Type 2 Diabetic Kidney Disease
Conditions
Keywords
SGLT2 inhibitors, Mineralocorticoid receptor antagonists, GLP-1 receptor agonists, Randomized controlled trial, angiotensin II receptor blocker, urinary albumin-to-creatinine ratio
Brief summary
This study employs a prospective, randomized, double-blind, parallel-controlled design, aiming to enroll adult participants with type 2 diabetic kidney disease (DKD) who meet the eligibility criteria. With an angiotensin receptor blocker (ARB) as the background therapy, all participants will be randomized in a 1:1:1:1 ratio into four treatment groups: Group 1 (G1): ARB + empagliflozin + finerenone placebo + mazdutide placebo; Group 2 (G2): ARB + empagliflozin + finerenone + mazdutide placebo; Group 3 (G3): ARB + empagliflozin + mazdutide + finerenone placebo; Group 4 (G4): ARB + empagliflozin + mazdutide + finerenone. The primary comparisons include G2 vs. G1, G3 vs. G1, G4 vs. G2, and G4 vs. G3, designed to evaluate the superiority of triple therapy over dual therapy, and quadruple therapy over triple therapy, in reducing the urine albumin-to-creatinine ratio (UACR).
Interventions
DRUGempagliflozin
Oral tablet, administered at a fixed dose of 10 mg once daily for 6 months.
DRUGFinerenone
Oral tablet, taken once daily for 6 months. Initial dose is 10 mg or 20 mg once daily adjusted based on baseline eGFR (20 mg for eGFR \>= 60 mL/min/1.73m²; 10 mg for eGFR 30-60 mL/min/1.73m²). Subsequent dose adjustments are guided by serum potassium levels and renal function.
DRUGMazdutide
Once-weekly subcutaneous injection for 6 months, following a mandatory dose-escalation schedule: initiated at 2 mg once weekly for 4 weeks, up-titrated to 4 mg once weekly for 4 weeks (if tolerated), and further increased to 6 mg once weekly as the target maintenance dose.
Oral tablet matching active finerenone in appearance and scheduling, without active ingredients, taken once daily for 6 months.
DRUGMazdutide Placebo
Once-weekly subcutaneous injection matching active mazdutide in appearance and scheduling, without active ingredients, for 6 months.
Standard background therapy, titrated to a stable dose for at least 4 weeks prior to enrollment and maintained throughout the 6-month study period.
Sponsors
Huijie Zhang
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years, with a confirmed diagnosis of type 2 diabetes mellitus (T2DM). * Receiving a standard dose of an Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin Receptor Blocker (ARB) therapy for at least 4 consecutive weeks prior to screening, with the dose expected to remain stable throughout the study period. * Body Mass Index (BMI) ≥ 24.0 kg/m2. * Mean urine albumin-to-creatinine ratio (UACR) ≥ 100 mg/g and \< 5000 mg/g, calculated from first morning void urine samples collected over 3 consecutive days. * Estimated glomerular filtration rate (eGFR) based on the CKD-EPI formula ≥ 30 mL/min/1.73m2 and ≤ 90 mL/min/1.73m2. * Serum potassium level ≤ 4.8 mmol/L. * Glycated hemoglobin (HbA1c) \< 11%. * Voluntarily understood and signed the written Informed Consent Form (ICF).
Exclusion criteria
* Definite diagnosis of non-diabetic kidney disease (e.g., IgA nephropathy, polycystic kidney disease, lupus nephritis, etc). * Personal or family history of medullary thyroid carcinoma (MTC), or a diagnosis of multiple endocrine neoplasia syndrome type 2 (MEN 2). * History of severe acute or chronic pancreatitis. * History of diabetic ketoacidosis (DKA). * Symptomatic hypotension during the screening period, or a resting systolic blood pressure (SBP) \< 110 mmHg. * Refractory hypertension, defined as a resting SBP \> 170 mmHg despite the concurrent use of three antihypertensive medications. * History of severe dehydration, severe diarrhea, or acute volume depletion within 30 days prior to screening. * History of acute kidney injury (AKI) within 30 days prior to screening. * Use of traditional Chinese medicines with potential proteinuria-lowering effects (e.g., Keluoxin capsules, Huangkui capsules, or Shenyan Kangfu tablets) within 30 days prior to screening. * Use of potassium-sparing diuretics (e.g., triamterene or amiloride) or mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone, or finerenone) within 2 months prior to screening. * Use of GLP-1 receptor agonists, GLP-1/GIP dual receptor agonists, or GLP-1/glucagon (GCG) dual receptor agonists within 6 months prior to screening. * Current use of strong CYP3A4 inhibitors (e.g., itraconazole or clarithromycin) or CYP3A4 inducers that may significantly interfere with finerenone metabolism. * Myocardial infarction, unstable angina, stroke, or hospitalization due to heart failure (NYHA Class III-IV) within 3 months prior to screening. * Active urogenital tract infection, or a history of urogenital tract infection associated with the prior use of SGLT2 inhibitors. * Women who are pregnant, planning to become pregnant, or lactating. * Inability to complete the 6-month follow-up due to general health conditions or geographic relocation. * Any other condition that, in the opinion of the investigator, renders the participant unsuitable for participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Month 6 | Baseline and Month 6 | Relative change of UACR from baseline to Month 6 will be utilized for comparison between the treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving UACR Reductions of ≥30% and ≥50% | Baseline and Month 6 | The proportion of patients in each group who achieve a clinical response, defined as a reduction of ≥30% and ≥50% in UACR compared to their respective baseline values. |
| Regression Rate of Albuminuria Stages | Baseline and Month 6 | The percentage of participants demonstrating a regression in albuminuria category, including regression from macroalbuminuria to microalbuminuria, or from microalbuminuria to normoalbuminuria. |
| Relative Change From Baseline in UACR at Day 30 | Baseline and Day 30 | Early relative change in UACR to evaluate the short-term response between treatment groups |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Baseline and Month 6 | eGFR is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to monitor renal function progression. |
| Change From Baseline in Body Weight and Body Mass Index (BMI) | Baseline and Month 6 | Evaluation of the metabolic impact of the multi-drug regimens on body weight (measured in kilograms) and BMI (measured in kg/m²). |
| Change From Baseline in Hemoglobin A1c (HbA1c) and Fasting Plasma Glucose (FPG) | Baseline and Month 6 | Assessment of glycemic control efficacy across different treatment groups. |
| Change From Baseline in Systolic Blood Pressure (SBP) | Baseline and Month 6 | Evaluation of the blood pressure-lowering effects between different treatment groups. |
| Change From Baseline in Serum Potassium Levels | Baseline and Month 6 | Monitoring the safety profile regarding potassium homeostasis, particularly concerning the use of the non-steroidal MRA (finerenone). |
| Incidence of Adverse Events of Special Interest (AESIs) | Through Month 6 | The percentage of participants experiencing predefined adverse events of interest, including hyperkalemia, symptomatic hypotension, urinary tract infections, hypoglycemia, and diabetic ketoacidosis. |
| Incidence of Acute Kidney Injury (AKI) | Through Month 6 | The percentage of patients who meet the clinical diagnostic criteria for Acute Kidney Injury during the treatment period. |
Countries
China
Contacts
CONTACTjingjing jiang, PhD
Outcome results
None listed