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Diabetes and Vascular Disease

ORF33-08 - Role of Steroid 5α-Reductase Type 1 in Cardiometabolic Diseases

Sunday, June 14, 2026
3:00 PM - 3:15 PM CT
Location: Room W183A
Disclosure(s):
Haolan Tu, BSc: No financial relationships to disclose



Introduction:
5α-Reductase (SRD5A1) inhibitors are frequently prescribed in men with prostate disease to attenuate 5α-dihydrotestosterone exposure, but are associated with increased risks of type 2 diabetes and steatosis, phenotypes also observed in Srd5a1-/- mice. We assessed the cardiovascular risk of 5α-reductase inhibitors in people with type 2 diabetes; and explored the SRD5A1 regulatory networks underpinning this metabolic dysfunction in liver and adipose tissue in humans.

Methods:
We conducted a retrospective population-based cohort study in 28,461 patients prescribed 5α-reductase inhibitors or tamsulosin (control) between 2006 and 2021 in the Scottish Diabetes Research Network-National Diabetes Dataset and IQVIA-Medical Research Data-UK. Cox proportional-hazard models were used to compare hazard ratios of incident major adverse cardiovascular events (MACE) between groups after propensity score-matching. The SRD5A1 co-expression networks in liver, visceral adipose, and subcutaneous adipose was constructed using two human transcriptomic datasets (GTEx: N=838, 55.0±13.0 years, 66.5% men; STARNET: N=600, 65.0±8.7 years, 70.3% men;). This was validated in an independent cohort of metabolic dysfunction-associated steatotic liver disease (MASLD) cases and controls (SteatoSITE; N=495, 52.5±13.3 years, 52.3% men).

Results:
5α-Reductase inhibitors use increased risk of incident MACE (HR 1.15 [95% CI: 1.03-1.30] and 1.26 [1.07-1.47]) in both datasets. This was consistently driven by myocardial infarction (HR 1.20 [1.03-1.40] and 1.33 [1.10-1.60], respectively) but not stroke or cardiovascular death. Synergistic interaction with concomitant prescriptions of exogenous glucocorticoids was not identified. Co-expression analysis of gene networks revealed stronger representation in visceral and subcutaneous adipose than in liver, suggesting that the effect of 5α-reductase variation may occur through local action within adipose tissue. Gene-ontology analysis of co-expressed genes in both subcutaneous and visceral adipose tissues suggested enrichments in inflammation pathways and lipid digestion and absorption. This was validated in patients with MASLD, where SRD5A1 expression was associated with key genes in insulin and lipid pathways that were dysregulated across stages of fibrosis development. Time-to-event analysis showed that patients with reduced SRD5A1 expression had faster progression to hepatic decompensation (log-rank test: p=0.004). We also identified a key set of steroid-regulated genes conserved across three datasets potentially underpinning the metabolic actions of SRD5A1.

Conclusion:
Pharmacological inhibition and genetic variations of 5α-reductase alter the risk of cardiometabolic dysfunction in human, possibly underpinned by inflammation, lipid accumulation, and abnormal insulin actions.