Sitagliptin Use in a Large Cohort of Chronic Hepatitis B with Concomitant Diabetes was Associated with Increased Risk of Severe Liver Fibrosis

Abstract

Background: Diabetes mellitus is associated with adverse liver-related outcomes including liver decompensation and hepatocellular carcinoma. Its specific interaction with chronic hepatitis B (CHB) and related liver fibrosis is not wellunderstood . Methods: We prospectively recruited consecutive CHB patients with concomitant type 2 diabetes mellitus . Anthropometry, metabolic parameters, liver biochemistry and virologic profiles were measured. Detailed diabetic history (duration, treatment, glycemic control, complications) was collected. Liver fibrosis and steatosis were assessed by transient elastography (Fibroscan, Echosens), with severe fibrosis defined following the European Association of the Study of the Liver guidelines for CHB (liver stiffness [LS]>9.0 kPa with normal alanine aminotransferase (ALT) level, or >12.0 kPa with ALT one to five times above the upper limit of normal) . Results: 755 diabetic CHB patients (mean age 63 .1±9 .6 years, 65 .7% male) were recruited . 488 (64 .6%) were on nucleoside analogue treatment for a median duration of 6.6 years. The median duration of diabetes was 8.8 (IQR 4.5– 14.7) years. Median LS was 6.8 (IQR 5.2–10.3) kPa, with 218 (28.9%) having severe liver fibrosis. 94 (12.5%) and 57 (7.5%) were on sitagliptin and other dipeptidyl peptidase-4 inhibitors (DPP-4is) respectively . By multivariable analysis, after controlling for CHB treatment status, metabolic comorbidities, diabetes duration, presence of diabetic complications and time-weighted glycosylated haemoglobin levels since diabetes diagnosis, the use of sitagliptin was independently associated with severe liver fibrosis (OR 2.04, 95%CI 1.19–3.48; p=0.009). Sitagliptin use for >3 years was similarly associated (OR 2 .68, 95% CI 1 .11-6 .51; p=0 .029) . Other DPP-4is did not show such association (p=0 .405) . Additional associated factors included severe steatosis (controlled attenuation parameter ≥280 dB/m) (OR 1.97, 95%CI 1.16–3.33; p=0.012) and the presence of diabetic microvascular complications (OR 1 .60, 95%CI 1 .07-2 .39; p=0 .024) . Statins treatment was the only negative predictor of severe liver fibrosis (OR 0.52, 95%CI 0 .35–0 .77; p=0 .001) . Conclusion: Sitagliptin use in diabetic CHB patients was associated with an increased risk of severe liver fibrosis. Its potential fibrogenic effect requires longitudinal and mechanistic validation. [https://doi.org/10.1002/hep.30941]