Berberine

Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids, found in plants such as Berberis species (barberry, Oregon grape), Hydrastis canadensis (goldenseal) and Coptis chinensis (Chinese goldthread). ^[1] It has been a component of traditional Chinese and Ayurvedic medicine for more than 2000 years, and it is the main active component of Rhizoma Coptidis, an herb used in traditional formulas for diabetes. ^{[2] [3]} Today berberine is used as a purified product that is easy to purchase as a nutraceutical supplement or non-prescription drug. ^[4] Its lipid-lowering and insulin-resistance-improving actions are its most studied properties in randomized clinical trials. ^{[5] [1]} An umbrella review of meta-analyses of randomized trials found effects of berberine on blood glucose, insulin resistance, blood lipids, body composition, inflammatory markers, colorectal adenomas and Helicobacter pylori infection compared with controls. ^[6]

Oral bioavailability is low because of poor absorption from the gut, P-glycoprotein-mediated efflux and rapid metabolism. ^[2] One recent review puts its oral bioavailability below 5%, a key translational barrier. ^[7] Berberine undergoes extensive metabolism (demethylation, demethylenation, reduction, hydroxylation and conjugation), and active metabolites such as berberrubine, columbamine and demethyleneberberine are thought to contribute to its hypolipidemic and hypoglycemic effects. ^[8] Basic, translational and clinical studies have identified molecular targets of berberine that include AMPK, SIRT1, the LDL receptor, PCSK9 and PTP1B. ^[2] Berberine is listed among natural PCSK9 inhibitors, and the cholesterol-lowering mechanisms proposed for such supplements include increased hepatic LDL-receptor expression and activation of AMPK signalling. ^{[9] [10]}

In a meta-analysis of 50 randomized trials involving 4,150 participants in type 2 diabetes, berberine alone reduced fasting plasma glucose by 0.59 mmol/L and LDL cholesterol by 0.30 mmol/L, and combined with glucose-lowering drugs it reduced HbA1c by 0.69%. ^[14] Another type 2 diabetes meta-analysis involving 3,048 patients found reductions in HbA1c of 0.63% and in fasting plasma glucose of 0.82 mmol/L, with a glucose-lowering effect that depended on baseline fasting glucose and HbA1c. ^[11] In subgroup analyses of an earlier meta-analysis, the glucose-lowering effect became unremarkable when treatment lasted more than 90 days, the dose exceeded 2 g/d, or patients were older than 60 years. ^[15]

The most common side effects are gastrointestinal, such as constipation and diarrhea. ^[6] In placebo-controlled lipid trials no serious adverse events were reported with berberine, while gastrointestinal adverse events tended to be more frequent than with placebo (2-23% vs 2-15%). ^[4] In type 2 diabetes, berberine alone or with oral glucose-lowering agents did not significantly increase the risk of hypoglycemia (RR 0.48, 95% CI 0.21 to 1.08). ^[11] The most common dosage in type 2 diabetes trials was 0.9-1.5 g/d, with treatment cycles typically lasting 1-3 months. ^[14] Repeated oral dosing (0.3 g three times daily) reduced CYP2D6, CYP2C9 and CYP3A4 activity in healthy subjects, which may cause herb-drug interactions, and because berberine displaces bilirubin from albumin it should be avoided in jaundice in pregnant women and infants. ^[2] None of the lipid-lowering natural products, including berberine, reduce lipid levels to the extent of statins, and berberine is judged to confer at most limited benefit in certain patient groups.