Abstract Body: Introduction: Heterozygous familial hypercholesterolemia (HeFH) is a severe genetic disorder that accelerates atherosclerosis and leads to premature cardiovascular diseases (CVDs). Minimally processed provegetarian diets are recommended in dietary and clinical guidelines worldwide for their cardioprotective properties. However, the impact of such diet on LDL-cholesterol (LDL-C) and other CVD risk factors has not yet been assessed in fully controlled feeding settings among adults with HeFH.

Hypothesis: We tested the hypothesis that a minimally processed provegetarian diet (MPVD) induces clinically significant improvements in plasma LDL-C levels (primary outcome) and other CVD risk factors compared to a standard American diet (SAD) among adults with HeFH.

Methods: In this randomized, crossover, controlled feeding trial, 50 adults with genetically confirmed HeFH, free of cholesterol-lowering medication, consumed a MPVD and a SAD for 4 weeks each in a random order under fully controlled feeding conditions. Fasting plasma atherogenic lipid levels and other CVD risk factors were measured at the end of each diet.

Results: Relative to the SAD, the MPVD induced a clinically significant reduction in LDL-C (−18.6%, 95% confidence interval (CI) −22.1%, −15.2%; P<0.0001). Stratified analyses revealed no evidence of effect modification due to sex, LDL-receptor genotype, and BMI. However, a greater reduction of LDL-C was observed in older participants (P_diet*age=0.02) and in those with lower lipoprotein(a) levels (P_diet*Lp(a)=0.02). The MPVD also reduced apolipoprotein B (−15.2%, 95%CI −18.3%, −12.0%), non-HDL-C (−18.0%, 95%CI −21.0%, −14.8%), triglycerides (−8.6%, 95%CI −14.4%, −2.2%), and systolic (−2 mm Hg, 95%CI −3.3 mm Hg, 0.0 mm Hg) and diastolic (−2 mm Hg, 95%CI −3.4 mm Hg, −0.5 mm Hg) blood pressure. Overall, the MPVD reduced the 10-year risk of CVD by 1.55% (P=0.03). Moreover, while the two diets were isocaloric and had the same macronutrient composition, the MPVD improved satiety compared to the SAD, with the effect being more important among men (P_diet*gender=0.03).

Conclusion: This study demonstrates that, compared to a standard American diet, a minimally processed provegetarian diet induces clinically significant reductions in LDL-C and other CVD risk factors in adults with HeFH. It paves the way for developing precision nutrition strategies that incorporate gender-specific counseling and underscores the critical role of diet modification in HeFH management.