Diabetes
Treatment May Improve Response to Pegylated Interferon/Ribavirin, and HCV Eradication
in Turn May Reduce Insulin Resistance
By
Liz Highleyman Researchers
have yet to fully understand the complex relationship between hepatitis
C virus (HCV) infection, liver
fibrosis and steatosis
(fat accumulation), and metabolic abnormalities such as elevated blood lipids
and insulin resistance (which
can progress to diabetes). Two
studies presented at the recent Digestive Disease Week
2007 conference last month in Washington, DC, shed further light on this issue,
with one showing that treatment for type 2 diabetes may help improve response
to interferon-based therapy for chronic hepatitis, while the other suggested that
effective HCV eradication can reduce insulin resistance. Diabetes
Treatment H.M.
Elgouhari and colleagues from Cleveland conducted a study to assess the rate of
sustained virological response (SVR)
in hepatitis C patients with and without diabetes mellitus, and to evaluate the
safety of combining insulin-sensitizing agents (ISAs) with pegylated
interferon plus ribavirin. The
investigators employed a case-controlled retrospective analysis of prospectively
collected data. They identified 61 patients with HCV and diabetes who were treated
with standard doses of pegylated interferon plus ribavirin between 2002 and 2004;
21 subjects also received ISAs. A control group of 61 HCV patients without diabetes
matched for HCV genotype and ethnicity treated during the same time period was
selected. Descriptive
statistics were performed to characterize both groups, and a univariate analysis
was done to compare variables of interest. Logistic regression was performed to
identify independent factors associated with treatment failure. Results
• Patients with diabetes had
a higher mean body mass index (BMI) than those without diabetes (32.4 vs 28.5).
• Diabetes patients were also
more likely to have advanced liver fibrosis (56% vs 28%; P = 0.003).
• SVR was observed in 14 of
61 patients with diabetes (23%) compared to 31 of 61 subjects without diabetes
(51%) (P = 0.001).
•
By univariate analysis, diabetes (P = 0.001), genotype
1 HCV (P = 0.005), and African-American ethnicity (P = 0.03) were associated
with lack of SVR.
•
Multivariate logistic regression identified diabetes (OR 3.9) and genotype 1 (OR
3.7) as independent predictors of treatment failure.
•
This association remained significant after adjusting for other relevant
variables including ethnicity and presence of advanced fibrosis.
•
Among patients with diabetes, the SVR rate was higher in patients
who were using ISAs (29%) compared to those who were not (20%), but this difference
did not reach statistical significance.
•
The rates of serious adverse events, early treatment discontinuation,
and ALT flares were similar between patients receiving and not receiving ISAs.
"Diabetes
mellitus is a predictor of treatment failure in HCV patients treated with [pegylated
interferon]/ribavirin," the investigators concluded. "Based on this
limited assessment, ISAs appear to be safe when combined with [pegylated interferon]/ribavirin
in diabetic HCV patients."
HCV
Eradication In
the second study, researchers from Kurume University School of Medicine in Japan
looked at the impact of hepatitis C treatment on insulin resistance.
As
background, they noted that they had previously shown that HCV down-regulates
hepatic expression of insulin receptor substrate (IRS) 1 and 2 -- key molecules
involved in insulin signaling -- through up-regulation of suppressor of cytokine
signaling 3. Thus, they wrote, "HCV itself seems to play an important role
for the development of insulin resistance."
The aim of the current
study was to examine the effects of HCV eradication on hepatic expression of IRS-1/2
and insulin resistance. The investigators analyzed 80 subjects with biopsy-proven
chronic HCV infection. Patients received interferon-alfa with or without ribavirin
for 6 months, and were classified into 3 groups 6 months after the completion
of therapy: •
Sustained responders (n = 26);
•
Relapsers (n = 11);
•
Non-responders (n = 43).
Insulin
resistance was assessed using the homeostasis model assessment method (HOMA-IR).
Hepatic expression of IRS-1/2 was evaluated by immunoblotting and immunostaining
in 14 sustained responders.
Results
•
Among non-responders, BMI decreased significantly from 22.9 to 21.5
at the end of follow-up (P < 0.05).
•
However, there were no significant changes in HOMA-IR values at the
end of follow-up compared with those before starting antiviral therapy (3.9 vs
3.7).
• Among relapsers,
no significant differences were seen in BMI (21.9 vs 22.0) or HOMA-IR values (3.5
vs 3.6) at the end of follow-up compared with those before starting therapy.
•
Among sustained responders, there was no significant difference in
BMI at the end of follow-up (22.3 s. 22.1), but HOMA-IR values decreased significantly
from 3.2 to 2.3 (P < 0.01).
•
Immunoblotting showed a 3-fold increase in hepatic expression of IRS-1/2
after HCV eradication.
•
Immunostaining revealed that increased IRS-1/2 expression occurred in hepatocytes,
but not in non-parenchymal cells.
In
conclusion, the researchers wrote, "We demonstrated that eradication of HCV
improves hepatic expression of IRS-1/2 and insulin resistance."
06/19/07 References
HM
Elgouhari, I Hanouneh, CO Zein, and others. Diabetes Mellitus is a Predictor of
Treatment Failure in hepatitis C Patients Treated with Peg IFN and RBV. Digestive
Disease Week 2007 (DDW 2007). Washington, DC. May 19-24, 2007. Abstract M1800.
T
Kawaguchi, T Ide, E Taniguchi, and others. Eradication of HCV Improves Hepatic
Expression of Insulin Receptor Substrate 1/2 and Insulin Resistance. DDW 2007.
Abstract 361.
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