Comparison of the Efficacy of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter-2 Inhibitors in Diabetic Patients with Steatotic Liver Disease (original) (raw)

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Yunmi Ko , Moon Haeng Hur , Youngsu Park , Jeayeon Park , Hyunjae Shin , Yun Bin Lee , Eun Ju Cho , Jeong-Hoon Lee , Su Jong Yu , Jung-Hwan Yoon , Yoon Jun Kim

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

Received: December 25, 2024; Revised: March 23, 2025; Accepted: March 25, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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• Abstract
• Graphical Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• SUPPLEMENTARY MATERIALS
• References

Background/Aims: There is currently insufficient evidence to recommend one oral hypoglycemic agent over another for diabetic patients to reduce hepatic steatosis or prevent advanced fibrosis. We aimed to evaluate the efficacy of dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes mellitus (DM) and metabolic dysfunction-associated steatotic liver disease (MASLD).
Methods: This study included diabetic patients with steatotic liver disease who newly received either a DPP-4i or an SGLT-2i as a second-line treatment between 2014 and 2021 at a single tertiary hospital. MASLD was categorized as MASLD-H (radiologic steatosis with a hepatic steatosis index [HSI]>36) or MASLD-I (radiologic steatosis only). Changes in the HSI and fibrosis-4 (FIB-4) index were compared at 1 and 3 years after treatment initiation.
Results: A total of 3,493 patients were consecutively enrolled, with 3,001 receiving DPP-4i treatment and 492 receiving SGLT-2i treatment. After applying propensity score matching, the SGLT-2i group showed a significantly greater reduction in the HSI than the DPP-4i group in the DM-MASLD population at both 1 year (DM-MASLD-H: DPP-4i vs SGLT-2i, –1.4% vs –3.7%, p<0.001; DM-MASLD-I: –1.3% vs –3.8%, p<0.001) and 3 years (DM-MASLD-H: –2.0% vs –4.0%, p=0.001; DM-MASLD-I: –2.4% vs –4.2, p=0.025). The FIB-4 indices of both groups increased; however, the increase at year 1 was more significant in the DPP-4i than in the SGLT-2i group (DM-MASLD-H: 11.4% vs 5.2%, p<0.001; DM-MASLD-I: 10.7% vs 4.3%, p=0.014).
Conclusions: In patients with DM-MASLD, SGLT-2i treatment was associated with a greater reduction in hepatic steatosis and delayed fibrotic progression than DPP-4i treatment.

Keywords: Fatty liver, Diabetes mellitus, type 2, Dipeptidyl-peptidase IV inhibitors, Sodium-glucose transporter 2 inhibitors

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, which refers to hepatic fat accumulation without excessive alcohol consumption and any secondary cause.1 Approximately 25% of the global population is currently estimated to have NAFLD, and it is anticipated that the proportion of NAFLD patients with advanced liver disease will continue to rise.2 Although NAFLD can progress to advanced hepatic fibrosis or hepatocellular carcinoma, no pharmacotherapy has been approved.

NAFLD and type 2 diabetes mellitus (DM) are closely related and negatively impact each other. DM can occur in populations with obesity due to insulin resistance, and ectopic fat accumulation in the liver has been reported to contribute to the development of DM.3 Approximately 50% of patients with DM are reported to have NAFLD. According to a meta-analysis, the overall prevalence of NAFLD among patients with DM is 55.5%, which is about two times higher than in the general population.4 To highlight the impact of metabolic disorders such as DM in patients with steatotic liver disease, the concept of metabolic dysfunction-associated fatty liver disease and, more recently, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed.5-7

There are currently insufficient data to recommend one oral hypoglycemic agent (OHA) over another to improve hepatic steatosis or prevent advanced fibrosis in patients with DM. Among the various OHAs, the sodium-glucose cotransporter-2 inhibitor (SGLT-2i), which induces glycosuria and weight loss, has shown promising results in liver diseases. Several randomized controlled trials (RCTs) have reported that patients with DM treated with SGLT-2i showed decreased hepatic fat content or abdominal fat area.8,9 These protective effect role of SGLT-2i on hepatic steatosis were also confirmed in animal models.10 Therefore, we aimed to evaluate the effects of SGLT-2i on hepatic steatosis and fibrosis in diabetic patients with MASLD, compared to those of dipeptidyl peptidase-4 inhibitor (DPP-4i), another commonly prescribed OHA.

1. Study population

This retrospective cohort study included adult patients with type 2 DM who were treated with either DPP-4i or SGLT-2i as a second-line therapy between 2014 and 2021 at a single tertiary center (Seoul National University Hospital) in South Korea. Type 2 DM was identified using the International Classification of Diseases, 10th revision diagnosis code. The index date was defined as the first day of treatment with either DPP-4i or SGLT-2i as second-line agents due to the reimbursement policy of health insurance. The DPP-4i group included patients treated with sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, anagliptin, teneligliptin, or evogliptin, while the SGLT-2i group included those who received dapagliflozin, empagliflozin, ipragliflozin, or ertugliflozin.

Exclusion criteria were as follows: (1) treatment with a thiazolidinedione or a glucagon-like peptide-1 agonist; (2) co-administration of DPP-4i and SGLT-2i; (3) patients who had not received metformin, sulfonylurea, or insulin treatment prior to the index date; (4) patients without DPP-4i or SGLT-2i prescription data; (5) DPP-4i or SGLT-2i treatment for less than 6 months; (6) confirmation of hepatocellular carcinoma, liver cirrhosis (LC) decompensation (i.e., varix, ascites, and hepatic encephalopathy), or liver transplantation before the index date or within 6 months; (7) alcoholic liver disease; and (8) incomplete data. This study received approval from the Institutional Review Board of Seoul National University Hospital (No. H-2111-112-1272). The requirement for informed consent was waived due to the retrospective design of current study and the anonymity of the patients’ data.

2. Variables and group definitions

For each patient, baseline characteristics were collected at the index date, including the initially prescribed antidiabetic agents, aspartate aminotransferase, alanine aminotransferase, and platelet count. We categorized into the DM-MASLD cohort into two groups using radiologic steatosis and/or the hepatic steatosis index (HSI). Radiologic steatosis was defined as the presence of hepatic steatosis on computed tomography or ultrasonography. To complement the limitations of radiologic steatosis, we included HSI as another noninvasive marker. The DM-MASLD-H (H; HSI plus imaging) group was defined as patients with type 2 DM who have radiologic evidence of steatotic liver and an HSI>36.11 We then defined the DM-MASLD-I (I; imaging) group, in which hepatic steatosis was determined based on radiologic evidence only, instead of HSI,6 and evaluated whether similar results were reproduced using this classification. The HSI serves as a noninvasive diagnostic tool to assess the severity of hepatic steatosis. The HSI can detect NAFLD with a specificity of 92.4% (95% confidence interval, 91.3% to 93.4%) at values greater than 36.0.11 Furthermore, in diabetic patients with hepatic steatosis, an HSI greater than 36 can predict steatotic liver disease with a sensitivity of 89.6%, a specificity of 95.2%, and an area under the receiver operating characteristics curve of 0.979.12 Accordingly, we set an HSI cutoff of 36 to identify hepatic steatosis in diabetic patients.

3. Outcome

The primary outcome was the change in HSI from baseline to 1 and 3 years in each treatment arm. As a secondary outcome, we compared the change in fibrosis-4 (FIB-4) index from baseline to 1 and 3 years between the two groups. The FIB-4 index serves as a surrogate marker for the degree of hepatic fibrosis in steatotic liver disease. A FIB-4 index <1.3 indicates a low risk of fibrosis, whereas an index >2.67 is categorized as a high risk of fibrosis, with a specificity of 96%.13 In addition, the cumulative incidence of LC-related outcomes (e.g., varix, ascites, or portosystemic encephalopathy) or liver-related outcomes was assessed. Liver-related outcomes included LC-related outcomes, as well as the occurrence of hepatocellular carcinoma, liver transplantation, or liver-related mortality.

4. Statistical analyses

The student t test and chi-square test were performed to compare continuous and categorical variables, respectively, between the DPP-4i and SGLT-2i groups. To balance the two treatment groups among patients with DM-MASLD 2:1 (DPP-4i:SGLT-2i) propensity score matching (PSM) was applied using a nearest-neighbor method with a caliper size of 0.2. The propensity score was calculated using variables including age, sex, body mass index (BMI), history of metformin, sulfonylurea or insulin use, history of dyslipidemia, glomerular filtration rate, and serum levels of total bilirubin, albumin, prothrombin time, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Hepatic steatosis was assessed using the HSI, while hepatic fibrosis was evaluated using the FIB-4 index. The aspartate aminotransferase to platelet ratio index (APRI) was also used to confirm our findings. The APRI has been used as a noninvasive marker for hepatic fibrosis, with a cutoff value of <0.5 effectively ruling out significant fibrosis, while a cutoff of >1.5 can be considered indicative of significant fibrosis.14 Changes in HSI or FIB-4 index before and after treatment with either DPP-4i or SGLT-2i were evaluated using the paired t test. The Kaplan-Meier method and log-rank test were used to evaluate LC-related and liver-related outcomes. Subgroup analyses were conducted to compare the effectiveness of the two drugs among either DM-MASLD-H or DM-MASLD-I patients with a BMI >25 kg/cm2. All statistical analyses were performed using R 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria). A p_-_value less than 0.05 was considered statistically significant.

RESULTS

Go to

• Abstract
• Graphical Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• SUPPLEMENTARY MATERIALS
• References

1. Baseline characteristics

A total of 31,317 patients with type 2 DM were screened for this study. After applying the exclusion criteria, 3,493 consecutive patients were classified as DM-MASLD-H (Fig. 1): 3,001 received DPP-4i and 492 received SGLT-2i treatment. The mean duration of treatment was 3.1 and 2.5 years in the DPP-4i and SGLT-2i groups, respectively. The baseline characteristics of the population with DM-MASLD-H are shown in Table 1. More than half of the patients in both groups had a BMI greater than 25 kg/m2. The SGLT-2i group was younger and had a greater proportion of males, compared to the DPP-4i group (both p<0.001). In the SGLT-2i group, the HSI was significantly higher at baseline, while the FIB-4 index was lower than in the DPP-4i group (both p<0.001). After applying the PSM, all baseline variables were well balanced.

Figure 1.Patient flow diagram. A total of 3,493 eligible DM-MASLD-H patients were included, and they were categorized into the DPP-4i or SGLT-2i group. DM, diabetes mellitus; MASLD-H, metabolic dysfunction-associated steatotic liver disease (HSI plus imaging); HSI_,_ hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Table 1. Baseline Characteristics of Patients with DM-MASLD-H before and after PSM

Data are presented as mean±SD or number (%). Continuous variables were compared using t-test and categorical variables were compared using the chi-square test. Propensity scores were computed using following variables: age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, GFR and serum levels of total bilirubin, albumin, PT, LDL-C, and HDL-C.

DM, diabetes mellitus; MASLD-H, metabolic dysfunction-associated steatotic liver disease (HSI plus imaging); PSM, propensity score matching; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; HSI_,_ hepatic steatosis index; FIB-4 index, fibrosis-4 index.

After evaluating hepatic steatosis based on radiologic evidence only, a total of 1,710 patients with DM-MASLD-I were identified. Of these, 1,446 and 264 patients received DPP-4i and SGLT-2i treatment, respectively. Baseline characteristics of the population with DM-MASLD-I are summarized in Table 2. Overall baseline characteristics of DM-MASLD-I were similar to those of DM-MASLD-H, and all variables were well balanced following PSM. The use of hepatoprotective agents, such as ursodeoxycholic acid, biphenyl-dimethyl-dicarboxylate, and/or silymarin ranged from 10% and 20% across the groups. In patients with DM-MASLD, both the DPP-4i and SGLT-2i groups showed reductions in weight and BMI over the 1- and 3-year follow-up periods. Similarly, hemoglobin A1c levels demonstrated a decreasing trend at 1 and 3 years compared to the baseline, with no significant differences between the two treatment groups (Supplementary Tables 1 and 2).

Table 2. Baseline Characteristics of Patients with DM-MASLD-I before and after PSM

Data are presented as mean±SD or number (%). Continuous variables were compared using t-test and categorical variables were compared using the χ2 test. Propensity scores were computed using following variables: age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, GFR and serum levels of total bilirubin, albumin, PT, LDL-C, and HDL-C.

DM, diabetes mellitus; MASLD-I, metabolic dysfunction-associated steatotic liver disease (imaging); PSM, propensity score matching; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; HSI_,_ hepatic steatosis index; FIB-4 index, fibrosis-4 index; NA, not available.

2. Changes in hepatic steatosis after DPP-4i or SGLT-2i treatment

Changes in hepatic steatosis among DM-MASLD-H patients after OHA treatment are shown in Fig. 2. In the population with DM-MASLD-H, the reduction in HSI was more prominent in the SGLT-2i group compared to the DPP-4i group at both 1 year and 3 years (DPP-4i vs SGLT-2i: –1.4%±8.0% vs –3.7%±7.5% at 1 year, p<0.001; –2.0%±8.5% vs –4.0%±8.0% at 3 years, p=0.001). Similarly, in the DM-MASLD-I population, patients treated with SGLT-2i demonstrated a more pronounced reduction in hepatic steatosis over time compared to those receiving DPP-4i (–1.3%±7.6% vs –3.8%±7.4% at 1 year, p<0.001; –2.4%±8.4% vs –4.2%±8.5% at 3 years, p=0.026) (Fig. 2). Furthermore, when patients were categorized into the “improved,” “no change,” and “worsened” groups based on an HSI cutoff of 36 at 1 and 3 years follow-ups, a greater proportion of those treated with SGLT-2i showed improvement in both the DM-MASLD-H and DM-MASLD-I cohorts (DM-MASLD-H: 10.4% vs 15.3% at 1 year; 12.0% vs 15.7% at 3 years; DM-MASLD-I: 9.8% vs 15.4% at 1 year; 12.4% vs 17.4% at 3 years) (Supplementary Fig. 1).

Figure 2.Mean percentage changes in the HSI after 1 year and 3 years of antidiabetic agent treatment in patients with DM-MASLD. Mean percentage changes in the HSI in the DM-MASLD-H group (A, B) and DM-MASLD-I group (C, D). Both groups were balanced using propensity score matching. Data are presented as the mean±SD. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

3. Changes in hepatic fibrosis after DPP-4i or SGLT-2i treatment

In the DM-MASLD-H cohort, both treatment groups showed an increase in the FIB-4 index over time. The increase was significantly greater in the DPP-4i group compared to the SGLT-2i group at year 1 (11.4%±36.5% vs 5.2%±26.7%, p<0.001) (Fig. 3), whereas it was comparable at year 3 (17.6%±78.9% vs 11.3%±35.0%, p=0.097). Similarly, in the DM-MASLD-I cohort, the DPP-4i group demonstrated a tendency of more pronounced fibrosis progression than the SGLT-2i group. The increase in the FIB-4 index was significantly greater in the DPP-4i group than the SGLT-2i group at year 1, while the difference was not significant at year 3 (10.7%±42.4% vs 4.3%±25.7% at 1 year, p=0.014; 18.0%±81.3% vs 12.3%±40.0% at 3 years, p=0.303) (Fig. 3).

Figure 3.Mean percentage changes in the FIB-4 index after 1 year and 3 years of antidiabetic agent treatment in patients with DM-MASLD. Mean percentage changes in the FIB-4 index in the DM-MASLD-H group (A, B) and DM-MASLD-I group (C, D). Both groups were balanced using propensity score matching. Data are presented as the mean±SD. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; FIB-4 index, fibrosis-4 index.

When hepatic fibrosis was assessed using APRI, a similar trend was observed, with fibrosis progression over time in both DM-MASLD-H and DM-MASLD-I cohorts. The DPP-4i group exhibited significant fibrosis progression, whereas the SGLT-2i group showed minimal fibrosis progression across the DM-MASLD population (DM-MASLD-H: 15.3%±66.1% vs –0.7%±43.4% at 1 year, p<0.001; 15.9%±132.1% vs –0.2%±55.0% at 3 years, p=0.011; DM-MASLD-I: 13.5%±68.5% vs –0.3%±44.5% at 1 year, p=0.002; 16.9%±193.9% vs 1.0%±66.1% at 3 years, p=0.183) (Supplementary Fig. 2).

4. Cumulative incidence of LC-related and liver-related outcomes

Figs 4 and 5 show the cumulative incidence of LC-related and liver-related outcomes, respectively. In the DM-MASLD-H cohort, LC-related outcomes occurred in 19 of 3,001 patients in the DPP-4i group and five of 492 patients in the SGLT-2i group, while liver-related outcomes were confirmed in 31 and six patients. There were no significant differences between the two groups before and after PSM (all p>0.05), and similar results were found in the DM-MASLD-I cohort.

Figure 4.Cumulative incidence of liver cirrhosis-related outcomes in patients with DM-MASLD-H (A, B) and DM-MASLD-I (C, D) before and after propensity score matching. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Figure 5.Cumulative incidence of liver-related outcomes in patients with DM-MASLD-H (A, B) and DM-MASLD-I (C, D) before and after propensity score matching. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

5. Subgroup analyses

Supplementary Tables 1 and 2 compared weight, BMI, hemoglobin A1c, HSI, and FIB-4 index at 1 and 3 years within each treatment group (DPP-4i and SGLT-2i) relative to baseline in the DM-MASLD-H and DM-MASLD-I cohorts, respectively. In the SGLT-2i group, HSI significantly decreased at both 1 and 3 years compared to baseline, whereas FIB-4 index was comparable to baseline at 1 year but significantly increased at 3 years.

The effectiveness of the DPP-4i (n=1,824) and SGLT-2i (n=412) was compared in the DM-MASLD-H patients with a BMI >25 kg/m2. The baseline characteristics of the two treatment groups were well balanced following a nearest-neighbor 2:1 PSM using variables including age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, glomerular filtration rate, and serum levels of total bilirubin, albumin, prothrombin time and low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, and triglyceride (Supplementary Table 3). The SGLT-2i group demonstrated a greater reduction in hepatic steatosis at both 1 and 3 years, and a smaller increase in hepatic fibrosis at 1 year compared to the DPP-4i group (Supplementary Figs 3 and 4). However, the change in the FIB-4 index at 3 years was comparable between the two groups (p=0.106). Similar results were reproduced in the DM-MASLD-I patients with a BMI >25 kg/m2 (Supplementary Table 4, Supplementary Figs 3 and 4).

This retrospective study compared the change in HSI or FIB-4 index among patients with DM-MASLD-H or DM-MASLD-I who received DPP-4i and SGLT-2i treatment as a second-line OHA. While both treatment groups showed a decrease in BMI, the SGLT-2i group exhibited a more significant reduction in liver steatosis at both 1 and 3 years, compared to the DPP-4i group. The FIB-4 index increased over time in both groups; however, hepatic fibrosis progression was more pronounced in the DPP-4i group than the SGLT-2i group.

While the mechanisms for the development of MASLD are multifactorial, type 2 DM is one of the major risk factors for the progression of MASLD.15 Insulin resistance, which often precedes type 2 DM, plays a critical role in the development of hepatic steatosis and its subsequent progression to steatohepatitis.16,17 Insulin resistance in muscle cells triggers decreased glycogen synthesis and elevated blood glucose levels, stimulating hepatic de novo lipogenesis, and ultimately leading to the accumulation of intrahepatic free fatty acids.17 Furthermore, insulin resistance and the subsequent hyperinsulinemia can increase the breakdown of free fatty acids in adipose tissue, resulting in abundant influx of free fatty acids into the liver and promoting hepatic lipogenesis.18 These conditions can contribute to the excessive accumulation of free fatty acids in the liver, which may induce inadequate hepatic β-oxidation and progress from steatohepatitis to fibrosis.16

Despite ongoing research on medications targeting the underlying mechanisms of MASLD, there are currently few pharmaceutical treatment options for steatotic liver disease.19 SGLT-2i is a relatively new class of antidiabetic drug, known for its ability to control blood glucose levels by inhibiting glucose reabsorption in the proximal tubules of the kidney, which can induce glycosuria.20 This SGLT-2i treatment can substantially reduce hepatic lipogenesis by decreasing blood glucose levels.21 SGLT-2i can also stimulate α-cells of the pancreas, increasing glucagon secretion, which can trigger β-oxidation in the liver, promoting the shift of carbohydrate to fatty acid metabolism.21 Furthermore, in vivo studies showed that SGLT-2i may reduce free radical generation, in addition to alleviating high glucose-induced oxidative stress.21,22 Previous RCTs have demonstrated that, compared to pioglitazone, empagliflozin effectively reduced liver fat and improved hepatic fibrosis in patients with type 2 DM and NAFLD,9,2 with similar findings supported by a Mendelian randomization study. Another prospective study using transient elastography to assess hepatic steatosis and fibrosis demonstrated that SGLT-2i may slow fibrosis progression.

Apart from SGLT-2i, DPP-4i is a commonly used agent that regulates blood glucose levels through the degradation of incretin hormones such as glucagon-like peptide-1, and through either augmentation of insulin secretion, or inhibition of glucagon release.26 According to an RCT, the DPP-4i sitagliptin was reported to be no more effective than a placebo in improving liver fat and fibrosis in patients with NAFLD.27 On the other hand, another RCT illustrated that sitagliptin ameliorated hepatic steatosis and hepatocyte ballooning, confirmed by liver biopsy after year 1.28 Nonetheless, studies comparing DPP-4i and SGLT-2i have suggested that SGLT-2i may be more effective. Some retrospective cohort studies demonstrated that the SGLT-2i group in DM-metabolic dysfunction-associated fatty liver disease not only exhibited a greater reduction in the fatty liver index compared to the DPP-4i group,29 but also showed a significant improvement in the FIB-4 index among type 2 DM patients.30

We showed that over a prolonged follow-up period, both DPP-4i and SGLT-2i groups in the DM-MASLD populations led to a decrease in hepatic steatosis, but a tendency toward progression of fibrosis. The slower progression of fibrosis in the SGLT-2i group may be attributed to a greater reduction in hepatic steatosis compared to the DPP-4i group. Fibrosis progression despite reduction in hepatic steatosis may result from persistent insulin resistance in patients with type 2 DM, which can promote chronic low-grade inflammation and lead to hepatic fibrosis.31 During the follow-up period, the differences in steatosis or fibrosis between the two treated groups were attenuated. This attenuation may result from the cumulative effect of various factors other than diabetes medications on outcomes.

Our study has several limitations. First, as a single-center retrospective study, selection bias may have been introduced. Due to the retrospective design, it was challenging to fully control external factors, such as lifestyle modification, which could influence hepatic steatosis and fibrosis.32 In addition, differences in compliance and variations in treatment duration among patients receiving triple therapy with metformin, sulfonylurea, and SGLT-2i may have posed limitations in evaluating outcomes. The use of hepatoprotective agents was another potential confounder. Despite our efforts to assess their use through hospital records, some patients may have obtained them from external sources or taken them as supplements, making it difficult to fully account for their potential effects. To mitigate residual potential biases, patients in both groups were enrolled consecutively and strict exclusion criteria were applied. Furthermore, PSM was used to balance the patient characteristics between the two treatment groups and reduce the impact of residual bias. Second, when comparing the effectiveness of the two medications on hepatic steatosis or fibrosis, we used noninvasive markers, HSI and FIB-4 index, instead of pathologic information from liver biopsies. Although other noninvasive methods with higher diagnostic accuracy, such as transient elastography or magnetic resonance imaging-proton density fat fraction, have been well established,33,34 these tests were not performed in most patients. In addition, even among those who underwent transient elastography or magnetic resonance imaging-proton density fat fraction, follow-up measurements were not performed regularly, limiting the ability to conduct longitudinal evaluations. The HSI and the FIB-4 index have been adopted by numerous studies as noninvasive tools showing effective and accurate identification of hepatic steatosis and fibrosis,11,1,, with area under the receiver operating characteristics curve values of 0.82 and 0.84, respectively. These indices enable longitudinal monitoring of changes using simple clinical parameters, including routine blood tests. Accordingly, these markers can serve as valuable tools for noninvasively and cost-effectively comparing the two antidiabetic drugs in both clinical and research settings.

In conclusion, type 2 DM may contribute to the progression of steatotic liver disease, and SGLT-2i may inhibit this progression in patients with DM-MASLD. Given that SGLT-2i is more effective in reducing hepatic steatosis and delaying fibrosis progression compared to the DPP-4i, it might be considered as a prioritized second-line OHA in patients with DM-MASLD.

Y.B.L. has received research grants from Samjin Pharmaceutical Co., Ltd. and Yuhan Corporation. J.H.L. has received research grants from Yuhan Corporation and GC Cell, and lecture fees from GC Cell, Daewoong Pharmaceutical Co., Ltd., and Gilead Sciences Korea Ltd. S.J.Y. has received research grants from Yuhan Corporation and Daewoong Pharmaceutical Co., Ltd. J.H.Y. has received research grants from Bayer AG, Daewoong Pharmaceutical Co., Ltd., and Bukwang Pharmaceutical Co., Ltd. Y.J.K. has received research grants from Roche Ltd., JW CreaGene Inc., Bukwang Pharmaceutical Co., Ltd., Handok Inc., Hanmi Pharm. Co., Ltd., Bristol-Myers Squibb Company, Yuhan Corporation, and PharmaKing Co., Ltd., and lecture fees from Bayer AG, Gilead Sciences Korea Ltd., MSD Korea Ltd., Yuhan Corporation, Samil Pharmaceutical Co., Ltd., CJ Pharmaceuticals, Bukwang Pharmaceutical Co., Ltd., and Handok Inc.

S.J.Y. and Y.J.K. are editorial board members of the journal but were not involved in the peer reviewer selection, evaluation, or decision process of this article. All other authors declare no conflicts of interest. No other potential conflicts of interest relevant to this article were reported.

Study concept and design: Y.K., M.H.H., J.H.Y., Y.J.K. Data acquisition: Y.K., M.H.H., Y.J.K. Data analysis and interpretation: Y.K., M.H.H., Y.J.K. Drafting of the manuscript: Y.K., M.H.H., Y.J.K. Critical revision of the manuscript for important intellectual content: Y.K., M.H.H., Y.P., J.P., H.S., Y.B.L., E.J.C., J.H.L., S.J.Y., J.H.Y., Y.J.K. Statistical analysis: Y.K., M.H.H. Approval of final manuscript: all authors.

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Article

Original Article

Comparison of the Efficacy of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter-2 Inhibitors in Diabetic Patients with Steatotic Liver Disease

Yunmi Ko , Moon Haeng Hur , Youngsu Park , Jeayeon Park , Hyunjae Shin , Yun Bin Lee , Eun Ju Cho , Jeong-Hoon Lee , Su Jong Yu , Jung-Hwan Yoon , Yoon Jun Kim

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

Received: December 25, 2024; Revised: March 23, 2025; Accepted: March 25, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: There is currently insufficient evidence to recommend one oral hypoglycemic agent over another for diabetic patients to reduce hepatic steatosis or prevent advanced fibrosis. We aimed to evaluate the efficacy of dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes mellitus (DM) and metabolic dysfunction-associated steatotic liver disease (MASLD).
Methods: This study included diabetic patients with steatotic liver disease who newly received either a DPP-4i or an SGLT-2i as a second-line treatment between 2014 and 2021 at a single tertiary hospital. MASLD was categorized as MASLD-H (radiologic steatosis with a hepatic steatosis index [HSI]>36) or MASLD-I (radiologic steatosis only). Changes in the HSI and fibrosis-4 (FIB-4) index were compared at 1 and 3 years after treatment initiation.
Results: A total of 3,493 patients were consecutively enrolled, with 3,001 receiving DPP-4i treatment and 492 receiving SGLT-2i treatment. After applying propensity score matching, the SGLT-2i group showed a significantly greater reduction in the HSI than the DPP-4i group in the DM-MASLD population at both 1 year (DM-MASLD-H: DPP-4i vs SGLT-2i, –1.4% vs –3.7%, p<0.001; DM-MASLD-I: –1.3% vs –3.8%, p<0.001) and 3 years (DM-MASLD-H: –2.0% vs –4.0%, p=0.001; DM-MASLD-I: –2.4% vs –4.2, p=0.025). The FIB-4 indices of both groups increased; however, the increase at year 1 was more significant in the DPP-4i than in the SGLT-2i group (DM-MASLD-H: 11.4% vs 5.2%, p<0.001; DM-MASLD-I: 10.7% vs 4.3%, p=0.014).
Conclusions: In patients with DM-MASLD, SGLT-2i treatment was associated with a greater reduction in hepatic steatosis and delayed fibrotic progression than DPP-4i treatment.

Keywords: Fatty liver, Diabetes mellitus, type 2, Dipeptidyl-peptidase IV inhibitors, Sodium-glucose transporter 2 inhibitors

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, which refers to hepatic fat accumulation without excessive alcohol consumption and any secondary cause.1 Approximately 25% of the global population is currently estimated to have NAFLD, and it is anticipated that the proportion of NAFLD patients with advanced liver disease will continue to rise.2 Although NAFLD can progress to advanced hepatic fibrosis or hepatocellular carcinoma, no pharmacotherapy has been approved.

NAFLD and type 2 diabetes mellitus (DM) are closely related and negatively impact each other. DM can occur in populations with obesity due to insulin resistance, and ectopic fat accumulation in the liver has been reported to contribute to the development of DM.3 Approximately 50% of patients with DM are reported to have NAFLD. According to a meta-analysis, the overall prevalence of NAFLD among patients with DM is 55.5%, which is about two times higher than in the general population.4 To highlight the impact of metabolic disorders such as DM in patients with steatotic liver disease, the concept of metabolic dysfunction-associated fatty liver disease and, more recently, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed.5-7

There are currently insufficient data to recommend one oral hypoglycemic agent (OHA) over another to improve hepatic steatosis or prevent advanced fibrosis in patients with DM. Among the various OHAs, the sodium-glucose cotransporter-2 inhibitor (SGLT-2i), which induces glycosuria and weight loss, has shown promising results in liver diseases. Several randomized controlled trials (RCTs) have reported that patients with DM treated with SGLT-2i showed decreased hepatic fat content or abdominal fat area.8,9 These protective effect role of SGLT-2i on hepatic steatosis were also confirmed in animal models.10 Therefore, we aimed to evaluate the effects of SGLT-2i on hepatic steatosis and fibrosis in diabetic patients with MASLD, compared to those of dipeptidyl peptidase-4 inhibitor (DPP-4i), another commonly prescribed OHA.

MATERIALS AND METHODS

1. Study population

This retrospective cohort study included adult patients with type 2 DM who were treated with either DPP-4i or SGLT-2i as a second-line therapy between 2014 and 2021 at a single tertiary center (Seoul National University Hospital) in South Korea. Type 2 DM was identified using the International Classification of Diseases, 10th revision diagnosis code. The index date was defined as the first day of treatment with either DPP-4i or SGLT-2i as second-line agents due to the reimbursement policy of health insurance. The DPP-4i group included patients treated with sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, anagliptin, teneligliptin, or evogliptin, while the SGLT-2i group included those who received dapagliflozin, empagliflozin, ipragliflozin, or ertugliflozin.

Exclusion criteria were as follows: (1) treatment with a thiazolidinedione or a glucagon-like peptide-1 agonist; (2) co-administration of DPP-4i and SGLT-2i; (3) patients who had not received metformin, sulfonylurea, or insulin treatment prior to the index date; (4) patients without DPP-4i or SGLT-2i prescription data; (5) DPP-4i or SGLT-2i treatment for less than 6 months; (6) confirmation of hepatocellular carcinoma, liver cirrhosis (LC) decompensation (i.e., varix, ascites, and hepatic encephalopathy), or liver transplantation before the index date or within 6 months; (7) alcoholic liver disease; and (8) incomplete data. This study received approval from the Institutional Review Board of Seoul National University Hospital (No. H-2111-112-1272). The requirement for informed consent was waived due to the retrospective design of current study and the anonymity of the patients’ data.

2. Variables and group definitions

For each patient, baseline characteristics were collected at the index date, including the initially prescribed antidiabetic agents, aspartate aminotransferase, alanine aminotransferase, and platelet count. We categorized into the DM-MASLD cohort into two groups using radiologic steatosis and/or the hepatic steatosis index (HSI). Radiologic steatosis was defined as the presence of hepatic steatosis on computed tomography or ultrasonography. To complement the limitations of radiologic steatosis, we included HSI as another noninvasive marker. The DM-MASLD-H (H; HSI plus imaging) group was defined as patients with type 2 DM who have radiologic evidence of steatotic liver and an HSI>36.11 We then defined the DM-MASLD-I (I; imaging) group, in which hepatic steatosis was determined based on radiologic evidence only, instead of HSI,6 and evaluated whether similar results were reproduced using this classification. The HSI serves as a noninvasive diagnostic tool to assess the severity of hepatic steatosis. The HSI can detect NAFLD with a specificity of 92.4% (95% confidence interval, 91.3% to 93.4%) at values greater than 36.0.11 Furthermore, in diabetic patients with hepatic steatosis, an HSI greater than 36 can predict steatotic liver disease with a sensitivity of 89.6%, a specificity of 95.2%, and an area under the receiver operating characteristics curve of 0.979.12 Accordingly, we set an HSI cutoff of 36 to identify hepatic steatosis in diabetic patients.

3. Outcome

The primary outcome was the change in HSI from baseline to 1 and 3 years in each treatment arm. As a secondary outcome, we compared the change in fibrosis-4 (FIB-4) index from baseline to 1 and 3 years between the two groups. The FIB-4 index serves as a surrogate marker for the degree of hepatic fibrosis in steatotic liver disease. A FIB-4 index <1.3 indicates a low risk of fibrosis, whereas an index >2.67 is categorized as a high risk of fibrosis, with a specificity of 96%.13 In addition, the cumulative incidence of LC-related outcomes (e.g., varix, ascites, or portosystemic encephalopathy) or liver-related outcomes was assessed. Liver-related outcomes included LC-related outcomes, as well as the occurrence of hepatocellular carcinoma, liver transplantation, or liver-related mortality.

4. Statistical analyses

The student t test and chi-square test were performed to compare continuous and categorical variables, respectively, between the DPP-4i and SGLT-2i groups. To balance the two treatment groups among patients with DM-MASLD 2:1 (DPP-4i:SGLT-2i) propensity score matching (PSM) was applied using a nearest-neighbor method with a caliper size of 0.2. The propensity score was calculated using variables including age, sex, body mass index (BMI), history of metformin, sulfonylurea or insulin use, history of dyslipidemia, glomerular filtration rate, and serum levels of total bilirubin, albumin, prothrombin time, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Hepatic steatosis was assessed using the HSI, while hepatic fibrosis was evaluated using the FIB-4 index. The aspartate aminotransferase to platelet ratio index (APRI) was also used to confirm our findings. The APRI has been used as a noninvasive marker for hepatic fibrosis, with a cutoff value of <0.5 effectively ruling out significant fibrosis, while a cutoff of >1.5 can be considered indicative of significant fibrosis.14 Changes in HSI or FIB-4 index before and after treatment with either DPP-4i or SGLT-2i were evaluated using the paired t test. The Kaplan-Meier method and log-rank test were used to evaluate LC-related and liver-related outcomes. Subgroup analyses were conducted to compare the effectiveness of the two drugs among either DM-MASLD-H or DM-MASLD-I patients with a BMI >25 kg/cm2. All statistical analyses were performed using R 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria). A p_-_value less than 0.05 was considered statistically significant.

RESULTS

1. Baseline characteristics

A total of 31,317 patients with type 2 DM were screened for this study. After applying the exclusion criteria, 3,493 consecutive patients were classified as DM-MASLD-H (Fig. 1): 3,001 received DPP-4i and 492 received SGLT-2i treatment. The mean duration of treatment was 3.1 and 2.5 years in the DPP-4i and SGLT-2i groups, respectively. The baseline characteristics of the population with DM-MASLD-H are shown in Table 1. More than half of the patients in both groups had a BMI greater than 25 kg/m2. The SGLT-2i group was younger and had a greater proportion of males, compared to the DPP-4i group (both p<0.001). In the SGLT-2i group, the HSI was significantly higher at baseline, while the FIB-4 index was lower than in the DPP-4i group (both p<0.001). After applying the PSM, all baseline variables were well balanced.

Figure 1. Patient flow diagram. A total of 3,493 eligible DM-MASLD-H patients were included, and they were categorized into the DPP-4i or SGLT-2i group. DM, diabetes mellitus; MASLD-H, metabolic dysfunction-associated steatotic liver disease (HSI plus imaging); HSI_,_ hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Table 1 . Baseline Characteristics of Patients with DM-MASLD-H before and after PSM.

Data are presented as mean±SD or number (%). Continuous variables were compared using t-test and categorical variables were compared using the chi-square test. Propensity scores were computed using following variables: age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, GFR and serum levels of total bilirubin, albumin, PT, LDL-C, and HDL-C..

DM, diabetes mellitus; MASLD-H, metabolic dysfunction-associated steatotic liver disease (HSI plus imaging); PSM, propensity score matching; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; HSI_,_ hepatic steatosis index; FIB-4 index, fibrosis-4 index..

After evaluating hepatic steatosis based on radiologic evidence only, a total of 1,710 patients with DM-MASLD-I were identified. Of these, 1,446 and 264 patients received DPP-4i and SGLT-2i treatment, respectively. Baseline characteristics of the population with DM-MASLD-I are summarized in Table 2. Overall baseline characteristics of DM-MASLD-I were similar to those of DM-MASLD-H, and all variables were well balanced following PSM. The use of hepatoprotective agents, such as ursodeoxycholic acid, biphenyl-dimethyl-dicarboxylate, and/or silymarin ranged from 10% and 20% across the groups. In patients with DM-MASLD, both the DPP-4i and SGLT-2i groups showed reductions in weight and BMI over the 1- and 3-year follow-up periods. Similarly, hemoglobin A1c levels demonstrated a decreasing trend at 1 and 3 years compared to the baseline, with no significant differences between the two treatment groups (Supplementary Tables 1 and 2).

Table 2 . Baseline Characteristics of Patients with DM-MASLD-I before and after PSM.

Data are presented as mean±SD or number (%). Continuous variables were compared using t-test and categorical variables were compared using the χ2 test. Propensity scores were computed using following variables: age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, GFR and serum levels of total bilirubin, albumin, PT, LDL-C, and HDL-C..

DM, diabetes mellitus; MASLD-I, metabolic dysfunction-associated steatotic liver disease (imaging); PSM, propensity score matching; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; HSI_,_ hepatic steatosis index; FIB-4 index, fibrosis-4 index; NA, not available..

2. Changes in hepatic steatosis after DPP-4i or SGLT-2i treatment

Changes in hepatic steatosis among DM-MASLD-H patients after OHA treatment are shown in Fig. 2. In the population with DM-MASLD-H, the reduction in HSI was more prominent in the SGLT-2i group compared to the DPP-4i group at both 1 year and 3 years (DPP-4i vs SGLT-2i: –1.4%±8.0% vs –3.7%±7.5% at 1 year, p<0.001; –2.0%±8.5% vs –4.0%±8.0% at 3 years, p=0.001). Similarly, in the DM-MASLD-I population, patients treated with SGLT-2i demonstrated a more pronounced reduction in hepatic steatosis over time compared to those receiving DPP-4i (–1.3%±7.6% vs –3.8%±7.4% at 1 year, p<0.001; –2.4%±8.4% vs –4.2%±8.5% at 3 years, p=0.026) (Fig. 2). Furthermore, when patients were categorized into the “improved,” “no change,” and “worsened” groups based on an HSI cutoff of 36 at 1 and 3 years follow-ups, a greater proportion of those treated with SGLT-2i showed improvement in both the DM-MASLD-H and DM-MASLD-I cohorts (DM-MASLD-H: 10.4% vs 15.3% at 1 year; 12.0% vs 15.7% at 3 years; DM-MASLD-I: 9.8% vs 15.4% at 1 year; 12.4% vs 17.4% at 3 years) (Supplementary Fig. 1).

Figure 2. Mean percentage changes in the HSI after 1 year and 3 years of antidiabetic agent treatment in patients with DM-MASLD. Mean percentage changes in the HSI in the DM-MASLD-H group (A, B) and DM-MASLD-I group (C, D). Both groups were balanced using propensity score matching. Data are presented as the mean±SD. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

3. Changes in hepatic fibrosis after DPP-4i or SGLT-2i treatment

In the DM-MASLD-H cohort, both treatment groups showed an increase in the FIB-4 index over time. The increase was significantly greater in the DPP-4i group compared to the SGLT-2i group at year 1 (11.4%±36.5% vs 5.2%±26.7%, p<0.001) (Fig. 3), whereas it was comparable at year 3 (17.6%±78.9% vs 11.3%±35.0%, p=0.097). Similarly, in the DM-MASLD-I cohort, the DPP-4i group demonstrated a tendency of more pronounced fibrosis progression than the SGLT-2i group. The increase in the FIB-4 index was significantly greater in the DPP-4i group than the SGLT-2i group at year 1, while the difference was not significant at year 3 (10.7%±42.4% vs 4.3%±25.7% at 1 year, p=0.014; 18.0%±81.3% vs 12.3%±40.0% at 3 years, p=0.303) (Fig. 3).

Figure 3. Mean percentage changes in the FIB-4 index after 1 year and 3 years of antidiabetic agent treatment in patients with DM-MASLD. Mean percentage changes in the FIB-4 index in the DM-MASLD-H group (A, B) and DM-MASLD-I group (C, D). Both groups were balanced using propensity score matching. Data are presented as the mean±SD. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; FIB-4 index, fibrosis-4 index.

When hepatic fibrosis was assessed using APRI, a similar trend was observed, with fibrosis progression over time in both DM-MASLD-H and DM-MASLD-I cohorts. The DPP-4i group exhibited significant fibrosis progression, whereas the SGLT-2i group showed minimal fibrosis progression across the DM-MASLD population (DM-MASLD-H: 15.3%±66.1% vs –0.7%±43.4% at 1 year, p<0.001; 15.9%±132.1% vs –0.2%±55.0% at 3 years, p=0.011; DM-MASLD-I: 13.5%±68.5% vs –0.3%±44.5% at 1 year, p=0.002; 16.9%±193.9% vs 1.0%±66.1% at 3 years, p=0.183) (Supplementary Fig. 2).

4. Cumulative incidence of LC-related and liver-related outcomes

Figs 4 and 5 show the cumulative incidence of LC-related and liver-related outcomes, respectively. In the DM-MASLD-H cohort, LC-related outcomes occurred in 19 of 3,001 patients in the DPP-4i group and five of 492 patients in the SGLT-2i group, while liver-related outcomes were confirmed in 31 and six patients. There were no significant differences between the two groups before and after PSM (all p>0.05), and similar results were found in the DM-MASLD-I cohort.

Figure 4. Cumulative incidence of liver cirrhosis-related outcomes in patients with DM-MASLD-H (A, B) and DM-MASLD-I (C, D) before and after propensity score matching. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Figure 5. Cumulative incidence of liver-related outcomes in patients with DM-MASLD-H (A, B) and DM-MASLD-I (C, D) before and after propensity score matching. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

5. Subgroup analyses

Supplementary Tables 1 and 2 compared weight, BMI, hemoglobin A1c, HSI, and FIB-4 index at 1 and 3 years within each treatment group (DPP-4i and SGLT-2i) relative to baseline in the DM-MASLD-H and DM-MASLD-I cohorts, respectively. In the SGLT-2i group, HSI significantly decreased at both 1 and 3 years compared to baseline, whereas FIB-4 index was comparable to baseline at 1 year but significantly increased at 3 years.

The effectiveness of the DPP-4i (n=1,824) and SGLT-2i (n=412) was compared in the DM-MASLD-H patients with a BMI >25 kg/m2. The baseline characteristics of the two treatment groups were well balanced following a nearest-neighbor 2:1 PSM using variables including age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, glomerular filtration rate, and serum levels of total bilirubin, albumin, prothrombin time and low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, and triglyceride (Supplementary Table 3). The SGLT-2i group demonstrated a greater reduction in hepatic steatosis at both 1 and 3 years, and a smaller increase in hepatic fibrosis at 1 year compared to the DPP-4i group (Supplementary Figs 3 and 4). However, the change in the FIB-4 index at 3 years was comparable between the two groups (p=0.106). Similar results were reproduced in the DM-MASLD-I patients with a BMI >25 kg/m2 (Supplementary Table 4, Supplementary Figs 3 and 4).

DISCUSSION

This retrospective study compared the change in HSI or FIB-4 index among patients with DM-MASLD-H or DM-MASLD-I who received DPP-4i and SGLT-2i treatment as a second-line OHA. While both treatment groups showed a decrease in BMI, the SGLT-2i group exhibited a more significant reduction in liver steatosis at both 1 and 3 years, compared to the DPP-4i group. The FIB-4 index increased over time in both groups; however, hepatic fibrosis progression was more pronounced in the DPP-4i group than the SGLT-2i group.

While the mechanisms for the development of MASLD are multifactorial, type 2 DM is one of the major risk factors for the progression of MASLD.15 Insulin resistance, which often precedes type 2 DM, plays a critical role in the development of hepatic steatosis and its subsequent progression to steatohepatitis.16,17 Insulin resistance in muscle cells triggers decreased glycogen synthesis and elevated blood glucose levels, stimulating hepatic de novo lipogenesis, and ultimately leading to the accumulation of intrahepatic free fatty acids.17 Furthermore, insulin resistance and the subsequent hyperinsulinemia can increase the breakdown of free fatty acids in adipose tissue, resulting in abundant influx of free fatty acids into the liver and promoting hepatic lipogenesis.18 These conditions can contribute to the excessive accumulation of free fatty acids in the liver, which may induce inadequate hepatic β-oxidation and progress from steatohepatitis to fibrosis.16

Despite ongoing research on medications targeting the underlying mechanisms of MASLD, there are currently few pharmaceutical treatment options for steatotic liver disease.19 SGLT-2i is a relatively new class of antidiabetic drug, known for its ability to control blood glucose levels by inhibiting glucose reabsorption in the proximal tubules of the kidney, which can induce glycosuria.20 This SGLT-2i treatment can substantially reduce hepatic lipogenesis by decreasing blood glucose levels.21 SGLT-2i can also stimulate α-cells of the pancreas, increasing glucagon secretion, which can trigger β-oxidation in the liver, promoting the shift of carbohydrate to fatty acid metabolism.21 Furthermore, in vivo studies showed that SGLT-2i may reduce free radical generation, in addition to alleviating high glucose-induced oxidative stress.21,22 Previous RCTs have demonstrated that, compared to pioglitazone, empagliflozin effectively reduced liver fat and improved hepatic fibrosis in patients with type 2 DM and NAFLD,9,2 with similar findings supported by a Mendelian randomization study. Another prospective study using transient elastography to assess hepatic steatosis and fibrosis demonstrated that SGLT-2i may slow fibrosis progression.

Apart from SGLT-2i, DPP-4i is a commonly used agent that regulates blood glucose levels through the degradation of incretin hormones such as glucagon-like peptide-1, and through either augmentation of insulin secretion, or inhibition of glucagon release.26 According to an RCT, the DPP-4i sitagliptin was reported to be no more effective than a placebo in improving liver fat and fibrosis in patients with NAFLD.27 On the other hand, another RCT illustrated that sitagliptin ameliorated hepatic steatosis and hepatocyte ballooning, confirmed by liver biopsy after year 1.28 Nonetheless, studies comparing DPP-4i and SGLT-2i have suggested that SGLT-2i may be more effective. Some retrospective cohort studies demonstrated that the SGLT-2i group in DM-metabolic dysfunction-associated fatty liver disease not only exhibited a greater reduction in the fatty liver index compared to the DPP-4i group,29 but also showed a significant improvement in the FIB-4 index among type 2 DM patients.30

We showed that over a prolonged follow-up period, both DPP-4i and SGLT-2i groups in the DM-MASLD populations led to a decrease in hepatic steatosis, but a tendency toward progression of fibrosis. The slower progression of fibrosis in the SGLT-2i group may be attributed to a greater reduction in hepatic steatosis compared to the DPP-4i group. Fibrosis progression despite reduction in hepatic steatosis may result from persistent insulin resistance in patients with type 2 DM, which can promote chronic low-grade inflammation and lead to hepatic fibrosis.31 During the follow-up period, the differences in steatosis or fibrosis between the two treated groups were attenuated. This attenuation may result from the cumulative effect of various factors other than diabetes medications on outcomes.

Our study has several limitations. First, as a single-center retrospective study, selection bias may have been introduced. Due to the retrospective design, it was challenging to fully control external factors, such as lifestyle modification, which could influence hepatic steatosis and fibrosis.32 In addition, differences in compliance and variations in treatment duration among patients receiving triple therapy with metformin, sulfonylurea, and SGLT-2i may have posed limitations in evaluating outcomes. The use of hepatoprotective agents was another potential confounder. Despite our efforts to assess their use through hospital records, some patients may have obtained them from external sources or taken them as supplements, making it difficult to fully account for their potential effects. To mitigate residual potential biases, patients in both groups were enrolled consecutively and strict exclusion criteria were applied. Furthermore, PSM was used to balance the patient characteristics between the two treatment groups and reduce the impact of residual bias. Second, when comparing the effectiveness of the two medications on hepatic steatosis or fibrosis, we used noninvasive markers, HSI and FIB-4 index, instead of pathologic information from liver biopsies. Although other noninvasive methods with higher diagnostic accuracy, such as transient elastography or magnetic resonance imaging-proton density fat fraction, have been well established,33,34 these tests were not performed in most patients. In addition, even among those who underwent transient elastography or magnetic resonance imaging-proton density fat fraction, follow-up measurements were not performed regularly, limiting the ability to conduct longitudinal evaluations. The HSI and the FIB-4 index have been adopted by numerous studies as noninvasive tools showing effective and accurate identification of hepatic steatosis and fibrosis,11,1,, with area under the receiver operating characteristics curve values of 0.82 and 0.84, respectively. These indices enable longitudinal monitoring of changes using simple clinical parameters, including routine blood tests. Accordingly, these markers can serve as valuable tools for noninvasively and cost-effectively comparing the two antidiabetic drugs in both clinical and research settings.

In conclusion, type 2 DM may contribute to the progression of steatotic liver disease, and SGLT-2i may inhibit this progression in patients with DM-MASLD. Given that SGLT-2i is more effective in reducing hepatic steatosis and delaying fibrosis progression compared to the DPP-4i, it might be considered as a prioritized second-line OHA in patients with DM-MASLD.

CONFLICTS OF INTEREST

Y.B.L. has received research grants from Samjin Pharmaceutical Co., Ltd. and Yuhan Corporation. J.H.L. has received research grants from Yuhan Corporation and GC Cell, and lecture fees from GC Cell, Daewoong Pharmaceutical Co., Ltd., and Gilead Sciences Korea Ltd. S.J.Y. has received research grants from Yuhan Corporation and Daewoong Pharmaceutical Co., Ltd. J.H.Y. has received research grants from Bayer AG, Daewoong Pharmaceutical Co., Ltd., and Bukwang Pharmaceutical Co., Ltd. Y.J.K. has received research grants from Roche Ltd., JW CreaGene Inc., Bukwang Pharmaceutical Co., Ltd., Handok Inc., Hanmi Pharm. Co., Ltd., Bristol-Myers Squibb Company, Yuhan Corporation, and PharmaKing Co., Ltd., and lecture fees from Bayer AG, Gilead Sciences Korea Ltd., MSD Korea Ltd., Yuhan Corporation, Samil Pharmaceutical Co., Ltd., CJ Pharmaceuticals, Bukwang Pharmaceutical Co., Ltd., and Handok Inc.

S.J.Y. and Y.J.K. are editorial board members of the journal but were not involved in the peer reviewer selection, evaluation, or decision process of this article. All other authors declare no conflicts of interest. No other potential conflicts of interest relevant to this article were reported.

AUTHOR CONTRIBUTIONS

Study concept and design: Y.K., M.H.H., J.H.Y., Y.J.K. Data acquisition: Y.K., M.H.H., Y.J.K. Data analysis and interpretation: Y.K., M.H.H., Y.J.K. Drafting of the manuscript: Y.K., M.H.H., Y.J.K. Critical revision of the manuscript for important intellectual content: Y.K., M.H.H., Y.P., J.P., H.S., Y.B.L., E.J.C., J.H.L., S.J.Y., J.H.Y., Y.J.K. Statistical analysis: Y.K., M.H.H. Approval of final manuscript: all authors.

SUPPLEMENTARY MATERIALS

• Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• SUPPLEMENTARY MATERIALS

Fig 1.

Figure 1.Patient flow diagram. A total of 3,493 eligible DM-MASLD-H patients were included, and they were categorized into the DPP-4i or SGLT-2i group. DM, diabetes mellitus; MASLD-H, metabolic dysfunction-associated steatotic liver disease (HSI plus imaging); HSI_,_ hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Fig 2.

Figure 2.Mean percentage changes in the HSI after 1 year and 3 years of antidiabetic agent treatment in patients with DM-MASLD. Mean percentage changes in the HSI in the DM-MASLD-H group (A, B) and DM-MASLD-I group (C, D). Both groups were balanced using propensity score matching. Data are presented as the mean±SD. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Fig 3.

Figure 3.Mean percentage changes in the FIB-4 index after 1 year and 3 years of antidiabetic agent treatment in patients with DM-MASLD. Mean percentage changes in the FIB-4 index in the DM-MASLD-H group (A, B) and DM-MASLD-I group (C, D). Both groups were balanced using propensity score matching. Data are presented as the mean±SD. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; FIB-4 index, fibrosis-4 index.

Fig 4.

Figure 4.Cumulative incidence of liver cirrhosis-related outcomes in patients with DM-MASLD-H (A, B) and DM-MASLD-I (C, D) before and after propensity score matching. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Fig 5.

Figure 5.Cumulative incidence of liver-related outcomes in patients with DM-MASLD-H (A, B) and DM-MASLD-I (C, D) before and after propensity score matching. DM, diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; MASLD-H, MASLD (HSI plus imaging); MASLD-I, MASLD (imaging); HSI, hepatic steatosis index; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Table 1 Baseline Characteristics of Patients with DM-MASLD-H before and after PSM

Data are presented as mean±SD or number (%). Continuous variables were compared using t-test and categorical variables were compared using the chi-square test. Propensity scores were computed using following variables: age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, GFR and serum levels of total bilirubin, albumin, PT, LDL-C, and HDL-C.

DM, diabetes mellitus; MASLD-H, metabolic dysfunction-associated steatotic liver disease (HSI plus imaging); PSM, propensity score matching; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; HSI_,_ hepatic steatosis index; FIB-4 index, fibrosis-4 index.

Table 2 Baseline Characteristics of Patients with DM-MASLD-I before and after PSM

Data are presented as mean±SD or number (%). Continuous variables were compared using t-test and categorical variables were compared using the χ2 test. Propensity scores were computed using following variables: age, sex, BMI, history of metformin, sulfonylurea or insulin use, history of dyslipidemia, GFR and serum levels of total bilirubin, albumin, PT, LDL-C, and HDL-C.

DM, diabetes mellitus; MASLD-I, metabolic dysfunction-associated steatotic liver disease (imaging); PSM, propensity score matching; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; HSI_,_ hepatic steatosis index; FIB-4 index, fibrosis-4 index; NA, not available.

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Vol.20 No.1

January 2026

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pISSN 1976-2283
eISSN 2005-1212

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