Vlado Perkovic

Description:Background: Insulin is a mainstay treatment for diabetes, but its use is associated with weight gain and hypoglycaemia. Data on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on insulin use in people with chronic kidney disease (CKD) is limited. Methods: We conducted a post-hoc analysis of the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. Effects of canagliflozin versus placebo on insulin use (initiation, dose intensification, reduction and discontinuation) in people with CKD and type 2 diabetes were evaluated using Cox regression models. The primary outcome was insulin initiation or >25% insulin dose intensification (in those not receiving and receiving insulin at baseline, respectively). Effects on kidney, cardiovascular and safety outcomes by baseline insulin use were also assessed. Results: Among 4401 participants, 2884 (65.5%) were receiving insulin at baseline; these participants were more likely to have lower estimated glomerular filtration rate, higher albuminuria and longer duration of diabetes (all P<0.001). Over a median on-treatment period of 2.0 years, canagliflozin reduced the need for insulin initiation or >25% dose intensification by 19% compared to placebo (HR 0.81, 95% CI 0.71-0.93), irrespective of baseline kidney function or albuminuria (both P-interaction>0.10). Sustained insulin dose reductions of >50% were achieved more frequently with canagliflozin than placebo (HR 1.49, 95% CI 1.15-1.91), although no difference in insulin discontinuation was observed between treatment arms. Effects of canagliflozin on kidney, cardiovascular and safety outcomes were consistent regardless of baseline insulin use (all P-interaction>0.05). Conclusions: In CKD and type 2 diabetes, canagliflozin reduces insulin use with consistent effects regardless of baseline kidney function. This supports the use of canagliflozin in people with CKD, not only for end organ protection, but also to improve glycaemic control and reduce exposure to insulin and its associated adverse effects.

Description:Background: Glucagon-like peptide 1 receptor agonists (GLP-1RA) reduce the incidence of major adverse cardiovascular events (MACE) in type 2 diabetes (T2D), although whether benefits extend to both subcutaneous and oral formulations remains unclear. Objective: In these meta-analyses, including new data from the Semaglutide cardiOvascular oUtcomes triaL (SOUL) (oral semaglutide) and Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial, we examined cardiovascular (CV) and kidney benefits and risks of long-acting (defined as having pharmacokinetics sufficient to provide 24-h activity) GLP-1RA in T2D. Methods: A systematic review of PubMed was conducted (to 7 February 2025). Methods: Randomized placebo-controlled CV and kidney outcomes trials of GLP-1RA with ≥500 individuals with T2D were included. Methods: A random-effects model was used to estimate hazard ratios (HRs) for MACE, its components, all-cause mortality, hospitalization for heart failure (HHF), a composite kidney outcome (kidney failure [kidney replacement therapy or persistent estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2], sustained ≥50% eGFR decline or nearest equivalent, or kidney-related death), worsening kidney function, and safety outcomes. Results: Across 10 trials (n = 71,351), long-acting GLP-1RA reduced incidence rate of MACE by 14% (HR 0.86 [95% CI 0.81, 0.90]; I2 = 27.6%), HHF by 14% (0.86 [0.79, 0.93]; I2 = 2.1%), and the composite kidney outcome by 17% (0.83 [0.75, 0.92]; I2 = 20.4%) and all-cause mortality by 12% (0.88 [0.82, 0.93]; I2 = 17.5%). A consistent 14% reduction was seen for all MACE components. There was no significant heterogeneity by GLP-1RA administration route (subcutaneous vs. oral). There were no increased risks of severe hypoglycemia, retinopathy, or pancreatic events. Conclusions: Trial-level meta-analyses preclude detailed subgroup analyses and may introduce ecological bias. Conclusions: As a group, long-acting GLP-1RA, including both injectable and oral formulations, reduce incidence of MACE, HHF, and kidney events and all-cause mortality in T2D.

Description: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. To describe the design and baseline results of the Global Kidney Patient Trials Network (GKPTN) and the design and structure of the global adaptive platform clinical trial Chronic Kidney Disease Adaptive Platform Trial Investigating Various Agents for Therapeutic Effect (CAPTIVATE) to find new therapeutic options and treatments for people with kidney disease. The GKPTN is a multicenter registry that started in May 2020 and is ongoing, while CAPTIVATE is a multicenter, multifactorial, phase 3, placebo-controlled adaptive platform randomized clinical trial that includes patients with CKD. The first participant was randomized in September 2024. The GKPTN recruits patients from kidney and endocrinology practices, and CAPTIVATE aims to recruit patients from GKPTN sites where possible. Both the GKPTN and CAPTIVATE recruit patients with nondialysis CKD. CAPTIVATE will test several investigational agents or combinations of agents, beginning with a mineralocorticoid receptor antagonist. The GKPTN monitors clinical characteristics, treatment, and outcomes to identify eligible clinical trial participants and provide a contemporary global picture of patients with CKD. The primary outcome of CAPTIVATE is to identify investigational agents or combinations of agents to reduce the rate of chronic estimated glomerular filtration rate (eGFR) decline. The default maximum sample size per treatment arm in each domain, based on bayesian simulations, is 500 participants, providing approximately 90% power to detect a clinically meaningful improvement of 2.6 mL/min/1.73 m2 in eGFR at the end of the 104-week study period. The GKPTN has enrolled 4334 patients across 119 sites in 8 countries (US, Australia, Argentina, China, Italy, Canada, Spain, and Japan). The mean (SD) participant age at enrollment was 64.5 (16.2) years, 2542 participants (58.7%) were female, and diabetic kidney disease was most frequently reported among patients for CKD etiology (1875 [43.3%]). Among the participants, the mean (SD) eGFR was 52.9 (29.3) mL/min/1.73 m2, and the median urinary albumin-to-creatinine ratio was 89 mg/g (coefficient of variation, 20-420 mg/g). In the GKPTN cohort, the mean eGFR decline was steeper among participants with a baseline eGFR of 60 mL/min/1.73 m2 or more (-2.29 [95% CI, -3.14 to -1.44]) compared with those with an eGFR of less than 60 mL/min/1.73 m2 (-1.16 [95% CI, -1.77 to -1.44]) and was progressively steeper in more severe albuminuria subgroups. The GKPTN registry and the CAPTIVATE trial have the potential to expand and optimize therapeutic options for people with CKD using an adaptive platform clinical trial design. ClinicalTrials.gov Identifiers: NCT04389827 and NCT06058585.

Description: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 with a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period. Results: The main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed. Conclusions: Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

Description:Higher proteinuria and lower estimated glomerular filtration rate (eGFR) are predictors of kidney failure in IgA nephropathy (IgAN); however, it is uncertain whether these markers modify response to corticosteroids. This post hoc analysis of the TESTING trial assessed the effects of methylprednisolone on kidney and safety outcomes by baseline proteinuria and eGFR. A total of 503 participants with IgAN and proteinuria ≥ 1 g/d were randomized to oral methylprednisolone (full-dose 0.6-0.8 mg/kg/d or reduced-dose 0.4 mg/kg/d) versus placebo. Participants were categorized according to baseline proteinuria (1-< 1.5, 1.5-< 3, ≥ 3 g/d) and eGFR (20-< 30, 30-< 45, 45-< 60, 60-120 ml/min per 1.73 m2). Over a mean follow-up of 4.2 years, methylprednisolone lowered the risk of the primary outcome (≥ 40% decline in eGFR, kidney failure, or death because of kidney disease) by 47% (hazard ratio: 0.53, 95% confidence interval [CI]: 0.39-0.72), with consistent effects regardless of baseline proteinuria (P-interaction = 0.53) or eGFR (P-interaction = 0.68). Similarly, methylprednisolone improved the decline in total eGFR slope and reduced proteinuria, regardless of baseline proteinuria or eGFR (all P-interaction > 0.10). The number of serious adverse events (SAEs) was higher with methylprednisolone than with placebo across all proteinuria and eGFR levels. Absolute benefits and harms varied by eGFR, such that for those with eGFR < 30 ml/min per 1.73 m2, absolute risk of SAEs may outweigh potential advantages. However, this subgroup was small, predominantly received full-dose methylprednisolone, and was older than those with eGFR ≥ 30 ml/min per 1.73 m2. Methylprednisolone improves kidney outcomes in IgAN at high risk of progression, irrespective of proteinuria or eGFR, although the risk-benefit balance may be less favorable in those with advanced disease plus other risk factors for corticosteroid-related toxicities.