Growth differentiation factor-15 and metabolic features in chronic heart failure: Insights from the SUPPORT Trial-GDF15 across the BMI spectrum

Background: GDF15 plays pivotal metabolic roles in nutritional stress and serves as a physiological regulator of energy balance. However, the patterns of GDF15 levels in underweight or obese patients with chronic heart failure (CHF) are not well-understood. Methods: We assessed serum GDF15 levels at baseline and 3 years and the temporal changes in 940 Japanese patients (642 paired samples), as a sub-analysis of the SUPPORT trial (age 65.9 +/- 10.1 years). The GDF15 levels were analyzed across BMI groups (underweight [<18.5 kg/m(2); n = 50], healthy weight [18.5-22.9; n = 27 5], overweight [23-24.9; n = 234], and obese [>= 25; n = 381]), following WHO recommendations for the Asian-Pacific population. Landmark analysis at 3 years assessed the association between GDF15 levels and HF hospitalization or all-cause death. Results: Compared to the healthy weight group, the underweight group included more females (54.0%) with advanced HF (NYHA class III; 20.0%) and exhibited increased GDF15 level (1764 pg/mL [IQR 1067-2633]). Obese patients, younger (64.2 years) and diabetic (53%), had a similar GDF15 level to the healthy weight group. A higher baseline GDF15 level was associated with worse outcomes across the BMI spectrum. GDF15 increased by 208 [21-596] pg/mL over 3 years, with the most substantial increase observed in the underweight group (by +28.9% [6.2-81.0]). Persistently high GDF15 levels (>= 1800 pg/mL) was independently associated with worse outcomes after 3 years (adjusted HR 1.8 [95%CI 1.1-2.9]). Conclusions: In underweight patients with CHF, GDF15 level was elevated at baseline and experienced the most significant increase over 3 years. Its consistent elevation suggested a worse outcome.