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Abstract

Background:

Tirzepatide (TZP) has demonstrated efficacy for glycemic control and weight loss in subjects with type 2 diabetes (T2D). However, previous clinical trials were not conducted under the treatment of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a background regimen nor were they limited to subjects with chronic kidney disease (CKD).

Objectives:

We evaluated the glycemic control of tirzepatide switching from conventional GLP-1 receptor agonists in subjects with T2D and CKD.

Design:

This was a prospective, two-arm, observational study performed at a single center.

Methods:

Eligible subjects were individuals with T2D and CKD who had been treated with dulaglutide for more than 3 months, with glycated hemoglobin (HbA1c) ⩾7.0%, and an estimated glomerular filtration rate ⩽60 mL/min/1.73 m². Subjects who switched to tirzepatide (TZP group) and those who continued dulaglutide (Dula group) were observed over 6 months. The primary outcome was a change in HbA1c over 6 months between the groups. Additional metabolic parameters, including body weight and the urine albumin-creatinine ratio (UACR), were evaluated. Adverse events in the TZP group were also investigated.

Results:

Of the 55 participants, 48 completed the study (TZP group, n = 23; Dula group, n = 25). Tirzepatide significantly reduced HbA1c and body weight compared with the Dula group over 6 months (both p < 0.01). UACR levels remained stable in the TZP group throughout the study period and increased significantly in the Dula group (p < 0.05). Gastrointestinal events and hypoglycemia were observed in the TZP group, and those subjects who suffered hypoglycemic symptoms were mostly insulin users.

Conclusion:

Tirzepatide might be an effective alternative treatment for subjects with T2D and CKD who did not achieve sufficient glycemic control with conventional GLP-1RAs, as well as preventing the progression of nephropathy.

Trial registration:

This study was registered with the University Hospital Medical Information Network (registration number UMIN 000051344, date: June 16, 2023). https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_his_list.cgi?recptno=R000058576

Keywords

chronic kidney disease gastric inhibitory polypeptide glucagon-like peptide-1 receptor agonist type 2 diabetes

Introduction

The prevalence of chronic kidney disease (CKD) is increasing worldwide.^1,2 Given that CKD leads to various outcomes, including death and cardiovascular events, its early and appropriate treatment is desired.³ Nevertheless, the pathogenesis and causes of CKD are complex, and comprehensive approaches are required for its treatment.⁴ Type 2 diabetes (T2D) is one of the most common underlying diseases of CKD. Furthermore, CKD complicated with T2D had a higher risk for developing cardiovascular diseases and microvascular complications.⁵ According to the J-DOIT3 study, a randomized controlled trial for subjects with T2D in Japan, intensive treatment, including glycemic control, was effective at preventing the onset and progression of renal events.⁶

Following the development of medications for diabetes mellitus, some of these drugs also showed benefit for albuminuria and CKD.⁷ Although sodium–glucose cotransporter-2 inhibitors (SGLT2i) are a representative anti-diabetes drug that is also useful for CKD,⁴ glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recently shown to also be effective for CKD.⁸ Considering the pathogenesis of CKD in patients with diabetes is multifaceted,⁹ mechanisms related to these therapeutic effects, other than glycemic control, have been suggested, although they are poorly understood at present.^10–13

Tirzepatide (TZP), the first glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor dual agonist, improved glycated hemoglobin (HbA1c) levels in clinical trials.¹⁴ Among these clinical trials, only the post hoc analysis of SURPASS-4 investigated the renal outcomes of tirzepatide; however, the comparator was insulin, and the background regimen was limited to oral glucose-lowering medications (either metformin, sulfonylurea, or SGLT2i).¹⁵ Despite the benefits of these interventions, alternative anti-diabetes medications for patients with CKD and T2D are limited because of the impaired renal function of these patients. As GLP-1RAs have steadily grown in importance, the effectiveness of the dual agonist for patients with T2D and CKD is expected. Here, we investigated the efficacy and safety of tirzepatide in Japanese subjects with T2D and CKD. Patients receiving treatment with GLP-1RAs, those who had switched to tirzepatide from conventional treatments, and those who continued GLP-1RAs were observed prospectively.

Subjects, materials, and methods

Study design and participants

We conducted a prospective, two-arm, observational study at a single center. Consecutive eligible Japanese subjects with T2D and CKD who attended the Department of Internal Medicine, Kushiro Red Cross Hospital, were recruited between June 2023 and December 2023. The inclusion criteria were as follows: aged ⩾20 years old, HbA1c ⩾7% (International Federation of Clinical Chemistry (IFCC): 53.0 mmol/mol), estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m². Eligible subjects had received treatment with dulaglutide at 0.75 mg/week as a pre-treatment for more than 3 months. Their metabolic parameters, including image findings over 6 months, were evaluated. A change in treatment was proposed to all subjects during the study period, and those who concurred were switched to tirzepatide from dulaglutide at baseline. Subjects who switched to tirzepatide formed the TZP group, and those who continued dulaglutide formed the Dula group. No other concomitant medications were changed unless necessary. However, adjustments were allowed at the discretion of the attending physician, such as when a reduction in medication was necessary. The administration of tirzepatide was started at 2.5 mg/week and increased to 5.0 mg/week at 1 month, then continued at 5.0 mg/week for all subjects in the TZP group. Key exclusion criteria were subjects on erythropoietin-stimulating agents, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors, and receiving maintenance hemodialysis or peritoneal dialysis. Other exclusion criteria are described in the Supplemental Material.

Study outcomes and examinations

The primary study outcome was the difference in the change in HbA1c between the groups after 24 weeks. The secondary outcomes were the difference in the change in biochemical data, including renal function and lipid metabolism, and image findings between the groups after 24 weeks. Regarding image examinations, computed tomography (CT) assessed the visceral and subcutaneous fat areas at the umbilical level. Body composition analysis (InBody 770; InBody USA, Cerritos, CA, USA) monitored the fat and muscle mass at baseline and after 6 months. Blood samples were collected after overnight fasting and were measured using standard techniques. Body mass and height were measured using a calibrated scale, and the body mass index (BMI) was calculated as the body mass (kg) divided by height (m²). Other data, including age, sex, diabetes medications, and medical history of the participants, were also collected by the attending physicians. The diagnosis and categories of CKD by eGFR and albuminuria followed international criteria.⁴ Creatinine-based eGFR (eGFRcr) and cystatin C-based eGFR (eGFRcys) were calculated using the following formulas: eGFRcr (mL/min/1.73 m²) = 194 × Cr^−1.094 (mg/dL) × age^−0.287 × 0.739 (if female), eGFRcys (mL/min/1.73 m²) = (104 × Cystatin-C^−1.094 (mg/L) × 0.996^age × 0.929 (if female)) − 8, according to the Japanese Society of Nephrology criteria.^16,17

Adverse events

In the TZP group, participants were monitored for the development of adverse events. The presence and severity of adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.), and the definitions of severe adverse events are described in the Supplemental Material. Participants were thoroughly informed about potential adverse events, including gastrointestinal symptoms, in accordance with the instructions of the drug manufacturer, and their condition was checked by the attending physician at each hospital visit.

Sample size and post hoc power

The sample size was calculated using data from a previous phase III trial of Japanese subjects with T2D.¹⁸ Assuming a mean difference of 1.1% (IFCC; 12.0 mmol/mol) and a standard deviation (SD) of 1.30% (IFCC: 14.2 mmol/mol) for the reduction of HbA1c, 22 subjects per group were needed for a power of 80% and a two-sided significance level of 5%. Considering a 15% dropout rate (three subjects per group), the target number of subjects per group was 25. As a comparison to the switching group, the number of subjects in the conventional treatment group was set to be the same as that of the switching group. The post hoc power calculation was verified using GPower^® version 3.1.9.6. (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany).

Statistics

Normally distributed data were expressed as the mean ± SD, and other data were expressed as the median (interquartile range) or number (proportion in %). For comparisons between two groups, the Student’s t test was performed for parametric data, and the Wilcoxon signed-rank test was performed for non-parametric data. For comparisons between baseline and 6 months in each group, a paired t test was performed for parametric data, and the Wilcoxon signed-rank test was performed for non-parametric data. Fisher’s exact test was used to compare categorical variables between the groups. Pearson’s correlation analysis was performed to compare the changes in HbA1c and baseline parameters in the TZP group, and multiple regression analysis was performed for items with significant differences determined by Pearson’s correlation analysis using a stepwise method, considering multicollinearity. Furthermore, Pearson’s correlation analysis was performed to compare the change in HbA1c and the change in metabolic parameters in the TZP group. We conducted an analysis of covariance (ANCOVA) to adjust for the possible influence of the baseline values. Estimated impacts of each parameter were calculated after adjustment using a multivariate model. All tests were two-sided, and p < 0.05 was considered to represent statistical significance. Statistical analyses were conducted based on the per protocol set (PPS) for efficacy and the full analysis set (FAS) for safety. Data were analyzed using JMP Pro 17.0.0 (SAS Inc., Cary, NC, USA) or GraphPad Prism 10.4.0 (621; GraphPad Software Inc., San Diego, CA, USA).

Results

Characteristics of the study subjects

Subjects were enrolled as shown in Figure 1. Of the 55 subjects, 48 completed the study (23 in the TZP group and 25 in the Dula group). Although the dropout rate was higher than expected in the TZP group (17.9%, n = 5), only one subject discontinued because of an adverse event, and most reasons were unrelated to adverse events. We evaluated the efficacy in 48 subjects in both groups based on the PPS, and the safety was assessed in 24 subjects from the TZP group based on the FAS.

Figure 1.

Flowchart of the enrollment of study subjects. All subjects met the eligibility criteria, and written consent was obtained from all subjects. We observed subjects who switched to TZP from conventional treatment (TZP group) and those who continued conventional treatments (Dula group). The TZP group comprised 23 subjects, and the Dula group comprised 25 subjects, after the exclusion of subjects for the reasons shown.

Table 1 shows the baseline characteristics of the participants in each group. The cohort mainly comprised subjects with obesity and visceral fat accumulation who were categorized as G3a–G3b and A2–3 by the CKD classification (Supplemental Table 1). There were no significant differences between the two groups at baseline; however, HbA1c and the urine albumin-creatinine ratio (UACR) were slightly higher in the TZP group compared with the Dula group (HbA1c; p = 0.11, UACR; p = 0.54). There were no significant differences in the use of concomitant medications between the two groups; SGLT2i were used slightly more frequently in the TZP group, whereas insulin was used more often in the Dula group (Table 1 and Supplemental Table 1).

Table 1.

Baseline characteristics.

Variables	Tirzepatide (N = 23)	Dulaglutide (N = 25)	p Value
Female sex (n)	14	12	0.40
Age (years)	73.0 (67.0, 76.0)	72.0 (58.0, 75.5)	0.54^a
Height (cm)	157.2 ± 10.4	159.7 ± 9.0	0.38
Body weight (kg)	67.5 ± 15.4	69.9 ± 16.3	0.61
BMI (kg/m²)	27.5 (22.7, 30.6)	26.3 (22.4, 30.3)	0.70^a
Waist circumference (cm)	95.2 ± 11.5	96.5 ± 13.2	0.72
Diabetes duration (years)	18.0 (12.0, 30.0)	22.0 (16.0, 26.0)	0.26^a
FPG (mg/dL)	144.0 (120.0, 174.0)	135.0 (117.0, 154.0)	0.38^a
HbA1c (%)	8.2 (7.4, 8.8)	7.4 (7.2, 8.4)	0.11^a
C-peptide (ng/mL)	2.7 (1.4, 4.7)	2.1 (1.3, 3.3)	0.27^a
BUN (mg/dL)	19.5 (15.4, 22.5)	22.9 (17.3, 28.4)	0.09^a
Cr (mg/dL)	1.1 (0.8, 1.3)	1.2 (1.0, 1.4)	0.34^a
eGFRcr (mL/min/1.73 m²)	43.5 ± 10.6	42.6 ± 12.1	0.77
CysC (mg/L)	1.5 (1.2, 1.7)	1.4 (1.3, 1.9)	0.53^a
eGFRcys (mL/min/1.73 m²)	45.1 ± 12.7	43.6 ± 15.7	0.72
UACR (mg/g·Cr)	279.1 (57.2, 1320.8)	142.1 (28.1, 652.7)	0.54^a
CT findings
Total fat area (cm²)	363.2 ± 141.5	349.7 ± 164.1	0.76
Subcutaneous fat area (cm²)	189.0 ± 68.9	168.2 ± 75.4	0.33
Visceral fat area (cm²)	180.3 (121.3, 209.8)	195.8 (76.8, 234.7)	0.61^a
VAT/SAT ratio	0.9 (0.5, 1.2)	1.0 (0.7, 1.4)	0.49^a

Values are expressed as mean ± SD or median (interquartile range).

Wilcoxon signed-rank test was applied to the following factors: Age, BMI, diabetes duration, FPG, HbA1c, CPR, BUN, Cr, CysC, UACR, visceral fat area, VAT/SAT ratio.

BMI, body mass index; BUN, blood urea nitrogen; Cr, creatinine; CT, computed tomography; CysC, cystatin C; eGFRcr, creatinine-based estimated glomerular filtration rate; eGFRcys, cystatin C-based estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; UACR, urinary albumin creatinine ratio; VAT/SAT, visceral adipose tissue/subcutaneous adipose tissue; α-GI, alpha glucosidase inhibitors.

Efficacy

As shown in Figure 2 and Table 2, an improvement in HbA1c over 6 months, the primary outcome of this study, was significantly greater in the TZP group than in the Dula group (p < 0.01). Considering that the baseline HbA1c was slightly higher in the TZP group, we performed ANCOVA for the change in HbA1c to validate this group difference. After adjustments were made by including the baseline HbA1c plus vital items, tirzepatide was shown to have significantly reduced HbA1c compared with that in the Dula group (p < 0.01; Supplemental Table 2).

Figure 2.

Study outcomes in each group. (a) Comparison of the changes in HbA1c between both groups at 6 months. (b) The changes in HbA1c in each group over 6 months. (c) Comparison of changes in the body weight between both groups over 6 months. (d) The changes in body weight in each group over 6 months. (a, c) The bar graphs represent the mean change in HbA1c or body weight for 6 months, and error bars represent the SD. The TZP group is represented in purple and the Dula group in gray. Individual subjects are shown as circles in each group. These changes were evaluated using the Student’s t test. (b, d) The changes in HbA1c or body weight over 6 months are shown as the mean and SD at each point. The TZP group is represented as purple squares and the Dula group in gray circles. In the Dula group, data for the HbA1c and body weight at 3 months were missing in one and two subjects, respectively. The changes were evaluated between baseline and each timepoint for each group using a paired t test. The differences in changes between groups at each timepoint were evaluated by the Student’s t test.

Table 2.

Comparison of parameter changes in each group and between two groups.

Variables	Amount of change for 6 months		Amount of change for 6 months		Change difference between groups
Variables	Tirzepatide (N = 23)	p Value	Dulaglutide (N = 25)	p Value	p Value
Body weight (kg)	−3.2 ± 2.7	<0.01	−0.3 ± 2.6	0.51	<0.01
BMI (kg/m²)	−1.3 ± 1.1	<0.01	−0.1 ± 0.9	0.53	<0.01
FPG (mg/dL)	−22.0 (−39.0, −9.0)	<0.01	2.0 (−21.5, 20.0)	0.82	<0.05
HbA1c (%)	−1.3 ± 1.0	<0.01	0.5 ± 1.2	0.05	<0.01
Cr (mg/dL)	0.0 (−0.1, 0.1)	0.11	0.0 (−0.1, 0.1)	0.69	0.10
eGFRcr (mL/min/1.73 m²)	2.3 (−2.4, 5.0)	0.09	−0.5 (−2.2, 2.8)	0.93	0.18
CysC (mg/L)	0.1 (−0.1, 0.2)	0.07	0.1 (0.0, 0.2)	<0.01	0.54
eGFRcys (mL/min/1.73 m²)	−2.4 (−7.2, 2.3)	0.08	−3.3 (−6.7, 0.9)	<0.01	0.74
UACR (mg/g·Cr)	−3.5 (−129.4, 117.7)	1.00	76.5 (4.8, 476.4)	<0.01	<0.05
CT findings
Total fat area (cm²)	−41.4 ± 46.9	<0.01	−5.7 ± 44.5	0.53	<0.01
Subcutaneous fat area (cm²)	−13.9 (−39.4, −1.2)	<0.01	−6.5 (−20.0, 3.9)	0.18	0.12
Visceral fat area (cm²)	−27.3 (−31.0, −5.5)	<0.05	−1.8 (−12.1, 6.5)	0.41	<0.05

Values are expressed as mean ± SD or median (interquartile range). We showed the amount of change for 6 months in each group. For comparison between the two groups, Student’s t test was performed for parametric data, and Wilcoxon signed-rank test was performed for non-parametric data. For comparison to baseline in each group, paired t test was performed for parametric data, and Wilcoxon signed-rank test was performed for non-parametric data.

BMI, body mass index; Cr, creatinine; CT, computed tomography; CysC, cystatin C; eGFRcr, creatinine-based estimated glomerular filtration rate; eGFRcys, cystatin C-based estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; UACR, urinary albumin creatinine ratio.

For secondary outcomes, tirzepatide significantly reduced body weight, fasting plasma glucose, and triglyceride (Table 2 and Supplemental Table 1). The renal outcomes comprising eGFR, Cr, and UACR did not change significantly in the TZP group over 6 months, although these indices deteriorated in the Dula group (Table 2 and Supplemental Table 1, p < 0.01 in the Dula group), resulting in a significant group difference for UACR (p < 0.05 between the groups). Similar results were obtained after adjusting for representative concomitant medications, which affected renal outcomes (Supplemental Table 3). Fat mass, including the visceral fat area by CT, and the muscle mass assessed by body composition analysis, was decreased in the TZP group compared with the Dula group (p < 0.05, Table 2 and Supplemental Table 1). Although there were no significant differences in the number of concomitant medications, the dose of insulin was decreased in the TZP group and increased in the Dula group (Supplemental Table 1).

To identify factors affecting a change in HbA1c, we conducted a correlation analysis between the change in HbA1c and baseline parameters in the TZP group (Table 3). The glycemic parameters and visceral fat area had negative coefficients with the change in HbA1c, and multiple regression analysis was performed for these significant factors. Finally, the baseline HbA1c was shown to be a significant independent factor (Table 4, p < 0.001). Regarding the change in HbA1c, the change in fasting plasma glucose and UACR had significant positive coefficients (Δfasting plasma glucose, p < 0.01; ΔUACR, p < 0.05, Supplemental Table 4). The change in visceral fat area, but not body weight and BMI, tended to have a positive correlation (p = 0.06, Supplemental Table 4).

Table 3.

Correlation analysis between the change of HbA1c and baseline parameters in tirzepatide group.

Variables	r	p Value
Age	0.1684	0.44
Height	−0.4634	<0.05
Body weight	−0.3614	0.09
BMI	−0.1145	0.60
Waist circumference	−0.2748	0.22
Diabetes duration	−0.4500	<0.05
FPG	−0.6281	<0.01
HbA1c	−0.7472	<0.01
C-peptide	−0.1791	0.41
BUN	0.0183	0.93
Cr	−0.2532	0.24
eGFRcr	−0.0600	0.79
CysC	−0.0255	0.91
eGFRcys	−0.1672	0.45
UACR	−0.3506	0.10
Total fat area	−0.2809	0.19
Subcutaneous fat area	0.0604	0.78
Visceral fat area	−0.4804	<0.05
VAT/SAT ratio	−0.4676	<0.05

Pearson’s correlation analysis was performed between the change of HbA1c and baseline parameters in tirzepatide group.

BMI, body mass index; BUN, blood urea nitrogen; Cr, creatinine; CysC, cystatin C; eGFRcr, creatinine-based estimated glomerular filtration rate; eGFRcys, cystatin C-based estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; UACR, urinary albumin creatinine ratio; VAT/SAT, visceral adipose tissue/subcutaneous adipose tissue.

Table 4.

Multiple linear regression analysis between the change of HbA1c and baseline parameters in tirzepatide group.

Variables	Estimates	SE	95% CI	p Value
Model 1
HbA1c	−0.740	0.169	−1.093 to −0.387	<0.01
Visceral fat area	−0.003	0.002	−0.006 to 0.001	0.13
Model 2
HbA1c	−0.738	0.174	−1.102 to −0.374	<0.01
Visceral fat area	−0.002	0.002	−0.006 to 0.001	0.15
Model 3
HbA1c	−0.689	0.168	−1.042 to −0.336	<0.01
Visceral fat area	−0.002	0.002	−0.005 to 0.001	0.24

Multiple regression analysis was performed on items with significant differences in the single regression analysis by stepwise method, considering multicollinearity. Model 1: unadjusted; Model 2: adjusted for age; Model 3: Model 2 plus sex.

CI, confidence interval; HbA1c, glycated hemoglobin; SE, standard error.

Safety

Adverse events were evaluated only for the TZP group (Supplemental Table 5). Only one subject required the discontinuation of tirzepatide for injection site pain (Figure 1), and no other severe adverse events defined using CTCAE v5 were observed. Most frequent adverse events were gastrointestinal symptoms. These occurred in those receiving 5.0 mg tirzepatide, and they were assessed as Grade 1 based on CTCAE v5 and were tolerable. Hypoglycemia was detected in two subjects with insulin treatment, and three of four subjects who experienced hypersomnia and dizziness also received insulin treatment. Their mean total insulin dose was approximately 20 units/day, and the category of renal function by eGFRcr was G3a (n = 3) and G3b (n = 2).

Sample size

Because the sample size was small in this study, we calculated the post hoc power for confirmation. The overall detection power value under a 5% α error was 0.9998 for a change in HbA1c between the TZP group and Dula group over 6 months.

Discussion

The present study demonstrated the efficacy and safety of tirzepatide for subjects with T2D and CKD pre-treated with dulaglutide for the first time. Tirzepatide decreased the HbA1c and body weight, and reduced the insulin dosage. Although gastrointestinal symptoms were observed, they were not serious, and no other severe adverse events were noted. Renal outcomes were unchanged in the TZP group, whereas those in the Dula group deteriorated over 6 months (Table 2). The UACR was significantly increased in the Dula group, suggesting tirzepatide might have reduced the progression of nephropathy. Additionally, our results showed that tirzepatide was effective when switching from dulaglutide in patients with T2D and CKD. Patients at high risk for cardiovascular diseases require more intensive and safer medications; however, treatment options are limited because of the insufficient renal function of these patients. Therefore, tirzepatide might be beneficial for patients with CKD who have poor glycemic control, even if they are using conventional GLP-1RAs. To the best of our knowledge, this is the first study to report the therapeutic effects of tirzepatide prospectively, in Japanese subjects with T2D and CKD, in a real-world clinical setting.

The SURPASS clinical trials reported the efficacy of tirzepatide worldwide,¹⁴ and the SURPASS J-mono and J-combo trials were conducted in Japanese subjects.^18,19 Each trial demonstrated a marked reduction in HbA1c and body weight, with no apparent racial differences. In these trials, the HbA1c reduction by 5.0 mg tirzepatide was 1.9%–2.7% (IFCC: 20.0–27.0 mmol/mol),¹⁴ which was slightly higher than our result. However, the background regimen and characteristics of subjects are important. No clinical trials have been conducted where GLP-1RAs were set as the background regimen nor limited to subjects with CKD, prospectively. For comparators, the SURPASS-2 and SURPASS J-mono trials reported differences between tirzepatide and GLP-1RAs, and semaglutide and dulaglutide, respectively.^18,20 Although the background regimens of subjects were diet and exercise therapy in the SURPASS J-mono trial, the difference in the change in HbA1c was 1.1% (IFCC: 12 mmol/mol) between those receiving 5.0 mg tirzepatide and 0.75 mg dulaglutide,¹⁸ which was similar to our results. The SURPASS-4 trial only performed a post hoc analysis of subjects with CKD.¹⁵ However, the proportion of subjects in the SURPASS-4 trial with eGFR <60 mL/min/1.73 m² was only 17% and a reduction in HbA1c was unclear for this population.^15,21 Additionally, participants in the present study were older and had more impaired renal function than those in the SURPASS J-mono and SURPASS-4 trials.^18,21 Even considering these differences, tirzepatide was shown to be effective in the present study.

Our results showed that tirzepatide significantly reduced fat accumulation, particularly in the visceral fat area (Table 2). Although baseline HbA1c was an independent factor for the change in HbA1c, correlation analysis also showed a significant negative correlation between the change in HbA1c and baseline visceral fat accumulation (Tables 3 and 4). Although the mechanism related to GIP/GLP-1 receptor dual agonist treatment for diabetes treatment is unclear, it might contribute to correcting the white adipose tissue blood flow and restoring the original fat buffering capacity.^22–24 Instead of decreasing the body weight, a reduction in the visceral fat area tended to be associated with an improvement in HbA1c (Supplemental Table 4, p = 0.06); thus, the efficacy of tirzepatide might be related to its effect on the adipose tissue. Visceral fat accumulation is clearly a risk factor for various metabolic diseases as well as cardiovascular events, and over 50% of Japanese patients with T2D are suspected of having visceral fat accumulation when their BMI exceeds 25 kg/m.^2,25,26 The baseline BMI in the present study was higher than 25 kg/m², and tirzepatide might be a valuable approach in clinical settings for those who are unable to reduce visceral fat sufficiently with conventional GLP-1RAs.

Recently, the FLOW study reported the efficacy of semaglutide, a GLP-1RA for CKD.⁸ The therapeutic mechanism for CKD might include decreasing inflammation, oxidative stress, and fibrosis in the kidneys.^10–13 Indeed, weight loss and an improvement in glycemic control might also be involved, suggesting semaglutide might have multifactorial effects.⁸ A post hoc analysis in the SURPASS-4 trial showed that tirzepatide reduced the annual rate of eGFR decline and did not increase the UACR when compared with insulin glargine.¹⁵ Although GIP receptor expression in the kidney has not been firmly established,^22,27 tirzepatide might affect vascular endothelial cells, inflammation, and perirenal fat in the kidney.¹⁵ Tirzepatide did not increase UACR when compared with dulaglutide in the present study (Table 2). Given the slight difference in the number of subjects who received concomitant medications with SGLT2i or insulin, we also evaluated the impact of these drugs on ΔUACR. The impact of switching to tirzepatide on the decrease in UACR was greater than that when using SGLT2i in combination (Supplemental Table 3). This should not be interpreted as the superiority of tirzepatide; however, it suggests that the potential effects of concomitant medications might have been, at the very least, attenuated. The change in HbA1c had a positive correlation with the change in UACR (Supplemental Table 4); therefore, it may be a potential option, particularly for patients with poorly controlled hyperglycemia and UACR, despite conventional GLP-1RA treatment. A significant difference in the reduction of the annual rate of eGFR decline was observed after 42 weeks in the post hoc analysis of the SURPASS-4 trial¹⁵; therefore, we think that further long-term observation would improve the therapeutic field of this drug. In addition, treatment options become increasingly limited with progressive renal impairment, given that insulin secretagogues carry a heightened risk of prolonged hypoglycemia in older patients. Indeed, the intensification of therapy in the Dula group appeared to have relied on insulin dose escalation and the addition of alpha-glucosidase inhibitors, which alone may not have been sufficient to achieve adequate HbA1c reduction. In this context, tirzepatide may represent a valuable therapeutic option for patients in a clinically challenging position with few available alternatives.

Regarding safety, gastrointestinal and hypoglycemic symptoms were observed mainly in the TZP group (Supplemental Table 5). Even when switching from GLP-1RAs, gastrointestinal symptoms were observed, and adverse events seemed to be more frequent at dosage of 5.0 mg. Subjects with hypoglycemic symptoms were all insulin users except for one, and therefore, a dosage adjustment may be required prior to administration for patients with CKD on insulin therapy. Moreover, it is important to consider that the muscle mass was significantly decreased in the TZP group (Supplemental Table 1). Another valuable finding of the present study was that tirzepatide had efficacy in older patients (Table 1), although it is indicated as a risk for sarcopenia in the elderly. CKD itself was reported to be a risk factor for sarcopenia^28,29; thus, additional investigation is necessary.

The strengths of this study were that we focused on subjects with CKD who were pre-treated with GLP-1RAs. Coincidentally, our prospective, two-arm study contained mainly older subjects. This might reflect that tirzepatide is effective for high-risk older patients in a real-world clinical setting. This study had several limitations. First, the sample size was small, and the dropout rate in the TZP group was higher than expected. Although the post hoc power calculation supported the statistical validity of the results, all statistical analyses were conducted based on the PPS. Second, this was an observational study, not a randomized controlled trial. All participants received explanations about the risk-benefit, including costs and adverse events. Treatment selection was determined based on participants’ individual discretion. Therefore, it is possible that the TZP group included subjects who were highly motivated for treatment or by increased concern regarding the inadequacy of their current therapeutic state. Although we addressed this issue by adjusting for baseline HbA1c (Supplemental Table 2), increased burdens—such as financial costs or the requirement for additional clinic visits during tirzepatide dose escalation (from 2.5 to 5.0 mg)—may also have contributed to the participant’s discretion, especially in those who had no intention of changing their treatment regimen. Additionally, selection bias might have been present to some extent, even though no significant differences in patient background were observed. Third, treatments other than the target medication were adjusted at the discretion of the attending physicians, consistent with the observational nature of the study. In practice, treatment intensification options were limited in both groups because of patient characteristics. However, it is important to note that the absence of defined criteria for treatment intensification may have contributed to the insufficient reduction in HbA1c observed in the Dula group. Finally, the observation period, race of subjects, and dosage of the drug were limited. Long-term observation or high-dose administration might have changed the renal outcomes, considering the maintenance dosage of tirzepatide for T2D is 5.0 mg in Japan, which is consistent with actual clinical practice.

In conclusion, this is the first report of a prospective, two-arm study of the efficacy of tirzepatide in subjects with T2D and CKD. As well as improving glycemic control, it might be beneficial in preventing the progression of nephropathy; however, attention should be paid to the risk of sarcopenia and hypoglycemia in insulin users. Tirzepatide might be an effective alternative for patients who have not achieved sufficient glycemic control with conventional GLP-1RAs.

Supplemental Material

sj-docx-1-tae-10.1177_20420188251378216 – Supplemental material for Efficacy and safety of tirzepatide in subjects with type 2 diabetes and chronic kidney disease: a prospective, two-arm observational study

Supplemental material, sj-docx-1-tae-10.1177_20420188251378216 for Efficacy and safety of tirzepatide in subjects with type 2 diabetes and chronic kidney disease: a prospective, two-arm observational study by Yuki Oe, Hiroshi Nomoto, Kyu Yong Cho, Takashi Omori, Koki Nakamura, Akihiro Takahashi, Yuka Suzuki, Jyunpei Yoshikawa, Akiko Kato-Sato, Shin Furukawa, Taro Nishio, Hirohiko Kitakawa, Aika Miya, Hiraku Kameda, Daigo Nakazawa, Akinobu Nakamura, Kiyoshi Sakai and Tatsuya Atsumi in Therapeutic Advances in Endocrinology and Metabolism

Supplemental Material

sj-docx-2-tae-10.1177_20420188251378216 – Supplemental material for Efficacy and safety of tirzepatide in subjects with type 2 diabetes and chronic kidney disease: a prospective, two-arm observational study

Supplemental material, sj-docx-2-tae-10.1177_20420188251378216 for Efficacy and safety of tirzepatide in subjects with type 2 diabetes and chronic kidney disease: a prospective, two-arm observational study by Yuki Oe, Hiroshi Nomoto, Kyu Yong Cho, Takashi Omori, Koki Nakamura, Akihiro Takahashi, Yuka Suzuki, Jyunpei Yoshikawa, Akiko Kato-Sato, Shin Furukawa, Taro Nishio, Hirohiko Kitakawa, Aika Miya, Hiraku Kameda, Daigo Nakazawa, Akinobu Nakamura, Kiyoshi Sakai and Tatsuya Atsumi in Therapeutic Advances in Endocrinology and Metabolism

Footnotes

Acknowledgements

The study was presented at the International Federation for the Surgery of OBESITY AND METABOLIC DISORDERS (IFSO) World Congress held in Melbourne, Australia. A presentation related to this study was published in the IFSO website. The authors would like to express their gratitude to all the patients and staff who participated in this study. We also thank J. Ludovic Croxford PhD, from Edanz () for editing a draft of this manuscript.

Author’s note

Address of another institution at which the study was performed: Department of Internal Medicine, Kushiro Red Cross Hospital, 21-14 Shinei-cho, Kushiro, Hokkaido 085-0032, Japan.

Declarations

ORCID iDs

Yuki Oe

Hiroshi Nomoto

Kyu yong Cho

Supplemental material

Supplemental material for this article is available online.

Open researcher and contributors

Corresponding author, Hiroshi Nomoto.

First author, Yuki Oe.

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Supplementary Material

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Efficacy and safety of tirzepatide in subjects with type 2 diabetes and chronic kidney disease: a prospective,two-arm observational study

Abstract

Background:

Objectives:

Design:

Methods:

Results:

Conclusion:

Trial registration:

Keywords

Introduction

Subjects, materials, and methods

Study design and participants

Study outcomes and examinations

Adverse events

Sample size and post hoc power

Statistics

Results

Characteristics of the study subjects

Efficacy

Safety

Sample size

Discussion

Supplemental Material

sj-docx-1-tae-10.1177_20420188251378216 – Supplemental material for Efficacy and safety of tirzepatide in subjects with type 2 diabetes and chronic kidney disease: a prospective, two-arm observational study

Supplemental Material

sj-docx-2-tae-10.1177_20420188251378216 – Supplemental material for Efficacy and safety of tirzepatide in subjects with type 2 diabetes and chronic kidney disease: a prospective, two-arm observational study

Footnotes

Acknowledgements

Author’s note

Declarations

ORCID iDs

Supplemental material

Open researcher and contributors

References

Supplementary Material