A Sequential Multiple Assignment Randomized Trial of Diet Treatments for Hepatic Steatosis and Cardiometabolic Risk in Adolescents

PROJECT SUMMARY/ABSTRACT This application is in response to NOT-HL-21-020: “NHLBI Announces Interest in Promoting Cardiovascular and Cardiometabolic Health in Early Stages of the Lifecourse” and addresses gaps delineated by both NHLBI and the American Heart Association (AHA). Major gaps exist in the treatment of NAFLD (now called metabolic-dysfunction associated steatotic liver disease [MASLD]), which is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Most of the ~7 million youth with MASLD will progress to ASCVD and in youth, even small increases in hepatic steatosis (HS) are directly related to peripheral dyslipidemia. MASLD disproportionately affects youth with Hispanic or Latino ancestry, and it is an exceptionally heterogeneous condition, with varying patterns of cardiometabolic factors, progression, and therapeutic response. Our work has shown that a registered dietician nutritionist provided very low-sugar diet improves hepatic steatosis, dyslipidemia, and insulin resistance and normalizes amino acid concentrations in adolescents with MASLD; however, the response is variable. Essential amino acids (EAA) provided as an oral supplement have also been shown to improve hepatic steatosis and dyslipidemia, as well as decrease appetite in adolescents with hepatic steatosis, however, the response was also heterogeneous. Based on this prior work, there is a clear need for innovation, applying precision medicine principles to develop therapeutic sequences that combine or switch treatments and optimize outcomes in disproportionately affected children. Our long-term goal is to improve outcomes for youth-onset MASLD. The overall objective for this R61/R33 application is to answer the scientific questions that underly the construction of an efficacious, precise adaptive intervention strategy of a registered dietician-provided very low-sugar diet and EAA protein supplement to improve hepatic steatosis and cardiometabolic risk factors in youth with MASLD. The rationale for using a sequential, multiple-assignment randomized trial (SMART) is that a SMART efficiently tests multiple scientific questions. This trial is a substantial innovation over a traditional double-blinded RCT because it acknowledges and integrates the wide variation in phenotype in MASLD. The evidence generated will yield an affordable, adaptable intervention that will be evaluated in a future large multicenter trial.