BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.
Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.
In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.
In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.
“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.
The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.
Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.
A total of 50 patients with pre- or early diabetes (hemoglobin A1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m2. Roughly half had a diagnosis of type 2 diabetes.
With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.
“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”
Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.