Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial)

Abstract

Aims/hypothesis Liraglutide, a daily injectable glucagon-like peptide-1 receptor (GLP-1r) agonist, has been shown to reduce liver fat content (LFC) in humans. Data regarding the effect of dulaglutide, a once-weekly GLP-1r agonist, on human LFC are scarce. This study examined the effect of dulaglutide on LFC in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods Effect of dulaglutide on liver fat (D-LIFT) was a 24 week, open-label, parallel-group, randomised controlled trial to determine the effect of dulaglutide on liver fat at a tertiary care centre in India. Adults (n = 64), who had type 2 diabetes and MRI-derived proton density fat fraction-assessed LFC of ≥6.0% at baseline, were randomly assigned to receive dulaglutide weekly for 24 weeks (add-on to usual care) or usual care, based on a predefined computer-generated number with a 1:1 allocation that was concealed using serially numbered, opaque, sealed envelopes. The primary endpoint was the difference of the change in LFC from 0 (baseline) to 24 weeks between groups. The secondary outcome measures included the difference of the change in pancreatic fat content (PFC), change in liver stiffness measurement (LSM in kPa) measured by vibration-controlled transient elastography, and change in liver enzymes. Results Eighty-eight patients were screened; 32 were randomly assigned to the dulaglutide group and 32 to the control group. Overall, 52 participants were included for per-protocol analysis: those who had MRI-PDFF data at baseline and week 24. Dulaglutide treatment resulted in a control-corrected absolute change in LFC of −3.5% (95% CI −6.6, −0.4; p = 0.025) and relative change of −26.4% (−44.2, −8.6; p = 0.004), corresponding to a 2.6-fold greater reduction. Dulaglutide-treated participants also showed a significant reduction in γglutamyl transpeptidase (GGT) levels (mean between-group difference −13.1 U/l [95% CI −24.4, −1.8]; p = 0.025) and non-significant reductions in aspartate aminotransferase (AST) (−9.3 U/l [−19.5, 1.0]; p = 0.075) and alanine aminotransferase (ALT) levels (−13.1 U/l [−24.4, 2.5]; p = 0.10). Absolute changes in PFC (−1.4% [−3.2, 0.3]; p = 0.106) and LSM (−1.31 kPa [−2.99, 0.37]; p = 0.123) were not significant when comparing the two groups. There were no serious drug-related adverse events. Conclusions/interpretation When included in the standard treatment for type 2 diabetes, dulaglutide significantly reduces LFC and improves GGT levels in participants with NAFLD. There were non-significant reductions in PFC, liver stiffness, serum AST and serum ALT levels. Dulaglutide could be considered for the early treatment of NAFLD in patients with type 2 diabetes. Trial registration ClinicalTrials.gov NCT03590626 Funding The current study was supported by an investigator-initiated study grant from Medanta-The Medicity's departmental research fund and a grant from the Endocrine and Diabetes Foundation (EDF), India.

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

“…Reduction of both liver fat content and hyperglycaemia in individuals with NAFLD has also been reported with exenatide [66][67][68][69][70][71], lixisenatide [72] and dulaglutide [73,74]. GLP-1RAs have several effects on liver function: they decrease liver enzymes [64,72,[75][76][77], EGP [78], lipotoxicity [64,66,75,79,80] and postprandial triacylglycerol concentrations [81,82]. Some of these hepatic effects might be mediated by a decrease in body weight.…”

Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials

“…The major strength of our study lies in the use of a systematic review methodology to identify all relevant RCTs (published up to 15 December 2020) that meet predefined inclusion criteria. This is the largest and most updated assessment to date on the efficacy of GLP-1 RAs to specifically treat NAFLD or NASH that has also included the most recently published RCTs using two long-acting GLP-1 RAs, such as dulaglutide and semaglutide [33,34]. In addition, most of the included RCTs have used magnetic resonancebased techniques, which have been shown to accurately quantify changes in liver fat content [58].…”

“…Figure S1 shows the results of the literature research and study selection. We initially identified 15 potentially relevant RCTs from PubMed, Scopus and ClinicalTrials.Gov databases until to 15 December 2020 [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. After examining the full text of these 15 articles, we excluded four studies [35][36][37][38] because of unsatisfactory inclusion criteria or unsatisfactory outcome measures, as specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.…”

A Meta-Analysis of the Effects of Glucagon-Like-Peptide 1 Receptor Agonist (GLP1-RA) in Nonalcoholic Fatty Liver Disease (NAFLD) With Type 2 Diabetes (T2D)

“…5,7,9-14 Some of the citations reported differences in raw mean without any statistical signi cance, while others reported the events in both arms only. [9][10][11][12][13] Since four different analytical techniques (Independent groups [difference, p], raw difference [independent groups, CI], independent groups [standard difference], independent groups [sample size, p]) were used to derive the effect size in the citations of interest, standardized mean difference was used to maintain uniformity of reporting. 5,7,[9][10][11][12][13][14] The biopsy resolution parameter was reported as a reduction in rate ratio and hence the nal effect size was analyzed using rate ratio.…”

“…D-LIFT and Dutour et al had standard of care in their control arm, while LEAN, and Newsome et al had placebo in the comparative arm. 9,5,7 We selected the highest dose of semaglutide (0.4 mg) in our analysis to prevent duplication, since Newsome et al included three doses of semaglutide in their study. LEAN study was performed on a pooled population of non-diabetic and T2D patients.…”