Background Recently developed exogenous ketone monoester supplements can acutely raise blood β-OHB and lower blood glucose without the need for other nutritional modifications or invasive procedures. However, unpleasant taste and the potential for gastrointestinal discomfort may make adherence to a supplement regimen challenging. Two novel ketone supplements have been developed that promise an improved consumer experience but differ in their chemical properties; it is currently unknown how these affect blood β-OHB and blood glucose compared to the original ketone monoester supplement. Methods In a double-blind randomized cross-over pilot study, N = 12 healthy individuals (29 +/- 5 years, BMI = 25 +/- 4 kg/m2, 42% female) participated in three experimental trials with a different ketone supplement providing 10 grams of active ingredient in each trial; (i) the monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, (ii) D-β-hydroxybutyric acid with R-1,3-butanediol, and (iii) R-1,3-butanediol. Blood β-OHB and glucose were measured via finger prick capillary blood samples at baseline and across 240 minutes post-supplementation. Supplement acceptability, hunger, and gastrointestinal distress were assessed via questionnaires. Results β-OHB was elevated compared to baseline in all conditions. Total and incremental area under the curve (both p < 0.05) and peak β-OHB (p < 0.001) differed between conditions with the highest values seen in the ketone monoester condition. Blood glucose concentration was reduced after consumption of each supplement, with no differences in total and incremental area under the curve across supplements. Supplement acceptability was greatest for D-β-hydroxybutyric acid with R-1,3-butanediol, with no effect on hunger or evidence of gastrointestinal distress across all supplements. Conclusions Despite differences in composition, all ketone supplements tested raised β-OHB with the highest values seen after ketone monoester ingestion. Blood glucose was lowered to a similar extent across the assessed time frame with all three supplements.

J.P.L. is supported by a Michael Smith Foundation for Health Research (MSFHR) Scholar Award (16890) and a Killam Accelerator Research Fellowship. J.P.L. is volunteer Chief Scientific Officer for the not-for-profit Institute for Personalized Therapeutic Nutrition. J.P.L. holds founder shares in Metabolic Insights Inc., a for-profit company that developed non-invasive metabolic monitoring devices.

NCT05273411

This work was funded by a Canadian Institutes of Health Research (CIHR) Project Grant to J.P.L. (PJT-169116).

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