Higher circulating FGF21, lower protein intake, and lower muscle mass: Associations with a higher risk of mortality.

Background and objectives: This population-based study explores associations of fibroblast growth factor 21 (FGF21), a key modulator of processes linked to protein metabolism, with protein intake and muscle mass, and their relationships with all-cause mortality.

Methods: In 6395 participants (mean age 54 years; 50% women), circulating FGF21 (immunoassay), protein intake (Maroni equation using 24-h urinary urea excretion; low intake defined as <0.8 g/kg/day), and muscle mass (24-h creatinine excretion rate indexed to height squared (CERI)) were documented.

Results: FGF21 concentration was 896 (540-1384) pg/mL, protein intake was 1.01 (0.85-1.19) g/kg/day, and CERI was 4.1 ± 0.9 mmol/day/m². Higher FGF21 was associated with higher odds of low protein intake (odds ratio per doubling: 1.48; 95% confidence interval [CI]: 1.38-1.58; p < 0.0001) and lower muscle mass (standardized beta: -0.08; 95% CI: -0.10; -0.06; p < 0.001). Over 10.4 years of follow-up, 955 deaths were registered. Higher FGF21 was associated with increased mortality (hazard ratio (HR) per doubling: 1.09; 95% CI: 1.02-1.16; p = 0.009). Conversely, higher protein intake (HR per doubling: 0.67; 95% CI: 0.56-0.81; p < 0.0001) and higher CERI (HR per standard deviation increase: 0.83; 95% CI: 0.76-0.90; p < 0.0001) were associated with a lower risk of mortality, independent of potential confounders. However, the FGF21-mortality association became non-significant after adjusting for protein intake.

Conclusion: Higher FGF21 was associated with higher odds of low protein intake. The observed association of higher FGF21 concentrations and risk mortality was predominantly attributable to lower protein intake. In contrast, both higher protein intake and higher muscle mass were independently associated with lower mortality risk, highlighting the potential relevance of protein intake and maintenance of muscle mass in long-term health.