Vlado Perkovic

The George Institute for Global Health · Renal and Metabolic Division

Aim SGLT2 inhibitors may be underused in older adults with type 2 diabetes due to concerns about safety and tolerability. This pooled analysis of the CANVAS Program and CREDENCE trial examined the efficacy and safety of canagliflozin according to age. Methods Pooled individual participant data from the CANVAS Program ( n = 10 142) and CREDENCE tri...

Importance Chronic kidney disease (CKD) is a global health priority affecting almost 1 billion people. New therapeutic options and clinical trial innovations such as adaptive platform trials provide an opportunity to efficiently test combination therapies. Objective To describe the design and baseline results of the Global Kidney Patient Trials Ne...

Background: The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway. Methods: In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria (defined as a...

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 and Aims In the FLOW trial, semaglutide reduced the risks of kidney and cardiovascular (CV) outcomes and death in participants with type 2 diabetes mellitus (T2D) and chronic kidney disease (CKD). These prespecified analyses assessed the effects of semaglutide on CV outcomes and death by CKD severity. Methods Participants were randomise...

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors both improve cardiovascular and kidney outcomes in persons with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitor...

Background: Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors are an oral treatment for anemia of chronic kidney disease (CKD). In this systematic review and meta-analysis, we assessed long-term safety of HIF prolyl hydroxylase inhibitors. Methods: We searched MEDLINE, Embase, and Cochrane databases for randomized trials comparing HIF...

Introduction The TESTING trial demonstrated that corticosteroids reduce the risk of kidney failure in patients with IgA nephropathy (IgAN) but increase the risk of serious adverse events. Reliable noninvasive biomarkers are needed to identify patients who would benefit most from corticosteroid therapy. Previous studies suggest glomerular macrophage...

Background Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor that reduces inflammation, fibrosis, and apoptosis. The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kidney disease. Methods We conducted a phase 2b study in adults with type 2 diabetes and eGFR 20 to <60 ml/min/1....

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...

People with type 2 diabetes and chronic kidney disease have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce CV and kidney events. The effect of combining both is unclear. FLOW trial participants with type 2 dia...

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 rac...

Background and hypothesis Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney, and cardiovascular outcomes in patients with CKD and T2D in two Phase 3 outcome trials. The FIND-CKD study investigates the effect of finerenone in adults with CKD without diabetes. Methods FIND-CKD (NCT05047263 and EU CT 2023–506897-11–00...

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...

Background: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. Methods: We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration...

Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. An unmet need for targeted disease-modifying treatments addressing its pathophysiology remains. There is compelling evidence for involvement of the alternative complement pathway (AP) in IgAN. Iptacopan binds to Factor B and specifically inhibits...

Key Points c The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD. c Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo. c Ver...

Clinical Trial registry name and registration number: ClinicalTrials.gov Identifiers: NCT02065791 (CREDENCE), NCT03036150 (DAPA-CKD), NCT03594110 (EMPA-KIDNEY). Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2024_09_23_CJASNSeptember19992.mp3

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...

Introduction The therapeutic effects of steroids in immunoglobulin A nephropathy (IgAN) global (TESTING) study reported that methylprednisolone reduces the risk of major kidney events in individuals with IgAN at high risk of disease progression compared to supportive care alone but is associated with increased serious adverse events (SAEs) primaril...

Background Patients with chronic kidney disease (CKD) are at higher risk for heart failure. The hypoxia inducible factor prolyl hydroxylase inhibitor daprodustat is an orally acting alternative to conventional injectable erythropoietin-stimulating agents (ESA) for the treatment of anemia in patients with CKD. Whether daprodustat affects the risk of...

Background Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine o...

Introduction The phase 3 DUPLEX trial is evaluating sparsentan, a novel, nonimmunosuppressive, single-molecule dual endothelin angiotensin receptor antagonist, in patients with focal segmental glomerulosclerosis (FSGS). Methods DUPLEX (NCT03493685) is a global, multicenter, randomized, double-blind, parallel-group, active-controlled study evaluati...

Background Metabolic acidosis is common in chronic kidney disease (CKD), but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. Methods In a Phase 3, double-blind, placebo-controlled trial, patients with CK...

OBJECTIVE The study was undertaken because it was unknown whether the duration of type 2 diabetes modifies the effects of sodium–glucose cotransporter 2 inhibitor canagliflozin on cardiovascular (CV) and kidney outcomes. RESEARCH DESIGN AND METHODS This post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program (N = 10...

BACKGROUND: This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention). METHODS AND RESULTS: This was a pooled participant-level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and R...

The global unmet need for kidney replacement therapy means that millions of people die every year as they cannot afford treatment. Peritoneal dialysis (PD) offers comparable survival to haemodialysis and is often more affordable, but one barrier to increasing access is that conventional manufacturing and distribution of PD fluid is costly. Here we...

Importance Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype. Objective To evaluate the associations between hypoglycemia and CV outcomes. Design, Setting, and Participan...

BACKGROUND An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin–angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longerterm treatment with sparsentan for FSGS are unknown. METHODS In this phase 3 trial, we enroll...

Background Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney failure and death in patients with chronic kidney disease (CKD) but are underused. We evaluated the number of patients with CKD in Australia that would be eligible for treatment and estimated the number of cardiorenal and kidney failure events that could be aver...

Background In the phase 2 RESCUE clinical trial, ziltivekimab, a fully human monoclonal antibody against the IL-6 ligand, significantly reduced the biomarkers of inflammation compared with placebo, in patients with CKD and systemic inflammation (high-sensitivity C-reactive protein ≥2 mg/L). The aim of this subanalysis of RESCUE trial data was to as...

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...

Introduction: Sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and the non-steroidal mineralocorticoid receptor antagonist finerenone all reduce cardiovascular events and mortality in patients with type 2 diabetes. However, the lifetime benefits of combination therapy with all three medicatio...

Introduction The prevalence of chronic kidney disease (CKD) in Australia varies substantially across reports. Using a large, nationally representative general practice data source, we determined the contemporary prevalence and staging of CKD in the Australian primary care. Methods We performed a retrospective, community-based observational study o...

Background Strategies to enable persistent use of renin–angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated. Methods We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clini...

Background The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR. However, the statistical method does not weigh the relative clinical importance of the end point components. A HCE accounts for the clinical importance of the end point components and enables combining dichotomous o...

Purpose of review Recent advances in the treatment of chronic kidney disease (CKD) have led to the development of several new agents that are kidney protective, particularly in people with diabetes. These agents include sodium/glucose cotransporter-2 inhibitors (SGLT-2 inhibitors), mineralocorticoid receptor antagonists (MRAs), and glucagon-like pe...

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...