7-Ketolithocholic Acid in Prediabetes

• 7-KLCA (Dietary supplement): This is a prospective, randomized, double blind, multicenter study. Subjects will be randomized in a 1:1 ratio; each subject will be included into one of the two intervention groups. Each subject will attend 6 visits in total Visit 1: Day -7 (Screening, Informed consent signature, sampling for laboratory tests) Visit 2: Day 0 (Eligibility assessment, enrolment, randomization, drug dispense; diary dispense) Visit 3: Week +4 (Telephone call, diary verification) Visit 4: Week +8 (same as Visit 3) Visit 5: Week +12 (sampling for laboratory tests like Visit 1. Diary verification. End of treatment) Visit 6: Week +16 (End of Study, EOS. Same as visit 5, excluding OGTT) The onset of Adverse Events and the use of Concomitant Medications will be verified and, if necessary, recorded at every visit. Both groups will undergo a low-glycaemic, hypocaloric diet, and recommended physical activity.
• Placebo (Dietary supplement): This is a prospective, randomized, double blind, multicenter study. Subjects will be randomized in a 1:1 ratio; each subject will be included into one of the two intervention groups. Each subject will attend 6 visits in total Visit 1: Day -7 (Screening, Informed consent signature, sampling for laboratory tests) Visit 2: Day 0 (Eligibility assessment, enrolment, randomization, drug dispense; diary dispense) Visit 3: Week +4 (Telephone call, diary verification) Visit 4: Week +8 (same as Visit 3) Visit 5: Week +12 (sampling for laboratory tests like Visit 1. Diary verification. End of treatment) Visit 6: Week +16 (End of Study, EOS. Same as visit 5, excluding OGTT) The onset of Adverse Events and the use of Concomitant Medications will be verified and, if necessary, recorded at every visit. Both groups will undergo a low-glycaemic, hypocaloric diet, and recommended physical activity.
• Diet and Physical Activity (Other): The dietary intervention in this study involves a low-glycaemic, hypocaloric diet, aimed at improving glycaemic control, reducing fasting plasma glucose, and supporting weight management, based on official recommendations from authoritative bodies such as the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Physical activity is a cornerstone of lifestyle intervention in prediabetes. It improves insulin sensitivity, glucose metabolism, and cardiovascular risk factors, and facilitates weight management \[2,24\]. Combining physical activity with dietary modifications enhances prevention of progression to type 2 diabetes. All of the following will be recommended: aerobic exercise, resistance training, reducing sedentary time, flexibility and balance exercises.

Primary outcomes

• Mean change in Fasting Plasma Glucose (FPG) [Baseline and Week 12]: Difference in the mean change in fasting plasma glucose (FPG) from baseline to Week 12 between the treatment and placebo groups.

Secondary outcomes

• Difference in mean changes in HbA1c, cholesterol, LDL, HDL, body weight and/or BMI, waist circumference, 2 hr oral glucose tolerance test. [Baseline and Week 12]: To observe the effects of 7-Ketolithocholic Acid associated with diet and physical activity on glycaemic metabolism, lipid profile and BMI/waist circumference.

Other outcomes

• Assessment of overall safety and tolerability of 7-KLCA (400mg) administered for 12 weeks. [Throughout the course of the study period (12 weeks).]: Number and description of Adverse Events and Serious Adverse Events (including laboratory changes) in the two groups of treatment (7-Ketolithocholic Acid 400 mg and placebo administered for 12 weeks).

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

1. Male and female participants aged ≥18 years and ≤70 years.
2. Ability and willingness to provide written informed consent.
3. Diagnosis of prediabetes, defined by the following metabolic criteria:

   * Impaired fasting glucose (IFG): fasting plasma glucose levels between 100 and 125 mg/dL.
   * Impaired glucose tolerance (IGT): plasma glucose levels between 140 and 199 mg/dL measured 2 hours after a standard oral glucose tolerance test (OGTT).
   * Elevated HbA1c: HbA1c values between 5.7% and 6.4% (or 42 and 47 mmol/mol).
4. Body mass index (BMI) in the range 25-31 kg/m2 (inclusive).
5. Willingness to strictly comply with a low-glycaemic, hypocaloric diet during the study period and maintain a food diary.
6. Willingness to comply with recommended physical activity during the study period and maintain an activity diary.
7. Women of childbearing potential must agree to not become pregnant during the study and to use effective contraception (according to Recommendations related to contraception and pregnancy testing in clinical trials.

Exclusion Criteria:

1. Previous or current diagnosis of diabetes mellitus.
2. Presence of hypertension, defined as blood pressure >130/85 mmHg.
3. Hypertriglyceridemia, defined as fasting blood triglyceride levels ≥ 200 mg/dL.
4. LDL cholesterol ≥ 190 mg/dL.
5. Current treatment with oral hypoglycaemic agents or use of supplements with hypoglycaemic effects.
6. Use of any medication (self-medication or prescription medication) or supplementation potentially acting on glucose and lipid parameters within 28 days before entry in the study (or at least 5 times the respective elimination half-life, whichever is longer).
7. Any medical condition or treatment that, in the opinion of the investigator, could interfere with the study outcomes or participant safety.
8. Use of vitamin K antagonist anticoagulant drugs (such as warfarin).
9. Pregnancy or breast-feeding.
10. Any other condition that would preclude adherence to the study protocol or informed consent process, including, but not limited, to active or uncontrolled metabolic, endocrine, cardiovascular, renal, hepatic, pulmonary, gastrointestinal, neurological, endocrinological, immunological, or psychiatric disease.
11. Subjects with any history of hypersensitivity to the product under study or its excipients (please refer to Appendix B for listing of ingredients).