Comparison of Exogenous Ketone Administration versus Dietary Carbohydrate Restriction on Myocardial Glucose Suppression: A Crossover Clinical Trial
Senthil Selvaraj, Kenneth B. Margulies, Supritha Dugyala, Erin K. Schubert, Ann Tierney, Zoltàn Arany, Daniel A. Pryma, Svati H. Shah, J. Eduardo Rame, Daniel P. Kelly, Paco E. Bravo
Abstract
The ketogenic diet (KD) is the standard of care to achieve myocardial glucose suppression (MGS) for assessing inflammation using <sup>18</sup>F-FDG PET. However, failure to suppress physiologic glucose uptake remains a significant diagnostic barrier. Although 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 whether exogenous ketone administration is noninferior to the KD to achieve MGS and whether serum β-hydroxybutyrate (BHB) levels can predict MGS. <b>Methods:</b> KEETO-CROSS (Ketogenic Endogenous versus Exogenous Therapies for myoCaRdial glucOse SuppresSion) is a crossover, noninferiority trial of the KD (endogenous ketosis) versus ketone ester ([KE] exogenous ketosis) drink. Twenty healthy participants were enrolled into 3 arms: weight-based KE drink, 24-h KD, and 72-h KD (<i>n</i> = 18 completed all arms). The primary outcome was achievement of complete MGS on PET (noninferiority 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. <b>Results:</b> The mean age was 30 ± 7 y, 50% were women, and 45% were nonwhite. The median achieved BHB levels (mmol/L) were 3.82 (25th–75th percentile, 2.55–4.97) (KE drink), 0.77 (25th–75th percentile, 0.58–1.02) (25th–75th percentile, 24-h KD), and 1.30 (25th–75th percentile, 0.80–2.24) (72-h KD). The primary outcome was achieved in 44% (KE drink), 78% (24-h KD), and 83% (72-h KD) of participants (noninferiority <i>P</i> = 0.97 and 0.98 for KE vs. 24-h and 72-h KD). Endogenous BHB levels robustly predicted MGS (AUROC, 0.88; 95% CI 0.71, 1.00). A BHB of 0.58 or more correctly classified 92% of scans. A point-of-care device provided comparable predictive value. <b>Conclusion:</b> 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 <sup>18</sup>F-FDG PET, with rapid facilitation by point-of-care testing, to reduce false-positive scans.