According to estimates, between 2.7 and 3.9 million people are infected with hepatitis C virus (HCV) in the US, with worldwide infection estimated to be about 185 million people.1-3 The majority of patients infected with HCV develop a chronic infection, which is the leading cause of liver-related complications in the Western world, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.4 In addition to the direct effects HCV has on the liver, extrahepatic complications can occur, often related to the immune-mediated mechanism of cryoglobulinemia, such as vasculitis, renal disease, and palpable purpura. Additionally, > 70 studies globally have associated HCV with insulin resistance and worsening glycemic control.5,6
The prevalence of patients infected with HCV that have comorbid type 2 diabetes mellitus (T2DM) is estimated to be about 30%.7,8 The landmark cross-sectional National Health and Nutrition Examination Survey III study found the prevalence of T2DM among HCV patients in the US aged > 40 years to be about 3-fold higher than those without HCV.9 These findings were further supported by a Taiwanese prospective community-based cohort study that found a higher incidence of T2DM in HCV-positive patients compared with HCV negative patients (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1).10 This relationship appears to be separate from the diabetogenic effect of cirrhosis itself as a significantly higher prevalence of DM has been observed in people with HCV when compared with people with cirrhosis due to other etiologies.11 Although the mechanism for this relationship is not fully understood and is likely multifactorial, it is believed to primarily be an effect of the HCV core protein increasing phosphorylation of insulin receptor substrate-1.6,12,13 The increased presence of the inflammatory cytokine, tumor necrosis factor-α, is also believed to play a role in the effects on insulinreceptor substrate-1 as well as mediating hepatic insulin resistance, stimulating lipolysis, down-regulating peroxisome proliferator-activated receptor-γ, and interfering with β-cell function.14-17
The relationship between HCV and T2DM has been further established by measured improvements in insulin resistance among patients undergoing HCV treatment with the pre-2011 standard of care—peginterferon and ribavirin.Kawaguchi and colleagues found sustained treatment responders to have a significant decrease in both the homeostatic model assessment-insulin resistance (HOMA-IR) score, representing insulin resistance, and the HOMA-β score, representing β-cell function.18 Improvements in the HOMA-IR score were further validated by Kim and colleagues and a nested cohort within the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial.19,20 Furthermore, Romero-Gómez and colleagues found that patients achieving a cure from HCV treatment defined as a sustained virologic response (SVR) had a nearly 50% reduced risk of impaired fasting glucose or T2DM over a mean posttreatment follow-up of 27 months.21
The recent development of direct-acting antivirals (DAAs) has marked significant HCV treatment advances in terms of efficacy and tolerability, leading current guidelines to emphasize that nearly all patients with HCV would benefit from treatment.22 Despite these guidelines, issues have been documented throughout the US with payors often limiting this costly treatment to only those with advanced fibrotic disease.23 Although the benefits of HCV treatment on reducing liver-related morbidity and mortality may be most appreciated in individuals with advanced fibrotic liver disease, improvements in insulin resistance would suggest potential morbidity and mortality benefits beyond the liver in many more at-risk individuals.24
Increasingly, cases are being reported of new DAA regimens having a significant impact on reducing insulin resistance as demonstrated by marked decreases in antihyperglycemic requirements, fasting blood glucose, and hemoglobin A1c (HbA1c).25-30 One striking case describes a patient being able to de-escalate his regimen from 42 daily units of insulin to a single oral dipeptidyl peptidase-4 inhibitor while maintaining goal HbA1c level over a 2-year time period.31 A database-driven study of veterans found a mean HbA1c drop of 0.37% in its overall included cohort of patients with T2DM who achieved SVR from HCV DAA treatment.32
Despite these data, the individual predictability and variable magnitude of improved insulin resistance based on baseline HbA1c remains unknown. The objective of this study was to assess the impact of HCV treatment with short course DAAs on glucose control in veteran patients with T2DM at a single center.