Sustained Virological Response Correlates With Reduction in the Incidence of Glucose Abnormalities in Patients With Chronic Hepatitis C Virus Infection RAFAEL SIM ´ O, MD 1 ALBERT LECUBE, MD 1 JOAN GENESC ` A, MD 2 JOAN IGNACI ESTEBAN, MD 2 CRISTINA HERN ´ ANDEZ, MD 1 OBJECTIVE — There is evidence to suggest that hepatitis C virus (HCV) infection is a high- risk condition for developing type 2 diabetes. However, there are no interventional studies that confirm that HCV infection causes diabetes. The main aim of this study was to compare the incidence of glucose abnormalities (diabetes plus impaired fasting glucose) between HCV- infected patients with or without sustained virological response (SVR) after antiviral therapy. RESEARCH DESIGN AND METHODS — Patients with normal fasting glucose (100 mg/dl) with biopsy-proven chronic hepatitis C without cirrhosis and with at least 3 years of follow-up after finishing antiviral therapy were included in the study (n = 234). Patients received interferon -2b (alone or with ribavirin) for 6 or 12 months according to genotype. Cumulative incidence of glucose abnormalities was evaluated by using the Kaplan-Meier method comparing subjects with and without a SVR to antiviral treatment. A multivariate Cox proportional hazards analysis was performed to explore the variables independently associated with the development of glucose abnormalities. RESULTS — During follow-up, 14 of 96 (14.6%) patients with SVR and 47 of 138 (34.1%) nonsustained responders developed glucose abnormalities (P = 0.001). Patients with SVR did not develop diabetes during follow-up, whereas nine cases of diabetes were detected in nonsus- tained responders (P = 0.007). After adjustment for the recognized predictors of type 2 diabetes, the hazard ratio for glucose abnormalities in patients with SVR was 0.48 (95% CI [0.24 – 0.98], P = 0.04). CONCLUSIONS — Our results provide evidence that eradication of HCV infection signifi- cantly reduces the incidence of glucose abnormalities in chronic hepatitis C patients. In addition, this study supports the concept that HCV infection causes type 2 diabetes. Diabetes Care 29:2462–2466, 2006 L arge community-based studies have found a strong association between hepatitis C virus (HCV) infection and type 2 diabetes (1,2), two common disorders that cause devastating long- term complications in a significant num- ber of patients. In addition, a high prevalence of both diabetes and impaired fasting glucose (IFG), an early predictor of diabetes, has been reported in patients with chronic hepatitis C compared with other chronic liver diseases (3–7). Fur- thermore, in HCV-infected patients with chronic hepatitis and normal transami- nases, we have detected a fivefold higher prevalence of diabetes than that found in anti-HCV–negative patients (24 vs. 5%, P = 0.003) (7). Therefore, it seems that the genuine connection between HCV in- fection and diabetes is initiated at the early stages of hepatic disease. HCV infection is characterized by a si- lent onset in most infected individuals, and recent studies (8 –10) indicate that the rate of progression to advanced liver disease is lower than previously assumed. Salomon et al. (10) estimated the median duration be- tween infection and cirrhosis to be 46 years for men infected at age 25 years, whereas in a cohort of women infected at this age, fewer than 30% would progress to cirrhosis even after 50 years of infection. This low progression rate is an important consider- ation when making decisions about treat- ment recommendations and health policy toward patients with chronic HCV infec- tion. Moreover, the large reservoir of chron- ically HCV-infected individuals under the age of 50 who became infected in the early 1980s (when the incidence rates were high- est) will reach the age at which diabetes typ- ically occurs during the next decade. This raises the intriguing question of whether the rise in HCV infection is contributing to the increasing prevalence of type 2 diabetes. The specific mechanisms by which HCV leads to type 2 diabetes are not fully understood, but an increase of insulin re- sistance associated with both steatosis and overproduction of proinflammatory cytokines could play a crucial role (11– 13). In vitro experiments with liver sam- ples indicate that HCV infection leads to a postreceptor defect in insulin receptor substrate 1, thereby contributing to insu- lin resistance (14). Furthermore, Shintani et al. (15) have recently shown direct ex- perimental evidence for the contribution of HCV in the development of insulin re- sistance using HCV core transgenic mice. Although there is growing evidence to support the concept that HCV infection is a risk factor for developing type 2 diabe- tes, there have been no interventional studies confirming this issue. The aim of this study was to analyze for the first time ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Diabetes Research Unit, Institut de Recerca Hospital Universitari Vall d’Hebron, Universitat Auto ´ noma de Barcelona, Barcelona, Spain; and the 2 Liver Unit, Institut de Recerca Hospital Universitari Vall d’Hebron, Universitat Auto ´ noma de Barcelona, Barcelona, Spain. Address correspondence and reprint requests to Dr. Rafael Simo ´ , Diabetes Research Unit, Endocrinology Division, Hospital Universitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail: rsimo@ir.vhebron.net. Received for publication 27 February 2006 and accepted in revised form 11 August 2006. Abbreviations: AST, aspartate aminotransferase; GT, glutamyltranspeptidase; HCV, hepatitis C virus; IFG, impaired fasting glucose; SVR, sustained virological response. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. DOI: 10.2337/dc06-0456 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Pathophysiology/Complications O R I G I N A L A R T I C L E 2462 DIABETES CARE, VOLUME 29, NUMBER 11, NOVEMBER 2006