Herbal medicines have been used for thousands of years in China and other Eastern countries and have regained popularity in Western Countries in the last two decades [
Multiple cardiovascular protective effects of
Some other herbs such as
The present study for the first time examined the effect of a commercially available multiherb formula containing the herbs mentioned above (Table
The multiherb formula tested in the study.
Herb extracts |
Weight |
Proportions |
---|---|---|
|
129 | 30% |
|
86 | 20% |
|
86 | 20% |
|
43 | 10% |
|
43 | 10% |
|
43 | 10% |
Subjects aged ≥18 years with dyslipidemia (familial or nonfamilial) were recruited from the patients who were regularly attending the Lipid Clinic in the Prince of Wales Hospital, Hong Kong. Dyslipidemia was defined as either having a documented history of dyslipidemia and receiving lipid-lowering therapy or having a documented elevated baseline fasting LDL-C cholesterol (≥4.1 mmol/L) or triglycerides ≥1.7 mmol/L based on local laboratory reference values. Patients were eligible if they had a plasma level of LDL-C ≥2.6 mmol/L or ≥1.8 mmol/L for those with high cardiovascular risk (because of a history of coronary heart disease (CHD), other clinical evidence of atherosclerosis, diabetes mellitus, or calculated 10-year CHD risk score >20%) following advice on a lipid-lowering diet with lipid-lowering treatment or if they had elevated plasma triglyceride concentrations (≥1.7 mmol/L) following advice on a lipid-lowering diet with or without lipid-lowering treatment.
Exclusion criteria included a history of myocardial infarction, stroke, coronary artery bypass surgery or other revascularization procedures, unstable angina, or angioplasty within 3 months of screening; elevated liver enzymes (alanine aminotransferase [ALT] > 1.5 × ULN) or renal impairment (plasma creatinine > 200
The study protocol and statement of informed consent were approved by the Joint Clinical Research Ethics Committee of The Chinese University of Hong Kong and New Territories East Cluster before the start of the study. The study was conducted in compliance with the Declaration of Helsinki and all participants gave written informed consent.
The herbal formula (blood fat droplets (control)) and matching placebo were manufactured and supplied by Vita Green Pharmaceutical (HK) Ltd (Hong Kong, China). This product is registered for use as a natural health product in Hong Kong. Pretreated
Ursolic acid was used as the quality marker of this herbal product and was quantified by HPLC. The mobile phase contained methanol-water-glacial acetic acid (88 : 12 : 0.2). UV detection was performed at 215 nm. The sample was defatted with petroleum ether and extracted using diethyl ether. The solvent was evaporated and the residue dissolved in methanol for injection. The specification is >0.01% ursolic acid in the final product. Heavy metal and toxic elements including arsenic, lead, and mercury were measured using in house methods. Microbial examination (total aerobic count, moulds and yeast count, and
The placebo capsule contained starch and artificial food colouring. The herb formula and placebo were identical in packing, appearance, and colour.
This study was a prospective, randomized, double-blinded, placebo-controlled, and parallel design study. After completion of a 2-week placebo run-in period, eligible patients were randomly assigned to receive the herbal formula or placebo which was consumed twice daily with or without food, four capsules in the morning and four capsules in the evening for a period of 12 weeks.
Randomization was performed using Random Allocation Software (Version 1.0, Isfahan University of Medical Sciences, Isfahan, Iran) that allows random lists to be generated with permuted block and designated seeds. Electronic and paper records of the randomization seed number and the randomization sequence were kept in the study center for operation. The allocation sequence was generated by Miao Hu (the first author), whereas participant enrollment and assignment were conducted by Brian Tomlinson and the study nurses. The patients, investigators, and the study staff were blinded to treatment assignment until the outcome assessment was completed.
Patients were assessed at baseline and at 6 and 12 weeks after the initiation of treatment with herb formula or placebo, with the last dose being consumed the evening before the visits. Anthropometric measurements, including body weight, waist circumference, hip circumference, and estimation of percentage body fat using an impedance device (TANITA Body Composition Analyzer BF-350, Tokyo, Japan), were performed by a research nurse. Blood pressure was measured by a semiautomatic sphygmomanometer (Critikon Dinamap; GE Medical Systems Information Technologies, Louisville, KY, USA). Fasting blood samples were taken for lipid profile, fasting glucose, and laboratory safety tests at the study visit. Adherence to study medication and tolerability were assessed at study visits. All subjects were asked to maintain their usual diet and other aspects of lifestyle during the study.
Some previous randomized, placebo-controlled studies with
All biochemistry tests including lipid profiles, glucose, glycated haemoglobin (HbA1c), and laboratory safety parameters (e.g., creatinine, creatine kinase, total bilirubin, alkaline phosphatase (ALP), and ALT) were performed by standard methods in the Chemical Pathology laboratory at the Prince of Wales Hospital, which has international laboratory accreditation. Total cholesterol level was measured by the enzymatic method (Centrichem Chemistry System, Baker Instruments Co. Allentown). High-density lipoprotein cholesterol (HDL-C) level was determined by using the fractional precipitation of dextran sulphate with manganous ion. Triglyceride levels were measured by the glyceryl dehydrogenase reaction following the hydrolysis of the triglyceride (Centrichem Chemistry System, Baker Instruments Co., Allentown). LDL-C concentrations were calculated according to the Friedewald formula or directly measured if the triglyceride level was greater than 4.5 mmol/L [
Per protocol analysis was performed in a blind manner in 40 patients who had completed all study visits. The primary end point of the study was percentage change in LDL-C from baseline at 12 weeks. The secondary end points included percentage changes in other lipid parameters, HbA1c, fasting plasma glucose, and laboratory safety tests at 6 and 12 weeks. Continuous variables were expressed as mean ± SD unless otherwise indicated. Skewed data were logarithmically transformed before analysis. The baseline characteristics and the primary and secondary outcomes between the two treatment groups were compared using Student’s
A total of 43 patients were recruited for the study and 1 patient withdrew consent. A total of 42 patients were randomized and two patients dropped out due to adverse effects (one in each group) (Figure
Baseline characteristics of the study participants.
Placebo |
Herb formula |
|
---|---|---|
Age, years |
|
|
Males, |
10 (50) | 6 (30) |
Body weight, kg |
|
|
Body mass index, kg/m2 |
|
|
Body fat, % |
|
|
Waist, cm |
|
|
SBP, mmHg |
|
|
DBP, mmHg |
|
|
Pulse, bpm |
|
|
Diabetes, |
8 (40) | 11 (55) |
Hypertension, |
14 (70) | 10 (50) |
FH, |
7 (35) | 5 (25) |
On lipid-lowering treatment | 9 (45) | 8 (40) |
On antidiabetic treatment | 5 (25) | 5 (25) |
Baseline TC, mmol/L |
|
|
Baseline HDL-C, mmol/L |
|
|
Baseline TG, mmol/L |
|
|
Baseline LDL-C, mmol/L |
|
|
Baseline non-HDL-C, mmol/L |
|
|
Fasting glucose, mmol/L |
|
|
HbA1c, % |
|
|
DBP: diastolic blood pressure; TC: total cholesterol; FH: familial hypercholesterolaemia; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; SBP: systolic blood pressure; TG: triglycerides.
CONSORT flowchart of study recruitment and completion of the study.
There were no significant changes in body weight between baseline and after treatment for each of the groups during the study (Table
Changes in body weight, lipids, and glucose at week 12.
Placebo ( |
Herb formula ( |
|
|||||
---|---|---|---|---|---|---|---|
Baseline | Week 12 | % change | Baseline | Week 12 | % change | ||
Body weight, kg |
|
|
|
|
|
|
0.310 |
TC, mmol/L |
|
|
|
|
|
|
0.362 |
HDL-C, mmol/L |
|
|
|
|
|
|
0.276 |
TG, mmol/L |
|
|
−6.7 (−18.3, 15.8) |
|
|
5.8 (−14.8, 16.3) | 0.383 |
LDL-C, mmol/L |
|
|
|
|
|
|
0.049 |
Non-HDL-C, mmol/L |
|
|
|
|
|
|
0.368 |
Fasting glucose, mmol/L |
|
|
|
|
|
|
0.432 |
HbA1c, % |
|
|
|
|
|
|
0.098 |
TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TG: triglycerides.
Data are presented as mean ± SD or median (interquartile range).
The percentage changes from baseline in LDL-C after 6 and 12 weeks of treatment.
There was no significant difference in the changes in other lipid parameters and fasting plasma glucose between the two groups (Table
Association between the baseline levels of glycated haemoglobin and the percentage changes in glycated haemoglobin after 12 weeks of treatment.
Both active treatment and placebo were well tolerated. Plasma biochemical parameters in the two groups are shown in Table
Changes in biochemical parameters at week 12.
Placebo ( |
Herb formula ( |
|
|||||
---|---|---|---|---|---|---|---|
Baseline | Week 12 | % change | Baseline | Week 12 | % change | ||
Creatinine, |
|
|
|
|
|
|
0.799 |
Creatine kinase, U/L |
|
|
−1.0 (−26.8, 10.1) |
|
|
1.2 (−7.5, 15.0) | 0.563 |
Total protein, g/L |
|
|
|
|
|
|
0.860 |
Urea, mmol/L |
|
|
|
|
|
|
0.041 |
Albumin, g/L |
|
|
|
|
|
|
0.092 |
Bilirubin, |
|
|
|
|
|
|
0.706 |
ALT, IU/L |
|
|
|
|
|
|
0.332 |
ALP, U/L |
|
|
|
|
|
|
0.672 |
Urate, mmol/L |
|
|
|
|
|
|
0.567 |
ALT: alanine aminotransferase; ALP: alkaline phosphatase; data are presented as mean ± SD or median (interquartile range);
A total of 28 adverse events were reported by 23 participants (12 in the placebo group and 11 in the active treatment group). Of the two patients who withdrew from the study, one patient randomized to the active treatment complained of stomach upset and one patient randomized to placebo developed acid reflux. Influenza and cough were the most common adverse events (
In this randomized clinical study of a multiherb product containing
It was shown that hawthorn fruit drink 250 mL (containing 1.4 mg hawthorn flavones) twice daily significantly decreased the plasma LDL-C, apolipoprotein B, and triglycerides by 10.4%, 7.4%, and 9.3%, respectively, in 30 Chinese patients with dyslipidemia in an early uncontrolled study [
There was no statistically significant difference in the percentage change in HbA1c levels between the herb formula and placebo during the study, although there was a significant decrease in HbA1c levels in the active treatment group, particularly in patients with higher baseline levels, which is a typical finding with many antihyperglycaemic drugs. This result may suggest a potential beneficial effect of this supplement on the overall glycaemic control in patients with abnormal metabolic states of glucose regulation, for example, impaired glucose tolerance and diabetes. Several lines of evidence suggest the effectiveness of
This study has several limitations which need to be considered. Firstly, there was significant difference in the baseline LDL-C levels between the placebo group and the active treatment group. This may be related to the small sample size. In this study, patients were selected if they had either elevated LDL-C and/or elevated triglycerides, and thus they may have different types of dyslipidemia, contributing to the different lipid profiles of the two groups in this small study. The small sample size is another major limitation of the study. The studied herb formula only showed a marginal effect on plasma LDL-C levels compared to placebo and the study is underpowered to detect small differences between the two groups. In addition, it would be useful to measure various apolipoprotein levels, for example, apoAI, apoB, and apoE, although these apolipoprotein levels are usually closely associated with particular plasma lipid levels. It would be helpful to identify and quantify the active components in this herbal formula and to test whether these active components reduce the plasma lipids in a dose-dependent manner, but the study was designed to examine the real-world lipid-lowering effect of this commercially available herbal product in patients with dyslipidemia using a recommended dose, and thus the dose-response was not assessed.
In conclusion, this randomized, placebo-controlled study conducted in an ambulatory outpatient setting showed a marginal beneficial effect of the multiherb formula on reducing plasma LDL-C levels in subjects with dyslipidemia without any noticeable adverse effects. The finding was consistent with some of the previous experimental
The authors have declared that there is no conflict of interests.
The study was partly supported by an unrestricted grant from Vita Green Pharmaceutical (HK) Ltd. This funding source had no role in the study design, the collection, analysis, or interpretation of data or in the writing of the paper. The herbal product and placebo were provided free of charge by Vita Green Pharmaceutical (HK) Ltd, Hong Kong. The authors thank the members of the research team who contributed to this project, especially Ms. Maybo Lin and Ms. Evelyn Chau for their excellent assistance in recruiting and monitoring of patients.