Efficacy of switching from dipeptidyl peptidase-4 inhibitors to dulaglutide in patients with type 2 diabetes

Background: Several reports showed that the effects of daily Glucagon-like peptidase-1 (GLP-1) receptor agonists for lowering plasma glucose and body weight are superior to those of dipeptidyl peptidase-4 (DPP-4) inhibitors, while the superiority of weekly GLP-1 receptor agonists, dulaglutide, is still unclear. The aim of this study was to evaluate the efficacy of dulaglutide therapy switching from DPP-4 inhibitors in patients with type 2 diabetes. Methods: We retrospectively evaluated the 79 Japanese patients with type 2 diabetes at the Diabetes Outpatient Clinic in Tomakomai City Hospital whose treatment was switched from DPP-4 inhibitors to dulaglutide. We investigated the change of hemoglobin A1c (HbA1c), casual plasma glucose (CPG) levels and body weight 4 weeks, 8 weeks and 12 weeks after switching from DPP-4 inhibitors to dulaglutide. In addition, we defined the group in which HbA1c was improved more than 1% as “improved group” (n = 37) and the group in which HbA1c was improved less than 1% as “non-improved group” (n = 42), and compared the patients’ background in both the groups. The subtraction of HbA1c at each weeks and baseline HbA1c was defined as ⊿HbA1c. Results: After switching to dulaglutide, HbA1c showed a significant decrease from 4 weeks later, and the effect was maintained even after 12 weeks. The “improved group” had lower estimated glomerular filtration rate (eGFR) and higher baseline HbA1c than the “non-improved group”. In the “improved group”, ⊿HbA1c showed a significant correlation with eGFR and baseline HbA1c. Conclusion: Switching from DPP-4 inhibitors to dulaglutide could improve HbA1c, especially in cases with low eGFR and high HbA1c.


KEYWORDS
Dulaglutide, glucagon-like peptidase-1, type 2 diabetes, dipeptidyl peptidase-4 inhibitor = 42), and compared the patients' background in both the groups. The subtraction of HbA1c at each weeks and baseline HbA1c was defined as ⊿HbA1c. Results: After switching to dulaglutide, HbA1c showed a significant decrease from 4 weeks later, and the effect was maintained even after 12 weeks. The "improved group" had lower estimated glomerular filtration rate (eGFR) and higher baseline HbA1c than the "non-improved group". In the "improved group", ⊿HbA1c showed a significant correlation with eGFR and baseline HbA1c. Conclusion: Switching from DPP-4 inhibitors to dulaglutide could improve HbA1c, especially in cases with low eGFR and high HbA1c.
Background GLP-1 is one of incretin hormones, which is secreted from small intestines via stimulation of oral ingestion [1][2][3]. It binds to GLP-1 receptors in pancreatic cells and increases 3 cyclic adenosine monophosphate, resulting in insulin secretion [4,5]. Then, GLP-1 is rapidly degraded and inactivated by . DPP-4 inhibitors are a group of incretinrelated drugs that have a hypoglycemic effect by inhibiting degradation of GLP-1 and by increasing concentration of endogenous active incretin [7]. Contrary to DPP-4 inhibitors, GLP-1 receptor agonists, which are classified into daily or weekly type, directly promote GLP-1 receptor activity. Therefore, GLP-1 receptor agonists are estimated to be potentially more effective in a decrease of plasma glucose levels than DPP-4 inhibitors.
Several reports showed that the effects of daily GLP-1 receptor agonists for lowering plasma glucose and body weight are superior to those of DPP-4 inhibitors [8], while the superiority of weekly GLP-1 receptor agonists, dulaglutide, is still unclear. In the current study, we aimed to clarify the effectiveness of dulaglutide therapy switching from DPP-4 inhibitors in patients with type 2 diabetes, and subsequently to explore the predictive factors for its anti-diabetic effect.

Ethics statement
The study was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. Approval was obtained from the institutional review board of Tomakomai City Hospital (approval number: 2018-6).

Study design and population
This was a single-center, single-armed, retrospective and observational study using data collected from medical records. Japanese patients with type 2 diabetes whose treatment was switched from DPP-4 inhibitors to dulaglutide at our department between April 2015 and May 2018 were registered in the present study. The patients who had a history of dulaglutide use were included. We excluded pregnant women and patients aged <18 4 years. First, we analyzed the patients including those whose concomitant drugs were switched or increased the dosage. Then, we also analyzed patients without those whose concomitant drugs were switched or increased the dosage.

Outcomes
Changes of body weight, CPG levels and HbA1c at baseline, 4, 8, and 12 weeks after switching from DPP-4 inhibitors to dulaglutide were evaluated. The subtraction of HbA1c at each weeks and baseline HbA1c was defined as HbA1c. Patients with and without over 1% reduction of HbA1c at 12 weeks from switching were classified as "improved group" and "non-improved group", respectively. To clarify the factors influencing the efficacy of dulaglutide therapy, the patients' medical records were retrospectively reviewed and the following demographic, clinical, and laboratory data at baseline were verified by the authors: age, sex, disease duration, body weight, body mass index (BMI), CPG level, HbA1c, eGFR and data about concomitant medications including insulin, metformin, glinide, sulfonylurea, -glucosidase inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and thiazolidine. In addition, safety of dulaglutide was analyzed by frequency of hypoglycemia and gastrointestinal adverse events which occurred in the observational period. Hypoglycemia was defined as signs attributable to hypoglycemia or CPG levels less than 70 mg/dL in spite of hypoglycemic symptoms. Definition of severe hypoglycemia was made by an episode requiring the assistance of another person to actively administer therapy, as determined by the investigator [9].

Statistical analysis
Continuous variables were expressed as mean ± standard deviation, and were compared using t-test. Categorical variables were expressed as number and percentage. Correlation of continuous variables between two groups was assessed by Pearson's coefficients.
5 Probability values less than 0.05 were considered to indicate statistical significance. All statistical analyses were performed using the JMP Pro software (ver. 12.0; SAS Institute Inc., Cary, NC, USA).

Patient enrollment and baseline characteristics
A total of seventy-nine patients (42 males and 37 females) with type 2 diabetes whose treatment drugs were switched from DPP-4 inhibitors to dulaglutide were enrolled in the study. The baseline clinical and metabolic characteristics of the patients are shown in Table1

Relationship between the efficacy and clinical characteristics
To reveal the factors associated with more than 1% of HbA1c improvement after switching to dulaglutide at 12 weeks, the baseline clinical characteristics were statistically compared between the improved and non-improved groups. Of 79 patients, 37 and 42 patients were divided into the improved and non-improved groups, respectively. The levels of eGFR were statistically lower in improved group (56.4 ± 22.0 mL/min/1.73m 2 ) than those in "non-improved group" (72.2 ± 21.2 mL/min/1.73m 2 ) (t-test, P < 0.01).

Safety
Hypoglycemia episode was not found during the observation periods, whereas 3 patients complained of nausea after switching from DPP-4 inhibitors to dulaglutide. However, as dulaglutide therapy was continued, nausea disappeared in all the patients. No patients discontinued dulaglutide during the follow-up period due to adverse events.

Discussion
In this study, switching from DPP-4 inhibitors to dulaglutide showed a significant improvement of HbA1c. However, it didn't contribute to weight loss and a decrease of CPG. HbA1c declined especially in patients with low eGFR and high levels of baseline Our study pointed out switching DPP-4 inhibitors to dulaglutide contributed to better glycemic control in type 2 diabetic patients, especially in those with renal dysfunction.
Dulaglutide has been reported to show higher blood concentration in patients with impaired renal function. This suggests that high concentrations of dulaglutide may lead to better anti-diabetic effect in patients with impaired renal function. Nausea and 8 hypoglycemia are major side effects of dulaglutide. However, it is generally considered that hypoglycemia less likely occurs because GLP-1 secretion depends on plasma glucose levels.
[13] There were no patients who had symptomatic hypoglycemia in our study. It is also known that nausea improves as time goes on. [14][15][16][17] Glycemic control is sometimes difficult in patients with renal dysfunction. As kidney function worsens, the risk of hypoglycemia and other adverse effects increases. [18][19][20] Therefore, in case of treatment of diabetes in patients with renal dysfunction, clinicians often face difficulty in selecting anti-diabetic agents. This study suggests that switching from DPP-4 inhibitors to dulaglutide would be effective and safe for controlling hyperglycemia in patients with impaired renal function.
Our study was single arm study that evaluated the efficacy of switching to dulaglutide from DPP-4 inhibitors. DPP-4 inhibitor is one of the most used drugs in patients with type 2 diabetes. The result of our study suggests dulaglutide is an effective second-line therapeutic option in the patients with type 2 diabetes with poor glycemic control who are treated with DPP-4 inhibitors.
The potential limitations of our study were small sample size, short study duration and retrospective design. To resolve these issues, our findings need to be validated in a larger population over a longer period. Furthermore, in this study, the effect of non-drug therapy such as diet exercise therapy was not taken into consideration. These factors may have contributed to anti-diabetic effect. In addition, the evaluation of unconscious hypoglycemia might be insufficient with our definition of hypoglycemia.

Conclusion
We demonstrated that switching from DPP-4 inhibitors to dulaglutide significantly improved HbA1c, particularly in patients with low eGFR and high HbA1c. It could be a useful treatment option for poorly controlled type 2 diabetes patients with impaired renal 9 function.

Declarations
Ethics approval and consent to participate Ethics approvals were received from Tomakomai City Hospital research ethics committee.

Consent for publication
Not applicable.

Availability of data and material
Not applicable

Competing interests
All authors have declared no conflicts of interest.

Funding
No specific funding was received to carry out the work described in this manuscript. 14 *t-test.

Figures
15 Figure 1 Body weight (A), casual plasma glucose (CPG) levels (B) and HbA1c (C) over 12 weeks after switching from DPP-4 inhibitors to dulaglutide including patients whose concomitant drugs were switched or increased the dosage. Diamond shapes show mean and its 95% confidence interval. Horizontal lines indicate standard deviation. *P < 0.005 (vs baseline, paired t-test), **P < 0.0001 (vs baseline, paired t-test).

Figure 2
Body weight (A), casual plasma glucose (CPG) levels (B) and HbA1c (C) over 12 weeks after switching from DPP-4 inhibitors to dulaglutide in patients without whose concomitant drugs were switched or increased the dosage. Diamond shapes show mean and its 95% confidence interval. Horizontal lines indicate standard deviation. *P < 0.005 (vs baseline, paired t-test), **P < 0.0001 (vs baseline, paired t-test).

Figure 3
Correlation between HbA1c at 12 weeks and baseline HbA1c (A) or estimated glomerular filtration rate (GFR) (B) after switching to dulaglutide from dipeptidyl peptidase-4 inhibitors including patients with whose concomitant drugs were switched or increased the dosage. Dots show individual results. Continuous lines were generated by regression analysis.

Figure 4
Correlation between HbA1c at 12 weeks and baseline HbA1c (A) or estimated glomerular filtration rate (GFR) (B) after switching to dulaglutide from dipeptidyl peptidase-4 inhibitors in patients without whose concomitant drugs were switched or increased the dosage. Dots show individual results. Continuous lines were generated by regression analysis.