Abstract
Background: Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GLP-1) receptor agonist, has recently been introduced in Japan; however, there are limited studies on its effectiveness in Japanese patients with type 2 diabetes diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD).
Patients and methods: This retrospective cohort study was conducted among 54 Japanese patients (29 men and 25 women) with type 2 diabetes and MASLD to assess the impact of switching from a GLP-1 receptor agonist (GLP-1RA) to tirzepatide. Before the switch, either dulaglutide or semaglutide was used as the GLP-1RA. Clinical findings were analyzed before and six months after switching to tirzepatide. Additionally, a multiple regression analysis was performed to determine whether characteristics and test results before switching to tirzepatide could predict the weight loss and MASLD suppression six months after initiation. The fatty liver index and fibrosis-4 (FIB-4) index were utilized as MASLD indicators. High-sensitivity C-reactive protein (hsCRP) levels from residual serum were measured as an indicator of chronic inflammation.
Results: Six months after switching to tirzepatide, significant reductions in body weight, hemoglobin A1c (HbA1c) level, fatty liver index, FIB-4 index, and hsCRP level were observed. The multiple regression analysis identified age, duration of type 2 diabetes, and HbA1c levels before the switch as significant independent predictors of weight loss rate. Also, the multiple regression analysis suggested that age before the switch may serve as a useful predictor of a decrease in fatty liver index. The effect of tirzepatide on appetite was less pronounced in the group that had used semaglutide before the switch compared with the group that had used dulaglutide; however, even in the semaglutide group, significant reductions in body weight, HbA1c levels, fatty liver index, and FIB-4 index were noted six months after the switch.
Conclusions: This study suggested the efficacy of switching from GLP-1RAs to tirzepatide among Japanese patients with type 2 diabetes and MASLD. Predictors of weight loss and fatty liver index reduction after switching to tirzepatide were identified. Additionally, we found that the therapeutic effect of tirzepatide can be expected even in patients who were using semaglutide before the switch.
Keywords: body weight loss, glucagon-like peptide-1 agonist (glp-1ra), masld, tirzepatide, type 2 diabetes
Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD), a form of fatty liver disease predominantly linked to metabolic syndrome, is rapidly increasing worldwide [1-3]. As MASLD advances from simple fatty liver disease to metabolic dysfunction-associated steatohepatitis (MASH), it can progress to liver cirrhosis and hepatocellular carcinoma [3-6]. The rise in obesity and type 2 diabetes has contributed to the growing prevalence of MASH [7], which is associated with both cardiovascular disease and liver-related mortality [4,8]. Consequently, various therapeutic agents are being developed to address this condition.
Recently, the connection between type 2 diabetes and MASLD has gained significant attention, with evidence confirming that diabetes medications, including thiazolidinediones, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2is), are effective in treating fatty liver [9-11]. Emerging evidence also suggests that SGLT2is can improve MASH and liver fibrosis [12-14]. In contrast, GLP-1RAs are effective in treating MASH but not in improving liver fibrosis [15]. Glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA tirzepatide [16,17] has been shown to significantly reduce body weight in placebo-controlled studies involving patients with type 2 diabetes and obesity [16-19], with findings indicating improvement in MASH and liver fibrosis biomarkers in this population [20,21]. Therefore, switching from GLP-1RAs to tirzepatide may benefit patients with inadequate MASLD management despite using GLP-1RAs.
Since tirzepatide was recently introduced in Japan, there are limited studies on its effectiveness in treating fatty liver, MASH, and liver fibrosis in Japanese patients with MASLD after switching from GLP-1RAs to tirzepatide. Therefore, this study aimed to confirm whether switching to tirzepatide has a positive effect on MASLD in Japanese patients with type 2 diabetes and MASLD. In this study, we performed a retrospective analysis of the therapeutic effects of switching from GLP-1RAs to tirzepatide in patients with type 2 diabetes and MASLD. As a result, six months after switching to tirzepatide, reductions in body weight and HbA1c were observed, along with decreases in the liver disease markers fatty liver index and fibrosis-4 (FIB-4) index. The amount of weight loss was significantly correlated with the reduction in the fatty liver index, suggesting that tirzepatide's improvement in MASLD is dependent on weight loss. Tirzepatide is expected to be a useful medication for patients with MASLD, a social issue, particularly those with obesity.
Materials and methods
Participants and survey period
We enrolled Japanese patients with type 2 diabetes from the internal medicine outpatient clinic at Nerima Hikarigaoka Hospital who had confirmed fatty liver disease through imaging tests (abdominal ultrasound, computed tomography, and magnetic resonance imaging). These patients had been treated with GLP-1RAs either alone or in combination with oral hypoglycemic agents or insulin for more than six months. They switched from GLP-1RAs to tirzepatide 2.5 mg/week after August 2023, with the dose increased to 5 mg/week four weeks later, and they used tirzepatide for a total of six months or more as of December 2024. The therapeutic effects of tirzepatide over the six-month period were then examined in this patient group (Figure 1).
Figure 1. Time course of this study.
T2DM, type 2 diabetes mellitus; MASLD, metabolic dysfunction associated steatotic liver disease; GLP-1RA, glucagon-like peptide-1 receptor agonist
Imaging tests were conducted within six months before switching to tirzepatide for all patients for diagnosing the presence of fatty liver [3]. The current study included 54 patients, excluding one under 20 years of age as of December 2024, six with a hemoglobin A1c (HbA1c) level of 10% or higher before switching to tirzepatide, and two who could not increase the tirzepatide dose to 5 mg/week due to side effects such as nausea and abdominal pain (Figure 2).
Figure 2. Flowchart of patient selection in this study.
After nine patients were excluded from a total of 63 Japanese patients with T2DM and MASLD according to the set exclusion criteria, the remaining 54 patients were included in the analysis
T2DM, type 2 diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c: hemoglobin A1c
Among patients with HbA1c >10%, many require insulin to relieve hyperglycemia, and there is a possibility that cases of “diabetic precoma,” which is a contraindication for tirzepatide, may be included. Therefore, these patients were excluded from the target population. The study period spanned from July 2023 to January 2025, with medical records from daily care retrospectively analyzed. The study protocol was approved by the certified review board of Nerima Hikarigaoka Hospital.
Survey items
We surveyed age, sex, body weight, body mass index (BMI), waist circumference, duration of type 2 diabetes, HbA1c, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), triglycerides (TGs), non-high-density lipoprotein cholesterol (non-HDL-C), estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), high-sensitivity C-reactive protein (hsCRP), fatty liver index, FIB-4 index, and the use of SGLT2is, metformin, insulin, statins, or fibrates. Additionally, the type of GLP-1RA used before switching to tirzepatide and whether appetite suppression occurred due to tirzepatide were noted. The UACR was measured through random urine tests at the outpatient clinic and converted to grams of creatinine (measured in mg/g). Additionally, residual blood samples before switching to tirzepatide were used to measure serum hsCRP levels. Serum hsCRP levels were measured using the immunoturbidimetric CRP-Latex assay (Kamiya Biomedical Co., Tukwila, WA), following the manufacturer’s protocol. The fatty liver index, developed by Bedogni et al., is a measure of fatty liver disease calculated using a formula that incorporates waist circumference, BMI, and TG and γ-GTP levels. A value between 30 and 59 suggests the presence of fatty liver, while a value of 60 or higher strongly indicates fatty liver [22]. This index is also commonly used to assess the progression of MASLD [23,24]. The FIB-4 index is a scoring system used to evaluate the degree of liver fibrosis based on AST, ALT, platelet count, and age [25]. A score ranging from 1.3 to 2.67 suggests the possibility of fibrosis progression, while a score of 2.67 or higher indicates that more than half of the patients may have liver cirrhosis or are close to developing it [26]. This index is widely utilized as a marker of disease progression in MASH [27]. The presence or absence of appetite suppression due to tirzepatide use was obtained from the electronic medical records recorded by the attending physician during the outpatient visit six months after switching to tirzepatide.
Evaluatory items
To evaluate efficacy, we conducted an analysis of changes in clinical findings before and six months after switching to tirzepatide, which included body weight, BMI, waist circumference, HbA1c, AST, ALT, γ-GTP, TGs, non-HDL-C, eGFR, UACR, hsCRP, the fatty liver index, and the FIB-4 index. We also performed a correlation analysis between changes in each parameter and changes in the fatty liver index, FIB-4 index, and UACR. Additionally, a stratified analysis was conducted based on the presence or absence of appetite suppression due to tirzepatide, the use of SGLT2is, and the type of GLP-1RAs used before switching to tirzepatide. Furthermore, simple and multiple regression analyses were performed using the weight loss rate and the decrease in fatty liver index six months after switching to tirzepatide as outcome variables. The change (Δ) in each parameter was calculated by subtracting the value before switching to tirzepatide from the value six months after the switch. The weight loss rate was calculated by subtracting the weight six months after switching to tirzepatide from the weight before the switch, dividing the result by the weight before the switch, and multiplying by 100. The reduction in the fatty liver index was determined by subtracting the fatty liver index six months after switching to tirzepatide from the fatty liver index before the switch.
Statistical analysis
Values are expressed as means ± standard deviations for normally distributed data and medians (ranges) for nonnormally distributed data. A paired t-test or Wilcoxon signed-rank sum test was used for time-course evaluation against preswitch values. Pearson's correlation coefficient was applied for correlation analysis, with nonnormally distributed values logarithmically transformed before analysis. The Student's t-test, Mann-Whitney U test, and Fisher's exact test were used for intergroup comparisons. Logistic regression analysis was used for comparative analysis, adjusted for age. All statistical analyses were performed using Prism 7 software (GraphPad Software Inc., San Diego, CA), with statistical significance set at p < 0.05.
Results
Patient background
The clinical characteristics of the enrolled subjects before switching to tirzepatide are summarized in Table 1.
Table 1. Clinical characteristics of the enrolled subjects before switching to tirzepatide.
Data are expressed as the mean ± standard deviation, the median (range), or number (%)
T2DM, type 2 diabetes mellitus; HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high sensitive C-reactive protein; FIB-4, fibrosis 4; SGLT2i, SGLT2, sodium glucose co-transporter 2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist
| Parameters | All subjects (n = 54) |
| Females, n (%) | 25 (46) |
| Age (years) | 57.2 ± 10.5 |
| Body weight (kg) | 71 (53.2-123.8) |
| Body mass index (kg/m2) | 26.8 (23-43.8) |
| Waist circumference (cm) | 88 (74-112) |
| Duration of T2DM (years) | 7.5 (1-29) |
| HbA1c (%) | 8.17 ± 0.97 |
| AST (U/L) | 29 (11-173) |
| ALT (U/L) | 39 (13-169) |
| γ-GTP (U/L) | 54 (13-163) |
| TG (mg/dL) | 246 (77-619) |
| non-HDL-C (mg/dL) | 140.5 (115-165) |
| eGFR (mL/minute/1.73 m2) | 71.5 (54-85) |
| UACR (mg/g) | 35 (3-112) |
| hsCRP (mg/L) | 3 ± 0.85 |
| Fatty liver index | 66.8 ± 16.9 |
| FIB-4 index | 1.30 ± 0.54 |
| SGLT2i, n (%) | 33 (61) |
| GLP-1RA before tirzepatide initiation, n (%) | |
| Dulaglutide | 24 (44) |
| Semaglutide | 30 (56) |
| Metformin | 47 (87) |
| Insulin | 8 (15) |
| Statin | 32 (59) |
| Fibrate | 35 (65) |
The median BMI was 26.8 kg/m² (range: 23-43.8 kg/m²), and the waist circumference was 88 cm (range: 74-112 cm). We did not use tirzepatide in patients with a BMI of less than 23 kg/m2, as the electronic package insert for tirzepatide indicated that its efficacy and safety have not been fully studied [28]. The HbA1c level was 8.17% ± 0.97%, exceeding the target range for glycemic control set by the Japan Diabetes Society (HbA1c < 7%). The median liver enzyme levels were elevated, with a predominance of increased ALT levels. The median eGFR was over 60 mL/minute/1.73 m², but the median UACR was 35 mg/g, indicating a high UACR in this group. The hsCRP level was elevated at 3 ± 0.85 mg/L (cutoff > 2), and the fatty liver index was high at 66.8 ± 16.9 (cutoff > 60). The FIB-4 index was 1.30 ± 0.54, with the mean value approaching the threshold (1.3), indicating potential liver fibrosis progression. SGLT2is were concomitantly used by over half of the patients (33 cases, 61%) and continued throughout the six-month study period. Before switching to tirzepatide, all patients were using either dulaglutide (24 cases, 44%) or semaglutide (30 cases, 56%) as their GLP-1RA, with no usage of other GLP-1RA options such as liraglutide. The dosages were 0.75 mg/week for dulaglutide and 1 mg/week for semaglutide. Metformin was concomitantly used in 47 cases (87%), insulin in eight cases (15%), statins in 32 cases (59%), and fibrates in 35 cases (65%), with all these medications maintained throughout the six-month study period.
Changes in parameters before and after switching to tirzepatide
Table 2 presents the changes in each parameter before and six months after switching to tirzepatide.
Table 2. Changes in parameters before and after switching to tirzepatide.
Data are expressed as the mean ± standard deviation or the median (range), and are compared using paired t test, or the Wilcoxon signed-rank sum test
HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4
| Parameters | All subjects (n = 54) | p value | |
| Before the switch | Six months after the switch | ||
| Body weight (kg) | 71 (53.2-123.8) | 67 (54.5-114.7) | <0.0001 |
| Body mass index (kg/m2) | 26.8 (23-43.8) | 26 (22-41.9) | <0.0001 |
| Waist circumference (cm) | 88 (74-112) | 84 (72-100) | <0.0001 |
| HbA1c (%) | 8.17 ± 0.97 | 7.28 ± 1.34 | <0.0001 |
| AST (U/L) | 29 (11-173) | 25 (10-42) | 0.0002 |
| ALT (U/L) | 39 (13-169) | 30 (12-57) | <0.0001 |
| γ-GTP (U/L) | 54 (13-163) | 51.5 (12-104) | 0.31 |
| TG (mg/dL) | 246 (77-619) | 131 (51-365) | <0.0001 |
| non-HDL-C (mg/dL) | 140.5 (115-165) | 122.5 (105-148) | <0.0001 |
| eGFR (mL/minute/1.73 m2) | 71.5 (54-85) | 64.5 (50-88) | 0.164 |
| UACR (mg/g) | 35 (3-112) | 24.5 (2-110) | 0.01 |
| hsCRP (mg/L) | 3 ± 0.85 | 2.24 ± 0.97 | <0.0001 |
| Fatty liver index | 66.8 ± 16.9 | 47.7 ± 20.4 | <0.0001 |
| FIB-4 index | 1.30 ± 0.54 | 0.96 ± 0.44 | <0.0001 |
Significant reductions were observed in all parameters except γ-GTP levels and eGFR after the switch. The median weight decreased by 4 kg, and the mean HbA1c declined by 0.89%. Additionally, decreases in the fatty liver index, FIB-4 index, UACR, and hsCRP were noted six months after switching to tirzepatide, indicating its potential to suppress MASLD, diabetic nephropathy, and chronic inflammation.
Correlation analysis of changes in parameters and changes in fatty liver index, FIB-4 index, and UACR before and after switching to tirzepatide
To explore factors associated with improvements in fatty liver disease, hepatic fibrosis, and diabetic nephropathy following the switch to tirzepatide, a correlation analysis was conducted using the changes in the fatty liver index, FIB-4 index, and UACR before and after the switch to tirzepatide (Table 3).
Table 3. Correlation analysis of changes in parameters and changes in the fatty liver index, FIB-4 index, and UACR before and after switching to tirzepatide.
The change (Δ) in each parameter was calculated by subtracting the value before the switch from the value six months after the switch. The body weight loss rate was calculated by subtracting the weight six months after the switch from the weight before the switch, dividing the result by the weight before the switch, and multiplying by 100. Pearson’s correlation coefficient was employed for correlation analyses. The values of items marked with an asterisk were log-transformed. In the table, the numbers on the left indicate R (Pearson correlation coefficient) and the numbers on the right indicate p values
HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4; N/A, not applicable
| Parameters | ΔFatty liver index | ΔFIB-4 index | ΔUACR |
| ΔBody weight (kg)* | 0.29, 0.0479 | 0.162, 0.276 | 0.367, 0.0354 |
| Weight loss rate (%) | -0.411, 0.002 | -0.2, 0.146 | -0.342, 0.0353 |
| ΔBody mass index (kg/m2) | 0.374, 0.005 | 0.218, 0.112 | 0.412, 0.0102 |
| ΔWaist circumference (cm)* | 0.328, 0.0178 | 0.173, 0.221 | 0.193, 0.252 |
| ΔHbA1c (%) | 0.379, 0.005 | 0.124, 0.373 | 0.121, 0.468 |
| ΔAST (U/L)* | 0.016, 0.926 | 0.140, 0.401 | 0.116, 0.563 |
| ΔALT (U/L)* | 0.248, 0.104 | 0.003, 0.983 | -0.071, 0.695 |
| Δγ-GTP (U/L)* | 0.167, 0.362 | 0.160, 0.381 | 0.080, 0.711 |
| ΔTG (mg/dL)* | 0.731, <0.0001 | -0.0251, 0.87 | 0.16, 0.365 |
| Δnon-HDL-C (mg/dL) | -0.0159, 0.909 | 0.253, 0.065 | -0.0272, 0.92 |
| ΔeGFR (mL/minute/1.73 m2) | -0.103, 0.459 | -0.0131, 0.925 | 0.156, 0.35 |
| ΔUACR (mg/g)* | 0.221, 0.182 | 0.274, 0.0964 | N/A |
| ΔhsCRP (mg/L) | 0.555, <0.0001 | 0.382, 0.004 | 0.511, 0.001 |
| ΔFatty liver index | N/A | 0.231, 0.0926 | 0.221, 0.182 |
| ΔFIB-4 index | 0.231, 0.0926 | N/A | 0.274, 0.0964 |
The changes in the fatty liver index were significantly positively correlated with changes in weight, BMI, waist circumference, HbA1c, TG, and hsCRP. Similarly, changes in the FIB-4 index exhibited a significant positive correlation with changes in hsCRP levels. For the UACR, significant positive correlations were observed with changes in weight, BMI, and hsCRP levels.
Factors predicting weight loss rate after switching to tirzepatide
Tirzepatide has been shown to improve various obesity-related metabolic disorders, primarily through weight reduction [16,18,19]. We conducted a series of analyses to evaluate whether the weight loss rate achieved by switching to tirzepatide could be predicted from clinical parameters before the switch. First, a simple regression analysis was performed, with the weight loss rate six months after switching to tirzepatide as the dependent variable and clinical findings before the switch as explanatory variables (Table 4).
Table 4. Association of weight loss rate after switching to tirzepatide with each explanatory factor in patients by univariate regression analysis.
The weight loss rate was calculated by subtracting the weight six months after the switch from the weight before the switch, dividing the result by the weight before the switch, and multiplying by 100. Independent variables are those before the switch
β, partial regression coefficient; CI, confidence interval; T2DM, type 2 diabetes mellitus; HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4; SGLT2i, SGLT2, sodium glucose co-transporter 2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist
| Independent variables | β | 95% CI | p value |
| Age (years) | -0.144 | -0.207 to -0.081 | <0.0001 |
| Sex (0: males, 1: females) | -1.312 | -2.832 to 0.207 | 0.089 |
| Body mass index (kg/m2) | 0.269 | 0.104 to 0.434 | 0.002 |
| Duration of T2DM (years) | -0.134 | -0.223 to -0.046 | 0.004 |
| HbA1c (%) | -2.086 | -2.646 to -1.526 | <0.0001 |
| AST (U/L) | 0.029 | -0.006 to 0.063 | 0.102 |
| ALT (U/L) | 0.026 | -0.011 to 0.063 | 0.162 |
| γ-GTP (U/L) | -0.025 | -0.053 to 0.003 | 0.078 |
| TG (mg/dL) | 0.001 | -0.007 to 0.009 | 0.815 |
| non-HDL-C (mg/dL) | 0.026 | -0.014 to 0.066 | 0.195 |
| eGFR (mL/minute/1.73 m2) | -0.036 | -0.110 to 0.037 | 0.324 |
| UACR (mg/g) | 0.010 | -0.014 to 0.034 | 0.414 |
| hsCRP (mg/L) | 0.183 | -0.736 to 1.102 | 0.691 |
| Fatty liver index | 0.047 | 0.002 to 0.092 | 0.040 |
| FIB-4 index | 1.034 | -0.385 to 2.453 | 0.150 |
| SGLT2i (0: no, 1: yes) | 0.388 | -1.207 to 1.982 | 0.628 |
| GLP-1RA (0: dulaglutide, 1: semaglutide) | -1.461 | -2.975 to 0.054 | 0.058 |
| Metformin (0: no, 1: yes) | 0.884 | -1.423 to 3.191 | 0.446 |
| Insulin (0: no, 1: yes) | 0.032 | -2.162 to 2.226 | 0.977 |
| Statin (0: no, 1: yes) | -0.072 | -1.658 to 1.514 | 0.928 |
| Fibrate (0: no, 1: yes) | -0.193 | -1.824 to 1.438 | 0.813 |
Significant factors identified in this analysis included age, BMI, duration of type 2 diabetes, HbA1c level, and fatty liver index before the switch. Subsequently, a multiple regression analysis was conducted using the weight loss rate as the dependent variable and the five significant factors identified in the simple regression analysis as explanatory variables (Table 5).
Table 5. Association of weight loss rate after switching to tirzepatide with each explanatory factor in patients by multivariate regression analysis.
The weight loss rate was calculated by subtracting the weight six months after the switch from the weight before the switch, dividing the result by the weight before the switch, and multiplying by 100. Independent variables are those before the switch. All independent variables are entered simultaneously into the model
*p, p in the model adjusted for gender
β, partial regression coefficient; CI, confidence interval; T2DM, type 2 diabetes mellitus; HbA1c, hemoglobin A1c
| Independent variables | β | 95% CI | p | *p |
| Age (years) | -0.060 | -0.112 to -0.009 | 0.023 | 0.025 |
| Body mass index (kg/m2) | 0.138 | -0.013 to 0.289 | 0.071 | 0.074 |
| Duration of T2DM (years) | -0.066 | -0.128 to -0.003 | 0.040 | 0.049 |
| HbA1c (%) | -1.769 | -2.310 to -1.229 | <0.0001 | <0.0001 |
| Fatty liver index | -0.027 | -0.065 to 0.012 | 0.169 | 0.192 |
This analysis revealed that age, duration of type 2 diabetes, and HbA1c level before the switch were independent predictors of weight loss rate. The significant difference among these three items persisted even in the model adjusted for gender.
Factors predicting a decline in the fatty liver index after switching to tirzepatide
We also explored whether the reduction in the fatty liver index after switching to tirzepatide could be predicted based on clinical parameters before the switch. Initially, a simple regression analysis was conducted, with the decline in the fatty liver index six months after the switch as the dependent variable and the clinical findings before the switch as explanatory variables (Table 6).
Table 6. Association of a decline in the fatty liver index after switching to tirzepatide with each explanatory factor in patients by univariate regression analysis.
The decline in the fatty liver index was determined by subtracting the fatty liver index six months after the switch from the fatty liver index before the switch. Independent variables are those before the switch
β, partial regression coefficient; CI, confidence interval; T2DM, type 2 diabetes mellitus; HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4; SGLT2i, SGLT2, sodium glucose co-transporter 2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist
| Independent variables | β | 95% CI | p |
| Age (years) | -0.417 | -0.735 to -0.099 | 0.011 |
| Sex (0: males, 1: females) | -2.052 | -9.082 to 4.978 | 0.561 |
| Body mass index (kg/m2) | 0.013 | -0.805 to 0.831 | 0.975 |
| Duration of T2DM (years) | -0.494 | -0.906 to -0.081 | 0.020 |
| HbA1c (%) | -2.340 | -5.923 to 1.242 | 0.196 |
| AST (U/L) | -0.028 | -0.188 to 0.131 | 0.723 |
| ALT (U/L) | -0.061 | -0.230 to 0.108 | 0.474 |
| γ-GTP (U/L) | -0.113 | -0.240 to 0.015 | 0.081 |
| TG (mg/dL) | 0.0130 | -0.023 to 0.049 | 0.474 |
| non-HDL-C (mg/dL) | 0.010 | -0.173 to 0.194 | 0.909 |
| eGFR (mL/minute/1.73 m2) | -0.070 | -0.404 to 0.264 | 0.676 |
| UACR (mg/g) | 0.021 | -0.088 to 0.130 | 0.705 |
| hsCRP (mg/L) | -2.377 | -6.477 to 1.723 | 0.250 |
| Fatty liver index | 0.056 | -0.154 to 0.266 | 0.596 |
| FIB-4 index | 3.787 | -2.662 to 10.236 | 0.244 |
| SGLT2i (0: no, 1: yes) | -2.502 | -9.683 to 4.678 | 0.488 |
| GLP-1RA (0: dulaglutide, 1: semaglutide) | 1.130 | -5.941 to 8.201 | 0.750 |
| Metformin (0: no, 1: yes) | 3.437 | -6.990 to 13.864 | 0.511 |
| Insulin (0: no, 1: yes) | -7.340 | -17.027 to 2.347 | 0.134 |
| Statin (0: no, 1: yes) | 2.565 | -4.557 to 9.688 | 0.473 |
| Fibrate (0: no, 1: yes) | -1.318 | -8.675 to 6.038 | 0.721 |
This analysis identified age and duration of type 2 diabetes before the switch as significant factors. Subsequently, a multiple regression analysis was performed using the decline in the fatty liver index as the dependent variable and the two significant factors from the simple regression analysis as explanatory variables (Table 7).
Table 7. Association of a decline in the fatty liver index after switching to tirzepatide with each explanatory factor in patients by multivariate regression analysis.
The decline in the fatty liver index was determined by subtracting the fatty liver index six months after the switch from the fatty liver index before the switch. Independent variables are those before the switch. All independent variables are entered simultaneously into the model
*p, p in the model adjusted for gender
β, partial regression coefficient; CI, confidence interval; T2DM, type 2 diabetes mellitus
| Independent variables | β | 95% CI | p | *p |
| Age (years) | -0.318 | -0.656 to 0.020 | 0.064 | 0.066 |
| Duration of T2DM (years) | -0.342 | -0.776 to 0.092 | 0.120 | 0.125 |
While neither factor reached statistical significance in the multiple regression model, age before the switch showed a trend toward significance as a potential predictor of fatty liver index reduction (p = 0.064). In addition, even in the model adjusted for gender, the p values for age were similar (p = 0.066).
Relationship between appetite suppression after switching to tirzepatide and changes in parameters
Tirzepatide enhances the action of GIP, which has appetite-suppressing effects, in addition to the appetite suppression seen with conventional GLP-1RAs [29], suggesting that the extent of appetite suppression significantly influences its efficacy. To evaluate this, we compared the changes in various parameters based on whether appetite suppression occurred after switching from GLP-1RAs to tirzepatide (Table 8).
Table 8. Relationship between appetite suppression after switching to tirzepatide and parameter changes.
Data are expressed as the mean ± standard deviation, the median (range), or number (%), and are compared using Student’s t test, the Mann-Whitney U test, or Fisher's exact test. Logistic regression analysis was used for comparative analysis, adjusted for age. The change (Δ) in each parameter was calculated by subtracting the value before the switch from the value six months after the switch. The weight loss rate was calculated by subtracting the weight six months after the switch from the weight before the switch, dividing the result by the weight before the switch, and multiplying by 100
*p, p in the model adjusted for age
HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4; SGLT2i, SGLT2, sodium glucose co-transporter 2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist, N/A, not available
| Parameters | Yes (n = 35) | No (n = 19) | p | *p |
| Females, n (%) | 14 (40) | 11 (58) | 0.259 | 0.302 |
| Age (years) | 54.5 ± 10.4 | 62.3 ± 8.76 | 0.007 | N/A |
| ΔBody weight (kg) | -2.9 (-9.2 to 1.7) | -1 (-4.9 to 0.2) | 0.001 | 0.037 |
| Weight loss rate (%) | 4.05 ± 2.97 | 1.76 ± 1.81 | 0.003 | 0.071 |
| ΔBody mass index (kg/m2) | -1.22 ± 0.93 | -0.45 ± 0.47 | 0.002 | 0.036 |
| ΔWaist circumference (cm) | -5 (-14 to 2) | -4 (-6 to 0) | 0.008 | 0.029 |
| ΔHbA1c (%) | -1.23 ± 0.88 | -0.25 ± 0.87 | 0.0002 | 0.012 |
| ΔAST (U/L) | -6 (-148 to 9) | -2 (-15 to 13) | 0.063 | 0.090 |
| ΔALT (U/L) | -9 (-126 to 3) | -4 (-21 to 12) | 0.001 | 0.009 |
| Δγ-GTP (U/L) | -5 (-59 to 19) | 2 (-21 to 30) | 0.018 | 0.027 |
| ΔTG (mg/dL) | -108 (-318 to 14) | -26 (-150 to 34) | 0.001 | 0.008 |
| Δnon-HDL-C (mg/dL) | -15.5 ± 21.8 | -16.2 ± 14.1 | 0.908 | 0.818 |
| ΔeGFR (mL/minute/1.73 m2) | -3.63 ± 17.2 | -2.32 ± 14.8 | 0.78 | 0.772 |
| ΔUACR (mg/g) | -12 (-91 to 91) | 7 (-24 to 44) | 0.0002 | 0.036 |
| ΔhsCRP (mg/L) | -1.29 ± 0.66 | 0.20 ± 0.68 | <0.0001 | 0.001 |
| ΔFatty liver index | -23.8 ± 11.3 | -10.6 ± 11.0 | 0.0001 | 0.004 |
| ΔFIB-4 index | -0.42 ± 0.52 | -0.19 ± 0.50 | 0.126 | 0.424 |
| SGLT2i, n (%) | 24 (69) | 9 (47) | 0.153 | 0.092 |
| GLP-1RA before tirzepatide initiation, n (%) | ||||
| Dulaglutide | 20 (57) | 4 (21) | 0.021 | 0.048 |
| Semaglutide | 15 (43) | 15 (79) | - | - |
| Metformin | 32 (91) | 15 (79) | 0.226 | 0.209 |
| Insulin | 3 (9) | 5 (26) | 0.113 | 0.188 |
| Statin | 20 (57) | 12 (34) | 0.775 | 0.620 |
| Fibrate | 23 (66) | 12 (34) | 1 | 0.899 |
In the group that experienced appetite suppression, the reductions in parameters, excluding AST, non-HDL-C, eGFR, and the FIB-4 index, were significantly greater. Furthermore, this group had a higher proportion of patients who had been using dulaglutide as their prior GLP-1RA and was significantly younger in age. Importantly, even after adjusting for age, the significant differences in parameter changes between the two groups persisted.
Relationship between co-use of SGLT2is and parameter changes
The effectiveness of SGLT2is in patients with MASLD has been widely documented [10,12-14]. Moreover, their use is recommended in the guidelines for MASLD both in Japan and other countries [4,30]. Consequently, the combined use of tirzepatide and SGLT2is is likely to increase in clinical practice. To evaluate the potential differences in the therapeutic effects of switching to tirzepatide based on SGLT2i usage, we analyzed the changes in various parameters between the SGLT2i combination and noncombination groups (Table 9).
Table 9. Relationship between co-use of SGLT2is and parameter changes.
Data are expressed as the mean ± standard deviation, the median (range), or number (%), and are compared using Student’s t test, the Mann-Whitney U test, or Fisher's exact test. The change (Δ) in each parameter was calculated by subtracting the value before the switch from the value six months after the switch. The weight loss rate was calculated by subtracting the weight six months after the switch from the weight before the switch, dividing the result by the weight before the switch, and multiplying by 100
HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4; SGLT2i, SGLT2, sodium glucose co-transporter 2 inhibitor
| Parameters | Yes (n = 33) | No (n = 21) | p |
| Females, n (%) | 14 (42) | 11 (52) | 0.579 |
| Age (years) | 58.5 ± 10.2 | 55.2 ± 10.8 | 0.271 |
| Appetite suppression yes, n (%) | 24 (73) | 11 (52) | 0.153 |
| ΔBody weight (kg) | -2.7 (-9.1 to 1.7) | -1.2 (-9.2 to 0.2) | 0.295 |
| Weight loss rate (%) | 3.39 ± 2.72 | 3.01 ± 3.03 | 0.628 |
| ΔBody mass index (kg/m2) | -0.98 ± 0.82 | -0.90 ± 0.98 | 0.748 |
| ΔWaist circumference (cm) | -5 (-14 to 2) | -3 (-10 to 0) | 0.030 |
| ΔHbA1c (%) | -0.97 ± 1.02 | -0.76 ± 0.94 | 0.452 |
| ΔAST (U/L) | -5 (-148 to 13) | -1 (-11 to 7) | 0.071 |
| ΔALT (U/L) | -8 (-126 to 11) | -6 (-22 to 12) | 0.307 |
| Δγ-GTP (U/L) | -3 (-59 to 29) | -2 (-36 to 30) | 0.505 |
| ΔTG (mg/dL) | -75 (-318 to 23) | -91 (-283 to 34) | 0.818 |
| Δnon-HDL-C (mg/dL) | -13.7 ± 19.1 | -19.0 ± 19.7 | 0.335 |
| ΔeGFR (mL/minute/1.73 m2) | -4.33 ± 17.3 | -1.33 ± 14.7 | 0.514 |
| ΔUACR (mg/g) | -8 (-82 to 44) | -3 (-91 to 91) | 0.972 |
| ΔhsCRP (mg/L) | -0.80 ± 0.87 | -0.70 ± 1.14 | 0.729 |
| ΔFatty liver index | -18.2 ± 11.4 | -20.7 ± 14.8 | 0.488 |
| ΔFIB-4 index | -0.29 ± 0.51 | -0.42 ± 0.54 | 0.351 |
Among the parameters assessed, a significantly greater reduction in waist circumference was observed in the SGLT2i combination group, while no significant differences were noted for other items.
Relationship between the type of GLP-1RA used before switching to tirzepatide and parameter changes
Tirzepatide, an incretin-related drug like GLP-1RAs, may increasingly replace existing GLP-1RAs depending on future large-scale clinical trial outcomes demonstrating its organ-protective effects. To assess whether the therapeutic effects of tirzepatide vary based on the type of GLP-1RA previously used, we analyzed the clinical outcomes according to the prior use of semaglutide or dulaglutide (Table 10).
Table 10. Relationship between the type of GLP-1RA used before switching to tirzepatide and parameter changes.
Data are expressed as the mean ± standard deviation, the median (range), or number (%), and are compared using Student’s t test, the Mann-Whitney U test, or Fisher's exact test. Logistic regression analysis was used for comparative analysis adjusted for age. The change (Δ) in each parameter was calculated by subtracting the value before the switch from the value six months after the switch. The weight loss rate was calculated by subtracting the weight six months after the switch from the weight before the switch, dividing the result by the weight before the switch, and multiplying by 100
*p, p in the model adjusted for age
HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4; GLP-1RA, glucagon-like peptide-1 receptor agonist; N/A, not available
| Parameters | Dulaglutide (n = 24) | Semaglutide (n = 30) | p | *p |
| Females, n (%) | 8 (33) | 17 (57) | 0.106 | 0.145 |
| Age (years) | 53.9 ± 11.0 | 59.9 ± 9.39 | 0.037 | N/A |
| Appetite suppression yes, n (%) | 20 (83) | 15 (50) | 0.021 | 0.048 |
| ΔBody weight (kg) | -3.15 (-9.2 to 1.7) | -1.2 (-8.5 to 0.2) | 0.024 | 0.259 |
| Weight loss rate (%) | 4.05 ± 3.13 | 2.59 ± 2.41 | 0.058 | 0.340 |
| ΔBody mass index (kg/m2) | -1.23 ± 0.98 | -0.72 ± 0.72 | 0.031 | 0.223 |
| ΔWaist circumference (cm) | -5 (-14 to 2) | -4 (-10 to 0) | 0.050 | 0.115 |
| ΔHbA1c (%) | -1.26 ± 1.00 | -0.58 ± 0.89 | 0.011 | 0.061 |
| ΔAST (U/L) | -5 (-148 to 7) | -2.5 (-19 to 13) | 0.28 | 0.282 |
| ΔALT (U/L) | -8.5 (-126 to 7) | -8 (-28 to 12) | 0.236 | 0.358 |
| Δγ-GTP (U/L) | -5.5 (-59 to 29) | 1 (-36 to 30) | 0.219 | 0.515 |
| ΔTG (mg/dL) | -75 (-318 to 24) | -79.5 (-279 to 34) | 0.958 | 0.528 |
| Δnon-HDL-C (mg/dL) | -11.3 ± 21.6 | -19.3 ± 16.8 | 0.128 | 0.108 |
| ΔeGFR (mL/minute/1.73 m2) | -3.42 ± 18.6 | -2.97 ± 14.4 | 0.921 | 0.786 |
| ΔUACR (mg/g) | -10.5 (-91 to 91) | -3.5 (-82 to 44) | 0.288 | 0.847 |
| ΔhsCRP (mg/L) | -1.04 ± 0.79 | -0.54 ± 1.06 | 0.059 | 0.233 |
| ΔFatty liver index | -18.5 ± 12.2 | -19.6 ± 13.3 | 0.75 | 0.251 |
| ΔFIB-4 index | -0.29 ± 0.36 | -0.38 ± 0.62 | 0.554 | 0.200 |
The group that had used semaglutide before switching to tirzepatide showed significantly fewer cases of appetite suppression postswitch compared with the dulaglutide group. Additionally, the semaglutide group exhibited smaller reductions in weight, BMI, and HbA1c levels. However, there were no significant differences between the groups regarding the reduction in MASLD markers such as the fatty liver index and FIB-4 index. Notably, a significant age difference was observed between the groups. After adjusting for age, the significant differences between the groups disappeared, except for the outcome of appetite suppression.
Changes in parameters before and after switching to tirzepatide in the group using semaglutide before the switch
The prior analysis indicated a comparatively lower therapeutic effect of tirzepatide in patients previously using semaglutide. Given the widespread use of semaglutide alongside dulaglutide among GLP-1RAs in Japan, we assessed whether switching to tirzepatide provided measurable benefits within this subgroup (Table 11).
Table 11. Changes in parameters before and after switching to tirzepatide in the group using semaglutide before the switch (n = 30).
Data are expressed as the mean ± standard deviation or the median (range), and are compared using the paired t-test or the Wilcoxon signed-rank sum test
HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; TG, triglyceride; non-HDL-C, non-high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; hsCRP, high-sensitive C-reactive protein; FIB-4, fibrosis 4
| Parameters | Before the switch | Six months after the switch | p |
| Body weight (kg) | 69.8 (56.1-95.8) | 66.9 (55-93.7) | <0.0001 |
| Body mass index (kg/m2) | 26.7 (23.1-31.5) | 25.8 (22.5-30.9) | <0.0001 |
| Waist circumference (cm) | 88 (74-101) | 84 (72-99) | <0.0001 |
| HbA1c (%) | 8.11 ± 1.63 | 7.55 ± 1.71 | 0.001 |
| AST (U/L) | 28 (11-46) | 25 (11-40) | 0.026 |
| ALT (U/L) | 38.5 (13-55) | 30 (15-51) | 0.002 |
| γ-GTP (U/L) | 54 (13-97) | 52.5 (13-98) | 1 |
| TG (mg/dL) | 250 (77-369) | 117.5 (51-354) | <0.0001 |
| non-HDL-C (mg/dL) | 144 (118-165) | 122 (105-145) | <0.0001 |
| eGFR (mL/minute/1.73 m2) | 70 (54-85) | 64 (52-86) | 0.206 |
| UACR (mg/g) | 35 (5-103) | 22.5 (3-109) | 0.147 |
| hsCRP (mg/L) | 2.71 ± 0.82 | 2.19 ± 1.10 | 0.009 |
| Fatty liver index | 63.1 ± 19.0 | 44.1 ± 18.9 | <0.0001 |
| FIB-4 index | 1.33 ± 0.56 | 0.96 ± 0.41 | 0.002 |
Our results demonstrated significant reductions across most parameters, excluding γ-GTP, eGFR, and UACR, six months after switching to tirzepatide. Notably, decreases in the fatty liver index and FIB-4 index highlighted improvements in liver-related outcomes, confirming that switching to tirzepatide yields therapeutic benefits even in patients transitioning from semaglutide.
Discussion
In this study, we conducted a retrospective analysis to assess the six-month therapeutic effects of switching from GLP-1RAs to tirzepatide in patients with type 2 diabetes and MASLD. Our results demonstrated a reduction in body weight and HbA1c levels, along with improvements in markers of MASLD and diabetic nephropathy in this population. The multiple regression analysis identified age, duration of type 2 diabetes, and HbA1c level before switching to tirzepatide as significant predictors of weight loss rate. Additionally, age before the switch may serve as a useful predictor of a decrease in the fatty liver index. Our study also revealed that the appetite-suppressing effect of tirzepatide varied depending on the type of GLP-1RA used prior to the switch. The tirzepatide treatment was effective even in the group that had been using semaglutide.
In this study, the decrease in the fatty liver index after switching to tirzepatide was associated with improvements in obesity and hypertriglyceridemia, suggesting that obesity-induced fatty liver disease improved with weight loss. These findings align with previous studies that have reported tirzepatide's effectiveness in improving MASLD biomarkers in patients with type 2 diabetes [20,21]. Furthermore, the SYNERGY-NASH study, which evaluated the efficacy and safety of tirzepatide in patients with MASH and hepatic fibrosis confirmed by liver biopsy, reported that the tirzepatide group significantly outperformed the placebo group in terms of MASH resolution, the primary endpoint, at 52 weeks [31]. In this previously reported study, the proportion of participants meeting the criteria for MASH resolution was 10% in the placebo group, 44% in the tirzepatide 5 mg group, 56% in the tirzepatide 10 mg group, and 62% in the tirzepatide 15 mg group. These results demonstrate that approximately half of the participants in each dose group achieved resolution of MASH and that tirzepatide has a strong inhibitory effect on MASLD. This study also showed improvements in liver fibrosis, nonalcoholic fatty liver disease activity score, and its individual components, such as steatosis, lobular inflammation, and hepatocyte ballooning [31]. In addition to weight loss, other mechanisms may contribute to tirzepatide's impact on liver pathology. The activation of GIP receptors in subcutaneous white adipose tissue has been shown to improve insulin sensitivity through increased postprandial TG uptake [32,33]. Moreover, animal model studies have demonstrated that GIP receptor agonists can improve insulin resistance independently of body weight changes [34]. Furthermore, clinical trials have demonstrated that tirzepatide improves insulin sensitivity more effectively than existing GLP-1RAs [35,36]. In animal models, improving insulin sensitivity in white adipose tissue has been shown to reduce ectopic fat deposition in the liver [37]. Therefore, it is possible that tirzepatide's direct protective effect on various tissues, including adipose tissue, plays a role in improving the pathology of MASLD. Further basic research is needed to confirm these mechanisms. In this study, the decrease in the UACR after switching to tirzepatide correlated with the decrease in body weight and BMI, suggesting that it may be influenced by weight loss. Indeed, it has been reported that improvement of obesity helps suppress renal events in patients with obesity and type 2 diabetes [38]. Recently, a post hoc analysis of the SURPASS-4 study compared eGFR trends in two groups of patients with type 2 diabetes and high cardiovascular risk: a tirzepatide group and an insulin glargine group. The results showed that tirzepatide slowed the rate of decline in eGFR [39]. Interestingly, the study also found that the change in eGFR did not correlate with the change in body weight, suggesting the possibility of a weight-independent pathway for renal protection. In fact, many basic mechanisms for the renal protective effect of tirzepatide have been reported [40]; however, the existence of a direct renal protective effect of tirzepatide requires further investigation through large-scale clinical trials.
The decrease in hsCRP levels after the switch in this study suggests that tripeptide has an anti-inflammatory effect, which aligns with previous reports [41]. As previous studies have shown that tripeptide reduces various cardiovascular risk markers such as hsCRP and leptin [41], it may be pertinent to investigate the cardiovascular event suppression effects among the participants in this study in the future.
Our multiple regression analysis indicated that young age, short duration of type 2 diabetes, and low HbA1c level before switching to tirzepatide were predictive factors for weight loss after the switch, and that young age before the switch may be a predictor for a decrease in the fatty liver index. Previous reports have identified high doses of tirzepatide, female sex, Caucasian/Asian race, young age, metformin use, good glycemic control, and low non-HDL-C levels as predictors of weight loss with tirzepatide use [42]. Additionally, low HbA1c levels and a short duration of diabetes have been identified as predictors of the blood glucose-lowering effect of tirzepatide [43]. Some overlap exists between the predictive factors in these previous reports and the findings in our study; hence, further research into predictors of MASLD improvement with tirzepatide, including prospective studies, may be necessary.
In this study, tirzepatide suppressed appetite in more than half of the patients. The decrease in the fatty liver index was significantly greater in the group that experienced appetite suppression, suggesting that the presence or absence of appetite suppression could be an indicator of tirzepatide's therapeutic effect. Additionally, the group that experienced appetite suppression was significantly more likely to have been using dulaglutide before the switch. Previous studies comparing the therapeutic effects of dulaglutide and semaglutide have shown that the dulaglutide group exhibited less weight loss and blood glucose suppression effects [44,45]. Therefore, it is possible that appetite suppression became relatively stronger after switching to tirzepatide among dulaglutide users due to weaker appetite suppression before the switch.
Our results also indicated that there was little difference in the effectiveness of switching to tirzepatide based on whether or not an SGLT2i was used in combination. As previously mentioned, SGLT2is are drugs that lower blood glucose levels independently of insulin by increasing urinary glucose excretion [46]. They are highly recommended in the guidelines for MASLD in Japan and other countries [4,30]. Moreover, the use of SGLT2is in combination with tirzepatide is expected to increase in the future. Therefore, our finding that the concomitant use of an SGLT2i does not suppress the therapeutic effects of tirzepatide may be significant.
We found that the appetite suppression effect was stronger in the group that had used dulaglutide before switching to tirzepatide. In our study, semaglutide, a GLP-1RA with a relatively strong appetite-suppressing effect, was used at the highest dose in Japan (1 mg/week) in the semaglutide group, which may have limited the effect of switching to tirzepatide. However, after adjusting for age, the significant differences between the two groups for each parameter, other than appetite suppression, disappeared, suggesting that the type of GLP-1RA used before switching had little impact on the therapeutic outcomes. Furthermore, in the semaglutide group, there was a significant decrease in weight, BMI, HbA1c level, fatty liver index, and FIB-4 index 6 months after switching to tirzepatide, indicating that even high-dose semaglutide users may benefit from switching to tirzepatide.
When introducing a new drug, the primary concern is adverse effects. In the above-mentioned prospective study on tirzepatide and MASLD, the most common adverse events observed in the tirzepatide group during the 52-week intervention period were gastrointestinal disorders, with the majority being mild or moderate in severity, and no patients experienced severe adverse effects. There is currently no data on the safety of very long-term use, and this will likely be clarified in future prospective studies.
This study had a few limitations. First, the majority of cases were switched to tirzepatide during a period when long-term prescriptions were not available, resulting in a high frequency of hospital visits and a dosage limit of 5 mg/week due to limited shipments. Therefore, in the future, it may be necessary to evaluate cases where tirzepatide was introduced following the lifting of long-term prescription restrictions. Second, the small number of subjects in this study prevented the simultaneous entry of all items previously reported as associated factors for effects of tirzepatide, such as metformin background therapy and non-HDL-C, into the multivariate analysis, potentially weakening the statistical power of the findings. Third, regarding the evaluation of fatty liver disease and liver fibrosis, this study did not involve interventions by a hepatologist, and liver biopsy was not performed. Fatty liver was diagnosed by imaging tests before switching to tirzepatide; however, due to the retrospective nature of this study, there were few cases where imaging tests were performed six months after the switch. Therefore, two markers, the fatty liver index and FIB-4 index, were used to evaluate changes before and after the switch. Fourth, this study did not include a control group that did not use tirzepatide. In Japan, prospective, long-term randomized controlled trials are eagerly awaited to investigate the effects of tirzepatide on MASLD. Also, future prospective studies in Japan are needed to provide insights into whether tirzepatide use influences the progression of liver pathology in patients with MASLD, particularly those that track changes in liver biopsy or imaging findings over the long term.
Conclusions
We conducted a retrospective analysis to assess the six-month therapeutic effects of switching from GLP-1RAs to tirzepatide in patients with type 2 diabetes and MASLD. This study suggested the efficacy of switching from GLP-1RAs to tirzepatide among Japanese patients with type 2 diabetes and MASLD. The multiple regression analysis identified age, duration of type 2 diabetes, and HbA1c level before switching to tirzepatide as significant predictors of weight loss rate. Additionally, we found that the therapeutic effect of tirzepatide varied depending on the type of GLP-1RA used prior to the switch and it can be expected even in patients who were using semaglutide before the switch. Tirzepatide demonstrates great potential for the management of MASLD by promoting weight loss, improving glycemic control, and reducing chronic inflammation compared to GLP-1RAs.
Acknowledgments
I would like to thank Dr. Yusuke Matsuda, Dr. Hiroshi Sekiguchi, and Dr. Masanobu Kawakami for their assistance in the collection of samples from subjects.
Disclosures
Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. The certified review board of Nerima Hikarigaoka Hospital issued approval 23071302.
Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Hideyuki Okuma
Acquisition, analysis, or interpretation of data: Hideyuki Okuma
Drafting of the manuscript: Hideyuki Okuma
Critical review of the manuscript for important intellectual content: Hideyuki Okuma
Supervision: Hideyuki Okuma
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