# Berberine signature and cardiometabolic diseases using randomized controlled trial, cohort study and Mendelian randomization

## TL;DR

This study explores how berberine affects heart and metabolic diseases using clinical trials and genetic data, finding potential protective effects.

## Contribution

A novel berberine response signature was developed and linked to reduced risks of ischemic heart disease and diabetes.

## Key findings

- The berberine signature was associated with lower ischemic heart disease risk (OR 0.85) and diabetes risk (OR 0.88) using Mendelian randomization.
- SHBG and PRSS2 may explain the protective effect on heart disease, while testosterone and other proteins may relate to diabetes risk reduction.

## Abstract

Berberine lowers both lipids and glucose, yet its role on cardiometabolic disease risk remain unclear. Based on a randomized controlled trial of berberine (registered in ClinicalTrials.gov on Dec 2018, NCT03770325), leveraging proteomics and sex hormones data, we built a signature reflecting response to berberine using elastic net regression. We then assessed its associations with ischemic heart disease (IHD) and diabetes in UK Biobank using logistic regression and for causal relationship, using bi-directional Mendelian randomization (MR), and estimates of each protein/hormone. The signature was related to lower IHD and diabetes risks (OR for IHD 0.85, 95% CI 0.79-0.91; diabetes 0.88, 0.80-0.96 using MR). SHBG and PRSS2 might explain the beneficial association with IHD; testosterone, SHBG, CCL5, CNDP1, F11, LCN2, and THBS4 might explain the association with diabetes, which provides insights for drug development. Our study suggests beneficial associations of berberine with IHD and diabetes, which requires confirmation in large clinical trials.