A Mechanistic Randomized Controlled Trial on the Cardiovascular Effect of Berberine

Study Overview
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Brief Summary
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Berberine is extracted from Coptis (Huanglian) and Phellodendron Chinese (Huangbai), to make into berberine tablets.1 Recent studies have shown that berberine has beneficial effects on cardiovascular disease (CVD) risk factors,1,2 such as lowering the risk of hyperlipidemia, diabetes, and hypertension.1 In a comprehensive systematic review and meta-analysis of 27 randomized controlled trials (RCTs), berberine effectively reduced low density lipoprotein cholesterol (LDL-c) (-0.65 mmol/L, 95% confidence interval (CI) -0.75 to -0.56), triglycerides (TG) (-0.39 mmol/L, 95% CI -0.59 to -0.19), total cholesterol (TC) (-0.66 mmol/L, 95% CI -1.02 to -0.31) and increased high density lipoprotein cholesterol (HDL-c) (0.07mmol/L, 95% CI 0.04 to 0.1).1 Notably, no serious adverse event has been reported in these trials,1 suggesting a good tolerability of berberine. The mechanism by which berberine exerts a protective role in atherosclerosis is unclear. Protoberberines have been identified as a new inhibitor of AKR1C3, an enzyme responsible for the regulation of steroid hormone action.3 The investigators propose to examine the effects of berberine on a set of well-established CVD risk factors including lipids, systolic and diastolic blood pressure, coagulation factors, adiposity, fasting glucose, insulin, and liver function, as well as to examine potential mediation via testosterone and/or sex hormone binding globulin using a mechanistic, randomized, double-blind, placebo-controlled trial in Chinese men with hyperlipidemia.

Detailed Description
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Objectives: to assess the effect of berberine on a set of well-established CVD risk factors, including lipids, systolic and diastolic blood pressure, coagulation factors, fasting glucose, insulin, adiposity (body mass index (BMI) and waist-hip ratio (WHR)) and the mediation via testosterone and/or sex hormone binding globulin using a mechanistic, parallel RCT. Study design: a mechanistic, randomized, double-blind, placebo-controlled, parallel trial in 84 Chinese men in Hong Kong. Interventions: the eligible participants will be randomized to take berberine (500 mg orally twice a day) or placebo for 12 weeks. Blood samples will be taken at baseline, 8-week and 12-week intervention. Data analysis and expected results: the investigators will use an intention to treat analysis, with multiple imputation for missing data. The investigators will compare the baseline characteristics of participants in the two arms using analysis of variance. The investigators will assess the effects of berberine on changes in CVD risk factors using analysis of variance, and the mediation using causal mediation analysis. Compared to the placebo group, the participants receiving berberine are expected to have lower burden of cardiovascular disease risk factors at the end of the intervention. These effects may be mediated or partly mediated by lowering testosterone.

Official Title
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Effect of Berberine on Cardiovascular Disease Risk Factors: a Mechanistic Randomized Controlled Trial

Conditions
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Cardiovascular Risk Factor

Intervention / Treatment
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* Drug: Berberine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men, who are aged 20 to 65 years of Chinese ethnicity with hyperlipidemia, defined as TG greater than 150 mg/dl (1.70 mmol/L), TC greater than 200 mg/dl (5.16 mmol/L), and/or LDL-c greater than 100 mg/dl (2.58 mmol/L) willing to make return visits not currently receiving hormone replacement therapy, such as testosterone replacement therapy, in the past 12 months not currently taking berberine or traditional Chinese medicine that contains berberine, in the past 1 month free of any congenital diseases, including familial hypercholesterolemia free of any infectious diseases, e.g. seasonal influenza free of anemia and glucose-6-phosphate dehydrogenase deficiency with no history of any chronic diseases including ischemic heart disease, myocardial infarction (heart attack), stroke, diabetes, cancer, liver/renal dysfunction, and gastrointestinal disorders. Exclusion Criteria: All women, and men, who did not meet the aforementioned inclusion criteria, and/or unable or unwilling to provide consent

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Berberine<br>berberine (500 mg orally twice a day) | Drug: Berberine<br>* Purified berberine (500 mg orally twice a day) in tablets for 12 weeks<br>|
| Placebo Comparator: Placebo<br>placebo (500 mg orally twice a day) | Drug: Placebo<br>* Placebo tablets, prepared with the same appearance, for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| lipid profile | LDL-cholesterol, HDL-cholesterol, triglycerides and total cholesterol in mmol/L | change from baseline lipid profile at 8 weeks | 
| lipid profile | LDL-cholesterol, HDL-cholesterol, triglycerides and total cholesterol in mmol/L | change from baseline lipid profile at 12 weeks | 
| blood pressure | systolic blood pressure and diastolic blood pressure in mmHg | change from baseline blood pressure at 8 weeks | 
| blood pressure | systolic blood pressure and diastolic blood pressure in mmHg | change from baseline blood pressure at 12 weeks | 
| thromboxane A2 | thromboxane A2 in mmol/L | change from baseline thromboxane A2 at 8 weeks | 
| thromboxane A2 | thromboxane A2 in mmol/L | change from baseline thromboxane A2 at 12 weeks | 
| testosterone | testosterone in mmol/L | change from baseline testosterone at 8 weeks | 
| testosterone | testosterone in mmol/L | change from baseline testosterone at 12 weeks | 
| body mass index (BMI) | weight and height will be combined to report BMI in kg/m^2 | change from baseline body mass index at 8 weeks | 
| body mass index (BMI) | weight and height will be combined to report BMI in kg/m^2 | change from baseline body mass index at 12 weeks | 
| waist hip ratio | waist circumstance and hip circumstance will be combined to report waist hip ratio | change from baseline waist hip ratio at 8 weeks | 
| waist hip ratio | waist circumstance and hip circumstance will be combined to report waist hip ratio | change from baseline waist hip ratio at 12 weeks | 
| fasting glucose | fasting glucose in mmol/L | change from baseline fasting glucose at 8 weeks | 
| fasting glucose | fasting glucose in mmol/L | change from baseline fasting glucose at 12 weeks | 
| fasting insulin | fasting insulin in mmol/L | change from baseline fasting insulin at 8 weeks | 
| fasting insulin | fasting insulin in mmol/L | change from baseline fasting insulin at 12 weeks | 
| liver function | Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), total bilirubin, Gamma-glutamyltransferase, total protein and albumin in mmol/L | change from baseline fasting insulin at 8 weeks | 
| liver function | Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), total bilirubin, Gamma-glutamyltransferase, total protein and albumin in mmol/L | change from baseline fasting insulin at 12 weeks | 
| sex hormone binding globulin (SHBG) | SHBG in nmol/L | change from baseline SHBG at 8 weeks | 
| sex hormone binding globulin (SHBG) | SHBG in nmol/L | change from baseline SHBG at 12 weeks | 
| thrombin time | thrombin time in sec | change from baseline thrombin time at 8 weeks | 
| thrombin time | thrombin time in sec | change from baseline thrombin time at 12 weeks |