Efficacy and Safety of Henagliflozin, Retagliptin, and Metformin Extended-Release Tablets in Chinese Patients With Type 2 Diabetes Mellitus

Efficacy and Safety of Henagliflozin, Retagliptin, and Metformin Extended-Release Tablets in Chinese Patients With Type 2 Diabetes Mellitus

Given the significant and growing burden of Type 2 Diabetes (T2DM) in China, there is a continuous need for effective, convenient, and well-tolerated treatment strategies. This Phase IV, multicenter, prospective, observational study aims to evaluate the real-world effectiveness and safety of a novel, once-daily, fixed-dose combination (FDC) tablet containing Henagliflozin (SGLT2 inhibitor), Retagliptin (DPP-4 inhibitor), and Metformin Extended-Release in Chinese patients with T2DM. The study plans to enroll approximately 300 patients across 30 sites, stratified into two cohorts: newly diagnosed, drug-naïve patients and those with inadequate glycemic control on a single prior oral antidiabetic drug. The primary objective is to assess the change in Glycated Hemoglobin (HbA1c) from baseline after 24 weeks of treatment. Key secondary objectives include evaluating the proportion of patients achieving HbA1c targets (<7.0% and ≤6.5%), assessing changes in other metabolic parameters such as body weight, blood pressure, fasting and postprandial glucose, and lipid profiles, and monitoring treatment adherence. The safety evaluation will comprehensively document all adverse events, with special attention to events of interest including hypoglycemia, urinary/genital infections, volume-related events, and diabetic ketoacidosis. The study design includes a screening period, a 2-week run-in with lifestyle intervention, a 24-week core treatment period where eligible patients receive the FDC therapy, and a final safety follow-up. Efficacy and safety assessments are scheduled at baseline, Week 4, Week 12, and Week 24. Statistical analysis will be primarily descriptive, focusing on changes from baseline for continuous endpoints and frequency distributions for categorical endpoints, with analyses conducted separately for the two patient cohorts. The study will be conducted in full compliance with Good Clinical Practice (GCP), the Declaration of Helsinki, and relevant Chinese regulations, requiring prior ethics committee approval and written informed consent from all participants. This real-world evidence study seeks to confirm the clinical benefits and safety profile of this triple-combination therapy observed in earlier controlled trials, providing practical insights into its use in routine management of T2DM within the Chinese healthcare context.

1. Rationale China faces a high and growing burden of Type 2 Diabetes (T2DM). This Phase IV study evaluates a novel, once-daily, oral triple-combination therapy in a real-world setting. The fixed-dose combination (FDC) contains Henagliflozin (SGLT2 inhibitor), Retagliptin (DPP-4 inhibitor), and Metformin XR. These agents have complementary mechanisms: SGLT2 inhibition increases urinary glucose excretion, DPP-4 inhibition enhances incretin effects, and metformin reduces hepatic glucose output and improves insulin sensitivity. Prior Phase III data showed superior glycemic efficacy of this triple combination versus dual therapy. This study aims to confirm its effectiveness and safety in routine clinical practice.

2. Objectives & Endpoints Primary Objective: To evaluate the change in HbA1c from baseline after 24 weeks of FDC treatment.

   Secondary Objectives: To assess the proportion of patients achieving HbA1c targets (<7.0%, ≤6.5%), glycemic control without hypoglycemia, adherence, and changes in other metabolic parameters (weight, blood pressure, lipids, glucose).

   Safety Objective: To evaluate the FDC's safety profile.

   Primary Endpoint: Change in HbA1c from baseline to Week 24.

   Key Secondary Endpoints: Proportions achieving HbA1c targets; changes in body weight, systolic/diastolic blood pressure, fasting/postprandial glucose, lipid profiles; adherence rate; hypoglycemic events.

   Safety Endpoints: Incidence of Adverse Events (AEs), Serious AEs (SAEs), and AEs of Special Interest (e.g., hypoglycemia, urinary/genital infections, volume depletion, diabetic ketoacidosis, acute kidney injury).

3. Study Design This is a multicenter, prospective, observational, dual-cohort study targeting 300 patients from ~30 sites.

   Cohort 1 (n≈100): Newly diagnosed, drug-naïve T2DM (HbA1c 8.0-11.0%).

   Cohort 2 (n≈200): Patients with inadequate control (HbA1c 7.0-11.0%) on one prior oral antidiabetic drug (OAD).

   Study Flow:

   Screening/Run-in (Up to 5 weeks): Eligibility confirmed. A 2-week run-in involves lifestyle intervention (all) + continuation of prior OAD (Cohort 2 only).

   Treatment (24 weeks): Eligible patients start FDC tablet (one tablet QD). Assessments at Weeks 4, 12, and 24.

   Safety Follow-up: Telephone follow-up 7 days after last dose.

4. Key Eligibility Inclusion: Age 18-70; T2DM diagnosis; meets Cohort 1 or 2 criteria; BMI >19 & ≤40 kg/m².

   Exclusion: Type 1 diabetes; significant cardiovascular/renal/hepatic disease; history of pancreatitis, recurrent UTIs/ genital infections; pregnancy.

5. Assessments Efficacy: HbA1c, fasting plasma glucose, 2h postprandial glucose (meal tolerance test), insulin/C-peptide, body weight, waist circumference, blood pressure, lipid profile, uric acid.

   Safety: Physical exams, vital signs, lab tests (hematology, biochemistry, renal/hepatic function, urinalysis), and continuous AE monitoring.

6. Statistical Plan

   Analysis Populations:

   Full Analysis Set (FAS): Primary efficacy population.

   Safety Set (SS): All patients receiving ≥1 dose.

   Analysis: Descriptive statistics. Changes from baseline presented as mean ± SD with 95% CI. Analyses performed separately for both cohorts. One interim analysis is planned.

7. Ethics & Compliance The study will be conducted per ICH-GCP, Declaration of Helsinki, and Chinese regulations. IRB/EC approval and written informed consent are mandatory prior to initiation. Participant confidentiality is protected.

8. Planned Timeline Site Activation & Enrollment: Nov 2025 - Jun 2026

Treatment & Follow-up: Through Dec 2026

Data Analysis & Reporting: 2027

Inclusion Criteria:

1. Male or female aged 18 to 70 years (inclusive) at the time of signing the informed consent form.

2. Diagnosed with type 2 diabetes mellitus.

3. Voluntarily participate in this study and sign the informed consent form. If a subject is unable to read the informed consent form (e.g., an illiterate subject), an impartial witness must be present during the entire informed consent discussion and must also sign the consent form.

4. At screening, the subject must meet either of the following two criteria:

   1. Newly diagnosed with type 2 diabetes within 90 days prior to screening, with no prior use of any antidiabetic medication, and a screening HbA1c level between 8.0% and 11.0% (inclusive).
   2. Treated with any one oral antidiabetic drug [metformin (with a stable daily dose ≥1000 mg or the maximum tolerated dose documented in the patient's medical record), an alpha-glucosidase inhibitor, a sulfonylurea, a glinide, a thiazolidinedione, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), a dipeptidyl peptidase-4 inhibitor (DPP-4i), a glucokinase activator, or an oral glucagon-like peptide-1 receptor agonist] for at least 60 days prior to screening, with a screening HbA1c level between 7.0% and 11.0% (inclusive). The subject should have been on a stable dose of the medication for at least 30 days prior to screening.

5. Body Mass Index (BMI) >19 kg/m² and ≤40.0 kg/m².

Exclusion Criteria

1. Type 1 diabetes mellitus, monogenic diabetes, diabetes due to pancreatic injury, or other forms of secondary diabetes (e.g., diabetes secondary to Cushing's syndrome or acromegaly).
2. Fasting C-peptide <1.0 ng/mL (0.34 nmol/L) as measured by the local laboratory.
3. Known or suspected hypersensitivity to the investigational product or related compounds.
4. Participation in any other investigational drug trial within 3 months prior to the start of this study.
5. Use of traditional Chinese herbal medicine for glycemic control within 2 months prior to screening (except for cumulative use ≤7 days).
6. History of acute metabolic complications (e.g., ketoacidosis, lactic acidosis, hyperosmolar coma/state) within the past 6 months.
7. History of decompensated heart failure (NYHA Class IV), unstable angina, stroke or transient ischemic attack, myocardial infarction, severe arrhythmia, or cardiac surgery or vascular reconstruction (including coronary artery bypass grafting or percutaneous coronary intervention) within the past 6 months.
8. Severe infection, significant trauma, or major surgery within 30 days prior to screening.
9. History of acute or chronic pancreatitis.
10. Patients with malignancy and a life expectancy of less than one year, active tuberculosis, or acute infection.
11. Current or history of recurrent urinary tract infections and/or genital infections.
12. Patients with a history of hypertension whose blood pressure remains uncontrolled despite antihypertensive medication: systolic blood pressure (SBP) >180 mmHg and/or diastolic blood pressure (DBP) >110 mmHg.
13. Systolic blood pressure <90 mmHg at the screening visit, or patients judged by the clinician to be hypovolemic.
14. Moderate to severe renal impairment (eGFR <45 mL/min/1.73m²), end-stage renal disease, or patients on dialysis.
15. Men or women of childbearing potential unwilling to use effective contraception during the trial, or women who are pregnant or breastfeeding.
16. Alanine aminotransferase (ALT) >3.0 x ULN and/or aspartate aminotransferase (AST) >3.0 x ULN and/or total bilirubin >2.0 x ULN (upper limit of normal).
17. Any other condition that, in the investigator's judgment, renders the patient unsuitable for participation in this clinical trial.