Continuation of Metformin Use After a Diagnosis of Cirrhosis Significantly Improves Survival of Patients With Diabetes
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LIVER FAILURE/CIRRHOSIS/PORTAL HYPERTENSION Continuation of Metformin Use After a Diagnosis of Cirrhosis Significantly Improves Survival of Patients With Diabetes Xiaodan Zhang,1 William S. Harmsen,2 Teresa A. Mettler,1 W. Ray Kim,1 Rosebud O. Roberts,3 Terry M. Therneau,2 Lewis R. Roberts,1 and Roongruedee Chaiteerakij1,4 The risks and benefits of metformin use in patients with cirrhosis with diabetes are debated. Although data on a protective effect of metformin against liver cancer develop- ment have been reported, metformin is frequently discontinued once cirrhosis is diagnosed because of concerns about an increased risk of adverse effects of metformin in patients with liver impairment. This study investigated whether continuation of metformin after cir- rhosis diagnosis improves survival of patients with diabetes. Diabetic patients diagnosed with cirrhosis between 2000 and 2010 who were on metformin at the time of cirrhosis diagnosis were identified (n 5 250). Data were retrospectively abstracted from the medical record. Survival of patients who continued versus discontinued metformin after cirrhosis diagnosis was compared using the log-rank test. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using Cox’s proportional hazards analysis. Overall, 172 patients continued metformin whereas 78 discontinued metformin. Patients who continued metformin had a significantly longer median survival than those who discontinued metfor- min (11.8 vs. 5.6 years overall, P < 0.0001; 11.8 vs. 6.0 years for Child A patients, P 5 0.006; and 7.7 vs. 3.5 years for Child B/C patients, P 5 0.04, respectively). After adjusting for other variables, continuation of metformin remained an independent predictor of bet- ter survival, with an HR of 0.43 (95% CI: 0.24-0.78; P 5 0.005). No patients developed metformin-associated lactic acidosis during follow-up. Conclusion: Continuation of metfor- min after cirrhosis diagnosis reduced the risk of death by 57%. Metformin should there- fore be continued in diabetic patients with cirrhosis if there is no specific contraindication. (HEPATOLOGY 2014;60:2008-2016) See Editorial on Page 1818 leading cause of mortality both in the United States and globally.1,2 The prevalence of type 2 diabetes in patients with cirrhosis has been reported as 37%, five times greater than in those without cirrhosis.3 Patients with C irrhosis is responsible for over 29,000 deaths annually in the United States and 1 million cirrhosis with diabetes have a greater risk of liver-related deaths annually worldwide, making it the 12th complications and death than patients with cirrhosis Abbreviations: AFP, alpha-fetoprotein; ALD, alcoholic liver disease; ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; CLD, chronic liver disease; HbA1c, glycated hemoglobin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; INR, inter- national normalized ratio; MELD, model for end-stage liver disease; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PH, portal hypertension; PT, prothrombin time; SD, standard deviation. From the 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN; 2Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN; 3Division of Epidemiology, Depart- ment of Health Sciences Research, Mayo Clinic College of Medicine, and Mayo Clinic Cancer Center, Rochester, MN; and 4Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. Received January 24, 2014; accepted April 29, 2014. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.27199/suppinfo. This work was supported by National Institutes of Health (NIH; grant nos.: CA128633 and CA165076; to L.R.R.), the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567), the Mayo Clinic Cancer Center (CA15083), and the Mayo Clinic Center for Clinical and Translational Science (NIH/NCRR CTSA grant no.: UL1 TR000135). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. 2008
HEPATOLOGY, Vol. 60, No. 6, 2014 ZHANG ET AL. 2009 without diabetes.4-9 Similarly, the risk of death from cir- Given the potential beneficial effects of metformin rhosis among diabetic patients was greater than in the on liver inflammation and carcinogenesis, we hypothe- general population, with a standardized mortality ratio sized that continuation of metformin use after the of 2.5, which is even higher than the mortality ratio of diagnosis of cirrhosis would improve the survival out- 1.3 conferred by cardiovascular disease in patients with come of diabetic patients. The primary aim of our diabetes.10 Therefore, it is important to improve study was to assess the survival difference between dia- cirrhosis-related mortality in diabetic patients. betic patients who continued taking metformin versus Metformin, a commonly prescribed oral hypoglyce- those who discontinued metformin after cirrhosis diag- mic agent, has a protective effect against cancer devel- nosis. We also investigated other factors determining opment and cancer mortality in type 2 diabetic survival outcomes in patients with cirrhosis with patients.11-13 Metformin use was associated with a diabetes. decreased risk of hepatocellular carcinoma (HCC) development in diabetic patients with chronic liver dis- ease (CLD).14 Metformin was also independently asso- Patients and Methods ciated with a reduction in HCC incidence and liver- Patients. All diabetic patients diagnosed with cir- related death in patients with type 2 diabetes and hep- rhosis between January 1, 2000 and December 31, atitis C virus (HCV)-induced cirrhosis.15 2010 and who were on metformin at cirrhosis diagno- Nonalcoholic fatty liver disease (NAFLD) appears sis were included in this study (n 5 250). Patients to partially mediate an increased risk of liver-related were categorized into two groups, that is, (1) those death among patients with diabetes. The presence of who continued metformin after cirrhosis diagnosis and NAFLD increased deaths in diabetic patients, with a (2) those who discontinued metformin after cirrhosis hazard ratio (HR) of 2.2, with 19% of deaths being diagnosis. Continuation of metformin use was defined liver related.16 Metformin prevented and reversed stea- as taking metformin for at least 3 months after cirrho- tosis and inflammation in a nondiabetic mouse model sis diagnosis, and discontinuation of metformin use of nonalcoholic steatohepatitis (NASH)17 and was defined as cessation of metformin within a 3- improved liver histology and alanine aminotransferase month period after the diagnosis of cirrhosis. The 3- (ALT) levels in patients with NASH.18,19 month period was arbitrarily chosen as a cutoff to Because of theoretical concerns about the increased allow time for health care providers to decide whether risk of lactic acidosis in diabetic patients with CLD, to continue or discontinue metformin. Metformin was many clinicians are reluctant to prescribe metformin typically discontinued within this time frame after cir- for diabetic patients with CLD and some recommend rhosis diagnosis in our cohort. discontinuation of metformin after the diagnosis of The diagnosis of cirrhosis was ascertained by histol- cirrhosis. However, the evidence that metformin indu- ogy (n 5 124) and/or by clinical features, namely, ces liver injury is weak.20 The incidence of lactic aci- portal hypertension (PH), morphologic characteristics dosis in diabetic patients treated with metformin is consistent with cirrhosis in cross-sectional radiologic low, with approximately 0.03-0.5 cases per 1,000 images (small-sized nodular liver 6 caudate lobe patient-years, and the incidence of lactic acidosis hypertrophy as well as PH indicated by the presence among diabetic patients who take metformin does not of collateral vessels, varices, and/or splenomegaly), differ from the incidence in diabetic patients not and/or thrombocytopenia (platelet count 6.5% or random glucose of 200 mg/dL with pres- tion with cirrhosis and diabetes. ence of symptoms). Exclusion criteria were as follows: Address reprint requests to: Lewis R. Roberts, M.B., Ch.B., Ph.D., Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail: firstname.lastname@example.org; fax: 507-284-0762. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27199 Potential conflict of interest: Nothing to report.
2010 ZHANG ET AL. HEPATOLOGY, December 2014 (1) a history of malignancy except for nonmelanoma Variables with P < 0.1 in the univariate model were skin cancer at cirrhosis diagnosis; (2) incomplete clini- included in the multivariate model. MELD score was cal information; (3) age
HEPATOLOGY, Vol. 60, No. 6, 2014 ZHANG ET AL. 2011 Table 1. Characteristics of Patients With Cirrhosis With Diabetes Variables Continued Metformin (n 5 172) Discontinued Metformin (n 5 78) P Value Age,* years 61.7 6 9.8 60.2 6 9.9 0.24 (range) (38-87) (36-81) Male, n (%) 100 (58.1) 42 (53.9) 0.52 Race, n (%) 0.96 White 150 (87.2) 69 (88.5) Nonwhite 17 (9.9) 8 (10.2) Unknown 5 (2.9) 1 (1.3) BMI, kg/m2† 34.3 (20.7-63.5) 34.8 (20.1-72.7) 0.55 Obesity, n (%) 112 (65.1) 54 (69.2) 0.56 Etiology of cirrhosis, n (%) 0.80 HBV 6 (3.5) 0 HCV 16 (9.3) 14 (18.0) ALD 19 (11.0) 10 (12.8) NASH 98 (57.0) 44 (56.4) Others 8 (4.7) 6 (7.7) Unknown 25 (14.5) 4 (5.1) MELD score* 8.9 6 3.0 10.6 6 4.4
2012 ZHANG ET AL. HEPATOLOGY, December 2014 Fig. 2. Survival of Child-Pugh class A (n 5 181) (A) and Child- Fig. 3. Survival of 142 patients with NASH-related cirrhosis (A) and Pugh class B/C (n 5 66) (B) patients with cirrhosis with diabetes 108 with non-NASH-related cirrhosis (B) who continued metformin ver- who continued metformin versus those who discontinued metformin. sus those who discontinued metformin. the benefit of continuation of metformin, we com- 30; 7.7 vs. 3.5 years; P 5 0.04) with an HR of 0.46 pared the survival of the diabetic patients who contin- (95% CI: 0.21-0.98; P 5 0.04; Fig. 2B). ued (n 5 121) versus discontinued metformin (n 5 When patients were categorized based on the etiol- 129) 1 year after cirrhosis diagnosis. The median sur- ogy of cirrhosis, the beneficial effect of metformin on vival of the patients who continued metformin survival was observed only in the NASH-related cir- remained significantly greater than that of the patients rhosis group. The median survival of patients with who discontinued metformin within 1 year after cir- NASH-related cirrhosis who continued metformin (n rhosis diagnosis (11.8 vs. 6.0 years; P < 0.0001; Sup- 5 98) versus discontinued metformin (n 5 44) was porting Fig. 2). 12.1 versus 5.1 years (P 5 0.0004) with an HR of The benefit of continuation of metformin on sur- 0.33 (95% CI: 0.17-0.63; P < 0.0001; Fig. 3A). Sur- vival was found regardless of severity of cirrhosis, as vival of those who continued versus those who discon- defined by Child-Pugh classification. Of the 181 Child tinued metformin was not statistically different in the A patients with cirrhosis, those who continued metfor- alcohol-, HCV-, and HBV-related cirrhosis groups, min (n 5 133) had a significantly greater median sur- likely a result of the small number of patients in each vival than those who discontinued metformin (n 5 group (29, 30, and 6 patients, respectively). Thus, to 48; 11.8 vs. 6.0 years; P 5 0.006) with an HR of obtain a larger number, we combined patients with death of 0.47 (95% CI: 0.27-0.82; P 5 0.009; Fig. cirrhosis from alcohol, HCV, HBV, other, and 2A). Similarly, in a pooled analysis, Child B (n 5 61) unknown etiologies into a non-NASH cirrhosis group and C (n 5 5) patients with cirrhosis who continued (n 5 108); no significant difference was observed in metformin (n 5 36) had a significantly greater median survival between the continued metformin and discon- survival than those who discontinued metformin (n 5 tinued metformin subgroups (Fig. 3B).
HEPATOLOGY, Vol. 60, No. 6, 2014 ZHANG ET AL. 2013 Eighty-one patients (43 of 172 [25%] in the contin- 1.07-1.18; P < 0.0001; Table 2). Given that the infor- ued metformin group and 38 of 78 [49%] in the dis- mation on AFP value was missing in 52 of 250 continued group) died during a median follow-up time (20.8%) patients, we also performed another multivar- of 5.2 years (range, 0.6-14.6). The median durations of iate analysis excluding the AFP value, and the primary follow-up were 4.8 (range, 0.6-14.6) and 5.4 years finding of an association between the continuation of (range, 0.6-13.6) in the continued and discontinued metformin use and survival remained unchanged (HR, groups, respectively. At the last follow-up visit, 129 0.38; 95% CI: 0.23-0.64; P 5 0.0002; Supporting (75%) and 40 (51%) patients in the continued and dis- Table 1). continued groups were alive, of whom 54 (41.9%) and 15 (37.5%) patients had been followed for at least 5 years, respectively. Of the 81 deceased patients, 39 Discussion (48%) had information on causes of death available in We conducted a clinic-/hospital-based cohort study the medical record (21 and 18 in the continued and to determine the outcomes and safety of metformin in discontinued metformin groups, respectively). The diabetic patients with cirrhosis. Continuation of met- causes of death included liver-related deaths (n 5 32; formin use after cirrhosis diagnosis was associated with 82% of those with available cause of death informa- significantly improved survival in diabetic patients, tion), pulmonary disease (n 5 3), and heart disease, regardless of severity of liver impairment. Our data renal failure, accident, and leukemia (n 5 1 for each). suggest that metformin is safe in diabetic patients with Predictors of Survival of Patients With Cirrhosis cirrhosis because no patients developed lactic acidosis With Diabetes. Continuation of metformin use was while receiving metformin in our cohort. significantly associated with better survival in patients In this study, metformin use was significantly associ- with cirrhosis with diabetes. In univariate analysis, con- ated with a 57% reduction in risk of all-cause mortality tinuation of metformin (HR, 0.43; 95% CI: 0.28-0.66; in diabetic patients with all stages of cirrhosis. Our find- P 5 0.0001) and high serum albumin level (HR, 0.53; ing suggested that metformin may prevent liver-related 95% CI: 0.36-0.77; P 5 0.001) were significantly associ- mortality because most patients (82%) died from liver- ated with better survival. By contrast, every 10-year related diseases. The mechanism by which metformin increase in age (HR, 1.59; 95% CI: 1.25-2.02; P 5 reduces mortality in patients with cirrhosis is currently 0.0001), male sex (HR, 1.77; 95% CI: 1.11-2.82; P 5 unknown. Given that metformin use had a protective 0.02), increased MELD score (HR, 1.08; 95% CI: 1.02- effect against death only in the subgroup of NASH- 1.13; P 5 0.007), loge bilirubin (HR, 1.39; 95% CI: related patients with cirrhosis, it is biologically plausible 1.07-1.82; P 5 0.015), serum creatinine (HR, 2.7; 95% that metformin may slow progression of liver fibrosis by CI: 1.51-4.87; P 5 0.0009), and every 10-ng/mL attenuating steatohepatitis. This hypothesis is supported increase in serum AFP (HR, 1.13; 95% CI: 1.09-1.17; P by evidence from recent studies.17-19 Metformin has < 0.0001) were significantly associated with worse sur- been demonstrated to reverse steatosis and inflammation vival. Etiology of cirrhosis was also associated with sur- in a mouse model with NASH, reduce hepatocellular vival; compared to the reference group with HBV- injury and improve ALT levels in NASH patients, and induced cirrhosis, patients with HCV, NASH, or other significantly decrease hepatic fat, necroinflammation, causes of cirrhosis had HRs in the 1.3-1.5 range, whereas and fibrosis in nondiabetic NASH patients.17-19 those with cirrhosis resulting from ALD had an HR of We did not find a significant survival benefit in sub- 3.8; however, none of these associations was statistically groups of patients with cirrhosis induced by HCV, significant. Ethnicity, ALT, platelet count, INR, PT, and HBV, or alcohol, possibly because of the small num- fasting plasma glucose were not associated with survival bers of patients, or the entire group of patients with (Table 2). non-NASH-induced cirrhosis. Additional studies in The benefit of metformin use on survival outcome larger cohorts are needed to determine whether met- remained significant after adjusting for other variables formin confers a survival benefit for diabetic patients (i.e., age, gender, albumin, MELD score, AFP level, with cirrhosis from causes other than NASH. and etiology of cirrhosis; Table 2). Continuation of Baseline liver function, as indicated by MELD score metformin use was independently associated with a and Child-Pugh classification, is known to be a strong 57% decrease in the risk of death with a HR of 0.43 predictor of survival in patients with cirrhosis. In our (95% CI: 0.24-0.78; P 5 0.005). By contrast, every study, MELD score was not associated with survival of 10-ng/mL increase in AFP value was associated with a patients with cirrhosis, likely because most patients 13% increased risk for mortality (HR, 1.13; 95% CI: had low MELD scores. We found that a significantly
2014 ZHANG ET AL. HEPATOLOGY, December 2014 Table 2. Cox Proportional Hazards Analysis of Variables Associated With Death of Patients With Cirrhosis With Diabetes Univariate Analysis Multivariate Analysis* Variables HR (95% CI) P Value Adjusted HR (95% CI) P Value Age, per 10 years 1.59 (1.25-2.02) 0.0001 1.29 (0.91-1.81) 0.15 Male 1.77 (1.11-2.82) 0.02 1.51 (0.78-2.92) 0.22 Race Nonwhite 1.00 (reference) White 2.33 (0.85-6.40) 0.10 BMI 0.25 (0.04-1.54) 0.14 Obesity 1.35 (0.85-2.10) 0.20 Etiology of cirrhosis 0.01 0.03 HBV 1.00 (reference) 1.00 (reference) HCV 1.37 (0.17-10.77) 0.39 (0.04-3.52) ALD 3.86 (0.51-29.25) 2.29 (0.29-18.27) NASH 1.32 (0.18-9.69) 0.97 (0.13-7.53) Others 1.42 (0.16-12.77) 0.71 (0.07-7.57) MELD score 1.08 (1.02-1.13) 0.0067 1.01 (0.93-1.09) 0.82 Laboratory results AST level 1.0 (0.996-1.004) 0.97 ALT level 0.998 (0.994-1.002) 0.41 Loge bilirubin 1.39 (1.07-1.82) 0.015 Albumin 0.53 (0.36-0.77) 0.001 0.53 (0.28-1.01) 0.06 Platelets 1.001 (0.998-1.004) 0.56 INR 1.27 (0.54-2.98) 0.59 Creatinine 2.70 (1.51-4.87) 0.0009 Fasting plasma glucose, 0.998 (0.994-1.003) 0.47 AFP, per 10 ng/mL† 1.13 (1.09-1.17)
HEPATOLOGY, Vol. 60, No. 6, 2014 ZHANG ET AL. 2015 fluctuations in blood sugar levels; hypoglycemia is a large enough to sustain the multivariate model that particular concern of physicians when prescribing oral would be needed to investigate the effect of metformin hypoglycemic agents. Therefore, some physicians prefer and, at the same time, provide valid estimates of the insulin to avoid hypoglycemia in diabetic patients with concomitant effects of other medications. We were not cirrhosis. However, metformin does not cause hypogly- able to confirm a benefit of metformin use on reduc- cemia and can be used in combination with insulin ing HCC incidence as a result of the limited number without increasing the risk of hypoglycemia. of patients who developed HCC in our cohort. More- Interestingly, AFP was an independent risk factor over, although we adjusted for MELD score to account for death of patients with cirrhosis with diabetes. for the influence of more-severe comorbidities in the Given that a rising AFP value is used as a predictor of decision to discontinue metformin, MELD score may HCC development, we investigated whether metfor- not completely account for the effects of all possible min decreased the risk of HCC development in our comorbidities. cohort. We did not find a significant association A number of research questions should be further between continuation of metformin and reduced HCC investigated. It is worth examining the effect of metfor- risk (data not shown). This result was inconsistent min on survival of patients with non-NASH cirrhosis in with the study by Chen et al., which reported that a larger cohort. Whether initiating metformin subsequent metformin reduced risk of HCC development by 7% to diagnosis of cirrhosis would improve survival of dia- per year.13 This inconsistency may result from the lim- betic patients needs to be answered. It will also be inter- ited number of patients who developed HCC in our esting to further investigate whether metformin has an cohort (n 5 10 [5.8%] in continued and 5 [6.4%] in antifibrotic effect by slowing down progression or revers- discontinued groups), because this cohort study was ing the degree of liver fibrosis. Given that the prevalence powered to address the difference in survival, instead of impaired glucose tolerance in patients with cirrhosis is of HCC incidence, in the patients with cirrhosis. The as high as 50%-60%, it will be of interest to investigate information on lack of apparent HCC risk reduction whether metformin also improves the outcomes of was provided as an underpowered secondary analysis. patients with cirrhosis with impaired glucose tolerance. The major strength of our study lies in the large In conclusion, we report on the novel observation of cohort of patients with cirrhosis with diabetes who an association between continuation of metformin use have various causes of cirrhosis and a wide range of after cirrhosis diagnosis and improved survival of dia- degrees of severity of liver impairment. To our knowl- betic patients. Our findings strongly suggest that contin- edge, this is the largest cohort of unselected patients uation of metformin improves the survival of NASH- with cirrhosis with diabetes in which the effect of met- related patients with cirrhosis with diabetes. Validation formin use has been investigated. We also provided of these results in a larger cohort would support contin- data on the safety of metformin use in patients with uation of metformin use in NASH-related cirrhosis. cirrhosis. Therefore, this study has contributed signifi- cantly to filling the knowledge gap in the debate on Acknowledgment: The authors thank Ms. Jennifer whether metformin can be safely prescribed to patients L. Rud for her secretarial assistance. with cirrhosis. Importantly, our study revealed the novel observation of an association between metformin use and improved survival in a cohort of patients with References cirrhosis with diabetes. 1. Mini~ no AM, Murphy SL, Xu J, Kochanek KD. Deaths: final data for Our study had a number of limitations. We were 2008. Natl Vital Stat Rep 2011;59:1-126. not able to take into consideration the effect of dose 2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. 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