1. Study design
This study is a prospective, single-center parallel-group trial conducted at the Third Hospital of Peking University. Pre-diabetic patients will be included in the study if they meet the inclusion and exclusion criteria. The participants will be stratified by gender (male: female =1:1) and then randomly allocated to the intervention and control groups using a random number table. Patients in the intervention group will be administered Dapagliflozin 10 mg/day in addition to lifestyle intervention, while patients in the control group will be given lifestyle intervention only. Recommended lifestyle interventions include 30 minutes of moderate intensity exercise per day, with a total calorie reduction of 300 calories, according to Intervention for Adults with Pre-diabetes: A Chinese Expert Consensus.
The specific goals of lifestyle intervention include achieving or approaching a BMI of 24 kg/m2 for overweight or obese individuals, or at least a 5% initial weight loss within 3-6 months. Patients should not initiate during the study an organized diet and/or exercise weight reduction program other than the lifestyle and dietary measures for diabetes treatment. Study participants should be instructed not to donate blood or blood products during the study.
Physical activity: For optimal physical fitness, it is highly recommended to incorporate a combination of aerobic and resistance exercises daily for a minimum of 30 minutes. Aerobic exercises, including brisk walking, jogging, cycling, and swimming, should be performed at least three times weekly. Resistance exercises, which entail the utilization of resistance training equipment or free weights (such as dumbbells and barbells), should be integrated into the exercise regimen at least twice a week, in conjunction with regular aerobic exercise.
Dietary intervention: It is recommended that the daily total energy requirement comprises of 45%-60% from carbohydrates, 25%-35% from fats, and 15%-20% from protein. Additionally, it is advised that the daily dietary energy intake be reduced by a minimum of 300 kCal. Furthermore, it is crucial to limit the intake of saturated fatty acids to less than 30% of the total fat intake, and restrict daily salt intake to no more than 6g. Lastly, it is not advisable to consume alcohol, or if consumed, it must be included in the total energy intake.
A sample size estimation is implemented for this trial based on the comparison of the intervention and control groups with respect to the primary efficacy end point, the change from baseline at 12 weeks in 2h plasma glucose on an oral glucose tolerance test (OGTT) (2h-PG). The estimated decrease of 2hPG in the intervention and the control group is 2% and 1%, respectively. Additionally, participants will be stratified according to gender, as one purpose of this study is to explore whether and to what extent the drug has adverse effects on various genitourinary system. After a careful search of the relevant literature, the ratio of male to female pre-diabetic patients is approximately 1:1. Therefore, under the assumption of an estimated 10% dropout rate at 12 weeks in this trial, a total sample size of 120 participants, including 30 participants allocating to the intervention group and 30 participants to the control group in each gender, will provide the trial with 80% power to demonstrate the superiority of treatment with the use of a two-sample t-test at a two-sided alpha level of 0.05. Previous studies have indicated that approximately 30% of patients are over the age of 50, so it is anticipated to include:
A. 42 males under 50 years old B. 18 men aged 50-65. C. 42 women under 50 years old. D. 18 women aged 50-65.
2. Research process 1) Screening period. Individuals who meet the inclusion criteria and demonstrate good adherence to medication regimens will be eligible for inclusion in the study, and will be randomly assigned to the intervention and control groups. Subsequently, their basic information will be collected, including age, sex, body mass index (BMI), blood pressure, abdominal circumference, smoking history, cardiovascular disease history, amputation history, use of hypoglycemic and/or slimming drugs, history of biochemical hypoglycemia serious liver disease history, malignant tumor history, stroke history, and urogenital infection history. Then participants will undergo serial blood and urine testing for blood glucose and other metabolism parameters. Male participants may also receive semen analysis voluntarily. Finally, patients in the intervention group will be administered Dapagliflozin 10 mg/day in addition to lifestyle intervention, while patients in the control group will be only given lifestyle intervention.
2\) Follow-up stage. The follow-up cycle will be computed subsequent to the initiation of the intervention. Telephone follow-up will be carried out at week 4 and week 8 to assess the subjects' adherence to the prescribed medication, evaluate any potential adverse drug reactions, and record the type and time of physical activities. Concurrently, we will conduct patient education, optimize their treatment plans, and collect the incidence of pregnancy. Corresponding data will be recorded on the case report form.
During the final visit, clinical information of the participants will be obtained, including body mass index (BMI), blood pressure (BP), and waist circumference (WC). For female participants, pregnancy will be confirmed. In addition, serial blood and urine tests will be performed to examine blood glucose and other metabolic parameters. Finally, a summary of the experiment's process will be documented.
3.Statistical analysis We will utilize SPSS 25.0 software for statistical analysis. All statistical tests are two-tailed tests, and a P value of less than or equal to 0.05 will be considered statistically significant. Continuous data will be presented as mean ± SD if the measurement data are normally distributed. An independent sample t-test will be used to compare the different therapeutic effects between the parameters with and without the intervention of SGLT-2 inhibitors. Counting data will be represented as medians and interquartile ranges \[IQRs\], and compared using a Chi-square test between groups. Spearman's correlation analysis and binary logistic regression analysis will be employed for correlation analysis.
