Highlights
- In a multicenter RCT involving 337 participants, 1 g/d of berberine for six months did not significantly reduce visceral adipose tissue (VAT) area or liver fat content compared to placebo.
- Berberine treatment resulted in significant reductions in low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hs-CRP).
- The safety profile of berberine was excellent, with adverse event rates comparable to the placebo group.
- Post hoc analysis suggests that patients with higher baseline inflammation may derive greater lipid-lowering benefits from berberine.
Introduction: The Metabolic Challenge of MASLD
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD, has emerged as a global health epidemic, closely linked with obesity, insulin resistance, and dyslipidemia. Central to the pathogenesis of MASLD is the accumulation of visceral adipose tissue (VAT), which serves as a major source of pro-inflammatory cytokines and free fatty acids that drive hepatic steatosis and systemic metabolic dysfunction. Despite its prevalence, pharmacological options for MASLD remain limited, leading researchers to explore botanical compounds with metabolic potential.
Berberine, an isoquinoline alkaloid found in several traditional medicinal plants, has gained significant attention as a potential therapeutic agent. Often referred to in lay media as “natural metformin,” berberine has demonstrated the ability to activate adenosine monophosphate-activated protein kinase (AMPK) and inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) in preclinical studies. While previous pilot studies suggested benefits in weight loss and liver fat reduction, large-scale, rigorous clinical evidence in diabetes-free populations has been lacking. The BRAVO (Berberine and Adiposity in Diabetes-Free Individuals With Obesity and MASLD) trial was designed to provide definitive evidence regarding its efficacy in these specific populations.
The BRAVO Trial: Study Design and Methodology
The BRAVO trial was a multicenter, double-blind, randomized, placebo-controlled clinical trial conducted across 11 hospitals in China. The study enrolled 337 diabetes-free individuals with obesity and MASLD between July and December 2023. Participants were required to have a body mass index (BMI) of at least 28 kg/m² or a BMI of 25 kg/m² with increased waist circumference, alongside confirmed MASLD.
Participants were randomly assigned in a 1:1 ratio to receive either oral berberine (1 g/d, administered as two 0.5 g doses) or a matching placebo for six months. The primary endpoints were the relative percentage change in VAT area and the absolute change in liver fat content, both precisely measured using computed tomography (CT) scans. Secondary endpoints included changes in glycemic markers, lipid profiles (LDL-C, triglycerides, ApoB), and inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP). The analysis followed the intention-to-treat principle, ensuring that all randomized participants were included in the evaluation of efficacy and safety.
Primary Outcomes: Visceral Adiposity and Hepatic Steatosis
The results of the BRAVO trial presented a nuanced picture of berberine’s metabolic impact. Regarding the primary outcomes, the study failed to meet its main objectives for fat reduction. At the end of the six-month intervention, there were no statistically significant differences between the berberine and placebo groups in terms of visceral adipose tissue area or liver fat content.
Visceral Adipose Tissue (VAT)
The mean relative change in VAT area for the berberine group compared to the placebo group was 1.4% (97.5% CI, -2.4% to 5.2%). This result indicates that berberine did not facilitate any more visceral fat loss than a placebo over the half-year duration of the study.
Liver Fat Content
Similarly, the absolute change in liver fat content showed no significant improvement with berberine compared to placebo (0.9% [97.5% CI, -0.4% to 2.1%]). These findings challenge the notion that berberine can act as a primary weight-loss or de-fatting agent for the liver in the absence of caloric restriction or intensive lifestyle modification.
Secondary Outcomes: Lipids, Apolipoproteins, and Inflammation
While the primary endpoints were negative, the secondary outcomes revealed significant clinical benefits of berberine in other areas of metabolic health. Berberine demonstrated a clear and statistically significant advantage over placebo in improving the lipidomic and inflammatory profile of participants.
Lipid Profile Improvements
Participants in the berberine arm experienced a significantly larger reduction in LDL-C levels compared to those in the placebo arm (-7.72 mg/dL [95% CI, -13.13 to -1.93]). Furthermore, apolipoprotein B (ApoB), a critical marker of atherogenic risk, was reduced by -3.42 mg/dL (95% CI, -6.33 to -0.51) in the berberine group. These results align with the known mechanism of berberine-mediated PCSK9 inhibition, which increases the expression of LDL receptors on hepatocytes.
Systemic Inflammation
One of the most notable findings was the reduction in hs-CRP levels. Berberine-treated individuals showed a significant decrease in hs-CRP compared to placebo (-0.072 mg/dL [95% CI, -0.140 to -0.004]). Post hoc analyses further indicated that this anti-inflammatory effect was most pronounced in participants who entered the study with higher baseline hs-CRP levels. This suggests that berberine may be particularly beneficial for patients with a high baseline inflammatory burden, a common feature in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH).
Safety and Tolerability Profile
The safety profile of berberine at a dose of 1 g/d was excellent. The trial reported high medication adherence rates—90.3% for the berberine group and 90.7% for the placebo group. The incidence of adverse events, including gastrointestinal symptoms which are often associated with berberine, was similar between the two study arms. No serious adverse events were linked to the intervention, confirming that berberine is a well-tolerated supplement for long-term use in this population.
Clinical Discussion: Reconciling Mixed Metabolic Signals
The BRAVO trial provides high-quality evidence that clarifies berberine’s role in metabolic therapy. The disconnect between its failure to reduce fat (VAT and liver fat) and its success in improving lipids and inflammation warrants closer clinical examination.
The lack of effect on adiposity may be due to the dose or the study population. While 1 g/d is a standard dose, some previous studies showing weight loss used higher doses or combined berberine with other lifestyle interventions. Furthermore, in individuals who are diabetes-free, the metabolic pathways that berberine influences might not be sufficient to overcome the homeostatic mechanisms preserving fat stores without a concurrent caloric deficit.
However, the significant reduction in LDL-C and hs-CRP suggests that berberine remains a valuable tool for cardiovascular risk reduction in patients with MASLD. Since cardiovascular disease is the leading cause of mortality in MASLD patients, the lipid-lowering and anti-inflammatory properties of berberine provide a meaningful clinical advantage, even in the absence of direct liver fat reduction. The findings support the use of berberine as an adjunct therapy for dyslipidemia and subclinical inflammation in the context of metabolic syndrome.
Expert Commentary
The BRAVO trial serves as a reminder that clinical outcomes do not always mirror biochemical expectations. While berberine’s activation of AMPK should theoretically promote lipid oxidation and fat reduction, the clinical reality in this 6-month RCT suggests that its primary strength lies in its PCSK9-inhibitory effects and its anti-inflammatory properties. For clinicians, this means berberine should perhaps be viewed more as a metabolic modulator and lipid-lowering agent rather than a weight-loss drug.
Conclusion
In this multicenter randomized clinical trial of diabetes-free individuals with obesity and MASLD, a 6-month treatment with 1 g/d of berberine did not reduce visceral adipose tissue area or liver fat content. However, it demonstrated clear benefits in reducing LDL-C, ApoB, and hs-CRP, particularly in those with higher baseline inflammation. With an excellent safety profile, berberine remains a viable option for managing the cardiovascular and inflammatory aspects of metabolic dysfunction, though it should not be relied upon as a primary treatment for reducing adiposity or hepatic steatosis.
Funding and ClinicalTrials.gov
This study was supported by grants from the National Key Research and Development Program of China and various regional health research funds. The trial is registered at ClinicalTrials.gov with the identifier NCT05647915.
References
Lei L, Wang B, Zhao L, et al. Berberine and Adiposity in Diabetes-Free Individuals With Obesity and MASLD: A Randomized Clinical Trial. JAMA Netw Open. 2026;9(1):e2554152. doi:10.1001/jamanetworkopen.2025.54152
