QUARTET-DKD: Quadruple Therapy for Type 2 Diabetic Nephropathy

QUAdruple Therapy With RASi, Empagliflozin, Finerenone, and Mazdutide in Type 2 Diabetes and Early Treatment of Nephropathy(QUARTET-DKD)

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).

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.