Metabolic benefits of ketohexokinase inhibition in individuals with MASLD: a randomized placebo-controlled crossover trial
In brief
Blocking fructose metabolism improved liver insulin sensitivity and reduced liver fat
In a 6-week randomized crossover trial of 15 people with metabolic dysfunction-associated steatotic liver disease, the drug PF-06835919 improved liver insulin sensitivity and reduced liver fat, without changing body weight. It also improved measures of glucose handling and fat metabolism, but the small, short study leaves the size and durability of these benefits, and their effect on clinical outcomes, unknown.
- Journal
- Nature metabolism (Q1)
- Published
- 7 October 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Evi J C Koene, Vera B Schrauwen-Hinderling, Jeremy Basset-Sagarminaga, Kim Brouwers, Yvonne M H Op den Kamp-Bruls, Julian Mevenkamp, et al.
- PMID
- 42844400
- DOI
- 10.1038/s42255-026-01626-5
Why clinicians should know about it
- Picked for Internal Medicine (top studies of the week, 11 October 2026): Ketohexokinase inhibition trial – metabolic disease relevance
Abstract
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 .
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.