Effectiveness of a Low-Calorie Diet Combined With Intensive Lifestyle Intervention Using Integrated Personalized Diabetes Management for Achieving Diabetes Remission in Patients With Type 2 Diabetes Mellitus

Participants will be randomized into two groups using block of four Group A: Intervention Group B: Standard care

Intervention group Phase 1: Intensive phase (Months 0-3) Month 0: Baseline assessment

• Data collection

• Demographics: sex, age, address, duration of diabetes, diabetes-related complications, comorbidities, current medications, drug/food allergies
• Physical examination: body weight, height, waist circumference, blood pressure, pulse rate
• Body composition analysis using bioelectrical impedance analysis (BIA)
• Fasting plasma glucose (FPG)
• Glycated hemoglobin (HbA1c)
• Fasting insulin
• Lipid profile
• Serum creatinine and electrolytes
• Liver function tests
• Urinalysis and spot urine albumin-to-creatinine ratio (UACR)
• Quality of life questionnaires: SF-36 and EQ-5D-5L
• Self-management questionnaire: Patient Activation Measure 13 (PAM-13)
• Mental health questionnaire: PHQ-2; if PHQ-2 ≥1, proceed with PHQ-9
• Education and support Structured diabetes remission education will be provided by certified diabetes educators, including physicians, nurses, dietitians, and exercise physiologists.
• Continuous Glucose Monitoring (CGM) Participants will wear a real-time CGM device (LinX CGM) for 15 days. Physicians will review the data via the LinX application every two weeks through telehealth consultations.
• Dietary intervention Participants will be provided with two low-calorie meals per day (400 kcal/meal; carb:protein:fat = 45:30:25) on Monday-Friday
• Nutrition education Participants will learn to calculate daily caloric intake (target ≤1,200 kcal/day) and record food intake on Saturdays and Sundays. Dietitians will review logs via telehealth every 2 weeks.
• Exercise program Participants will perform a 2-minute walk test and receive a personalized exercise plan. Exercise logs will be reviewed biweekly via telehealth with exercise physiologists.

Month 1

• Physical examination: body weight, height, waist circumference, blood pressure, pulse rate
• CGM for 15 days
• Medication review and adjustment
• Behavioral education reinforcement Month 2
• Physical examination: body weight, height, waist circumference, blood pressure, pulse rate
• CGM for 15 days
• Medication review and adjustment
• Behavioral education reinforcement Month 3
• Physical examination: body weight, height, waist circumference, blood pressure, pulse rate
• Body composition via BIA
• Laboratory investigations: FPG, HbA1c, fasting insulin, Lipid profile, creatinine, electrolytes, liver function tests, urinalysis, UACR
• Questionnaires: SF-36, EQ-5D-5L, PAM-13, and PHQ-2 (if PHQ-2 ≥1, proceed with PHQ-9)
• Satisfaction and experience questionnaire regarding CGM use Phase 2: Maintenance Phase (Months 3-6) During this 3-month phase, health educators will reinforce behavioral strategies aimed at achieving diabetes remission, with a daily caloric intake target not exceeding 1,500 kcal. Participants' body weight will be monitored monthly via telehealth.

Month 6: Final assessment

• Physical examination: body weight, height, waist circumference, blood pressure, pulse rate
• Body composition via BIA
• Laboratory investigations: FPG, HbA1c, fasting insulin, Lipid profile, creatinine, electrolytes, liver function tests, urinalysis, UACR
• Questionnaires: SF-36, EQ-5D-5L, PAM-13, and PHQ-2 (if PHQ-2 ≥1, proceed with PHQ-9)

Standard care group Participants will undergo data collection and follow-up with physicians at months 0, 3, and 6, following standard diabetes care. They will also receive diabetes remission education from certified diabetes educators at month 0, and a behavioral reinforcement session with health educators at month 3, similar to the intervention group.

Inclusion criteria

• Diagnosed with type 2 diabetes mellitus with HbA1c level of 6.0 to 9.0%. Participants with HbA1c of 6.0 to 6.4% were required to be receiving oral glucose lowering medication.
• Diagnosed with type 2 diabetes mellitus for less than 6 years.
• Body mass index of 23 kg/m2 or greater.

Exclusion criteria

• Receiving more than two oral glucose-lowering medications.
• Receiving insulin therapy.
• Use of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) within 3 months before study enrollment.
• Use of medications known to affect HbA1c within 3 months before study enrollment, including corticosteroids, vitamin C (excluding vitamin C obtained from natural dietary sources or fruits), vitamin E, trimethoprim-sulfamethoxazole, or hydroxyurea.
• History of diabetic ketoacidosis or hyperglycemic hyperosmolar state within the previous 6 months.
• Unstable psychiatric disorders within the previous 2 years, including major depressive disorder, bipolar disorder, or schizophrenia.
• Pregnant or breastfeeding women, or women planning to become pregnant within 12 months.
• Presence of any of the following medical conditions based on medical history and clinical records, including chronic kidney disease with an estimated glomerular filtration rate less than 45 mL/min/1.73 m2, liver cirrhosis or hepatitis with alanine aminotransferase or aspartate aminotransferase more than 3 times the upper limit of normal, chronic alcohol abuse, hypothyroidism with thyroid-stimulating hormone more than 10 uIU/mL, HIV infection, anemia (hemoglobin less than 10 g/dL), iron deficiency, vitamin B12 deficiency, folate deficiency, thalassemia, glucose-6-phosphate dehydrogenase deficiency, hemolytic anemia, or hemoglobin more than 16 g/dL, heart failure or ischemic heart disease within the previous 6 months.
• History of blood donation or blood transfusion within the previous 3 months.
• Uncontrolled diabetic retinopathy or other uncontrolled retinal disease, including maculopathy, based on medical records.
• Signs, symptoms, or a history of malignancy within 5 years before screening, except for basal cell carcinoma, squamous cell carcinoma of the skin, or other carcinoma in situ.
• Major surgery within 90 days before enrollment or planned major surgery within 6 months after enrollment.
• No access to a smartphone capable of supporting the study application and internet-based data transmission.
• Unable to maintain communication with the study investigators according to the study protocol.