Brendon Neuen, MBBS, PhD

Welcome to Kidney Compass: Navigating Clinical Trials!

Kidney Compass: SMART-C at ASN Kidney Week 2025

Kidney Compass: Navigating Clinical Trials

, Brendon Neuen, MBBS, PhD, doubles as a host and special guest as he offers host Shikha Wadhwani, MD, MS, a deep dive into the latest data from the the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) at the 

American Society of Nephrology (ASN) Kidney Week 2025

the large-scale meta-analyses provide comprehensive evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently reduce the risk of 

 progression, kidney failure, and related adverse outcomes across all levels of kidney function and albuminuria, regardless of diabetes status.

In the first analysis, the SMART-C team evaluated 70,361 participants from 10 randomized, placebo-controlled trials of SGLT2 inhibitors. Participants had a mean (SD) age of 64.8 (SD, 8.7) years, and 35.0% were female. During a median follow-up of 3 years, 2314 participants (3.3%) experienced CKD progression and 988 (1.4%) reached kidney failure.

SGLT2 inhibitors reduced the risk of CKD progression by 38% (25.4 vs 40.3 events per 1000 patient-years; hazard ratio [HR], 0.62 [95% CI, 0.57–0.68]), with consistent efficacy across eGFR categories:

≥60 mL/min/1.73 m²: HR, 0.61 (95% CI, 0.52–0.71)

45 to <60 mL/min/1.73 m²: HR, 0.57 (95% CI, 0.47–0.70)

30 to <45 mL/min/1.73 m²: HR, 0.64 (95% CI, 0.54–0.75)

<30 mL/min/1.73 m²: HR, 0.71 (95% CI, 0.60–0.83); 

Similar protection was observed across urinary albumin-to-creatinine ratio (UACR) levels, with HRs of 0.58 (95% CI, 0.44–0.76) for ≤30 mg/g, 0.74 (95% CI, 0.57–0.96) for 30–300 mg/g, and 0.57 (95% CI, 0.52–0.64) for >300 mg/g (

 for trend = .49). SGLT2 inhibitors also attenuated annual eGFR decline across all subgroups, including those without diabetes.

A complementary meta-analysis of 58,816 participants, including 48,946 with diabetes and 9870 without diabetes, across 8 clinical trials confirmed the broad efficacy and safety of SGLT2 inhibitors. Treatment significantly reduced kidney disease progression (HR, 0.65 [95% CI, 0.60–0.70] in diabetes; HR, 0.74 [95% CI, 0.63–0.85] without diabetes), acute kidney injury (HR, 0.77 [95% CI, 0.69–0.87] and HR, 0.72 [95% CI, 0.56–0.92]), all-cause hospitalization (HR, 0.90 [95% CI, 0.87–0.92] and HR, 0.89 [95% CI, 0.83–0.95]), and all-cause death (HR, 0.86 [95% CI, 0.80–0.91] and HR, 0.91 [95% CI, 0.78–1.05]).

Check out this interview with presenting investigator Natalie Staplin, PhD, for more on the 8-trial meta-analysis!

The magnitude of benefit was consistent across albuminuria strata (UACR ≥ 200 mg/g vs <200 mg/g), although absolute risk reductions were greater in those with higher baseline albuminuria.

 include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for

include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others.

Neuen BL, Fletcher RA, Anker SD, et al. SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis. 

 Published online November 07, 2025. doi:

Staplin N, Roddick AJ, Neuen BL, et al. Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria: A Meta-Analysis. 

Podcasts

Discover groundbreaking insights on SGLT2 inhibitors and their impact on kidney health, cardiovascular outcomes, and patient care at ASN Kidney Week.

Kidney Compass: The Future of Cardiovascular-Kidney-Metabolic Trial Design

, host Brendon Neuen, MBBS, PhD, is joined by Richard Pratley, MD, medical director at the Advent Health Diabetes Institute, and Muthiah Vaduganathan, MD, MPH, codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, to discuss the evolving landscape of clinical trials in cardiovascular-kidney-metabolic (CKM) syndrome, exploring how various study designs, patient engagement, and infrastructure development are reshaping research and evidence generation in this growing field.

A central focus of the discussion is the value and nuances of different trial designs, focusing specifically on SURPASS CVOT. The cardiovascular outcome study is the first to directly compare 2 incretin-based therapies, tirzepatide, a dual GIP/GLP-1 receptor agonist, and dulaglutide, a GLP-1 receptor agonist, among patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD).

Topline results showed tirzepatide achieved the primary objective by demonstrating a non-inferior rate of major adverse cardiovascular events (MACE-3), including cardiovascular death, heart attack or stroke, versus dulaglutide. Additionally, while not controlled for multiplicity-adjusted type-1 error, tirzepatide showed improvements on key measures of A1C, weight, renal function and all-cause mortality.

The speakers noted the active control design of the trial with a prespecified hierarchy of testing, highlighting the proven noninferiority of tirzepatide and its lack of association with excess cardiovascular risk, but no proven superiority. Additionally, the group discussed the use of imputed placebo analysis based on data from the REWIND trial of dulaglutide, allowing comparison of tirzepatide against a virtual placebo group and suggesting tirzepatide reduced major adverse cardiovascular events while remaining safe.

With the ability to conduct placebo controlled trials getting “narrower and narrower,” especially in areas like the incretin space, the speakers emphasize the importance of trial designs like SURPASS CVOT, additionally drawing parallels to the FLOW trial of semaglutide for diabetic kidney disease and assessing the possibility of applying a similar imputed placebo design to evaluate new incretin based therapies in CKD.

With standards of care shifting so rapidly in nephrology, the group explores how trials may need to be adjusted moving forward, discussing the need to account for more patients being on background therapy, mandate local standards of care, and incorporate aspects like active comparison against a traditional, accepted standard of care.

The trio goes on to describe potential trial designs for incretin-based therapies, citing the continued need for large outcomes-based trials and potential strategies to minimize placebo exposure as well as the pros and cons of different trial designs. Despite these challenges, the group notes that the difficulties in trial design are far outweighed by the benefits of bringing highly effective drugs to patients to decrease the risk of CKD progression and the cardiovascular consequences of CKD.

Editors’ note: Relevant disclosures for 

 include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for 

 include Novo Nordisk, Merck, Bayer, Eli Lilly and Company, Rivus Pharmaceuticals, and others. Relevant disclosures for 

 include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others.

Brooks A. SURPASS-CVOT: Tirzepatide Bests Dulaglutide for Cardiovascular Protection. HCPLive. July 31, 2025. Accessed September 29, 2025. 

https://www.hcplive.com/view/surpass-cvot-tirzepatide-bests-dulaglutide-cardiovascular-protection

Isaacs D, Bellini N. Diabetes Dialogue: FLOW Trial and Semaglutide's Benefit in Chronic Kidney Disease. HCPLive. May 25, 2024. Accessed September 29, 2025. 

https://www.hcplive.com/view/diabetes-dialogue-flow-trial-and-semaglutide-s-benefit-in-chronic-kidney-disease

Neuen B, Wadhwani S. Kidney Compass: FLOW Insights from Kidney Week 2024, with Katherine Tuttle, MD. HCPLive. October 28, 2024. Accessed September 29, 2025. 

https://www.hcplive.com/view/kidney-compass-flow-insights-from-kidney-week-2024-with-katherine-tuttle-md

Neuen is joined by Richard Pratley, MD, and Muthiah Vaduganathan, MD, MPH, to discuss the evolving landscape of CKM trial design.

Shaping the Next Era of IgA Nephropathy Treatment, With Brendon Neuen, MBBS, PhD

 is evolving at an unprecedented pace. Multiple new therapies are now available and others are progressing through clinical development, raising critical questions about how to best use these treatments in practice.

In the past few years, the US Food and Drug Administration (FDA) has granted accelerated approval to Novartis’ iptacopan (Fabhalta) and atrasentan (Vanrafia) as well as full approval to Travere Therapeutics’ sparsentan (Filspari) and Calliditas Therapeutics’ budesonide (Tarpeyo) delayed release capsules.

In a recent systematic review and meta-analysis of pooled phase 2 and phase 3 trial data for nonimmunosuppressive antiproteinuric therapies, corticosteroids, B-cell modulating agents, and complement inhibitors, Brendon Neuen, MBBS, PhD, a senior research fellow with the George Institute for Global Health and director of the Kidney Trials Unit with Royal North Shore Hospital, and a team of investigators found all 4 therapeutic classes reduce proteinuria, but to varying degrees.

Kidney function outcomes followed a similar pattern, with data from trials reporting eGFR slope over > 12 months indicating benefits for all drug classes, but with some evidence that effects varied by class.

“What I'm really looking forward to seeing, and I think many others are looking forward to as well, is the safety data from ongoing phase 3 trials of the immunological therapies, particularly the B cell related therapies, APRIL and BAFF inhibitors, because of the tremendous potential that these agents have in preventing kidney function decline,” Neuen told 

. “If the safety data is as good as what is suggested in earlier phase studies, I think that will really help guide treatment selection in IgA nephropathy.”

However, in the absence of head-to-head data, the practical question of sequencing therapies remains unsettled, with Neuen referencing a 

recent episode of Kidney Compass on the VISIONARY trial

 with guest Vlado Perkovic, MBBS, PhD, dean and scientia professor of Medicine at UNSW Sydney.

“I think this is where cost, availability, and other practicalities are going to come into play,” Neuen said. “Of course, it's always going to be preferable to target the immunological basis of the disease. But in many health care settings around the world, these agents may not be available, or if they are, they may be available at considerable costs.”

From a practical perspective, he says clinicians will be accessing therapies readily available to them, likely meaning nonimmunological antiproteinuric therapies will be used first and additional therapies will be added later.

Looking ahead, Neuen says he sees a “great opportunity” to explore a more personalized approach to IgAN therapeutics, but notes there are challenges in doing so with so many therapies available and limited ability to determine which patients will respond to which treatment.

“We're obviously not there yet, but I think that's the great opportunity and a real call to arms in terms of mechanistic research to identify biomarkers so that we can sequence these therapies and prioritize individuals for whom these drugs may work better,” Neuen said.

Editors’ note: Relevant disclosures for

include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others.

Campbell P. Atrasentan (Vanrafia) Receives Accelerated Approval in IgA Nephropathy. HCPLive. April 3, 2025. Accessed September 24, 2025. 

https://www.hcplive.com/view/atrasentan-vanrafia-receives-accelerated-approval-in-igan

Brooks A. FDA Approves Travere Therapeutics’ Sparsentan to Slow Kidney Function Decline in Adult Primary IgAN. HCPLive. September 5, 2024. Accessed September 24, 2025. 

https://www.hcplive.com/view/fda-approves-travere-therapuetics-sparsentan-for-proteinuria-reduction-in-adult-primary-igan

Campbell C. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. HCPLive. August 8, 2024. Accessed September 24, 2025. 

https://www.hcplive.com/view/iptacopan-receives-accelerated-approval-for-reducing-proteinuria-in-iga-nephropathy

Kim D, Neuen BL, Perkovic V, Wong MG. Effects of Therapies on Proteinuria and Estimated Glomerular Filtration Rate in IgA Nephropathy: Meta-Analysis of Randomized Trials. Clin J Am Soc Nephrol. 

Videos

Neuen describes varying treatment effects with 4 different classes of IgAN therapeutics and future opportunities for personalized treatment.

Innovation in IgAN: Exploring New Therapies and Combination Approaches, With Brendon Neuen, MBBS, PhD

“Therapeutic options for IgA nephropathy have expanded so rapidly in the last few years, and we now have multiple agents approved by regulatory agencies like the US FDA to reduce proteinuria and reduce kidney function decline,” Brendon Neuen, MBBS, PhD, a senior research fellow with the George Institute for Global Health and director of the Kidney Trials Unit with Royal North Shore Hospital, told 

. “The question that is being asked by clinicians now and is increasingly relevant, is how do we use these drugs? Which ones should we preferentially use, and can we use them in combination?"

To clarify how available treatments compare, Neuen and a team of investigators conducted a systematic review and meta-analysis in which they pooled phase 2 and phase 3 trial data for nonimmunosuppressive antiproteinuric therapies, corticosteroids, B-cell modulating agents, and complement inhibitors. Treatment effects on proteinuria and eGFR slope were pooled overall and by drug class.

Findings showed all 4 therapeutic classes reduce proteinuria, but to varying degrees. Nonimmunosuppressive therapies achieved about a 34% reduction, while corticosteroids and B-cell modulating agents produced 45–50% reductions. Complement inhibitors also showed benefit with about a 35% reduction, though the available data are more limited.

Kidney function outcomes followed a similar pattern, with data from trials reporting eGFR slope over > 12 months indicating benefits for all drug classes, but with some evidence that effects varied by class. Specifically, nonimmunosuppressive therapies slowed eGFR decline by roughly 28%, corticosteroids by 52%, and B-cell–directed agents by as much as 73%.4

“We have to be a little bit careful about these indirect comparisons across trials because these are very different populations across the studies,” Neuen explained. “What it does suggest, or at least raise the possibility of, is that how we reduce proteinuria is at least as important as to what extent we reduce proteinuria. What this highlights is the really important role of targeting the underlying immunological basis of the disease, where we see that the rates of GFR decline are substantially improved, in particular with the B cell modulating agents.”

Looking ahead, Neuen points to the need for safety data on the B-cell modulating agents, citing a current lack of complete 2-year eGFR slope data and accompanying safety data. From a research perspective, he raises questions about how to best evaluate these therapies in combination and generate evidence supporting the potential role of combination therapy for IgAN.

 include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others.

Campbell P. Atrasentan (Vanrafia) Receives Accelerated Approval in IgA Nephropathy. HCPLive. April 3, 2025. Accessed September 22, 2025. 

Brooks A. FDA Approves Travere Therapeutics’ Sparsentan to Slow Kidney Function Decline in Adult Primary IgAN. HCPLive. September 5, 2024. Accessed September 22, 2025. 

Campbell C. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. HCPLive. August 8, 2024. Accessed September 22, 2025. 

Neuen reviews recent advances in IgAN treatment and findings from a systematic review and meta-analysis guiding their use in clinical practice.

Brendon Neuen, MBBS, PhD

Articles