VIRAL HEPATITIS
Treatment of Insulin Resistance with Metformin in
Naı̈ve Genotype 1 Chronic Hepatitis C Patients
Receiving Peginterferon Alfa-2a Plus Ribavirin
Manuel Romero-Gómez,1 Moisés Diago,2 Raúl J. Andrade,3 José L. Calleja,4 Javier Salmerón,5
Conrado M. Fernández-Rodrı́guez,6 Ricard Solà,7 Javier Garcı́a-Samaniego,8 Juan M. Herrerı́as,9 Manuel De la Mata,10
Ricardo Moreno-Otero,11 Óscar Nuñez,12 Antonio Olveira,13 Santiago Durán,14 and Ramón Planas,14 on behalf of the
Spanish TRIC-1 (Treatment of Resistance to Insulin in Hepatitis C Genotype 1) group
Insulin resistance affects sustained virological response (SVR) in chronic hepatitis C. To
know whether adding metformin to standard antiviral treatment improves SVR, we conducted a prospective, multicentered, randomized, double-blinded, placebo-controlled trial
in 19 Spanish hospitals, including 123 consecutive patients with genotype 1 chronic hepatitis C and insulin resistance. Patients were randomized to receive either metformin (arm A;
n ⴝ 59) or placebo (arm B; n ⴝ 64) in addition to peginterferon alfa-2a (180 ␮g/week) and
ribavirin (1000-1200 mg/day). The primary end point was SVR, and secondary endpoints
were viral clearance at weeks 12, 24, and 48, and changes in the homeostasis model assessment (HOMA) index over the first 24 weeks. There were no differences between arms at
baseline. In the intent-to-treat analysis, SVR was observed in 53% versus 42% in arm A and
arm B, respectively (P ⴝ NS). In the subgroup analyses, SVR was higher in females (n ⴝ 54)
receiving metformin: arm A, 58% (15/26) versus 29% (8/28) arm B (P ⴝ 0.03). In the per
protocol analysis (PPA; n ⴝ 101), SVR was 67% in arm A and 49% in arm B (P ⴝ 0.06). Viral
decline during the first 12 weeks was greater in females receiving metformin: ⴚ4.88 (1.18)
versus ⴚ4.0 (1.44) (P ⴝ 0.021), whereas no differences were seen in males. The triple
therapy was well tolerated, but diarrhea was more often seen in arm A (34% versus 11%; P <
0.05). Conclusion: Adding metformin to peginterferon and ribavirin was safe and improved
insulin sensitivity. Although the study failed to show a statistically significant difference
between arms, it did show an improved SVR in females. (HEPATOLOGY 2009;50:1702-1708.)
H
epatitis C is a major healthcare problem, and
current therapies have achieved sustained response in more than a half of infected patients.
Factors associated with nonresponse are host-viral genotype 1, high viral load, advanced fibrosis, and insulin resistance.1 Sustained virological response (SVR) decreases
when insulin sensitivity is impaired.1,2 Also, impaired
fasting glucose has been independently associated with
lower SVR rate.3 Insulin resistance is thought to be promoted by hepatitis C virus (HCV) itself and, after clearance of the virus, insulin resistance improves
concomitantly with the reduction in the risk of glucose
abnormalities and diabetes.1,3,4 HCV proteins lead to insulin resistance, promoting the degradation of insulin re-
Abbreviations: HCV, hepatitis C virus; HOMA, homeostasis model assessment; IR, insulin resistance; PPA, per protocol analysis; PPAR-␥, peroxisome proliferatoractivated receptor-gamma; SD, standard deviation; SVR, sustained virological response.
From the 1Unit for the Clinical Management of Digestive Diseases and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHD),
Hospital Universitario de Valme, Sevilla, Spain; 2Hepatology Section, Hospital General de Valencia, Spain; 3Hepatology Unit and CIBEREHD, Hospital Virgen de la
Victoria, Málaga, Spain; 4Digestive Diseases Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain; 5Digestive Disease Service and CIBEREHD, Hospital San
Cecilio, Granada, Spain; 6Gastroenterology Unit, Hospital Universitario Fundación Alcorcón, Madrid, Spain; 7Hepatology Section, Hospital del Mar, Barcelona, Spain;
8Gastroenterology Service and CIBEREHD, Hospital Carlos III, Madrid, Spain; 9Gastroenterology Service, Hospital Universitario Virgen Macarena, Sevilla, Spain;
10Hepatology Section and CIBEREHD, Hospital Universitario Reina Sofı́a, Córdoba, Spain; 11Digestive Diseases Service and CIBEREHD, Hospital de la Princesa,
Madrid, Spain; 12Hepatology Unit, Hospital Gregorio Marañón, Madrid, Spain; 13Gastroenterology Service, Hospital La Paz, Madrid, Spain; 14Gastroenterology and
Hepatology Unit and CIBEREHD, Hospital Germans Trias i Pujol, Barcelona, Spain.
Received June 18, 2009; accepted July 18, 2009.
Supported by a non-restrictive grant from Roche Farma SA.
Presented at the 59th Annual Meeting of the American Association for the Study of the Liver Diseases, October 31 to November 4, 2008, San Francisco, CA.
1702
HEPATOLOGY, Vol. 50, No. 6, 2009
ceptor substrate 1.5 Transgenic mice expressing core
HCV protein developed insulin resistance and steatosis.6
Insulin resistance and steatosis promoted by the virus
have been found to be associated with improvement in
viral fitness,7 and this seems to be a defense mechanism
against viral clearance. Lifestyle, exercise, diet, and insulin-sensitizing drugs could improve insulin resistance.
Metformin is an oral biguanide that lowers blood glucose
and insulin secretion and improves the individual’s lipid
profile, mainly because of suppression of hepatic glucose
output and increased glucose uptake in skeletal muscle.8
Because insulin resistance can be successfully treated with
biguanides, we proposed that sustained virological response could be improved by adding metformin to the
standard of care for patients with chronic hepatitis C genotype 1 and insulin resistance.
ROMERO-GÓMEZ ET AL.
1703
Table 1. Pretreatment Characteristics of the Patients
Randomized to the Two Treatment Arms
Characteristic
Arm A
Arm B
P
Age, years
Females
HOMA-IR
Viral load (lg10)
HVL, ⬎400,000 IU/mL
Fibrosis; Sydney Index
Weight, kg
ALT, U/L
AST, U/L
GGT, U/L
Platelets, ⫻103/␮L
Cholesterol, mg/dL
47.1 (8.5)
26/59
4.31 (2.24)
6.33 (0.73)
54/59 (92%)
0.44 (0.27)
78.7 (14.6)
90.1 (69.4)
58.4 (41.8)
65.1 (54.2)
219 (54)
171 (27)
47.7 (8.9)
28/64
4.42 (2.62)
6.48 (0.76)
58/64 (91%)
0.46 (0.32)
83.0 (18.3)
98.7 (85.3)
66.5 (60.5)
84.2 (72)
213 (54)
178 (39)
0.69
0.97
0.78
0.28
0.95
0.75
0.16
0.54
0.43
0.12
0.58
0.26
Values are expressed as mean (SD).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase;
GGT, gamma glutamyltransferase; HOMA, homeostasis model assessment; HVL,
high viral load; IR, insulin resistance.
Patients and Methods
Selection of Patients. Eligible patients were those
who were 18 years of age or older, were infected with
genotype 1 (determined by INNO-LIPA assay, Innogenetics), and had a quantifiable serum HCV RNA for more
than 6 months together with an elevated serum alanine
aminotransferase level, nondiabetic, and homeostasis
model assessment (HOMA) index greater than 2 (Table
1). Liver biopsy was not mandatory. Liver fibrosis was
calculated using the Sydney index (a noninvasive method
for the prediction of liver fibrosis based on a formula that
includes age, plasma cholesterol concentration, aspartate
aminotransferase, alcohol consumption, and HOMA index9 that has been validated in Spanish patients with chronic
hepatitis C).10 Patients were ineligible if they had other liver
diseases, showed contraindications to peginterferon or ribavirin, or had previously received antiviral drugs.
Study Design. Patients were randomly assigned into
this prospective, multicentered, randomized, double-
blinded, placebo-controlled trial (registered in ClinicalTrials.gov; #NCT00546442). The study was conducted
in 19 Spanish centers. All sites received approval from
their ethics committees. Each patient provided written
informed consent for participation. Patients were randomly assigned in a 1:1 ratio to receive either metformin
425 mg three times daily for the first month and 850 mg
three times daily from week 4 to 48 (arm A; n ⫽ 59) or
placebo (arm B; n ⫽ 64) in addition to peginterferon
alfa-2a (Pegasys; Roche Farma, Madrid, Spain) 180 ␮g
weekly and ribavirin 1000 to 1200 mg daily. Patients were
followed-up over 24 weeks to confirm SVR.
Laboratory Analyses. An overnight (12-hour) fasting
blood sample was taken for routine analyses, including
aminotransferases (alanine aminotransferase, aspartate
aminotransferase), alkaline phosphatase, gamma-glutamyltransferase, platelets, glucose, cholesterol, and triglycerides. All patients had positive anti-HCV as
measured using EIA3 (Abbott Laboratories, Chicago, IL)
Address reprint requests to: Manuel Romero-Gómez, M.D., Ph.D., UCM Digestive Diseases and CIBERHD, Hospital Universitario de Valme, Universidad de Sevilla,
Avda de Bellavista s/n, 41014 Sevilla, Spain. E-mail: [email protected]; fax: (⫹34)-955-01-58-99.
Copyright © 2009 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.23206
Potential conflict of interest: M.R.-G.: consulting fees from Roche, Novartis, Bristol-Myers Squibb, AstraZenenca; lecture fees from Roche, Schering-Plough, Novartis,
Bristol-Myers Squibb; unrestricted research grant support from Roche, Schering-Plough, Gilead; M.D.: consulting fees from Roche and Novartis; lecture fees from Roche,
Schering-Plough, Novartis, Bristol-Myers Squibb; R.J.T.: consulting fees from Schering-Plough, Madaus, Novartis, Bristol-Myers Squibb; lecture fees from Roche,
Schering-Plough, Novartis, Janssen, Bristol-Myers Squibb; grant support from Roche, Schering-Plough, SAE Consortium; J.L.C.: consulting fees from Roche, Novartis,
Bristol-Myers Squibb; grant support from Roche, Schering-Plough, Gilead; J.S.: consulting fees from Novartis, Bristol-Myers Squibb, Schering-Plough; grant support from
Roche; C.M.F.-R.: consulting fees from Schering-Plough, Roche-Farma, Bristol-Myers Squibb; lecture fees from Schering-Plough, Roche-Farma, Bristol-Myers Squibb;
grant support from Roche-Farma and Schering-Plough; R.S.: consulting fees from Roche, Novartis, Bristol-Myers Squibb, Sigma-Tau, Gilead; lecture fees from Roche,
Schering-Plough, Gilead, Novartis, Bristol-Myers Squibb; grant support from Roche, Gilead; J.G.-S.: consulting fees from Roche, Bristol-Myers Squibb, Novartis; lecture
fees from Roche, Gilead Sciences; grant support from Roche and Gilead Sciences; J.M.H.: consulting fees from AstraZeneca and lectures from Roche Farma; M.D.l.M.:
consulting fees from Schering-Plough; grant support from Roche; R.M.-O.: consulting and grants from Roche-Farma and Schering-Plough; S.D.: Consulting fees from
Novo-Nordisk, Lilly, Boheringher Ingelheim, AstraZeneca; lecture fees from MSD, Servier, Roche-Farma, Novo-Nordisk and Lilly; R.P.: consulting fees from Roche-Farma,
Novartis, Bristol-Myers Squibb; lecture fees from Gilead, Roche-Farma, Novartis, and Bristol-Myers Squibb; grant support from Gilead and Roche-Farma.
1704
ROMERO-GÓMEZ ET AL.
HEPATOLOGY, December 2009
Fig. 1. Flow of
through the study.
and positive HCV RNA in serum. Hepatitis B surface antigen, anti-hepatitis B core, and anti-human immunodeficiency virus were tested using commercially available kits
(Abbott Laboratories, Chicago, IL). All patients were negative for hepatitis B surface antigen and anti-human immunodeficiency virus. Serum insulin levels were measured by
electrochemiluminescence immunoassay, using an autoanalyzer Elecsys 1010/2010 (Elecsys Modular Analytics E170;
Roche, Basel, Switzerland). Blood lactate levels was measured by a commercially available kit (Immulite Diagnostic
Products, Los Angeles, CA). The insulin resistance index was
calculated on the basis of fasting values of plasma glucose and
insulin according to the HOMA model formula: Insulin
resistance (HOMA IR) ⫽ fasting insulin (mUI/L) ⫻ fasting
glucose (mmol/L) ⫼ 22.5
Efficacy Assessments. The primary end-point was
SVR, defined as undetectable serum HCV RNA level
(⬍10 IU/mL) at 24 weeks after the conclusion of treatment.
The secondary end-points were: (1) viral clearance
(HCV RNA ⬍ 10 IU/mL) at weeks 12, 24, and 48; (2)
changes in the HOMA index over the first 24 weeks.
Virological breakthrough was defined as a detectable
HCV RNA level during treatment in patients who had
had undetectable HCV RNA at week 24. Virological relapse was defined as a detectable HCV RNA level during
follow-up in patients who had had undetectable HCV
RNA at week 48.
Safety Assessments. Safety was assessed by means of
clinical examinations and laboratory tests at weeks 4, 8,
12, 24, 48, and 72. Stepwise reductions of peginterferon
participants
alfa-2a, ribavirin, and metformin were permitted in managing clinically significant adverse events, or laboratory
abnormalities recorded.
Statistical Analyses. Sample size estimation was
based on the assumption that metformin improving insulin resistance could increase SVR rate in 28%.1 The estimated sample size was 124 patients, with a 10% rate of
loss-to-follow-up, type I error of 0.05, and type II of 0.2
(Fisher’s exact two-sided test).
Intention-to-treat analysis included all 123 randomized cases, and a per-protocol analysis (PPA) included 101
patients. Excluded from the PPA were patients with adherence to less than 80% of the dose and duration of
peginterferon (n ⫽ 9) and ribavirin (n ⫽ 4) and those
with daily average intake of metformin less than 50%
(1275 mg/day) (n ⫽ 9) (Fig. 1). All data were analyzed
using SPSS version 15.0 for Windows (Chicago, IL).
Comparisons between paired groups were with the
Mann-Whitney U test, the student t test, chi-squared, or
Fisher’s exact test. Backward logistic regression was applied in the multivariate analysis.
Funding and Study Logistics. The study was funded
by a nonrestrictive grant from Roche Farma SA. The
funding body had no part in the collection and evaluation
of data, or in the writing of the manuscript and the decision to publish. The trial was designed by the principal
investigator (M.R.-G.) together with the academic investigators constituting the TRIC-1 group (see Appendix).
The logistics of data collection were managed by p-value
S.A. (Sevilla, Spain) and the academic investigators, and a
copy was logged with the study promoter. The principal
HEPATOLOGY, Vol. 50, No. 6, 2009
ROMERO-GÓMEZ ET AL.
1705
investigator (M.R.-G.) together with p-value S.A. performed the statistical analyses and vouch for the integrity
and completeness of the data.
Results
Of 125 patients initially recruited, 123 were randomly
assigned to a treatment group and received at least one
dose of medication; two patients were excluded because of
not having met the full criteria for inclusion (one patient
was already taking metformin, and the other was found to
be infected by a different viral genotype). The two treatment groups were well matched for age, sex, and other
variables measured on entry into the trial (Table 1).
Virological Response. In the intention-to-treat analysis (n ⫽ 123), viral clearance was seen in 54% (32/59) of
patients versus 48% (31/64) at week 12; in 75% (45/59)
versus 75% (48/64) at week 24; in 71% (42/59) versus
63% (40/64) at week 48; and in 53% (31/59) versus 42%
(27/64) at week 72 (in other words, SVR rate) in arm A
and arm B, respectively. Virological breakthrough was
slightly higher in patients receiving placebo 17% (8/48)
versus 7% (3/45), but this difference was not statistically
significant. Relapse rate was similar in both arms: 11 of 59
patients (19%) in arm A and 12 of 64 patients (19%) in
arm B; P ⫽ 0.98.
In the PPA (n ⫽ 101), viral clearance was achieved in
67% (31/46) versus 53 (29/55), P ⫽ 0.13 at week 12; in
96% (44/46) versus 78% (43/55), P ⫽ 0.01 at week 24; in
91% (42/46) versus 69% (38/55), P ⬍ 0.01 at week 48; in
67% (31/46) versus 49% (27/55), P ⫽ 0.06 at week 72 in
arm A and arm B, respectively.
Subgroup Analysis. In females (n ⫽ 54), adding metformin to peginterferon alfa-2a plus ribavirin resulted in a
doubling of the SVR rate in 15 of 26 patients (58%) in
arm A versus 8 of 28 patients (29%) in arm B; P ⫽ 0.03)
(Fig. 2). Viral decline during the first 12 weeks was greater
in females taking metformin than placebo (mean [standard deviation (SD)]) ⫺4.88 (1.18) versus ⫺4.0 (1.44);
P ⫽ 0.02), whereas no viral decline was noted in males.
Furthermore, no cases of breakthrough were seen in females with metformin therapy (females with HCV RNA
negative at week 24 (n ⫽ 41), with 4 of 20 patients experiencing breakthrough in arm B but none in arm A (0 of
21); P ⫽ 0.05.
Changes in Insulin Resistance. The decline in
HOMA index in patients receiving metformin was significantly higher than in patients receiving placebo. In arm
A, the HOMA index decreased from 4.3 (2.2) to 2.6 (1.7)
and in arm B from 4.6 (2.7) to 3.8 (2.1); P ⫽ 0.001.
However, no difference was seen in weight loss in either
treatment arm. By the end-of-follow-up, women receiving metformin had a mean body weight decrease of 1.3 kg
Fig. 2. Rates of viral clearance in patients randomly assigned to
receive Metformin ⫹ Pegalfa2a ⫹ Ribavirin (arm A) or Placebo ⫹
Pegalfa2a ⫹ Ribavirin (arm B) in the intention-to-treat analysis, perprotocol analysis and females subset analysis. A sustained virological
response was defined as undetectable serum HCV RNA level (⬍10
UI/mL) at week 24 after the end of treatment.
(SD: 5.4) versus 1.1 kg (SD: 5.6) in women receiving
standard care; P ⫽ NS. In men, body weight decreased by
1.1 kg (SD: 6.1) in patients receiving metformin versus
0.9 kg (SD: 5.5) in patients on placebo; P ⫽ NS. Chages
in body weight did not influence SVR. However, HOMA
less than 2 at week 24 was more often seen in arm A (55%)
than in arm B (14%), and this goal was associated with
higher SVR (see below).
Predictors of SVR. In the univariate analysis, higher
baseline viral load and calculated fibrosis (the noninvasive
Sydney Index) were associated with nonresponse of 6.52
(0.73) versus 6.28 (0.75) log10 HCV RNA (P ⫽ 0.08) and
0.52 (0.32) versus 0.38 (0.25) in the Sydney Index (P ⫽
0.01). During treatment, the HCV RNA decline in the
first 12 weeks of 3.04 (1.65) versus 1.11 (0.35) log10
HCV RNA, P ⫽ 0.0001, and the HOMA-IR decline
during the first 24 weeks was associated with sustained
response; that is, 19 of 28 patients (68%) with a
HOMA-IR less than 2 at week 24 achieved SVR, whereas
25 of 56 patients (45%) with HOMA at 24 weeks greater
than 2 achieved SVR (P ⫽ 0.05).
Using reverse stepwise logistic multivariate regression
analysis, the independent variable related to SVR was
HCV RNA at week 12 (hazard ratio, 0.15; 95% confidence interval: 0.07-0.34) (Table 2).
Safety. The percentage of patients reporting adverse
events or serious adverse events was similar in the two
groups. The adverse events reported were those typical of
interferon-based treatments, which include fatigue, headache, insomnia, and myalgia. Diarrhea was more often
seen in patients assigned to arm A than in patients receiving placebo (36% versus 11%; P ⬍ 0.05). However, the
1706
ROMERO-GÓMEZ ET AL.
HEPATOLOGY, December 2009
Table 2. Univariate and Multivariate Analysis of Host and Viral Factors Associated with Sustained Virological Response
Univariate Analysis
Parameter
Baseline VL; log10
HOMA-IR
Weight; kg
Age; years
Sydney Index
VL w12; log10
Sex
么
乆
Treatment arm
A
B
HOMA 24 weeks
ⱕ2
⬎2
Non-SVR
SVR
Multivariate Analysis BLR
P
HR (95%CI)
P
0.08
0.24
0.75
0.30
0.01
0.0001
0.71 (0.39–1.29)
1.07 (0.86–1.34)
1.05 (065–1.45)
1.01 (0.96–1.08)
0.77 (0.04–15.5)
0.15 (0.07–0.34)
0.22
0.82
0.56
0.77
0.86
0.0001
6.52 (0.73)
4.61 (2.7)
80.5 (18)
48.2 (9.2)
0.52 (0.32)
3.04 (1.65)
6.28 (0.75)
4.1 (2.1)
81.5 (12.2)
46.5 (8.2)
0.38 (0.25)
1.11 (0.35)
34/69 (49%)
31/54 (57%)
35/69 (51%)
23/54 (43%)
0.37
0.79 (0.33–1.86)
0.93
28/59 (48%)
37/64 (59%)
31/59 (53%)
27/64 (42%)
0.25
1.51 (0.66–3.43)
0.25
9/28 (32%)
31/56 (56%)
19/28 (68%)
25/56 (45%)
0.045
1.12 (0.84–1.49)
0.43
Values presented as mean (SD) or hazard ratio (95%CI).
Abbreviations: BLR, backward linear regression; CI, confidence interval; HR, hazard ratio; HOMA, homeostasis model assessment; VL, viral load.
diarrhea was well tolerated and did not lead to any withdrawals from the trial. Two patients in each treatment
group had to discontinue because of adverse events (Table
2). Doses of metformin or placebo were modified in 37%
of patients in arm A and 38% in arm B (P ⫽ NS). Serum
lactate was monitored during treatment, and no patient
developed lactic acidosis or hyperlactatemia.
Discussion
The combination of metformin, peginterferon alfa-2a,
and ribavirin was well tolerated by the patients. It improved insulin resistance in more than 50% of patients
and increased SVR rate in 10% of patients with hepatitis
C genotype 1 and HOMA greater than 2. This was related
to a trend toward a low rate of breakthrough in patients
receiving metformin; the response at week 24 and relapse
rate were similar in both arms. However, in the PPA, viral
clearance was significantly higher in the metformin group
at weeks 24 and 48, which supports the proposition of a
better antiviral activity of peginterferon alfa-2a and ribavirin in patients receiving metformin. Despite raising
SVR by 10% (a clinically relevant increase), this difference did not reach statistical significance, which could be
attributable, at least in part, to a type 2 error in sample size
calculation. That there is a trend in the intention-to-treat
analysis and significance in the PPA and female subanalysis strongly supports this hypothesis. Despite the sample
calculation being based on the available data, our subsequent findings of the study suggest that there were not
enough patients enrolled in the study to achieve statistically significant differences. Metformin is an oral biguanide, which is one of the most widely prescribed
therapeutic agents for the control of type 2 diabetes. Met-
formin controls glucose levels by suppression of hepatic
glucose output, by increasing insulin-mediated glucose
disposal, and by decreasing fatty acid oxidation and synthesis of very-low-density lipoprotein.11 During HCV
replication, core protein promotes unfolded protein response that causes dysfunction of endoplasmic reticulum
and mitochondria.12,13 Indeed, HCV proteins promote
insulin receptor substrate 1 degradation by several mechanisms, including oxidative stress, down-regulation of
PPAR, and enhancing TNF production in a genotypedependent manner. In genotype 1, the degradation of
insulin receptor substrate 1 has been shown to be induced
by mammalian target of rapamycin and, in genotype 3, by
suppressor of cytokine signaling 7 and peroxisome proliferator-activated receptor-gamma (PPAR-␥). Thus, metformin could be useful in the management of this
comorbidity because of its ability to increase the binding
of insulin to its receptors and to increase phosphorylation
as well as the tyrosine kinase activity of insulin receptors14
through, mainly, the action of phosphorylation of hepatic
adenosine-monophosphate-activated protein kinase by
STK11 (formerly LKB1).15 Pioglitazone was shown not
to improve either viral response or insulin sensitivity in
five previously nonresponding individuals.16 In treatment-naı̈ve patients, pioglitazone in combination with
peginterferon alfa-2b and ribavirin improved insulin sensitivity and hepatic steatosis.17 Elgouhari et al.18 had
shown that the combination therapy improved early virological kinetics over the first 4 weeks and the end-oftreatment response, but not SVR.18 The low number of
patients (n ⫽ 40) precluded subset analysis and comparisons with the current study. However, the mechanism of
action of insulin-sensitizer drugs in the setting of patients
HEPATOLOGY, Vol. 50, No. 6, 2009
with hepatitis C appears to be different and could be
related to viral genotype. Metformin improved insulin
sensitivity in patients with hepatitis C genotype 1. Theoretically, PPAR-␥ agonist appears to be indicated in the
management of patients with genotype 3 HCV infection
(in whom insulin resistance appears as a consequence of
decreased PPAR-␥ activity). Furthermore, metformin
could be preferred because it acts directly in the liver,
whereas PPAR-␥ agonist shows an effect on peripheral
metabolism. Further prospective studies using different
insulin sensitizers in a large cohort of patients with hepatitis C with different genotypes are required to demonstrate whether these data could be translated into clinical
practice.
In women, metformin increased the SVR rate significantly. This sex-related difference has not been previously
reported in the management of hepatitis C. Spontaneous
viral clearance has been seen more often in women than in
men.19 However, no sex-related impact has been reported
on the clinical course of the infection or in SVR rate.
Some weak evidence supports the influence of sex on the
therapeutic effects of metformin: (1) metabolic syndrome
pathophysiology and diabetes-related complications appear to be vary in relation to sex, and vitamin K supplementation appears to improve insulin resistance in men
but not in women20; (2) some therapeutic effects of metformin appear to be sex dependent, that is, metformin
promotes greater short-term weight loss in women than in
men, but these differences were not observed in diabetic
control subjects21,22; (3) STK11 (formerly LKB1) plays a
major role in metformin sensitivity,23 and some genetic
alterations appear to have a clinical impact that is sex
dependent, such as the risk of malignancies in PeutzJegher syndrome.24 In women, metformin therapy has
been associated with a greater decrease of HCV RNA
during the first 12 weeks of treatment and a lower breakthrough rate. These data support the hypothesis that, in
women, metformin improves the antiviral activity of
peginterferon and ribavirin. It remains to be explored
whether genetic alterations in the STK11 gene or nuclear
factors such as estrogens are implicated in the ability of
metformin to improve antiviral activity.
Two biguanides (phenformin and buformin) have
been withdrawn from the pharmacopeias because of evidence of lactic acidosis associated with their use. Despite
cases of lactic acidosis having been reported with the use
of metformin, a recent systematic review demonstrated no
increased risk for lactic acidosis in patients without contraindications to metformin use.25 In the current study,
blood lactate level was monitored during treatment, and
no patients developed lactic acidosis or hyperlactatemia.
Metformin was associated with mild diarrhea, which was
ROMERO-GÓMEZ ET AL.
1707
well tolerated, and no patient withdrew from the study
because of this adverse event. Thus, metformin used together with peginterferon alfa-2a and ribavirin in the
treatment of hepatitis C seems to be safe and well tolerated. The perceived contraindication of metformin for
patients with alterations in liver function needs to be reevaluated.
In our study, metformin improved insulin sensitivity,
with more than half the number of patients achieving
HOMA less than 2 by week 24. This end point was also
related to the probability of achieving SVR. Nevertheless,
metformin-induced improvement in insulin sensitivity is
not the sole action of this drug, and the mechanism by
which metformin improves the antiviral activity of peginterferon ⫹ ribavirin warrants further investigation.
In summary, treating patients with hepatitis C genotype 1 and insulin resistance using metformin improves
insulin sensitivity, is safe, and increases SVR rate in patients who reached HOMA lower than 2 at week 24 of
therapy and in women, in whom, in the current study, the
therapy doubled the SVR rate.
Acknowledgment: Editorial assistance was provided by
Dr. Peter R. Turner.
Appendix
The Spanish TRIC-1 group members (and their affiliations):
Lourdes Grande, Ana Madrazo, Santiago Durán (Hospital Universitario de Valme, Sevilla, Spain); Marı́a Luisa
Moreno, Celia Pérez (Hospital General de Valencia,Valencia, Spain); Mercedes Robles (Hospital Virgen de la
Victoria, Málaga, Spain); Ignacio de la Torre, Juan Revilla
(Hospital Puerta de Hierro, Madrid, Spain); Luis Rodrı́guez, Ana Gila (Hospital San Cecilio, Granada, Spain);
Marı́a Luisa Gutiérrez, Sonia Alonso (Hospital Universitario Fundación Alcorcı́n, Madrid, Spain); Dolors Gimenez (Hospital del Mar, Barcelona, Spain); Juan Manuel
Herrerı́as, Marı́a Isabel Carmona (Hospital Universitario
Virgen Macarena, Sevilla, Spain); Manuel De la Mata,
Francisca Nuñez (Hospital Universitario Reina Sofı́a,
Córdoba, Spain); Antonio Olveira, José Carlos Erdozain
(Hospital La Paz, Madrid, Spain); Óscar Nuñez (Hospital
Universitario Gregorio Marañon, Madrid, Spain); Javier
Garcı́a-Samaniego, Miriam Romero, Angelica Moreno
(Hospital Carlos III, Madrid, Spain); Ricardo MorenoOtero, Marı́a Trapero (Hospital de la Princesa, Madrid,
Spain); Ramón Planas, Rosa Morillas, Pilar Giner (Hospital Universitari Germans Trias i Pujol, Badalona,
Spain); Francisco Jorquera, Josı́ Luis Olcoz (Hospital
General de León, León, Spain); Blas Dalmau (Hospital
Parc Taulı̀, Barcelona, Spain); Manuel Garcı́a-Bengo-
1708
ROMERO-GÓMEZ ET AL.
echea, Juan J. Arenas (Hospital de Donostia, San Sebastian, Spain); Eduardo Rodrı́guez (Hospital General de
Alarcos, Ciudad Real, Spain); Rafael Martvı́n-Vivaldi
(Hospital Universitario Virgen de las Nieves, Granada,
Spain); Carmen Ramı́rez, Cristina Carreño, José
Moreno-Cruzado (Roche Farma, SA, Madrid, Spain)
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