The potential for current sodium and potassium production to support a global switch to the use of potassium-enriched salt: a desktop research study.

OBJECTIVE: Switching regular salt (sodium chloride) for salt enriched with potassium chloride (25% potassium chloride, 75% sodium chloride) has been shown to reduce blood pressure and the risk of cardiovascular diseases. We sought to define the potential for current production of sodium chloride and potassium chloride to support a global switch to the use of potassium-enriched salt. DESIGN: We summarised data from geological surveys, government reports and trade organisations describing the global production and supply of sodium chloride and potash (the primary source of potassium chloride) and compared this to potential requirements for potassium-enriched salt. SETTING: Global. SUBJECTS: N/A. RESULTS: Approximately 280 million tonnes of sodium chloride were produced in 2020 with China and the United States the main producers. Global production of potash from which potassium chloride is extracted was about 44 million tonnes with Canada, Belarus, Russia and China providing 77% of the world's supply. There were 48 countries in which potassium-enriched salt is currently marketed with 79 different brands identified. Allowing for loss of salt between manufacture and consumption, a full global switch from regular salt to potassium-enriched salt would require about 9.7 million tonnes of sodium chloride to be replaced with 9.7 million tonnes of potassium chloride annually. CONCLUSIONS: Significant up-scaling of the production of potassium chloride and the capacity of companies able to manufacture potassium-enriched salt, as well as a robust business case for the switch to potassium chloride, would be required.

Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i meta-analysis cardio-renal trialists consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across three patient populations (diabetes at high risk for atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. placebo were meta-analyzed across trials and examined across key subgroups (established ASCVD, prior MI, diabetes, prior HF, albuminuria, CKD stages and risk groups). RESULTS: A total of 78,607 patients across 11 trials were included: 42,568 (54.2%), 20,725 (26.4%), and 15,314 (19.5%) were included from trials of patients with diabetes at high risk for ASCVD, HF, or CKD, respectively. SGLT2i reduced the rate of MACE by 9% (HR 0.91 [95% CI 0.87-0.96], p<0.0001) with a consistent effect across all three patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in CV death (HR 0.86 [0.81-0.92], p<0.0001), with no significant effect for MI in the overall population (HR 0.95 [0.87-1.04], p=0.29), and no effect on stroke (HR 0.99 [0.91-1.07], p=0.77). The benefit for CV death was driven primarily by reductions in HF death and sudden cardiac death (HR 0.68 [0.46-1.02] and HR 0.86 [0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pint=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of ASCVD, diabetes, kidney function or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of CV death, particularly HF and sudden cardiac death, without a significant effect on MI in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.

Natriuretic Peptides and Prognosis in Patients with Type 2 Diabetes Mellitus and High Risk for Cardiovascular Events.

BACKGROUND: Prognosis of individuals with and without an established heart failure (HF) diagnosis and similarly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels is not well known. METHODS: CANVAS (Canagliflozin Cardiovascular Assessment Study) trial participants were stratified according to baseline NT-proBNP quartiles and history of HF at baseline. Adjusted event rates per 1000 patient-years follow-up for hospitalizations for HF (HHF), cardiovascular mortality, and kidney events were assessed, and hazard ratios (HR) were calculated using Cox proportional hazard models. RESULTS: Of the 3507 participants with available NT-proBNP concentrations, 471 (13.4%) had history of HF. Incidence rate per 1000 patient-years for HHF increased across the NT-proBNP quartiles in patients with (0, 2.8, 13.4 and 40.1; P<0.001) and without (1.8, 3.1, 6.0 and 19.1; P<0.001) HF, with significantly higher risk in patients with HF compared to those without (with HF: quartile 3 HR 9.28 [1.15, 75.05]; P=0.04; without HF: quartile-4 HR 4.86, [2.08, 11.35]; P<0.001). Similar higher risk for kidney events was seen in HF patients (with HF: quartile-4 HR 6.94, [2.66, 18.08]; P=0.001; without HF: quartile-4th HR 4.85 [3.02, 7.80]; P=0.001). Similar trends were seen for cardiovascular mortality. CONCLUSIONS: Among patients with type 2 diabetes and cardiovascular risk, an elevated NT-proBNP level was associated with worse HF and kidney outcomes in general regardless of history of HF, however presence of a clinical diagnosis of HF at baseline was associated with incrementally higher risk particularly in higher NT-proBNP quartiles.

Secondary Analysis of the Salt Substitute and Stroke Study (SSaSS): Effects of Potassium-Enriched Salt on Cardiac Outcomes.

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.

The contribution of sodium reduction and potassium increase to the blood pressure lowering observed in the Salt Substitute and Stroke Study.

The Salt Substitute and Stroke Study (SSaSS) demonstrated significant reductions in systolic blood pressure (SBP), and the risk of stroke, major cardiovascular events and total mortality with the use of potassium-enriched salt. The contribution of sodium reduction versus potassium increase to these effects is unknown. We identified four different data sources describing the association between sodium reduction, potassium supplementation and change in SBP. We then fitted a series of models to estimate the SBP reductions expected for the differences in sodium and potassium intake in SSaSS, derived from 24-h urine collections. The proportions of the SBP reduction separately attributable to sodium reduction and potassium supplementation were calculated. The observed SBP reduction in SSaSS was -3.3 mmHg with a corresponding mean 15.2 mmol reduction in 24-h sodium excretion and a mean 20.6 mmol increase in 24-h potassium excretion. Assuming 90% of dietary sodium intake and 70% of dietary potassium intake were excreted through urine, the models projected falls in SBP of between -1.67 (95% confidence interval: -4.06 to +0.73) mmHg and -5.33 (95% confidence interval: -8.58 to -2.08) mmHg. The estimated proportional contribution of sodium reduction to the SBP fall ranged between 12 and 39% for the different models fitted. Sensitivity analyses assuming different proportional urinary excretion of dietary sodium and potassium intake showed similar results. In every model, the majority of the SBP lowering effect in SSaSS was estimated to be attributable to the increase in dietary potassium rather than the fall in dietary sodium.

Autoantibodies to Erythropoietin Receptor and Clinical Outcomes in Patients With Type 2 Diabetes and CKD: A Post Hoc Analysis of CREDENCE Trial.

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.

The effect of salt substitution on frequency and severity of headache: results from the SSaSS cluster-randomised controlled trial of 20,995 participants.

BACKGROUND: Headache is one of the most common neurological symptoms. Headache disorders are associated with a high global burden of disease. Prior studies indicate that short-to-medium term sodium reduction reduces headache symptom. This study evaluated the effects of long-term reduced-sodium, added-potassium salt on headache frequency and severity in rural China. METHODS: The Salt substitute and stroke study (SSaSS) was an open-label cluster-randomised trial in rural China designed to evaluate the effect of salt substitution on mortality and cardiovascular events. Participants included adults with a history of prior stroke and those aged ≥60 years with uncontrolled high blood pressure (BP). Villages were randomly assigned in a 1:1 ratio either to intervention with salt substitute (75% sodium chloride and 25% potassium chloride by mass) or to control with continued use of regular salt (100% sodium chloride). In this pre-specified analysis, between-group differences in headache frequency and severity were evaluated. The study was registered with ClinicalTrials.gov (identifier number: NCT02092090). RESULTS: A total of 20,995 participants were included in the trial (mean age 64.3 years, 51% female, mean follow-up 4.7 years). At final follow-up at the end of the study, headache outcome data including frequency and severity of headaches was available for 16,486 (98%) of 16,823 living participants. Overall, 4454/16,486 (27%) individuals reported having headache: 27.4% in the intervention group (2301/8386) vs 26.6% in the control group (2153/8100) (RR 1.04, 95% CI: 0.93, 1.16, p = 0.48). There was no difference in headache severity between intervention and control groups (p = 0.90). CONCLUSION: Long term salt substitution did not reduce the frequency or severity of headaches in this population.

Potassium-Enriched Salt Substitutes: A Review of Recommendations in Clinical Management Guidelines.

Excess dietary sodium intake and insufficient dietary potassium intake are both well-established risk factors for hypertension. Despite some successful initiatives, efforts to control hypertension by improving dietary intake have largely failed because the changes required are mostly too hard to implement. Consistent recent data from randomized controlled trials show that potassium-enriched, sodium-reduced salt substitutes are an effective option for improving consumption levels and reducing blood pressure and the rates of cardiovascular events and deaths. Yet, salt substitutes are inconsistently recommended and rarely used. We sought to define the extent to which evidence about the likely benefits and harms of potassium-enriched salt substitutes has been incorporated into clinical management by systematically searching guidelines for the management of hypertension or chronic kidney disease. We found incomplete and inconsistent recommendations about the use of potassium-enriched salt substitutes in the 32 hypertension and 14 kidney guidelines that we reviewed. Discussion among the authors identified the possibility of updating clinical guidelines to provide consistent advice about the use of potassium-enriched salt for hypertension control. Draft wording was chosen to commence debate and progress consensus building: strong recommendation for patients with hypertension-potassium-enriched salt with a composition of 75% sodium chloride and 25% potassium chloride should be recommended to all patients with hypertension, unless they have advanced kidney disease, are using a potassium supplement, are using a potassium-sparing diuretic, or have another contraindication. We strongly encourage clinical guideline bodies to review their recommendations about the use of potassium-enriched salt substitutes at the earliest opportunity.

Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria.

BACKGROUND: Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known. METHODS: We used data from 2 SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), 2 ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney, and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE. RESULTS: Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% CI, 0.55-0.76) for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI, 3.0-5.7), with a number needed to treat of 23 (95% CI, 18-33). For a 50-year-old patient commencing combination therapy, estimated major adverse cardiovascular event-free survival was 21.1 years compared with 17.9 years for conventional care (3.2 years gained [95% CI, 2.1-4.3]). There were also projected gains in survival free from hospitalized heart failure (3.2 years [95% CI, 2.4-4.0]), chronic kidney disease progression (5.5 years [95% CI, 4.0-6.7]), cardiovascular death (2.2 years [95% CI, 1.2-3.0]), and all-cause death (2.4 years [95% CI, 1.4-3.4]). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for major adverse cardiovascular events (2.4 years [95% CI, 1.1-3.5]), chronic kidney disease progression (4.5 years [95% CI, 2.8-5.9]), and all-cause death (1.8 years [95% CI, 0.7-2.8]). CONCLUSIONS: In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.

Switching the World's Salt Supply-Learning from Iodization to Achieve Potassium Enrichment.

Sodium is an essential dietary component, but excess sodium intake can lead to high blood pressure and an increased risk of cardiovascular disease. Many national and international bodies, including the World Health Organization, have advocated for population-wide sodium reduction interventions. Most have been unsuccessful due to inadequate sodium reduction by food industry and difficulties in persuading consumers to add less salt to food. Recent research highlights potassium-enriched salt as a new, feasible, acceptable, and scalable approach to reducing the harms caused by excess sodium and inadequate potassium consumption. Modeling shows that a global switch from regular salt to potassium-enriched salt has the potential to avert millions of strokes, heart attacks, and premature deaths worldwide each year. There will be many challenges in switching the world's salt supply to potassium-enriched salt, but the success of universal salt iodization shows that making a global change to the manufacture and use of salt is a tractable proposition. This in-depth review of universal salt iodization identified the importance of a multisectoral effort with strong global leadership, the support of multilateral organizations, engagement with the salt industry, empowered incountry teams, strong participation of national governments, understanding the salt supply chain, and a strategic advocacy and communication plan. Key challenges to the implementation of the iodization program were costs to government, industry, and consumers, industry concerns about consumer acceptability, variance in the size and capabilities of salt producers, inconsistent quality control, ineffective regulation, and trade-related regulatory issues. Many of the opportunities and challenges to universal salt iodization will likely also be applicable to switching the global salt supply to iodized and potassium-enriched salt.

Criterion validation of nutrient profiling systems: a systematic review and meta-analysis.

BACKGROUND: Nutrient profiling systems (NPSs) use algorithms to evaluate the nutritional quality of foods and beverages. Criterion validation, which assesses the relationship between consuming foods rated as healthier by the NPS and objective measures of health, is essential to ensure the accuracy of NPSs. OBJECTIVE: We examined and compared NPSs that have undergone criterion validity testing in relation to diet-related disease risk and risk markers. METHODS: Academic databases were searched for prospective cohort and cross-sectional studies published before November, 2022. NPSs were eligible if they incorporated multiple nutrients or food components using an algorithm to determine an overall summary indicator (e.g., a score or rank) for individual foods. Studies were included if they assessed the criterion validity of an eligible NPS. Validation evidence was first summarized in narrative form by NPS, with random effects meta-analysis where ≥2 prospective cohort studies assessed the same NPS and outcomes. RESULTS: Of 4519 publications identified, 29 describing 9 NPSs were included in the review. The Nutri-Score NPS was assessed as having substantial criterion validation evidence. Highest compared with lowest diet quality as defined by the Nutri-Score was associated with significantly lower risk of cardiovascular disease (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59, 0.93; n = 6), cancer (HR: 0.75; 95% CI: 0.59, 0.94; n = 5), all-cause mortality (HR: 0.74; 95% CI; 0.59, 0.91; n = 4) and change in body mass index (HR: 0.68; 95% CI: 0.50, 0.92; n = 3). The Food Standards Agency NPS, Health Star Rating, Nutrient Profiling Scoring Criterion, Food Compass, Overall Nutrition Quality Index, and the Nutrient-Rich Food Index were determined as having intermediate criterion validation evidence. Two other NPSs were determined as having limited criterion validation evidence. CONCLUSIONS: We found limited criterion validation studies compared with the number of NPSs estimated to exist. Greater emphasis on conducting and reporting on criterion validation studies across varied contexts may improve the confidence in existing NPSs.

Treatment effect of canagliflozin for patients on therapy for heart failure: Pooled analysis of the CANVAS program and CREDENCE trial.

BACKGROUND: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that has been shown to reduce cardiovascular events in diabetic patients with and without heart failure (HF). Whether the clinical benefits and safety profile of canagliflozin are different in those on a beta blocker and an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (BB + RAASi) is unknown. METHODS: We pooled participants with HF at baseline from the CANVAS Program and CREDENCE trial and assessed major adverse cardiovascular events and its components; hospitalization for heart failure (HHF); HHF or CV death; all-cause mortality; a renal composite; and a combined renal and CV composite. RESULTS: Of 14,543 participants, 2113 had HF at baseline, and 1280 were on BB + RAASi. In those with a history of HF, participants on BB + RAASi therapy were more likely to have coronary atherosclerotic disease (82 vs 72%, p < 0.001), history of myocardial infarction (42 vs 29%, p < 0.001), higher mean body mass index (34 vs 32 kg/m2, p < 0.001), and lower mean estimated glomerular filtration rate (67 vs 70 mL/min/1.73 m2, p < 0.01). They were also more likely to be on insulin, a statin, antithrombotic agent, and a diuretic (all p < 0.001). In unadjusted analysis and when adjusted for selected baseline factors, there was no heterogeneity in canagliflozin treatment effect except for HHF/CV death in those on baseline BB + RAASi vs. those not on baseline BB + RAASi (Pheterogeneity = 0.02). CONCLUSION: Canagliflozin mostly improved CV and kidney outcomes in participants with a history of HF irrespective of use of BB + RAASi at baseline, with possible greater benefit on HHF/CV death in participants on BB + RAASi.

Factors influencing the time to ethics and governance approvals for clinical trials: a retrospective cross-sectional survey.

BACKGROUND: The findings from multi-centre trials are central to the practice of evidence-based medicine, enabling the development and implementation of new treatments. The time it takes to commence clinical trials at sites can be long, and ethics and governance approvals are key steps on the pathway to site activation. The goal of this study was to explore factors influencing the times to ethics approval, governance approval and site activation for multi-centre clinical trials. METHODS: This paper assessed the associations of trial characteristics (disease area and trial phase), site characteristics (government or private ownership, country) and characteristics of the ethics and governance processes (scope guidelines, mutual acceptance requirements and triage of projects by risk) with times to approvals and activation. Median times were compared between site initiations that were and were not exposed to each characteristic using non-parametric tests in univariable and multivariable regressions. RESULTS: There were data from 150 site activations done across 91 sites, 16 trials and 5 countries from November 2013 to November 2021. The overall median time to activation was 234 days (range 74 to 657), with ethics approval taking a median of 48 days (0 to 369) and governance approval a median of 34 days (0 to 489). Both the univariable and multivariable analyses identified associations of disease area, particularly oncology (p univariable = 0.012, p multivariable = 0.044), use of scope guidelines (p < 0.001, p = 0.020) and use of a triage process (p < 0.001, 0.043) with shorter median times for governance approval. These characteristics (all p < 0.001) plus early trial phase (p = 0.028) were also predictive of shorter median times for ethics approval in univariable analyses, but none remained predictive in multivariable models (all p > 0.054). The only factors associated with reduced overall time to site activation in both univariable and multivariable analyses were the early trial phase (p < 0.001, p = 0.013) and mutual acceptance of ethics approvals (p = 0.031, p = 0.030). INTERPRETATION: Times to ethics and governance approvals were only one third of total trial start-up time. Factors influencing times to approval and activation were somewhat inconsistent across analyses, but it seems likely that the introduction of selected governance and ethics processes can reduce approval times.

Sodium-based paracetamol: impact on blood pressure, cardiovascular events, and all-cause mortality.

BACKGROUND AND AIMS: Effervescent formulations of paracetamol containing sodium bicarbonate have been reported to associate with increased blood pressure and a higher risk of cardiovascular diseases and all-cause mortality. Given the major implications of these findings, the reported associations were re-examined. METHODS: Using linked electronic health records data, a cohort of 475 442 UK individuals with at least one prescription of paracetamol, aged between 60 and 90 years, was identified. Outcomes in patients taking sodium-based paracetamol were compared with those taking non-sodium-based formulations of the same. Using a deep learning approach, associations with systolic blood pressure (SBP), major cardiovascular events (myocardial infarction, heart failure, and stroke), and all-cause mortality within 1 year after baseline were investigated. RESULTS: A total of 460 980 and 14 462 patients were identified for the non-sodium-based and sodium-based paracetamol exposure groups, respectively (mean age: 74 years; 64% women). Analysis revealed no difference in SBP [mean difference -0.04 mmHg (95% confidence interval -0.51, 0.43)] and no association with major cardiovascular events [relative risk (RR) 1.03 (0.91, 1.16)]. Sodium-based paracetamol showed a positive association with all-cause mortality [RR 1.46 (1.40, 1.52)]. However, after further accounting of other sources of residual confounding, the observed association attenuated towards the null [RR 1.08 (1.01, 1.16)]. Exploratory analyses revealed dysphagia and related conditions as major sources of uncontrolled confounding by indication for this association. CONCLUSIONS: This study does not support previous suggestions of increased SBP and an elevated risk of cardiovascular events from short-term use of sodium bicarbonate paracetamol in routine clinical practice.

Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial.

BACKGROUND: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear. METHODS: Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min-1·1.73 m-2], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed. RESULTS: The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all P<0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52-6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48-3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08-1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64-2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24-1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54-5.56]) was associated with risk of the primary outcome. CONCLUSIONS: Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02065791.

Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes.

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.

Cost-effectiveness of ultra-low-dose quadruple combination therapy for high blood pressure.

OBJECTIVE: To determine the cost-effectiveness and cost-utility of a quadpill containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg and bisoprolol 2.5 mg in comparison with irbesartan 150 mg for people with hypertension who are either untreated or receiving monotherapy. METHODS: We conducted a within-trial and modelled economic evaluation of the Quadruple UltrA-low-dose tReaTment for hypErTension trial. The analysis was preplanned, and medications and health service use captured during the trial. The main outcomes were incremental cost-effectiveness ratios (ICERs) for cost per mm Hg systolic blood pressure (BP) reduction at 3 months, and modelled cost per quality-adjusted life year (QALY) over a lifetime. RESULTS: The within-trial analysis showed no clear difference in cost per mm Hg BP lowering between randomised treatments at 3 months ($A10 (95% uncertainty interval (UI) $A -18 to $A37) per mm Hg per person) for quadpill versus monotherapy. The modelled cost-utility over a lifetime projected a mean incremental cost of $A265 (95% UI $A166 to $A357) and a mean 0.02 QALYs gained (95% UI 0.01 to 0.03) per person with quadpill therapy compared with monotherapy. Quadpill therapy was cost-effective in the base case (ICER of $A14 006 per QALY), and the result was sensitive to the quadpill cost in one-way sensitivity analysis. CONCLUSIONS: Quadpill in comparison with monotherapy is comparably cost-effective for short-term BP lowering. In the long-term, quadpill therapy is likely to be cost-effective. TRIAL REGISTRATION NUMBER: ANZCTRN12616001144404.

Protocol for a randomized controlled trial of medically tailored meals compared to usual care among individuals with type 2 diabetes in Australia.

BACKGROUND: '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. OBJECTIVE: 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. METHODS: 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. DISCUSSION: 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.

Outcomes of a state-wide salt reduction initiative in adults living in Victoria, Australia.

PURPOSE: To assess any effects of a state-wide sodium reduction intervention on sodium intake, sources of dietary sodium and discretionary salt use at a population level. METHODS: Data (24-h urinary sodium excretion, self-report survey, a 24-h dietary recall) were collected cross-sectionally at baseline (2016/2017) and follow-up (2020) from adults in Victoria, Australia. Intervention activities included consumer awareness advertising campaign, public debate generation via mass media, strengthening existing policy initiatives and supporting food innovation with industry. RESULTS: There were 339 participants at baseline and 211 at follow-up, with 144 and 90 of participants completing a 24-h dietary recall, respectively. There was no difference in adjusted 24-h urinary sodium excretion between baseline and follow-up (134 vs 131 mmol/24 h; p = 0.260). There were no differences in the percentage of participants adding salt during cooking (63% vs 68%; p = 0.244), adding salt at the table (34% vs 37%; p = 0.400) or regularly taking action to control salt/sodium intake (22% vs 21%; p = 0.793). There were large differences in the quantity of dietary sodium sourced from retail stores (57% vs 77%, p < 0.001), and less sodium was sourced from foods at fresh food markets (13% vs 2%; p ≤ 0.001) at follow-up. No large differences were apparent for foods with different levels of processing or for food groups. CONCLUSION: There was no clear population-level effect of the 4-year multi-component Victorian Salt Reduction Intervention on sodium intake with Victorian adults continuing to consume sodium above recommended levels. The findings indicate that more intensive and sustained efforts aiming at the retail and food industry with national level support are likely to be required to achieve a measurable improvement in sodium intake at a state level.

The effect of mycoprotein intake on biomarkers of human health: a systematic review and meta-analysis.

BACKGROUND: Mycoprotein is a fungal source of protein that is increasingly consumed as an ingredient in meat analogs. OBJECTIVES: This study aimed to systematically review and meta-analyze the effects of mycoprotein intake on selected biomarkers of human health. METHODS: This study was registered in PROSPERO (CRD42022308980). We searched the PubMed, Scopus, and Embase databases to identify randomized control trials in any language until 16 August, 2022. Trials were included if they administered a mycoprotein intervention against a nonmycoprotein control arm and if reported outcomes included blood lipids, blood glucose, insulin, blood pressure, or body weight. Eligible trials were assessed for risk of bias using the Cochrane risk-of-bias tool for randomized trials. An inverse-variance-weighted, random-effects meta-analysis model was used to assess the effects of intake across each biomarker. RESULTS: Nine trials that included 178 participants with a mean follow-up of 13 d were included, with 4 reporting on blood lipids and 5 reporting on postprandial blood glucose or insulin. The overall reduction of total cholesterol was -0.55 mmol/L (95% CI: -0.85 to -0.26; P < 0.001) in the mycoprotein group compared to control, but no clear effects on HDL cholesterol, LDL cholesterol, or TGs were found (all P > 0.05). There were no reductions in postprandial blood glucose concentrations at 30, 60, 90 or 120 min. Postprandial blood insulin concentration was reduced by -76.51 pmol/L (95% CI: -150.75 to -2.28; P = 0.043) at 30 min, with no detectable effects at 60, 90, or 120 min. CONCLUSIONS: Mycoprotein intake may have important effects on blood lipids, but the evidence base is limited by the small sample sizes and short intervention periods of the contributing trials. The protocol for this systematic review has been registered in PROSPERO as CRD42022308980.