Abstract: Diabetes affects millions of people globally, predominantly type 2 diabetes mellitus (T2DM), characterized by high blood glucose levels. Due to high blood sugar levels, individuals with T2DM are at increased risk of various health complications, prompting many to explore additional treatments alongside conventional ones. Berberine, a natural compound found in plants, has gained attention as a complementary therapy for T2DM. Berberine works in multiple ways, including improving glucose and lipid metabolism, reducing inflammation, and affecting gut bacteria. Clinical trials have shown that berberine can help manage blood sugar levels, insulin sensitivity, and cholesterol in T2DM patients, often as effectively as common medications like metformin.

Though generally safe, berberine may cause mild digestive issues and interact with certain drugs. More research is needed to understand its long-term effects fully. Health-care practitioners should discuss berberine’s potential benefits and risks with patients, integrating it into personalized treatment plans alongside conventional therapies.

Introduction

Diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels resulting from insulin resistance or deficiency. The International Diabetes Federation estimates that in 2021, 573 million adults aged 20–79 years were living with diabetes. This number is to rise to 783 million by 2045. Diabetes is indeed responsible for 6.7 million deaths in 2021, which equates to an estimated one death every five seconds.[i] Risk factors associated with diabetes include obesity, endothelial dysfunction, vascular inflammation, and dyslipidemia,[ii] all of which puts individuals with type 2 diabetes mellitus (T2DM) at elevated risks of cardiovascular complications,[iii] end-stage renal disease,[iv] and hypertension.[v] Nevertheless, research indicates that people with T2DM also have increased susceptibility to depression,[vi] thyroid-gland disorders,[vii] and chronic obstructive pulmonary disease (COPD).[viii] In addition to conventional treatments, many patients with diabetes explore complementary therapies. Berberine, a natural alkaloid found in several plants, has shown promising results in the treatment of T2DM. This review aims to evaluate the current evidence on the efficacy and safety of berberine as a complementary therapy for T2DM.

Possible Mechanism of Action

Berberine has been shown to improve glycemic control, lipid metabolism, and inflammation in both animal and human models. Several mechanisms of action have been proposed, including activation of adenosine monophosphate–activated protein kinase (AMPK), inhibition of dipeptidyl peptidase‑4 (DPP‑4), and modulation of gut microbiota. AMPK is a key enzyme involved in glucose and lipid metabolism, and activation of AMPK has been shown to improve insulin sensitivity and reduce inflammation.[ix] DPP‑4 is an enzyme that degrades glucagon-like peptide‑1 (GLP‑1), a hormone that stimulates insulin secretion and reduces glucagon secretion.  Some studies suggest that berberine may contribute to increased GLP-1 levels and improved glycemic control, potentially through DPP-4 inhibition, among other mechanisms. A review discussed the therapeutic effects of berberine on metabolic diseases, noting that DPP‑4 inhibition is one of the possible mechanisms contributing to its glucose-lowering properties.[x] Berberine has also been shown to modulate gut microbiota, which plays a crucial role in glucose and lipid metabolism.[xi]

Clinical Studies

Berberine v. Metformin

Results from a systematic evaluation investigating the use of metformin and the supplement berberine for T2DM suggest that combining these may be more effective than using metformin or berberine alone. This study employed a rigorous method, evaluating the efficacy and safety of both treatments in randomized controlled trials (RCTs). Notably, the study found no statistically significant difference in the effectiveness of the supplement berberine compared to metformin on fasting glucose levels when used as monotherapy (single-drug treatment).[xii]

Efficacy of berberine versus metformin on fasting plasma glucose (FPG)

The analysis compared the effects of berberine versus metformin on fasting plasma glucose (FPG) levels in six trials. Additionally, nine trials evaluated the combined effect of berberine and metformin against metformin alone. Due to substantial heterogeneity (I² > 50%), a random-effects (RE) model was utilized for analysis. Subgroup analysis revealed a statistically significant reduction in FPG levels when berberine was combined with metformin compared to the metformin-only group (MD = −1.49, 95% CI [−2.22, −0.76], p < 0.0001). Interestingly, no significant difference was observed between standalone berberine and metformin (MD = 0.13, 95% CI [−0.27, 0.54], p = 0.53).[xiii]

Efficacy of Berberine and Metformin Treatment on 2hPG

The study compared the effects of berberine versus metformin and berberine combined with metformin on 2hPG levels in five and nine trials, respectively. Due to significant variation between studies (heterogeneity, I² > 50%), a random-effects model was used for analysis. The results revealed a statistically significant reduction in 2hPG levels when berberine was combined with metformin compared to the metformin-only group (MD = −1.89, 95% CI [−2.94, −0.84], p = 0.0004). Interestingly, no significant difference was observed between standalone berberine and metformin for 2hPG (MD = 0.11, 95% CI [−1.38, 1.60], p = 0.88).[xiv]

Efficacy of Berberine and Metformin Treatment on HbA1c

Similar analyses were conducted for HbA1c levels, with five trials comparing berberine versus metformin and seven trials evaluating the combination against metformin. Again, high heterogeneity necessitated the use of a random-effects model. Subgroup analysis revealed a significant reduction in HbA1c levels with the combined therapy compared to metformin alone (MD = −0.65, 95% CI [−0.91, −0.40], p < 0.00001). No significant difference was observed between berberine and metformin (MD = −0.17, 95% CI [−0.49, 0.16], p = 0.31).[xv]

Berberine
Another comprehensive analysis of randomized controlled trials (RCTs) published up to July 1, 2022, investigated the effects of berberine supplementation (BBR) on cardiovascular disease (CVD) risk factors in adults. This analysis—which included studies identified through a thorough search of PubMed/Medline, Scopus, and Web of Science databases—revealed significant reductions in fasting blood glucose (FBG), with a weighted mean difference (WMD) of −7.74 mg/dL (95% CI [−10.79, −4.70], p < 0.001). Similarly, berberine supplementation significantly decreased insulin levels (WMD −3.27 mg/dL, 95% CI [−4.46, −2.07], p < 0.001) and HbA1c (WMD −0.45%, 95% CI [−0.68, −0.23], p < 0.001).

Furthermore, berberine demonstrated a lipid-lowering effect, with significant reductions observed in serum triglycerides (WMD −23.70 mg/dL, 95% CI [−30.16, −17.25], p < 0.001), total cholesterol (WMD −20.64 mg/dL, 95% CI [−23.65, −17.63], p < 0.001), and LDL cholesterol (WMD −9.63 mg/dL, 95% CI [−13.87, −5.39], p < 0.001). Additionally, berberine supplementation improved insulin sensitivity, as evidenced by a significant decrease in HOMA‑IR (WMD −1.04, 95% CI [−1.55, −0.52], p < 0.001) and a modest reduction in systolic blood pressure (WMD −5.46 mmHg, 95% CI [−8.17, −2.76], p < 0.001), weight (WMD −0.84, 95% CI [−1.34, −0.34], p < 0.001), body mass index (WMD −0.25 kg/m², 95% CI [−0.46, −0.04], p = 0.020), while it increased high-density lipoprotein (HDL; WMD 1.37 mg/dl, 95% CI [0.41, 2.23], p = 0.005).[xvii]

Berberine supplementation demonstrated a dose-dependent effect on various metabolic parameters. The analysis revealed that 1 g/d of BBR was most effective in reducing triglycerides (TG), total cholesterol (TC), and body weight. Meanwhile, a higher dose of 1.8 g/d produced the most significant improvement in insulin levels and HOMA‑IR. Interestingly, the optimal dose for increasing HDL‑C appeared to be substantially higher, at 5 g/d. Furthermore, the timeframe for achieving optimal effects varied across outcomes. Fasting blood glucose (FBG) displayed the greatest improvement at 40 weeks post–supplementation initiation, while diastolic blood pressure (DBP) and waist circumference required a longer duration of 50 weeks to reach their most favourable effect.[xviii]

Another systematic search for meta-analyses on berberine’s efficacy and safety was conducted using PubMed, Cochrane Library, and Embase databases, encompassing studies published from inception to June 30, 2022. The methodological quality and certainty of evidence within these meta-analyses were evaluated using the AMSTAR‑2 and GRADE systems, respectively. Eleven eligible meta-analyses, published in peer-reviewed journals between 2013 and 2022, were identified from a total of 235 publications. Analyses revealed significant effects of berberine supplementation compared to controls on blood glucose levels, insulin resistance, blood lipid profile, body composition, inflammatory markers, colorectal adenoma prevalence, and Helicobacter pylori eradication.[xix]

Safety

Berberine is generally considered safe when used at recommended doses. However, some studies have reported mild gastrointestinal symptoms, such as diarrhea and constipation, among patients taking berberine.[xx] Berberine has also been shown to interact with several medications, including cyclosporine, and should be used with caution in patients taking cyclosporine medications.[xxi], [xxii] Exposure to berberine has been linked to a harmful buildup of bilirubin in infants.[xxiii] Therefore, berberine might also be unsafe for infants and may also be unsafe for use during pregnancy or while breast-feeding because of possible effects on the fetus or infant.

Conclusion and Further Direction

In conclusion, diabetes is a complex and multifactorial disease that requires a comprehensive approach to management. Botanical medicines, such as berberine, have emerged as a promising complementary therapy for diabetes management, with numerous studies demonstrating their beneficial effects on glycemic control, lipid profiles, and other related metabolic parameters. The mechanism of action of berberine is thought to involve the regulation of several pathways, including the AMPK pathway, inflammation, and oxidative stress. However, some limitations exist in the current research on berberine for diabetes management. Further research is warranted to establish the optimal dosage and duration of treatment and explore the long-term efficacy and safety of berberine. In addition, the mechanisms of action of berberine in diabetes and its complications are still not fully understood and require further investigation. Health-care practitioners should be aware of the potential benefits and risks of berberine and should work with patients to develop individualized treatment plans that incorporate evidence-based therapies.