Effects of Berberine on Preventing Cardiovascular Disease and Diabetes Mellitus (ABCD)

Assess the Effects of Berberine on Preventing Cardiovascular Disease and Diabetes Mellitus Among Individuals With High Cardiometabolic Risk

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypertension; Dyslipidemias; PreDiabetes; Atherosclerotic Cardiovascular Disease; Abdominal Obesity
• Intervention / Treatment: Drug: Berberine plus lifestyle intervention; Behavioral: Placebo plus lifestyle intervention

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.

• Study Type: Interventional
• Enrollment (Actual): 2024
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Fuwai Hospital, Chinese Academy of Medical Sciences, National Center for Cardiovascular Diseases

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: berberine group; Berberine hydrochloride plus lifestyle intervention	Drug: Berberine plus lifestyle intervention; 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.
Placebo Comparator: placebo group; Placebo plus lifestyle intervention	Behavioral: Placebo 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The distribution of glycemic status at 1 year after randomization	Categorized as normal glucose metabolism, prediabetes, and diabetes	Intervention Period: 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of glycemic-related parameters	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)	Intervention Period: 1 year
Changes of lipid-related parameters	Including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and lipoprotein(a)	Intervention Period: 1 year
Change of inflammation-related marker	Including high-sensitivity C-reactive protein (hs-CRP)	Intervention Period: 1 year
Change of physical examination measures	Including body mass index (BMI) and waist circumference	Intervention Period: 1 year
Changes of other parameters	Including urinary albumin-to-creatinine ratio (UACR), serum uric acid, and metabolic syndrome score	Intervention Period: 1 year
Change of depressive symptoms	Measured by Patient Health Questionnaire-9 (PHQ-9)	Intervention Period: 1 year
Time to first occurrence of composite endpoint of major cardiovascular event and diabetes	cardiovascular death, non-hemorrhagic stroke, myocardial infarction, arterial revascularization, and diabetes	Intervention Period: 1 year
Time to new-onset diabetes	Diabetes is determined by oral glucose tolerance test, clinical diagnosis or use of glucose-lowering medications.	Intervention Period: 1 year
Normalization of glucose parameters	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%.	Intervention Period: 1 year
Time to newly diagnosed cancer	all events of cancer or classified by primary sites	Intervention Period: 1 year
Exploratory biomarker analyses	Including serum trimethylamine, trimethylamine N-oxide, dopamine, berberine metabolites, and lipidomics analyses; urinary berberine metabolite analyses; and gut microbiota sequencing analyses.	Intervention Period: 1 year
Time to first occurrence of composite endpoint of major cardiovascular event and diabetes	cardiovascular death, non-hemorrhagic stroke, myocardial infarction, arterial revascularization, and diabetes	Entire follow-up period: 4 years
Time to new-onset diabetes	Diabetes is determined by oral glucose tolerance test, clinical diagnosis or use of glucose-lowering medications.	Entire follow-up period: 4 years
Time to first occurrence of composite endpoint of major cardiovascular event 1	cardiovascular death, non-hemorrhagic stroke, myocardial infarction, arterial revascularization	Entire follow-up period: 4 years
Time to first occurrence of composite endpoint of major cardiovascular event 2	cardiovascular death, non-hemorrhagic stroke, myocardial infarction	Entire follow-up period: 4 years
Time to newly diagnosed cancer	all events of cancer or classified by primary sites	Entire follow-up period: 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subgroup analysis 1 for primary outcome measure	Age (<55，55-65，≥65)	Intervention Period: 1 year
Subgroup analysis 2 for primary outcome measure	Sex (male, female)	Intervention Period: 1 year
Subgroup analysis 3 for primary outcome measure	Body mass index (<28kg/m2, ≥28kg/m2)	Intervention Period: 1 year
Subgroup analysis 4 for primary outcome measure	Statin use (yes, no)	Intervention Period: 1 year
Subgroup analysis 5 for primary outcome measure	HbA1c median	Intervention Period: 1 year
Subgroup analysis 6 for primary outcome measure	Hs-CRP tertiles	Intervention Period: 1 year
Subgroup analysis 7 for primary outcome measure	LDL-C tertiles	Intervention Period: 1 year
Subgroup analysis 8 for primary outcome measure	Triglyceride tertiles	Intervention Period: 1 year
Subgroup analysis 9 for primary outcome measure	HDL-C tertiles	Intervention Period: 1 year
Safety assessment during the intervention period	Including serious adverse events, non-serious adverse events of special interest, and treatment discontinuation for any reason	Intervention Period: 1 year

Collaborators and Investigators

• Sponsor: China National Center for Cardiovascular Diseases
• Investigators: Principal Investigator: Jing Li, PhD, National Center for Cardiovascular Diseases; Principal Investigator: Haibo Zhang, MD, National Center for Cardiovascular Diseases

Publications and helpful links

General Publications

• Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004 Dec;10(12):1344-51. doi: 10.1038/nm1135. Epub 2004 Nov 7.
• Kong WJ, Vernieri C, Foiani M, Jiang JD. Berberine in the treatment of metabolism-related chronic diseases: A drug cloud (dCloud) effect to target multifactorial disorders. Pharmacol Ther. 2020 May;209:107496. doi: 10.1016/j.pharmthera.2020.107496. Epub 2020 Jan 27.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 20, 2023
• First Submitted That Met QC Criteria: February 20, 2023
• First Posted (Actual): March 1, 2023

Study Record Updates

• Last Update Posted (Actual): December 31, 2025
• Last Update Submitted That Met QC Criteria: December 25, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Diabetes Mellitus; Overweight; Lipid Metabolism Disorders; Arteriosclerosis; Arterial Occlusive Diseases; Obesity; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Hypertension; Dyslipidemias; Atherosclerosis; Prediabetic State; Obesity, Abdominal; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Heterocyclic Compounds, 4 or More Rings; Benzylisoquinolines; Berberine Alkaloids; Berberine
• Other Study ID Numbers: 2021-CXGC04-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: All the IPD that underlie results in the publication with study protocol and SAP will be shared to the public on the study website upon request with a protocol after approval from the ABCD steering committee. The access criteria and URL of the study website is not established yet.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No