Abdominal Obesity, Atherosclerotic Cardiovascular Disease, Dyslipidemias, Hypertension, PreDiabetes
Conditions
Brief summary
This multicenter, double-blinded, randomized controlled trial aims to evaluate the effect of berberine on preventing cardiovascular disease and diabetes mellitus among individuals with high cardiometabolic risk in China.
Detailed description
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.
Interventions
berberine hydrochloride 500mg twice a day plus lifestyle intervention. Lifestyle intervention is based on Chinese guideline for primary prevention of cardiovascular diseases, and Chinese guideline for management of type 2 diabetes mellitus, coronary heart disease, myocardial infarction and stroke. Intervention includes health education on smoking, alcohol consumption, diet, physical activity and weight loss, etc.
BEHAVIORALPlacebo plus lifestyle intervention
Placebo with identical shape, colour, odour and taste twice a day plus lifestyle intervention. Lifestyle intervention is based on Chinese guideline for primary prevention of cardiovascular diseases, and Chinese guideline for management of type 2 diabetes mellitus, coronary heart disease, myocardial infarction and stroke. Intervention includes health education on smoking, alcohol consumption, diet, physical activity and weight loss, etc.
Sponsors
China National Center for Cardiovascular Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The distribution of glycemic status at 1 year after randomization | Intervention Period: 1 year | Categorized as normal glucose metabolism, prediabetes, and diabetes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of inflammation-related marker | Intervention Period: 1 year | Including high-sensitivity C-reactive protein (hs-CRP) |
| Change of physical examination measures | Intervention Period: 1 year | Including body mass index (BMI) and waist circumference |
| Changes of other parameters | Intervention Period: 1 year | Including urinary albumin-to-creatinine ratio (UACR), serum uric acid, and metabolic syndrome score |
| Change of depressive symptoms | Intervention Period: 1 year | Measured by Patient Health Questionnaire-9 (PHQ-9) |
| Time to first occurrence of composite endpoint of major cardiovascular event and diabetes | Intervention Period: 1 year | cardiovascular death, non-hemorrhagic stroke, myocardial infarction, arterial revascularization, and diabetes |
| Time to new-onset diabetes | Intervention Period: 1 year | Diabetes is determined by oral glucose tolerance test, clinical diagnosis or use of glucose-lowering medications. |
| Normalization of glucose parameters | Intervention Period: 1 year | Meeting all three criteria: 1) Fasting plasma glucose (FPG)\<6.1 mmol/L; 2) 2-hour postprandial blood glucose (2hPG)\<7.8 mmol/L; 3) HbA1c\<5.7%. |
| Time to newly diagnosed cancer | Intervention Period: 1 year | all events of cancer or classified by primary sites |
| Exploratory biomarker analyses | Intervention Period: 1 year | Including serum trimethylamine, trimethylamine N-oxide, dopamine, berberine metabolites, and lipidomics analyses; urinary berberine metabolite analyses; and gut microbiota sequencing analyses. |
| Time to first occurrence of composite endpoint of major cardiovascular event 1 | Entire follow-up period: 4 years | cardiovascular death, non-hemorrhagic stroke, myocardial infarction, arterial revascularization |
| Time to first occurrence of composite endpoint of major cardiovascular event 2 | Entire follow-up period: 4 years | cardiovascular death, non-hemorrhagic stroke, myocardial infarction |
| Changes of glycemic-related parameters | Intervention Period: 1 year | Including hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) |
| Changes of lipid-related parameters | Intervention Period: 1 year | Including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and lipoprotein(a) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Subgroup analysis 3 for primary outcome measure | Intervention Period: 1 year | Body mass index (\<28kg/m2, ≥28kg/m2) |
| Subgroup analysis 4 for primary outcome measure | Intervention Period: 1 year | Statin use (yes, no) |
| Subgroup analysis 5 for primary outcome measure | Intervention Period: 1 year | HbA1c median |
| Subgroup analysis 6 for primary outcome measure | Intervention Period: 1 year | Hs-CRP tertiles |
| Subgroup analysis 7 for primary outcome measure | Intervention Period: 1 year | LDL-C tertiles |
| Subgroup analysis 8 for primary outcome measure | Intervention Period: 1 year | Triglyceride tertiles |
| Subgroup analysis 9 for primary outcome measure | Intervention Period: 1 year | HDL-C tertiles |
| Safety assessment during the intervention period | Intervention Period: 1 year | Including serious adverse events, non-serious adverse events of special interest, and treatment discontinuation for any reason |
| Subgroup analysis 1 for primary outcome measure | Intervention Period: 1 year | Age (\<55，55-65，≥65) |
| Subgroup analysis 2 for primary outcome measure | Intervention Period: 1 year | Sex (male, female) |
Countries
China
Outcome results
None listed