International Journal of Endocrinology

International Journal of Endocrinology / 2013 / Article
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Clinical Study | Open Access

Volume 2013 |Article ID 587140 | https://doi.org/10.1155/2013/587140

Takumi Hirata, Kengo Tomita, Toshihide Kawai, Hirokazu Yokoyama, Akira Shimada, Masahiro Kikuchi, Hiroshi Hirose, Hirotoshi Ebinuma, Junichiro Irie, Keisuke Ojiro, Yoichi Oikawa, Hidetsugu Saito, Hiroshi Itoh, Toshifumi Hibi, "Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)", International Journal of Endocrinology, vol. 2013, Article ID 587140, 9 pages, 2013. https://doi.org/10.1155/2013/587140

Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)

Academic Editor: Ilias Migdalis
Received23 May 2013
Accepted16 Jul 2013
Published13 Aug 2013

Abstract

Aim. This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. Methods. This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 20 mg once a day ( ) or losartan at a dose of 50 mg once a day ( ) for 12 months. Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen (L/S) ratio, as well as several parameters of glycemic and lipid metabolism, were compared before and after 12 months. Results. The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from to  mEq/L (mean ± SD), ) and a significant increase in L/S ratio ( ) evaluated by CT scan, while these parameters were not changed in the losartan group. Conclusion. Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.

1. Introduction

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease throughout the world [1]. NAFLD is characterized by hepatic steatosis in the absence of significant alcohol use, hepatotoxic medication, or other known liver diseases [2]. NAFLD represents a spectrum ranging from simple fatty liver to nonalcoholic steatohepatitis (NASH), which is an aggressive form of NAFLD leading to cirrhosis and hepatocellular carcinoma [36]. Recently, it has been established that NAFLD is commonly associated with metabolic syndrome, including type 2 diabetes, obesity, dyslipidemia, and hypertension and consequently is associated with cardiovascular mortality [610]. The potential need for treatment of NAFLD is recognized, in order to improve cardiovascular and liver-related outcomes, and several therapeutic interventions to treat various components of metabolic syndrome have been evaluated [1012].

Angiotensin II receptor blockers (ARBs), which are highly selective for the angiotensin II type 1 (AT1) receptor and block diverse effects of angiotensin II, are commonly used to treat hypertension [13]. Recently, ARBs have been expected to be effective for treatment of NAFLD, due to targeting of the mechanisms of insulin resistance and hepatic injury via suppression of the renin-angiotensin system (RAS), which has been suggested to be involved in the pathways of liver damage. It has been reported that an ARB, losartan, showed significant improvement in aminotransferase levels and serum markers of fibrosis in hypertensive patients with NASH [14]. Moreover, losartan has been reported to decrease the number of activated hepatic stellate cells, which play a pivotal role in the progression of hepatic fibrosis [15]. These results suggest that losartan might be therapeutically efficacious for NASH.

Telmisartan, another ARB, has been reported to have a partial agonistic effect on peroxisome proliferator-activated receptor (PPAR)-γ in addition to the effect of angiotensin II blockade [16, 17]. So, telmisartan is expected to have more potent effects in NAFLD than those of losartan, via PPARγ activation, which promotes hepatic fatty acid oxidation, decreases hepatic lipogenesis, and increases peripheral and hepatic insulin sensitivity [18, 19]. In fact, it is reported that telmisartan attenuated steatohepatitis progression in an animal model [20]. In addition, telmisartan has been reported to improve insulin resistance and liver injury, based on measurement of homeostasis model assessment-insulin resistance (HOMA-IR) and serum aminotransferase (ALT) levels in humans [21].

In the present study, we tested the hypothesis that telmisartan might have a more potent effect on NAFLD and biochemical markers of insulin resistance than does losartan.

2. Materials and Methods

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Review Board of Keio University. Written informed consent was obtained from each subject before participation in the study. This study was assigned the UMIN-ID, UMIN000000540.

2.1. Subjects

We screened patients with type 2 diabetes between 20 to 80 years of age with both NAFLD and hypertension. NAFLD was defined as fatty liver on ultrasonography, and aspartate aminotransferase (AST) level over 30 IU/L, and/or alanine aminotransferase (ALT) level over 40 IU/L. A detailed history of alcohol consumption was taken by physicians. All patients consumed less than 20 g of pure alcohol per day, and were negative for hepatitis B serological tests, antibody to hepatitis C virus, and autoantibodies, including anti-mitochondrial antibody and anti-nuclear antibody. Hypertension was defined as systolic blood pressure (SBP) over 140 mmHg and/or diastolic blood pressure (DBP) over 90 mmHg. Patients using antihypertensive agents were also included. Exclusion criteria included the presence of AST > 100 IU/L and/or ALT > 100 IU/L, severe hypertension (i.e., SBP > 200 mmHg, DBP > 120 mmHg), malignancy and recent major macrovascular disease (i.e., cardiovascular disease or stroke within past 3 months), insulin, biguanide or thiazolidinedione treatment for diabetes mellitus, and drug allergy to ARBs.

2.2. Study Design

This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to the telmisartan (T) group (receiving a standard dose of 20 mg once daily, ) or losartan (L) group (receiving a standard dose of 50 mg once daily, ). Patients using other antihypertensive agents were randomly switched to telmisartan or losartan. Medication was not masked, and treatment had to be taken daily at the same hour in the morning, with no concomitant medication or alcohol consumption allowed. Either the patient or the medical staff was aware of the treatment group allocation. All 19 subjects received dietary instructions using a meal-exchange plan from nutritionists. The ideal dietary caloric intake for each patient was calculated as the ideal body weight (kg) × 25 kcal/kg. It was confirmed by questionnaire that the physical activity level was almost constant in each subject throughout the study period.

The included patients were followed for 12 months, with two-monthly visits.

Anthropometric measurements, blood pressure (BP), heart rate (HR), and several clinical and biochemical parameters of glycemic control, lipid metabolism, and liver function were checked at every visit. Body fat area as determined by computed tomographic (CT) scanning at the umbilical level, hepatic fat content based on the liver-to-spleen (L/S) ratio according to CT attenuation values, inflammatory markers, and serum bile acid level were determined before and after 12 months.

2.3. Measurements

Blood pressure was determined in the sitting position after a 10-minute rest. Body weight was measured at the clinic under the same conditions for each patient. Blood samples were taken from each subject before breakfast in the early morning, after overnight bed rest.

Fasting plasma glucose (FPG) was determined by the glucose oxidase method. Hemoglobin A1c (HbA1c) was determined by high-performance liquid chromatography (Toso, Tokyo, Japan) and presented as the equivalent value for the National Glycohemoglobin Standardization Program (NGSP). Serum immunoreactive insulin (IRI) was measured by an enzyme immunoassay using a commercially available kit. Homeostasis model assessment-insulin resistance (HOMA-IR) was calculated by the formula: fasting plasma insulin (μU/mL) × fasting plasma glucose (mg/dL)/405. HOMA-β was calculated by the formula: fasting plasma insulin (μU/mL) × 360/(fasting plasma glucose (mg/dL) − 63) [22]. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and free fatty acids (FFAs) were measured enzymatically by an autoanalyzer (Hitachi, Tokyo, Japan). As biochemical parameters, AST, ALT, gamma glutamyl transpeptidase (γGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine (CR), uric acid (UA), sodium (Na), potassium (K), ferritin, and creatine phosphokinase (CPK) were measured. Inflammatory markers such as hyaluronic acid (Hyal), 7S domain of type IV collagen (4Col7S), high-sensitivity C-reactive protein (hs-CRP), procollagen III peptide (P-3-P), zinc (Zn), total adiponectin, and interleukin (IL)-6 were analyzed at the Special Reference Laboratory (SRL, Tokyo, Japan). We also measured bile acid (BA) components by high-performance liquid chromatography, because BAs might be related to lipid absorption and cholesterol catabolism [23].

Subcutaneous and visceral fat distribution was determined by measuring a −150 Hounsfield unit (HU) to −50 HU area using the method of CT scanning at the umbilical level as described previously [24]. V/S ratio was calculated as visceral fat area (VFA)/subcutaneous fat area (SFA). An index of fat deposition in the liver based on the liver-to-spleen (L/S) ratio according to CT attenuation values was also determined. The mean HU values of the liver and spleen were determined in the parenchyma of the right (CT-L1) and left lobe (CT-L2) of the liver and approximately the same size area of the spleen (CT-Spleen), avoiding blood vessels, artifacts, and heterogeneous areas. L/S ratio was calculated as [((CT-L1) + (CT-L2))/2]/(CT-Spleen).

2.4. Statistical Analyses

Continuous variables are presented as mean ± standard deviation. Continuous variables were compared between the telmisartan group and losartan group using the Mann-Whitney test for independent samples. Differences in each baseline treatment between groups were analyzed by chi-squared test. Differences in each parameter between the start and after 12 months in each group were analyzed using the Wilcoxon’s matched-pair signed-rank test. A value less than 0.05 was considered to be statistically significant. Statistical analyzes were carried out using StatView 5.0 software (SAS Institute, Cary, NC, USA).

3. Results

3.1. Baseline Characteristics

Baseline characteristics of the subjects in both groups are shown in Table 1. There were no significant differences in most parameters including duration of diabetes, anthropometric measurements, BP, biochemical measurements, and inflammatory markers between the T group and L group. In spite of randomization, there were significant differences in two parameters between the two groups at baseline; serum FFA (  mEq/L in T group versus  mEq/L in L group ( )) and L/S ratio ( in T group versus in L group ( )).


ParametersTelmisartanLosartanP-value

(male/female) 12 (6/6)7 (3/4)
Age (years) 0.612
Duration of diabetes (years) 0.523
Height (cm) 0.673
Body mass index (kg/m2) 0.735
Waist circumference (cm) 0.899
Hip circumference (cm) 0.257
Systolic blood pressure (mmHg) 0.526
Diastolic blood pressure (mmHg) 0.611
Pulse (beats/min) 0.205
Biochemical markers
 Fasting plasma glucose (mg/dL) 0.571
 Hemoglobin A1c (%) 0.444
 Glycoalbumin (%) 0.447
 Immunoreactive insulin (μU/mL) 0.955
 Total cholesterol (mg/dL) 0.447
 High-density lipoprotein cholesterol (mg/dL) 0.290
 Triglyceride (mg/dL) 0.866
 Free fatty acids (mEq/L) 0.001
 Aspartate aminotransferase (IU/L) 0.372
 Alanine aminotransferase (IU/L) 0.583
γ Glutamyl transpeptidase (IU/L) 0.612
 Alkaline phosphatase (IU/L) 0.800
 Lactate dehydrogenase (IU/L) 0.353
 Blood urea nitrogen (mg/dL) 0.704
 Creatinine (mg/dL) 0.283
 Uric acid (mg/dL) 0.582
 Na (mEq/L) 0.447
 K (mEq/L) 0.966
 u-Microalbumin (μg/mL) 0.375
 Ferritin (ng/mL) 0.767
 Creatine phosphokinase (IU/L) 0.899
HOMA-IR 0.865
HOMA-β 0.865
Complete blood count
 White blood cells (×103/μL) 0.052
 Hemoglobin (g/dL) 0.865
 Platelets (×103/μL) 0.163
Inflammatory markers
 Hyaluronic acid (ng/mL) 0.446
 7S domain of type 4 collagen (ng/mL) 0.445
 High-sensitivity CRP (mg/dL) 0.964
 Procollagen-3-peptide (U/mL) 0.175
 Zn (μg/dL) 0.612
 Total adiponectin (μg/mL) 0.400
 Interleukin-6 (pg/mL) 0.309
Bile acids (BA)
 Total BA (μmol/L) 0.331
 Primary BA (μmol/L) 0.135
 Secondary BA (μmol/L) 0.966
CT scan
 Visceral fat (cm2) 0.673
 Subcutaneous fat (cm2) 0.877
 V/S ratio 0.612
 CT-L1 (HU) 0.025
 CT-L2 (HU) 0.063
 CT-Spleen (HU) 0.866
 L/S ratio 0.035
Baseline treatment for hypertension [ (%)]0.973
 Naive5 (41.7)3 (42.9)
 Other ARB or ACE inhibitor3 (25.0)2 (28.6)
 Calcium channel blocker4 (33.3)2 (28.6)
Baseline treatment for diabetes mellitus [ (%)]0.123
 Diet only12 (100.0)5 (71.4)
 Sulphonylurea+α-glucosidase inhibitor0 (0.0)2 (28.6)
Baseline treatment for lipid abnormality [ (%)]0.603
 Diet only10 (83.3)5 (71.4)
 HMG-CoA reductase inhibitor (statin)2 (16.7)2 (28.6)

Data are mean ± SD. Parameters were compared between groups (telmisartan versus losartan) by Mann-Whitney test or chi-squared test.
3.2. Changes in Anthropometric Measurements and BP

No subject terminated the trial because of adverse events.

Body weight and waist and hip measurements did not change in both groups. Both groups showed a significant decrease in SBP ( versus  mmHg in T group ( ), versus  mmHg in L group ( )) after 12 months. Concerning DBP, a statistically significant decrease was found in the T group ( versus  mmHg ( )), whereas the decrease in the L group did not reach statistical significance ( versus  mmHg ( )) (Table 2).


ParametersGroup0 month12 monthsP-valueDifferenceP-value

Body mass index (kg/m2)T 0.875
L 0.398 0.447
Waist circumference (cm)T 0.247
L 0.091 0.310
Hip circumference (cm)T 0.500
L 0.655 0.754
Systolic blood pressure (mmHg)T 0.045
L 0.046 0.933
Diastolic blood pressure (mmHg)T 0.032
L 0.116 0.446
Pulse (beats/min)T 0.397
L 0.273 0.397

Data are presented as mean SD. Parameters at 0 and 12 months of treatment were compared by Wilcoxon's matched-pair signed-rank test. Differences are shown as [value at 12 months − value at 0 month]. Differences between groups (telmisartan (T) versus losartan (L)) were compared by Mann-Whitney test.
3.3. Changes in Biochemical Measurements

Liver enzyme levels such as AST, ALT, and γGT did not show significant change in both groups after 12 months. While TC, HDL-C, and TG levels did not show significant change in both groups after 12 months, FFA level showed a significant decrease in the T group ( versus  mEq/L ( )) whereas the change in the L group was not significant ( versus  mEq/L ( )).

FPG level did not change in both groups after 12 months. Regarding HbA1c level, the L group showed a significant increase ( versus % ( )), while the change in the T group was not significant ( versus % ( )).

UA level showed a significant decrease in the L group ( versus  mg/dL ( )), while it showed a significant increase in the T group ( versus  mg/dL ( )). Consequently, the difference in changes was also statistically significant.

Levels of other inflammatory markers and bile acids did not show significant change in both groups after 12 months (Tables 3 and 4).


ParametersGroup0 month12 monthsP-valueDifferenceP-value

Aspartate aminotransferase (IU/L)T 0.583
L >0.999 0.672
Alanine aminotransferase (IU/L)T 0.261
L 0.344 0.672
γ Glutamyl transpeptidase (IU/L)T 0.683
L 0.463 0.471
Total cholesterol (mg/dL)T 0.505
L 0.345 0.525
Triglyceride (mg/dL)T 0.433
L 0.866 0.899
HDL cholesterol (mg/dL)T 0.283
L 0.343 >0.999
Free fatty acids (mEq/L)T 0.005
L 0.237 0.007
Fasting plasma glucose (mg/dL)T 0.247
L 0.078 0.031
IRI (μU/mL)T 0.720
L 0.498 0.396
Hemoglobin A1c (%)T 0.552
L 0.017 0.001
HOMA-IRT >0.999
L 0.686 0.770
HOMA-βT 0.374
L 0.043 0.062
Creatinine (mg/dL)T 0.149
L 0.655 0.274
Uric acid (mg/dL)T 0.016
L 0.046 0.002
Primary bile acids (μmol/L)T 0.534
L 0.345 0.447
Secondary bile acids (μmol/L)T 0.906
L 0.735 0.554
Microalbumin in urine (μg/mL)T 0.173
L 0.173 0.884

Data are presented as mean SD. Parameters at 0 and 12 months of treatment were compared by Wilcoxon's matched-pair signed-rank test. Differences are shown as [value at 12 months − value at 0 month]. Differences between groups (telmisartan (T) versus losartan (L)) were compared by Mann-Whitney test.
HDL: high-density lipoprotein, IRI: immunoreactive insulin, and HOMA-IR: homeostasis model assessment-insulin resistance.

ParametersGroup0 month12 monthsP-valueDifferenceP-value

Hyaluronic acid (ng/mL)T 0.091
L 0.345 0.310
7S domain of type 4 collagen (ng/mL)T 0.723
L 0.834 0.419
High-sensitivity C-reactive protein (mg/dL)T 0.155
L 0.176 0.077
Procollagen-3-peptide (U/mL)T 0.656
L 0.351 0.766
Zinc (μg/dL)T 0.139
L 0.735 0.374
Total adiponectin (μg/mL)T 0.553
L 0.753 0.561
Interleukin-6 (pg/mL)T 0.158
L 0.173 0.766

Data are presented as mean SD. Parameters at 0 and 12 months of treatment were compared by Wilcoxon's matched-pair signed-rank test. Differences are shown as [value at 12 months − value at 0 month]. Differences between groups (telmisartan (T) versus losartan (L)) were compared by Mann-Whitney test.
3.4. Changes in Fat Distribution and Fat Deposition in Liver

Visceral and subcutaneous fat area did not change in both groups after 12 months. Consequently, V/S ratio did not change in both groups. Regarding L/S ratio, a significant increase was found in the T group ( versus ( )), while it did not change in the L group ( versus ( )) (Table 5).


ParametersGroup0 month12 monthsP-valueDifferenceP-value

Visceral fat area (cm2)T 0.695
L 0.345 0.353
Subcutaneous fat area (cm2)T 0.875
L