Table 1.

Completed clinical trials with berberine in the metabolic syndrome based on clinicaltrials.gov (accessed on 10 Fabruary 2022).

Title	Conditions	Phase	Subjects	Duration	Interventions Given	Measures	Results in Berberine or Nutraceutical Combination Groups
A Mechanistic Randomized Controlled Trial on the Cardiovascular Effect of Berberine	Cardiovascular risk factor	Phase 2 Phase 3	84 men of Chinese ethnicity aged 20 to 65 years with hyperlipidemia, not currently receiving hormone replacement therapy such as testosterone replacement therapy in the past 12 months; not currently taking berberine or traditional Chinese medicine that contains berberine in the past 1 month; free of congenital diseases, infectious diseases, anemia, and glucose-6-phosphate dehydrogenase deficiency; and no history of any chronic diseases. including ischemic heart disease, myocardial infarction (heart attack), stroke, diabetes, cancer, liver/renal dysfunction, and gastrointestinal disorders	12 weeks	Berberine verus placebo	Lipid profile LDL-cholesterol, HDL-cholesterol Triglycerides and total cholesterol Blood pressure Systolic blood pressure and diastolic blood pressure in mmHg Thromboxane A2 Testosterone Body mass index (BMI) Waist-to-hip ratio Fasting glucose Fasting insulin Liver function: Alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, gamma-glutamyltransferase, total protein, and albumin Sex hormone binding globulin (SHBG) Thrombin time	Reduction in total cholesterol and HDL-C Berberine was safe with no serious adverse events Reduction in LDL-C Increase in testosterone in males No differences in triglycerides, thromboxane A2, blood pressure, BMI, or waist-to-hip ratio [8]
Long-term efficacy and tolerability of a nutraceutical combination (red yeast rice, policosanols, and berberine (MBP-NC)) in patients with low-moderate risk of hypercholesterolemia: a double-blind, placebo-controlled Study of the	Hypercholesterolemia	Phase 4	60 adults between 18 and 60 years with newly diagnosed primary hypercholesterolemia, not previously treated, after a run-in period of 3 weeks on a stable hypolipidic diet, with a body mass index between 18,5 ad 29,9 Kg/m2, serum low-density lipoprotein cholesterol above 150 mg/dL, and an estimated 10-year cardiovascular risk of <20% according to the Framingham risk scoring	Assessement after 4, 12 and 24 weeks of treatment.	Nutraceutical combination of red yeast rice extract (monacolins), berberine, and policosanols after dinner, in addition to the hypolipidic diet versus placebo	Level of cholesterol Level of tryglicerides	A significant reduction in total cholesterol and LDL-C at week 4 No significant changes in the concentrations of HDL-C, fasting glucose, and serum triglycerides in any of the groups MBP-NC was safe and well-tolerated [9]
effects of Armolipid Plus on cholesterol levels and endothelial function (mixture of berberine, policosanol, and red yeast)	Hyperlipidemia Endothelial dysfunction	Not Applicable	50 adults aged between 18 and 70 with total cholesterol levels > 220 mg/dL; LDL-cholesterol > 130 mg/dL; and with concomitant pathology, such as diabetes, chronic heart failure, coronary artery disease, arterial hypertension, and dysthyroidism, if stable in the previous three months	6 weeks	Mixture of berberine, policosanol, red yeast versus placebo	Percentage change from baseline of total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and Triglycerides (Tg) plasma concentrations Improvement of endothelial dysfunction	Significant reduction in the homeostasis model assessment of insulin resistance (HOMA-IR index) Significant decrease in total and low-density lipoprotein cholesterol Triglycerides, high density lipoprotein cholesterol, and oral glucose tolerance test (OGTT) were not affected Significant reductions in blood glucose and insulin after the standard mixed meal Increase in flow-mediated dilation (FMD) and a significant reduction in arterial systolic blood pressure [10]
Nutraceutical combination in patients with low-grade systemic inflammation (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg, and coenzyme Q 10 mg)	Atherosclerosis inflammation Hypercholesterolemia	Phase 4	100 adults aged 25 to 75 with suboptimal LDL cholesterol levels (LDL 100–160 mg/dL) and hsCRP levels of >2 mg/L, randomized after 30 days of a low-cholesterol diet	3 months	Nutraceutical combination: red yeast rice extract (monacolins), policosanol, berberine, folic acid, coenzyme Q10, and astaxanthin with a low-cholesterol/low-saturated fat diet and a regular aerobic physical activity schedule versus a low-cholesterol/low-saturated fat diet and a regular aerobic physical activity schedule + placebo	Change in LDL cholesterol Change from baseline in circulation endothelial microparticles Change in CRP	Significant reduction in total and LDL cholesterol hsCRP significantly reduced LDL cholesterol change was positively associated with hsCRP and EMP changes hsCRP and EMP changes were associated with each other [11]
The efficacy and tolerability of coleosoma nutraceutical formulations in dyslipidemic subjects (fermented red rice, berberine, and chitosan)	Dyslipidemias	Phase 2	39 adults aged 18 to 75 with non-HDL cholesterol ≥ 160 mg/dL	12 weeks	Coleosoma-patented dietary supplement composed of berberin, fermented red rice from monascus purpureus (monacolin K), chitosan, and coenzyme Q10	Change in non-HDL Change in non-HDL cholesterol Change in free plasma glucose Change in body mass index Change in waist-to-hip ratio Change in HbA1C (%) Difference in the HbA1C value Change in LDL cholesterol, triglycerides, and HDL cholesterol Difference in the LDL Cholesterol, triglycerides, and HDL cholesterol Change in ApoB/Apo A1 ratio Difference in the ApoB/Apo A1 ratio Change in inflammatory cytokines (IL-1, IL6, IL-10, hsPCR, and TNF-α) Difference in the inflammatory cytokine values Change in insulin Difference in the insulin value Change in the hormone profile (glucagon, active GLP-1, and GIP) Change in endothelial progenitor cells	Significantly reduced non-HDL-C Non-HDL-C significantly decreased Significant correlation between baseline level of non-HDL-C and the reduction observed after 12 weeks of treatment Significant reduction in LDL-C and apolipoprotein (Apo) B No changes were observed between treatment arms in HDL-C, triglycerides, fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), waist circumference, and body mass index Differences in ApoB/ApoA ratio did not reach statistical significance [12]
Combined effects of bioactive compounds on the lipid profile (red yeast rice and policosanol composed of berberine, folic acid, and coenzyme Q10 (Armolipid Plus ®, Rottapharm))	Hyperlipidemia Low-density-lipoprotein-type Elevated triglycerides	Phase 2 Phase 3	118 adults with LDL-C plasma levels ≥ 130 mg/dL and ≤189 mg/dL that did not require lipid-lowering drug treatment according to the ATPIII guidelines, as well as adults that did not have cardiovascular disease, stroke, intermittent claudication, diabetes mellitus, renal issues, or effects/contraindications to lipid-lowering drug therapy	12 weeks	Armolipid Plus (red yeast, astaxanthin, berberine, policosanol, coenzyme Q10, and folic acid) versus placebo	LDL-C levels Cardiovascular risk Criteria for Metabolic Syndrome Levels of triglycerides and cholesterol high-density lipoprotein (HDL-C)	Plasma LDL-C reduced TC was reduced ApoB-100 was reduced The ratios of TC/HDL-C were reduced The ratios of LDL-C/HDL-C were reduced The ratios of ApoB-100/ApoA-1 were reduced No statistically significant changes were observed in TG and HDL-C levels The body mass index was reduced The weight loss observed in the AP consumption group had no significant impact on LDL-C reduction, Apo B-100, TC/HDL-C ratio, or on the ApoB/ApoA1 ratio Non-significant contribution of weight-loss to LDL-C reduction [13]
Effects of nutraceutical therapies on endothelial function, platelet accumulation, and coronary flow reserve	Hypercholesterolemia Endothelial dysfunction	Not Applicable	Adults aged between 18 and 70 years with hypercholesterolemia that did not require statins or were statin-intolerant	8 weeks	Combination A (Armolipid Plus): policosanol, red yeast rice (monacolin K), berberine, astaxantine, folic acid and coenzyme Q10 or combination B: berberine, red yeast rice powder (monacolin K), and leaf extract of Morus alba	Effects on endothelial function Evaluation of treatment tolerability Reasons for treatment discontinuation Effects on lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) Effects on metabolic indexes (glucose levels) Effects on metabolic indexes (insulin plasma levels and insulin sensitivity index (HOMA index)) Effects on platelet aggregation Effects on coronary flow reserve	Reduced LDL cholesterol below 130 mg/dL in 56.5% of patients (Combination A) Reduced plasma levels of triglycerides, total and LDL cholesterol, and increased HDL cholesterol Total and LDL cholesterol reduction (Combination B). Reduced plasma levels of glycated hemoglobin, fasting glucose, and insulin, as well as the HOMA index (Combination B) [14]
Study of berberine hydrochloride in the prevention of colorectal adenomas recurrence	Colorectal adenoma	Phase 2	1108 adults sged 18–75 who had at least one, and no more than 6, histologically confirmed colorectal adenomas that were removed within 6 months before recruitment, whose adenoma was not completely removed during a previous colonoscopy; a history of familial adenomatous polyposis or hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome); or a history of subtotal/total gastrectomy or partial bowel resection	3 years	Berberine hydrochloride versus placebo	Recurrence rates of colorectal adenoma The incidence of all polypoid lesions or advanced colorectal adenoma or colorectal cancer The incidence of all polypoid lesions or advanced colorectal adenoma or colorectal cancer Changes in fecal microflora	Berberine 0,3 g twice daily was effective and safe The risk of the recurrence of colorectal adenoma was reduced [15]
Berberine effects on clinical symptoms and metabolic disturbance in patients with schizophrenia	Schizophrenia	Phase 4	65 adults aged 18 to 65 years who met the diagnosis of schizophrenia according to the DSM-IV, and have undergone monotherapy of atypical antipsychotics for 4 weeks or more, with at least 60 for positive and negative syndrome scale	8 weeks	Berberine plus any atypical antipsychotic drug as the basic treatment	Positive and Negative Syndrome Scale Changes in Insulin Changes in TC Changes in TG Changes in HDL-C Safety of berberine Changes in CRP Changes in IL-1β Changes in IL-6 Changes in TNF-α	Lowering the concentration of TC and LDL-C in the plasma Significant decrease in fasting insulin and homeostasis model assessment-insulin resistance BMI and serum PRL concentrations have an influence on the improvement of fasting insulin, and homeostasis model assessment-insulin resistance in the berberine group, but not in the placebo group The patient’s response to berberine is BMI-dependent Patients with higher serum prolactin levels had a weaker effect of berberine treatment [16]
Berberine treat metabolic syndrome in schizophrenia	Metabolic syndrome Schizophrenia	Not Applicable	Adult females aged 18–60 with a diagnosis of schizophrenia, undergoing monotherapy of atypical antipsychotics for 2 weeks or more, including olanzapine, clozapine, risperidone, and perphenazine, with a diagnosed metabolic syndrome depending on the guidelines for the prevention and treatment of dyslipidemia in Chinese adults in 2007	8 weeks	Berberine in adjunctive group	Serum fasting blood glucose Serum triglyceride and serum low-density lipoprotein Systolic blood pressure Waistline circumference Diastolic blood pressure	Control of weight gain and other metabolic symptoms associated with antipsychotic therapy as an adjuvant Significant differences in body weight, BMI, and leptin Significant positive correlations with changes in body weight There was no significant difference in adverse events between the two groups [17]
Berberine hyperglycemic clamp	Diabetes mellitus	Phase 1	15 adult healthy males, aged 18–45 with BMI 18–25 kg/m2 and a normal oral glucose tolerance test prior to the study, with no family history of diabetes mellitus, and with no medication treatment within 4 weeks prior to the baseline visit, as well as during the study	2 weeks	Berberine versus placebo	Differences in serum insulin levels Differences in serum C-peptide levels Differences in glucose infusion rates Differences in blood glucose levels Heart rate and QT-interval duration	Increase in glucose-dependent insulin secretion Berberine had no effect on insulin secretion at low glucose levels At high glucose levels, insulin release was stimulated by berberine in a dose-dependent manner. Blockade of KCNH6 channels by berberine increased insulin secretion in a glucose-dependent or hyperglycemic manner Berberine did not cause hypoglycemia [18]
Efficacy and safety of berberine in the treatment of diabetes with dyslipidemia	Type 2 diabetes mellitus Metabolic syndrome	Phase 3	120 adults aged 25–70 with newly diagnosed type 2 diabetes, according to the 1999 World Health Organization criteria, with dyslipidemia with a TG of > 150 mg/dL (1.70 mmol/L), and/or TC > 200 mg/dL (5.16 mmol/L), and/or LDL-C > 100 mg/dL (2.58 mmol/L), according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP: ATPIII) without previous treatment and with BMI 19–40 kg/m2	3 months	Berberine versus placebo	Fasting glucose levels OGTT 2 h glucose levels HbA1c Serum triglycerides Serum total cholesterol HDL-C LDL-C Glucose disposal rate BMI Blood pressure	After 3 months of treatment, plasma glucose levels in the front and under loads were significantly reduced [17]
Therapeutic effects of berberine in patients with type 2 diabetes	Type 2 diabetes	Phase 1 Phase 2	70 adults aged 25 to 75 with a clinical diagnosis of type 2 diabetes with HbA1c > 7.0% or FBG > 7.0 mmol/L with stable or worsening glycemic control for at least 3 months	13 weeks	Berberine versus metformin	HbA1c Blood glucose Blood lipids	Identical effect in the regulation of glucose metabolism (HbA1c, FBG, PBG, fasting insulin, and postprandial insulin), such as metformin. Better regulation of lipid metabolism than metformin-triglycerides, and total cholesterol was significantly lower than in the metformin group Significantly decreased HbA1c levels (HbA1c was comparable to that of metformin) [19]