Vlado Perkovic

The George Institute for Global Health · Renal and Metabolic Division

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...

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...

Aim To estimate the lifetime benefit of a combination treatment of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors and mineralocorticoid‐receptor antagonists (MRA) in patients with type 2 diabetes and chronic kidney disease (CKD). Materials and Methods The cumulative effect of combination treatment was derived from trial‐level estimates of the...

Background Although sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney failure and death in patients with chronic kidney disease (CKD), they are underused in routine clinical practice. We evaluated the number of patients with CKD in Australia that would be eligible for treatment with an SGLT2 inhibitor and estimated the nu...

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 There remains substantial variation in the reported prevalence of CKD in Australia. Using a large, nationally-representative general practice data source in Australia, we determined the contemporary prevalence and staging of CKD in Australian primary care. Methods We performed a retrospective, community-based observational study using h...

Background and Aims Heart failure (HF) is a common cardiovascular (CV) complication in chronic kidney disease (CKD) [1]. Two CV outcome trials (ASCEND-ND [NCT02876835][2] and ASCEND-D [NCT02879305][3]) have provided the principal assessment of CV risk with daprodustat in CKD: both studies showed noninferiority of daprodustat to erythropoiesis-stimu...

Background and Aims IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis and has limited treatment options, especially for high-risk patients. Approximately 30-45% of IgAN patients progress to end-stage kidney disease over a period of 20-25 years and proteinuria is the strongest predictor of disease progression [1]. BION-1301 i...

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...

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....

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 cardiov...

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, rando...

Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents...

Background In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin improved kidney and cardiovascular outcomes and reduced the rate of estimated glomerular filtration decline (eGFR slope) in patients with type 2 diabetes a...

Introduction: Sparsentan is a novel single-molecule dual endothelin angiotensin receptor antagonist with hemodynamic and anti-inflammatory properties and is not an immunosuppressant. The ongoing phase 3 PROTECT trial examines sparsentan in adults with IgA nephropathy (IgAN). Methods: The PROTECT trial (NCT03762850) is a multicenter, internationa...

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...

National strategies for addressing chronic kidney disease (CKD) are crucial to improving kidney health. We sought to describe country-level variations in non-communicable disease (NCD) strategies and CKD-specific policies across different regions and income levels worldwide. The International Society of Nephrology Global Kidney Health Atlas (GKHA)...

Introduction: Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy because of its role in immunoglobulin A nephropathy (IgAN) pathophysiology. Iptacopan (LNP023), a proximal complement inhibitor that specifically binds to factor B and inhibits the AP, reduced proteinuria and attenuated AP activation in a Phase 2...

Background: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We re...

Background: The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305). Methods: ASCEND-ND randomized 3 872 patien...

Introduction: Bidirectional associations between hypoglycemia and cardiovascular (CV) outcomes were evaluated in 2 CV outcome trials of the DPP-4 inhibitor, linagliptin. Methods: CARMELINA and CAROLINA trials evaluated CV outcomes with linagliptin vs placebo or glimepiride, respectively, in adults with type 2 DM at high CV ± kidney risk; of the 2,...

Background: Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progressi...

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...

Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with heightened risks of stroke/systemic embolisation and bleeding. In this review we outline the evidence for AF stroke prevention in kidney disease, identify current knowledge gaps, and give recommendations for anticoagulation at various stages of chronic...

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 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...

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...

Aims Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease. Yet, after the initiation of statin therapy, the relative contributions of these processes may differ in patient groups, such as those with and without impaired kidney function. Methods and results Among 9151 stable statin-treated post-myocardial infarction patien...

Due to its possible neuroprotective effects, we hypothesize that canagliflozin may reduce adverse mental health outcomes in type 2 diabetes (T2D). In this exploratory analysis of the CANVAS program and CREDENCE trials, we aim to investigate this hypothesis as well as the frequency of psychiatric disorders in patients with T2D. The trials collective...

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...

Introduction: Diabetes is the most common cause of end stage kidney disease. Therapies such as sodium-glucose co-transporter-2 inhibitors have been identified over the last decade as effective oral hypoglycemic agents that also confer additional cardio and kidney protection. Knowledge of their mechanism of action and impact on patients with diabet...

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...

Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a sub‐study of the SONAR trial which enrolled adults wit...

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...

Introduction: The sodium glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin (CANA) reduced cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) at high CV risk in the CANVAS Program. CANA has been shown to reduce markers of inflammation in small clinical studies. Higher interleukin-6 (IL-6) levels, a key inflammatory mediator,...

Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D) that increases the risk of kidney failure and cardiovascular (CV) disease. Data from CV outcomes trials suggest that glucagon-like peptide-1 receptor agonists have kidney-protective effects. The FLOW trial (NCT03819153) will evaluate kidney outcomes with OW semaglutide i...

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...

Importance: The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain. Objective: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline. Design, setting, and participants: An international, multicenter, do...

BACKGROUND AND AIMS Chronic kidney disease (CKD) in type 2 diabetes (T2D) is the most common cause of kidney failure. Despite treatment advances, there is still a large unmet need to prevent CKD progression, which can increase the risk for cardiovascular (CV) disease and kidney failure. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have bene...

Objectives The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict heart failure (HF) risk. Background The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) i...

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 To develop a risk prediction model for the occurrence of severe acute kidney injury (AKI) in intensive care unit (ICU) patients receiving fluid resuscitation.Methods We conducted a secondary analysis of the Crystalloid vs. Hydroxyethyl Starch Trial (CHEST) trial, a blinded randomized controlled trial that enrolled ICU patients who receiv...

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...

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported. Objective: To evaluate the efficacy and safety of daprodustat vs da...

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...

Background: Clinical trials in chronic kidney disease enrich the trial population for patients with a high renal and cardiovascular risk by including patients with elevated urinary albumin creatinine ratio (UACR) and low estimated glomerular filtration rate (eGFR). Approximately half of all screen failures in these trials are attributed to UACR an...

Aim - Canagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy. Methods - The CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100mg daily or placebo. Neuropathy events were defined post-hoc as any rep...

Introduction The burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the variations in national prevalence within Asia. We aimed to consolidate available data and quantify estimates of the CKD burden in this region. Methods We system...

Background: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes (T2D). Methods: Pooled (N=12,637) and by-trial data from SUSTAIN 6 (N=3297) and LEADER (N=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persisten...

Background and objectives: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. Tumor Necrosis Factor Receptor (TNFR)-1, TNFR-2 and Kidney Injury Marker (KIM)-1 are known to be associated with...

Background Studies have suggested that sodium glucose co‐transporter 2 inhibitors exert anti‐inflammatory effects. We examined the association of baseline growth differentiation factor‐15 (GDF‐15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with t...

Background Anaemia is common in chronic kidney disease (CKD), and assessment of the risks and benefits of new therapies is important. Methods The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3–5, not using erythropoiesis-stimulating...

Background and objectives Atrasentan reduces the risk of kidney failure but increases the risk of edema and, possibly, heart failure. Patients with severe CKD may obtain greater absolute kidney benefits from atrasentan but may also be at higher risk of heart failure. We assessed relative and absolute effects of atrasentan on kidney and heart failur...

Background Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibit...

BACKGROUND Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibit...

BACKGROUND Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesisstimulating agent darbepoetin alfa, are unknown. METHODS In this randomized, open-label, phase...

BACKGROUND Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS In this randomized, open-label, phas...

Introduction: Despite optimal current care, up to 30% of individuals suffering from immunoglobulin A nephropathy (IgAN) will develop kidney failure requiring dialysis or kidney transplantation. The Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study was designed to assess the benefits and risks of steroids in people with I...

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...

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 biomar...

Background Whether early reduction in albuminuria with atrasentan treatment predicts its longterm kidney protective effect is unknown. Methods To assess long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled diabetic patients with chronic kidney disease (stage 2-4) and a urinary albumin creatinine ratio (U...

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 the...

Background Verinurad is a human uric acid transporter (URAT1) inhibitor known to decrease serum uric acid (sUA) levels and may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval: 4%, 62%) among patients with type 2...

Background Verinurad is a human uric acid transporter (URAT1) inhibitor known to decrease serum uric acid (sUA) levels and may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval: 4%, 62%) among patients with type 2...

The TESTING (Therapeutic Evaluation of STeroids in IgA Nephropathy Global) study is a multicenter, double-blinded, randomised, placebo-controlled trial designed to evaluate the long-term efficacy and safety of oral methylprednisolone, on a background of routine renin angiotensin system (RAS) inhibitor therapy, in preventing kidney events in patient...