Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C

doi:10.1016/j.jhep.2007.11.022

Journal of Hepatology

Volume 48, Issue 5, May 2008, Pages 721-727

https://doi.org/10.1016/j.jhep.2007.11.022 Get rights and content

Background/Aims

To investigate the effect of sustained virological response (SVR) on impaired fasting glucose (IFG) and/or type 2 diabetes (T2DM); to assess the influence of glucose abnormalities on the SVR rate.

Methods

1059 patients with chronic HCV; normal glucose (< 100 mg/dl) in 734, IFG (between 100 and 125 mg/dl) in 218, and T2DM (⩾126 mg/dl) in 107 cases, were treated with interferon plus ribavirin over 24 or 48 weeks, depending on viral genotype.

Results

The SVR rate was lower in patients with IFG and/or T2DM than in patients with normal glucose concentrations [143/325 (44%) vs. 432/734 (58.8%); P = 0.002]. In the follow-up, abnormal glucose concentrations were observed in 74 of 304 (24.3%) non-responders and in 49 of 430 (11.4%) sustained responders (log-rank: 13.8; P = 0.00002). Reverse stepwise logistic regression analysis identified the independent variables predictive of IFG or T2DM development as: sustained response (OR: 0.44; 95%CI = 0.20–0.97; P = 0.004) and fibrosis stage (OR: 1.46; 95%CI = 1.06–2.01;P = 0.02). Family history of DM, steatosis, gender, HCV viral load, genotype, triglycerides, cholesterol and BMI did not enter the multivariate analysis equation.

Conclusions

SVR reduces the risk of IFG and/or T2DM development in patients with chronic hepatitis C while altered glucose metabolism impairs sustained response to viral treatment.

Introduction

The development of type 2 diabetes mellitus depends on environmental, genetic and diet-related factors. Data supporting a link between hepatitis C infection, insulin resistance and type 2 diabetes mellitus [1] include: (1) insulin resistance is higher in chronic hepatitis C than in other chronic liver diseases, despite the same fibrosis stage, body mass index, age and family history of diabetes [2]; (2) in transgenic mice, the expression of HCV core protein is associated with insulin resistance, following a fat-enriched diet, and with type 2 diabetes development [3]; (3) clearance of the virus following successful treatment is related to a fall in the insulin resistance index measured by the homeostasis model of assessment (HOMA) [4]; (4) cross-sectional studies have found higher prevalence of diabetes mellitus in patients with chronic hepatitis C than in healthy subjects, or in those suffering from other chronic liver diseases [5]; (5) case-cohort studies have demonstrated a higher incidence of type 2 diabetes mellitus during follow-up in patients with hepatitis C, as compared to non-infected subjects [6]. The mechanisms by which hepatitis C impairs insulin sensitivity and promotes diabetes include: increased tumour necrosis factor (TNF-α) production [7] and over-expression of suppressor of cytokines signal 3 (SOCS-3) [8] which have been shown to interfere with the intracellular signalling pathway of insulin.

The main aim of the current study was to assess the effect of sustained virological response, together with host and viral factors, on the incidence of impaired fasting glucose and/or type 2 diabetes mellitus in patients with chronic hepatitis C being treated with combined interferon plus ribavirin. Further, we sought to assess the impact of baseline glucose status on sustained virological response rate.

Section snippets

Patient population

Patients from 11 Spanish hospitals were recruited and treated according to routine clinical practice. Patients (n = 1059; male = 649 (61.2%) and females = 410 (38.8%); mean age = 48 ± 11 years, range = 20–75) with biopsy-proven chronic hepatitis C and HCV RNA positive were recruited. They were receiving treatment with combination therapy of standard interferon plus ribavirin (n = 183), or peginterferon alfa-2a plus ribavirin (n = 501), or peginterferon alfa-2b plus ribavirin (n = 368). Viral genotype

Factors associated with sustained virological response

Patients with SVR were younger (46.2 ± 10.4 vs. 50.4 ± 10.4 years; P < 0.001), had lower glucose concentrations (5.4 ± 1.31 mmol/L vs. 5.75 ± 1.58 mmol/L; P < 0.001), lower baseline HCV RNA load (5.74 ± 0.6 log₁₀ vs. 5.88 ± 0.49log₁₀; P < 0.05), lower triglyceride concentrations (1.05 ± 0.66 mmol/L vs. 1.14 ± 0.79 mmol/L; P < 0.05), and higher total cholesterol concentrations (4.48 ± 1.0 mmol/L vs. 4.31 ± 0.96 mmol/L, P < 0.005). There were no significant associations with gender, body mass index, and levels of ALT, AST or

Discussion

Our results showed that the eradication of hepatitis C virus reduced by half the incidence of type 2 diabetes and/or impaired fasting glucose in the course of post-treatment follow-up. Further, sustained response and fibrosis stage were the variables that were independently predictive of the development of abnormal glucose concentrations. The significance was maintained even when analysed together with variables that are known to be strongly related to the risk of developing diabetes such as

Acknowledgement

We thank Dr. Peter Turner for Editorial assistance.

References (26)

Y. Shintani et al.
Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance
Gastroenterology
(2004)
M. Romero-Gomez et al.
Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients
Gastroenterology
(2005)
H. Knobler et al.
Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association
Am J Gastroenterol
(2003)
T. Kawaguchi et al.
Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3
Am J Pathol
(2004)
S.H. Mehta et al.
Hepatitis C infection and incident type 2 diabetes
Hepatology
(2003)
J.M. Hui et al.
Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression
Gastroenterology
(2003)
J.M. Petit et al.
Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C
J Hepatol
(2001)
R. Narita et al.
Insulin resistance and insulin secretion in chronic hepatitis C virus infection
J Hepatol
(2004)
S.H. Kim et al.
Comparison of the 1997 and 2003 American Diabetes Association classification of impaired fasting glucose: impact on prevalence of impaired fasting glucose, coronary heart disease risk factors, and coronary heart disease in a community-based medical practice
J Am Coll Cardiol
(2006)
M. Romero-Gomez et al.
Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C
Am J Gastroenterol
(2003)

M. Romero-Gómez

Hepatitis C and insulin resistance

WJG

(2006)

A. Lecube et al.

Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: a case-control study

Diabetes Care

(2006)

A. Lecube et al.

Glucose abnormalities in patients with hepatitis C virus infection: epidemiology and pathogenesis

Diabetes Care

(2006)

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Insulin resistance in children with chronic hepatitis C and its association with response to IFN-alpha and ribavirin
2021, Revista de Gastroenterologia de Mexico
El objetivo de nuestro estudio fue evaluar la asociación entre la resistencia a la insulina y la respuesta al IFN-alfa y ribavirina en pacientes pediátricos con hepatitis C crónica.
El estudio incluyó a 26 pacientes con hepatitis C crónica (edad promedio: 12.5 ± 1.96 años, M/F: 3.33). Previo ayuno se evaluaron la glucosa, la insulina y los niveles de péptido C, en conjunto con valores de HOMA-IR, HOMA-B y QUICKI. Se determinó la asociación entre estos parámetros y la respuesta al tratamiento.
Cinco (19.2%) de los 26 pacientes analizados (2 [21.4%] con respuesta al tratamiento y 3 [16.6%] sin respuesta al tratamiento) presentaron resistencia a la insulina (p = 1.00). No existieron diferencias significativas entre los pacientes con y sin respuesta al tratamiento respecto a la glucosa, la insulina, los niveles de péptido C o los valores de HOMA-IR, HOMA-B y QUICKI (p > 0.05).
No se estableció una asociación significativa entre la resistencia a la insulina y la respuesta al IFN-alfa y ribavirina en niños con hepatitis C crónica.
The aim of our study was to evaluate the association between insulin resistance and the response to IFN-alpha and ribavirin in pediatric patients with chronic hepatitis C.
Twenty-six patients with chronic hepatitis C (mean age: 12.5 ± 1.96 years, M/F:3.33) were included in the study. Fasting glucose, insulin, and C-peptide levels, together with HOMA-IR, HOMA-B, and QUICKI values, were assessed. The association between those parameters and treatment response was determined.
Five (19.2%) of the 26 patients analyzed (2 [21.4%] with treatment response and 3 [16.6%] with no treatment response) had insulin resistance (p=1.00). There were no significant differences between the patients with and without treatment response with respect to fasting glucose, insulin, and C-peptide levels or HOMA-IR, HOMA-B, and QUICKI values (p>0.05).
No significant association was establihed between insulin resistance and response to IFN-alpha and ribavirin, in children with chronic hepatitis C.
Managing diabetes and liver disease association
2018, Arab Journal of Gastroenterology
Citation Excerpt :
NAFLD severity was found to be associated with gut dysbiosis and a shift in the metabolic function of the gut microbiota [117]. Altered glucose metabolism impairs sustained virological response (SVR) to interferon viral treatment, while SVR reduces the risk of IFG and/or T2 DM development in patients with chronic hepatitis C [118]. The presence of T2 DM or haemodialysis did not affect SVR in DAAs treatment [119].
There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening.
Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival.
Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia
Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial
Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention.
The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients.
In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted.
This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.
Impact of IL-28B gene polymorphism on chronic hepatitis-C patients progression with diabetes and non-diabetes
2022, Egyptian Journal of Medical Human Genetics
Recipient IL28B genotype CT is a predictor of new onset diabetes mellitus in liver transplant patients with chronic hepatitis C
2022, International Journal of Diabetes in Developing Countries
Insights on the disruption of glucose metabolism and hepatic insulin resistance induced by hepatitis C virus
2022, Metabolism and Target Organ Damage
Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients
2022, Frontiers in Endocrinology

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^☆: The authors who have taken part in the research of this paper declared that they do not have a relationship with the manufacturers of the drug involved either in the past or present and they did not receive funding from the manufacturers to carry out their research. They did not receive funding from any source to carry out this study.

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Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C☆

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patient population

Factors associated with sustained virological response

Discussion

Acknowledgement

Gastroenterology

Gastroenterology

Am J Gastroenterol

Am J Pathol

Hepatology

Gastroenterology

J Hepatol

J Hepatol

J Am Coll Cardiol

Am J Gastroenterol

Hepatitis C and insulin resistance

WJG

Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: a case-control study

Diabetes Care

Glucose abnormalities in patients with hepatitis C virus infection: epidemiology and pathogenesis

Diabetes Care