Bruce Neal

• MB ChB, PhD, FRCP(UK)
• The University of Sydney

Importance The direct effect of consumption of salt substitutes on recurrent stroke and mortality among patients with stroke remains unclear. Objective To evaluate the effects of salt substitutes vs regular salt on the incidence of recurrent stroke and mortality among patients with stroke. Design, Setting, and Participants The Salt Substitute and...

Aims The sodium–glucose cotransporter 2 inhibitor canagliflozin reduces the risk of heart failure (HF) hospitalization or cardiovascular death and chronic kidney disease (CKD) progression among patients with type 2 diabetes at high cardiovascular risk or with CKD. Patients with type 2 diabetes commonly have coexisting HF or CKD that require treatme...

Background Online grocery shopping is a growing source of food purchases in many countries. We investigated the effect of nudging consumers towards purchases of lower sodium products using a web browser extension. Methods This trial was conducted among individuals with hypertension who shopped for their groceries online in Australia. From July 202...

Background Excess dietary sodium intake has been associated with death and disability. WHO has released global sodium benchmarks for packaged foods to support countries to reduce population sodium intake. This study aimed to assess the potential health effect, costs, and cost effectiveness of implementing these WHO sodium benchmarks in India. Meth...

Background Patients with type 2 diabetes often have coexistent heart failure or chronic kidney disease (CKD) that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized. The sodium glucose cotransporter-2 inhibitor canagliflozin reduces the risk of hospitalization...

Background Potassium-enriched salt is a proven dietary intervention for reducing risk of stroke, cardiovascular disease, and premature mortality when used instead of regular table salt. Potassium-enriched salt products are available globally, but the on-pack health claims, product features, and instructions for use are diverse. Objectives The obje...

Background: Patients with type 2 diabetes often have coexistent heart failure or chronic kidney disease (CKD) that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized. The sodium glucose cotransporter-2 inhibitor canagliflozin reduces the risk of hospitalizatio...

Background and hypothesis Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post-hoc analysis of the CREDENCE trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether t...

Background Associations of dietary sodium and potassium intake with fracture risk are inconsistent and the effects of salt substitute on fracture incidence are unknown. We assessed the effect of salt substitute compared to regular salt intake on fracture incidence using data from the Salt Substitute and Stroke Study (SSaSS). Methods SSaSS was a cl...

Background and objective Despite compelling evidence of the efficacy of reduced-sodium salt in lowering blood pressure and cardiovascular disease risk, it is currently an underutilized intervention. To inform the approaches needed to scale-up use of reduced-sodium salt, it is important to understand how it is perceived by consumers. This study syst...

Objective: To compare uptake of the voluntary Health Star Rating front-of-pack nutrition labelling system with uptake of a mostly mandatorycountry-of-origin label in Australia over a similar period. Methods: We used data on numbers and proportions of products carrying health stars and country-of-origin labelling recorded annuallybetween 2015 and 2...

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 d...

Aim To investigate type III collagen (COL III) turnover in participants from the CANVAS Program biomarker substudy. Methods Biomarkers of COL III formation (PRO‐C3) and COL III degradation fragments (C3M and CTX‐III) were assessed in baseline and year 3 plasma from patients enrolled in CANVAS, investigating the effect of canagliflozin in participa...

Aim To modify the Australian and New Zealand Health Star Rating to account for ultra‐processing and compare the alignment of the modified ratings with NOVA classifications and the current Australian Dietary Guidelines classifications of core (recommended foods) and discretionary (foods to limit). Methods Data was cross‐sectionally analysed for 25...

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 resu...

Switching between similar food and beverage products may reduce greenhouse gas emissions (GHGe). Here, using consumer data linked to 23,550 product-specific GHGe values, we estimated annual GHGe attributable to product purchases consumed at home in Australia and calculated reductions from specific switches. Potential changes to mean Health Star Rat...

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 tri...

Background Multiple Australian jurisdictions reported the introduction of measures to speed the processing of research projects addressing the Severe Acute Respiratory Syndrome 2 SARS-CoV-2 (COVID-19) pandemic. The goal of this study was to compare the times taken for ethics committee and governance approvals of projects before and after the pandem...

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 s...

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...

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 d...

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 con...

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 populat...

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...

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone all individually reduce cardiovascular, kidney and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of...

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 electroni...

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...

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 underlyin...

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 i...

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 eval...

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 indiv...

Background Sodium glucose cotransporter‐2 inhibitors reduce systolic blood pressure (SBP), but whether they affect SBP variability is unknown. There also remains uncertainty regarding the prognostic value of SBP variability for different clinical outcomes. Methods and Results Using individual participant data from the CANVAS (Canagliflozin Cardiov...

Background The Victorian Salt Reduction Partnership (VSRP) implemented a media advocacy strategy (intervention) to stimulate food manufacturers to reduce sodium levels across targeted Australian packaged foods between 2017 and 2019. This study assessed changes in sodium levels of targeted and non-targeted packaged foods during the intervention (201...

Introduction Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. Research design and methods We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The...

Background Clinical trials are at the heart of medical research, 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. Methods This paper explores factors influencing the times to ethics...

Background Dietary sodium has a dose-response relationship with cardiovascular disease, and sodium intake in Sweden exceeds national and international recommendations. Two thirds of dietary sodium intake comes from processed foods, and adults in Sweden eat more processed foods than any other European country. We hypothesized that sodium content in...

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 P...

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There is a paucity of high-quality evidence on the effectiveness and safety of salt reduction strategies, particularly for older people, who have the most to benefit but are at higher risk of adverse effects. Here, we conducted a clinical trial in which 48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382...

Importance: Hypertension is the leading risk factor for premature death worldwide. Multiple blood pressure-lowering therapies are available but the potential for maximizing benefit by personalized targeting of drug classes is unknown. Objective: To investigate and quantify the potential for targeting specific drugs to specific individuals to max...

Rationale & objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the CREDENCE study. Study design: Secondary analysis of a randomized controlled...

From 2015 to 2020 a state-wide salt-reduction initiative was launched in Victoria, Australia, including an awareness campaign focused on parents with children <18 years of age. To evaluate the impact of the campaign on salt-related knowledge, attitudes and behaviors (KABs) we have assessed trends in salt-related KAB pre- and post-delivery of the ca...

Objective: In 2015, the Victorian Salt Reduction Partnership launched a 4-year multifaceted salt reduction intervention designed to reduce salt intake by 1 g/d in children and adults living in Victoria, Australia. Child-relevant intervention strategies included a consumer awareness campaign targeting parents and food industry engagement seeking to...

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 program. Materials and methods: Clinically relevant improvements in cardiovascular risk fact...

Background To reduce excess dietary sodium consumption, Nigeria’s 2019 National Multi-sectoral Action Plan (NMSAP) for the Prevention and Control of Non-communicable Diseases includes policies based on the World Health Organization SHAKE package. Priority actions and strategies include mandatory sodium limits in processed foods, advertising restric...

Background: The SSaSS (Salt Substitute and Stroke Study) recently reported definitive effects of a potassium-enriched salt on cardiovascular outcomes and death. Quantifying the amount of potassium-enriched salt used by trial participants is important for understanding the magnitude of the effect of potassium-enriched salt on risk reduction and how...

Background: In 2021, the World Health Organization (WHO) set sodium benchmarks for packaged foods to guide countries in setting feasible and effective sodium reformulation programs. We modeled the dietary and health impact of full compliance with the WHO's sodium benchmarks in Australia and compared it to the potential impact of Australia's 2020 s...

Increased consumption of unhealthy processed foods, particularly those high in sodium, is a major risk factor for cardiovascular diseases. The nutrition information on packaged foods can help guide consumers toward products with less sodium and support government actions to improve the healthiness of the food supply. The aims of this study were to...

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Background The worldwide control rate for hypertension is dismal. An inadequate number of physicians to treat patients with hypertension is one key obstacle. Innovative health system approaches such as delegation of basic tasks to non-physician health workers (task-sharing) might alleviate this problem. Massive scale up of population-wide hypertens...

Background Consumption of ultra-processed foods is associated with increased risk of obesity and non-communicable diseases. Little is known about current patterns of ultra-processed foods intake in Australia. The aim of this study was to examine the amount and type of ultra-processed foods purchased by Australian households in 2019 and determine wh...

Background People with type 2 diabetes mellitus (T2DM) have elevated cardiovascular (CV) risk, including for hospitalization for heart failure (HHF). Canagliflozin reduced CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS (CANagliflozin cardioVascular Assessment Study) Program and the CREDENCE (Canagliflozin a...

Background Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without di...

BACKGROUND Even modest reductions in blood pressure (BP) can have important impacts for population-level morbidity and mortality from cardiovascular disease (CVD). Two promising approaches are (1) the SaltSwitch smartphone application (app), which enables users to scan the barcode of a packaged food using their smartphone camera and receive an imme...

Background Even modest reductions in blood pressure (BP) can have an important impact on population-level morbidity and mortality from cardiovascular disease. There are 2 promising approaches: the SaltSwitch smartphone app, which enables users to scan the bar code of a packaged food using their smartphone camera and receive an immediate, interpreti...

Sodium glucose cotransporter 2 (SGLT2) inhibitors are associated with cardiovascular and renal benefits across a broad range of patients, with no increase in total serious adverse events. We evaluated the evidence with respect to amputation and fracture risks for this drug class. Overall, SGLT2 inhibitors are not associated with an increased risk o...

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 outc...

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce systolic blood pressure (SBP), but whether they affect SBP variability is unknown. There also remains uncertainty about the prognostic value of SBP variability for clinical outcomes. Methods: We conducted a post-hoc analysis of the CANVAS Program and CREDENCE trial in individuals...

Objectives: The potential for using routinely collected data for medical research in China remains unclear. We sought to conduct a scoping review to systematically characterise nation-wide routinely collected datasets in China that may be of value for clinical research. Methods: We searched public databases and the websites of government agencies,...

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 eff...

Background There is growing interest in Food is Medicine programs that incorporate food-based interventions into health care for patients with diet-related conditions. Objectives We aimed to test the feasibility of a “produce prescription” program and its impact on diet quality for people with type 2 diabetes (T2D) experiencing food insecurity in...

Front-of-pack labelling (FoPL) aims to promote healthier diets by altering consumer food purchasing behaviour. We quantify the impact of the voluntary Health Star Rating (HSR) FoPL adopted by New Zealand (NZ) in 2014, on (i) the quantity of foods purchased by HSR scores and food groups and (ii) the quantities of different nutrients purchased. We us...

Objectives The Salt Substitute and Stroke Study (SSaSS) recently reported blood pressure-mediated benefits of a potassium-enriched salt substitute on cardiovascular outcomes and death. This study assessed the effects of salt substitutes on a breadth of outcomes to quantify the consistency of the findings and understand the likely generalisability o...

Background The sodium‐glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardio...

Background: Salt substitution (ie, replacement of table and cooking salt with potassium-enriched salt substitutes) is a promising strategy to reduce blood pressure and prevent cardiovascular disease, particularly in countries like India where there is high sodium intake, mainly from discretionary salt, and low potassium intake. Life-threatening hy...

Background Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood...

OBJECTIVE To examine whether the circulating substrate mix may be related to the incidence of heart failure (HF) and cardiovascular (CV) mortality and how it is altered by canagliflozin treatment. RESEARCH DESIGN AND METHODS We measured fasting glucose, free fatty acids (FFA), glycerol, β-hydroxybutyrate, acetoacetate, lactate, and pyruvate concen...

Individuals with diabetic kidney disease (DKD) are at risk for progression, heart failure, and death. We assessed the association of KidneyIntelX, a bioprognostictest validated for DKD progression, with a composite time-to-event endpoint of 57% eGFR decline, kidney failure, heart failure hospitalization (HFH) , or death in a posthoc analysis of a s...

Background High dietary sodium intake is a leading cause of hypertension. A major source of dietary sodium is salt added to processed food products available in retail food environments. The fast-growing online grocery shopping setting provides new opportunities for salt reduction interventions that support consumers in choosing healthier options....

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 canaglif...

Key Points KidneyIntelX, a bioprognostic test for assessing risk of CKD progression, risk stratified individuals for kidney, heart failure, and death outcomes in the Canagliflozin Cardiovascular Assessment Study. Individuals scored as high risk seemed to derive more of benefit from treatment with canagliflozin versus placebo. These findings may ser...

Aims: The effect of sodium-glucose co-transporter 2 inhibitors on atrial fibrillation/flutter (AF/AFL) is unclear. We assessed the effects of canagliflozin on the incidence of AF/AFL and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. Materials and methods: Participants with T2D and high risk of cardiovascu...

Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk...

Objective Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial. Methods The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified...

Background: : The Salt Substitute and Stroke Study (SSaSS) ─ a five-year cluster randomized controlled trial, demonstrated that replacing regular salt with a reduced-sodium added-potassium salt substitute reduced the risks of stroke, major adverse cardiovascular events and premature death among individuals with prior stroke or uncontrolled high blo...

Objectives: To estimate the overall health impact in India of nationwide salt substitution (i.e., replacement of regular salt used at home for cooking or at the table with potassium-enriched reduced-sodium salt substitute). Methods: We used a comparative risk assessment framework to estimate 1) the number of cardiovascular disease (CVD) deaths aver...

Aims: Patients with type 2 diabetes mellitus (T2D) and PAD have a markedly elevated risk of macrovascular events and death. The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin has well-established cardiorenal benefits but net effects in patients with PAD remain uncertain. We sought to define the proportional and absolute benefits o...