Comparison of Exogenous Ketone Administration versus Dietary Carbohydrate Restriction on Myocardial Glucose Suppression: A Crossover Clinical Trial.

The ketogenic diet (KD) is standard-of-care to achieve myocardial glucose suppression (MGS) for assessing inflammation using 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). However, failure to suppress physiologic glucose uptake remains a significant diagnostic barrier. While extending the duration of KD may be effective, exogenously delivered ketones may provide a convenient, reliable, and same-day alternative. The aims of our study were to determine 1) whether exogenous ketone administration is non-inferior to the KD to achieve MGS, and 2) whether serum beta-hydroxybutyrate [BHB] levels can predict MGS. Methods: KEETO-CROSS is a crossover, non-inferiority trial of the KD (endogenous ketosis) versus ketone ester (KE, exogenous ketosis) drink. Twenty healthy participants were enrolled into three arms: 1) weight-based KE drink 2) 24-hour KD, and 3) 72-hour KD (N = 18 completed all arms). The primary outcome was achievement of complete MGS on PET (non-inferiority margin 5%). The area under receiver operating characteristics (AUROC) of endogenous BHB levels (analyzed in a laboratory and by point-of-care device) for predicting MGS was analyzed in 37 scans completed on the KD. Results: Mean age was 30±7 years, 50% were female, 45% were non-white. Median (25th-75th percentile) achieved BHB levels (mmol/L) were 3.82 (2.55-4.97) (KE drink), 0.77 (0.58-1.02) (24-hour KD), and 1.30 (0.80-2.24) (72-hour KD). The primary outcome was achieved in 44% (KE drink), 78% (24-hour KD), and 83% (72-hour KD) of participants (non-inferiority P = 0.97 and 0.98 for KE vs. 24-hour and 72-hour KD). Endogenous BHB levels robustly predicted MGS (AUROC 0.88, 95%CI 0.71, 1.00). BHB >0.58 correctly classified 92% of scans. A point-of-care device provided comparable predictive value. Conclusion: In healthy volunteers, KE was inferior to KD for achieving MGS. Serum BHB is a highly predictive biomarker for MGS and can be clinically implemented upstream of FDG-PET, with rapid facilitation by point-of-care testing, to reduce false positive scans.