Endogenous versus Exogenous Ketosis to Suppress Myocardial Glucose Uptake on FDG-PET: KEETO-CROSS

Background: The ketogenic diet (KD) is the gold standard to achieve myocardial glucose suppression (MGS) for evaluating inflammation using 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). However, incomplete MGS occurs in 15-20% of participants without inflammation, leading to repeat testing with excess radiation exposure, inaccurate diagnosis with inappropriate immunosuppression, and extra costs to the healthcare system. While extending the duration of KD may be an effective option, limited data suggest exogenous ketones may provide a convenient and reliable diagnostic alternative to the KD to achieve MGS. In addition, whether serum ketone levels (reflected by beta-hydroxybutyrate (BHB)) can serve as a biomarker reflecting achievement of appropriate MGS has not been evaluated.

Methods: KEETO-CROSS is a randomized, crossover, non-inferiority, open-label trial of the KD (endogenous ketosis) versus ketone ester (KE, exogenous ketosis) drink. Nineteen healthy participants were enrolled into three sequential arms: 1) weight-based (714 mg/kg) KE drink 1 hour before FDG-PET (N=18), 2) 24 hours of KD (N=18), and 3) 72 hours of KD (N=17). The primary outcome was adjudicated in a blinded manner as complete MGS on PET (defined as FDG uptake in all heart walls lower than blood pool activity), assessed using McNemar’s test with a non-inferiority margin of 5%. The predictive value of endogenous levels of BHB for MGS was analyzed using area under receiver operating characteristics (AUROC) for all 35 scans completed on the KD.

Results: The mean age was 30+7 years, 53% were female, 53% were white, and average BMI was 24.2+3.2 kg/m². Mean achieved BHB levels in mmol/L were 3.81+1.61 (KE drink), 0.77+0.37 (24 hour KD), and 1.46+0.84 (72 hour KD) (Figure 1A). The primary outcome was achieved in 44% (KE drink), 78% (24 hour KD), and 88% (72 hour KD) of participants (p=0.07 and 0.022 for KE vs. 24 and 72 hour KD, respectively), failing to meeting the non-inferiority margin. Endogenous levels of BHB robustly predicted MGS (AUROC 0.98, 95% CI 0.95, 1.00) (Figure 1B). BHB levels <0.34 mmol/L and >0.58 correctly classified MGS failure and success, respectively, in all (100%) scans completed on the KD.

Conclusions: In healthy volunteers, KE was inferior to the KD for achieving MGS, though 20% of healthy volunteers still failed dietary modification at the standard 24 hour assessment and 10% even at 72 hours. BHB is a highly accurate biomarker for predicting MGS. Our study has identified BHB thresholds which can be implemented clinically upstream of FDG-PET to reduce non-diagnostic and false positive scans.

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