Effects of Berberine on Preventing Cardiovascular Disease and Diabetes Mellitus

The trial aims to evaluate the efficacy and safety of berberine treatment for individuals with high cardiometabolic risk. Potential eligible patients will be recruited from about 100 medical centers in China. After a 4-to-6-week run-in period with berberine, all the eligible participants will be randomized (1:1) to berberine 500mg twice a day plus lifestyle intervention (Arm A) or placebo plus lifestyle intervention (Arm B). The participants will be followed up at month 3 and month 6, and once every 3 months thereafter, and be followed up for 3 years.

Inclusion criteria

• Participants aged ≥40 years old
• Participants with prediabetes, defined as glycated hemoglobin (HbA1c) between 5.7% and 6.4%
• Participants with body mass index>25kg/m2, or abdominal obesity (i.e., waist circumference ≥85 cm in female or waist circumference ≥90 cm in male)
• Participants with established atherosclerosis cardiovascular diseases (ASCVD), or with at least two cardiovascular risk factors: (a) hypertension (b) aged ≥45(male) / 55 (female), (c) current smoker, (d) HDL-C<1mmol/L or TG≥2.3mmol/L
• Participants with established ASCVD required LDL-C≤70 mg/dL (1.8mmol/L) for participants with ASCVD or receiving optimized LDL-C-lowering therapy (at least moderate-intensity statin therapy, unless contraindicated or intolerant)

Exclusion criteria

• Participants with FPG≥7.0 mmol/L, diagnosed with diabetes or taking oral glucose-lowering drugs
• Participants diagnosed with acute coronary syndrome, stroke, transient ischemic attack, or undergoing cardiac surgery or cardiac intervention (i.e., implantation of cardiac closure devices, cardiac resynchronization therapy, or catheter ablation), percutaneous coronary intervention or valvuloplasty/other cardiac valve repair or implantation surgery within the 3 months before randomization
• Participants who plan to perform coronary and/or non coronary revascularization surgery, or cardiac surgery within 6 months after randomization
• Participants diagnosed with heart failure or left ventricular ejection fraction<40%, severe cardiac valvular disease, cardiomyopathy, congenital heart disease
• Conditions known to interfere with the accuracy of HbA1c measurement, including rheumatoid arthritis, hemolytic anemia, aplastic anemia, hemoglobinopathies, splenomegaly, splenectomy, vitamin B12 deficiency, alcoholism, long-term high-dose aspirin use, or chronic use of anesthetics or hydroxyurea
• Recipients of major organ transplants (e.g., lung, liver, heart, bone marrow, kidneys, etc.)
• Participants diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Participants taking berberine or drug containing berberine in the past 1 month
• Participants with any adverse reaction to berberine
• Participants with severe constipation, diarrhea, and/or severe chronic intestinal diseases (e.g., ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc.)
• Participants who plan to have weight loss surgery, plan to take or currently taking drugs for weight loss
• Participants with active liver diseases, or alanine aminotransferase (ALT) / aspartate aminotransferase (AST) > 3 times upper limit of normal
• Estimated glomerular filtration rate (eGFR) < 45 ml/(min×1.73m2)
• Women who are pregnant or breastfeeding, or those who plan to be pregnant during the trial
• Participants with malignant tumors, or other serious diseases with life expectancy of less than 3 years
• Participants with mental disorders, cognitive disorders, or other serious diseases that could affect study participation
• Participants who participated or have been participating other trials during the last 3 months
• Any other conditions that may hinder the compliance to the study intervention or follow-up visit