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Improvement in Glycemic Control of Type 2 Diabetes
After Successful Treatment of Hepatitis C Virus
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"Eradication of HCV has been shown to reduce the risk of hepatocellular carcinoma, to improve liver fibrosis, and to decrease the risk of other complications of chronic liver disease (39). However, the effects of HCV eradication on the extrahepatic manifestations of HCV have not been well studied in the new era of DAAs. Our study supports the idea that HCV eradication leads to a reduction in HbA1c in patients with diabetes."
"Our study supports the idea that HCV eradication leads to a reduction in HbA1c in patients with diabetes....
In summary, glycemic control improves in patients with diabetes after DAA-induced SVR. Patients not only have an improvement in HbA1c level after achieving SVR, they are also less likely to require insulin. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes. ....hepatitis C virus (HCV) infection is associated with a higher prevalence of type 2 diabetes mellitus (T2DM) .In addition, HCV proteins increase the release of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, which then upregulate gluconeogenesis and enhance lipid accumulation in the liver
Future studies are needed to confirm our findings, to determine how durable the SVR-induced improvement in glycemic control is over time, and to assess the long-term effect on complications of diabetes such as nephropathy, neuropathy, and cardiovascular disease.
It is well established that the microvascular complications of diabetes, including nephropathy, neuropathy, and retinopathy, improve with lowered HbA1c level ....Therefore, early treatment of HCV could potentially slow the onset and progression of microvascular diabetes complications.....Prior studies (45) have demonstrated an association between central adiposity related to T2DM and hepatic steatosis. The decrease in HbA1c level achieved by medications such as thiazolidinediones or glucagon-like peptide 1 receptor agonists in patients with diabetes has been shown to improve hepatic fat content (46). As our study has shown an improvement in HbA1c levels with the successful eradication of HCV, treatment may also improve hepatic steatosis, which frequently accompanies HCV-related liver disease......We reported that DAA-induced SVR was associated with a nonsignificant decrease in the proportion of patients with diabetes who were receiving antidiabetic medications and in the number of classes of antidiabetic medications and a significant decrease in the proportion of patients receiving insulin. The elimination of insulin after SVR was achieved was more common in patients who had relatively well-controlled diabetes at baseline (HbA1c ≤7.2%) than in those with a baseline HbA1c level of >7.2%.....Providers should be aware that glycemic control could improve after DAA-induced SVR and should be closely monitored for the need to remove insulin from therapy.
.....Recent studies (47) have even shown that patients with compensated HCV cirrhosis have higher rates of decompensation when they have diabetes and IR and that IR was a predictor of overall mortality. Thus, it is tempting to speculate that HCV eradication might prevent the development of decompensated cirrhosis not only by the elimination of the fibrotic and hepatotoxic effects of HCV, but also by reducing HbA1c levels and improving IR in patients with T2DM, but future long-term studies are necessary to demonstrate this.......It is important to note that the lowering of HbA1c levels represents only one mechanism by which HCV eradication could potentially influence cardiovascular risk. HCV infection also causes the development of circulating low-density immune complexes that induce an inflammatory response (42), which could improve after HCV eradication. On the other hand, a virologic cure has been shown to result in increases in serum cholesterol and LDL cholesterol levels (43,44), which may aggravate early atherosclerotic lesions and increase cardiovascular risk. Thus, the net effect of HCV eradication on long-term cardiovascular risk remains to be determined.
.....Among 2,435 patients with diabetes who were infected with HCV and were treated with interferon-free and ribavirin-free regimens, the average age was 62.2 years; the average BMI was 30.2 kg/m2; and the vast majority were male (97.5%), had genotype 1 HCV (99.3%), and were treated with LDV/SOF (56.2%) or SMV plus SOF (38.3%) (Table 1). The most common racial/ethnic group was non-Hispanic black (43.6%) followed by non-Hispanic white (38.3%) and Hispanic (5.4%). Cirrhosis (37.3%) and even decompensated cirrhosis (10.4%) were common, with 75.2% of patients receiving at least one antidiabetic medication and 42.2% of patients receiving insulin.....The drop in HbA1c level associated with SVR was restricted to patients with a high baseline HbA1c level. Among patients with a pretreatment mean HbA1c of >7.2% (55 mmol/mol; the mean pretreatment HbA1c level in our study population), the decrease in mean HbA1c level was significantly greater in the SVR group (0.98 ± 1.4%) compared with the no-SVR group (0.65 ± 1.5%), with an AMD of 0.34 (P = 0.02) (Table 2). Among patients with HbA1c ≤7.2% (55 mmol/mol), there was no significant difference between patients with and without SVR in the change in HbA1c level. Also the significant drop in HbA1c level associated with SVR was restricted to patients without cirrhosis and not to patients with cirrhosis (Table 2)...... The baseline number of classes of antidiabetic medications pretreatment was similar in the group that achieved SVR (1.15 ± 0.9) and the group that did not (1.16 ± 0.9). The number of classes of antidiabetic medications decreased slightly after antiviral treatment, more so in the patients who achieved SVR than in those who did not, but this difference was not statistically significant (Table 3). Also, the proportion of patients who were receiving treatment with antidiabetic drugs decreased slightly more in patients who achieved SVR than in those who did not, but this difference was not statistically significant......The proportion of patients receiving treatment with insulin decreased more significantly in patients who achieved SVR (from 41.3% to 38%) than in patients who did not (who actually had a slight increase in the proportion of patients receiving treatment with insulin from 49.8% to 51.0%; AMD -4.2%; P = 0.04) (Table 3). This reduction in insulin use in patients achieving SVR compared with patients in whom treatment failed was more profound among patients with a low pretreatment HbA1c level of ≤7.2% (55 mmol/mol). Also the reduction in insulin use in patients achieving SVR was not associated with a concomitant increase in the use of metformin (i.e., it was not caused by the substitution of metformin for insulin in patients with improved liver function after SVR, who prior to treatment were felt to be ineligible for treatment with metformin). In fact, use of metformin also decreased from before to after antiviral treatment by 2.2% in patients achieving SVR and by 1.9% in patients for whom treatment failed......Comparing the post-treatment to pretreatment periods, weight increased slightly more in patients with SVR than in those for whom treatment failed (Table 4). Hemoglobin concentration decreased significantly more in patients for whom treatment failed than in patients who achieved SVR. Serum creatinine level increased slightly and equally in patients who did and did not achieve SVR.”
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Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus
Diabetes Care 2017 Sep - Justine Hum,1 Janice H. Jou,1 Pamela K. Green,2 Kristin Berry,2 James Lundblad,3 Barbara D. Hettinger,3 Michael Chang,1 and George N. Ioannou2,4
1Division of Gastroenterology, Portland Veterans Affairs Medical Center, Portland, OR 2Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System,
Seattle, WA 3Division of Endocrinology, Portland Veterans Affairs Medical Center, Portland, OR 4Division of Gastroenterology, Veterans Affairs
Puget Sound Healthcare System and University of Washington, Seattle, WA
Abstract
OBJECTIVE Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. We aimed to investigate whether eradication of HCV infection with direct-acting antiviral (DAA) agents is associated with improved glycemic control in patients with diabetes.
RESEARCH DESIGN AND METHODS We identified 2,435 patients with diabetes who underwent interferon-free and ribavirin-free DAA-based antiviral treatment for HCV in the national Veterans Affairs health care system. Changes in average hemoglobin A1c (HbA1c) level and use of antidiabetic medications 1 year before and after antiviral treatment were compared between patients who achieved sustained virologic response (SVR) and those who did not.
RESULTS Among patients with elevated baseline HbA1c, the drop 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 dropped 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.
CONCLUSIONS DAA-based eradication of HCV is associated with improved glycemic control in patients with diabetes as evidenced by decreased mean HbA1c and decreased insulin use. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes.
Introduction
Epidemiological studies have shown that hepatitis C virus (HCV) infection is associated with a higher prevalence of type 2 diabetes mellitus (T2DM) (1-6). Additionally, in patients with risk factors for the metabolic syndrome, the presence of chronic HCV infection increases the risk of the development of T2DM by 11-fold (7). Molecular mechanisms provide explanations by which HCV infection might increase the risk of the development of T2DM or worsen glycemic control in patients with established T2DM. For example, HCV proteins increase serine and threonine phosphorylation of insulin receptor substrate-1, which contributes to insulin resistance (IR) (8-11). In addition, HCV proteins increase the release of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, which then upregulate gluconeogenesis and enhance lipid accumulation in the liver (12-14).
If HCV infection indeed worsens glycemic control, then HCV eradication (known as sustained virologic response [SVR]) may improve glycemic control in patients with diabetes. In support of this hypothesis, previous interferon-based studies suggested that successful clearance of HCV could lead to improvement in IR (15-19). Patients without diabetes demonstrated improvement in an oral glucose tolerance test before and after treatment of HCV (16). Two other studies in patients without diabetes showed improvement in HOMA-IR, a measure of IR, from baseline to 20 weeks after successful treatment with interferon and ribavirin therapies in 96 patients from the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial (18) (including 21 who achieved SVR) and 89 patients from Japan (19) (including 29 who achieved SVR). To our knowledge, there have been no large studies looking at glycemic control in patients with diabetes after the eradication of HCV.
Additionally, clearing the virus may prevent the development of IR in the future, as shown in a study (15) where achieving SVR caused a two-thirds reduction in the risk of T2DM development in HCV-positive patients treated with interferon. However, these studies were confounded by treatment-induced weight loss, a common side effect of interferon, which was a component of all HCV antiviral regimens prior to 2014.
It is unclear whether HCV eradication achieved by interferon-free, direct-acting antiviral (DAA) regimens results in improvement in glycemic control of patients with T2DM. The aim of this study is to compare patients with diabetes who achieve SVR with those who do not with respect to glycemic control as assessed by changes in hemoglobin A1c (HbA1c) levels and use of medications for treatment of diabetes before and after antiviral treatment with DAA agents.
Results
Baseline Characteristics
Among 2,435 patients with diabetes who were infected with HCV and were treated with interferon-free and ribavirin-free regimens, the average age was 62.2 years; the average BMI was 30.2 kg/m2; and the vast majority were male (97.5%), had genotype 1 HCV (99.3%), and were treated with LDV/SOF (56.2%) or SMV plus SOF (38.3%) (Table 1). The most common racial/ethnic group was non-Hispanic black (43.6%) followed by non-Hispanic white (38.3%) and Hispanic (5.4%). Cirrhosis (37.3%) and even decompensated cirrhosis (10.4%) were common, with 75.2% of patients receiving at least one antidiabetic medication and 42.2% of patients receiving insulin.
Compared with patients for whom treatment failed, those who achieved SVR were less likely to have cirrhosis (35.3% vs. 54.5%) and decompensated cirrhosis (9.3% vs. 20%) and were less likely to be receiving antidiabetic medications (74.8% vs. 78.0%) or insulin (41.3% vs. 49.8%). There were notable differences in albumin levels, INR, bilirubin, platelet count, and FIB-4 scores between the two groups (Table 1), with the treatment failure group displaying markers of more severe liver disease. Patients who achieved SVR were more likely to be treated with LDV/SOF and less likely to be treated with SMV plus SOF than patients for whom treatment failed.
Change in HbA1c Associated With SVR
Pretreatment HbA1c level was similar in patients who achieved SVR (7.20% [55 mmol/mol]) and those who did not (7.27% [56 mmol/mol]). The drop in average HbA1c level after treatment was greater in those achieving SVR, (from 7.2% [55 mmol/mol] to 6.82% [51 mmol/mol], a mean drop of 0.37 ± 1.2%) than in those for whom treatment failed (from 7.27% [56 mmol/mol] to 7.08% [54 mmol/mol], a mean drop of 0.19 ± 1.3%), yielding a mean difference (0.37% minus 0.19%) of -0.18% (P = 0.03). After adjusting for all the baseline characteristics listed in Table 2, the adjusted mean difference (AMD) in the HbA1c drop between the SVR and treatment failure groups was 0.13 (P = 0.1).
The drop in HbA1c level associated with SVR was restricted to patients with a high baseline HbA1c level. Among patients with a pretreatment mean HbA1c of >7.2% (55 mmol/mol; the mean pretreatment HbA1c level in our study population), the decrease in mean HbA1c level was significantly greater in the SVR group (0.98 ± 1.4%) compared with the no-SVR group (0.65 ± 1.5%), with an AMD of 0.34 (P = 0.02) (Table 2). Among patients with HbA1c ≤7.2% (55 mmol/mol), there was no significant difference between patients with and without SVR in the change in HbA1c level. Also the significant drop in HbA1c level associated with SVR was restricted to patients without cirrhosis and not to patients with cirrhosis (Table 2).
Change in Antidiabetic Medication Use Associated With SVR
The baseline number of classes of antidiabetic medications pretreatment was similar in the group that achieved SVR (1.15 ± 0.9) and the group that did not (1.16 ± 0.9). The number of classes of antidiabetic medications decreased slightly after antiviral treatment, more so in the patients who achieved SVR than in those who did not, but this difference was not statistically significant (Table 3). Also, the proportion of patients who were receiving treatment with antidiabetic drugs decreased slightly more in patients who achieved SVR than in those who did not, but this difference was not statistically significant.
The proportion of patients receiving treatment with insulin decreased more significantly in patients who achieved SVR (from 41.3% to 38%) than in patients who did not (who actually had a slight increase in the proportion of patients receiving treatment with insulin from 49.8% to 51.0%; AMD -4.2%; P = 0.04) (Table 3). This reduction in insulin use in patients achieving SVR compared with patients in whom treatment failed was more profound among patients with a low pretreatment HbA1c level of ≤7.2% (55 mmol/mol). Also the reduction in insulin use in patients achieving SVR was not associated with a concomitant increase in the use of metformin (i.e., it was not caused by the substitution of metformin for insulin in patients with improved liver function after SVR, who prior to treatment were felt to be ineligible for treatment with metformin). In fact, use of metformin also decreased from before to after antiviral treatment by 2.2% in patients achieving SVR and by 1.9% in patients for whom treatment failed.
Impact of Changes in Body Weight, Hemoglobin Concentration, and Serum Creatinine Level on the Drop in HbA1c Associated With SVR
Comparing the post-treatment to pretreatment periods, weight increased slightly more in patients with SVR than in those for whom treatment failed (Table 4). Hemoglobin concentration decreased significantly more in patients for whom treatment failed than in patients who achieved SVR. Serum creatinine level increased slightly and equally in patients who did and did not achieve SVR. When additionally adjusting for changes in weight, hemoglobin concentration, and serum creatinine level, the associations between SVR and HbA1c drop or antidiabetic medication use were essentially unchanged.
Conclusions
Our results suggest that the eradication of HCV with DAA therapy leads to improved glycemic control in patients with T2DM. HbA1c values decreased and the proportion of patients receiving insulin decreased in patients who achieved SVR compared with those for whom treatment failed. Patients with poorer glycemic control at baseline who had a higher pretreatment HbA1c level had an even greater improvement, nearly a 1% drop in the HbA1c, associated with SVR.
In the U.S., an estimated 9.8% of the population, or 29.1 million people, have diabetes, and 1.4% of the population, or 3.5 million people, have HCV (36,37). T2DM is nearly four times more likely to develop in patients with HCV than in patients without HCV (38). Thus, the treatment of HCV has the potential to impact a remarkable proportion of the population not only with respect to liver disease but also diabetes control.
Eradication of HCV has been shown to reduce the risk of hepatocellular carcinoma, to improve liver fibrosis, and to decrease the risk of other complications of chronic liver disease (39). However, the effects of HCV eradication on the extrahepatic manifestations of HCV have not been well studied in the new era of DAAs. Our study supports the idea that HCV eradication leads to a reduction in HbA1c in patients with diabetes. It is well established that the microvascular complications of diabetes, including nephropathy, neuropathy, and retinopathy, improve with lowered HbA1c level (40,41). Therefore, early treatment of HCV could potentially slow the onset and progression of microvascular diabetes complications. Given the study period, we were unable to evaluate whether improved glycemic control was durable beyond the 15-month period after antiviral treatment and whether the effects subsequently lead to reductions in the long-term risk of diabetic complications since interferon-free DAA regimens have only been available since 2014.
It is important to note that the lowering of HbA1c levels represents only one mechanism by which HCV eradication could potentially influence cardiovascular risk. HCV infection also causes the development of circulating low-density immune complexes that induce an inflammatory response (42), which could improve after HCV eradication. On the other hand, a virologic cure has been shown to result in increases in serum cholesterol and LDL cholesterol levels (43,44), which may aggravate early atherosclerotic lesions and increase cardiovascular risk. Thus, the net effect of HCV eradication on long-term cardiovascular risk remains to be determined.
Prior studies (45) have demonstrated an association between central adiposity related to T2DM and hepatic steatosis. The decrease in HbA1c level achieved by medications such as thiazolidinediones or glucagon-like peptide 1 receptor agonists in patients with diabetes has been shown to improve hepatic fat content (46). As our study has shown an improvement in HbA1c levels with the successful eradication of HCV, treatment may also improve hepatic steatosis, which frequently accompanies HCV-related liver disease.
Recent studies (47) have even shown that patients with compensated HCV cirrhosis have higher rates of decompensation when they have diabetes and IR and that IR was a predictor of overall mortality. Thus, it is tempting to speculate that HCV eradication might prevent the development of decompensated cirrhosis not only by the elimination of the fibrotic and hepatotoxic effects of HCV, but also by reducing HbA1c levels and improving IR in patients with T2DM, but future long-term studies are necessary to demonstrate this.
We reported that DAA-induced SVR was associated with a nonsignificant decrease in the proportion of patients with diabetes who were receiving antidiabetic medications and in the number of classes of antidiabetic medications and a significant decrease in the proportion of patients receiving insulin. The elimination of insulin after SVR was achieved was more common in patients who had relatively well-controlled diabetes at baseline (HbA1c ≤7.2%) than in those with a baseline HbA1c level of >7.2%. This de-escalation of insulin is clinically relevant as it can be a cumbersome medication for patients to administer, can lead to hypoglycemic episodes if administered incorrectly, and is a frequent reason for medication noncompliance. Providers should be aware that glycemic control could improve after DAA-induced SVR and should be closely monitored for the need to remove insulin from therapy.
Antidiabetic medications, in particular insulin and sulfonylureas, have been implicated in increasing the risk of hepatocellular carcinoma, because the medications effectively increase the serum levels of insulin, a growth-promoting hormone (48-50). Therefore, it is possible that the decrease in insulin use after successful treatment with DAAs may also have antihepatocarcinogenic effects.
One limitation of our study is that we are unable to assess whether patients received additional medications outside the VA system. Previous studies (51) showed that patients who are enrolled and actively engaged in the VA health care system receive almost all their medications from the VA system. Although we adjusted for a large number of potential confounders, it is impossible to exclude the possibility that the drop in HbA1c level that we observed in association with SVR was related to unmeasured confounding. For example, lifestyle changes such as better eating habits and exercise can also change the HbA1c level and may also be associated with SVR, but these were not measured in this study.
In summary, glycemic control improves in patients with diabetes after DAA-induced SVR. Patients not only have an improvement in HbA1clevel after achieving SVR, they are also less likely to require insulin. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes. Future studies are needed to confirm our findings, to determine how durable the SVR-induced improvement in glycemic control is over time, and to assess the long-term effect on complications of diabetes such as nephropathy, neuropathy, and cardiovascular disease.
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