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: roberts.lewis@mayo.edu; 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
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