Effect of Sodium Glucose Co-Transporter 2 Inhibitors on Liver Fat Mass and Body Composition in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus
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Background and Objective
Sodium glucose co-transporter 2 inhibitors increase urinary glucose excretion and reduce visceral adiposity and body weight, but their efficacy on patients with nonalcoholic fatty liver disease has not been sufficiently investigated. The aim of this study was to assess the effect of sodium glucose co-transporter 2 inhibitors on liver fat mass and body composition in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus.
We retrospectively analyzed 17 patients with nonalcoholic fatty liver disease and type 2 diabetes who received sodium glucose co-transporter 2 inhibitors between November 2016 and July 2017. Changes in liver fat, subcutaneous and visceral fat, body composition, and liver function-related parameters were assessed after 24 weeks of sodium glucose co-transporter 2 inhibitor treatment and compared to baseline values.
Ten patients received dapagliflozin at 5 mg/day and seven patients received canagliflozin at 100 mg/day for 24 weeks. All patients completed the study without any serious adverse effects and achieved body weight loss and improved glycated hemoglobin levels. Liver fat mass evaluated by proton magnetic resonance spectroscopy was significantly reduced (19.1% vs. 9.2%, p < 0.01), and so were both subcutaneous and visceral fat mass. The body fat/body weight ratio decreased, whereas the skeletal muscle mass/body weight ratio increased. Liver function (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase) improved significantly.
Sodium glucose co-transporter 2 inhibitor treatment not only improved glycemic control but also reduced liver fat mass in patients with nonalcoholic fatty liver disease and type 2 diabetes. Body weight loss was primarily attributable to a reduction in fat mass, especially visceral fat. Thus, sodium glucose co-transporter 2 inhibitors could potentially serve as a therapeutic agent for patients with nonalcoholic fatty liver disease and type 2 diabetes.
Sodium glucose co-transporter 2 inhibitor treatment improved glycemic control and reduced liver fat mass in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus.
Body weight reduction was mostly due to a reduction in fat mass, especially visceral fat, rather than skeletal muscle mass.
Sodium glucose co-transporter 2 inhibitors may be highly useful therapeutic agents for patients with nonalcoholic fatty liver disease and type 2 diabetes.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with an estimated prevalence rate of 25% worldwide . Nonalcoholic fatty liver disease comprises a wide spectrum and ranges from nonalcoholic fatty liver, which rarely progresses to advanced liver diseases, to nonalcoholic steatohepatitis, which can lead to liver fibrosis and hepatocellular carcinoma [2, 3]. Previous studies identified a strong association between NAFLD and obesity, with a positive correlation between body mass index (BMI) and fatty liver . Nonalcoholic fatty liver disease is considered a component of metabolic syndrome mediated by obesity-induced insulin resistance . Furthermore, NAFLD is an independent risk factor for cardiovascular disease and chronic kidney disease [6, 7, 8] and is also significantly associated with the risk of incident type 2 diabetes mellitus (T2DM) [9, 10]. Many cross-sectional studies [11, 12, 13] demonstrated that T2DM is involved in the progression of liver fibrosis and hepatocellular carcinoma. Thus, proper management of T2DM is important to improve the prognosis of patients with NAFLD.
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) suppress the reabsorption of glucose in the kidney and increase urinary glucose excretion, and thereby improve insulin resistance in patients with T2DM by decreasing blood glucose and body weight (BW) . Furthermore, SGLT2i have been shown to reduce cardiovascular events and exert renal protective effects [15, 16]. Recently, the benefits of SGLT2i treatment on liver function were reported in patients with NAFLD and T2DM [17, 18, 19, 20, 21], and the beneficial effects of SGLT2i on fatty liver in patients with T2DM were reviewed . However, few studies have focused on changes in liver fat accumulation after SGLT2i treatment. In this study, we assessed the effect of SGLT2i treatment on liver fat accumulation in patients with NAFLD and T2DM by magnetic resonance imaging (MRI), and analyzed body composition and various parameters related to liver function.
2.1 Study Design and Patient Population
We retrospectively analyzed consecutive patients with NAFLD and T2DM who received SGLT2i monotherapy for more than 24 weeks at the Department of Gastroenterology and Hepatology, Tokai University Oiso Hospital (Kanagawa, Japan) between November 2016 and July 2017. These patients had not received anti-diabetic medication and did not respond to nutrition or exercise intervention for at least 24 weeks.
Nonalcoholic fatty liver disease was diagnosed based on imaging techniques [abdominal ultrasonography and/or computed tomography (CT)] or liver biopsy (steatosis in 5% or more of hepatocytes). The T2DM diagnosis was made according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus . Exclusion criteria were the presence of alcoholic liver diseases (alcohol consumption > 30 g/day for men and 20 g/day for women) , chronic viral hepatitis, autoimmune hepatitis, drug-induced liver injury, biliary tract disease, decompensated liver cirrhosis, hepatocellular carcinoma, history of diabetic ketoacidosis, active ongoing urinary tract infections, addition of other anti-diabetic drugs during the study period, and presence of severe comorbidities such as heart, respiratory, and/or renal dysfunction (estimated glomerular filtration rate < 45 mL/min/1.73 m2).
After SGLT2i treatment was started, patients were required to visit the outpatient clinic every 1 or 2 months. Patients received diet and exercise therapy instructions from a dietician every 2 months during SGLT2i treatment. These nutrition and exercise interventions were the same as those given prior to treatment. Adverse events were recorded on each visit and the severity assessed according to the Common Terminology Criteria for Adverse Events Version 4.0.
2.2 Laboratory and Clinical Parameters
We collected baseline information such as age, sex, BW, BMI (calculated as weight in kg/height in m2), concomitant metabolic disease, and laboratory parameters. Diagnosis of metabolic diseases was based on defined characteristics and the patient’s medication regimen. Hypertension was diagnosed in patients with systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg, or in those taking antihypertensive medication. Patients with serum triglyceride (TG) levels ≥ 150 mg/dL and/or high-density lipoprotein cholesterol (HDL-C) levels < 40 mg/dL, or those taking lipid-lowering medication were diagnosed with dyslipidemia. Hyperuricemia was present in patients with serum uric acid levels > 7.0 mg/dL, or in those taking uric acid-lowering medication.
Blood samples were obtained in the outpatient clinic in the morning following a 12-h overnight fast. Laboratory parameters included blood cell counts and levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase, creatinine, blood urea nitrogen, uric acid, TG, total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, glycated hemoglobin (HbA1c), fasting plasma glucose, fasting insulin, and ferritin. HbA1c was expressed as National Glycohemoglobin Standardization Program units (%). Insulin resistance was evaluated by homeostasis model assessment-insulin resistance (HOMA-IR) using the following formula: HOMA-IR = fasting insulin (IU/mL) × plasma glucose (mg/dL)/405 . Two non-invasive hepatic fibrosis scores were calculated according to the following formula: AST to platelet ratio index (APRI) = [AST (IU/L)/ULN (IU/L)] × 100/platelet count (109/L), where ULN is the upper limit of normal , and Fibrosis 4 (FIB-4) index = [age (years) × AST (IU/L)]/[platelet count (109/L)] × √ALT (IU/L)] .
2.3 Quantification of Liver Fat Mass
Liver fat was determined by proton magnetic resonance spectroscopy (1H-MRS) [28, 29, 30, 31, 32]. Magnetic resonance imaging was performed using a 1.5 T unit (Signa HDxt Version 16, GE Healthcare, Milwaukee, WI, USA) with an eight-channel body array coil. For spectroscopy analysis, we used SAGE Version 7 (GE Healthcare). A 30 × 30 × 30 mm3 voxel was positioned in the liver right lobes with careful avoidance of ducts and vasculature. The power spectrum was calculated from the obtained magnetic resonance signal, and curve fitting was performed by the Lorenz curve. The area under the curve in the frequency range of water and fat was determined, and the fat/water ratio in the liver was calculated. The scanning parameters were as follows: pulse sequence: Probe-P, repetition time: 1149.0 ms, echo time: 27.0 ms, number of excitations: 2.00, acquisition matrix: 1 × 1, and scan time: 23 s with breath hold. Magnetic resonance imaging was conducted with the patient lying in the supine position. We started magnetic resonance spectroscopy imaging as a routine hepatic MRI sequence in August 2015, and performed this examination every 6 months to quantitatively evaluate liver fat in NAFLD patients.
2.4 Evaluation of Body Composition
Body composition was evaluated using InBody 770 (InBody Japan, Tokyo, Japan), a body composition analyzer equipped with simultaneous multi-frequency impedance measurement technology. In addition, the visceral fat area (VFA) and subcutaneous fat area (SFA) were analyzed by CT scans (Aquilion 128; Siemens Healthineers, Erlangen, Germany) using Fat Scan software (N2 System Corporation, Hyogo, Japan). A single cross-sectional scan at the level of the umbilicus (the fourth and fifth lumbar disc position) was selected for quantification [33, 34].
2.5 Statistical Analysis
The values obtained after the 24-week treatment were compared with baseline values using the Wilcoxon signed-rank test. We also evaluated the correlations between changes in 1H-MRS fat/water ratio and other variables using the Spearman coefficient. All analyses were performed using SPSS Version 24 (SPSS Japan, Tokyo, Japan), and p values < 0.05 were considered statistically significant.
2.6 Ethical Approval
This study was approved by the Institutional Review Board for Clinical Research at Tokai University (No. 17R-376). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
3.1 Patients’ Characteristics
Clinical characteristics of the patients in this study
Body weight (kg)
3.2 Effect of Sodium-Glucose Co-Transporter 2 Inhibitors on Liver Fat Mass and Body Composition
3.3 Effect of Sodium-Glucose Co-Transporter 2 Inhibitors on Clinical Parameters
Changes in laboratory findings at baseline and after 24 weeks of SGLT2i treatment in patients with NAFLD and type 2 diabetes mellitus
Fasting insulin (μU/mL)
Platelet count (× 104/μL)
eGFR (mL/min/1.73 m2)
Uric acid (mg/dL)
Mild adverse events observed during 24 weeks of SGLT2i treatment included itching of the genital area in two patients (11.8%) and urinary tract infection in one patient (5.9%). There were no serious adverse events.
In this study, we demonstrated that SGLT2i treatment not only reduced BW but also improved liver fat accumulation in patients with NAFLD and T2DM. The observed weight loss was mostly due to a reduction in body fat mass rather than skeletal muscle mass.
Deposition of fat in the liver occurs as a consequence of increased free fatty acid influx from food or fat cells, increased de novo lipid synthesis in the liver, or decreased free fatty acid oxidation and TG trafficking . In clinical practice, abdominal ultrasonography is generally used to diagnose fatty liver. Nevertheless, this imaging technique has low sensitivity and low reproducibility in the quantification of liver fat , and the diagnosis may be influenced by the skill level of the operator. Although liver biopsy was regarded as the gold standard for the diagnosis and histological assessment of NAFLD, it has several limitations such as sampling error, invasiveness, and inter-observer differences . The liver-to-spleen ratio may be obtained by a CT scan to quantify liver fat accumulation , but its disadvantages include radiation exposure and inadequate sensitivity to detect minor steatosis and slight changes in fat content . An ideal device to monitor liver fat content should be non-invasive, safe, sensitive, accurate, and repeatable, which renders MRI the method of choice . Proton magnetic resonance spectroscopy can accurately determine the fat/water ratio in hepatic tissue by measuring the chemical shift of protons in water and lipids [31, 41]. In fact, results obtained by 1H-MRS were proven to be highly correlated with actual hepatic steatosis [29, 30]. The present study demonstrated significant a reduction in liver fat mass evaluated by 1H-MRS after 24 weeks of SGLT2i treatment in patients with NAFLD and T2DM. These results are in agreement with two previous studies using MRI. The E-LIFT trial  conducted in India showed a significant reduction in liver fat mass evaluated by MRI-proton density fat fraction after 20 weeks of empagliflozin treatment, and the LEAD trial  conducted in Japan demonstrated a significant reduction in liver fat mass evaluated by MRI hepatic fat fraction after 24 weeks of luseogliflozin treatment. In our study, liver fat mass reduction was significantly correlated with BW reduction, which is consistent with the results of the LEAD trial. Changes in serum ferritin, fasting insulin, HOMA-IR, and body fat mass were also significantly correlated with liver fat mass reduction.
In contrast to SGLT2i, sitagliptin, an oral antidiabetic drug that inhibits dipeptidyl peptidase IV, did not improve liver fat mass evaluated by MRI-proton density fat fraction after 24 weeks of treatment [44, 45]. A recent meta-analysis showed that treatment with another antidiabetic drug, metformin (a biguanide agent), did also not achieve a reduction in liver fat mass . Pioglitazone reduced liver fat mass  but was associated with a risk of BW gain. However, glucagon-like peptide-1 receptor agonists have been reported to reducing liver fat content and BW [48, 49, 50], similar to SGLT2i.
In this study, the ratio between skeletal muscle mass and BW significantly increased, whereas the body fat mass to BW ratio significantly decreased with 24 weeks of SGLT2i treatment. Decreasing body fat mass without a loss of skeletal muscle mass is an important aspect of NAFLD treatment, which is why the relationship between sarcopenia (characterized by a decrease in skeletal muscle mass and muscle strength ) and NAFLD has gained much attention. Approximately 12% of patients with NAFLD are diagnosed with sarcopenia . In a Korean study, even 22.7% of patients with NAFLD were identified with sarcopenia and it was an independent risk factor for nonalcoholic steatohepatitis and significant fibrosis . Mizuno et al.  reported that the reduction in serum ALT levels within 12 months was significantly greater in patients with an increased SF ratio compared with those with a decreased SF ratio. The precise mechanisms are unknown, but changes in adipokines, myokines, and hepatokines may be involved. In our study, SGLT2i administration increased both skeletal muscle percentage and the SF ratio, suggesting that SGLT2i does not induce sarcopenia.
Baseline median VFA was 139 cm2 in this study, exceeding the cut-off value of 100 cm2 that indicates visceral obesity based on the proposed definition of the Japan Society for the Study of Obesity. It decreased by 12.8% after 24 weeks of SGLT2i treatment. Only a few reports have demonstrated a decrease in visceral fat caused by SGLT2i [55, 56, 57]. Recently, results of SGLT2 inhibitors on body composition and metabolic parameters in a Japanese population have been reported (LIGHT Study); luseogliflozin 52-week treatment resulted in body fat reduction, and minimal muscle and bone mineral content reductions in moderately obese Japanese patients with T2DM . The changes in body content by SGLT2i were similar to our study, and it was also consistent that the changes of VFA and BW were significantly correlated. The excess accumulation of visceral fat is linked to the onset of arteriosclerotic diseases such as T2DM, dyslipidemia, and hypertension [58, 59, 60]. Decreasing visceral fat mass improves insulin resistance, hypertension, and dyslipidemia, and hence reduces the risk of cardiovascular diseases [61, 62].
In this study, serum TG levels, uric acid levels, and the TG/HDL-C ratio decreased significantly. The decrease in TG appears to be a result of improved insulin resistance because of diminished VFA . Maruyama et al.  reported a correlation between the TG/HDL-C ratio and small dense LDL-C levels, which are associated with the occurrence of cardiovascular events . The decrease in the TG/HDL-C ratio observed in our study may reflect lower small dense LDL-C levels, which would be in agreement with a previous study using dapagliflozin . Increased serum uric acid levels are a known risk factor for cardiovascular events . Sodium glucose co-transporter 2 inhibitor treatment decreased uric acid levels by mechanisms yet unknown. Sodium glucose co-transporter 2 inhibitors may promote uric acid excretion into the urine via glucose transporter 9 activation by inhibiting SGLT2-mediated glucose reabsorption [68, 69]. Decreased serum TG levels, uric acid levels, and the TG/HDL-C ratio resulting from SGLT2i treatment may lead to the prevention of future cardiovascular events.
There are currently six types of SGLT2i-based drugs on the market in Japan. Although some of these drugs (e.g., canagliflozin and sotagliflozin) exert mild or moderate inhibitory effects on intestinal and renal SGLT1 as well , there are no documented differences in the clinical effect of the available SGLT2i-based drugs . We did not observe any obvious differences between the two drugs we used in our study (dapagliflozin and canagliflozin) with regard to the improvement of liver fat mass, BW, and various metabolic pathways.
A recent study showed that a BW loss of at least 7% was necessary to improve the NAFLD Activity Score, a histological scoring system composed of hepatic steatosis, lobular inflammation, and ballooning degeneration [47, 72]. In our study, SGLT2i treatment for 24 weeks resulted in a 9.4% BW reduction and hence might improve the NAS; however, we did not perform any liver biopsies.
In patients with NAFLD, liver fibrosis was identified as the most important factor contributing to liver-related death . Furthermore, T2DM is a significant risk factor for advanced liver fibrosis . It is therefore important to analyze whether SGLT2i treatment can improve liver fibrosis. In this study, the APRI but not the FIB-4 index improved significantly. Although reports have indicated that SGLT2i treatment significantly reduces the FIB-4 index after a follow up of 24 weeks , 26 weeks , and 48 weeks , other reports found no significant reduction in the FIB-4 index [43, 78], showing that there is no consensus. No studies have reported significant reductions in APRI with SGLT2i treatment. Because we had not performed liver biopsies after the 24-week SGLT2i treatment, we could not accurately assess whether there were improvements in histologic fibrosis. Akuta et al.  reported that 24 weeks of treatment with canagliflozin in patients with NAFLD and T2DM achieved histological improvement; scores of the fibrosis stage decreased by 33% compared with the pretreatment. However, long-term observations are necessary to determine whether SGLT2i improves liver fibrosis in patients with NAFLD and T2DM.
Some patients experienced itching of the genital area (11.8%) and urinary tract infection (5.9%) during SGLT2i treatment. These known adverse effects were mild and did not interrupt treatment. Sodium glucose co-transporter 2 inhibitors therefore appeared sufficiently safe.
Our study has some limitations. We included only a small number of patients and lacked a placebo group, which may limit the strength of our conclusions. Furthermore, this was a retrospective study and we cannot completely exclude the possibility of selection bias. In addition, the treatment period was comparatively short. Nevertheless, our study suggests potential benefits and safety of SGLT2i treatment in patients with NAFLD and T2DM. Further large-scale and long-term prospective studies are warranted to confirm our results.
In this study, we showed that SGLT2i treatment not only improved glycemic control but also reduced liver fat mass in patients with NAFLD and T2DM. Importantly, BW reduction was mostly due to a reduction in fat mass, especially visceral fat, rather than skeletal muscle mass. Thus, SGLT2i are highly useful therapeutic agents for patients with NAFLD and T2DM.
We thank Yuhei Otsuka at the Department of Radiology, Tokai University Oiso Hospital, Kanagawa, Japan for technical support with 1H-MRS. We also thank Editage (http://www.editage.jp) for English language editing.
YA, KS, KA, HS, ET, and RD planned this study’s content, collected patient’s data, and wrote the manuscript. KT, SH, MT, TM, and TK provided technical or material support. YA drafted the manuscript. All authors analyzed the data, reviewed the manuscript, and approved the final version for publication.
Compliance with Ethical Standards
No sources of funding were received for this article.
Conflict of interest
Yoshitaka Arase, Koichi Shiraishi, Kazuya Anzai, Hirohiko Sato, Erika Teramura, Kota Tsuruya, Shunji Hirose, Ryuzo Deguchi, Masao Toyoda, Tetsuya Mine, and Tatehiro Kagawa have no conflicts of interest that are directly relevant to the content of this article.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board for Clinical Research at Tokai University (No. 17R-376).
As this was a retrospective study, formal consent was not required.
All data generated or analyzed during this study are included in this published article.
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