Abstract
Objective
The study aimed to evaluate the long-term effects of combination therapy comprising dulaglutide and long-acting insulin, on glycemic control in patients with type 2 diabetes.
Methods
This retrospective observational study included 20 patients with type 2 diabetes who underwent blood glucose management with intensive insulin therapy for a limited period. All patients were switched from intensive insulin therapy to combination therapy comprising dulaglutide and long-acting insulin. Hemoglobin A1c was evaluated before and 4, 12, and 24 weeks after starting combination therapy. Continuous glucose monitoring was conducted before and 1 and 24 weeks after starting combination therapy.
Results
Hemoglobin A1c levels were significantly reduced after 4, 12, and 24 weeks of combination therapy (− 2.2% ± 0.4%, P < 0.0001; − 3.7% ± 0.8%, P = 0.0003; and − 3.6% ± 0.8%, P = 0.0005, respectively). Glycemic variability (% coefficient of variation) was significantly decreased after 1 and 24 weeks of combination therapy (− 5.7% ± 2.1%, P = 0.011; and − 8.7% ± 2.4%, P = 0.003, respectively) and the percentage of readings and time > 250 mg/dL at 24 weeks was significantly improved (− 2.2% ± 0.8%, P = 0.019).
Conclusion
Combination therapy with dulaglutide and long-acting insulin resulted in better blood glucose control than intensive insulin therapy, which persisted for 24 weeks. Combination therapy also reduced blood glucose fluctuations and the number of self-injections needed.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13340-022-00592-z.
Keywords: Dulaglutide, Long-acting insulin, Blood glucose fluctuation, Hemoglobin A1c, Type 2 diabetes
Introduction
The glucagon-like peptide-1 (GLP-1) receptor agonist is a therapeutic agent for diabetes that suppresses the activity of dipeptidyl peptidase-4. Since the action of the GLP-1 receptor agonist is blood glucose dependent, it does not usually cause hypoglycemia and can also result in weight loss [1]. As Japanese patients with type 2 diabetes mellitus (T2DM) tend to have a decreased insulin secretory capacity [2], they may have an increased risk of severe hypoglycemia and weight gain when undergoing insulin therapy [3].
The use of GLP-1 receptor agonists can help to reduce the insulin dose in patients with T2DM [4]. Dulaglutide and long-acting insulin combination therapy has been reported to be an effective long-term treatment option for patients with T2DM [5]. Continuous glucose monitoring (CGM) shows daily fluctuations in blood glucose levels, and a previous systematic review reported the therapeutic effectiveness of CGM in patients with diabetes [6].
However, there are few reports on the long-term therapeutic effects of dulaglutide and long-acting insulin combination therapy [5]. In addition, few studies have analyzed the effects of dulaglutide using CGM [7, 8]. In this study, we aimed to examine the long-term therapeutic effects of dulaglutide and long-acting insulin combination therapy. Furthermore, we also aimed to evaluate the effects of combination therapy on blood glucose fluctuations using CGM.
Materials and methods
Participants
This single-center, retrospective study was conducted at Chigasaki Municipal Hospital between April 2017 and March 2019. We included patients with T2DM who were admitted to the hospital for diabetes care between April 2017 and March 2019 and were discharged on dulaglutide and long-acting insulin combination therapy. All included patients received this therapy for at least 24 weeks and were evaluated with CGM. The exclusion criteria consisted of the following: < 16 years of age, steroid use, cancer, contraindications to drugs used in this study, serious infectious disease, and severe trauma. The study was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects issued by the Ministry of Health, Labour and Welfare (Tokyo, Japan). The study protocol was approved by the Institutional Review Board of Chigasaki Municipal Hospital (ID: 2020-04, date of approval: June 11, 2020). The details of this study were published on the Chigasaki Municipal Hospital website, and the Ethics Council waived the requirement for informed consent.
Study design
An outline of the study design and timeline is shown in Fig. 1, including the therapy method, date of evaluating outcomes, CGM period, and the hospitalization period. All orally administered hypoglycemic agents were discontinued after admission, and insulin was only continued in patients who were already taking it. On the day after admission, hemoglobin A1c (HbA1c), fasting blood glucose, and C-peptide levels were measured by blood sampling; body weight and body fat percentage were measured with an impedance device (InBody770®, InBody Japan, Japan). Patients underwent intensive insulin therapy (IIT) during their hospital stay. The insulin dose was adjusted to maintain a fasting blood glucose level of 70–130 mg/dL and a casual blood glucose level of 70–180 mg/dL. While in the hospital and before initiating dulaglutide, patients began wearing a CGM device (FreeStyle Libre Pro®, Abbot, United States). On or after the 3rd day of wearing the CGM device, dulaglutide (0.75 mg/week) administration was initiated, and simultaneously, rapid-acting insulin was discontinued, while long-acting insulin was continued. Except for insulin and dulaglutide, no hypoglycemic agents were added to the regimens during hospitalization. All patients were discharged within a week of changing treatment. During hospitalization, nutritional guidance and exercise therapy were explained, and guidance was continued during outpatient visits. After discharge, the amount of long-acting insulin was adjusted according to standard glycemic control as in the case of IIT during hospitalization. Outpatient visits were performed 4, 12, and 24 weeks after the treatment change, and HbA1c, body weight, and insulin levels were further evaluated. The CGM device was again used to assess glycemic variations 24 weeks after the initiation of dulaglutide.
Fig. 1.
Outline of the study design and timeline. Down arrow indicates the date on which therapy was changed. Filled inverted triangle indicates the date on which hemoglobin A1c, body weight, and the amount of insulin were evaluated. Open inverted triangle indicates the date on which CGM was evaluated. Open square indicates 1 day; Left right arrow indicates the period of CGM, hospitalization, or post-discharge. Changed from IIT to dulaglutide 0.75 mg + long-acting insulin therapy on day 0. CGM, continuous glucose monitoring; IIT, intensive insulin therapy; OHA, orally administered hypoglycemic agent
Outcomes
The primary end point was the change in HbA1c from baseline to 24 weeks. HbA1c levels were assessed on admission and 4, 12, and 24 weeks after initiation of dulaglutide. As secondary end points, body weight and the amount of long-acting insulin used were assessed on admission and 4, 12, and 24 weeks after the initiation of dulaglutide. In addition, CGM was used to assess glycemic variations on the day before initiating dulaglutide (while undergoing IIT), and 1 and 24 weeks after the initiation of dulaglutide.
Continuous glucose monitoring
The CGM devices were worn twice, first when switching treatment, and second 24 weeks after changing treatment. During the first period, CGM was used to evaluate glycemic fluctuations during IIT (on or after the 2nd day of wearing the CGM device) and 1 week after switching the treatment (on or after the 10th day of wearing the CGM device). During the second period, CGM was evaluated on the 7th day of wearing the device. The glycemic fluctuations during the period of IIT were assessed during hospitalization, while the glycemic fluctuations 1 and 24 weeks after changing treatment were evaluated during outpatient visits. CGM data were reported as the mean glucose values, glycemic variability (% coefficient of variation [%CV]), time in range (TIR) (% of readings and time 70–180 mg/dL), time above range (TAR) (Level 1: % of readings and time 181–250 mg/dL; Level 2: % of readings and time > 250 mg/dL), and time below range (TBR) (Level 1: % of readings and time 54–69 mg/dL; Level 2: % of readings and time < 54 mg/dL) [9, 10]. Mean blood glucose, %CV, TIR, TAR Level 1, TAR Level 2, TBR Level 1, and TBR Level 2 were compared before initiating dulaglutide, and 1 and 24 weeks after initiation.
Statistical analysis
Differences between groups were determined using the Wilcoxon signed-rank test. P values < 0.05 were considered statistically significant. Statistical analyses were performed using JMP Pro (version 15.0.0, SAS Institute Inc., Cary, NC, USA).
Results
The following patient characteristics (median, interquartile range [IQR]) were documented at baseline: patients’ age, 71.9 (65.0–79.7) years; duration of diabetes mellitus, 15.0 (6.0–20.7) years; body weight, 60.5 (50.2–65.7) kg; body mass index (BMI), 23.5 (20.0–24.6) kg/m2; HbA1c, 10.1% (7.9–11.9%); and fasting C-peptide level, 1.1 (0.4–1.6) ng/mL (Table 1). Four of the 20 patients were already on insulin therapy (one on IIT, and three on long-acting insulin therapy) before hospitalization and undergoing IIT. These patients tended to be older with poorly controlled diabetes, a long history of diabetes, and decreased insulin secretion. While the average BMI was not high, the high percentage of body fat suggested a loss of muscle mass. The insulin doses used for IIT on the day before starting dulaglutide were rapid-acting insulin (22.5 units/day; IQR, 11.5–31.0 units/day) and long-acting insulin (11.8 units/day; IQR, 6.0–16.0 units/day).
Table 1.
Baseline participant characteristics
| Baseline characteristics | IQR | |
|---|---|---|
| Sex (male/female) | 7/13 | |
| Age (years) | 71.9 | 65.0–79.7 |
| Disease duration (years) | 15.0 | 6.0–20.7 |
| Body weight (kg) | 60.5 | 50.2–65.7 |
| BMI (kg/m2) | 23.5 | 20.0–24.6 |
| Body fat (%) | 28.1 | 23.3–35.5 |
| HbA1c (%) | 10.1 | 7.9–11.9 |
| Glycoalbumin (%) | 29.0 | 19.3–31.7 |
| Fasting glucose (mg/dL) | 126.5 | 98.7–146.5 |
| Fasting C-peptide (ng/mL) | 1.1 | 0.4–1.6 |
| Bolus insulin (units/day) | 22.5 | 11.5–31.0 |
| Basal insulin (units/day) | 11.8 | 6.0–16.0 |
| Glargine/degludec | 17/3 | |
| OHA administration (DPP-4i/BG/SU/glinide/αGI/pioglitazone) | 4/8/2/2/7/3 | |
| Previous IIT | 1 | |
| Previous BOT | 3 | |
| Untreated | 2 |
Data are presented as the median value with IQR, except for data on sex and treatment on admission, which are presented as frequencies
αGI α glucosidase inhibitor, BG biguanide, BMI body mass index, BOT basal supported oral therapy, DPP-4i dipeptidyl peptidase-4 inhibitor, HbA1c hemoglobin A1c, IIT intensive insulin therapy, IQR interquartile range, OHA oral hypoglycemic agents, SU sulfonylurea
Compared to the baseline, HbA1c levels (mean, ± standard error [SE], P value) were significantly reduced at 4 weeks (− 2.2% ± 0.4%, P < 0.0001); 12 weeks (− 3.7% ± 0.8%, P = 0.0003); and 24 weeks (− 3.6% ± 0.8%, P = 0.0005) after the initiation of dulaglutide (Fig. 2A). Body weight measurements were not significantly different from those at baseline (62.1 kg) at 4, 12, and 24 weeks (61.6 kg, P = 0.37; 61.2 kg, P = 0.24; and 61.9 kg, P = 0.76, respectively) (Fig. 2B). Compared to baseline, the amount of long-acting insulin used was significantly reduced at 4 weeks (− 2.3 U ± 0.7U, P < 0.003), 12 weeks (− 2.70U ± 1.1U, P = 0.002), and 24 weeks (− 2.9 U ± 1.0 U, P = 0.008) after the initiation of dulaglutide (Fig. 2C).
Fig. 2.
Effect of dulaglutide (0.75 mg) and long-acting insulin combination therapy on hemoglobin A1c levels, body weight, and daily dose of long-acting insulin. a Hemoglobin A1c; b body weight; c daily dose of long-acting insulin. *P < 0.001 compared to the baseline; HbA1c hemoglobin A1c
The 24-h glycemic variations during IIT and 1 and 24 weeks after the initiation of dulaglutide are shown in Fig. 3. An improvement in postprandial hyperglycemia was observed at 1 and 24 weeks compared to that during IIT; however, the mean glucose level during ITT (130.9 mg/dL) was not significantly different from those at 1 and 24 weeks after the initiation of dulaglutide (128.1 mg/dL, P = 0.81; and 129.3 mg/dL, P = 0.96, respectively) (Table 2). Significant reductions in %CV values were observed at 1 week (− 5.7% ± 2.1 mg/dL, P = 0.011) and 24 weeks (− 8.7 mg/dL ± 2.4 mg/dL, P = 0.003) compared to those at the time of IIT. TIR, TAR Level 1, TBR Level 1, and TBR Level 2 at 1 and 24 weeks were not significantly different from those recorded during IIT; however, TAR Level 2 at 24 weeks was significantly improved (− 2.2% ± 0.8%, P = 0.019). The CGM results according to the time of day are shown in Supplementary Table 1.
Fig. 3.
Continuous glucose monitoring analysis of 24-h glycemic variation. Data present the time course of mean blood glucose during intensive insulin therapy (IIT) and at 1 and 24 weeks after the switch to dulaglutide (0.75 mg) and long-acting insulin. Error bars show the standard error of mean blood glucose during each period
Table 2.
Continuous glucose monitoring results on intensive insulin therapy and after 1 and 24 weeks of combination therapy
| IIT | 1 week | P valuea | 24 weeks | P valueb | |
|---|---|---|---|---|---|
| Mean (mg/dL) | 130.9 ± 6.1 | 128.1 ± 5.3 | 0.81 | 129.3 ± 5.9 | 0.96 |
| %CV (%) | 37.1 ± 1.9 | 31.4 ± 1.5 | 0.011 | 28.4 ± 3.2 | 0.003 |
| TIR (%) | 72.9 ± 3.0 | 78.5 ± 3.2 | 0.052 | 79.5 ± 3.2 | 0.19 |
| TAR level 1 (%) | 14.9 ± 2.6 | 13.8 ± 2.8 | 0.52 | 14.0 ± 3.0 | 0.78 |
| TAR level 2 (%) | 2.9 ± 0.7 | 1.2 ± 0.6 | 0.063 | 0.7 ± 0.4 | 0.019 |
| TBR level 1 (%) | 5.0 ± 1.2 | 6.1 ± 1.8 | 0.97 | 4.9 ± 1.7 | 0.67 |
| TBR level 2 (%) | 4.2 ± 2.0 | 0.2 ± 0.2 | 0.052 | 0.9 ± 0.5 | 0.16 |
Data are presented as the mean value with standard error; avalue after 1 week of combined therapy compared to the ITT value; bvalue after 24 weeks of combined therapy compared to the ITT value
%CV, coefficient of variation; IIT, intensive insulin therapy TAR, time above range; TBR, time below range; TIR, time in range
Discussion
The results of this study show that dulaglutide and long-acting insulin combination therapy can have a sustained therapeutic effect for 24 weeks. Furthermore, they reveal that switching from IIT to dulaglutide and long-acting insulin combination therapy can reduce the required insulin dose and blood glucose fluctuations due to postprandial hyperglycemia. No weight gain or weight loss was observed over the 24-week follow-up period.
Previous studies have reported greater reductions in HbA1c and body weight with dulaglutide therapy compared with long-acting insulin therapy [11, 12], as well as weight loss following the administration of a combination therapy consisting of dulaglutide (1.5 mg) and long-acting insulin [5]. While glycemic control improved after the administration of dulaglutide (0.75 mg) and long-acting insulin in this study, no changes in body weight were observed. The improvement in glycemic fluctuation was primarily due to the suppression of postprandial blood glucose levels. This effect could be attributed to an increase in insulin secretion due to GLP-1 [13], improved insulin resistance [14], suppressed glucagon secretion [13], gastrointestinal motility [15], and appetite [16].
There are several possible advantages of using dulaglutide and long-acting insulin together. For example, the weight-suppressing effect of dulaglutide counteracts the weight-gaining effect of insulin. This may have accounted for the lack of weight change in this study. This discrepancy with prior studies that have reported weight loss with the use of 1.5 mg dulaglutide may have been due to the lower dose of 0.75 mg (currently approved for use in Japan) used in the present study. Weight loss and sarcopenia have been shown to adversely affect their prognosis in older patients [17]. As this combination therapy is not associated with excessive weight loss or gain, it may be particularly suitable for older patients with sarcopenia who are non-obese.
The administration of dulaglutide and long-acting insulin combination therapy allowed us to discontinue fast-acting insulin therapy and reduce long-acting insulin therapy, even in patients with T2DM who had decreased endogenous insulin secretion. The therapeutic effect of dulaglutide remains evident when there is a decrease in insulin secretion [18]. However, the therapeutic effect of GLP-1 receptor agonists decreases when there is a reduction in insulin secretory capacity [19]. The continuous administration of long-acting insulin possibly stabilizes the fasting blood glucose level, thus preventing glucose toxicity and improving insulin secretory capacity [20].
There are some limitations to this study that should be considered. First, as this was a single retrospective observational study, we were unable to directly and accurately evaluate treatment effectiveness. Second, we only included patients who continued to undergo CGM and returned for follow-up over 24 weeks after the treatment change; thus, there may have been a selection bias. Third, all patients in this study were hospitalized, and glycemic control was performed with IIT. Elimination of glucose toxicity by administering insulin therapy may have long-term effects [21]. Considering the time period associated with the evaluation of HbA1c, the HbA1c level may have been affected by IIT during hospitalization, and at 12 weeks after the treatment change. Fourth, personalized nutritional advice was provided during hospitalization, which could have affected dietary management after discharge [22]. There may have been differences between inpatients and outpatientsin their dietary content and amount of activity, which may have affected the results. Fifth, the sample size was too small to perform multivariate analyses of the factors associated with the primary and secondary outcomes. Finally, this study did not include a qualitative evaluation of changes in body weight based on muscle mass and body fat percentage.
Additional randomized controlled trials are required to evaluate and confirm the therapeutic effects of switching from IIT to the combined long-acting insulin and dulaglutide therapy, as well as other candidate drugs. Future studies should evaluate patients who have undergone IIT for at least several months prior to the administration of combination therapy. The effects of switching from IIT to a combination therapy should also be assessed in the outpatient setting.
Conclusions
The results of this study suggest that the combined administration of dulaglutide and long-acting insulin can maintain favorable blood glucose levels over an extended period, even in patients with a long history of T2DM and decreased insulin secretion. Switching from IIT to dulaglutide and long-acting insulin combination therapy not only reduces the number of insulin self-injections, but also provides greater suppression of blood glucose fluctuations. Future randomized controlled trials are required to confirm the effectiveness of this combination therapy.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We would like to thank Editage (www.editage.com) for English language editing.
Author contributions
KI contributed to conception, design, data collection, analysis, interpretation writing the first draft, and editing. YK contributed to methodology, MH, HT, and SS contributed to the conception, data collection, and interpretation. YT contributed to supervision. All authors read and approved the final manuscript.
Declarations
Conflict of interest
Yasuo Terauchi has received honoraria from MSD, Ono Pharmaceutical Co. Ltd., Boehringer Ingelheim, Takeda, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Sanwa Kagaku Kenkyusho, Novo Nordisk A/S, Eli Lilly, Sanofi, Sumitomo Dainippon Pharma, Shionogi, Bayer Yakuhin, Astellas Pharma, and AstraZeneca and subsidies or donations from MSD, Ono Pharmaceutical Co. Ltd., Boehringer Ingelheim, Novartis, Takeda, Daiichi Sankyo, Sanwa Kagaku Kenkyusho, Novo Nordisk A/S, Eli Lilly, Sanofi, and Sumitomo Dainippon Pharma. Shinobu Satoh has received honoraria from Novo Nordisk Pharma Ltd. and Eli Lilly. Kondo Yoshinobu has received honoraria from Novo Nordisk Pharma Ltd. Kohei Ito, Haruka Tamura, and Masanori Hasebe declare that they have no conflict of interest.
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and/or with the Helsinki Declaration of 1964 and later versions.
Informed consent
An alternative of informed consent was obtained from all patients for being included in the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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