Frederik Persson

Introduction. The risk of kidney failure (KF) varies among people with diabetes and chronic kidney disease. We aimed to investigate whether the risk of progression to KF differs by biopsy-proven type of kidney disease in type 2 diabetes (T2D). Methods. In this registry-based longitudinal cohort study, we identified all Danish adults with T2D who had a clinical kidney biopsy performed between 1994 and 2022. Using Poisson regression, we calculated the cumulative risk of KF with death as a competing risk. Results. We included 1203 individuals in the study, of which 1164 could be included in the final analysis: 483 had Diabetic Nephropathy (DN), 117 had mixed disease (coexistence of DN and non-DN (NDN)), and 564 had NDN. The risk of KF [95% CI] was 35% [29-42%] in DN, 18% [14-23%] in NDN and 33% [24-43%] in mixed disease after 3 years, and 47% [40-54%] in DN and 23% [18-29%] in NDN after 5 years. The 5xyear risk was not estimated for mixed disease due to the low number of cases. In DN, there was a significantly higher risk of KF from 3 to 5 years after the biopsy compared to NDN. In mixed disease, there was a significantly higher risk of KF compared to NDN after 3 years. There was no significant difference in the risk of KF between DN and mixed disease, however, the study may have been underpowered to detect a meaningful difference. Conclusion. Biopsy-proven DN and mixed disease are associated with an increased risk of KF compared to NDN in T2D. The study underscores the severity of kidney disease in T2D when histopathological changes caused by diabetes are present.

Background: Clinical guidelines recommend combined use of renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1RA) and nonsteroidal mineralocorticoid receptor antagonists (nsMRA) to reduce cardiorenal risk. However, eligibility for combination treatment and the potential effects of implementation on preventing mortality remain unclear. Methods: We conducted a microsimulation study using data from the National Health and Nutrition Examination Survey (NHANES 2007–2016 and 2017–2020). The model incorporated acute treatment effects of RASi, SGLT2i, GLP1RA, and nsMRA on estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and serum potassium. Eligibility for combination treatment was assessed for each participant according to 73 clinical practice guideline recommendations and inclusion criteria from recently published clinical trials. Primary outcomes included: 1) the percentage of participants eligible for single or combination treatment with RASi, SGLT2i, GLP1RA, and nsMRA, and 2) the projected potential number of annually averted all-cause and cardiovascular deaths. Results: Of 8,152 adults, 15% had type 2 diabetes (DM), 14% had chronic kidney disease (CKD) and 5% had DM and CKD (DKD). Among all U.S. adults, 19% were treated with RASi, 1% with SGLT2i, 1% with GLP1RA and none with nsMRA. The dual-therapy associated with the highest eligibility was RASi+SGLT2i, with 15% of the U.S. population eligible (DM subgroup: 70%; CKD subgroup: 50%; DKD subgroup: 84%). The triple-therapy with the highest eligibility was RASi+SGLT2i+GLP1RA, with 11% overall eligibility (DM: 69%; CKD: 33%; DKD: 83%). Eligibility for quadruple-therapy was 4% overall (DM: 22%; CKD: 17%; DKD: 40%). Based on our microsimulation model, fewer individuals with diabetes were eligible for triple-therapy with RASi+SGLT2i+GLP1RA compared to dual-therapy with RASi+SGLT2i, but triple-therapy was projected to prevent 2-fold more potential all-cause and cardiovascular deaths versus dual-therapy. Conclusions: Under the assumptions of our microsimulation model, eligibility for combined treatment with cardiorenal protective therapies was prevalent, particularly in adults with type 2 diabetes and/or CKD.

Background and Hypothesis: Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for its glucose-lowering effects in people with type 2 diabetes (T2D), as well as its cardiovascular and kidney-protective properties. However, it remains unclear whether semaglutide influences blood concentrations of endogenous filtration markers like creatinine, cystatin C, beta-trace protein (BTP), and beta-2 microglobulin (B2M). We investigated the effect of semaglutide on these filtration markers and the performance of estimated glomerular filtration rate (eGFR) equations compared with measured glomerular filtration rate (mGFR). Methods: Post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial. Individuals with T2D and albuminuria were randomized in a 1:1 ratio to receive semaglutide 1 mg weekly or matching placebo for 26 weeks on top of empagliflozin. mGFR was determined by 99m-Tc-DTPA plasma clearance and eGFR was calculated using CKD-EPI equations based on plasma creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of creatinine, cystatin C, BTP, and B2M (eGFRpanel). Outcomes included change in filtration marker concentration, mGFR, and eGFR from baseline to end-of-treatment, as well as eGFR performance compared to mGFR at each timepoint. Results: Among 48 participants (median age 70 years; 16.7% female), semaglutide treatment was associated with a small but significant increase in plasma creatinine and BTP compared with placebo, whereas there was no significant change in cystatin C or B2M. Semaglutide treatment was not associated with a significant change in mGFR (median [IQR] change of 0 [-7.5 to 10.3] mL/min/1.73 m2) compared with placebo (median [IQR] change of -2 [-11.3 to 3.0] mL/min/1.73 m2). Both eGFRcre and eGFRcys were consistently outperformed by eGFRcomb and eGFRpanel at baseline and end-of-treatment. Conclusion: Semaglutide treatment was associated with a small increase in plasma creatinine and BTP but not cystatin C or B2M, and eGFRcomb yielded the most reliable estimates of mGFR.

Context: Renin-angiotensin system inhibitors (RASi), sodium glucose cotransporter-2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (nsMRA), and glucagon-like peptide-1 receptor agonists (GLP-1RA) are key components of guideline-directed medical treatments (GDMT) for chronic kidney disease (CKD) with type 2 diabetes (T2D). However, the combined use of these medications remains uncommon in clinical practice, in part, due to the absence of specific guidance on implementing combination treatment. Herein, we aim to (1) summarize the evidence supporting combination GDMT in CKD with T2D, (2) propose a practical algorithm to guide the accelerated implementation of quadruple treatment, and (3) discuss strategies to improve the uptake of combination treatment. Evidence Acquisition: We searched PubMed from inception to present for English-speaking studies using the search terms: “renin-angiotensin system inhibitor,” “sodium glucose cotransporter-2 inhibitor,” “nonsteroidal mineralocorticoid receptor antagonist,” “glucagon-like peptide-1 receptor agonist,” and “diabetes.” We focused on clinical guidelines, randomized controlled trials (RCTs), and, if necessary, large observational studies. Evidence Synthesis: SGLT2i, nsMRA, and GLP-1RA confer early cardiovascular and kidney protection through independent mechanisms, allowing them to be combined. RCTs support the use of each agent on top of “standard care,” and multiple clinical guidelines endorse combination treatment. However, the optimal order and timing for medication initiation and the approach to managing treatment-related side effects remain uncertain, thereby limiting the uptake of combination treatment. Conclusion: Current evidence supports the use of combination GDMT in CKD with T2D. We propose a combination treatment algorithm that may combat clinical inertia and achieve greater cardiorenal risk reduction in high-risk patients with CKD and T2D.

Introduction Sodium-glucose cotransporter (SGLT) inhibitors have shown substantial benefit in reducing cardiovascular and kidney events across diverse clinical populations, but the underlying physiological mechanisms remain unclear. However, existing mechanistic studies on renal and cardiovascular haemodynamics show variability in design, have limited statistical power and yield inconsistent outcomes, thus limiting the ability to draw generalisable conclusions. To address this gap, we conducted a systematic review and proposed the first meta-analysis to aggregate individual participant-level data from mechanistic studies to identify consistent physiological patterns and enhance understanding of the therapeutic effects of SGLT inhibition. Methods and analysis Gold-standard measured glomerular filtration rate (mGFR) was selected as the primary outcome for this systematic review, which aimed to identify all completed mechanistic studies investigating the effects of SGLT inhibition. Electronic databases including Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; and Cochrane Central Register of Controlled Trials were searched using a detailed search strategy. In total, 24 studies (n=1296) were identified. This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key variables including demographics, medical history, concomitant medications, vital signs, mGFR, renal haemodynamics, urine and plasma biochemistry, tubular sodium handling, echocardiography, cardiac output monitoring, arterial stiffness and fluid volume will be extracted. A one-stage individual participant data meta-analysis under a Bayesian framework will be conducted, using hierarchical models to simultaneously analyse data from all eligible studies. The risk of bias due to missing results will be assessed. Sensitivity analyses and subgroup evaluations will be incorporated to explore sources of heterogeneity and assess robustness of findings. Ethics and dissemination Ethics approval was obtained from University Health Network, Toronto, Canada. Findings from the Mechanisms of SGLT Inhibitor Action and Physiological Mediators (MOSAIC) meta-analysis will be published in peer-reviewed journals and results will be disseminated at scientific conferences. PROSPERO registration number CRD420251001413.

Background and Aims Chronic kidney disease (CKD) significantly contributes to global morbidity and mortality. Early, targeted intervention offers an ideal strategy for mitigating this burden. Peptidomic changes inform on CKD onset and progression and hold insights for treatment strategies. We investigated the molecular effects of six different therapeutic interventions in silico in all possible combinations on the urine peptidome, aiming to identify the most beneficial treatment for individual patients. Method This study predicted major adverse kidney events (MAKE), defined as a ≥40% decline in estimated glomerular filtration rate (eGFR) or kidney failure (median follow up time of 1.50 (95%CI 0.35, 5.0)), using the urinary peptidomic classifier CKD273 in a retrospective cohort of 935 participants. The impact of various treatments on urinary peptidomic profiles, assessed from previous studies of four different drug-based interventions (MRA, SGLT2i, GLP1-RA and ARB), one dietary intervention (olive oil) or from exercise, was applied. Treatment effects were quantified through fold changes in peptide abundance after treatment, recalibrated to align with outcomes observed in randomized controlled trials and applied to patient-specific urinary profiles, simulating intervention effects and recalculation of CKD273 scores for each individual. For combination treatments, the effects of multiple interventions were combined to model their cumulative impact. Results Simulated interventions demonstrated a significant reduction in median CKD273 scores, from 0.57 (IQR: 0.19–0.81) before to 0.039 (IQR: -0.192–0.363) after intervention (paired Wilcoxon test, P < 0.0001), when the most beneficial treatment or combination of treatments was applied individually. The combination of all available treatments was found optimal only for 17.6% of the patients and not the most frequently predicted optimal intervention. Patients with higher baseline CKD273 scores required more complex intervention combinations to achieve the greatest reduction in scores. The findings present potential individualized treatment strategies in CKD management. Conclusion This study supports the feasibility of in silico predicting effects of therapeutic interventions on CKD progression. By identifying the most beneficial treatment combinations for individual patients, this approach paves the way for precision medicine in CKD. Urinary peptidomics data from different types of intervention were applied in silico to predict the impact of treatment, with the extent of the impact being calibrated to fit the observed effect in large randomized trials. The personalized optimal combination of interventions was determined in 935 patients, based on the impact on CKD273. The results indicate that guiding personalized treatment based on urine peptide data is possible and may substantially improve patient management.

Key Points: Risk modelling analysis of DEPICT trials show that dapagliflozin reduced estimated cardiovascular and kidney disease risk in T1D persons. Greatest reduction in estimated ESKD risk was accompanied by an expected rise in eGFR, after 4 weeks post drug discontinuation. Dedicated outcome trials with SGLT2 inhibitors are warranted in T1D persons with CKD or CVD for best determination of efficacy and risks. Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve glycemia and reduce insulin requirements in type 1 diabetes (T1D) and type 2 diabetes. Although SGLT2 inhibitors lower cardiovascular disease (CVD) and ESKD risk in type 2 diabetes, no dedicated cardiorenal outcome trials in T1D have been conducted to date. Using validated risk prediction models, this study evaluated the effect of SGLT2 inhibition on estimated CVD and ESKD risk in a T1D cohort. Methods: Demographics, medical history, and biomarkers were extracted from 1473 participants with T1D enrolled in the Dapagliflozin Evaluation in Patients with Inadequately Controlled Type -1 and -2 trials. Data at baseline, 24, 52, and 56 weeks (4 weeks after drug cessation) were used to estimate 10-year CVD and 5-year ESKD risk using the Steno T1 Risk Engine (SRE) and Scottish Diabetes Research Network (SDRN) risk prediction models. Risk reduction was determined on the basis of relative change in risk from baseline between participants receiving dapagliflozin (pooled 5 and 10 mg) versus placebo. Subgroup analyses were conducted by age, sex, diabetes duration, CVD risk, and CKD status at baseline. Results: The relative change in 10-year estimated CVD risk (SRE: –6.50% [–8.04% to –4.95%] and SDRN: –6.77% [–8.40% to –5.13%]; all P < 0.001) and 5-year ESKD risk (SRE: –4.48% [–7.68% to –1.28%]; P = 0.006) were lower at the end of 24 weeks of dapagliflozin treatment compared with placebo. Furthermore, the greatest relative change in 5-year ESKD risk was observed at week 56 (SRE: –12.84% [–16.65% to –9.03%]; P < 0.001), in conjunction with an expected rise in eGFR after drug washout. Subgroup analysis revealed larger relative lowering in 10-year CVD risk in those with CKD compared with those without (SRE: –11.3% versus –5.9%, and SDRN: –11.9% versus –6.1%, respectively; all P _interaction < 0.02). Conclusions: Dapagliflozin improves estimated CVD and ESKD risk in participants with T1D, emphasizing the need for cardiorenal outcome trials in people living with T1D.

Aim: Time‐restricted eating (TRE) limits the time for food intake to typically 6–10 h/day without other dietary restrictions. The aim of the RESET2 (the REStricted Eating Time in the treatment of type 2 diabetes) trial is to investigate the effects on glycaemic control (HbA_1c) and the feasibility of a 1‐year TRE intervention in individuals with overweight/obesity and type 2 diabetes. The aim of the present paper is to describe the protocol for the RESET2 trial.Methods: RESET2 is a randomised, controlled, parallel‐group, open‐label trial. One hundred and sixty individuals with type 2 diabetes (HbA_1c >53 mmol/mol (>7.0%)), and Body Mass Index ≥25 kg/m² will be randomised to standard care plus TRE, or to standard care and habitual living. Both the intervention and control group will follow standard diabetes care including regular clinical visits 3–4 times/year. The intervention is divided into two periods: (1) a 3‐month TRE period with a fixed eating window with a self‐selected timing to obtain data from the participants' experiences with TRE and (2) a 9‐month individually adjusted TRE period. Participants in the TRE group will be instructed to reduce their eating window by a minimum of 3 h/day compared to the habitual eating window and with an eating window of 8–10 h/day. Test days will be scheduled at baseline, after 3 months and after 1 year. The primary outcome is HbA_1c (evaluated 3 months and 1 year after randomisation) and secondary outcomes are body weight, fat mass, continuous glucose monitoring derived time‐in‐range and use of antidiabetic medicine (evaluated 1 year after randomisation). Additionally, we will conduct a process evaluation to assess whether the TRE intervention functioned as hypothesised.

Aims: This study aimed to explore the effect of discontinuation of long‐term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study. Materials and Methods: An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone ( n = 50) or placebo ( n = 65) for a median of 2.5 years, were re‐examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin‐creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow‐up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium. Results: No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI −12, 55; p = 0.28) nor the placebo (5%; 95% CI −13, 26; p = 0.63) group at follow‐up. No difference in UACR between the groups was observed at follow‐up (relative difference in geometric mean: 11%, 95% CI −26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05). Conclusions: UACR did not change after discontinuation of long‐term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys.