Real-World Effectiveness of Liraglutide Versus Dulaglutide In Japanese Patients With Type 2 Diabetes: A Retrospective Study

doi:10.21203/rs.3.rs-795616/v1

Real-world data comparing the effectiveness of various glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in type 2 diabetes mellitus (T2DM) are limited. We investigated the clinical effectiveness of liraglutide and dulaglutide in Japanese T2DM in a real-world setting. This retrospective study included 179 patients with T2DM who were treated with GLP-1 RA for at least 12 months (liraglutide, n=97; dulaglutide, n=82). Changes in glycated hemoglobin (HbA1c) at the end of 12-month treatment were evaluated. Compared with the liraglutide group, the dulaglutide group included significantly older patients with longer disease duration, lower body mass index, and higher proportion of dementia cases. HbA1c was significantly lower at 12 months in both groups (liraglutide, 8.9 to 7.6%; dulaglutide, 8.8 to 7.5%). Hierarchical regression analysis showed no differences in the extent of changes in HbA1c at 12 months between the two agents, after adjustment for differences in patient characteristics and drug adjustments during the 12-month period. High baseline HbA1c, the addition of GLP-1 RA treatment, and in-hospital initiation of GLP-1 RA treatment were identified as significant contributing factors to HbA1c reduction. Although patient characteristics were different between the two treatment groups, comparable HbA1c-lowering effects were noted in real-world settings.

Endocrinology & Metabolism

Cellular Metabolism

Liraglutide

Dulaglutide

Type 2 diabetes

GLP-1 receptor agonist

Glucagon-like peptide − 1 (GLP-1), an incretin hormone secreted by L-cells in the distal ileum and colon¹, has various effects, including glucose-dependent enhancement of insulin secretion², inhibition of glucagon secretion³, appetite suppression⁴, and suppression of gastric emptying⁵. Various GLP-1 receptor agonists (GLP-1 RAs) are available in the market at present. GLP-1 RAs can effectively lower blood glucose levels and facilitate weight loss with a low risk of hypoglycemia; hence, they are commonly used in patients with type 2 diabetes mellitus (T2DM). Furthermore, some GLP-1 RAs are reported to reduce the risk of 3-point major adverse cardiovascular events (MACE) ^{6, 7}, and a meta-analysis of four large-scale clinical studies that assessed GLP-1 RAs concluded that these agents can reduce the risk of cardiovascular events and all-cause mortality⁸.

Controlled clinical trials have demonstrated that GLP-1 RAs have distinct effects in terms of lowering glycated hemoglobin (HbA1c) levels and facilitating weight loss, as well as adverse reactions, such as nausea, vomiting, and diarrhea^{8, 9}. In Japan, dulaglutide and liraglutide are the most widely used GLP-1 RAs in routine clinical practice¹⁰. In a randomized controlled trial (RCT), dulaglutide (up to 1.5 mg/week) was reported to be non-inferior to liraglutide (up to 1.8 mg/day) ¹¹. In a Japanese comparative study of these agents used at different doses, HbA1c-lowering effects after 52 weeks of treatment were greater with dulaglutide (up to 0.75 mg/week) than liraglutide (up to 0.9 mg/day) ¹². However, the above study evaluated patients who were not taking antidiabetic drugs or had discontinued antidiabetic monotherapy, thereby differing greatly from real-world clinical situations. In real-world settings, only a few studies have investigated the effectiveness of liraglutide and dulaglutide in patients with T2DM, including those treated concomitantly with more than one oral hypoglycemic agent and insulin. To establish real-world evidence, we retrospectively examined changes in HbA1c after 12 months of GLP-1 RA treatment and compared liraglutide and dulaglutide.

Patient demographics

The analysis included 179 patients with T2DM who continued GLP-1 RA treatment for at least 12 months, consisting of 97 patients treated with liraglutide and 82 patients treated with dulaglutide. The selection of GLP-1 RA for treatment of these patients, and specifically with liraglutide and dulaglutide was based on the clinical assessment and judgment by the attending physicians. Table 1 summarizes the clinical characteristics of the study patients. Compared with patients of the dulaglutide group, those of the liraglutide group were significantly younger, had shorter duration of T2DM, higher BMI, and used fewer classes of oral glucose-lowering agents. The prevalence of micro- and macro-vascular complications was similar in the two groups, though a higher prevalence of dementia was noted in the dulaglutide group. HbA1c levels were similar in the two groups (liraglutide group: 8.9 ± 1.7%, dulaglutide group: 8.8 ± 1.7%). Dementia was more common in patients of the liraglutide group. There was bias associated with drug adjustment at the initiation of GLP-1 RAs: ‘reduce’ accounted for 45.4% in the liraglutide group, higher than in the dulaglutide group (28.0%), whereas ‘switch’ accounted for 38.1% in the liraglutide group, lower than in the dulaglutide group (61.0%). In both groups, approximately one-third of the patients had an inpatient initiation of GLP-1 RA. For all patients, liraglutide and dulaglutide were administered at 0.89 ± 0.26 mg/day and 0.75 mg/week, respectively, for 12 months.

Table 1

Baseline characteristics of the study patients.
	Liraglutide	Dulaglutide	P value
n	97	82
Age (years)	60.7 ± 12.5	68.6 ± 10.1	< 0.001
Sex (men/women)	51/46	40/42	0.714
Duration of diabetes (year)	13.9 ± 8.5	17.4 ± 9.8	0.011
Body weight
Body mass index (kg/m²)	27.8 ± 6.0	24.1 ± 4.6	< 0.001
Systolic blood pressure (mmHg)	132 ± 20	128 ± 17	0.146
Diastolic blood pressure (mmHg)	75 ± 12.6	72 ± 10.5	0.085
PG (mg/dL)	181 ± 67	177 ± 72	0.752
HbA1c (%)	8.9 ± 1.7	8.8 ± 1.7	0.746
AST (U/L)	27.1 ± 19.6	24.3 ± 17.4	0.248
ALT (U/L)	31.5 ± 31.4	24.3 ± 17.4	0.065
GGT (U/L)	46.4 ± 37.6	40.1 ± 66.8	0.441
eGFR (mL/min/1.73 m²)	65.4 ± 30.2	59.5 ± 22.8	0.154
UACR (mg/g Cre)	816 ± 2212	279 ± 715	0.070
LDL-C (mg/dL)	104 ± 36	103 ± 36	0.843
HDL-C (mg/dL)	49.3 ± 14.6	57.1 ± 15.3	0.001
Triglycerides (mg/dL)	175 ± 136	140 ± 65	0.122
Hypertension (%)	80 (82.5)	56 (68.3)	0.027
Dyslipidemia (%)	87 (89.7)	66 (80.5)	0.082
Antihypertensive agents (%)	77 (79.4)	52 (63.4)	0.018
Antilipidemic agents (%)	73 (75.3)	53 (64.6)	0.121
Glucose-lowering agents used
None (%)	20 (20.6)	5 (6.1)	0.005
DPP-4 inhibitors (%)	61 (62.9)	67 (81.7)	0.005
Sulfonylurea (%)	12 (12.4)	16 (19.5)	0.190
Glinide (%)	13 (13.4)	27 (32.9)	0.002
Biguanides (%)	43 (44.3)	32 (39.0)	0.473
Thiazolidine (%)	23 (23.7)	18 (22.0)	0.780
α-glucosidase inhibitors (%)	21 (21.6)	16 (19.5)	0.725
SGLT-2 inhibitors (%)	8 (8.2)	15 (18.3)	0.045
Insulin (%)	55 (56.7)	35 (41.2)	0.062
Number of oral antidiabetic agent classes	1.9 ± 1.2	2.3 ± 1.1	0.007
Retinopathy (%)	50 (51.5)	41 (50.0)	0.837
Nephropathy (%)	50 (51.5)	37 (45.1)	0.392
Peripheral neuropathy (%)	62 (63.9)	50 (61.0)	0.685
Coronary heart disease (%)	19 (19.6)	12 (14.6)	0.845
Cerebrovascular disease (%)	14 (14.4)	11 (13.4)	0.383
Dementia (%)	4 (4.1)	14 (17.1)	0.004
GLP-1RA treatment modality (%)			0.010
Add-on	16 (16.5)	9 (11.0)
Switch	37 (38.1)	50 (61.0)
Reduce	44 (45.1)	23 (28.0)
Inpatient initiation of GLP-1 RA treatment	36 (37.1)	26 (31.7)	0.449

Data are mean ± standard deviation, or n (%).

Comparisons between liraglutide and dulaglutide by the Student's t-test or Wilcoxon rank-sum test. Categorical values were tested by –χ² test. P values are for differences between the two groups.

PG, plasma glucose; HbA1c, glycated hemoglobin; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyl transferase; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio; LDL-C, low-density cholesterol; HDL-C, high-density cholesterol; DPP-4, dipeptidyl peptidase-4; SGLT-2, sodium-glucose cotransporter 2; GLP-1 RA, glucagon-like peptide-1 receptor agonist.

Efficacy

Figure 1 summarizes the effects of each treatment on HbA1c in the two groups. HbA1c was significantly lower at 12 months in both groups, relative to the respective value at baseline (before treatment), from 8.9%±1.7 to 7.6%±1.7% with liraglutide treatment and from 8.8%±1.7 to 7.5%±1.1% with dulaglutide therapy (Fig. 1). There were no significant differences in the effects of the two treatments on HbA1c at 6 and 12 months. The percentage of patients who achieved HbA1c < 7% at 12 months was significant, compared to that at baseline, in both the liraglutide and dulaglutide groups (liraglutide: 11.3% → 40.2%; dulaglutide: 13.4% → 31.7%, Fig. 2). Similarly, the percentage of patients with HbA1c ≥ 8% significantly decreased in both groups, with no difference observed in the distribution of HbA1c at 12 months between the two groups.

Table 2 shows the effect of 12-month treatment with liraglutide and dulaglutide on various parameters, relative to the baseline. There was no significant difference between the two groups in terms of plasma glucose levels. In contrast, the proportion of insulin users was unchanged in the dulaglutide group but significantly decreased in the liraglutide group. Significant differences were also observed in total insulin dose and basal insulin dose between the two groups. Body weight significantly decreased in both groups, though the changes in body weight over the 12-month period differed significantly between the two groups (liraglutide vs. dulaglutide: -3.1 ± 5.1 kg vs. -1.0 ± 3.5 kg, P = 0.002). Liraglutide tended to reduce systolic blood pressure, and significantly decreased diastolic blood pressure; however, no significant differences were observed between the two agents. Both treatments significantly reduced LDL-C and significantly increased HDL-C, but there was no significant difference between the two groups.

We employed hierarchical multiple regression analysis to determine the factors that contributed to the observed changes in HbA1c after 12 months of treatment (Table 3). In the unadjusted model, the change in HbA1c after 12 months of treatment correlated positively with the duration of diabetes, number of classes of oral glucose-lowering agents, use of insulin, and reducing or switching to GLP-1 RA treatment, and negatively with baseline plasma glucose, baseline HbA1c, presence of dementia, and inpatient initiation of GLP-1 RA treatment. However, there was no clear correlation with the type of GLP-1 RA. Next, we performed multivariate analysis using Model 1, Model 2 (Model 1 adjusted for differences in patient characteristics between the GLP-1 RAs), and Model 3 (Model 2 adjusted for drug adjustments during the 12 months). In Model 3, baseline HbA1c, GLP-1 RA treatment modality, and inpatient initiation of GLP-1 RA treatment correlated with the observed changes in HbA1c after 12 months, but no difference was detected between the two types of GLP-1 RAs.

Finally, we determined the factors that contributed to the observed changes in HbA1c after 12 months of treatment using univariate and multivariate analyses (Supplemental Tables 1 and 2). Multivariate analysis identified baseline HbA1c, baseline plasma glucose, and inpatient initiation of GLP-1 RA treatment as significant independent factors that contributed to the change in HbA1c over the 12-month liraglutide treatment. Similarly, baseline HbA1c and GLP-1 RA treatment modalities were identified as significant factors that contributed to the observed changes in HbA1c over the 12-month dulaglutide treatment.

Table 2

Effects of treatment on various clinical and laboratory parameters.
	Liraglutide (n = 97)				Dulaglutide (n = 82)
	0 month	12 months	Change	P*	0 month	12 months	Change	P*	P**
Body weight	71.5 ± 17.5	68.5 ± 16.5	-3.1 ± 5.1	< 0.001	60.0 ± 13.5	58.9 ± 13.3	-1.0 ± 3.5	0.009	0.002
Systolic blood pressure (mmHg)	132 ± 20	128 ± 17	-3.7 ± 20.7	0.062	128 ± 17	128 ± 16	0.1 ± 15.8	0.965	0.194
Diastolic blood pressure (mmHg)	75 ± 13	72.4 ± 12.9	-2.4 ± 12.4	0.041	72 ± 12	72 ± 11	0.7 ± 11.4	0.596	0.095
PG (mg/dL)	181 ± 67	171 ± 72	-9.0 ± 74.0	0.233	170 ± 75	151 ± 63	-16.9 ± 77.7	0.126	0.485
AST (U/L)	27.1 ± 19.6	24.4 ± 13.0	-2.6 ± 19.5	0.183	24.3 ± 11.9	26.2 ± 14.1	1.9 ± 12.1	0.155	0.068
ALT (U/L)	31.5 ± 31.5	26.9 ± 22.2	-4.6 ± 29.3	0.124	24.4 ± 17.5	26.2 ± 16.5	1.9 ± 12.1	0.320	0.081
GGT (U/L)	43.6 ± 40.3	40.3 ± 34.3	-3.3 ± 24.3	0.194	39.7 ± 67.5	40.5 ± 85.6	0.8 ± 26.7	0.807	0.306
eGFR (mL/min/1.73 m²)	65.4 ± 30.2	62.9 ± 27.8	-2.5 ± 12.5	0.051	59.5 ± 22.8	59.1 ± 24.2	-0.4 ± 10.1	0.704	0.228
UACR (mg/g Cre)	830 ± 2382	836 ± 2341	6.0 ± 630.8	0.938	212 ± 711	281 ± 949	69.0 ± 345.6	0.193	0.564
LDL-C (mg/dL)	104 ± 36	92.8 ± 30.1	-11.6 ± 34.9	0.002	103 ± 36	94.8 ± 29.1	-8.5 ± 35.2	0.036	0.559
HDL-C (mg/dL)	49.5 ± 14.6	51.8 ± 12.9	2.3 ± 9.7	0.024	57.1 ± 15.3	61.3 ± 16.7	4.2 ± 14.8	0.013	0.310
Triglycerides (mg/dL)	174 ± 137	180 ± 210	5.7 ± 107.6	0.611	141 ± 66	137 ± 74	-3.9 ± 52.4	0.506	0.470
Insulin treatment (%)	55 (56.7)	33 (34.0)	―	< 0.001	35 (43.2)	31 (37.8)	―	0.503
Total insulin dose (units/day)	21.1 ± 16.2	9.1 ± 11.5	-11.9 ± 15.3	< 0.001	12.9 ± 12.8	9.8 ± 12.1	-3.2 ± 11.4	0.077	0.002
Basal insulin dose (units/day)	13.4 ± 9.7	8.3 ± 9.5	-5.1 ± 9.4	< 0.001	9.3 ± 7.4	4.3 ± 7.5	-0.9 ± 6.5	0.386	0.015
Bolus insulin dose (units/day)	12.6 ± 9.4	1.9 ± 4.5	-10.7 ± 9.2	< 0.001	11.2 ± 8.8	4.6 ± 8.1	-6.6 ± 11.8	0.048	0.182
Augmentation (%)	―	15 (15.5)				19 (23.2)			0.190

Data are mean ± standard deviation, or n (%).

*P-value for comparisons between 0 and 12 months, by the paired t-test or Wilcoxon signed-rank test. **P-value for difference in changes from baseline between liraglutide and dulaglutide, by Student's t-test or Wilcoxon rank sum test.

PG, plasma glucose; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyl transferase;, eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio; LDL-C, low-density cholesterol; HDL-C, high-density cholesterol.

Table 3

Hierarchical model of multivariate linear regression analysis with changes in HbA1c at 12 months as the dependent variable in patients with type 2 diabetes mellitus.
Variables	Unadjusted		Model 1		Model 2		Model 3
Variables	β (95% CI)	P-value	β (95% CI)	P-value	β (95% CI)	P-value	β (95% CI)	P-value
GLP-1 RA treatment
Liraglutide (reference)
Dulaglutide	0.009 (-0.498, 0.562)	0.905	-0.047 (-0.577, 0.243)	0.423	-0.019 (-0.545, 0.407)	0.775	-0.031 (-0.599, 0.376)	0.652
Duration of diabetes	0.182 (0.007, 0.063)	0.014	0.103(-0.002, 0.042)	0.074	0.116 (-0.001, 0.046)	0.065	0.104 (-0.005, 0.045)	0.112
PG	-0.191 (-0.009, -0.001)	0.011	-0.056 (-0.005, 0.002)	0.366	-0.052 (-0.005, 0.002)	0.423	-0.061 (-0.005, 0.002)	0.360
HbA1c at 0M	-0.648 (-0.815, -0.573)	< 0.001	-0.480 (-0.662, -0.366)	< 0.001	-0.499(-0.695, -0.380)	0.065	-0.506 (-0.706, -0.384)	< 0.001
Dementia	-0.202 (-2.056, -0.337)	0.007	-0.053 (-1.008, 0.383)	0.376	-0.047(-1.019, 0.470)	0.467	-0.053 (-1.058, 0.437)	0.413
Number of oral antidiabetic agent classes at 0M	0.257 (0.176, 0.622)	0.001	0.092 (-0.050, 0.336)	0.145	0.082(-0.074, 0.330)	0.212	0.096 (-0.100, 0.401)	0.237
Insulin treatment at 0M	0.202 (0.201, 1.235)	0.007	0.709 (-0.147, 0.709)	0.196	0.069(-0.198, 0.692)	0.274	0.066 (-0.387, 0.863)	0.453
GLP-1RA treatment modality
Add-on (reference)
Reduce	0.493 (1.067, 2.540)	< 0.001	0.185 (0.044, 1.306)	0.036	0.175(-0.026, 1.322)	0.059	0.210 (0.067, 1.486)	0.032
Switch	0.472 (0.965, 2.399)	< 0.001	0.200 (0.085, 1.341)	0.026	0.183 (-0.003, 1.313)	0.051	0.193 (0.020, 1.363)	0.044
Initiation of GLP-1 RA treatment
Outpatient (reference)
Inpatient	-0.408 (-2.032, -1.019)	< 0.001	-0.167 (-1.123, -0.128)	< 0.001	-0.184 (-1.221, -0.161)	0.011	-0.187 (-1.242, -0.162)	0.011
Body mass index at 0M					0.026 (-0.034, 0.051)	0.697	0.037 (-0.031, 0.055)	0.586
Age at 0M					-0.014 (-0.023, 0.019)	0.839	-0.008 (-0.023, 0.020)	0.917
HDL-C at 0M					-0.054 (0.021, 0.008)	0.401	-0.055 (-0.021, 0.008)	0.391
Hypertension					-0.054 (-1.136, 0.676)	0.617	-0.027 (-1.028, 0.801)	0.806
Antihypertensive agents					0.044 (-0.691, 1.042)		0.025 (-0.773, 0.975)	0.820
ΔNumber of classes of oral glucose-lowering agents							0.058 (-0.185, 0.381)	0.494
Insulin treatment at 12M							0.069 (-0.279, 0.798)	0.343
ΔTotal insulin dose							0.085 (-0.010, 0.036)	0.274
Augmentation							-0.052 (-0.773, 0.305)	0.393
			R² = 0.481		R² = 0.467		R² = 0.467
			P < 0.001		P < 0.001		P < 0.001

PG, plasma glucose; HbA1c, glycated hemoglobin; HDL-C, high-density cholesterol; GLP-1 RA, glucagon-like peptide-1 receptor agonist; M, month.

Safety

Adverse reactions were observed in 27 patients (27.8%) of the liraglutide group and 20 patients (24.4%) of the dulaglutide group (P = 0.602). Only mild adverse reactions were observed in both groups. The reported adverse reactions in the liraglutide group were nausea (n = 20), constipation (n = 8), and diarrhea (n = 1). Liraglutide dose reduction was required in one patient due to the adverse reactions. Hypoglycemia was observed in one patient. In the dulaglutide group, nausea (n = 7), diarrhea (n = 6), hepatic dysfunction (n = 3), and hypoglycemia (n = 2) were reported. Gastrointestinal symptoms were reported early after the initiation of treatment but resolved spontaneously.

The present study compared the efficacy and safety of GLP-1 RAs, liraglutide and dulaglutide, in Japanese patients with T2DM in real-world settings. In a previously published RCT in Japanese patients, dulaglutide had greater HbA1c-lowering effects than liraglutide¹². However, the use of other drugs and patient characteristics in that RCT differed from those in real-world clinical practice. In the present study conducted in a clinical setting, the patient characteristics varied greatly. First, BMI was higher in the liraglutide group. Regarding the weight-reducing effects, a significant body weight reduction has been reported with both liraglutide and dulaglutide compared with placebo, with reported weight loss of 2.3 kg (95% CI, 2.0-2.5) ¹³ and 1.46 kg (1.25–1.67), respectively¹⁴. However, in the AWARD-6 study using the same two agents, liraglutide (up to 1.8 mg/day) was significantly more effective in reducing body weight than dulaglutide (up to 1.5 mg/week) ¹¹. Furthermore, in a Japanese phase III clinical study, body weight reduction by dulaglutide was negligible (0.18 ± 0.08 kg) after 26 weeks of treatment¹⁵. These results may partly explain why dulaglutide is commonly used in non-obese patients in real-world clinical practice. In addition, the injection frequency is once a day for liraglutide, compared with once weekly for dulaglutide. Dulaglutide appears to be a common choice in elderly patients who could have difficulty with daily injections. This may also explain why the present study detected higher dulaglutide usage in patients with dementia who often require assistance. In terms of concomitant use of other medications, the dulaglutide group consisted of a high proportion of elderly patients with a lower rate of insulin use, compared with the liraglutide group. The present study included several patients who used more than one oral glucose-lowering agents, unlike previously reported RCT in Japanese patients. In this study, we performed hierarchical multiple regression analysis with adjustment for baseline patient characteristics, as well as for insulin dose and changes in medications, including oral glucose-lowering agents, during the 12-month treatment period. However, no differences were detected in the effects of the two drugs on HbA1c.

Our study identified three parameters to be associated with changes in HbA1c over the 12-month treatment period after adjustment for various confounders (Table 3). First, baseline HbA1c; patients with high baseline HbA1c levels were more likely to show improved post-treatment HbA1c levels. Next, GLP-1 RA treatment modality; compared with ‘add-on,’ the rate of improvement in HbA1c at 12 months was modest in ‘switch’ and ‘reduce.’ Similar findings have been reported following liraglutide treatment¹⁶. In clinical practice, treatment is often switched from dipeptidyl peptidase–4 inhibitors to GLP-1 RAs. In such cases, it is necessary to consider that any improvement in HbA1c after 12-month treatment would be smaller than that after the addition of GLP-1 RAs. Third, initiation of GLP-1 RA treatment during hospitalization was more effective in lowering HbA1c levels than applying the same treatment at the outpatient setting. In this regard, patients who started GLP-1 RA treatment during their admission to the hospital had higher baseline HbA1c levels than those who underwent outpatient initiation (9.7 ± 1.8 vs. 8.4 ± 1.4%, P < 0.001). Interestingly, their HbA1c levels at 12 months were similar (7.4 ± 1.5 vs. 7.6 ± 1.4%, P = 0.284). Accordingly, Δ HbA1c (at 12 months) were − 2.3 ± 2.2% for inpatient initiation vs. -0.7 ± 1.3% for outpatient initiation (P < 0.001), indicating the effectiveness of inpatient initiation. According to a study by Dungan et al.¹⁷, an individualized inpatient diabetes education and transition program can be associated with a significant reduction in HbA1c, which is dependent on baseline HbA1c, old age, insulin initiation, and earlier enrollment. In contrast, it has been reported that inpatient insulin initiation in elderly patients is more likely to be linked with increased mortality and emergency department visits due to hypoglycemia after hospital discharge, compared with oral glucose-lowering agents¹⁸. However, the risk of hypoglycemia with GLP-1 RA is low. The proportion of patients who developed hypoglycemia was also markedly low in the present study. To our knowledge, there are no reports on the effectiveness of inpatient GLP-1 RA initiation, calling for further investigation of this issue.

Several studies reported the weight-reducing effects of liraglutide^{11, 13, 19, 20}. The same effect was also observed in the present study. However, when we limited the analysis to the data of non-obese patients only (those with BMI < 25 kg/m²) in order to determine the possible effect of differences in baseline BMI, we found that the change in body weight from baseline to 12 months was similar in the two groups (liraglutide: 1.9 ± 4.1 kg, dulaglutide: 0.7 ± 2.8 kg, P = 0.104).

GLP-1 RAs are reported to help reduce HbA1c, body weight, and insulin dose among insulin users^21–23. Although there are no studies that directly compared changes in insulin dose after GLP-1 RA initiation (liraglutide vs. dulaglutide), our results showed significantly lower total insulin dose used by patients of the liraglutide group compared with those of the dulaglutide group after 12-month treatment. However, this difference became insignificant when adjusted for baseline total insulin dose (data not shown), indicating that the effects of the two agents on insulin dose reduction were comparable. Conversely, the dosing interval for liraglutide is once daily, whereas that for dulaglutide is once weekly, and it has been reported that dulaglutide scored higher on the Diabetes Treatment Satisfaction Questionnaire and Diabetes Therapy-Related Quality of Life²⁴. Although the present study did not examine treatment satisfaction, GLP-1 RA requiring only weekly injections was considered easier to maintain by elderly patients and patients with dementia, who would have difficulty with daily self-injection.

Several reports compared the real-world use of GLP-1 RAs, but most comparisons were restricted to treatment maintenance^{25, 26} and cost-effectiveness²⁷. In contrast, our study examined changes in HbA1c levels. Few studies have investigated the real-world use of GLP-1 RAs in Japanese patients. Although more than 900 patients were enrolled in the JDDM-57 study²⁸, HbA1c was analyzed after only 6 months of treatment with GLP-1 RAs. Despite the small sample size, the present study examined the contributing factors to changes in HbA1c induced by GLP-1 RAs in Japanese patients. We anticipate our data to help establish real-world evidence for the role of these factors in GLP-1 RA treatment.

Our study has several limitations. First, the sample size was relatively small, as described earlier, and the study was conducted in patients at a single institution treated by diabetologists; therefore, the results may not be generalizable to the entire population. However, since diabetologists often initiate the administration of GLP-1 RAs in Japan, our findings are considered plausible as real-world data at least in Japan. Second, the plasma glucose data were somewhat unreliable because not all blood samples were collected in a fasting state. However, evaluation of HbA1c, which was the primary endpoint, should be sufficient for the purpose of this study. Third, since liraglutide was the first to be launched in the Japanese market, there was a selection bias that dulaglutide could not be used in patients enrolled early in this study. In addition, the approved maximum dose of liraglutide in Japan under the public health system is 1.8 mg/day, and thus a higher dose of liraglutide was prescribed only in a few patients in the present study. Therefore, it is important to update this study in future investigations to establish more-up-date real-world evidence.

In conclusion, we have demonstrated in the present retrospective study the presence of significant differences in the characteristics of patients treated with liraglutide or dulaglutide in real-world settings, implying that GLP-1 RAs were selected according to individual patient characteristics. Conversely, even after adjustment for differences in patient characteristics between the two agents and drug adjustments after GLP-1 RA initiation, the effects of the two agents on HbA1c levels at 12 months of treatment were comparable, suggesting that baseline HbA1c, GLP-1 RA treatment, and inpatient initiation of GLP-1 RA treatment may help reduce the HbA1c levels in real-world settings.

Patients

This retrospective study included patients with T2DM who received outpatient or inpatient care at the Hospital of the University of Occupational and Environmental Health, Japan between September 2010 and August 2019, who underwent GLP-1 RA treatment for the first time, and who continued treatment with liraglutide or dulaglutide for at least 12 months. The following exclusion criteria were applied: patients with type 1 diabetes mellitus, severe infection or serious trauma, and hepatic dysfunction (transaminase level at least 3-fold higher than the normal upper limit). In addition, we also excluded patients who had used GLP-1 RA previously. This study was approved by the Institutional Ethics Review Committee of the UOEH Hospital, Japan (approval #H27-186). Informed consent was obtained from the participants, and the study was performed in accordance with the Declaration of Helsinki.

Biochemical and clinical measurements

We collected patient data, including age, sex, disease duration, body mass index (BMI), arterial blood pressure, presence of diabetic microangiopathy or macroangiopathy, presence of hypertension, dyslipidemia, as well as use of glucose-lowering agents, antihypertensive agents, and antilipidemic medications. Blood and urine samples were collected either in a fasting or non-fasting state. In addition, the levels of plasma glucose, HbA1c, aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides were measured. HbA1c levels (%) were measured using a high-performance liquid chromatography method with a Tosoh HLC-723 G8 analyzer (Tosoh Co., Kyoto, Japan) and expressed in National Glycohemoglobin Standardization Program (NGSP) equivalent values, calculated based on the following equation: HbA1c (NGSP) = HbA1c (Japan Diabetes Society [JDS]) (%) + 0.4% ²⁹⁾.

Baseline drug adjustments at liraglutide or dulaglutide initiation were categorized as follows: ‘add-on,’ when the number of classes of glucose-lowering agents increased; ‘switch,’ when the number of classes of glucose-lowering agents remained unchanged; ‘reduce,’ when the number of classes of glucose-lowering agents decreased. In addition, if the number of the glucose-lowering agents increased during the 12-month period of GLP-1 RA treatment, the patient was recorded as ‘augmentation.’

Statistical analysis

Normally distributed continuous variables are expressed as mean ± standard deviation. Categorical variables were evaluated using the χ² test. Student's t-test or Wilcoxon rank-sum test was employed to compare the two groups, depending on the data distribution pattern. We applied the paired t-test or Wilcoxon signed-rank test depending on data distribution to assess changes within the group. Differences between liraglutide and dulaglutide were tested using Student's t-test or Wilcoxon rank-sum test. HbA1c target achievement at baseline and 12 months were compared using McNemar’s test.

Univariate linear regression analysis was performed to assess the effects of GLP-1 RAs on changes in HbA1c at 12 months. Hierarchical regression analysis was performed using Models 1, 2, and 3. In Model 1, all the selected variables were parameters with a P-value < 0.05 in the univariate linear regression analysis. In Model 2, patient background factors showing a difference between the two GLP-1 RAs (age, BMI, HDL-C, hypertension, and the use of antihypertensive agents) were added to Model 1. In Model 3, factors related to drug adjustments during the 12-month treatment period (change in the number of oral glucose-lowering agents at 12 months, insulin treatment at 12 months, change in total insulin dose at 12 months, and diabetes augmentation for 12 months) were added to Model 2. Missing data were imputed using the last observation carried forward method.

Statistical significance was set at P < 0.05. All statistical analyses were performed using SPSS version 25.0 (SPSS Inc., Armonk, NY).

Data availability

All data generated or analyzed during this study are included in this published article and its Supplementary information file.

Acknowledgments

The authors thank Ms. N. Sakaguchi for the excellent technical assistance.

Author contributions

Affiliation

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan

Kenichi Tanaka, Yosuke Okada, Akemi Tokutsu, and Yoshiya Tanaka

Contributions

K.T., and Y.O. formulated the concept and design of the study. K.T., T.A. and Y.O. acquired, analyzed and interpreted the data. K.T. drafted the text of the main manuscript and prepared tables and figures. K.T., Y.O. and Y.T. revised the manuscript. Y.T. supervised the manuscript. All authors reviewed the manuscript.

ADDITIONAL INFORMATION

Supplementary Information

Additional supporting information is found online in the Supporting Information section at the end of the article.

Corresponding author

Correspondence to Prof. Yoshiya Tanaka.

Ethics declaration and competing interests

The authors declare no competing interests.

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No competing interests reported.

Real-World Effectiveness of Liraglutide Versus Dulaglutide In Japanese Patients With Type 2 Diabetes: A Retrospective Study

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Abstract

Figures

Introduction

Results

Patient demographics

Efficacy

Safety

Discussion

Patients And Methods

Patients

Biochemical and clinical measurements

Statistical analysis

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1