Metabolic benefits of ketohexokinase inhibition in individuals with MASLD: a randomized placebo-controlled crossover trial.

High fructose consumption, particularly from sugar-sweetened beverages, contributes to cardiometabolic disease. Here we study the metabolic effects of 6-week pharmacological inhibition with PF-06835919 of ketohexokinase, the enzyme that catalyses the first committed step of fructose metabolism, in a randomized placebo-controlled crossover trial in 15 participants with metabolic dysfunction-associated steatotic liver disease. The primary outcome was hepatic insulin sensitivity, measured by insulin-stimulated suppression of endogenous glucose production. Secondary outcomes included fat distribution, peripheral and adipose tissue insulin sensitivity, and fat oxidation. While PF-06835919 treatment did not affect body weight, it improved hepatic insulin sensitivity and reduced intrahepatic lipid and saturated fatty acid content. Besides these beneficial hepatic effects, PF-06835919 also improved insulin-stimulated glucose disposal, adipose tissue insulin sensitivity, adipose tissue distribution and nocturnal fat oxidation. These changes are accompanied by changes in very low-density lipoprotein particle size distribution and circulating hepatokines. These results show that inhibition of fructose metabolism has beneficial metabolic effects that extend beyond the organs that metabolize fructose. ClinicalTrials.gov identifier: NCT05463575 .