Common diabetes medications have been identified as a possible treatment for atrial fibrillation

Common diabetes medications have been identified as a possible treatment for atrial fibrillation

Cleveland Clinic researchers have identified a common diabetes drug, metformin, as a possible treatment for atrial fibrillation.

The study, published in Cell Reports Medicine, built on ongoing collaborative research at the Cleveland Clinic to support further investigation of metformin as a candidate for drug repurposing. Researchers used advanced computing and genetic sequencing to determine that metformin's targets overlap significantly with genes that are dysregulated in atrial fibrillation.

It is difficult to find medications or procedures to treat atrial fibrillation due to possible serious side effects. There is a significant need for new treatments for atrial fibrillation as no new drugs have been approved for more than a decade.”

Mina Chung, MD, senior author of the study, Cleveland Clinic Division of Cardiovascular Medicine in the Heart, Vascular and Thoracic Institute

“It's not like we've found a new drug target that will take 20 years to test in individuals,” said Jessica Castrillon Lal, the study's first author and a fifth-year graduate student in the Cleveland Clinic Molecular Medicine program.

"We can save more than 10 years in the drug development pipeline. We already have the information there. We just need to test it in a very computationally efficient way, such as with artificial intelligence technology," said study co-senior author Feixiong Cheng, Ph.D., associate staff at the Genomic Medicine Institute at Cleveland Clinic's Lerner Research Institute.

The analysis found that metformin targeted 30 genes associated with atrial fibrillation and had direct effects on gene expression in eight of them. Eight other drug candidates emerged in the analysis, but researchers were able to identify metformin as the most promising candidate through testing and reviewing the results of extensive patient data sets.

Castrillon Lal is a researcher in Dr. Cheng's lab, which uses network medicine approaches to find potential drugs for other uses, creating vast networks of molecular interactions. For this study, researchers compiled a list of 2,800 FDA-approved treatments by analyzing three data sources: a map of interactions between proteins called an “interactome”; a network of genes associated with atrial fibrillation; and the molecular or genetic targets of each drug.

Atrial fibrillation is the most common form of cardiac arrhythmia worldwide and can lead to complications such as stroke and heart failure. Treatments primarily aim to prevent the arrhythmia by using drugs that target the electrical system, including the ion channels in the heart, or by using catheter ablation to isolate the pulmonary veins where atrial fibrillation occurs.

However, side effects, limited success, and possible complications can limit these approaches.

The research was carried out in collaboration with laboratories led by Dr. Chung, Dr. Cheng, David Van Wagoner, Ph.D.; Jonathan Smith, Ph.D., Division of Cardiovascular and Metabolic Sciences; and John Barnard, Ph.D., Division of Quantitative Health Sciences at Lerner Research Institute.

Previous work by Dr. Chung, Smith, Van Wagoner and Barnard had also identified the enzyme AMPK as a potential key regulator of metabolic stress. Metabolic stress is associated with atrial fibrillation.

This work is related to a recent $14.2 million grant from the NIH to explore new treatments for atrial fibrillation using genomic data. The researchers further corroborated the results of the network analyzes with experiments on live beating heart cells grown from human stem cells, showing beneficial effects of metformin on gene expression.

Source:

Cleveland Clinic

Reference:

Lal, J.C., et al. (2022) Transcriptomics-based network medicine approach identifies metformin as a reusable drug for atrial fibrillation. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2022.100749.

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