Diabetic Kidney Disease Clinical Trials: An Analysis of Current Research and Treatment Approaches

Diabetic kidney disease remains a critical area of clinical research, with numerous trials evaluating new therapeutic approaches to slow disease progression and preserve kidney function. Current research is exploring multiple drug classes and mechanisms, ranging from SGLT2 inhibitors to novel mineralocorticoid receptor antagonists and investigational compounds. Understanding the landscape of these trials can help patients and caregivers recognize what treatments are under investigation and what the broader research agenda addresses.

SGLT2 Inhibitors and Combination Strategies in Ongoing Trials

Sodium-glucose cotransporter 2 (SGLT2) inhibitors represent one of the most extensively studied drug classes in diabetic kidney disease research. The TRUTH-DKD trial, published in November 2025, is directly comparing tofogliflozin against metformin in 120 patients with type 2 diabetes and diabetic kidney disease, with enrollment targeting participants with an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) between 30 and 2000 mg/gCr 2. The study's design reflects a shift in diabetes management, where evidence for SGLT2 inhibitor benefits in reducing cardiovascular and renal events has grown substantially compared with older therapies. Beyond monotherapy, combination approaches are being evaluated. The CONFIDENCE trial demonstrated that simultaneous initiation of finerenone and empagliflozin produced additive benefits over monotherapy, with UACR reductions of 51% in combination-treated participants at 180 days compared with 34-36% in monotherapy groups 5. Among the 800 participants in CONFIDENCE, 23% were using a glucagon-like peptide 1 receptor agonist (GLP-1 RA) at baseline, and combination therapy remained effective in this subgroup, with hyperkalemia incidence rates of 9.0% among GLP-1 RA users and 9.5% among non-users 5.

The SUGARNSALT trial, conducted through the University of Washington Diabetes Institute, takes a different focus by examining sotagliflozin, a dual SGLT1/SGLT2 inhibitor, in persons with type 1 diabetes and moderate to severe diabetic kidney disease 4. This trial represents an important research direction because type 1 diabetes populations have historically been underrepresented in kidney disease trials. Participants in SUGARNSALT have an eGFR between 20 and 60 mL/min/1.73 m2 and UACR of at least 100 mg/g. The treatment duration is 3 years with an 8-week washout period, reflecting the long-term commitment required in kidney disease research to detect meaningful changes in eGFR decline.

Mineralocorticoid Receptor Antagonists: Traditional and Novel Approaches

Mineralocorticoid receptor antagonists (MRAs) represent another major research focus. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, is being evaluated in multiple trials. The SAFE-K study (Spironolactone Alternate Dosing vs Finerenone in Elevated Potassium) is designed to compare the safety profile of finerenone versus alternate-day spironolactone in patients with heart failure and diabetic kidney disease at high risk for hyperkalemia 8. This comparison directly addresses a clinical challenge: mineralocorticoid receptor antagonists provide renal and cardiovascular protection but can elevate serum potassium levels, potentially limiting their use in patients with advanced kidney disease. A real-world observational study (FINE-REAL) tracking 1,916 participants with a median follow-up of 260 days found that finerenone was initiated at 10 mg/day in 81% of participants and 20 mg/day in 19%, with 26% of those starting at 10 mg eventually increasing to 20 mg during follow-up 28. Hyperkalaemia occurred in 8% of participants overall but led to discontinuation in only 1% and hospitalization in 0.3%, with no fatal outcomes 28. For African American veterans, a dedicated trial is investigating finerenone and empagliflozin, addressing a critical research gap, as previous landmark studies included minimal African American participation (only 4.7% in key finerenone trials) despite African Americans experiencing chronic kidney disease at significantly higher rates 13.

A trial examining the combination of dapagliflozin and spironolactone in elderly patients with early diabetic nephropathy receiving high-dose renin-angiotensin system inhibitors enrolled 168 elderly outpatients, exploring whether combination therapy offers greater albuminuria reduction with acceptable hyperkalemia risk 9. Additional research evaluates balcinrenone, a non-steroidal mineralocorticoid receptor antagonist in combination with dapagliflozin in patients with chronic kidney disease and albuminuria 27.

Investigational and Novel Drug Classes

Beyond established drug classes, trials are investigating completely novel mechanisms. The ANCHOR-POC trial (NCT07271186), sponsored by Regeneron Pharmaceuticals, is assessing ANGPTL3 inhibition through a combination of small-interfering RNA (ALN-ANG3) and an ANGPTL3 antibody (evinacumab) in a randomized, double-blind, placebo-controlled Phase 2 study 1. This trial is recruiting 270 participants with diabetic kidney disease across multiple U.S. locations, including sites in Alabama, Arkansas, California, and other states. The dual mechanism (siRNA plus antibody) represents emerging therapeutic innovation targeting a pathway beyond traditional glucose control and blood pressure management. The HTD1801 trial (Negentropy), a mechanistic Phase 2 study being conducted by the Institute of Medicinal Biotechnology at the Chinese Academy of Medical Sciences, is randomizing 75 participants to HTD1801 or placebo twice daily for 12 weeks, examining effects on urinary albumin-to-creatinine ratio and renal function decline in type 2 diabetes and chronic kidney disease 7. The Kidney ABC trial (R3R01) is a Phase 2 study evaluating an ABCA1 inducer for effects on albuminuria levels in diabetic kidney disease, with recruitment ongoing at Copenhagen University Hospital at Herlev 10.

Kidney autologous cell therapy represents a distinctly different investigational approach. A Phase 2 randomized clinical trial (NCT05018416) assessed rilparencel, an autologous cell therapy composed of cells obtained by kidney biopsy, in 53 participants with diabetes and eGFR 20-50 mL/min/1.73 m2 6. In Cohort 1, which received two rilparencel injections into the kidney cortex 3 months apart, the annual eGFR slope improved from -5.84 mL/min/1.73 m2/year in the pre-injection period to -1.27 mL/min/1.73 m2/year after the last injection, representing a 78% improvement in the rate of kidney function decline 6. No serious adverse events related to rilparencel therapy were reported, and the interventional procedures were well tolerated with an acceptable safety profile 6.

GLP-1 Receptor Agonists and Metabolic Pathways

Glucagon-like peptide 1 receptor agonists continue to be evaluated in kidney disease trials. The SOUL trial examined the effects of oral semaglutide in 9,650 participants with type 2 diabetes, atherosclerotic cardiovascular disease, and/or chronic kidney disease, with a mean baseline eGFR of 73.8 mL/min/1.73 m2 17. Although oral semaglutide did not significantly reduce adverse kidney outcomes (five-point composite occurred in 8.4% of semaglutide recipients versus 9.0% of placebo recipients), it did slow the rate of eGFR decline from -2.06 mL/min/1.73 m2 annually with placebo to -1.67 mL/min/1.73 m2 annually with semaglutide 17. A prespecified secondary analysis of the FLOW trial evaluated semaglutide effects by baseline mineralocorticoid receptor antagonist (MRA) use, with 257 participants on MRA therapy and 3,276 not using MRA at baseline 18. Semaglutide reduced the risk of the primary kidney outcome by 49% in MRA users and 21% in non-MRA users 18.

Montelukast, a cysteinyl leukotriene inhibitor, is being investigated for its effects on inflammation in diabetes. The MIRACLE-T2D trial at the University of Colorado is recruiting 110 participants to evaluate whether montelukast improves kidney, eye, and vascular function in adults with type 2 diabetes and kidney disease 14. A separate trial, SMART 2D, is focusing on adolescents and young adults aged 14-24 with early-onset type 2 diabetes, exploring montelukast's potential to limit diabetic kidney and cardiovascular disease complications in this population 26. These trials reflect emerging recognition that inflammation driven by proinflammatory lipid mediators contributes to diabetic complications beyond hyperglycemia alone.

Combination Therapy and Rapid Initiation Strategies

Recent trials are examining whether initiating multiple guideline-directed therapies simultaneously offers advantages over sequential, staggered initiation. The RAPID-CKM trial is evaluating whether an Epic electronic health record-based clinician notification improves initiation of guideline-directed cardio-kidney-metabolic therapies in adults with type 2 diabetes and confirmed albuminuria 25. A related pilot trial, RAPID-CKD, tests the feasibility, safety, and effectiveness of rapidly starting finerenone, semaglutide, lisinopril, and an SGLT2 inhibitor simultaneously in a structured and closely monitored manner 24. This approach challenges current practice patterns where medications are typically initiated sequentially over months. The TRIDENT 2.0 study is an observational trial enrolling participants already undergoing kidney biopsy or surgery as part of routine clinical care, comparing kidney tissue patterns in those taking SGLT2 inhibitors with similar participants not using these medications, to determine whether SGLT2 inhibitors produce detectable biological changes at the tissue level 20.

Traditional Medicine and Specialized Populations

Clinical research extends beyond pharmaceutical compounds to traditional medicine approaches. The DKD-1 trial at China Medical University Hospital is a randomized controlled pilot evaluating a traditional Chinese medicine formula as add-on therapy to standard treatment in patients with diabetic kidney disease 11. Similarly, the Shenzhuo Formula trial is a randomized controlled clinical trial examining treatment of macroalbuminuria in diabetic kidney disease with evaluation of inflammation-modulating mechanisms 21. These trials reflect global diversity in investigational approaches and the inclusion of non-Western medical traditions in kidney disease research. The allopurinol trial at Mayo Hospital examined whether allopurinol with lisinopril offered additional kidney protection compared with lisinopril alone in 80 type 2 diabetic patients with normal serum uric acid, tracked over one year for changes in serum creatinine and spot urine albumin 12.

Trial Infrastructure and Regulatory Landscape

Diabetic kidney disease trials operate within a structured regulatory framework designed to ensure participant safety and data quality. The ICH Good Clinical Practice (GCP) guidelines establish international standards for trial conduct, with the ICH GCP clinical trials registry serving as a central repository for active, recruiting, and completed studies 1. The FINERENONE FIRST-2.0 China study represents an observational real-world effectiveness and safety study tracking 5,000 patients starting finerenone treatment, collecting data from electronic health records in everyday clinical practice settings 22. Study locations for trials such as ANCHOR-POC span multiple geographic regions; for example, ANCHOR-POC is recruiting at 57 sites across 17 U.S. states 1. Enrollment deadlines for actively recruiting trials extend years into the future, such as the ANCHOR-POC study enrollment deadline of April 7, 2028. Participants in these trials face specific eligibility requirements. The ANCHOR-POC trial requires type 2 diabetes with HbA1c between 6.5 and 10%, eGFR 30-90 mL/min/1.73 m2 using the 2021 CKD-EPI equation, and albuminuria criteria meeting study specifications 1. Understanding these parameters helps patients recognize whether they might meet eligibility criteria for participating in research.

Key Endpoints and Measurement Approaches

Current trials employ standardized endpoints to measure efficacy and safety. The urinary albumin-to-creatinine ratio (UACR) serves as a primary or secondary outcome in the majority of trials, reflecting its clinical significance as a marker of glomerular filtration barrier integrity. The UACR is typically stratified into categories: albuminuria below 30 mg/g (normoalbuminuria), 30-299 mg/g (microalbuminuria), and 300 mg/g or higher (macroalbuminuria). Trial designs often stratify participants by baseline UACR category to ensure balanced allocation across severity levels. The estimated glomerular filtration rate (eGFR) decline represents another critical endpoint, with trials measuring annual eGFR slope changes pre- and post-intervention. Composite endpoints frequently incorporate time to first occurrence of persistent eGFR reduction of 50% or greater from baseline, onset of kidney failure (eGFR <15 mL/min/1.73 m2 or need for dialysis), initiation of kidney replacement therapy, or death from kidney or cardiovascular causes. Hyperkalemia monitoring is mandatory in trials involving mineralocorticoid receptor antagonists or renin-angiotensin system inhibitors, given the risk of elevated serum potassium with these agents. Safety assessments include serious adverse events, treatment-emergent adverse events, and rates of treatment discontinuation due to safety concerns. Trials typically conduct assessments at baseline, during treatment periods at specified intervals (weekly, monthly, or quarterly), and at final visits. The duration of follow-up varies widely, from 12 weeks in mechanistic studies (such as HTD1801) to 3 years in longer-term trials (such as SUGARNSALT), to extended periods exceeding 4 years in landmark cardiovascular trials including diabetic kidney disease subgroups.

Sources

1. ICH GCP Clinical Trials Registry - Study to Assess the Effects of Angiopoietin-like Protein 3 (ANGPTL3) Inhibition in Adult Participants With Diabetic Kidney Disease (ANCHOR-POC), NCT07271186, Regeneron Pharmaceuticals
2. Springer Nature Link - Effect of Tofogliflozin on Urinary Albumin-to-Creatinine Ratio vs. Metformin in Diabetic Kidney Disease: Rationale and Study Protocol of the TRUTH-DKD Trial, Published November 18, 2025
3. ICH GCP Clinical Trials Registry - Proteinuria in Normotensive Diabetic Patients: ARBs Alone or in Combination of SGLT2i, NCT07586371
4. Cleveland Clinic - The SUGARNSALT Trial: Effectiveness and Safety of Sotagliflozin in Slowing Kidney Function Decline in Persons With Type 1 Diabetes and Moderate to Severe Diabetic Kidney Disease
5. PubMed/NCBI - Impact of Baseline GLP-1 Receptor Agonist Use on Albuminuria Reduction and Safety With Simultaneous Initiation of Finerenone and Empagliflozin in Type 2 Diabetes and Chronic Kidney Disease (CONFIDENCE Trial)
6. PubMed/NCBI - A Randomized Clinical Trial of Kidney Autologous Cell Therapy in Diabetic Kidney Disease, NCT05018416
7. ICH GCP Clinical Trials Registry - A Mechanistic Study on the Effect of HTD1801 Versus Placebo on Kidney Function in Patients With Type 2 Diabetes and Chronic Kidney Disease (Negentropy), NCT07496177
8. ICH GCP Clinical Trials Registry - Spironolactone Alternate Dosing vs Finerenone in Elevated Potassium: K Safety Study (SAFE-K), NCT07523867
9. ScienceDirect - Effect of Dapagliflozin-Spironolactone Combination Therapy Versus Monotherapy on Albuminuria Reduction and Hyperkalemia Risk in Elderly Patients With Early Type 2 Diabetic Nephropathy Receiving High-Dose RASi
10. deltatrials - The Evaluation of the Drug R3R01 for the Excretion of Protein in the Urine in Patients With Diabetic Kidney Disease (Kidney ABC), NCT06600412
11. ICH GCP Clinical Trials Registry - Effect of Chinese Herbal Medicine on Renal Function in Diabetic Kidney Disease, NCT07657351
12. ICH GCP Clinical Trials Registry - ALLOPURINOL AND LISINOPRIL FOR DIABETIC KIDNEY PROTECTION: A COMPARATIVE STUDY IN NORMOURICEMIC TYPE 2 DIABETICS, NCT07177898
13. ICH GCP Clinical Trials Registry - Finerenone and Empagliflozin Study for African American Veterans with Diabetic Kidney Disease
14. ICH GCP Clinical Trials Registry - MIRACLE-T2D Montelukast Intervention for Renal, Cardiovascular and Eye Health in Type 2 Diabetes, NCT07685886
15. Journal of Precision Clinical Medicine - Randomized Controlled Clinical Trial of Shenzhuo Formula in the Treatment of Macroalbuminuria in Diabetic Kidney Disease and its Inflammation-Modulating Mechanisms
16. UW Diabetes Institute - Sugar N Salt: Effectiveness and Safety of Sotagliflozin in Slowing Kidney Function Decline in Persons With Type 1 Diabetes and Moderate to Severe Diabetic Kidney Disease
17. PubMed/NCBI - Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial
18. PubMed/NCBI - Effects of Semaglutide With or Without Concomitant Mineralocorticoid Receptor Antagonist Use in Participants With Type 2 Diabetes and Chronic Kidney Disease: A FLOW Trial Prespecified Secondary Analysis
19. ICH GCP Clinical Trials Registry - Sodium Glucose Co-Transporter 2 Inhibitors on Estimated Glomerular Filtration Rate in Diabetic Versus Non-Diabetic Chronic Kidney Disease Patients, NCT07302464
20. ICH GCP Clinical Trials Registry - Transformative Research in Diabetic Nephropathy 2.0 (TRIDENT 2), NCT07444203
21. Journal of Precision Clinical Medicine - Randomized Controlled Clinical Trial of Shenzhuo Formula in Treatment of Macroalbuminuria in Diabetic Kidney Disease
22. ICH GCP Clinical Trials Registry - Finerenone FIRST-2.0 China Study: Evaluating Safety and Effectiveness for Diabetic Kidney Disease
23. ICH GCP Clinical Trials Registry - SMART 2D: Study of Montelukast's Effects on Renal and Cardiovascular Health in Adolescents and Young Adults With Type 2 Diabetes, NCT07409714
24. ICH GCP Clinical Trials Registry - RAPID-CKD: Simultaneous Initiation of 4 Guideline-Directed Therapies for Chronic Kidney Disease, NCT07547878
25. ICH GCP Clinical Trials Registry - RAPID-CKM: RAndomized EHR-based Prescribing to Improve Disease-modifying Therapies for Cardio-Kidney-Metabolic Care, NCT07605390
26. ICH GCP Clinical Trials Registry - Finerenone for Regression of Albuminuria in Type 2 Diabetes With Chronic Kidney Disease, NCT07667517
27. PubMed/NCBI - Balcinrenone in Combination With Dapagliflozin Compared With Dapagliflozin Alone in Patients With Chronic Kidney Disease and Albuminuria, Phase 2b Clinical Trial
28. PubMed/NCBI - Dosing, Treatment Patterns and Safety of Finerenone Use in Routine Care: An Interim Analysis of the Prospective, Real-World and Observational FINE-REAL Study