|Year : 2017 | Volume
| Issue : 4 | Page : 187-195
Effect of new direct-acting antiviral drugs on insulin resistance and glycemic control after treatment of chronic hepatitis C virus infection in type 2 diabetic patients
Alaa E.M Hashim1, Hanaa T Kandeel2, Olfat M Hendy3, Khaled El-Mola1, Fathyia M El-Raey1, Mohamed S.M Attia1
1 Department of Tropical Medicine, Faculty of Medicine, Al-Azhar University, Egypt
2 Department of Endocrinology and Metabolism, Faculty of Medicine for Girls, Cairo, Egypt
3 Department of Clinical Pathology, National Liver Institute, Menoufia University, Shebeen El-Kom, Egypt
|Date of Web Publication||19-Jul-2018|
Mohamed S.M Attia
Department of Tropical Medicine, Al-Azhar University Hospital, New Damietta
Source of Support: None, Conflict of Interest: None
Background Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. The benefits of eradicating HCV infection with direct-acting antiviral (DAAs) may go well beyond avoiding the damage caused by chronic liver inflammation, to include declines in glycated hemoglobin percent and other metabolic parameters. The present study was designed to evaluate the effect of new DAAs drugs, used for treatment of HCV, on insulin resistance and glycemic control at the end of treatment and 3 months after end of treatment of HCV infection in patient with type 2 diabetic mellitus (T2DM) in Damietta Governorate.
Patients and methods This study included 75 T2DM patients with chronic HCV infection. Patients were divided according to level of glycosylated hemoglobin percent into three groups. All patients received DAAs and were monitored by A1C%, homeostasis model assessment-insulin resistance, and fasting blood sugar before, at the end of treatment, and 12 week after the end of treatment. Patients were allocated into two groups: the first group included 57 (76%) patients with improved glycemic control (IGC) and the second group included 18 (24%) patients with nonimproved glycemic control (NIGC).
Results In IGC group, 45 (78.9%) patients needed to decrease the dose of antidiabetic treatment. There were no significant differences between IGC and NIGC groups regarding sex and liver condition. The percentage of patients with old age, those with positive family history of T2DM, and those with long duration of T2DM were significantly higher in NIGC group compared with IGC.
Conclusion Diabetic patients receiving DAAs should be closely monitored during reduction of antidiabetic drugs, especially regarding insulin and sulfonylurea, to avoid hypoglycemic events. Improvement of glycemic control with DAAs is seen more in younger patients without family history of T2DM and short duration of diabetes mellitus.
Keywords: antidiabetic drugs; antiviral drugs, diabetes, glycated hemoglobin, hepatitis C virus, insulin resistance, insulin, oral hypoglycemic
|How to cite this article:|
Hashim AE, Kandeel HT, Hendy OM, El-Mola K, El-Raey FM, Attia MS. Effect of new direct-acting antiviral drugs on insulin resistance and glycemic control after treatment of chronic hepatitis C virus infection in type 2 diabetic patients. Al-Azhar Assiut Med J 2017;15:187-95
|How to cite this URL:|
Hashim AE, Kandeel HT, Hendy OM, El-Mola K, El-Raey FM, Attia MS. Effect of new direct-acting antiviral drugs on insulin resistance and glycemic control after treatment of chronic hepatitis C virus infection in type 2 diabetic patients. Al-Azhar Assiut Med J [serial online] 2017 [cited 2018 Dec 17];15:187-95. Available from: http://www.azmj.eg.net/text.asp?2017/15/4/187/237137
| Introduction|| |
Hepatitis C virus (HCV) is a major cause of chronic liver disease, including cirrhosis and liver cancer. The WHO has reported that 170 million people are chronically infected with HCV globally . The highest prevalence of HCV infection worldwide is in Egypt (15%), where 90% of HCV infection is genotype 4 .
Patients with chronic HCV infection have significantly increased prevalence of type 2 diabetic mellitus (T2DM), which is a common comorbid condition in approximately one-thirds of HCV-infected individuals, possibly owing to a direct or indirect effect of the virus on insulin sensitivity .
Studies show that HCV impairs glucose metabolism directly via viral proteins and indirectly by altering proinflammatory cytokine levels. The direct effect is owing to HCV core protein that prevents the insulin receptor substrate-1 association with its insulin receptor by increasing insulin receptor substrate-1 degradation through upregulation of serine/threonine phosphorylation or increased activity of suppressor of cytokine signaling 3 . These direct actions on the insulin-signaling pathway impair downstream signaling and appropriate regulation of glucose metabolism . An indirect effect of HCV on insulin sensitivity has also been suggested to be owing to increased production of proinflammatory cytokines (interleukin 6 and tumor necrosis factor-α) from sinusoidal liver cells, which interfere with insulin-signaling pathways and lead to insulin resistance (IR) .
Recently, there is a hope for total cure and eradication of HCV with the revolution of the new direct-acting antiviral (DAA) therapy . However, the consequences of viral eradication and the safety of these medications are not yet established. Positive and negative metabolic changes were noted from small studies .
The present study was designed to evaluate the effect of new DAAs, used for treatment of HCV, on IR and glycemic control at end of treatment and 3 months after treatment of HCV infection in patient with T2DM in Damietta Governorate.
| Patients and methods|| |
This prospective cohort study was conducted on 75 patients with T2DM and chronic HCV infection who were recruited from the outpatients of the Departments of Tropical Medicine of Al-Azhar University Hospital (New Damietta), between January 2017 and August 2017. The study protocol was approved by the Ethics Committee of the Al-Azhar University Faculty of Medicine, and the selected participants gave prior consent to participate in the study.
Patients not candidates for HCV treatment according to the guidelines of national committee for control of viral hepatitis, established by the Egyptian MOHP; were patients with Child C cirrhosis (score ≥9); had platelets count less than 50 000/mm; had hepatocellular carcinoma, except 6 months after intervention aiming at cure with no evidence of activity by dynamic imaging (computed tomography or MRI); extra hepatic malignancy except after 2 years of disease-free interval, except in case of lymphomas and chronic lymphocytic leukemia; treatment can be initiated immediately after remission based on treating oncologist report; pregnancy or inability to use effective contraception; and inadequately controlled diabetic mellitus (HBA1c>9) were excluded.
Moreover, obese patients with BMI more than 30; patients with hepatitis B virus and HCV coinfection; patients with any endocrinal disease which may affect blood glucose or induce IR, proved by history and examination including Cushing disease, hyperthyroidism and acromegaly; patients receiving any drugs which may induce IR such as corticosteroid, antihypertensive (β blocker and thiazide), and statin; and patients with other comorbidity as chronic renal disease were also excluded.
Patients were subdivided into the following three groups according to glycosylated hemoglobin (HBA1c) percent: group I included 25 patients with HBA1c% level less than 6.5, group II included 25 patients with HBA1c% level ranged from 6.6 to 7.5, and group III included 25 patients with HBA1c% level ranged from 7.6 to 8.9.
| Methods|| |
- All patients were subjected to the following before treatment:
- Full history taking with special emphasis on history of alcohol drinking, drug intake, hypertension, smoking, diabetic mellitus regarding duration of disease, and type of antidiabetic treatment; family history of diabetic mellitus; history of any endocrinal disease and other comorbid condition; and previous treatment with anti-HCV medicines (e.g. peg interferon plus ribavirin, sofosbuvir plus ribavirin, or other combination regimens).
- Full clinical assessment including general and abdominal examination with stress on anthropometric measurements including height (cm), body weight (kg), and waist circumference (cm). BMI was calculated for each patient.
- Abdominal ultrasonography (US).
- ECG: patients more than or equal to 65 years old should undergo further cardiological assessment by echocardiography and cardiological consultation before therapy.
- Laboratory investigations included complete blood count (CBC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin, serum bilirubin (total and direct), international randomized ratio, α-fetoprotein, serum creatinine, and viral hepatitis markers. HCV antibody and hepatitis B surface antigen were detected by enzyme-linked immunosorbent assay, and quantitative HCV-RNA was detected by PCR assay. Pregnancy test (for females), fasting blood glucose, postprandial blood glucose, and HBA1c level (%) were also done. Fasting insulin level was measured using the biotinylated insulin enzyme-linked immunosorbent assay kit, and IR was calculated according to the homeostasis model assessment (HOMA) test by the following formula: fasting glucose (mg/dl)×fasting insulin (μU/ml)/405 .
- All patients were followed up to the end of treatment and up to 12 weeks after the end of treatment by the following:
- Measurement of quantitative HCV-RNA.
- Fasting blood sugar (FBS), 2 hour post prandial blood glucose (2HPPBG), HBA1c%, and fasting insulin level.
- IR was calculated at end of treatment and at 12 week after end of treatment to assess the effect of DAAs on IR and glycemic control.
- Assessment of glycemic control.
All patients were advised to maintain their usual diet regimen and physical activity, and for better evaluation of the improvement in IR and glycemic control, we used a composite end-point given by the reduction of FPG (of a minimum of 20 mg/dl) or HOMA-IR (of a minimum of 0.5) or HBA1c (of a minimum of 0.5%).
The collected data were organized, tabulated, and statistically analyzed using statistical package for the social sciences (SPSS) version 22 (SPSS Inc., Chicago, Illinois, USA), running on IBM-compatible computer. Quantities data were presented as mean and SD, whereas qualitative data were presented as number and percent distribution. Comparison between two means was done by unpaired samples (t) test, whereas comparison between two means at two different points of time was done using paired samples (t) test. When comparing more than two means, the one-way analysis of variance test was used, whereas comparing the same mean at more than two points of time, the repeated analysis of variance was used. Correlation between two parameters was done by calculation of Spearman’s correlation coefficient (r). It was proportional if the sign is positive and inverse if the sign is negative; mild if r less than 0.3, moderate if r extending between 0.3 and 0.7, and powerful if r more than 0.7. For interpretation of results, the P value less than 0.05 was considered significant.
| Results|| |
Females had higher prevalence (52%) than males (48%), and group I was younger than groups II and III.
There were no significant differences between the groups regarding BMI and waist circumference (before and after therapy) ([Table 1]).
|Table 1 Comparison of weight and waist circumference in different times of the study|
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Sustained virologic response (SVR) after 3 months was obtained in 71 (94.6%) patients. According to the aforementioned criteria of improvement in glycemic control, there was statistically significant improvement in FBS, HOMA-IR, and HBA1c in 57 (76.0%) patients after 3 months of DAA therapy compared with pretreatment levels [improved glycemic control (IGC group)]; the remaining 18 (24.0%) patients did not achieve improvement in glycemic control during the period of study [nonimproved glycemic control (NIGC group)] ([Table 2] and [Table 3]).
|Table 2 Comparison of laboratory characteristic in groups before and after treatment|
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|Table 3 Comparison of glycated hemoglobin in studied populations at 3 and 6 month|
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The treatment of diabetes mellitus was in the form of insulin in 19 (25.3%) patients, oral antidiabetic drugs in 39 (52.0%) patients, and combined insulin and oral in 17 (22.7%) patients. A total of 45 (60%) patients needed to decrease the dose of antidiabetic treatment, 28 patients needed to decrease the insulin dose, two patients who had controlled HBA1c at baseline (HBA1c≤6.5) needed to stop insulin, and 15 patients needed to decrease the glimepiride dose. None of the IGC patients needed to decrease their metformin or DPP4 inhibitor doses. After 3 months of DAA therapy, the mean value of reduction of FPG in the IGC group was 25 mg/dl with a maximum reduction of 40 mg/dl (from 140 to 100 mg/dl) observed in one patient in group III; the mean reduction of HBA1c was 1.1% with a maximum reduction of 1.3% (from 8.7 to 7.4%) observed in one patient in group III; the mean reduction of HOMA-IR was 0.91 with a maximum reduction of 2.6 (from 7.5 to 4.9) observed in one patient in group II (data not tabulated).
There were no significant differences between glycemic control marker (FBS, HBA1c and HOMA-IR) values before initiation of therapy and values at the end point of follow-up between groups (i.e. the glycemic control before therapy has no effect on glycemic improvement at the end of the study) ([Table 4]).
There was a negative significant correlation between FBS difference (decrease of FBS) and each of age, BMI, and disease duration. Similarly, there was statistically significant negative correlation between HOMA-IR difference and HBA1c difference in studied populations ([Table 5]).
|Table 5 Correlation between net effect on diabetic control markers and age, BMI, and duration of disease|
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The improvement of HOMA-IR and HBA1c after 3 month of treatment end was significantly associated with younger age (P<0.001), low BMI (P<0.001), less disease duration (P<0.001), low FBS, negative family history (P<0.001) and not associated with liver condition (P>0.40) and viral load (P>0.45) ([Table 6] and [Table 7]). In the IGC group, no patients experienced hypoglycemia. There was statistically significant improve of ALT, AST, and total bilirubin, whereas there was statistically significant progressive increase of platelets ([Table 8]).
|Table 6 Comparison between improved glycemic control and nonimproved glycemic control regarding age, BMI, disease duration, family history, basal glycated hemoglobin, basal homeostasis model assessment-insulin resistance, fasting and postprandial blood sugar, viral load, and liver ultrasound|
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|Table 7 Comparison between improved glycemic control and nonimproved glycemic control regarding age, BMI, disease duration, family history, basal glycated hemoglobin, basal homeostasis model assessment-insulin resistance, fasting and postprandial blood sugar, viral load, and liver ultrasound|
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|Table 8 Comparison of laboratory characteristic in groups before and after 12 weeks of treatment|
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| Discussion|| |
In our study, females had higher prevalence (52%) than males (48%). This observation was in disagreement with Niu et al. , who found the prevalence of HCV infection in males significantly higher than that of females. Our finding may be explained by that obesity is the major risk factor of T2DM in both sexes, but obesity is more common in women than men.
More than half of the diabetic patients are middle aged, and incidence rises with increasing ages in both sexes . In this work, there was statistically significant decrease of age in group I (45.84+6.19 years) when compared with either group II (50.88+5.74 years) or group III (50.76+4.40 years). This observation may in part be attributed to short duration of T2DM in group I (1–7 years), and in another part to selection of patients according to HBA1c levels, which increased steadily as age increased as reported by Inoue et al. . Who study Effects of age and sex in the diagnosis of T2DM using glycated hemoglobin in Japan.
There was no statistically significant difference among the studied groups regarding pretreatment anthropometric measurements. This finding is in agreement with Ciancio et al.  who reported nonsignificant difference of baseline anthropometric measurements between diabetic patients treated with DAAs.
Regarding disease duration, it ranged from 1 to 11 years; the duration of T2DM was significantly longer in the NIGC group compared with the IGC control group. This agrees with the study of Dawood et al. . Prolonged duration of T2DM may lead to more β-cell failure and so improvement in IR does not lead to marked improvement in glycemic control.
Regarding the treatment of diabetes mellitus, it was in the form of insulin in 19 (25.3%) patients, oral antidiabetic drugs in 39 (52.0%) patients, and combined insulin and oral in 17 (22.7%) patients. In the IGC group, 45 (78.9%) patients needed to decrease the dose of antidiabetic treatment, 28 patients needed to decrease the insulin dose, two patients who had controlled HBA1c at baseline (HBA1c≤6.5) needed to stop insulin and 15 patients needed to decrease the glimepiride dose. None of the IGC patients needed to decrease their metformin or DPP4 inhibitor doses, which may be expected as hypoglycemia rarely occurs with metformin and DPP4 inhibitors. One study suggested that the antiviral effects of danoprevir may decrease IR in patients with HCV genotype1 . Another study found that HCV suppression with DAA therapy produced a significant improvement in glycemic control regardless of genotype . In contrast, a third study found that DAA therapy with sofosbuvir and ledipasvir led to the development of new-onset T2DM . In another Egyptian study  that included 460 T2DM patients with chronic HCV genotype 4 infection, 400 patients received DAAs and 60 patients did not receive DAAs. Patients with sustained virological response after 3 months of DAAs (378 patients) were allocated into two groups: first group included 292 (77.2%) patients with IGC and second group included 86 (22.8%) patients with NIGC. In IGC group, 78 (26.7%) patients needed to decrease their dose of antidiabetic treatment.
Regarding family history, the percentage of patients with positive family history of T2DM was significantly lower in the IGC group compared with the NIGC control group. In patients without family history of T2DM, the possibility of IR is likely due to HCV infection only, so the eradication of HCV infection helps to improve IR and glycemic control, unlike those with inherited IR. It might be useful to classify patients with hereditary IR or HCV-induced IR to define better the effect of HCV eradication on these distinct populations, but this is not always possible. Absence of family history of T2DM may help in this differentiation. This agrees with the Egyptian study of Dawood et al. .
In the present work, there were no statistically significant differences between group I, II, and III before initiation of therapy regarding laboratory investigations, except statistically significant increase of FBS, fasting blood insulin, HOMA-IR, and HBA1c in groups II and III when compared with group I. This is explained by criteria of selection of patients according to HBA1c. Regarding glycemic control markers (FBS, HBA1c, and HOMA-IR), there were no significant differences between values before initiation of therapy and values at the end point of follow-up between groups (i.e. the glycemic control before therapy has no effect on glycemic improvement at the end of the study). In contrast with Hum et al.  who reported the decrease in HBA1c level associated with SVR was restricted to patients with a high baseline HBA1c level more than 7.2% in diabetic patients treated with DAA drugs.
In general, the enzyme alanine aminotransferase occurs primarily in liver cells. Ordinarily, this soluble enzyme is present at low levels in sera when liver function is normal. Elevated ALT values are usually seen in parenchymal liver diseases characterized by destruction of hepatocytes. Generally, ALT activity is more specific for the liver than AST and its increased serum concentrations are rarely observed in conditions other than parenchymal liver disease .
In progressive chronic viral disease with lasting liver injury, ALT leaks from the liver causing persistently enhanced serum activity. Consequently, normalization of ALT after therapy generally serves as a leading biomarker for absence of hepatocellular injury. Therefore, it is regularly accepted that that elevation of ALT by at least 2×UNL is mandatory for screening individuals for liver disease, particularly when other risk factors are present (alcohol consumption, intravenous drug user (IVDU), homosexuality, blood/blood derivates transfusion, maternal positivism, etc.) .
During and after treatment, there was statistically significant improvement of ALT and AST, whereas there was statistically significant progressive increase of platelets. These results are in agreement with those reported by Radovanovic et al.  about normalization of alanine aminotransferase predicts successful antiviral treatment in patients with chronic hepatitis C, which showed strong association between normal ALT values and SVR (70.6 vs. 72.6%, respectively), which confirms similar results of other authors . Moreover, a recent report from Korea showed that normalization of ALT was a useful response predictive factor for viral elimination not only for SVR but also for a rapid viral response after 4 weeks of treatment . Moreover, the same was reported by Reddy et al.  where statistically significant improvements from baseline to post-treatment week 4 were observed in the analysis population overall in albumin, ALT, AST, bilirubin, and platelet counts (P<0.001) for all patients with genotype 1 HCV infection and compensated cirrhosis treated with ledipasvir and sofosbuvir.
Improvement of HBA1c and blood glucose in studied populations at the end of therapy (at 3 months) was seen in 55 (73.3%) patients of all studied populations, whereas at 6 months (3 months after stoppage of treatment), it was seen in 57 (76.0%) of patients. This is in agreement with Hum et al.  who aimed to investigate whether eradication of HCV infection with DAAs agents is associated with improved glycemic control in patients with diabetes. Overall, 2435 patients with diabetes who underwent interferon-free and ribavirin-free DAA-based antiviral treatment for HCV in the national Veterans Affairs health care system were identified. Changes in average HBA1c level and use of antidiabetic medications 1 year before and after antiviral treatment were compared between patients who achieved SVR and those who did no. Among patients with elevated baseline HBA1c, the decrease in HBA1c associated with antiviral treatment was greater in those who achieved SVR (0.98%) than in those who sustained treatment failure (0.65%) (adjusted mean difference 0.34, P=0.02). Use of antidiabetic medications decreased more in patients who achieved SVR than in those who sustained treatment failure, especially for the use of insulin, which decreased significantly from 41.3 to 38% in patients achieving SVR compared with a slight increase from 49.8 to 51% in those who sustained treatment failure. The same was reported by Pavone et al.  where rapid decline of fasting glucose and HBA1c was observed in HCV diabetic patients treated with DAA agents. This is in contrast to Stine et al.  who reported unaffected HBA1c level by eradication of chronic HCV in diabetic patients with and without cirrhosis treated with DDAs. The explanation may in part be attributable to clinical management of diabetes and hyperglycemia with pharmacologic therapy rather than a primary process of viral clearance itself as nearly one-third of our cohort had increasing dosages of their antihyperglycemic therapy.
Improvement of HOMA-IR and fasting blood insulin in studied groups at the end of therapy was seen in 54 (72.0%) patients in all studied groups, whereas at 6 months, 55 (73.3%) patients improved. This result agreed with Kim et al.  who analyzed 28 patients with HCV infection who receive combination treatment of 180 µg of pegylated interferon α-2a and ribavirin at our institution from May 2004 to November 2006. IR was calculated according to the HOMA-IR method. It resulted in 22 (78.6%) patients achieving SVR, where the fasting plasma glucose level significantly decreased after antiviral treatment. Fasting serum insulin and HOMA-IR also significantly decreased after antiviral treatment. This finding is in contrast with Shehab-Eldin et al.  who found marked increase in fasting insulin and HOMA-IR after study of glucose homeostasis in 80 patients chronically infected with HCV, diagnosed by quantitative PCR, were subjected to physical examination and anthropometric measurements. In addition, FBS, fasting insulin, CBC, bilirubin, AST, ALT, serum albumin, and serum creatinine were assessed at the beginning of the study. HOMA-IR, β-cell percent, BMI, and eGFR were calculated. All patients received DAA drugs±ribavirin for 3 months. All parameters were reassessed at end of treatment of HCV-infected patients with DAA drugs. Meissner et al.  also reported no improvement of IR after treatment with DAA despite lowering of HBA1c in nondiabetic patients.
In our study, 55 (73.3%) patients showed improvement of FBS, HOMA-IR, and HBA1c at the end of therapy, and improvement was significantly associated with younger age and low BMI. This disagrees with Pashun et al.  who found significant improvement in diabetic control after successful HCV treatment with DAA therapy, and this improvement in insulin requirements and HBA1c persisted following viral clearance despite an increase in the patient’s BMI.
The improvement also related to less disease duration, low FBS, and negative family history. However, liver condition and viral load have no statistically significance, and this may be due to all patients in study being Child A. Viral load assessment before, during, and after therapy is an important tool for predicting the treatment outcome. Although viral load does not correlate with the severity of liver injury or the progression of the disease, a low baseline viral load (<600 000–800 000 IU/ml or less) is an independent predictor of SVR regardless of genotype in many studies ,,,, and patients with pretreatment high viral loads have worse long-term outcomes than patients with low viral loads.
In our study, there were 20 (26.7%) patients who did not reach the end-point of glycemic improvement at the end of therapy, and this may explained by three factors: first, the etiology of T2DM in HCV-infected individuals has been postulated to result from either hepatogenous T2DM resulting from advanced liver disease or classical T2DM due to virally mediated IR ; second, HCV infection may affect glucose level by an autoimmune mechanism on β-cells and is not related to IR; and third, some of the patients in the NIGC group already had normal FPG and HBA1c.
Furthermore, weight and waist circumference did not changed significantly over time in the study period, when compared with their original values. These results are in agreement with those reported by Dawood et al.  about factors associated with improved glycemic control by DAA agent treatment in Egyptian T2DM patients with chronic hepatitis C genotype 4. They found no significant differences between IGC and NIGC groups as regards age, sex, and BMI. The findings disagree with those in Azad et al. who found weight gain among diabetic patients cured of HCV with sofosbuvir/ledipasvir.
The evidence for the effect of DAA therapy on T2DM is conflicting. One study suggested that the antiviral effects of danoprevir may decrease IR in patients with HCV genotype 1 . Another study found that HCV suppression with DAA therapy produced a significant improvement in glycemic control regardless of genotype . In contrast, a third study found that DAA therapy with sofosbuvir and ledipasvir led to the development of new-onset T2DM .
In the current study, the patients with normal baseline FPG and HBA1c did not experience hypoglycemia, which excluded the direct hypoglycemic effect of DAAs.
The clinical effect of successful antiviral therapy on the long-term outcome of T2DM in diabetics is outside the scope of this study and remains largely unknown. This is mainly owing to the lack of prospective studies that specifically address this important issue. According to a nationwide population-based research conducted in Taiwan , antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. The reduction rate of T2DM complications is impressive: patients given antiviral treatment showed an 84% reduction in the risk of end-stage renal disease, 47% in that of ischemic stroke, and 36% in acute coronary syndrome compared with the untreated cohort. In diabetic patients, good glycemic control prevents the onset and progression of short-term and long-term diabetes-related complications .
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]