What this is
- This retrospective study compares the effectiveness of liraglutide and dulaglutide in Japanese patients with type 2 diabetes mellitus (T2DM).
- It included 179 patients treated with either GLP-1 receptor agonist for at least 12 months.
- The study aimed to assess changes in glycated hemoglobin () levels and identify contributing factors to these changes.
Essence
- Liraglutide and dulaglutide show comparable effectiveness in lowering levels in Japanese patients with T2DM after 12 months of treatment.
Key takeaways
- levels decreased significantly in both treatment groups after 12 months, with liraglutide reducing from 8.9% to 7.4% and dulaglutide from 8.7% to 7.5%.
- No significant differences in the extent of reduction were observed between liraglutide and dulaglutide after adjustment for baseline characteristics.
- High baseline levels, the modality of GLP-1 RA treatment, and inpatient initiation of treatment were significant factors influencing reduction.
Caveats
- The study's sample size was relatively small and conducted at a single institution, limiting generalizability.
- Some plasma glucose data were unreliable due to non-fasting sample collection, though evaluation was deemed sufficient.
- Selection bias may have influenced results, as liraglutide was available earlier in Japan than dulaglutide.
Definitions
- HbA1c: A measure of average blood glucose levels over the past two to three months, used to assess diabetes control.
AI simplified
Introduction
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 diarrhea8,9. 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 a real-world setting, 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. In this study, we used stabilized propensity score-based inverse probability of treatment weighting (IPTW) in order to reduce selection bias and confounding by observed covariates.
Results
Patient demographics after adjustment by stabilized propensity score-based IPTW
| Before IPTW | After IPTW | |||||||
|---|---|---|---|---|---|---|---|---|
| Liraglutide | Dulaglutide | P value | SMD | Liraglutide | Dulaglutide | P value | SMD | |
| n | 97 | 82 | 97 | 72 | ||||
| Age (years) | 60.7 (12.5) | 68.6 (10.1) | < 0.001 | 0.7 | 63.3 (10.9) | 64.7 (11.3) | 0.419 | 0.13 |
| Sex (men/women) | 51/46 | 40/42 | 0.714 | 0.08 | 49/48 | 36/36 | 1 | 0.01 |
| Duration of diabetes (year) | 13.9 (8.5) | 17.4 (9.8) | 0.011 | 0.38 | 14.5 (9.6) | 16.5 (10.7) | 0.193 | 0.2 |
| Body weight (kg) | 71.5 (17.5) | 59.3 (11.9) | < 0.001 | 0.82 | 66.0 (16.6) | 62.1 (12.1) | 0.096 | 0.27 |
| Body mass index (kg/m)2 | 27.8 (6.0) | 24.1 (4.6) | < 0.001 | 0.69 | 26.0 (5.4) | 24.6 (3.8) | 0.096 | 0.29 |
| Systolic blood pressure (mmHg) | 132.3 (19.8) | 127.7 (16.8) | 0.146 | 0.25 | 130.3 (19.1) | 128.8 (17.2) | 0.609 | 0.08 |
| Diastolic blood pressure (mmHg) | 75.3 (12.6) | 71.5 (10.5) | 0.085 | 0.33 | 74.4 (11.8) | 74.0 (10.5) | 0.81 | 0.04 |
| PG (mg/dL) | 180.5 (66.6) | 177.2 (72.0) | 0.752 | 0.05 | 177.6 (58.9) | 175.2 (66.0) | 0.799 | 0.04 |
| HbA1c (%) | 8.9 (1.7) | 8.8 (1.7) | 0.746 | 0.08 | 8.9 (1.5) | 8.7 (1.7) | 0.368 | 0.1 |
| AST (U/L) | 27.1 (19.6) | 24.2 (11.9) | 0.248 | 0.18 | 23.4 (16.4) | 23.3 (10.9) | 0.959 | 0.01 |
| ALT (U/L) | 31.5 (31.4) | 24.3 (17.4) | 0.065 | 0.28 | 26.7 (26.2) | 25.2 (19.9) | 0.683 | 0.06 |
| GGT (U/L) | 46.4 (37.6) | 40.1 (66.8) | 0.441 | 0.12 | 42.2 (36.6) | 38.0 (53.5) | 0.543 | 0.09 |
| eGFR (mL/min/1.73 m)2 | 65.4 (30.2) | 59.5 (22.8) | 0.154 | 0.22 | 63.4 (29.8) | 60.4 (25.2) | 0.491 | 0.11 |
| Hypertension (%) | 80 (82.5) | 56 (68.3) | 0.027 | 0.33 | 75 (77.3) | 48 (66.7) | 0.124 | 0.24 |
| Dyslipidemia (%) | 87 (89.7) | 66 (80.5) | 0.082 | 0.26 | 85 (87.6) | 61 (84.7) | 0.586 | 0.08 |
| Antihypertensive agents (%) | 77 (79.4) | 52 (63.4) | 0.018 | 0.36 | 73 (75.3) | 46 (63.9) | 0.109 | 0.25 |
| Antilipidemic agents (%) | 73 (75.3) | 53 (64.6) | 0.121 | 0.23 | 64 (66.0) | 43 (59.7) | 0.404 | 0.13 |
| Glucose-lowering agents used | ||||||||
| None (%) | 20 (20.6) | 5 (6.1) | 0.005 | 0.44 | 14 (14.4) | 11 (15.3) | 0.857 | 0.03 |
| DPP-4 inhibitors (%) | 61 (62.9) | 67 (81.7) | 0.005 | 0.43 | 67 (69.1) | 53 (73.6) | 0.52 | 0.1 |
| Sulfonylurea (%) | 12 (12.4) | 16 (19.5) | 0.19 | 0.19 | 21 (21.6) | 11 (15.3) | 0.296 | 0.16 |
| Glinide (%) | 13 (13.4) | 27 (32.9) | 0.002 | 0.48 | 14 (14.4) | 19 (26.4) | 0.053 | 0.29 |
| Biguanides (%) | 43 (44.3) | 32 (39.0) | 0.473 | 0.11 | 37 (38.1) | 27 (37.5) | 0.932 | 0.01 |
| Thiazolidine (%) | 23 (23.7) | 18 (22.0) | 0.78 | 0.04 | 20 (20.6) | 19 (26.4) | 0.379 | 0.14 |
| α-glucosidase inhibitors (%) | 21 (21.6) | 16 (19.5) | 0.725 | 0.05 | 20 (20.6) | 12 (16.7) | 0.517 | 0.1 |
| SGLT-2 inhibitors (%) | 8 (8.2) | 15 (18.3) | 0.045 | 0.3 | 10 (10.3) | 9 (12.5) | 0.639 | 0.07 |
| Insulin (%) | 55 (56.7) | 35 (41.2) | 0.062 | 0.31 | 48 (49.5) | 35 (48.6) | 0.911 | 0.02 |
| Number of oral antidiabetic agent classes | 1.9 (1.2) | 2.3 (1.1) | 0.007 | 0.01 | 2.0 (1.1) | 2.1 (1.2) | 0.664 | 0.01 |
| Retinopathy (%) | 50 (51.5) | 41 (50.0) | 0.837 | 0.03 | 60 (61.9) | 35 (48.6) | 0.102 | 0.27 |
| Nephropathy (%) | 50 (51.5) | 37 (45.1) | 0.392 | 0.13 | 49 (50.5) | 31 (43.1) | 0.337 | 0.15 |
| Peripheral neuropathy (%) | 62 (63.9) | 50 (61.0) | 0.685 | 0.06 | 70 (72.2) | 46 (63.9) | 0.252 | 0.18 |
| Coronary heart disease (%) | 19 (19.6) | 12 (14.6) | 0.845 | 0.13 | 19 (19.4) | 11 (15.3) | 0.487 | 0.11 |
| Cerebrovascular disease (%) | 14 (14.4) | 11 (13.4) | 0.383 | 0.03 | 16 (16.5) | 9 (12.5) | 0.469 | 0.11 |
| Dementia (%) | 4 (4.1) | 14 (17.1) | 0.004 | 0.43 | 15 (15.5) | 8 (11.1) | 0.414 | 0.13 |
| GLP-1RA treatment modality (%)† | 0.01 | 0.47 | 0.602 | 0.13 | ||||
| Add-on | 16 (16.5) | 9 (11.0) | 11 (11.2) | 11 (15.3) | ||||
| Switch | 37 (38.1) | 50 (61.0) | 54 (55.1) | 41 (56.9) | ||||
| Reduce | 44 (45.1) | 23 (28.0) | 33 (33.7) | 20 (27.8) | ||||
| Inpatient initiation of GLP-1 RA treatment | 36 (37.1) | 26 (31.7) | 0.449 | 0.11 | 39 (40.2) | 24 (33.3) | 0.361 | 0.14 |
Efficacy
Finally, we determined the factors that contributed to the observed changes in HbA1c after 12 months of treatment using univariate and multivariate analyses in non-adjusted data (Supplemental Tables,). 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 modality were identified as significant factors that contributed to the observed changes in HbA1c over the 12-month dulaglutide treatment. S1 S2
HbAlc levels at baseline and 6 and 12 months of treatment after adjustment by stabilized propensity score-based inverse probability of treatment weighting. Data are mean (95% CI). **P < 0.01. baseline, by Wilcoxon signed-rank test.P < 0.05 for between the two groups, by Wilcoxon rank-sum test.glycated hemoglobin. vs HbA1c †
HbA1c target achievement at baseline and 12 months after adjustment by stabilized propensity score-based inverse probability of treatment weighting. **P < 0.01, by McNemar’s test.glycated hemoglobin. HbA1c
| Liraglutide (n = 97) | Dulaglutide (n = 72) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 0 month | 12 months | Change | P* | 0 month | 12 months | Change | P* | P** | |
| Body weight | 66.0 (16.6) | 63.2 (16.4) | − 2.7 (4.5) | < 0.001 | 62.1 (12.1) | 61.1 (12.4) | − 1.0 (3.2) | 0.012 | 0.005 |
| Systolic blood pressure (mmHg) | 130.3 (19.1) | 129.4 (17.8) | − 0.9 (20.2) | 0.679 | 128.8 (17.2) | 126.4 (15.5) | − 2.4 (16.1) | 0.227 | 0.616 |
| Diastolic blood pressure (mmHg) | 74.4 (11.8) | 73.2 (11.5) | − 1.2 (11.2) | 0.303 | 74.0 (10.5) | 72.6 (10.0) | − 1.4 (10.7) | 0.286 | 0.928 |
| PG (mg/dL) | 177.6 (58.9) | 178.4 (65.6) | 0.8 (71.8) | 0.917 | 175.2 (66.0) | 156.3 (64.4) | − 18.8 (70.4) | 0.026 | 0.078 |
| AST (U/L) | 23.4 (16.5) | 23.5 (12.1) | 0.1 (16.5) | 0.954 | 23.4 (10.9) | 26.9 (15.7) | 3.6 (15.3) | 0.053 | 0.166 |
| ALT (U/L) | 26.7 (26.2) | 23.8 (20.9) | − 2.9 (24.2) | 0.242 | 25.3 (20.0) | 28.3 (19.5) | 3.0 (19.4) | 0.202 | 0.094 |
| GGT (U/L) | 39.6 (32.1) | 36.0 (30.4) | − 3.6 (20.5) | 0.093 | 38.8 (56.7) | 40.5 (71.8) | 1.7 (25.0) | 0.597 | 0.121 |
| eGFR (mL/min/1.73 m)2 | 63.4 (29.8) | 60.6 (27.3) | − 2.8 (10.9) | 0.013 | 60.4 (25.2) | 59.0 (26.9) | − 1.4 (10.5) | 0.262 | 0.407 |
| Insulin treatment (%) | 48 (49.5) | 42 (43.3) | – | 0.5 | 35 (48.6) | 26 (36.1) | – | 0.031 | |
| Total insulin dose (units/day) | 15.5 (15.6) | 9.7 (9.4) | − 5.8 (15.8) | 0.005 | 14.9 (13.0) | 10.6 (13.7) | − 4.3 (10.6) | 0.015 | 0.607 |
| Basal insulin dose (units/day) | 10.3 (9.6) | 9.0 (7.9) | − 1.3 (10.6) | 0.362 | 10.2 (7.3) | 9.2 (10.0) | − 1.0 (6.7) | 0.34 | 0.906 |
| Bolus insulin dose (units/day) | 10.8 (9.3) | 2.2 (4.2) | − 8.6 (9.6) | < 0.001 | 11.7 (7.4) | 3.8 (8.0) | − 7.8 (9.7) | 0.005 | 0.798 |
| Augmentation (%) | – | 15 (15.5) | – | 17 (23.6) | 0.196 | ||||
| Variables | Univariate | Multivariate | ||
|---|---|---|---|---|
| β (95% CI) | P-value | β (95% CI) | P-value | |
| GLP-1 RA treatment | ||||
| Liraglutide (reference) | ||||
| Dulaglutide | 0.070 (− 0.300, 0.812) | 0.365 | 0.012 (− 0.356, 0.444) | 0.828 |
| Duration of diabetes | 0.230 (0.015, 0.068) | 0.003 | 0.400 (− 0.013, 0.032) | 0.4 |
| PG at 0 M | − 0.202 (− 0.010, − 0.002) | 0.008 | − 0.104 (− 0.007, 0.001) | 0.097 |
| HbA1c at 0 M | − 0.641 (− 0.857, − 0.592) | < 0.001 | − 0.418 (− 0.630, − 0.317) | < 0.001 |
| Hypertension | 0.191 (0.166, 1.381) | 0.013 | < 0.001 (− 0.520, 0.519) | 0.999 |
| Nephropathy | 0.212 (0.229, 1.308) | 0.006 | 0.049 (− 0.252, 0.605) | 0.417 |
| Coronary heart disease | 0.193 (0.203, 1.627) | 0.012 | 0.102 (− 0.071, 1.043) | 0.087 |
| Dementia | − 0.322 (− 2.474, − 0.941) | 0.001 | − 0.091 (− 1.135, 0.174) | 0.149 |
| Number of oral antidiabetic agent classes at 0 M | 0.185 (0.057, 0.540) | 0.001 | 0.108 (− 0.024, 0.375) | 0.084 |
| Insulin treatment at 0 M | 0.337 (0.698, 1.737) | < 0.001 | 0.114 (− 0.052, 0.877) | 0.081 |
| GLP-1RA treatment modality | ||||
| Add-on (reference) | ||||
| Reduce | 0.493 (1.104, 2.679) | < 0.001 | 0.245 (0.302, 1.596) | 0.004 |
| Switch | 0.402 (0.718, 2.212) | < 0.001 | 0.224 (0.193, 1.448) | 0.011 |
| Initiation of GLP-1 RA treatment | ||||
| Outpatient (reference) | ||||
| Inpatient | − 0.504 (− 2.376, − 1.390) | < 0.001 | − 0.217 (− 1.358, − 0.267) | 0.004 |
| R= 0.5302 | ||||
| P < 0.001 | ||||
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) in non-adjusted data. 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.
Discussion
The present study compared the efficacy and safety of GLP-1 RAs, liraglutide and dulaglutide, in Japanese patients with T2DM in a real-world setting. We used stabilized propensity score-based IPTW in order to reduce selection bias and confounding by observed covariates. 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. 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 using stabilized propensity score-based IPTW, the change in HbA1c level was lower in the liraglutide treatment group at 6 months, but there was no difference in the HbA1c level at 12 months, indicating similar HbA1c-lowering effect by the two agents.
Our study identified three characteristics that were associated with changes in HbA1c over the 12-month treatment period (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 treatment13. 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. Although patients who started GLP-1 RA treatment during admission to the hospital had higher baseline HbA1c levels than those who underwent outpatient initiation (9.7% [SD: 1.5] vs. 8.3% [SD: 1.4], P < 0.001), their HbA1c levels at 12 months were lower (7.1% [SD: 1.4] vs. 7.6% [SD: 1.5], P = 0.032). This result is quite interesting, but it is likely that unmeasured confounding factors and/or differences in follow-up care patterns contributed to this effect, and therefore, further investigation is warranted in the future.
Several studies reported the weight-reducing effects of liraglutide and dulaglutide, with weight loss of 2.3 kg (95% confidence interval [CI] 2.0–2.5) in one study6 and 1.46 kg (95% CI 1.25–1.67) in another14. 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 after 26 weeks of treatment15. Our results also showed that liraglutide was more effective in reducing body weight than dulaglutide. These results may partly explain why liraglutide is commonly used in obese diabetics in real-world clinical practice.
GLP-1 RAs are reported to help reduce HbA1c, body weight, and insulin dose among insulin users16–18. Although there are no studies that directly compared changes in insulin dose after GLP-1 RA initiation (liraglutide vs. dulaglutide), our results showed total and bolus insulin dose significantly decreased in liraglutide and dulaglutide, no significant differences were observed between the two agents.
Several reports compared the real-world use of GLP-1 RAs, but most comparisons were restricted to treatment maintenance19,20 and cost-effectiveness21. In contrast, our study examined changes in HbA1c levels. A real-world study from Taiwan22 showed there was a statistically significant change in HbA1c at 12 months from baseline in each treatment group (dulaglutide: − 1.06% [SD: 1.70] and liraglutide: − 0.83% [SD: 1.61]), with a significant between-group difference in HbA1c reduction of − 0.23% (95% CI − 0.38 to − 0.08%). A study from United States also showed that treatment with dulaglutide significantly reduced HbA1c compared with liraglutide23. These results are different from our study, probably due to differences in drug dosage; the dose of dulaglutide in about 40% of the patients of the above study was 1.5 mg/week.
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 study10, 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. Finally, propensity score is only appropriate when the strongly ignorable treatment assignment assumption is satisfied24. However, there is no reliable way to test this assumption. Conventionally, consideration is given to C-statistics and propensity score-adjusted estimates of variables, but these also have no standard criteria. In this study, the estimates of the propensity score-adjusted estimates of variables are very close in each group compared to the pre-adjustment, although some variables remained significant, but it is uncertain whether these sufficiently satisfied the strongly ignorable treatment assignment assumption.
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 a real-world setting, implying that GLP-1 RAs were selected according to individual patient characteristics. Even after reducing the selection bias and confounding using stabilized propensity score-based IPTW between liraglutide and dulaglutide treatments, the effects of these two agents on HbA1c levels after 12 months of treatment were comparable. Our results also suggest that baseline HbA1c level, GLP-1 RA treatment modality, and inpatient initiation of GLP-1 RA treatment may be associated with reduction in HbA1c levels in a real-world setting.
Patients and methods
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 threefold 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 University of Occupational and Environmental Health (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), and estimated glomerular filtration rate (eGFR) 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%25.
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’.
Stabilized propensity score-based IPTW
To adjust for baseline patient characteristics between the two groups, the calculated stabilized propensity scores were weighted using the ‘proportion of patients receiving dulaglutide to all patients/propensity score’ in the dulaglutide group and the ‘proportion of patients receiving liraglutide to all patients/1 − propensity score’ in patients treated with liraglutide as the weighting coefficient on stability26. To calculate the stabilized propensity scores, multivariable logistic regression analysis was performed with the concomitant use of dulaglutide as the dependent variable and the following independent variables: age, sex, disease duration, BMI, HbA1c, AST, ALT, eGFR, dyslipidemia, dementia, GLP-1RA treatment modality (add-on, switch or reduce), initiation of GLP-1 RA treatment (outpatient or inpatient), number of oral antidiabetic agent classes, glucose-lowering agents (none, DPP-4 inhibitors, biguanides, SGLT-2 inhibitors, insulin), insulin dose. The area under the curve of the propensity scores model was 0.869 (95% CI 0.818–0.919).
Statistical analysis
Variables are expressed as mean (standard deviation) or number (%) of patients. 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 and multivariate logistic regression analyses were performed to assess the effects of GLP-1 RAs on changes in HbA1c at 12 months. Factors with P < 0.05 on univariate linear regression analysis and the type of GLP-1 RA treatment were entered into multivariate linear regression analysis. Missing data were imputed using the last observation carried forward method, and the results did not differ with or without imputation. Statistical significance was set at P < 0.05. All statistical analyses were performed using SPSS version 25.0 (SPSS Inc., Armonk, NY).
Supplementary Information
Supplementary Legends. Supplementary Figure S1. Supplementary Table S1. Supplementary Table S2.