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2013

AOPXXX10.1177/1060028013503108Annals of PharmacotherapyHarris and Smith

Review Article-Emergency Medicine-Drug Information Rounds

Safety and Efficacy of Metformin in Patients With Type 2 Diabetes Mellitus and Chronic Hepatitis C

Annals of Pharmacotherapy 47(10) 1348­–1352 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013503108 aop.sagepub.com

Kira Harris, PharmD, BCPS1, and Lisa Smith, PharmD, BCPS1

Abstract Objective: To evaluate the safety and efficacy of metformin in patients with type 2 diabetes mellitus (T2DM) and chronic hepatitis C virus (HCV) with or without cirrhosis and hepatocellular carcinoma (HCC). Data Sources: A PubMed (1946-August 2013) search using the keywords type 2 diabetes mellitus, metformin, hepatitis C virus, cirrhosis, and hepatocellular carcinoma was conducted. The references in published articles were reviewed to identify additional references for inclusion. Study Selection and Data Extraction: Studies written in English, evaluating metformin use in human patients with T2DM and chronic HCV were included. Data Synthesis: Eight studies met criteria for inclusion. Two prospective, randomized controlled trials showed increased benefit with metformin on virological response in patients with insulin resistance receiving HCV treatment. A prospective observational study evaluated metformin exclusively in patients with T2DM and HCV and showed significant reductions in the occurrence of HCC, liver-related death, and liver transplant. Four retrospective case control studies showed a decreased risk of HCC with metformin treatment in patients with T2DM and chronic liver disease. Finally, a retrospective cohort study indicated an increased survival rate in patients with diabetes and HCC undergoing radiofrequency ablation. Although diarrhea was increased in patients receiving metformin, no serious adverse effects, including lactic acidosis, were reported. Conclusions: Metformin may provide benefit in the treatment of HCV and in reducing the risk of HCC in patients with T2DM and HCV. Further long-term, randomized controlled trials are needed to adequately assess the safety and efficacy of metformin therapy in patients with comorbid diabetes and chronic HCV. Keywords metformin, type 2 diabetes mellitus, chronic hepatitis C virus Received 6 August 2013

Request What are the safety and potential benefits of metformin in patients with type 2 diabetes mellitus (T2DM) with coexisting chronic hepatitis C?

Response Background Metformin is recommended as a first-line treatment option by both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE).1,2 Although evidence for the use of metformin in the treatment of T2DM is strong, it carries a warning for use in patients with hepatic disease because of an increased risk of lactic acidosis.3 Recent

diabetes treatment guidelines stress the importance of individualizing treatment plans based on patient-specific parameters.1,2 Therefore, the use of metformin in the presence of hepatitis C virus (HCV) infection was examined. Chronic HCV is a metabolic disease that increases HCVrelated insulin resistance (IR) in patients with T2DM and in approximately 35% of patients without T2DM. The mechanisms include free-fatty-acid accumulation, resulting in excess very-low-density lipoprotein cholesterol production by the liver. Increased tumor necrosis factor–α and 1

Wingate University School of Pharmacy, Wingate, NC, USA

Corresponding Author: Kira Harris, Wingate University School of Pharmacy, PO Box 159, 515 N Main St Wingate, NC 28174, USA.

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Harris and Smith Table 1.  Summary of Prospective Trials Evaluating Metformin Use in Patients With Chronic HCV and T2DM or IR. Citation

Patients (n) 9

Duration

Patient Population

Interventions

Genotype 1 chronic HCV and IR undergoing HCV treatment Genotype 1 chronic HCV and IR undergoing HCV treatment T2DM and compensated HCV cirrhosis

Metformin 500 mg TID/Placebo

SVR

59.2%/38.8% (p = .043)

Metformin 850 mg TID/Placebo

SVR

52.5%/42.2% (p = NS)

Metformin (dose varied)/ No metformin therapy

HCC diagnosis

9.5%/31.2% (p = .001)

Yu et al (2012)

98

72 weeks

Romero-Gomez et al (2009)11

123

72 weeks

Nkontchou et al (2011)12

100

5 years

Primary Outcome

Results

Abbreviations: HCV, hepatitis C virus; T2DM, type 2 diabetes mellitus; IR, insulin resistance; TID, three times daily; SVR, sustained virological response; HCC, hepatocellular carcinoma.

interleukin-6 are inflammatory mediators that increase hepatocyte inflammation.4,5 In addition to obesity, nonalcoholic fatty liver disease, and T2DM, IR can reduce response to chronic HCV treatment, increase risk for cirrhosis, and increase risk for the development of hepatocellular carcinoma (HCC) or recurrence of HCC.6,7 Ways to reduce HCV IR include treatment with pegylated interferon and ribavirin, which reduces hepatic inflammation. Metformin may improve the efficacy of chronic HCV treatment and prevent HCC development and recurrence by improving HCV IR.8,9 Despite the potential for improvement in T2DM and HCV IR, drug information sources warn that metformin should be avoided in patients with impaired liver function,3 making its appropriateness uncertain. The postulated theory for concern is that liver dysfunction is a hypoxic state, which increases the risk for lactic acidosis. However, the risk has never been quantified, and only minimal case reports are found in the literature.10 If metformin improves HCV IR, slows the progression of liver dysfunction, potentially increases the sustained virological response (SVR) rate of chronic HCV treatment, and reduces the risk for HCC and recurrence of HCC, it would be a desirable option for patients with T2DM and chronic HCV with or without cirrhosis and HCC. This article summarizes the efficacy and safety profiles of metformin in patients with T2DM and chronic HCV with or without cirrhosis and HCC.

Literature Review Following a literature search and evaluation, 8 trials were included in this review. Three prospective trials—2 evaluating the effect of metformin on SVR when given in conjunction with HCV therapy and 1 evaluating the effect of metformin on the incidence of HCC—are summarized in Table 1. Table 2 provides a summary of retrospective studies examining metformin and its effect on HCC incidence as

well as its effect on mortality in patients with previously diagnosed HCC undergoing radiofrequency ablation (RFA). The effect of metformin on SVR in patients with chronic HCV and IR (as defined by HOMA index >2) receiving HCV treatment with peginterferon and ribavirin has been studied in 2 prospective, placebo-controlled, randomized trials.9,11 All participants had genotype-1 HCV with detectable HCV RNA levels but without liver cirrhosis or HCC and had not previously received antiviral treatment. Those in the treatment groups received metformin 500 to 850 mg 3 times daily in addition to HCV treatment for 48 weeks and were then followed for an additional 24 weeks. In both studies, metformin treatment resulted in an improvement in SVR of 10% to 20% compared with placebo, but only in 1 study did it reach statistical significance, at 72 weeks. IR, as measured by the HOMA index, was significantly reduced by metformin treatment when compared with placebo in both trials starting at week 12 and continuing through week 72. Although diarrhea was significantly more common in those receiving metformin (14%-36% vs 5%-11%) compared with placebo, it was mild and well tolerated. No serious adverse effects requiring treatment discontinuation, lactic acidosis, or hyperlactemia occurred in either study.9,11 The results of this study suggest that metformin may be used safely in patients with chronic HCV and may provide benefit in virological response. The application of this study is limited because patients with diagnosed diabetes were excluded, but there is some suggestion that IR was improved, which would also benefit patients with T2DM. The studies also did not address the safety of metformin therapy in patients with preexisting cirrhosis or HCC or the long-term safety of metformin therapy in patients with diabetes and HCV. One prospective, observational study evaluated the effect of metformin on the development of HCC in 100 patients with T2DM and compensated HCV cirrhosis. Although the criteria for compensated HCV cirrhosis were not provided, the baseline characteristics revealed that most patients had

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Table 2.  Summary of Retrospective Trials Evaluating Metformin Use in Patients With Chronic Liver Disease and T2DM. Citation

Study Design

Patients (n) Patient Population

8

Lai et al (2012) Population-based 96 745 cohort study Donadon et al (2010)13

Retrospective case-control study

1573

Donadon et al (2009)14

Retrospective case-control study

1573

Donadon et al (2010)15

Retrospective case-control study

2924

Chen et al (2011)16

Retrospective cohort study

135

Study Groups (n)

Primary Outcome

Patients in the Patients with T2DM Incidence of Taiwan National (19 349)/Patients HCC (per 10 Health Insurance without T2DM (77 000 personProgram 396) years) Patients admitted HCC (465)/Liver Prevalence of to Pordenone cirrhosis (618)/ T2DM General Hospital Control group (490) Patients admitted HCC (465)/Liver Prevalence of to Pordenone cirrhosis (618)/ T2DM General Hospital Control group (490) Patients admitted HCC (610)/Liver Prevalence of to Pordenone cirrhosis (618)/ T2DM General Hospital Control group (1696) Patients with Patients with 5-Year survival HCC undergoing T2DM (53)/With rate radiofrequency metformin (21)/ ablation Without metformin (32)/Patients without T2DM (82)

Results 21/10.4; HR = 2.03

31.2% (OR = 2.5 vs control)/ 23.3%/12.6% 31.2% (OR = 3.1 vs control)/ 23.3% (OR = 2.1 vs control)/ 12.6% 31.2% (OR = 3.1 vs control) /23.3%/12.6% 41.3%/60.5%/26.2%/64.7%

Abbreviations: T2DM, type 2 diabetes mellitus; HCC, hepatocellular carcinoma; HR, hazard ratio; OR, odds ratio; HCV, hepatitis C virus

liver enzyme levels between 1 and 3 times the upper limit of normal. Diabetes therapy was managed by an independent practitioner and consisted of diet alone for 29 participants, metformin monotherapy for 23, metformin plus insulin for 2, insulin secretagogues for 17, and insulin therapy for 28. The presence of metformin in the participants’ treatment regimens remained consistent throughout the trial. Over a median follow-up of 5 years, HCC confirmed by histology or noninvasive criteria occurred in 9.5% of those treated with metformin and 31.2% of those not treated with metformin (p = .001). In addition, liver-related death or liver transplant occurred significantly less in patients treated with metformin compared with those not treated with metformin (5.9% vs 17.4%, respectively; p = .013). Of note, the incidence of HCC, liver-related death, and liver transplant was similar between patients treated with diet alone and with insulin or insulin secretagogues. No adverse effects, including lactic acidosis, were observed in patients receiving metformin therapy.12 This study suggests that not only is it likely that metformin is safe, but it also may improve outcomes and prevent progression of cirrhosis to HCC in patients with T2DM and chronic HCV as long as liver enzymes are below 3 times the upper limit of normal. The results of this study should be considered with caution given the limitations of its observational nature. Adverse effects may be deceptively low because patients were previously tolerating therapy prior to study enrollment. A randomized controlled trial

would provide additional information related to safety and efficacy in this population. A 5-year retrospective cohort study using insurance claims data was conducted in Taiwan to determine the risk of developing HCC associated with T2DM. The association of comorbidities, including HCV and hepatitis B virus, as well as antihyperglycemic agents with the incidence of HCC was also examined. Prestudy antihyperglycemic agents were continued throughout the study. The results showed an increased risk in HCC for patients with comorbid T2DM and HCV (hazard ratio [HR] = 15.2; 95% CI = 8.35-27.8) compared with patients without either diagnosis; however, the percentage of patients with both conditions was extremely small (1.7%). Of the 19 349 patients with diabetes, 16 094 received metformin for a mean duration of 2.5 years, and 3835 used a thiazolidinedione for a mean duration of 1.3 years. Patients receiving metformin and thiazolidinediones had a decreased incidence of HCC (HR = 0.49, CI = 0.37-0.66, and HR = 0.56, CI = 0.37-0.84, respectively) compared with patients not receiving these medications. Other antihyperglycemic agents, including sulfonylureas, insulin, and α-glucosidase inhibitors, showed no significant difference in HCC risk. Although this study did include a large sample with a longer duration of metformin therapy and suggests a benefit for metformin therapy in the development of HCC, it did not include many patients with coexisting T2DM and chronic HCV.8

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Harris and Smith Three retrospective case-control studies conducted in 1 hospital in Italy examined the relationship between T2DM and antihyperglycemic agents and the development of HCC.13-15 Each enrolled between 1576 and 2924 patients and compared 3 study groups: patients with HCC, patients with liver cirrhosis, and control patients without liver disease. T2DM was present in 31.2% of patients with HCC, 23.2% of patients with liver cirrhosis, and 12.6% of control patients. HCV infection was present in 39.1% to 57.6% of patients with HCC, 38.9% to 46.1% of patients with cirrhosis, and 5.3% of patients in the control group. In all 3 studies, a higher incidence of HCC was found in patients with T2DM, HCV, and both. In 1 study, metformin use was present in 9% of patients with HCC, 27.1% of patients with liver cirrhosis, and 24.2% of control patients. When compared with both the control group and the liver cirrhosis group, metformin was associated with a significantly lower odds ratio (OR) for HCC (OR = 0.149, Pp = .0054, and OR = 0.163, p = .0006, respectively) when compared with sulfonylureas. Specific ORs of HCC are not reported but were also significantly reduced with metformin when compared with insulin.13 Two of these studies examined the effects of antihyperglycemic agents more closely. In these, metformin use was present in 9.5% to 15.9% of patients with HCC, 40.2% to 70.7% of patients with liver cirrhosis, and 24.6% to 31.2% of control patients. Sulfonylurea therapy was present in 51% to 84.1% of patients with HCC, 16.8% to 29.3% of patients with liver cirrhosis, and 53% to 68.8% of control patients. Finally, insulin therapy was present in 39.5% of patients with HCC, 43% of patients with liver cirrhosis, and 20.9% to 22.4% of control patients. The mean duration of insulin therapy was 83 months, whereas that of oral antihyperglycemic agents was 125 months. In both studies, insulin or sulfonylurea therapy was found to have an OR of 2.99 to 3.06 (p = .007 and p = .005) for HCC, whereas metformin was found to have an OR of 0.33 (p = .006 and p = .0005) for HCC when compared with controls.14,15 Although the results from these studies again suggest a potential benefit of metformin therapy in reducing the risk of HCC, the retrospective nature allows only an association to be established. In addition, these studies selfselect for patients tolerating metformin therapy because patients had been receiving therapy prior to study enrollment; therefore, safety cannot be as readily evaluated. These studies do include a larger population of patients with both T2DM and HCV and a longer duration of metformin therapy, but it is difficult to determine the number of patients with both conditions and receiving metformin therapy. A retrospective cohort study examined the effect of metformin on mortality in 135 patients with early-stage HCC undergoing RFA. T2DM was present in 39.3% of patients, of whom 39.6% were receiving metformin therapy. Among patients with T2DM and receiving metformin therapy, 52.4% were also infected with HCV. In patients with T2DM,

metformin was associated with a significant decrease in mortality (HR = 0.24; p = .02) and tumor recurrence (p = .45). In a dose-response analysis, there was no difference seen in low- (750 mg/d) metformin. There were no significant side effects of metformin therapy noted, including hypoglycemia or lactic acidosis. There was no significant difference seen in mortality or tumor recurrence with insulin or sulfonylurea therapy.16 This study provided a larger sample of patients with both T2DM and chronic HCV who were receiving metformin therapy and provided additional information regarding metformin safety in this population. The results do continue to support the use of metformin therapy for improved outcomes in patients with preexisting HCC and T2DM; however, it is a small, retrospective study which may limit its application.

Summary HCV is becoming increasingly associated with IR and development of T2DM. In addition, it appears that the presence of both HCV and T2DM may significantly increase the risk of developing liver cirrhosis and HCC.8,9,13-15 In light of these risks, it is important to determine the most appropriate treatment for these patients. Because metformin is recommended as first-line therapy for patients with diabetes and may improve IR, it should be considered a viable option; however, current recommendations advise caution when using metformin because of the risk of lactic acidosis. Metformin may provide additional benefits in patients with coexisting HCV, including improved virological response in patients undergoing HCV treatment; reduced HCC risk in patients with T2DM and chronic liver disease, including HCV; and improved mortality in patients with diabetes and HCC undergoing RFA. Other antihyperglycemic agents, including insulin and sulfonylureas, have not shown similar benefits. In all studies, there were no serious adverse events reported, including lactic acidosis. Although more prospective, randomized controlled trials are needed to confirm safety and efficacy, it is reasonable to conclude that metformin will remain a first-line option for patients with T2DM and chronic compensated HCV, especially those with compensated liver cirrhosis or those with HCC undergoing RFA. As always, patients should be monitored for increased diarrhea and lactic acidosis. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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References 1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2013;36:S11-S66. 2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19:327-336. 3. Lexi-Drugs Online [Internet Database]. Metformin. Hudson, OH: Lexi-Comp. https://online.lexi.com/lco/action/doc/ retrieve/docid/patch_f/7260 4. Serfaty L, Capeau J. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver Int. 2009;29(suppl 2):13-25. 5. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987-1000. 6. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444. 7. Popov VB, Lim JK. Impact of insulin-sensitizing agents on risk for liver cancer and liver-related death in diabetic patients with compensated hepatitits C cirrhosis. J Clin Endocrinol Metab. 2011;96:2398-2400. 8. Lai SW, Chen PC, Liao KF, et al. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population based cohort study. Am J Gastroenterol. 2012;107:46-52.

9. Yu JW, Sun LJ, Zhao YH, et al. The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance. Int J Infect Dis. 2013;16:e436-e441. 10. Brackett CC. Clarifying metformin’s role and risks in liver dysfunction. J Am Pharm Assoc. 2010;50:407-410. 11. Romero-Gomez M, Diago M, Andrade RJ, et al. Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin. Hepatology. 2009;50:1702-1708. 12. Nkontchou G, Cosson E, Aout M, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011;96:2601-2608. 13. Donadon V, Balbi M, Valent F, Avogaro A. Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma. World J Gastroenterol. 2010;16:3025-3032. 14. Donadon V, Balbi M, Ghersetti M, et al. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol. 2009;15:2506-2511. 15. Donadon V, Balbi M, Dal Mas M, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int. 2010;30:750-758. 16. Chen T, Lin C, Huang P, Wen C. Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. Hepatology. 2011;26:858-865.

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Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C.

To evaluate the safety and efficacy of metformin in patients with type 2 diabetes mellitus (T2DM) and chronic hepatitis C virus (HCV) with or without ...
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