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Background and objective 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. Methods 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. [ABSTRACT FROM AUTHOR]

Aims: To provide an overview of the primary outcomes and key clinical implications of the CANVAS Program and CREDENCE trial, which were event‐driven, double‐blind randomized controlled trials that established the efficacy and safety of canagliflozin in those with type 2 diabetes (T2D) and high cardiovascular risk (CV) or albuminuric chronic kidney disease (CKD). Methods and Results: The CANVAS programme (CANVAS and CANVAS‐R trials) randomized 10 142 people with T2D and high CV risk to canagliflozin or placebo and followed them for a median of 126 weeks. The primary efficacy outcome was met, with canagliflozin treatment associated with a 14% reduction in major adverse CV events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.75 to 0.97; p < 0.001) as compared to placebo. The CREDENCE trial randomized 4401 individuals with T2D and albuminuric CKD to canagliflozin or placebo and followed them for 109 weeks. The CREDENCE trial also met its primary endpoint; canagliflozin treatment was associated with a 30% reduction in the composite of kidney failure, sustained doubling of serum creatinine level, or death from kidney or CV causes (HR 0.70, 95% CI 0.59 to 0.82; p < 0.001). Substantial reductions in hospitalization for heart failure (CANVAS: HR 0.67, 95% CI 0.52 to 0.87; CREDENCE: HR 0.61, 95% CI 0.47 to 0.80) and other key CV and kidney outcomes were also identified. Relative clinical benefits were consistent across subgroups defined by baseline age, sex, kidney function and history of CV disease but absolute benefits were greatest in those at highest baseline risk. Total serious adverse events were less common with canagliflozin treatment. Concerns about amputation and fracture risk observed in the CANVAS Program were not seen in CREDENCE and appear to have been spurious chance findings. Conclusion: Canagliflozin reduced important CV, kidney and mortality outcomes in those with T2D and high CV risk or CKD across diverse patient groups, with a good safety profile. Taken together with the other sodium‐glucose cotransporter‐2 inhibitor CV and renal outcomes trials, these landmark findings have changed the treatment landscape for patients worldwide. [ABSTRACT FROM AUTHOR]

Aim: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups. Materials and Methods: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end‐stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes. Secondary outcomes included: (i) cardiovascular death or heart failure (HF) hospitalization; (ii) cardiovascular death, myocardial infarction (MI) or stroke; (iii) HF hospitalization; (iv) doubling of the SCr level, ESKD or kidney death; (v) cardiovascular death; (vi) all‐cause death; and (vii) cardiovascular death, MI, stroke, or hospitalization for HF or for unstable angina. Results: The 4401 patients were divided into six geographic region subgroups: North America (n = 1182, 27%), Central and South America (n = 941, 21%), Eastern Europe (n = 947, 21%), Western Europe (n = 421, 10%), Asia (n = 749, 17%) and Other (n = 161, 4%). The analyses included four racial groups: White (n = 2931, 67%), Black or African American (n = 224, 5%), Asian (n = 877, 20%) and Other (n = 369, 8%). Canagliflozin reduced the relative risk of the primary composite outcome in the overall trial by 30% (hazard ratio 0.70, 95% confidence interval 0.59‐0.82; P = 0.00001). Across geographic regions and racial groups, canagliflozin consistently reduced the primary composite endpoint without evidence of heterogeneity (interaction P values of 0.39 and 0.91, respectively) or significant safety outcome differences. Conclusions: Canagliflozin reduces the risk of kidney and cardiovascular events similarly across geographic regions and racial groups. [ABSTRACT FROM AUTHOR]

Aims: People with type 2 diabetes (T2D) face high risks of heart failure (HF) hospitalizations that are often recurrent, especially as kidney function declines. We examined the effects of canagliflozin on total HF events by baseline kidney function in patients with T2D at high cardiovascular risk and/or with chronic kidney disease. Methods and results: Leveraging pooled participant‐level data from the CANVAS programme (n = 10 142) and CREDENCE trial (n = 4401), first and total HF hospitalizations were examined. Cox proportional hazards models were built for the time to first HF hospitalization, and proportional means models based on cumulative mean functions were used for recurrent HF hospitalizations. Treatment effects were evaluated overall as well as within baseline estimated glomerular filtration rate (eGFR) strata (<45, 45–60, and >60 ml/min/1.73 m2). HF hospitalizations were independently and blindly adjudicated. Among 14 540 participants with available baseline eGFR values, 672 HF hospitalizations occurred over a median follow‐up of 2.5 years. Among participants who experienced a HF hospitalization, 357 had a single event (201 in placebo‐treated patients and 156 in canagliflozin‐treated patients), 77 had 2 events, and 39 had >2 events. Canagliflozin reduced risk of first HF hospitalization (hazard ratio 0.58, 95% confidence interval [CI] 0.48–0.70) consistently across baseline eGFR strata (pinteraction = 0.84). Canagliflozin reduced total HF hospitalizations overall (mean event ratio 0.63, 95% CI 0.54–0.73) and across eGFR subgroups (pinteraction = 0.51). Canagliflozin also reduced cardiovascular death and total HF hospitalizations (mean event ratio 0.72, 95% CI 0.65–0.80) and across eGFR subgroups (pinteraction = 0.82). The absolute risk reductions were numerically larger, and numbers needed to treat were smaller when evaluating total events versus first events alone. These observed HF benefits were highly consistent across the range of eGFR, with larger absolute benefits in participants who had worse kidney function at baseline. Conclusions: In individuals with T2D at high cardiovascular risk and/or with chronic kidney disease, canagliflozin reduced the total burden of HF hospitalizations, with consistent benefits observed across the kidney function spectrum. Clinical Trial Registration: ClinicalTrials.gov Identifier: CANVAS (NCT01032629), CANVAS‐R (NCT01989754), CREDENCE (NCT02065791). [ABSTRACT FROM AUTHOR]

Aim: To validate the Klinrisk machine learning model for prediction of chronic kidney disease (CKD) progression in patients with type 2 diabetes in the pooled CANVAS/CREDENCE trials. Materials and Methods: We externally validated the Klinrisk model for prediction of CKD progression, defined as 40% or higher decline in estimated glomerular filtration rate (eGFR) or kidney failure. Model performance was assessed for prediction up to 3 years with the area under the receiver operating characteristic curve (AUC), Brier scores and calibration plots of observed and predicted risks. We compared performance of the model with standard of care using eGFR (G1‐G4) and urine albumin‐creatinine ratio (A1‐A3) Kidney Disease Improving Global Outcomes (KDIGO) heatmap categories. Results: The Klinrisk model achieved an AUC of 0.81 (95% confidence interval [CI] 0.78‐0.83) at 1 year, and 0.88 (95% CI 0.86‐0.89) at 3 years. The Brier scores were 0.020 (0.018‐0.022) and 0.056 (0.052‐0.059) at 1 and 3 years, respectively. Compared with the KDIGO heatmap, the Klinrisk model had improved performance at every interval (P <.01). Conclusions: The Klinrisk machine learning model, using routinely collected laboratory data, was highly accurate in its prediction of CKD progression in the CANVAS/CREDENCE trials. Integration of the model in electronic medical records or laboratory information systems can facilitate risk‐based care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The Australian culturally and linguistically diverse (CALD) communities may be at higher risk of salt intake than recommended given the use of a combination of discretionary sources and exposure to processed foods within a western country. This survey aimed to understand the knowledge, attitudes, and behaviors toward dietary salt and the acceptability of salt substitutes in the CALD communities. An online cross‐sectional survey was conducted among adults who self‐reported being a part of a CALD community, which was defined as non‐Indigenous cultural groups in Australia having cultural or linguistic connections with their overseas place of birth, ancestry or ethnic origin, religion, preferred language or language spoken at home. A total of 218 respondents opened the survey link. A total of 196 completed the entire survey. The majority of respondents (162, 83%) were aware that high salt intake causes serious health problems. Altogether 134 (69%) respondents were aware that there is a recommended amount for daily salt consumption although only 59 (44%) knew precise recommendations as <5 g salt per day. Around one quarter of the respondents rarely or never looked for ‟low in salt" or ‟reduced salt" messages on food labels when shopping. Over half specified they always or often added salt during cooking or preparing foods in the household. Almost 4 in 5 CALD respondents were willing to reduce their salt intake for health and 3 in 4 were open to trying a salt substitute. Further research into the utility of a salt substitute intervention in the Australian CALD community is warranted. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population‐specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial. Methods: Individual participant data were pooled and analysed in subgroups according to population‐specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed‐effect models were used. Results: A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (Pheterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95). Conclusions: The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population‐specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial. [ABSTRACT FROM AUTHOR]

Background: To explore the perspectives of GPs, non-GP specialists, and allied health professionals on the role of primary care in diagnosing and managing chronic breathlessness, the barriers faced, and the resources needed to optimise care of patients with chronic breathlessness. Methods: This was a qualitative study involving focus group discussions that included 35 GPs, non-GP specialists, and allied health professionals. Topics explored included: (1) views on the role of primary care in diagnosing and managing chronic breathlessness; (2) barriers to optimal assessment in primary care; and (3) facilitators to further optimise the care of patients with chronic breathlessness. Results: All participants considered that primary care has a central role to play in the assessment and management of chronic breathlessness, but greater access to referral services, suitable funding structures, and upskilling on the use of diagnostic tests such as spirometry and electrocardiography are required for this to be realised. Both GPs and non-GP specialists described great potential for developing better linkages, including new ways of referral and online consultations, greater ease of referral to allied health services, even if conducted virtually, for patients with functional causes of breathlessness. Participants identified a need to develop integrated breathlessness clinics for patients referred by GPs, which would ensure patients receive optimal care in the shortest possible time frame. Conclusions: GPs are crucial to achieving optimal care for breathless patients, especially given the multifactorial and multimorbid nature of breathlessness; however, there are significant gaps in services and resources at present that limit their ability to perform this role. Breathlessness is a common symptom in about one in 10 adults. This qualitative study that included 35 GPs, multidisciplinary specialists, and allied health professionals aims to understand the role of primary care in management of chronic breathlessness. GPs are crucial to achieving optimal care for breathless patients, especially given the multifactorial and multimorbid nature of breathlessness; however, the study presented significant gaps in services and resources at present, which limit their ability to perform this role. [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]

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. [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]

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. [ABSTRACT FROM AUTHOR]

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]

NAFLD fibrosis score was estimated using the formula: NAFLD fibrosis score = -1.675 + 0.037 × age (year) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio - 0.013 × platelet count (×109/L) - 0.66 × albumin (g/dl). NAFLD fibrosis score identified 1289 (29%) at a high risk of advanced liver fibrosis (NAFLD fibrosis score > 0.675). We also evaluated whether these non-invasive biomarkers of hepatic steatosis and fibrosis predict the risk of cardiovascular, kidney and mortality outcomes, and assessed the effect of canagliflozin on clinical outcomes across different levels of steatosis and fibrosis risk. Keywords: cardiovascular disease; clinical trial; diabetic nephropathy; fatty liver disease EN cardiovascular disease clinical trial diabetic nephropathy fatty liver disease 1413 1418 6 04/04/23 20230501 NES 230501 BACKGROUND Non-alcoholic fatty liver disease (NAFLD) occurs commonly in people with type 2 diabetes and is associated with the risk of progression to non-alcoholic steatohepatitis (NASH) and liver fibrosis.[1] NAFLD is also associated with incident cardiovascular events and chronic kidney disease (CKD) in people with type 2 diabetes, reflecting common pathways that underpin these cardiometabolic conditions.[2] However, despite this, few therapeutic options are available to treat NAFLD and reduce the risk of advanced liver fibrosis and cirrhosis.[3] Large cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of cardiovascular events and kidney failure in patients with type 2 diabetes.[[4]] SGLT2 inhibitors also exert favourable effects on metabolic variables including blood glucose, body weight and blood pressure,[6] which are key risk factors for the development and progression of NAFLD. [Extracted from the article]

Objective: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6.Research Design and Methods: Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multivariable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model.Results: The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively.Conclusions: In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6-lowering therapy on CV, kidney, and safety outcomes remains to be tested. [ABSTRACT FROM AUTHOR]

Aims: To test the hypothesis that the reduction in urinary kidney injury molecule‐1 (KIM‐1) observed with the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein‐1 (MCP‐1) by assessing the proportion of the effect of canagliflozin on KIM‐1 that is mediated through its effects on MCP‐1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. Material and methods: We measured KIM‐1 and MCP‐1 levels in urine samples from the CANVAS trial at baseline and Week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM‐1 and MCP‐1 were standardized by urinary creatinine (Cr). The proportion of the effect of canagliflozin that is mediated through UACR and MCP‐1/Cr on KIM‐1/Cr was estimated with G‐computation. Results: In total, 763 patients with micro‐ or macroalbuminuria (17.6% of the total cohort) were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At Year 1, canagliflozin compared to placebo reduced UACR, MCP‐1/Cr and KIM‐1/Cr by 40.4% (95% CI 31.0, 48.4), 18.1% (95% CI 8.9, 26.4) and 30.9% (95% CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM‐1/Cr mediated by its effect on UACR and in turn on MCP‐1/Cr was 15.2% (95% CI 9.4, 24.5). Conclusion: Canagliflozin reduces urinary KIM‐1, suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP‐1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post hoc analysis suggests that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of canagliflozin on the incidence of atrial fibrillation/atrial flutter (AF/AFL) and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. Materials and Methods: Participants with type 2 diabetes and high risk of cardiovascular disease or chronic kidney disease were included and randomly assigned to canagliflozin or placebo. We explored the effects of canagliflozin on the incidence of first AF/AFL events and AF/AFL‐related complications (ischaemic stroke/transient ischaemic attack/hospitalization for heart failure). Major adverse cardiovascular events and a renal‐specific outcome by baseline AF/AFL status were analysed using Cox regression models. Results: Overall, 354 participants experienced a first AF/AFL event. Canagliflozin had no detectable effect on AF/AFL (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67‐1.02) compared with placebo. Subgroup analysis, however, suggested a possible reduction in AF/AFL in those with no AF/AFL history (HR 0.78, 95% CI 0.62‐0.99). Canagliflozin was also associated with a reduction in AF/AFL‐related complications (HR 0.74, 95% CI 0.65‐0.86). There was no evidence of treatment heterogeneity by baseline AF/AFL history for other key cardiorenal outcomes (all Pinteraction > 0.14). Meta‐analysis of five sodium‐glucose cotransporter‐2 (SGLT2) inhibitor trials demonstrated a 19% reduction in AF/AFL events with active treatment (HR 0.81, 95% CI 0.72‐0.92). Conclusions: Overall, a significant effect of canagliflozin on the incidence of AF/AFL events could not be shown, however, a possible reduction in AF/AFL events in those with no prior history requires further investigation. Meta‐analysis suggests SGLT2 inhibition reduces AF/AFL incidence. [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]

First, across a broad spectrum of patients with heart failure, those with concurrent PAD compared with those without PAD had an ~50% greater risk of the primary outcome of worsening heart failure or cardiovascular death. The reluctance to prescribe SGLT2 inhibitors to those with PAD extended to include patients perceived to be at increased risk of PAD because of exposure to factors that may modulate PAD risk. Graph: Graphical Abstract This editorial refers to 'Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER', by Jawad H. Butt I et al i . https://doi.org/10.1093/eurheartj/ehad276. [Extracted from the article]

This editorial refers to 'Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis', by A. Elhakeem I et al i . https://doi.org/10.1093/eurheartj/ehac726. Unfortunately, some pregnancy exposures such as hypertensive and metabolic disorders of pregnancy, which are known to be associated with both maternal and offspring long-term cardiometabolic health, were not available.[5],[6] Offspring BMI in adolescence and young adulthood was also not included. Hopefully, The Assisted Reproductive Technology and Future Health (ART-Health) Cohort Collaboration, will be able to assist in answering these questions over time. [Extracted from the article]

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]

Aim: To define the proportional and absolute benefits of the sodium‐glucose co‐transporter‐2 inhibitor canagliflozin in patients with type 2 diabetes (T2D) with and without peripheral arterial disease (PAD). Materials and Methods: We pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401). In this post hoc analysis, the main outcomes of interest were major adverse cardiovascular events (MACE: non‐fatal myocardial infarction, non‐fatal stroke or cardiovascular death), kidney outcomes, and extended major adverse limb events (MALE). Cox proportional hazards models were used to assess canagliflozin treatment effects in those with and without PAD. Absolute risk reductions per 1000 patients treated for 2.5 years were estimated using Poisson regression. Results: Of 14 543 participants, 3159 (21.7%) had PAD at baseline. In patients with PAD, canagliflozin reduced MACE (hazard ratio, 0.76; 95% confidence interval, 0.62‐0.92), with similar relative benefits for other cardiovascular and kidney outcomes in participants with or without PAD at baseline (all Pinteraction >.268). There was no increase in the relative risk of extended MALE with canagliflozin, irrespective of baseline PAD history (Pinteraction >.864). The absolute benefits of canagliflozin were greater in those with PAD. Conclusions: Patients with T2D and PAD derived similar relative cardiorenal benefits from canagliflozin treatment but higher absolute benefits compared with those without PAD, with no increase in extended MALE. [ABSTRACT FROM AUTHOR]

Background. The fracture pathophysiology associated with type 2 diabetes and chronic kidney disease (CKD) is incompletely understood. We examined individual fracture predictors and prediction sets based on different pathophysiological hypotheses, testing whether any of the sets improved prediction beyond that based on traditional osteoporotic risk factors. Methods. Within the CREDENCE cohort with adjudicated fracture outcomes, we assessed the association of individual factors with fracture using Cox regression models. We used the Akaike information criteria (AIC) and Schwartz Bayes Criterion (SBC) to assess six separate variable sets based on hypothesized associations with fracture, namely, traditional osteoporosis, exploratory general population findings, cardiovascular risk, CKD-mineral and bone disorder, diabetic osteodystrophy, and an all-inclusive set containing all variables. Results. Fracture occurred in 135 (3.1%) participants over a median 2.35 [1.88–2.93] years. Independent fracture predictors were older age (hazard ratio [HR] 1.04, confidence interval [CI] 1.01–1.06), female sex (HR 2.49, CI 1.70–3.65), previous fracture (HR 2.30, CI 1.58–3.34), Asian race (HR 1.74, CI 1.09–2.78), vitamin D therapy requirement (HR 2.05, CI 1.31–3.21), HbA1c (HR 1.14, CI 1.00–1.32), prior cardiovascular event (HR 1.60, CI 1.10–2.33), and serum albumin (HR 0.41, CI 0.23–0.74) (lower albumin associated with greater risk). The goodness of fit of the various hypothesis sets was similar (AIC range 1870.92–1849.51, SBC range 1875.60–1948.04). Conclusion. Independent predictors of fracture were identified in the CREDENCE participants with type 2 diabetes and CKD. Fracture prediction was not improved by models built on alternative pathophysiology hypotheses compared with traditional osteoporosis predictors. [ABSTRACT FROM AUTHOR]

Aims Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post hoc analysis of CANVAS Programme and CREDENCE trial. Methods and results Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Programme) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was canagliflozin 100 or 300 mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI, and type 1 MI or type 2 MI. A total of 421 first MI events in the CANVAS Programme and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed [hazard ratio (HR) 0.89; 95% confidence interval (CI) 0.75, 1.05]. Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93). Conclusion Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Programme and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation. Trial registration ClinicalTrials.gov identifiers: NCT01032629, NCT01989754, and NCT02065791. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims  Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin–angiotensin–aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. Methods and results  The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin–angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64–0.95, P  = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61–0.98, P  = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71–1.20, P  = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. Conclusion  Among patients treated with renin–angiotensin–aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia. [ABSTRACT FROM AUTHOR]

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. Summary: 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. [ABSTRACT FROM AUTHOR]

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 HbA1c (≤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 HbA1c > 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 HbA1c (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 HbA1c. [ABSTRACT FROM AUTHOR]

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. Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease, and is associated with significant mortality and morbidity. In the CREDENCE trial, canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In the current analysis we sought to determine whether the effect of canagliflozin on HHF/CV death differed in subgroups defined by key baseline participant characteristics. Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Canagliflozin was associated with a reduction in the relative risk of HHF/CV death regardless of age, sex, history of heart failure or CV disease, and the use of loop diuretics or glucagon‐like peptide‐1 receptor agonists (all pinteraction >.114). The absolute benefit of canagliflozin was greater in those at highest baseline risk, such as those with CV disease (50 fewer events/1000 patients treated over 2.5 years vs. 20 fewer events in those without CV disease) or advanced kidney disease (estimated glomerular filtration rate [eGFR] 30–45 mL/min/1.73m2: 61 events prevented/1000 patients treated over 2.5 years vs. 23 events in eGFR 60–90 mL/min/1.73m2). Canagliflozin consistently reduces the proportional risk of HHF/CV death across a broad range of subgroups with greater absolute benefits in those at highest baseline risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Women who have had hypertension in pregnancy, both pre‐eclampsia and gestational hypertension, have a two‐ to three‐fold increased risk of cardiovascular disease later in life. It is unclear whether this is an unmasking of latent risk, the result of damage to the vascular tree during pregnancy, or both. Irrespective of the underlying pathophysiology, these women are uniquely identified sufficiently early in their lives for lifestyle interventions, if adopted, to improve their long‐term health. Currently, follow‐up of these women is inadequate and implementation of a coordinated follow‐up program, and further research into how best to provide it, is urgently needed. [ABSTRACT FROM AUTHOR]

Aims: The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes. Methods and results: The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed‐effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all Pdifference < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54–0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93–1.36), Pheterogeneity < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin‐to‐creatinine ratio, were similar between groups (all Pdifference > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (−0.52% vs. −0.64%, Pheterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all Pheterogeneity > 0.07). Conclusions: Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes. [ABSTRACT FROM AUTHOR]