Cesarone MR, Hu S, Belcaro G, Cornelli U, Feragalli B, et al. Non-Interactions of Berberine Supplementation in Borderline Hyperlipidemia Prevention (Asymptomatic Early Atherosclerosis Subjects) and Under Chronic Therapies: A Pilot Registry Study (BERINT)

Maria Rosaria Cesarone; Shu Hu; Gianni Belcaro; Umberto Cornelli; Beatrice Feragalli; Marcello Corsi; Valeria Scipione; Claudia Scipione; Roberto Cotellese; Morio Hosoi; David Cox; Francesca Coppazuccari

Research Article

Austin J Cardiovasc Dis Atherosclerosis. 2024; 11(2): 1065.

Non-Interactions of Berberine Supplementation in Borderline Hyperlipidemia Prevention (Asymptomatic Early Atherosclerosis Subjects) and Under Chronic Therapies: A Pilot Registry Study (BERINT)

Maria Rosaria Cesarone¹; Shu Hu¹; Gianni Belcaro¹*; Umberto Cornelli¹; Beatrice Feragalli²; Marcello Corsi¹; Valeria Scipione¹; Claudia Scipione¹; Roberto Cotellese²; Morio Hosoi¹; David Cox¹; Francesca Coppazuccari¹

¹IRVINE3 Labs and OOLEX Project, Chieti-Pescara University, Chieti, Italy

²Department of Or Biotec Sciences, Chieti-Pescara University, Chieti, Italy

*Corresponding author: Gianni Belcaro, IRVINE3 Labs and OOLEX Project, Chieti-Pescara University, Chieti, Italy. Email: gianni@belcarocardres.it

Received: November 29, 2024; Accepted: December 11, 2024; Published: December 18, 2024

Abstract

The aim of this pilot, non-interaction, supplement registry study was to evaluate the possible interactions between chronic therapies, as antiplatelet agents, anticoagulants, anti-hypertensives, diabetic management and thyroid management, and a formulation of berberine supplementation (Berbevis™ as Sophy^® tablets) that resulted effective to control borderline hyperlipidemia (as a natural, preventive management), the early evolution of asymptomatic atherosclerosis.

No side effects or tolerability issues were observed during the add-on of the supplement. The compliance was very good, with >96% of the capsules correctly used. The control and supplement groups resulted comparable. There was no significant variation in bleeding time, platelets and routine blood tests. Also, anticoagulant values were comparable in berberine and control group (INR and factor Xa).

The relative results for antihypertensives, antidiabetics and drugs for thyroid management, show non-interaction and the groups were comparable. Berberine supplementation did not change the main target measurements at end-observation. The thyroid management was extended to 8 weeks without changes in the hormones values.

In the absence of major risk conditions, after berberine supplementation no evidence of negative interaction during undergoing selected chronic therapies were reported. Non-interaction profiles must be considered for any supplement used in large number of patients, in order to avoid any possible unusual side effects or tolerability problems.

Keywords: Berberine; Borderline hyperlipidemia; Phytosome™; Safety; Non-interaction

Introduction

Natural supplements are useful for several preventive applications and conditions, with beneficial activity in healthy subjects and patients under chronic drug therapies. Supplements include several complex compounds not linked in their action to a single product or molecule. These products can be used without prescription and are generally considered safe. However, patients using these supplements often are under chronic drug therapies, such as antiplatelet agents and anticoagulants, anti-hypertensive drugs, diabetic management drugs, thyroid hormones substitutes. Therefore, it is necessary to check any potential interference of the supplement that may arise with the standard pharmacological therapy. Patients treated with oral anticoagulants are growing up: the proportion of subjects consuming Direct Oral Anticoagulants (DOACs) has increased from 7.4% in 2011 to 66.8% in 2019, with an increase in DOAC users from 0.20 million to 3.50 million and a concomitant decrease in warfarin treated from 2.48 million to 1.74 million [1-8].

It is possible that about 10 million subjects are chronically treated with an antiplatelet agent for long periods during their life [9]. The safety in this case should be as high as possible [3].

The use of antiplatelet, anticoagulants, anti-hypertensive or antidiabetic drugs could be associated to botanical supplements that would of benefit. It is therefore essential that the supplement is safe and do not interfere with the activity of chronic therapies. Indeed, the consumption of multiple drugs is considered a risk factor for falls through the adverse effects of drug-drug and/or drug-disease interactions [10].

Berberine is an alkaloid produced by Ramnuncolaceae and Berberidaceae (Berberis, Mahonia, Coptis) [11-19]; discovered in the 1930s [20] berberine was originally utilized for its anti-diarrheal properties due to the antimicrobial activity against enteric bacteria [21,22]. Interestingly, more recent studies highlighted berberine antidiabetic and anti-lipidemic effects that are useful in weight control and for a healthy metabolic profile [11,12]. The aim of this pilot, supplement registry study was to evaluate the safety and noninteraction, of a supplement containing berberine phospholipids to control borderline hyperlipidemic subjects during undergoing selected chronic therapies and in the absence of major risk conditions [20,23-26]. This condition is considered sub-clinical.

Material and Methods

Population

The study was conducted in Italy in 2023-24. In this pilot, noninterference clinical study, subjects undergoing selected chronic therapies, antiplatelet, anticoagulant, antihypertensive, thyroid replacement and antidiabetic drugs, and in the absence of major risk conditions, were included. Patients treated with any other additional medication were excluded from the study.

Participants followed for the above chronic therapies at least for 3 months entered in the study. This pilot was conducted in subjects using only a single treatment/management, as follows:

- 20 subjects under antiplatelet therapy (10 Acetyl-salicylic acid and 10 clopidogrel) were supplemented for 10 days;

- 10 subjects under anticoagulant therapy (coumarin) were supplemented for 2 weeks;

- 11 subjects under new anticoagulants therapy (DOAC) (6 with Dabigatran and 5 with Rivaroxaban) were supplemented for 4 weeks;

- 10 subjects under Anti-hypertensive therapy (ACE inhibitor) were supplemented for 2 weeks;

- 10 subjects under antidiabetic therapy (metformin) were supplemented for 4 weeks;

- 20 subjects under thyroid hormone replacement therapy (Levothyroxine) were supplemented for 2 and 8 weeks. T3: triiodothyronine, T4: thyroxine; TSH: Thyroid-stimulating hormone were measured.

These subjects were otherwise asymptomatic and in wellcontrolled management (sub-clinical condition), verified in previous routinely visits. The Body Mass Index (BMI) was <28.

Outcomes’ measurements

The target measurements were considered for:

- Antiplatelets: bleeding time

- The anticoagulant coumadin: INR

- The new anticoagulants (DOAC): Coagulation factor Xa was assayed;

- Anti-hypertensive agents: bleeding time and blood pressures;

- Metformin: fasting glucose and Glycated Hemoglobin (GHb);

- Thyroid replacement therapy (hypothyroidism) (Eutirox): blood hormonal levels.

Normal thyroid hormonal levels were considered: Tiroxine (fT4) 5–12 μg/dL; (fT3) 3.5 – 6.5 pmol/L; (TSH) 0.15-3.5 mU/L.

Bleeding time is a clinical test performed to evaluate not only platelet function but the global activity of the coagulation (1-6). A standardized incision was performed and timing at the cessation of bleeding was measured.

Normal bleeding time is considered to be:

• Duke – Less than 3 minutes

• IVY – Less than 8 minutes

Times greater than 5 minutes in the Duke method and 10 minutes in the IVY method are concerning for coagulopathy.

As clinical significance, clinicians need a global coagulation test to assess the adequacy of primary hemostasis. The IVY method is the most common. The patient’s arm is positioned at the level of the heart, and a blood pressure cuff inflated to 40 mmHg. After cleansing with alcohol, a standardized device is utilized to make a 10mm long and 1mm deep incision on the volar forearm. Using a timer, the blood is blotted twice a minute. The time stops when there is no further bleeding after blotting. Oxidative stress was measured with a drop of blood from a finger using a Diacron System, Parma, Italy as previously described in details [27,28].

The normal International Normalized Ratio (INR) was considered to be 0.8 to 1.1.

Supplementation

Berberine (Berbevis™, as Sophy^® tablets) was supplemented at 550 mg Berberine phospholipids (containing 28-32% berberine) twice a day for a minimum of 10 days to a maximum of 8 weeks (see Population section for any detail).

Supplement studies define the activity of Pharma Standard (PS) supplements and preventive, subclinical applications [24-26,29]. The best fields of application for PS supplements are subclinical, or preclinical borderline applications or the supplementary management of risk conditions.

Statistical Analysis

A number of at least 8 subjects for each group (drug + drug add-on with supplements) was considered necessary to evaluate differences in the target parameters [18]. All results and data were considered as non-parametric; the Mann-Whitney U-test and the ANOVA were used for symptoms/complaints (Sigma plot) [30,31].

A predictive analysis according to Siegel was performed at the end of the study [32].

Results

Results obtained are shown in Tables 1-4.

No side effects or tolerability issues were reported after berberine supplementation. The compliance to the supplement was very good, with >96% of the tablets, correctly used. The control and the supplement groups resulted all comparable.

There was no significant variation (Table 1a, 1b and 1c) in platelets and routine blood tests between the two groups. Also, anticoagulant values (INR and factor Xa) were comparable in the berberine and in the control group.

Table 1a: INR, platelets, blood tests and Mean bleeding time levels in patients with two different anticoagulant therapies, before and after 10 days of berberine supplementation.




  
     
    Patients

      (M/F)
    INR
    Platelets
    Blood tests
    Bleeding time

      (Mean sec, SD)
  
  
    Acetyl-salicylic acid
    10 (5/5)
    NV
    NV
    NV
    385.2, 88.0
  
  
    Acetyl-salicylic acid+berberine
    10 (5/5)
    NV
    NV
    NV
    391.0, 79.0 NS
  
  
    Clopidogrel
    10 (5/5)
    NV
    NV
    NV
    388.0, 86.0
  
  
    Clopidogrel+berberine
    10 (5/5)
    NV
    NV
    NV
    388.0, 81.0 NS
  
  
    M.    Male, F: Female; Mean, SD age: 44.2, 2.0 (Acetyl-salicylic acid) and 44.0,    1.7 (Clopidogrel). 

      INR: International    Normalized Ratio; NS: not statistically significant; NV: normal value; SD:    standard deviation.



Table 1a: INR, platelets, blood tests and Mean bleeding time levels in patients
with two different anticoagulant therapies, before and after 10 days of berberine
supplementation.

Table 1b: Mean INR in patients with coumarin anticoagulant therapy, before and after two weeks of berberine supplementation.




  
     
    Patients

      (M)
    INR

      (Mean,SD)
  
  
    Warfarin
    5
    2.98, 0.22
  
  
    Warfarin+ berberine
    5
    2.88, 0.23 NS
  
  
    M. Male; Mean, SD age:    47.8, 2.2; INR: International Normalized Ratio; NS: not statistically    significant; NV: normal value; SD: standard deviation.



Table 1b: Mean INR in patients with coumarin anticoagulant therapy, before
and after two weeks of berberine supplementation.

	Patients (M)	Xa (%)
Dabigatran	6	100
Dabigatran + berberine	6	100
Rivaroxaban	5	100
Rivaroxaban+berberine	5	100
M. Male; Mean, SD age:46.2, 1.3 (dabigatran), 45.2, 2.2 (rivaraxoban); Xa: Coagulation factor X; SD: standard deviation.

	Patients (M)	Xa (%)	Bleeding time (Mean sec, SD)	BIood pressure	H rate/min
ACE inhibitor	5/5	100	381.2, 83	121/85	73.3, 2
ACE inhibitor +berberine	5/5	100	379.82, 82 NS	120/84 NS	73.0, 1.9 NS
M. Male; Mean, SD age:43.2, 1.6; Xa: Coagulation factor X; NV: normal value; SD: standard deviation; NS: not statistically significant; H. Frequency rate.

	Patients (M/F)	Fast glucose	GL Hb
Metformin	10 (5/5)	109.0, 3.0	6.03, 0.2
Metformin+berberine	10 (5/5)	106.0, 2.3 NS	6.0, 0.22
M: Male, F: Female; Mean, SD age:48.4, 2.0; GL Hb: Glycated Haemoglobin; SD: standard deviation.

	Patients (M/F)	T3	T4	TSH	Symptoms
Levothyroxine	10 (4/6)	3.8;0.3	11.2;0.1	1.9:0.2	0
Levothyroxine +berberine 2w	10 (4/6)	3.7;0.2	11.3 0.8	1.87;0 0.3	0
Levothyroxine +berberine 8w	10 (4/6)	3.7;0.3	11;0.6	1.96:0.3	0
M. Male, F: Female; Mean, SD; age: 44.3±1.1; w: weeks; SD: standard deviation; T3: triiodothyronine, T4: thyroxine; TSH: Thyroid-stimulating hormone.