Dulaglutide Added to Standard Care Lowers Liver Fat Content in Patients With T2D, NAFLD

Dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, significantly reduces liver fat content (LFC) and improves γ-glutamyl transpeptidase (GGT) levels in patients with type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD), when used in combination with standard T2D treatment, a study published in Diabetologia found.

Although previous data show liraglutide, a separate GLP-1 receptor agonist, reduces LFC content, data regarding the effect of dulaglutide are scarce. Dulaglutide is currently approved for the improvement of glycemic control in individuals with T2D and for the reduction of major adverse cardiovascular events in adults with T2D, with and without established cardiovascular disease.

NAFLD is common among individuals with T2D, while “the presence of T2D in individuals with NAFLD is a risk factor for its progression to non-alcoholic steatohepatitis (NASH), a severe form of NAFLD that can further progress to liver fibrosis, cirrhosis and hepatocellular carcinoma,” the researchers wrote.

In individuals with T2D, GLP-1 receptor agonists have been proven to improve insulin sensitivity, reduce fatty acid accumulation, and modulate gut microbiota among additional benefits. Dulaglutide has also shown better patient acceptability than other GLP-1 receptor analogues.

In a randomized controlled trial, researchers recruited individuals from an endocrine outpatient clinic in India. All participants (n = 52) were over age 20, had a baseline MRI-proton density fat fraction (PDFF)–assessed LFC of ≥6.0%, and had T2D.

Patients were randomized (1:1) to receive either dulaglutide 0.75 mg via subcutaneous injection each week for 4 weeks, followed by 1.5 mg weekly for 20 weeks in addition to standard treatment, or standard treatment alone.

All participants were also instructed to restrict intake of simple carbohydrates and fat and to exercise for at least 45 minutes a day for at least 5 days a week. At weeks 12 and 24 patients returned to the clinic for follow-up visits.

Investigators found:

• Dulaglutide treatment resulted in a control-corrected absolute change in LFC of −3.5% (95% CI: −6.6 to −0.4; P = .025) and relative change of −26.4% (95% CI: −44.2 to −8.6; P = .004), corresponding to a 2.6-fold greater reduction
• Dulaglutide-treated participants showed a significant reduction in GGT levels (mean between-group difference: −13.1 U/l [95% CI: −24.4 to −1.8]; P = .025)
• Treatment was associated with non-significant reductions in aspartate aminotransferase (−9.3 U/l [95% CI: −19.5 to 1.0]; P = .075) and alanine aminotransferase levels (−13.1 U/l [95% CI: −24.4 to 2.5]; P = .10)
• Absolute changes in pancreatic fat fraction (−1.4% [95% CI: −3.2 to 0.3]; P = .106) and liver stiffness measurement (−1.31 kPa [95% CI: −2.99 to 0.37]; P = .123) were not significant when comparing the 2 groups

Three patients in the treatment arm of the study dropped out of the trial due to upper gastrointestinal upset in the first weeks of treatment.

As body weight reduction is a class effect of all GLP-1r agonists, dulaglutide-treated participants showed a significant reduction in body weight compared with the control participants over the 24 weeks. Weight reduction was also a significant driving factor in the decrease of LFC.

Because all patients in both arms of the trial were taking other medications for T2D and comorbidities, minor interactions of co-prescribed medications on liver fat cannot be ruled out, marking a limitation to the study.

“Paired biopsy-based studies are needed to see whether liver fat reduction following dulaglutide treatment leads to improvement in NASH and fibrosis scores,” researchers concluded.

Reference

Kuchay MS, Krishan S, Mishra SK, et al. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomized controlled trial (D-LIFT trial). Diabetologia. Published online August 31, 2020. doi:10.1007/s00125-020-05265-7