A proposed benefit of GLP-1 agonists confirmed in a human study.
The adverse effects of diabetes on the liver have been widely studied and documented. Of interest is the presence of non-alcoholic fatty liver disease (NAFLD), which is highly associated with type 2 diabetes. NAFLD carries the risk of progression to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatic cancer, and until the discovery of glucagon-like peptide 1 (GLP1) agonists, was particularly difficult to treat, often leading to poor outcomes. Prior animal and in vitro studies have demonstrated that GLP1 analogs can improve liver fat content (LFC), but human trials have been few and far between. In May 2015, Diabetes In Control reported on a small, phase-2 study (the LEAN trial) suggesting the benefit of liraglutide in reducing LFC in 9 of 23 patients with NASH, compared to 2 of 22 patients in the placebo arm. However, the only restriction placed regarding diabetes was exclusion if uncontrolled diabetes (defined by Hb-A1C > 9%) was present. Of the patients in the treatment arm, only 9 were reported to have type 2 diabetes, and there was no report of how many of the 9 responders had diabetes. More recently, The Journal of Clinical Endocrinology and Metabolism reported on a study examining the effects of liraglutide on LFC in patients with uncontrolled type 2 diabetes, the LIRA-NAFLD study.
LIRA-NAFLD was a prospective, single-center study looking at 68 NASH patients with type 2 diabetes, on metformin and/or a sulfonylurea or glinide, and/or insulin, in whom use of liraglutide was indicated based on poor diabetes control, defined by Hb-A1C > 7%). Exclusion criteria were severe hepatic or renal impairment, abuse of alcohol or drugs, treatment with DPP4 inhibitors in the previous 3 months, or prior treatment with thiazolidinediones or any GLP1 agonist. The comparator group was a parallel study of 16 patients at the same center, with the same characteristics, whose LFC was determined at baseline and 6 months after intensification of their diabetes treatment with insulin. All LFC measurements were done via proton spectroscopy at baseline and following 6 months of treatment. The 68 study patients received an initial dose of liraglutide 0.6 mg daily for one week, followed by 1.2 mg daily for the remainder of 6 months.
The paired-t test was used to compare differences between baseline and 6-month post liraglutide data. Statistical significance was determined by the Fisher and Yates method, and multivariate analyses were done using stepwise multivariate linear regression.
Baseline characteristics of the 68 study patients were consistent with type 2 diabetes, including increased body mass index, elevated triglycerides, and decreased serum HDL-C. Following 6 months of liraglutide 1.2 mg daily, observations were significant reductions in Hb-A1C (from 9.8% ± 2.1% to 7.3% ± 1.1%; p<0.0001), mean body weight (99.5 kg ± 19.6 kg to 95.9 kg ± 19.2 kg; p<0.0001), and LFC (17.3% ± 10.9% to 11.9% ± 9.3%; p=0.005), with a significant increase in plasma adinopectin (3216 mcg/L ± 2687 mcg/L to 4272 mcg/L ± 2398 mcg/L; p<0.0001), a protein with a pivotal role in glucose uptake and lipid catabolism, which inversely measures in relation to weight. Typically, diminished adinopectin levels are associated with increased risk for diabetes and NASH. Other improvements in NASH associated laboratory values included ALT, AST (NS), GGT, LDL-C (NS), HDL-C, triglycerides, visceral fat area and subcutaneous fat area.
By way of comparison, in the comparator group, following 6 months of insulin intensification, a significant reduction in HbA1C was observed, but not in changes in body weight or in LFC.
In a previous study (A. Tang et al.), administration of liraglutide did not demonstrate significant reductions in LFC in 18 patients compared to those seen with LIRA-NAFLD. It is speculated that the considerably lower baseline characteristics in the Tang study (e.g. HbA1C, triglycerides, and fat content) reflected the diminished returns on liraglutide therapy. Additionally, the Tang study only ran for 3 months, suggestive that shortened duration of treatment may not be sufficient to see effects on LFC. Regarding LIRA-NAFLD, the presence of significant weight loss induced by liraglutide may be a primary contributor to decreased markers of NASH, which are known to respond to changes in weight.
One important finding in the aforementioned LEAN trial was the effect of liraglutide on the progression of NASH to hepatic fibrosis, where only 9% in the liraglutide progressed, versus 36% in the control group. The implication is that a 6-month treatment period with liraglultide 1.2 mg daily may significantly slow this progression, certainly opening the door for possible future studies.
- Non-alcoholic fatty liver disease can progress to serious hepatic conditions including cirrhosis and hepatic carcinoma.
- Type 2 diabetes and accompanying obesity is associated with potentially dangerous elevations with liver fat content.
- Addition of liraglutide to type 2 diabetes patients who are poorly controlled by conventional therapy may result in significant weight loss and subsequent reduction in liver fat content.
Petit JM, Cercueil JP, Loffroy R, Denimal D, Bouillet B, Fourmont C, et al. Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study. J Clin Endocrinol Metab. 2017;102(2):407-15.
Tang A, Rabasa-Lhoret R, Castel H, Wartelle-Bladou C, Gilbert G, Massicotte-Tisluck K, et al. Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial. Diabetes Care. 2015;38(7):1339-46.
Mark T. Lawrence, University of Colorado-Denver, School of Pharmacy NTPD