GLP-1 Receptor Agonists May Protect Against Some Autoimmune Diseases but Increase Risk of Others | Research

The takeaway

Genetic analysis suggests GLP-1 receptor agonists may protect against type 1 diabetes, hypothyroidism, primary biliary cholangitis, and rheumatoid arthritis, but could increase the risk of Graves' disease, ulcerative colitis, and psoriasis.

4 protected, 3 at risk
Out of 18 autoimmune diseases studied, GLP-1R agonists showed protective effects against 4 diseases and increased risk for 3 others

What the researchers found

Using 22 significant cis-eQTL single-nucleotide polymorphisms as genetic instruments, the study found that increased GLP-1R gene expression had a significant protective effect on type 1 diabetes, hypothyroidism, primary biliary cholangitis (PBC), and rheumatoid arthritis (RA). Conversely, it was associated with increased risk of Graves' disease (GD), ulcerative colitis (UC), and psoriasis.

Positive control analysis confirmed the methodology's validity: GLP-1R agonists were significantly associated with reduced obesity risk (OR = 0.826, p = 0.021) and reduced type 2 diabetes risk (OR = 0.886, p < 0.001), consistent with their known clinical effects. Results were validated across two independent databases (IEU OpenGwas and FinnGen) via meta-analysis.

Why it matters

With millions of people now taking GLP-1 receptor agonists for diabetes and obesity, understanding their effects on autoimmune diseases is crucial. This study provides the first systematic genetic evidence that these peptide drugs may have both beneficial and harmful effects on different autoimmune conditions, which could guide prescribing decisions for patients with or at risk of these diseases.

How the study worked

The researchers used Mendelian randomization (MR), a method that uses genetic variants as natural experiments to infer causal relationships. They identified 22 genetic variants (cis-eQTLs) that influence GLP-1 receptor expression and used these as proxies for GLP-1R agonist exposure. They tested associations with 18 autoimmune diseases using data from two large genetic databases (IEU OpenGwas and FinnGen), then combined results via meta-analysis.

What this study cannot tell us

Mendelian randomization estimates causal effects from genetic proxies, not actual drug exposure, so results may not perfectly reflect clinical drug effects. The study could not account for dosing, duration, or specific GLP-1R agonist used. The genetic data is primarily from European populations, limiting generalizability. Some autoimmune diseases had relatively small case numbers in the databases, which could affect statistical power.

How to read the evidence

Mendelian randomization provides stronger causal evidence than observational studies by using genetic variants to minimize confounding, but it is not equivalent to a randomized controlled trial. The use of two independent databases and meta-analysis strengthens the findings, though clinical confirmation is still needed.

When this study was published

Published in 2025, this is timely research given the rapid expansion of GLP-1 receptor agonist prescribing worldwide and growing interest in their non-metabolic effects.

The bigger picture

This study contributes to the rapidly expanding understanding of GLP-1 receptor agonist effects beyond metabolism. As these peptide drugs become some of the most widely prescribed medications globally, mapping their impact on autoimmune and inflammatory conditions is essential. The mixed results — protective for some autoimmune diseases, potentially harmful for others — underscore the complexity of immune modulation by incretin-based peptides.

Questions still open

Should patients with Graves' disease, ulcerative colitis, or psoriasis be monitored more closely when starting GLP-1 receptor agonists?
What mechanisms explain why GLP-1R activation protects against some autoimmune diseases but increases risk of others?
Do clinical trial data and real-world evidence confirm these genetically predicted associations?

Common questions

What is Mendelian randomization and why was it used here?

Mendelian randomization uses naturally occurring genetic variants as 'natural experiments' to test whether something (like GLP-1R activation) causes a health outcome. Because genes are assigned randomly at conception, this method can estimate causal effects without the confounding that plagues observational studies — though it's not as definitive as a clinical trial.

Should people on GLP-1 medications worry about autoimmune disease?

The study suggests both protective and risk-increasing effects depending on the specific autoimmune disease. For most patients, the known benefits of GLP-1 receptor agonists likely outweigh the potential risks. However, patients with Graves' disease, ulcerative colitis, or psoriasis should discuss these findings with their doctor to weigh the risks and benefits.

Read the original research

Exploring glucagon-like peptide-1 receptor agonists as potential disease-modifying agents in autoimmune diseases.

Journal of autoimmunity, 153, 103414

View on PubMed ↗Publisher’s paper ↗

Citation

Yang, Yuanyuan; Liu, Wencong; Zhang, Zechang; Zhang, Yujia; Wang, Xuebin; Wang, Jing; Cai, Huaifang; Liu, Yichan; Meng, Ran; Fu, Yuqi; Luo, Hongmin; Yang, Lei; Liu, Wenxuan. (2025). Exploring glucagon-like peptide-1 receptor agonists as potential disease-modifying agents in autoimmune diseases.. Journal of autoimmunity, 153, 103414. https://doi.org/10.1016/j.jaut.2025.103414