Long-term Follow-up of Diabetic and Non-diabetic Patients With Chronic Hepatitis C Successfully Treated With Direct-acting Antiviral Agents

Alessia Ciancio; Davide G. Ribaldone; Anna Dotta; Chiara Giordanino; Marco Sacco; Sharmila Fagoonee; Rinaldo Pellicano; Giorgio M. Saracco


Liver International. 2021;41(2):276-287. 

In This Article

Abstract and Introduction


Background and Aims: Clearance of hepatitis C virus (HCV) is associated with improved glycometabolic control in patients with diabetes mellitus (DM) but whether this effect is maintained over the long term with a reduction in liver-related events (LRE) is still debated. To address these issues, we conducted a long-term prospective study on diabetic and non-diabetic patients with chronic hepatitis C cured by direct antiviral agents (DAAs).

Methods: Among 893 recruited patients, 15.7% were diabetic (Group 1) and 84.3% non-diabetic (Group 2); changes in fasting glucose (FG) and glycated haemoglobin (HbA1c) levels were assessed in Group 1 while the incidence of LRE was established in the whole cohort. Differences between groups were evaluated and independent predictors of unfavourable clinical outcome were established.

Results: After a mean follow up of 44.5 months, a significant reduction in FG and HbA1c values was found in Group 1. Death was reported in 5.7% of patients in Group 1 vs 1.6% in Group 2 (P = .003), hepatocellular carcinoma (HCC)-free survival was significantly lower in Group 2 (P = .015) as well as LRE-free survival in Group 1 cirrhotic patients (P = .0006). After adjustment for baseline variables, cirrhosis and albumin levels emerged as independent predictors of LRE; low albumin levels, DM and central obesity were associated with HCC risk in cirrhotic patients while insulin therapy emerged as unfavourable predictor among diabetics.

Conclusions: SVR achieved by DAAs is associated with long-term improvement of glycometabolic control in diabetic patients, but among cirrhotics DM still exerts a detrimental effect on the liver.


Type 2 diabetes mellitus (DM) is considered an extrahepatic manifestation of chronic hepatitis C (CHC),[1–3] even though the mechanisms whereby hepatitis C virus (HCV) infection causes DM have not been completely clarified. Some studies[4,5] have shown that the virus can interfere with insulin signalling, eventually inducing alterations in glucose homeostasis. In particular, recent reports[6,7] have suggested the role of viral replication in inducing death of pancreatic beta cells and upregulation of several hepatokines known to cause insulin resistance (IR). Thus, it is reasonable to hypothesize that viral clearance might be accompanied by an improvement in glucose abnormalities. Two recent reviews[8,9] reported that the majority of the studies published so far found a significant glycaemic amelioration after achievement of sustained virological response (SVR) by direct-acting antiviral agents (DAAs); however, some studies[10–13] failed to observe any significant glycometabolic changes. The issue of the long-term beneficial effect of SVR on glycaemic control in diabetic patients was addressed by few reports[10,12,14–19] showing conflicting and contradictory results. Despite the fact that most of the studies reporting improvement in glycaemic parameters showed de-escalation/withdrawal of antidiabetic therapy in a consistent number of patients,[8,9] data regarding classes and dosages of drugs are often incomplete and discrepant.

Moreover, owing to the lack of prospective studies with long-term follow-up, the clinical outcome of diabetic patients with SVR remains largely unknown.

In order to address these issues, we conducted a prospective study on HCV-positive patients with or without DM successfully treated by DAAs aiming at monitoring potential long-term glycometabolic improvement as well as its impact on liver-related clinical outcome.