Wellness Care, Australia
Received: November 01, 2021 Published: November 19, 2021
*Corresponding author: Wayne Reilly, Wellness Care Australia Pty Ltd, 61 Holsworthy St Coorparoo Qld Australia
Medical intervention to reduce the risk of atherosclerosis using lipid modulating medications has been a target for reducing cardiovascular risk for over 40 years. Lipid lowering medications, HMG-CoA reductase inhibitors (Statin’s), and more recently PCSK9 inhibitors (PCSK9i (protein convertase subtilisin/kexin type 9 inhibitors) are now and in the future will be the main stay therapy for reducing Atherosclerosis. However, the uncertainty of statin induced myalgia and other bad publicity via the media and internet reports has caused many patients to opt out of statin therapy. Berberine and is quinoline alkaloid has had several clinical trials demonstrating potential in managing cardiovascular disease risk. Berberine is a safe and natural alternative for modulating circulating lipids including LDL-C, however possible drug interactions, due to its effects on P450 enzymes, does indicate some caution should be exercised.
Dyslipidemia and cardiovascular disease have been identified by the World Health Organisation as the number one cause of death globally, and high levels of LDL cholesterol  are a major risk factor contributing to this. Numerous studies have identified cardiovascular medications as the best way to achieve this goal. A meta-analysis by Baigent etal in 2010 reviewed 26 cholesterol clinical trials which included 170,000 participants1. Their results showed a relative risk reduction in total mortality of 10% per 1 mmol/L reduction in LDL-C with a P value< 0.0011. In their review a significant reduction in deaths from coronary disease and a further reduction in major vascular events which equated to a 22% reduction per 1 mmol/L of circulating LDL-C. Current clinical data supports  the belief that LDL-C is the real target for reducing CVD risk . Another cross-sectional CVD study in the Netherlands, involving 1249 patients with heterozygous familial hypercholesterolemia (heFH), only 21 % of patients achieved an LDL-C target of 2.5 mmol/L considered to be a safe target level for these patients3. A similar failure is found in severe primary hypercholesterolemia patients, including those with familial hypercholesterolemia. Familial  hypercholesterolemia (FH) is an autosomal dominant disorder involving mutations in the LDL receptor gene leading to defective plasma LDL-C catabolism and increased levels of circulating LDL-C 4,5.
Myalgia still remains the most common adverse  event
reported with statin therapy. Statin -myositis is associated with
muscle symptoms and a in severe cases a substantially elevated
serum creatinine kinase (CK). In rare circumstances statinassociated
myopathy is found to occur at a 1 in 1000 to 1 in 10,000
people on statin treatment 6. In contrast, statin-associated muscle
symptoms (SAMS) in which CK concentrations are normal or only
slightly elevated, are  much more common and have prevalence
of 7–29 %6. The most promising natural product that results in
cholesterol lowering, based on recent clinical trials, is Berberine,
and is quinoline alkaloid, commonly found in several medicinal
herbs including Copts sentences, Hydrates canadensis and
Rhododendrons amongst others 7. Most recently Berberine has
been shown to be a natural inhibitor of PCSK9 (protein convertase
subtilisin/kexin type 9), acting in a similar fashion as other PCSK9
Inhibitors Eg Vedolizumab, a monoclonal antibody targeting PCSK9
in hyperlipidaemia which often lowers LDL below 1.5mmol/L8.
Interestingly, Berberine has also  been demonstrated to lower
fasting triglyceride (TG) levels and in a clinical trial, reduced body
weight as well as improve dyslipidemia in high fat diet-fed (HFD)
rats. Hence, the understanding the cardiovascular protective
effects of Berberine appears to be mounting . In several recent
clinical trials Berberine has shown significant reductions in LDL-C. One study found total cholesterol to drop from 5.4mmol/l to
4.6mmol/L after 18 weeks with the LDL-C concentration dropping
from 3.5 mmol/L to 2.7mmol/L 9. Also, a systematic review, in
2013 examining  Berberine supplementation, evaluated eleven
randomized controlled trials (including a total of 874 participants)
the review identified a significant reduction in total cholesterol,
triglycerides and LDL-C except for HDL-C which was increased
across the 11 trials with an average LDL-C reduction of 0.65mmol/
An important consideration when using Berberine is its drug interactions. A study examining the effect of longterm administration of 900mg a [8,9] day of Berberine identified significantly decreased CYP2D6 activity with mild modification of CYP2C9 and CYP3A4 activities, but no effect on CYP1A2 and CYP2C19 function11. The CYP2D6 enzyme metabolizes a quarter of all prescribed drugs. It is recognised that 5-10% Individuals homozygous for two inactive copies of CYP2D6 are known as poor metabolisers resulting in higher plasma concentrations of the substrate drugs when compared to the wild type CYP2D6 alleles. Individuals heterozygous for one inactive allele of CYP2D6 are known as  intermediate metabolisers, and homozygous individuals with active copies of active CYP2D6 alleles are known as ultrarapid metabolisers. Thus, in any population a number of individuals given prescribed Berberine doses of 1500mg/day will possibly have drug interactions with their other prescribed medications if they are modified by CYP2D6. My data with  Berberine administered to eight (8) adult individuals for 12 weeks at 500mg of Berberine three times a day, showed an avrage reduction in LDL-C of 0.65mmol/L (reported in Table 1. Seven out of the eight (8) individuals had varying reductions of LDL-C over 12 weeks. One patient who had no reduction in LDL-C had an adverse reaction with the Berberine. He exhibited  total inhibition of his Hydroxyurea being administered for controlled Essential Thrombocythemia. There had been no reported adverse effects reported for Hydroxyurea and CYP2D6. This observation requires further investigation. Vacuumed is a human monoclonal antibody that inhibits PCSK9 binding to the LDL-C receptor on the hepatocytes and disrupts LDL-C / PCRK9 receptor complex increasing  LDL-C receptor recycling to the surface of the hepatocyte and its removal of LDL-C.
Table 1: Case reports for an uncontrolled group of volunteers four (4) females and four (4) males, aged 50 to 70 years, given 500mg of Berberine, 3 times a day with meals for 12 weeks. The average reduction with LDL-C was 0.65mmol/L. This reduction was in line with the metaanalysis completed in 2013. Case 9 is a patient given biweekly injections of 140 mg/mL of evolocumab, for 12 weeks
Another important  consideration with Berberine is that it is poorly absorbed into circulation with most of an oral Berberine dose accumulating in the gut. Its absorption depends on the conversion of Berberine to dihydroberberine which requires the enzyme nitro reductase for this to occur12. Hence, an important factor in Berberine absorption is the intestinal microbiota, the metabolite dihydroberberine has been shown to have a 5-10-fold higher absorption rate than Berberine. In the absence of Nitro reductase producing bacteria this conversion does not occur. Enterococcus faecium  and Bacteroides fragilis have both been shown to produce nitro reductase enzymes and in culture have been shown to convert Berberine to dihydroberberine. Animal data supports dehydroarene possesses a stronger lipid-lowering effect, indicating that the gastrointestinal tract is a potential target for increasing the hypolipidemic effect of Berberine12. Both Berberine and dihydroberberine have recently shown to have antiinflammatory effects modulated by NF-κB and MAPK signaling pathways  and this effect adds to their use in cardiovascular disease.
Berberine is a useful for lowering LDL-C, but the degree is
variable. The effectiveness of the biological effect is linked to the
gut biome and the presence of nitro reductase enzyme producing
bacteria. The probable adverse reaction with other prescription
medicines via P450 enzymes especially CYP2D6 may limit its use
in many circumstances and the observed inhibition of Hydroxyurea
by Berberine needs to be confirmed.
The PURE study showed that socioeconomic factors play an important role in CVD and stroke14. So, lifestyle change with better dietary choices and frequent exercise, should be part of our recommendations for reducing CVD risk. There is enough evidence to recommend combinations of complementary medicines like Bergamot, Berberine, phytosterols, Niacin and fibre add additional approaches to lifestyle change to improve lipid profiles and deliver more available and appropriate CVD risk reduction measures. It is important to remember that changes in circulating lipids do take time and it would be unrealistic to expect significant change in LDL-C and its atherogenic subfractions with Berberine in less than 6 months of intervention .
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