| Title: | Evidence of a Protective Effect of Metformin on Abdominal Aortic Aneurysm Risk: Insights From an Observational Study and Mendelian Randomisation Analysis Using Putative Metformin Targets |
| Journal: | Annals of Human Genetics |
| Published: | 23 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42487515/ |
| DOI: | https://doi.org/10.1111/ahg.70049 |
Publication 21404
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Abstract
AIMS: There is no proven treatment to prevent the growth or rupture of abdominal aortic aneurysm (AAA). As an aneurysm enlarges over time, the risk of fatal aortic rupture increases. Metformin, a drug usually prescribed to treat Type 2 diabetes, has previously been associated with reduced AAA risk in observational studies. Our aim was to assess whether there was a causal association between metformin treatment and AAA using Mendelian randomisation (MR).</p>
METHODS: Logistic regression analysis was conducted in UK Biobank with 2972 AAA cases and 89,160 propensity-matched controls. In addition, two-sample MR analysis was performed, using a genetic proxy for metformin consisting of variants associated with both gene expression of seven metformin drug targets and decreased glycated haemoglobin (HbA1c) levels. Effect sizes for HbA1c were obtained from within UK Biobank, and for AAA risk from AAAgen, a multi-ancestry meta-GWAS analysis of 39,221 cases and 1,086,107 controls.</p>
RESULTS: We found evidence of a protective association between self-reported metformin treatment and reduced AAA risk in the observational analysis, OR 0.49 (95% CI: 0.41-0.59, p = 1.5 × 10-14). MR results support this finding, with an estimated decrease in AAA risk of 43%, OR = 0.57 (95% CI: 0.38-0.88, p = 0.010) per one standard deviation (sd) decrease in HbA1c via metformin gene targets, equivalent to the effect of a prescribed dose of metformin. This effect is specific to metformin target genes and was not seen using a general untargeted instrument.</p>
CONCLUSION: Our observational study found evidence that metformin use reduces the risk of developing AAA. The MR results support this finding, providing evidence that the association may be causal. Clinical trials are warranted to assess the efficacy of metformin to reduce the risk of aneurysm growth and rupture in people with AAA.</p>
12 Keywords
- Aged
- Aortic Aneurysm, Abdominal
- Diabetes Mellitus, Type 2
- Female
- Glycated Hemoglobin
- Humans
- Hypoglycemic Agents
- Male
- Mendelian Randomization Analysis
- Metformin
- Middle Aged
- Risk Factors
6 Authors
- Katie Louise Saxby
- Svetlana Stoma
- Frank Dudbridge
- Nilesh J. Samani
- Matthew J. Bown
- Christopher P. Nelson
1 Application
| Application ID | Title |
|---|---|
| 6077 | Telomere length measurement in UK Biobank: advancing understanding of biological ageing and age-related diseases |
Enabling scientific discoveries that improve human health