Fuling Yunhua Granules and Dihuang Baoyuan Granules in Adults With Type 2 Diabetes and Inadequate Glycemic Control on Metformin Therapy

Inclusion Criteria:

1. Age 18 to 70 years (inclusive), male or female;
2. Body weight ≥50 kg for men and ≥45 kg for women at both screening and baseline; body mass index (BMI) between 23.0 and 35.0 kg/m2 (inclusive) at both visits;
3. Diagnosed with type 2 diabetes mellitus (T2DM) for at least 3 months according to the diagnostic criteria of the Chinese Guidelines for the Prevention and Treatment of Diabetes;
4. On a stable dose of metformin hydrochloride (≥1500 mg/day, or maximum tolerated dose ≥1000 mg/day) for at least 12 weeks during the 3 months prior to screening, while maintaining diet control and exercise therapy;
5. Glycated hemoglobin (HbA1c) ≥7.5% and <11.0% at screening (local laboratory); HbA1c ≥7.0% and <11.0% at baseline (central laboratory);
6. Fasting plasma glucose (FPG) <13.9 mmol/L at both screening and baseline;
7. Traditional Chinese Medicine (TCM) syndrome differentiation consistent with spleen Yin deficiency, Yin deficiency with internal heat accompanied by spleen dampness and stomach heat, and phlegm-fluid retention pattern;
8. Able to understand the procedures and methods of this study, willing to strictly abide by the clinical research protocol to complete this study, maintain the same diet and exercise habits throughout the trial, and voluntarily sign the informed consent form (ICF).

Exclusion Criteria:

1. History of allergic reaction to any component of the study drugs, intolerance or allergy to SGLT2 inhibitors, or history of significant allergic or hypersensitivity reaction to concomitant medications specified in this trial;

2. Non-type 2 diabetes mellitus: type 1 diabetes, gestational diabetes, or special types of diabetes (such as diabetes due to pancreatic injury, Cushing syndrome, or acromegaly);

3. History of acute diabetic complications within 6 months before screening (diabetic ketoacidosis, hyperosmolar hyperglycemic state, or lactic acidosis);

4. History of diabetic chronic complications with unstable condition or requiring treatment within 6 months before screening (proliferative retinopathy, severe diabetic neuropathy, or intermittent claudication, etc.);

5. Personal or family history of medullary thyroid C-cell hyperplasia, focal hyperplasia, or carcinoma (including sporadic, familial, or localized multiple endocrine neoplasia [MEN] type 2A or 2B syndrome);

6. History of acute or chronic pancreatitis, symptomatic gallbladder disease, or pancreatic injury, or other high-risk factors for pancreatitis deemed unsuitable for this trial by the investigator;

7. History of organ transplantation, or severe autoimmune diseases in the past or present (including but not limited to rheumatoid arthritis, systemic lupus erythematosus, and vasculitis);

8. History of recurrent urinary tract or reproductive system infections;

9. Diagnosed with malignant tumors within 5 years before screening (except for cured basal cell carcinoma of the skin or carcinoma in situ of the cervix), or currently under evaluation for potential malignancy;

10. Thyroid dysfunction that cannot be controlled with stable drug dosage at screening;

11. Any disease that may cause hemolysis or red blood cell instability affecting HbA1c measurement at screening (such as hemolytic anemia or thalassemia);

12. Severe trauma or severe acute infection that may affect glycemic control within 3 months before screening;

13. Severe cardiovascular disease within 6 months before screening, such as heart failure (New York Heart Association [NYHA] grade III-IV), myocardial infarction, coronary artery bypass grafting or percutaneous coronary intervention, sustained and clinically significant arrhythmia (such as second- or third-degree atrioventricular block, or QTcF interval prolongation [≥450 ms in males and ≥470 ms in females]), acute coronary syndrome, transient ischemic attack, hemorrhagic stroke, or ischemic stroke, deemed unsuitable for this trial by the investigator;

14. Diseases that may significantly affect drug absorption, distribution, metabolism and excretion within 6 months before screening: inflammatory bowel disease, peptic ulcer, history of gastrointestinal or rectal bleeding, history of major gastrointestinal surgery (such as gastrectomy, gastrointestinal anastomosis, or intestinal resection), etc.;

15. History of major surgery (intrathoracic, intracranial, abdominal, etc.) within 6 months before screening, or planned surgery during the study that may affect study completion or compliance;

16. Severe hypoglycemic event (Grade 3 or above) or recurrent unexplained hypoglycemic events (at least 3 episodes per month with blood glucose <3.9 mmol/L or symptomatic hypoglycemia) within 6 months before randomization;

17. Use of antihyperglycemic agents other than metformin within 2 months before screening, including but not limited to: alpha-glucosidase inhibitors (such as acarbose), thiazolidinediones, DPP-4 inhibitors, glucokinase activators, SGLT-2 inhibitors, or insulin (except for cumulative use ≤7 days due to concomitant disease, stress status, or perioperative period); or drugs that may affect glucose metabolism, including growth hormone therapy, and long-term or intermittent systemic glucocorticoids (intravenous or oral administration for >2 consecutive weeks or repeated courses, excluding inhaled or topical use);

18. Use of any immunosuppressant within 6 months before screening, or use of any drug that the investigator judges may affect trial results;

19. Medical or non-medical weight management within 3 months before screening, including unapproved weight management drugs or products, or weight change ≥5% within 3 months before screening (based on participant self-report), or weight change ≥5% (gain or loss) between randomization and screening;

20. Any laboratory test meets any of the following criteria at screening:

    Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN) ×2.5, or total bilirubin (TBIL) > ULN ×1.5; Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated using the CKD-EPI formula; Fasting triglycerides (TG) >5.7 mmol/L; Fasting C-peptide <0.8 ng/mL (or 0.26 nmol/L); Hemoglobin <100 g/L;

21. Hepatitis B surface antigen (HBsAg) positive at screening (if HBsAg positive, HBV DNA testing is required), or hepatitis C virus (HCV) antibody positive, or human immunodeficiency virus (HIV) antibody positive, or Treponema pallidum antibody positive;

22. Blood pressure poorly controlled at screening and baseline (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg);

23. Blood donation or massive blood loss (>400 mL) within 3 months before screening;

24. Participated in any interventional drug clinical trial within 3 months before screening (except screening failures without treatment);

25. Pregnant or lactating women, or men or women of childbearing potential who plan to become pregnant during the study or are unwilling to take medically recognized contraceptive measures;

26. Known or suspected alcohol dependence (defined as >14 units of alcohol per week; 1 unit equals 357 mL beer with 5% alcohol content, 45 mL spirits with 40% alcohol content, or 147 mL wine with 12% alcohol content) or drug abuse at screening;

27. Severe psychiatric disorder or language barrier that prevents adequate understanding and cooperation, or any other condition that the investigator considers makes the participant unsuitable for this study.