Serum <scp>IGF</scp> ‐1 and the Risk of Cardio‐Kidney Outcomes in Metabolic Dysfunction‐Associated Steatotic Liver Disease

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) increases cardiovascular and kidney disease risk. Insulin-like growth factor 1 (IGF-1) regulates metabolic and vascular function, but its role in long-term cardio-kidney outcomes (CKO) in MASLD remains unclear. This study examined the association between MASLD, IGF-1 levels and CKO. METHODS: In this prospective cohort study, we used data from 214 512 UK Biobank participants without baseline cardiovascular or chronic kidney disease (CKD). Participants were categorized into four groups: no-MASLD and MASLD stratified by age- and sex-specific tertiles of serum IGF-1 (T1-T3). The primary outcome was a composite CKO; secondary outcomes were incident CKD and 3-point major adverse cardiovascular events (3P-MACE). RESULTS: Over a median 13-year follow-up, 20 395 CKOs occurred. MASLD increased event rates across all IGF-1 tertiles (p < 0.001), with a significant interaction observed between MASLD and IGF-1 levels (P for interaction = 0.014). In multivariable Cox models, MASLD remained independently associated with CKO risk, strongest in the lowest IGF-1 tertile (T1: adjusted hazards ratio [aHR], 1.24 [95% CI: 1.18-1.30] vs. no-MASLD). Similar trends were observed for incident CKD (T1: aHR, 1.35 [95% CI: 1.22-1.49]) and 3P-MACE (T1: aHR, 1.26 [95% CI: 1.18-1.35]). Subgroup analyses indicated consistent associations across sex, BMI and diabetes, with stronger effects in participants < 65 years and markedly greater CKD risk among those with baseline albuminuria. CONCLUSION: MASLD independently predicted CKO, particularly among individuals with low IGF-1 levels. Incorporating IGF-1 into clinical evaluations may improve risk stratification beyond conventional metabolic factors.