Effect of Dulaglutide on Liver Fat in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: Randomized Controlled Trial (D-LIFT Trial)

Abstract

Background: Liraglutide, a 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 patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).

Methods: Effect of dulaglutide on liver fat (D-LIFT) was an investigator-initiated, 24-week, parallel-group, open-label, randomized controlled study at a tertiary care center in India. Adults with type 2 diabetes and LFC of at least 5.6% at baseline when assessed by MRI-derived proton density fat fraction (PDFF) were eligible. Patients were randomly assigned 1:1 by a computer-based system to receive subcutaneous dulaglutide weekly for 24 weeks (add-on to usual care) or usual care for 24 weeks. Liver fat measurements were obtained at weeks 0 and 24. 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) by vibration-controlled transient elastography (VCTE), and change in liver enzymes. The trial is registered with clinicaltrials.gov (NCT03590626).

Findings: Eighty-six patients were screened and 32 were randomly assigned to dulaglutide and 32 to control. Dulaglutide treatment resulted in a control-corrected absolute change of -3.5% (95% CI, -6.6 to -0.4, p = 0.025) and relative change in LFC of -26.4% (95% CI, -42.2 to -8.6, p = 0.004), corresponding to a 2.6-fold greater reduction. Dulaglutide-treated patients also showed a significant reduction in serum gamma-glutamyl transpeptidase (GGT) levels (control-corrected mean difference -13.1 U/L, 95% CI, -24.4 to -1.7, p = 0.025); and nonsignificant reduction in serum aspartate aminotransferase (AST) levels (-9.3 U/L, 95% CI, -19.5 to 1.0, p = 0.075), and serum alanine aminotransferase (ALT) levels (-9.27 U/L, 95% CI, -12.5 to 2.8, p = 0.10). Absolute change in PFC (-1.4%, 95% CI, -3.2 to 0.3, p = 0.106) and LSM by VCTE (-1.3 kPa, 95% CI, -2.99 to 0.37, p = 0.123) were not significant between the two groups.

Interpretation: Dulaglutide treatment significantly reduced liver fat in patients with type 2 diabetes and NAFLD. Dulaglutide also significantly reduced serum GGT levels. There was nonsignificant reduction in pancreatic fat, liver stiffness, serum AST and serum ALT concentrations. Dulaglutide could be considered for the early treatment of NAFLD in patients with type 2 diabetes.

Trial Registration: The trial is registered with clinicaltrials.gov (NCT03590626).

Funding Statement: The current study was supported by investigator-initiated study
grant to M Shafi Kuchay from Institute’s departmental research fund and grant from
Endocrine and Diabetes Foundation, India (EDF).

Declaration of Interests: MSK has received speaker honorarium from Novartis, Sanofi, Wockhardt Limited, AstraZeneca and Novo Nordisk; SKM has received speaker honorarium from Sanofi, Novartis, AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Lupin Limited and Abbott India Limited. JSW has received speaker honorarium from Boehringer Ingelheim, Novartis, Sanofi, Abbott India Limited, Wockhardt Limited, AstraZeneca and Novo Nordisk. AM has received speaker honorarium from Johnson and Johnson, Amgen, Sanofi, Novartis, AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Lupin Limited and Abbott India Limited. The all other authors who have taken part in this study declared that they have nothing to disclose regarding funding or conflict of interest with respect to this manuscript.

Ethics Approval Statement: The clinical trial protocol was approved by the institutional review board and Ethics Committee (MICR-861/2018). Informed written consent was obtained from all the participants.