New Triple Therapy in Newly Diagnosed Type 2 Diabetes

Combination Therapy With Semaglutide, Empagliflozin and Pioglitazone Versus Standard Therapy in Newly Diagnosed Type 2 Diabetes: a Multi-center Randomized Controlled Trial

The goal of this clinical trial is to learn the efficany of combination therapy with semaglutide, empagliflozin and pioglitazone versus standard therapy in newly diagnosed type 2 diabetes. The main objectives to achieve are:

1. To compare efficacy of the triple combination therapy against standard therapy in achieving type 2 diabetes remission in patients newly diagnosed with T2DM.
2. To compare the effects on β-cell function and glycemic control of the triple combination therapy against standard therapy in patients newly diagnosed with T2DM

Researchers will compare drug new triple combination therapy with semaglutide, empagliflozin, and pioglitazone to standard therapy (metformin-based treatment) to see if new triple combination therapy works better in achieving type 2 diabetes remission .

Participants will:

1. Take new triple combination therapy or a standard therapy every day for 6 months
2. Visit the clinic once every 0.5-1 month for checkups and tests
3. Keep a diary of their fingertip blood glucose and adverse events

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: Group A (triple combination therapy group); Drug: Group B (standard therapy group)

• Study Type: Interventional
• Enrollment (Estimated): 296
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hai Li, MD, PHD; Phone Number: +86-15920362668; Email: lihai8@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • The First Affiliated Hospital of Sun Yat-Sen University
      • Contact: Hai Li, MD, PHD; Phone Number: +86-15920362668; Email: lihai8@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, 18 years≤age≤75 years at the time of signing informed consent.
2. Newly diagnosed with type 2 diabetes, or diagnosed within 1 years according to the WHO diagnostic criteria.
3. Individuals who had not received previous antidiabetic therapy, or had not received antidiabetic therapy within 3 months prior to screening, or had not received antidiabetic therapy for more than 3 consecutive months or a combined total of more than 3 months in the past 2 years.
4. 6.5%≤HbA1c≤9.0% at screening confirmed by central laboratory analysis.
5. BMI≥24 kg/m2.

Exclusion Criteria:

1. Individuals with type 1 diabetes or special types of diabetes.
2. Allergy or intolerance to investigational drugs.
3. Estimated Glomerular Filtration Rate (eGFR) <20 mL/min/1.73 m².
4. Individuals with heart failure in New York Heart Association [NYHA] class III or IV in the 6 months prior to randomization.
5. History of bladder cancer or hematuria.
6. History of Multiple Endocrine Neoplasia Type 2 (MEN 2) or relevant family history.
7. History or family history of Medullary Thyroid Carcinoma (MTC), or susceptibility to MTC due to hereditary conditions.
8. History of fasting blood glucose≥13.9 mmol/L or the necessity for insulin use due to severe infection, diabetic foot, etc.
9. History of acute diabetic complications: including diabetic ketoacidosis, hyperglycemic hyperosmolar state, lactic acidosis.
10. Severe diabetic microvascular complications: proliferative retinopathy, or urinary AER>300mg/g, or urinary protein positive, quantitative >0.5g/24h.
11. Uncontrolled painful diabetic neuropathy and significant diabetic autonomic neuropathy.
12. Severe diabetic macrovascular complications: myocardial infarction, stroke or hospitalization for unstable angina and/or transient ischemic attack and/or peripheral arterial disease required for vascular intervention or amputation within the 12 months prior to screening.
13. Blood pressure persistently higher than 180/110 mmHg and not controllable to ≤160/100 mmHg within 1 week.
14. Alanine Aminotransferase (ALT) ≥2.5 times the upper normal limit, total bilirubin ≥1.5 times the upper normal limit.
15. Hemoglobin <100g/L or requiring regular blood transfusion.
16. Use of medicines potentially affecting blood glucose for more than 1 week cumulatively in the past 12 weeks, such as corticosteroids, growth hormone analogs, estrogen/progestogen, high-dose diuretics, antipsychotic drugs, etc.
17. Participation in another trial involving medicine therapy within the past 3 months.
18. Expected lifespan less than 2 years as per the investigator's clinical judgment, e.g., but not limited to malignancy.
19. Pregnant or lactating females, or females of childbearing potential who cannot or are unwilling to use adequate contraception.
20. Deemed unsuitable for participation in this clinical trial at the discretion of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (triple combination therapy group); semaglutide, empagliflozin, and pioglitazone treatment. 1) Initiate with Semaglutide 0.25 mg once weekly (qw) + Empagliflozin 10 mg once daily (qd) + Pioglitazone 15 mg once daily (qd); 2) After 1 month, if blood glucose is not controlled, adjust to Semaglutide 0.5 mg qw + Empagliflozin 20 mg qd + Pioglitazone 30 mg qd. If Semaglutide is well-tolerated, increase to 1 mg qw after 1 week; 3)If blood glucose remains uncontrolled after 1 month, add basal insulin therapy.	Drug: Group A (triple combination therapy group); 1) Initiate with Semaglutide 0.25 mg once weekly (qw) + Empagliflozin 10 mg once daily (qd) + Pioglitazone 15 mg once daily (qd); 2) After 1 month, if blood glucose is not controlled, adjust to Semaglutide 0.5 mg qw + Empagliflozin 20 mg qd + Pioglitazone 30 mg qd. If Semaglutide is well-tolerated, increase to 1 mg qw after 1 week; 3)If blood glucose remains uncontrolled after 1 month, add basal insulin therapy.
Active Comparator: Group B (standard therapy group); metformin-based treatment is recommended when not contraindicated. 1).Initiate with Metformin monotherapy, titrate to the target dose of 1000 mg twice daily (bid) within 1 month or to the maximum tolerated dose (if Metformin is not tolerated, switch to Linagliptin 5 mg qd); 2) After 1 month, if blood glucose is not controlled, add a second antidiabetic drug, Empagliflozin 20 mg qd; 3) After another month, if blood glucose remains uncontrolled, add Semaglutide 0.25 mg qw, then increase to 0.5 mg qw after 1 month. If well-tolerated, increase to 1.0 mg qw after 1 week; 4) If blood glucose remains uncontrolled after 1 month, add basal insulin therapy.	Drug: Group B (standard therapy group); metformin-based treatment is recommended when not contraindicated. 1).Initiate with Metformin monotherapy, titrate to the target dose of 1000 mg twice daily (bid) within 1 month or to the maximum tolerated dose (if Metformin is not tolerated, switch to Linagliptin 5 mg qd); 2) After 1 month, if blood glucose is not controlled, add a second antidiabetic drug, Empagliflozin 20 mg qd; 3) After another month, if blood glucose remains uncontrolled, add Semaglutide 0.25 mg qw, then increase to 0.5 mg qw after 1 month. If well-tolerated, increase to 1.0 mg qw after 1 week; 4) If blood glucose remains uncontrolled after 1 month, add basal insulin therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diabetic remission rate	Diabetic remission rate at 6 months after discontinuation of medication (percentage of patients with HbA1c <6.5% at 6 months after discontinuation of medication)	6 months after discontinuation of medication

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diabetic remission rate	Diabetic remission rate at 3 and 12 months after discontinuation of medication and the time of diabetic remission	3 and 12 months after discontinuation of medication
Time required to achieve glycemic goal	The time required to achieve glycemic goal(FBG <6.1mmol/L, 2h PPG <8.0mmol/L or HbA1c<6.5%)	6 months of medication
EQ-5D-5L questionnaires, quality of life	EQ-5D-5L questionnaires, assessment of quality of life. The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflects the patient's own judgement.	At baseline, at 6 months of medication treatment, and at 3, 6, and 12 months after discontinuation of medication
Incremental cost per additional remission	Incremental cost per additional remission at 6 months after discontinuation of medication	6 months after discontinuation of medication
HbA1c	HbA1c level at baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication	baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication
Blood glucose level	Fasting and 2-hour postprandial blood glucose level at baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication	baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication
Blood insulin level	Fasting and 2-hour postprandial insulin level at baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication	baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication
Blood C-peptide level	Fasting and 2-hour postprandial C-peptide level at baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication	baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication
Pancreatic β-cell function	HOMA-B at baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication	baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication
Insulin resistance	HOMA-IR at baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication	baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication
Weight changes	Weight at baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication	baseline, at 6 months of medication, and at 3, 6, and 12 months after discontinuation of medication
Time in range (TIR)	Time within the target blood glucose range (3.9-10.0 mmol/L)	At baseline, at 6 months of medication treatment, and at 6 months after discontinuation of medication
Incremental cost per additional improvement in Time in Range (TIR)	Incremental cost per additional improvement in Time in Range (TIR) at 6 months of medication treatment, and at 6 months after discontinuation of medication	6 months of medication treatment, and at 6 months after discontinuation of medication
Incremental cost per QALY gained	Incremental cost per QALY gained, derived from EQ-5D-5L assessments at baseline, at 6 months of medication treatment, and at 3, 6, and 12 months after discontinuation of medication	at baseline, at 6 months of medication treatment, and at 3, 6, and 12 months after discontinuation of medication

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: March 3, 2025
• First Submitted That Met QC Criteria: April 20, 2025
• First Posted (Actual): April 27, 2025

Study Record Updates

• Last Update Posted (Actual): April 27, 2025
• Last Update Submitted That Met QC Criteria: April 20, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus
• Other Study ID Numbers: New Triple-2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No