A Mechanistic Randomized Controlled Trial on the Cardiovascular Effect of Berberine

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Risk Factor
• Intervention / Treatment: Drug: Berberine; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Li Ka Shing Faculty of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Men, who are

  1. aged 20 to 65 years
  2. of Chinese ethnicity
  3. 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)
  4. willing to make return visits
  5. not currently receiving hormone replacement therapy, such as testosterone replacement therapy, in the past 12 months
  6. not currently taking berberine or traditional Chinese medicine that contains berberine, in the past 1 month
  7. free of any congenital diseases, including familial hypercholesterolemia
  8. free of any infectious diseases, e.g. seasonal influenza
  9. free of anemia and glucose-6-phosphate dehydrogenase deficiency
  10. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Food and Health Bureau, Hong Kong
• Investigators: Principal Investigator: Jie Zhao, PhD, The University of Hong Kong

Publications and helpful links

General Publications

• Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol. 2015 Feb 23;161:69-81. doi: 10.1016/j.jep.2014.09.049. Epub 2014 Dec 10.
• Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res. 2008 Aug;22(8):999-1012. doi: 10.1002/ptr.2399.
• Skarydova L, Hofman J, Chlebek J, Havrankova J, Kosanova K, Skarka A, Hostalkova A, Plucha T, Cahlikova L, Wsol V. Isoquinoline alkaloids as a novel type of AKR1C3 inhibitors. J Steroid Biochem Mol Biol. 2014 Sep;143:250-8. doi: 10.1016/j.jsbmb.2014.04.005. Epub 2014 Apr 24.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Actual): November 1, 2020
• Study Completion (Actual): November 1, 2020

Study Registration Dates

• First Submitted: December 3, 2018
• First Submitted That Met QC Criteria: December 6, 2018
• First Posted (Actual): December 10, 2018

Study Record Updates

• Last Update Posted (Actual): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: 15162621

Drug and device information, study documents

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