factors were defined as a reduction in glycated haemoglobin ≥1.0%, systolic blood pressure ≥10 mmHg, body weight ≥3 kg, urinary-albumin-creatinine ratio ≥30%, uric acid ≥0.5 mg/dl, and an increase in haemoglobin of ≥1.0 g/dl from baseline to week 26. Participants were categorized according to the number of improvements in cardiovascular risk markers: zero, one, two, three, or four or more risk marker improvements. The Cox proportional hazard regression adjusted for treatment assignment, demographic variables and laboratory measurements was performed to determine the association between the number of risk marker improvements and risk of a composite cardiovascular, heart failure or kidney outcomes., Results: We included 9487 (93.5%) participants with available data at baseline and week 26. After week 26, 566 composite cardiovascular, 370 heart failure/cardiovascular death and 153 composite kidney outcomes occurred. The multivariable adjusted hazard ratios associated with four or more improvements in risk markers versus no risk marker improvement were 0.67 (95% CI 0.48, 0.92), 0.58 (95% CI 0.39, 0.87) and 0.49 (95% CI 0.25, 0.96) for the three outcomes respectively. We observed a trend of decreased hazard ratios across subgroups of increasing number of risk marker improvements (p for trend = .008, .02 and .047, respectively)., Conclusions: In patients with type 2 diabetes, improvements in multiple risk markers were associated with a reduced risk of cardiovascular and kidney outcomes as compared with no risk marker improvement., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: High dietary sodium intake is a leading cause of hypertension. A major source of dietary sodium is salt added to processed food products available in retail food environments. The fast-growing online grocery shopping setting provides new opportunities for salt reduction interventions that support consumers in choosing healthier options., Methods: The SaltSwitch Online Grocery Shopping randomized controlled trial is investigating the feasibility, acceptability, and effectiveness of a novel intervention for lowering salt consumption and blood pressure amongst people with hypertension who shop for groceries online. The intervention is based on a bespoke web browser extension that interfaces with a major retailer's online store to highlight and interpret product sodium content and suggest similar but lower-sodium alternatives. The primary outcome of interest is change in mean systolic blood pressure between individuals randomized (1:1) to the intervention and control (usual online shopping) arms at 12 weeks. Secondary outcomes are diastolic blood pressure, spot urinary sodium and sodium:potassium ratio, sodium purchases, and dietary intake. Intervention implementation and lessons for future uptake will be assessed using a mixed methods process evaluation. Participants with hypertension who shop online for groceries and exhibit high sodium purchasing behavior are being recruited across Australia. A target sample size of 1,966 provides 80% power (2-sided alpha = 0.05) to detect a 2 mm Hg difference in systolic blood pressure between groups, assuming a 15 mm Hg standard deviation, after allowing for a 10% dropout rate., Discussion: This trial will provide evidence on an innovative intervention to potentially reduce salt intake and blood pressure in people with hypertension. The intervention caters to individual preferences by encouraging sustainable switches to similar but lower-salt products. If effective, the intervention will be readily scalable at low cost by interfacing with existing online retail environments., (Copyright © 2022. Published by Elsevier Inc.)

Aim: Canagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy., Methods: The CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100 mg daily or placebo. Neuropathy events were defined post-hoc as any reported adverse event consistent with a peripheral or autonomic neuropathy event. The effect of canagliflozin and predictors of neuropathy events were estimated using Cox regression analysis. In sensitivity analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, and non-autonomic neuropathy events., Results: Almost half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years of follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). Independent factors associated with higher risk of experiencing neuropathy events were non-white race, younger age, higher glycated haemoglobin and lower estimated glomerular filtration rate. The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, P = 0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, P = 0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, P = 0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, P = 0.77). The lack of effect on neuropathy events was consistent in subgroup analyses., Conclusion: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial. Future large randomized studies with prespecified neuropathy endpoints are required to determine the impact of sodium glucose cotransporter 2 inhibitors on diabetic neuropathy., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms., Methods: MAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05)., Discussion: Currently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design., Trial Registration: Australian Clinical Trials ACTRN12618001707257 . Registered on 16 October 2018., (© 2021. The Author(s).)

Purpose of Review: There is an increasing recognition of the importance of sex in susceptibility, clinical presentation, and outcomes for heart failure. This review focusses on heart failure with reduced ejection fraction (HFrEF), unravelling differences in biology, clinical and demographic features and evidence for diagnostic and therapeutic strategies. This is intended to inform clinicians and researchers regarding state-of-the-art evidence relevant to women, as well as areas of unmet need., Recent Findings: Females are well recognised to be under-represented in clinical trials, but there have been some improvements in recent years. Data from the last 5 years reaffirms that women presenting with HFrEF women are older and have more comorbidities like hypertension, diabetes and obesity compared with men and are less likely to have ischaemic heart disease. Non-ischaemic aetiologies are more likely to be the cause of HFrEF in women, and women are more often symptomatic. Whilst mortality is less than in their male counterparts, HFrEF is associated with a bigger impact on quality of life in females. The implications of this for improved prevention, treatment and outcomes are discussed. This review reveals distinct sex differences in HFrEF pathophysiology, types of presentation, morbidity and mortality. In light of this, in order for future research and clinical medicine to be able to manage HFrEF adequately, there must be more representation of women in clinical trials as well as collaboration for the development of sex-specific management guidelines. Future research might also elucidate the biochemical foundation of the sex discrepancy in HFrEF., (© 2021. The Author(s).)

Aims/hypothesis: Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control., Methods: We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (<10, 10 to 16, >16 years) and HbA 1c (≤53.0 mmol/mol [<7.0%], >53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance <0.05)., Results: At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA 1c  > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0-18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA 1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37., Conclusions/interpretation: In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA 1c ., (© 2021. The Author(s).)

Purpose of Review: This narrative review synthesizes sex differences in guideline-directed medical therapy (GDMT) use and response among female patients with heart failure with reduced ejection fraction (HFrEF), discusses female representation in HFrEF clinical trials, and outlines future areas of investigation to reduce sex disparities in HFrEF care globally., Recent Findings: Observational registries suggest sex-specific disparities persist in GDMT rates, and there may be key sex-specific differences in optimal dosing of GDMT in HFrEF patients. Underrepresentation of female patients in HF clinical trials is a key barrier, and sex disparities in HF clinical trial leadership may influence sex-specific knowledge generation of medical management of HFrEF patients. There are important sex-specific differences in GDMT use and response among female HFrEF patients that warrant further study. Increasing female representation in HFrEF clinical trials, diversifying HF trial leadership, and embedding sex-specific approaches in the lifecycle of research from conception to reporting are essential to decreasing sex disparities in clinical care of all HFrEF patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims/hypothesis: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS)., Methods: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression., Results: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes., Conclusions/interpretation: Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin., (© 2021. The Author(s).)

The overall incidence of sudden cardiac death is considerably lower among women than men, reflecting significant and often under-recognized sex differences. Women are older at time of sudden cardiac death, less likely to have a prior cardiac diagnosis, and less likely to have coronary artery disease identified on postmortem examination. They are more likely to experience their death at home, during sleep, and less likely witnessed. Women are also more likely to present in pulseless electrical activity or systole rather than ventricular fibrillation or ventricular tachycardia. Conversely, women are less likely to receive bystander cardiopulmonary resuscitation or receive cardiac intervention post-arrest. Underpinning sex disparities in sudden cardiac death is a paucity of women recruited to clinical trials, coupled with an overall lack of prespecified sex-disaggregated evidence. Thus, predominantly male-derived data form the basis of clinical guidelines. This review outlines the critical sex differences concerning epidemiology, cause, risk factors, prevention, and outcomes. We propose 4 broad areas of importance to consider: physiological, personal, community, and professional factors.

Background: High salt intake is a major modifiable risk factor of hypertension which is prevalent in India. It is not yet clear if salt substitutes reduce blood pressure (BP) among Indian hypertensive patients., Objectives: Examine the acceptability, usage, and BP effects of a reduced-sodium and added-potassium salt substitute among hypertensive patients., Methods: We enrolled 502 participants with hypertension (aged 61.6 ± 12.0 y, 58.8% women) from 7 villages in rural India. Participants were randomly assigned to receive either regular salt (100% sodium chloride) or the salt substitute (70% sodium chloride/30% potassium chloride blend), and advised to replace all home salt use. The primary outcome was the change in systolic BP (SBP) from baseline to 3 mo comparing the salt substitute and regular salt groups. Secondary outcomes included the change in diastolic BP (DBP), 24-h urinary biomarkers, and self-reported use and satisfaction with the study salt provided., Results: A total of 494 (98%) participants completed 1 mo and 476 (95%) participants completed the 3-mo follow-up. At 3 mo, the salt substitute intervention significantly decreased the average SBP by 4.6 mmHg (95% CI: 3.0, 6.2, P < 0.001) and DBP by 1.1 mmHg (95% CI: 0.2, 2.1 mmHg, P = 0.02). There was a significant increase in 24-h urinary potassium excretion in the salt substitute group by 0.24 g/d (95% CI: 0.12, 0.35 g/d, P < 0.001) and a decrease in the urinary sodium to potassium ratio by 0.71 (95% CI: 0.55, 0.87, P < 0.0001) compared with the control group. Participants reported that they used the study salt nearly every day of the week (mean ± SD, 6.3 ± 1.8 d) and rated the taste of the study salts similarly., Conclusion: The reduced-sodium added-potassium salt led to a substantial reduction in SBP in hypertensive patients, supporting salt substitution as an effective, low-cost intervention for BP lowering in rural India. This trial was registered at clinicaltrials.gov as NCT03909659., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

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 (BP 2 ) 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: BP 2 will provide evidence regarding the feasibility and effectiveness of postpartum LBC interventions and structured clinical follow-up in improving cardiovascular health markers after HDP., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)