Effects of switching from liraglutide to semaglutide or dulaglutide in patients with type 2 diabetes: A randomized controlled trial

ABSTRACT

Introduction

Few studies have examined the effects of glucagon‐like peptide‐1 receptor agonist switching, particularly in Japanese patients. Therefore, we aimed to investigate the effects of switching from liraglutide to semaglutide or dulaglutide on blood glucose, body weight, and the occurrence of adverse effects in clinical practice.

Materials and Methods

This was an open‐label, prospective, randomized, parallel‐group controlled trial. Patients with type 2 diabetes treated with liraglutide (0.6 or 0.9 mg) at Yokosuka Kyosai Hospital in Japan were recruited from September 2020 to March 2022 and, after obtaining informed consent, randomly assigned to the semaglutide or dulaglutide group (1:1). Changes in the glycated hemoglobin level from baseline to weeks 8, 16, and 26 were evaluated post‐treatment.

Results

Initially, 32 participants were enrolled, of whom 30 completed the study. Glycemic control was significantly better in the semaglutide group than in the dulaglutide group (−0.42 ± 0.49% vs −0.00 ± 0.34%, P = 0.0120). Body weight significantly decreased in the semaglutide group (−2.6 ± 3.6 kg, P = 0.0153), whereas no change was observed in the dulaglutide group (−0.1 ± 2.7 kg, P = 0.8432). We found a significant difference in body weight between the groups (P = 0.0469). The proportion of participants who reported adverse events was 75.0% and 18.8% in the semaglutide and dulaglutide groups, respectively. One patient in the semaglutide group had difficulty continuing treatment due to severe vomiting and weight loss.

Conclusions

Switching from once‐daily liraglutide to once‐weekly semaglutide 0.5 mg significantly improved glycemic control and body weight compared with switching to once‐weekly dulaglutide 0.75 mg.

Switching from once‐daily liraglutide to once‐weekly semaglutide 0.5 mg significantly improved glycemic control and body weight compared with switching to once‐weekly dulaglutide 0.75 mg.

INTRODUCTION

Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) promote insulin secretion in a blood glucose‐dependent manner to reduce the likelihood of the occurrence of hypoglycemia. Simultaneously, the secretion of glucagon is suppressed. GLP‐1RAs also delay gastric emptying, suppress appetite, and can be expected to have a weight‐loss effect ¹ , ² , ³ . Liraglutide, a once‐daily human GLP‐1RA, has been shown to reduce the incidence of the 3‐point major adverse cardiac events (i.e., cardiovascular death, non‐fatal myocardial infarction, and non‐fatal stroke) compared with a placebo ⁴ . Similar findings were observed in patients treated with semaglutide ⁵ . In addition, dulaglutide does not result in significant between‐group differences in the rate of cardiovascular death or non‐fatal myocardial infarction but significantly reduces the rate of non‐fatal stroke ⁶ . Based on these findings, both the American Diabetes Association ⁷ and Japanese guidelines ⁸ recommend the use of GLP‐1RAs as effective therapeutic agents that can help patients to maintain a normal life and promote longevity in healthy people.

In Japan, there are few reports of clinically adequate, prospective comparative studies on the effects of switching between GLP‐1RAs. Therefore, this study aimed to investigate the effects of switching from once‐daily liraglutide to once‐weekly semaglutide or dulaglutide on blood glucose levels and body weight and the increase or decrease in the incidence of adverse effects. Furthermore, we planned to use the Japanese version of the Diabetes Treatment Satisfaction Questionnaire (DTSQ) ⁹ to assess the patients’ acceptance of treatment.

MATERIALS AND METHODS

Study design

This was an open‐label, randomized, parallel‐group clinical trial. Patients with type 2 diabetes treated with liraglutide (0.6 or 0.9 mg) at Yokosuka Kyosai Hospital in Japan were recruited from September 2020 to March 2022 and, after obtaining informed consent, randomly assigned to the semaglutide or dulaglutide group (1:1) (Figure 1). Patients in the semaglutide group received 0.25 mg of semaglutide for 4 weeks, followed by 0.5 mg, and patients in the dulaglutide group received 0.75 mg of dulaglutide. The study used semaglutide SD, a dedicated single‐use pen injector with a fixed injection needle. All patients were asked to visit the hospital at 0, 8 ± 2, 16 ± 2, and 26 ± 2 weeks; they were allowed to take sugar‐free drinks but no food (Figure S1). We continued instructing the patients throughout the study period regarding diet and exercise therapy. Blood glucose testing was performed by each individual, who was instructed to test twice weekly, approximately four times daily. The patients completed the DTSQ before the start of the study and at week 26. During the study, patients were monitored for adverse effects, such as hypoglycemia, gastrointestinal disturbances, and constipation/diarrhea. We defined hypoglycemia as blood glucose levels below 70 mg/dL or symptoms of hypoglycemia.

Figure 1.

Schematic representation of patient selection and management in the study.

Participants

The inclusion criteria were as follows: (i) patients who were older than 20 years at the time of registration (regardless of sex), (ii) patients diagnosed with type 2 diabetes, (iii) patients being treated with liraglutide (0.6 or 0.9 mg), (iv) patients who had not been treated with a new diabetes drug for more than 3 months, and (v) patients who agreed to participate in this study.

The exclusion criteria were as follows: (i) patients with severe liver damage (up to three times the upper limit of the normal levels of aspartate transaminase (AST) and alanine transaminase (ALT) recorded within 28 days before enrollment); (ii) patients with severe congestive heart failure and acute heart failure; (iii) patients being treated with steroids; (iv) patients with a history of diabetic ketoacidosis or diabetic coma within the past 6 months; (v) patients with cancer currently undergoing treatment; (vi) patients who received surgery and had a severe infectious disease along with severe trauma before and after surgery; (vii) patients with contraindications or allergic reactions to the study drugs; (viii) patients who were pregnant, possibly pregnant, or lactating during the treatment period; (ix) patients who had participated in a clinical trial concurrently within 3 months before inclusion in this study; and (x) patients who were deemed to be inappropriate for inclusion in the study at the discretion of the doctor.

Calculation of sample size

Because semaglutide reduced the glycated hemoglobin (HbA1c) levels by 1.5 ± 0.06% and dulaglutide reduced the levels by 1.1 ± 0.05% (SUSTAIN 7) ¹⁰ , a standard deviation of 0.6 and power of 80% were calculated to demonstrate the superiority of semaglutide. Therefore, it was determined that to detect a significant difference, 42 cases would be required. Considering dropouts, 50 cases (25 in each group) were enrolled as the target number of cases. However, the study was terminated early with a total of 32 cases owing to the announcement that the production and export of semaglutide SD would be temporarily halted in February 2022 in Japan.

Endpoints

The primary endpoint was the difference in the HbA1c level during the 26 weeks between the groups. Secondary endpoints were the differences between the following parameters: fasting plasma glucose (FPG), systolic blood pressure, diastolic blood pressure, pulse rate, lipid profile, serum creatinine, estimated glomerular filtration rate (eGFR), uric acid, AST, ALT, gamma‐glutamyl transpeptidase, urine albumin to creatinine ratio, adverse events, and DTSQ scores.

Statistical analysis

The results are expressed as mean ± standard deviation. Differences in data between baseline and week 26 in each group were compared using a paired t‐test. In addition, we analyzed the statistical significance of the differences between the groups using the Student's t‐test or Mann–Whitney's U test. Values of P <0.05 were considered statistically significant, and the analyses were performed using the JMP 16 (SAS Institute Inc., Cary, NC, USA).

Ethics statement

This study conformed to the provisions of the Declaration of Helsinki and was approved by the Institutional Review Board of Yokosuka Kyosai Hospital. The protocol was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry (identification no.: UMIN000040044). We obtained written informed consent from the patients before the start of the intervention.

RESULTS

Baseline characteristics

Table 1 presents the baseline characteristics of the patients. Of the 32 enrolled patients, 16 were assigned to the semaglutide group and 16 to the dulaglutide group; 15 patients in each group completed the study. Treatment before initiation of medication is shown in Table S1. The average duration of diabetes was 12.3 ± 11.2 years, and the average duration of liraglutide therapy was 15.2 ± 5.4 months. At baseline, renal function was significantly lower (P = 0.0158), and serum C‐peptide immunoreactivity levels were significantly higher (P = 0.0470) in the dulaglutide group than in the semaglutide group; however, no significant differences were observed in the other parameters, such as age, HbA1c, FPG, blood pressure, and body weight, between the groups. No patients with stage 4 or 5 chronic kidney disease were enrolled.

Table 1.

Patient characteristics

	Total	Semaglutide group	Dulaglutide group	P
Sex, male, n (%)	32 (81.3)	16 (68.8)	16 (93.8)
Liraglutide (0.6/0.9 mg)	20/12	10/6	10/6
Age (years)	62.1 ± 11.5	61.5 ± 11.2	62.7 ± 12.0	0.7746
Duration of diabetes (years)	12.3 ± 11.2	13.4 ± 10.6	11.1 ± 12.0	0.5687
Duration of liraglutide therapy (months)	15.2 ± 5.4	15.9 ± 5.6	14.4 ± 5.4	0.4243
Body weight (kg)	72.5 ± 17.4	72.3 ± 20.2	72.7 ± 14.9	0.9497
Body mass index (kg/m2)	25.9 ± 5.3	27.0 ± 6.6	25.1 ± 3.9	0.3704
Systolic blood pressure (mmHg)	130.9 ± 15.8	129.3 ± 18.3	132.4 ± 13.2	0.5849
Diastolic blood pressure (mmHg)	84.2 ± 11.1	83.6 ± 10.6	84.9 ± 11.9	0.7440
Pulse rate (bpm)	81.5 ± 12.1	83.8 ± 10.4	79.3 ± 13.5	0.2936
AST (IU/L)	24.7 ± 8.2	22.9 ± 6.9	26.4 ± 9.2	0.2342
ALT (IU/L)	26.3 ± 15.4	22.4 ± 9.5	30.1 ± 19.1	0.1569
eGFR (mL/min/1.73 m2)	67.0 ± 20.2	73.9 ± 21.4	58.6 ± 16.7	0.0158
HbA1c (%)	6.4 ± 0.7	6.4 ± 0.8	6.5 ± 0.6	0.8534
FPG (mg/dL)	121.8 ± 14.0	122.3 ± 16.0	121.3 ± 12.2	0.8342
CPR (ng/mL)	2.6 ± 1.0	2.3 ± 0.7	3.0 ± 1.1	0.0470

ALT, alanine transaminase; AST, aspartate transaminase; CPR, C‐peptide immunoreactivity; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin.

Efficacy

The change in the primary endpoint, HbA1c, is shown in Figure 2. At 26 weeks, based on the changes in HbA1c from baseline, it was observed that semaglutide was significantly superior to dulaglutide in controlling HbA1c levels (semaglutide: −0.42 ± 0.49% vs dulaglutide: −0.00 ± 0.34%, P = 0.0120). Each group had one insulin user; however, no insulin dosage changed during the study period. Additionally, no changes were observed in other diabetes medications.

Figure 2.

Changes in HbA1c and BW. ^# P < 0.05, ^## P < 0.01. BW, body weight; HbA1c, glycated hemoglobin.

Table 2 shows the differences between the groups in the parameters at baseline and week 26. A significant decrease was found in the fasting serum glucose level from baseline to week 26 in the semaglutide group (−10.3 ± 14.0 mg/dL, P = 0.0129). In contrast, we observed no change in the dulaglutide group (+0.1 ± 14.6 mg/dL, P = 0.9732). No significant difference was found in the FPG level between the groups (Figure S2; P = 0.0513). Additionally, a significant decrease was observed in body weight from baseline to week 26 in the semaglutide group (−2.6 ± 3.6 kg, P = 0.0153), whereas no change was observed in the dulaglutide group (−0.1 ± 2.7 kg, P = 0.8433). A significant difference was found in body weight between the groups (P = 0.0469). However, no differences were observed between the groups regarding the changes in serum creatinine, eGFR, urine albumin/creatinine ratio, liver function, and lipid levels.

Table 2.

Comparison of parameters before and after treatment with semaglutide or dulaglutide

	Semaglutide group			Dulaglutide group
	Baseline	Week 26	P1	Baseline	Week 26	P2	P3
HbA1c (%)	6.5 ± 0.8	6.1 ± 0.5	0.0052	6.5 ± 0.6	6.5 ± 0.5	1.0000	0.0120
FPG (mg/dL)	121.9 ± 16.0	111.5 ± 15.1	0.0129	121.3 ± 12.6	121.4 ± 18.3	0.9732	0.0513
BW (kg)	73.4 ± 20.4	70.8 ± 21.5	0.0153	74.4 ± 13.7	74.3 ± 14.5	0.8433	0.0469
sBP (mmHg)	127.0 ± 17.3	128.3 ± 11.9	0.6496	133.5 ± 13.1	130.7 ± 16.6	0.3963	0.3420
dBP (mmHg)	84.0 ± 10.8	84.5 ± 11.5	0.8549	85.7 ± 11.8	83.9 ± 15.4	0.4369	0.5120
PR (bpm)	83.1 ± 10.4	88.1 ± 10.9	0.0030	78.5 ± 13.6	76.0 ± 13.7	0.0389	0.0003
Cr (mg/dL)	0.8 ± 0.3	0.8 ± 0.2	0.9311	1.1 ± 0.3	1.1 ± 0.3	0.6497	0.7374
eGFR	75.0 ± 21.6	73.7 ± 18.4	0.6217	58.5 ± 17.2	59.3 ± 16.9	0.6143	0.4914
ACR (mg/gCr)	38.7 ± 36.7	37.0 ± 39.6	0.8279	234.7 ± 574.2	324.3 ± 538.2	0.4986	0.4915
UA (mg/dL)	5.3 ± 1.0	5.0 ± 0.9	0.1957	5.6 ± 1.1	5.7 ± 1.1	0.5103	0.1040
CPR (ng/mL)	2.3 ± 0.7	2.6 ± 1.8	0.4437	2.9 ± 1.1	3.0 ± 1.5	0.9680	0.5458
TG (mg/dL)	120.8 ± 51.5	107.9 ± 43.7	0.2105	114.1 ± 50.1	123.9 ± 52.3	0.2937	0.0997
HDL‐C (mg/dL)	51.9 ± 12.3	51.3 ± 15.8	0.7867	48.9 ± 12.1	51.5 ± 12.9	0.1391	0.2580
LDL‐C (mg/dL)	86.5 ± 14.4	83.9 ± 14.2	0.4637	80.7 ± 21.8	82.9 ± 23.0	0.5595	0.3485

P1: Comparison of changes between baseline and week 26 in the semaglutide group. P2: Comparison of changes between baseline and week 26 in the dulaglutide group. P3: Comparison of changes in each parameter between the semaglutide and dulaglutide groups at week 26.

ACR, albumin: creatinine ratio; BW, body weight; CPR, C‐peptide immunoreactivity; Cr, creatinine; dBP, diastolic blood pressure; eGFR, glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; HDL‐C, high density lipoprotein cholesterol; LDL‐C, low density lipoprotein cholesterol; PR, pulse rate; sBP, systolic blood pressure; TG, triglycerides; UA, uric acid.

We found no significant difference in the blood pressure measured in the examination room between the groups. The mean pulse rate increased significantly in the semaglutide group (+4.9 ± 5.3 bpm, P = 0.0030) and decreased significantly in the dulaglutide group (−2.5 ± 4.3 bpm, P = 0.0389). A significant difference was found between the groups (P = 0.0003).

Adverse effects

Table S2 shows the percentage of participants who reported adverse events during the 26 week study period; 75.0% (12/16) and 18.8% (3/16) patients in the semaglutide and dulaglutide groups, respectively. One patient in the semaglutide group had difficulty continuing treatment owing to severe vomiting and weight loss. Decreased appetite with dysgeusia was the most common adverse effect in the semaglutide group (6/16). Two patients in the dulaglutide group complained of constipation (2/16). Liver dysfunction, hypoglycemia, gallbladder disease, and pancreatitis were not observed during the study period. A close examination by an ophthalmologist was performed before and after the start of treatment, and no worsening of retinopathy was observed (Table S3).

Changes in DTSQ scores

All patients showed a significant increase in treatment satisfaction. Treatment satisfaction was significantly increased in the semaglutide and dulaglutide groups; however, we found no significant difference between the groups (P = 0.6889; Table 3). Additionally, the frequency of hyperglycemia and hypoglycemia among patients in both groups decreased rather than significantly. No significant difference was found between the groups (P = 0.9250).

Table 3.

Diabetes treatment satisfaction questionnaire (DTSQ) scores

	Total			Semaglutide (n = 16)			Dulaglutide (n = 15)
	Baseline	Week 26	P1	Baseline	Week 26	P2	Baseline	Week 26	P3	P4
No.1 current treatment	4.3 ± 1.6	4.9 ± 1.0	0.0172	4.1 ± 1.5	4.7 ± 0.6	0.1643	4.6 ± 1.8	5.2 ± 1.3	0.0572	1.0000
No.2 frequency of hyperglycemia	2.4 ± 1.4	1.7 ± 1.5	0.0254	2.8 ± 1.3	1.9 ± 1.2	0.0170	2.0 ± 1.4	1.6 ± 1.7	0.3478	0.5126
No.3 frequency of hypoglycemia	0.9 ± 1.4	1.0 ± 1.3	0.9053	0.9 ± 1.4	1.1 ± 1.4	0.6833	0.9 ± 1.4	0.8 ± 1.3	0.6534	0.5974
No.4 convenience	3.5 ± 1.6	4.7 ± 1.4	0.0050	3.4 ± 1.8	4.5 ± 1.4	0.0519	3.9 ± 1.6	4.9 ± 1.6	0.0642	0.7045
No.5 flexibility	3.3 ± 1.5	4.4 ± 1.2	0.0002	3.3 ± 1.4	4.3 ± 1.0	0.0262	3.5 ± 1.7	4.7 ± 1.4	0.0025	0.6396
No.6 understanding	4.1 ± 1.4	4.5 ± 1.2	0.0620	3.9 ± 1.4	4.4 ± 0.9	0.1350	4.5 ± 1.4	4.7 ± 1.4	0.5103	0.5830
No.7 recommend	3.9 ± 1.3	4.8 ± 1.2	0.0061	3.5 ± 1.3	4.7 ± 0.8	0.0075	4.3 ± 1.3	4.9 ± 1.5	0.1989	0.3909
No.8 continue	3.9 ± 1.7	4.6 ± 1.5	0.0367	3.7 ± 1.5	4.1 ± 1.5	0.3443	4.4 ± 1.8	5.1 ± 1.4	0.1165	0.8436
Treatment satisfaction	23.1 ± 7.1	28.1 ± 6.7	0.0003	21.8 ± 7.1	26.7 ± 4.8	0.0247	25.1 ± 7.0	29.5 ± 8.0	0.0163	0.6889
Frequency of hyperglycemia and hypoglycemia	3.3 ± 2.1	2.7 ± 2.3	0.1108	3.7 ± 1.9	3.0 ± 2.0	0.2627	2.9 ± 2.3	2.4 ± 2.6	0.2722	0.9250

P1: Comparison of changes between baseline and week 26 in all cases. P2: Comparison of changes between baseline and week 26 in the semaglutide group. P3: Comparison of changes between baseline and week 26 in the dulaglutide group. P4: Comparison of changes in each parameter between the semaglutide and dulaglutide groups at week 26.

Regarding the subscales of the DTSQ, the scores of all patients who were switched from once‐daily liraglutide to once‐weekly therapy significantly improved in the following subscales: ‘Current treatment’, ‘Frequency of hyperglycemia’, ‘Convenience’, ‘Flexibility’, ‘Recommendation’, and ‘Continue’. In addition, significantly large improvements were observed in the scores of ‘Frequency of hyperglycemia’, ‘Flexibility’, and ‘Recommendation’ in the semaglutide group. In contrast, a significant improvement was observed only in the ‘Flexibility’ scores in the dulaglutide group. However, the difference in the scores on any subscale was not significant between the groups.

DISCUSSION

To date, only a limited number of comparative studies on GLP‐1RAs have been reported, and few studies have examined the effects of GLP‐1RA switching, particularly in Japanese patients. Therefore, we examined the effects of switching from once‐daily liraglutide to once‐weekly semaglutide 0.5 mg or dulaglutide 0.75 mg on glycemic control and other parameters in an actual clinical setting.

The existing clinical studies comparing the effects of GLP‐1RAs on HbA1c levels include a phase III trial of dulaglutide ¹¹ and a phase III trial of semaglutide (SUSTAIN 7) ¹⁰ . In the phase III trial of dulaglutide, efficacy and safety were compared between liraglutide 0.9 mg and dulaglutide 0.75 mg in treating type 2 diabetes mellitus in Japanese patients; it was found that dulaglutide was non‐inferior to liraglutide over a 26 week study period, which is consistent with the findings of this study. Additionally, although not in Japanese patients, a comparison of the efficacy and safety with dulaglutide in the SUSTAIN 7 trial showed that semaglutide 0.5 mg is more effective than dulaglutide 0.75 mg in improving blood glucose levels after 40 weeks. In this study, the effects of semaglutide 0.5 mg in improving blood glucose control were stronger than those of dulaglutide 0.75 mg, even in actual clinical practice.

GLP‐1RAs reduce body weight in a dose‐dependent manner ³ , ¹² , ¹³ . For example, liraglutide 3.0 mg has been shown to maintain weight loss continuously for 3 years as an anti‐obesity drug ¹⁴ and is currently approved as an anti‐obesity drug in the US, the EU, and Australia. However, it has been suggested that the dose of 0.9 mg per day used until 2019 in Japan has a strong blood sugar‐decreasing effect but no significant effects on appetite control and weight loss ¹⁵ . In Japanese patients, the administration of semaglutide 0.5 mg resulted in −2.2 kg at 30 weeks ¹⁶ and −1.4 kg at 56 weeks ¹⁷ , which implies that the drug is less effective in Japan than in other countries; however, a significant reduction was still observed. Based on these findings, it was clinically confirmed that in Japanese patients, dulaglutide 0.75 mg does not cause any change in body weight. In contrast, semaglutide 0.5 mg can be expected to reduce body weight by approximately 2 kg over 26 weeks. This result may be explained by the fact that the effects of GLP‐1 receptor agonists on the brain differ between semaglutide and dulaglutide ¹⁸ , ¹⁹ .

A meta‐analysis of liraglutide and exenatide reported an increase in the pulse rate ²⁰ . As suggested by studies on dulaglutide ²¹ and semaglutide ⁵ , this is believed to be a result of the combined effects of GLP‐1RAs. However, there are no available reports comparing pulse rates on switching between GLP‐1Ras. The results of this study suggest that in Japanese patients, the pulse rate increases when the GLP‐1RA is switched from liraglutide to semaglutide 0.5 mg and decreases when liraglutide is switched to dulaglutide 0.75 mg.

Regarding DTSQ ratings, a previous study of diabetes treatment satisfaction in patients being treated with liraglutide and dulaglutide in Japan revealed a significant increase in treatment satisfaction in the dulaglutide group ²² , which is consistent with the results of this study. The frequency of hyperglycemia and hypoglycemia may reflect the patient's perception of the SMBG data since each individual took blood glucose measurements in this study. A crossover study would have been necessary to determine the original satisfaction level between patients treated with semaglutide and dulaglutide. However, this could not be performed due to the discontinuation of the product.

A decreasing trend was found in the frequency of hypoglycemia and hyperglycemia in both groups; however, no significant difference was observed. The degree of change in the HbA1c level resulting from hypoglycemic agents in patients with diabetes depends on the baseline HbA1c level ²³ , ²⁴ , ²⁵ . Therefore, it is possible that the participants in this study had good glycemic control and did not exhibit significant changes. Nevertheless, these results indicate that changing from once‐daily liraglutide to a once‐weekly GLP‐1RA increases treatment satisfaction, regardless of glycemic control or weight loss.

Although worsening of diabetic retinopathy was suggested in the SUSTAIN 7 trial ¹⁰ , no worsening of retinopathy was observed in this study. Risk factors for diabetic retinopathy include poor glycemic control over several years, and it has been suggested that a substantial improvement in blood glucose levels is an aggravating factor ²⁶ , ²⁷ . However, in this study, there was no rapid improvement in blood glucose levels; therefore, it is possible that there were no effects on retinopathy.

This study had some limitations. First, the planned number of participants was reduced owing to the temporary suspension of the sale of semaglutide SD. Second, the follow‐up period was limited, and there was no double‐blind methodology. Third, differences were found in the baseline eGFR data between the groups. However, it is unclear whether this difference affected the results of this study as the hypoglycemic effects of these drugs depend on the eGFR or have not yet been reported. Therefore, to address these potential problems, the results of this study should be replicated in longitudinal observational studies conducted in larger populations.

In conclusion, glycemic control and body weight were significantly improved in the semaglutide group, in which once‐daily liraglutide was switched to once‐weekly semaglutide 0.5 mg, compared with the dulaglutide group, in which once‐daily liraglutide was switched to once‐weekly dulaglutide 0.75 mg.

AUTHOR CONTRIBUTIONS

TI, MS, YI, and YT designed this study. TI collected the laboratory data. TI and YT wrote the manuscript.

DISCLOSURE

YT has received honoraria for lectures from MSD K.K.; Ono Pharmaceutical Co., Ltd; Nippon Boehringer Ingelheim Co., Ltd; Novartis Pharma K.K.; Takeda Pharmaceutical Co., Ltd; Mitsubishi Tanabe Pharma Corp.; Daiichi Sankyo Co., Ltd; Sanwa Kagaku Kenkyusho Co., Ltd; Kowa Pharmaceutical Co., Ltd; Novo Nordisk Pharma Ltd; Eli Lilly Japan K.K.; Sanofi K.K.; Sumitomo Pharma Co., Ltd; Bayer Yakuhin, Ltd; and AstraZeneca K.K., and has obtained research support from MSD K.K.; Ono Pharmaceutical Co., Ltd; Nippon Boehringer Ingelheim Co., Ltd; Novartis Pharma K.K.; Takeda Pharmaceutical Co., Ltd; Mitsubishi Tanabe Pharma Corp.; Daiichi Sankyo Co., Ltd; Sanwa Kagaku Kenkyusho Co., Ltd; Novo Nordisk Pharma Ltd; Eli Lilly Japan K.K.; Sanofi K.K.; Sumitomo Pharma Co., Ltd; Bayer Yakuhin, Ltd; Astellas Pharma, Inc.; Pfizer Japan, Inc.; and AstraZeneca K.K. TI, MS, and YI declare that they have no conflicts of interest.

Approval of the research protocol: The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution, and it conforms to the provisions of the Declaration of Helsinki. Institutional Review Board of Yokosuka Kyosai Hospital, Approval No. 20‐30.

Informed consent: All informed consent was obtained from the subject(s) and/or guardian(s).

Registry and the registration no. of the study/trial: University Hospital Medical Information Network (UMIN) clinical trial registry, Registration No.: UMIN000040044, Approval date April 03, 2020.

Animal studies: N/A.

Supporting information

Table S1 Medication combinations

Table S2 Adverse effects

Table S3 Changes in retinopathy

Figure S1 Study design.

Figure S2 Changes in FPG and pulse rate.