Effects of antidiabetic agents on steatosis and fibrosis biomarkers in type 2 diabetes: A real-world data analysis

Abstract

Background & aims: There is intense research for drugs able to reduce disease progression in nonalcoholic fatty liver disease. We aimed to test the impact of novel antidiabetic drugs (dipeptidyl-peptidase-4 inhibitors - DPP-4Is, glucagon-like peptide-1 receptor agonists - GLP-1RAs, sodium-glucose cotransporter-2 inhibitors - SGLT-2Is) on non-invasive biomarkers of steatosis (fatty liver index, FLI) and fibrosis (Fibrosis-4 score, FIB-4) in patients with type 2 diabetes (T2D).

Methods: Clinical, anthropometric and biochemical parameters were retrospectively analysed in 637 consecutive T2D patients switched from metformin w/wo sulfonylureas and/or pioglitazone to DPP-4Is, GLP-1RAs and SGLT-2Is in a tertiary care setting. 165 patients maintained on original treatments served as controls. The effects on FLI and FIB-4 at 6- and 12-month follow-up were analysed by logistic regression after adjustment for baseline differences, computed by propensity scores, and additional adjustment for changes in glycosylated hemoglobin (HbA1c) and body mass index.

Results: Body mass index, HbA1c and aminotrasferases significantly decreased following switching to GLP-1RAs and SGLT2-Is, compared with both controls and DPP-4Is, whereas only HbA1c was reduced on DPP-4Is. FLI and FIB-4 were reduced on GLP-1RA and SGLT-2I; logistic regression analysis confirmed a significant improvement of both biomarkers after adjustment for propensity score. The shift of FIB-4 values towards the category ruling out advanced fibrosis was maintained after additional adjustment for confounders. These effects were confirmed in a sensitivity analysis on effect size.

Conclusions: Glucagon-like peptide-1 receptor agonists and SGLT-2Is improve biomarkers of steatosis and fibrosis, in keeping with beneficial effects on liver disease progression, and should be considered the treatment of choice in T2D.

Keywords: NAFLD; dipeptidyl-peptidase-4 inhibitors; glucagon like peptide-1 receptor agonists; sodium-glucose cotransporter-2 inhibitors; surrogate biomarkers.

FIGURE 1

Changes in BMI, glycosylated haemoglobin and alanine aminotransferase levels at 6 and 12 mo in the groups treated by the different glucose‐lowering drug classes. Data are expressed as mean and 95% confidence interval. CTRL represents continuous treatment with metformin ± sulfonylureas and/or pioglitazone. *Significantly different from CTRL values. ^$Significantly different from the corresponding value of the DPP‐4I group. ALT, alanine transaminase; BMI, body mass index; CTRL, controls; DPP‐4Is, dipeptidyl‐peptidase‐4 inhibitors; GLP‐1RAs, glucagon‐like peptide‐1 receptor agonists; SGLT‐2Is, sodium‐glucose cotransporter‐2 inhibitors

FIGURE 2

Changes in surrogate biomarkers of steatosis and fibrosis (fatty liver index and Fibrosis‐4 score, respectively) at 6 and 12 mo by the different T2DM drug classes. Data are expressed as mean and 95% confidence interval. CTRL represent treatment with metformin w/wo sulfonylureas and/or pioglitazone. *Significantly different from control values. ^$Significantly different from the corresponding value of the DPP‐4I group. CTRL, controls; DPP‐4Is, dipeptidyl‐peptidase‐4 inhibitors; GLP‐1RAs, glucagon‐like peptide‐1 receptor agonists; SGLT‐2Is, sodium‐glucose cotransporter‐2 inhibitors

FIGURE 3

Changes in FLI and FIB‐4 class at 6‐ and 12‐mo follow‐up vs baseline in subjects with and without (CTRL) switch in their antidiabetic treatment. Data are expressed as percent of cases within the class and as absolute numbers. Decreased by 1 class indicates an improvement of at least one category of FLI and FIB‐4 (FLI from > 60% to the intermediate area (30%‐60%) or from the intermediate area to < 30%; FIB‐4 from > 2.67 to intermediate values (1.30‐2.67) or from intermediate values to < 1.30). Increased by 1 class is the opposite. ^#Changes in FLI status at 6 mo; °Changes in FLI status at 12 mo; ^Changes in FIB‐4 status at 6 mo; *Changes in FIB‐4 status at 12 mo. CTRL, controls; DPP‐4Is, dipeptidyl‐peptidase‐4 inhibitors; FIB‐4, Fibrosis‐4 score; FLI, fatty liver index; GLP‐1RAs, glucagon‐like peptide‐1 receptor agonists; SGLT‐2Is, sodium‐glucose cotransporter‐2 inhibitors

FIGURE 4

Logistic regression analyses of improvement in surrogate biomarkers of steatosis (A – FLI) and fibrosis (B – FIB‐4 score) at 12 mo after switching treatment to the new classes of glucose‐lowering drugs. Data are expressed as odds ratio (OR) and 95% confidence interval vs the control group (CTRL) and vs DPP‐4I treatment. Analyses were adjusted for propensity score (PS, upper panels), calculated on baseline demographic data, BMI and HbA1c. In the lower panels, the analyses were additionally adjusted for changes in metabolic parameters (percent changes in BMI and absolute changes in HbA1c). BMI, body mass index; CTRL, controls; DPP‐4Is, dipeptidyl‐peptidase‐4 inhibitors; FIB‐4, Fibrosis‐4 score; FLI, fatty liver index; GLP‐1RAs, glucagon‐like peptide‐1 receptor agonists; HbA1c, glycosylated A1c haemoglobin; SGLT‐2Is, sodium‐glucose cotransporter‐2 inhibitors