Wednesday, August 29, 2018

How response to HCV treatment impacts the incidence of type 2 diabetes

Impact of Sustained Virologic Response on Risk of Type 2 Diabetes Among Hepatitis C Patients in the United States 
J. Li; T. Zhang; S. C. Gordon; L. B. Rupp; S. Trudeau; S. D. Holmberg; A. C. Moorman; P. R. Spradling; E. H. Teshale; J. A. Boscarino; M. A. Schmidt; Y. G. Daida; M. Lu

J Viral Hepat. 2018 Aug;25(8):952-958. 

Data regarding the impact of hepatitis C (HCV) therapy on incidence of type 2 diabetes mellitus are limited. We used the data from the longitudinal Chronic Hepatitis Cohort Study-drawn from four large US health systems-to investigate how response to HCV treatment impacts the risk of subsequent diabetes. Among HCV patients without a history of type 2 diabetes mellitus or hepatitis B, we investigated the incidence of type 2 diabetes from 12 weeks post-HCV treatment through December 2015. Cox proportional hazards models were used to test the effect of treatment status (sustained virologic response [SVR] or treatment failure) and baseline risk factors on the development of diabetes, considering any possible risk factor-by-SVR interactions, and death as a competing risk. Among 5127 patients with an average follow-up of 3.7 years, diabetes incidence was significantly lower among patients who achieved SVR (231/3748; 6.2%) than among patients with treatment failure (299/1379; 21.7%; adjusted hazard ratio [aHR] = 0.79; 95% CI: 0.65-0.96). Risk of diabetes was higher among African American and Asian American patients than White patients (aHR = 1.82 and 1.75, respectively; P < .05), and among Hispanic patients than non-Hispanics (aHR = 1.86). Patients with BMI ≥ 30 and 25-30 (demonstrated higher risk of diabetes aHR = 3.62 and 1.72, respectively; P < .05) than those with BMI < 25; patients with cirrhosis at baseline had higher risk than those without cirrhosis (aHR = 1.47). Among a large US cohort of patients treated for HCV, patients who achieved SVR demonstrated a substantially lower risk for the development of type 2 diabetes mellitus than patients with treatment failure.

Discussion Only 
Full text available online @ Medscape 
In a large US cohort of patients treated for HCV, we found that the achievement of SVR independently reduced the risk of T2D. There were no SVR-by-covariate interactions detected, meaning the SVR effect was consistent across patient demographic characteristics and clinical conditions at the time of treatment, including serum alanine aminotransferase (ALT) levels.

We observed an independent effect of HCV-related cirrhosis on increasing T2D incidence after adjusting for other covariates as well as SVR status. This effect has been reported previously; univariate analyses in a smaller European study (n = 365) showed that increasing fibrosis score was a risk factor for the development of T2D.[2] We did not observe a significant effect of ALT in either univariate or multivariate analyses. It is possible, however, that the lack of a significant finding was a consequence of a relatively large proportion (20%) of missing ALT data and/or the strong correlation between ALT and cirrhosis, which may have diminished the observed effect of ALT.

Race has been previously identified as a factor associated with increased the risk of T2D in the general US population and among patients with HCV in Europe.[9,10] Our results are consistent with these findings, although the effects we observed were larger than those reported in other studies; the risk of T2D was 92% higher among African American patients and 75% higher among ASINPI patients compared with Whites, after adjusting for BMI and other covariates.

Some studies have suggested that sex and HCV genotype are associated with the risk of T2D, but these results have not been consistent.[9] In our study, sex was a significant risk factor in univariate analysis, but was not significant after adjusting for other covariates. HCV genotype was not significantly associated with T2D incidence in either univariate or multivariate analyses.

Our study has some limitations. Data available to calculate baseline BMI and to impute FIB4 score were incomplete, given our reliance on electronically collected observational data as well as the inclusion of some patients treated beginning in the early 1990s. Additionally, our study was largely limited to the interferon era of HCV treatment. However, the CHeCS "dynamic" sampling design, which adds new patients to the cohort at regular intervals while continuing to follow the existing patients, has allowed us to begin the preliminary analyses of the impact of DAA regimens on the incidence of T2D.

Debate remains regarding whether and how HCV infection might increase the risk of T2D.[11,12] Although some studies have found that T2D occurs more frequently among subsets of HCV-infected versus uninfected individuals,[13–15] other studies suggest that observed increases in the risk of T2D may be a consequence of HCV-related elevation in ALT,[16,17] perhaps further confounded by high BMI and/or cirrhosis.[18] We found that cirrhosis, but not baseline ALT, independently increased the risk of T2D in all treatment groups. Although we observed that successful HCV treatment reduced the risk of future diabetes, our analysis could not evaluate whether this risk reduction resulted from viral eradication, from subsequent reductions in inflammation or fibrosis, or through some other mechanism. Future analyses may help elucidate these mechanisms.

Additionally, although we observed that the absence of successful antiviral therapy increases HCV patients' risk of T2D, a number of studies have suggested that T2D and insulin resistance reduce response to antiviral therapy, particularly interferon-based treatments.[19–22] This two-way association illustrates the complex relationship between T2D, HCV and SVR, and may have introduced bias into the observed effect of SVR on the risk of T2D. We excluded patients previously diagnosed with T2D from our analysis, but due to the observational nature of our study, comprehensive identification of each patient with potentially elevated glucose and insulin resistance was not feasible. To address this issue, we performed a sensitivity analysis of patients with available glucose assessments, excluding those with fasting or random glucose levels greater than 110 mg/dl. Exclusion of these patients produced results similar to our main analysis.

Another limitation is that our assessment of the association between independent baseline covariates and the risk of T2D incidence was restricted to treated patients. Given the absence of variable-by-SVR interactions and the increasing uptake of DAA treatment in the HCV patient population, we expect that our observations regarding the impact of race and cirrhosis on the development of T2D may be generalizable to a broader population of patients with HCV.

In conclusion, among a geographically and racially diverse cohort of more than 5000 patients from US healthcare systems, successful HCV treatment was associated with significant reductions in the incidence of T2D. African American and ASINPI race as well as the presence of cirrhosis appear to increase the risk of developing T2D among those without SVR. Therefore, patients with these risk factors should be monitored closely for T2D prevention and care.

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