The Administration of Xultophy for Diabetic Patients on Hemodialysis

Background: Recent diabetic treatments include Insulin Degludec/ liraglutide (IDeg/Lira, Xultophy) in clinical practice. Authors have continued clinical research concerning diabetes, chronic renal failure, dialysis, and others. Subjects and Methods: Ten patients with type 2 diabetes mellitus (T2DM) undergoing hemodialysis were investigated. They showed that ages 74.5 ± 5.9 years, M/F=6/4, BMI 21.1± 3.8kg/m2, hemodialysis duration 8.1 ± 5.7 years. At the beginning, fundamental data were Cre 8.2 ± 1.9 mg/dL, HbA1c 6.5 ± 0.8%. Xultophy was started on 5-12 doses and continued for 6 months with the same or 1-4 increased doses for better glycemic variability. Results: Out of 10 subjects, the changes in HbA1c showed a decrease in 7, stable in 2, and an increase in 1. HbA1c value was 6.2 ± 0.8% in average at 6 months. There were no remarkable adverse effects by Xultophy for 6 months. Discussion and Conclusion: Xultophy was started at 5-12 doses, which were remarkably lower doses than usual doses with satisfactory efficacy. One of the reasons may be from the characteristic of the patients, who were diabetic with undergoing hemodialysis. Another factor is possibly from liraglutide, which has hepatic clearance with potential vascular protective effects. These results are expected to become reference data for future research.


Introduction
As to the fundamental therapy for T2DM, comprehensive lifestyle changes such as meal, weight control, and exercise remain as first-line treatment. However, most patients require dual or triple oral hypoglycemic agents (OHAs) to keep adequate glucose variability [1,2]. There are some main guidelines concerning diabetic management, such as the 2019 consensus report of the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA), and 2020 ADA guidelines. They recommend the stepwise addition of several kinds of agents for diabetes. In such cases, some aspects should be considered, including drug characteristics, administration route, costs, adverse effects, patient preference, as well as present comorbidities such as heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and chronic kidney disease (CKD) [1,2].
Co-administration of a glucagon-like protein-1 receptor agonist (GLP-1 RA) and long-acting basal insulin as a treatment of type 2 diabetes mellitus (T2DM) to achieve improved glycemic control in patients with T2DM is based on a solid understanding of the complementary physiological mechanisms of the actions of both agents [3]. Ample clinical data support combining these agents for the treatment of T2DM. It means an approach which is endorsed as a third-line treatment in the consensus report by the ADA and EASD on the management of hyperglycemia in T2DM [4].
From some large cardiovascular outcome trials (CVOTs), recent diabetic guidelines showed the recommendation of sodium-glucose cotransporter 2 inhibitor (SGLT2i) or GLP-1RA for patients with highrisk states of kidney disease CKD, HF, ASCVD, regardless of the HbA1c values [1,2]. The combined therapy of basal insulin plus a GLP-1RA has been one beneficial method to strengthen the effective treatment with injectable agents. By both complementary actions, combined agents can improve glucose variability, associated with the reduction of adverse effects [5,6]. From these, Insulin Degludec/liraglutide (IDegLira, Xultophy™) has been a fixed-ratio combination of long-acting basal insulin analog and also GLP-1RA for recent therapy of T2DM [7,8].
Our research group has been involved in clinical practice especially concerning diabetes, chronic renal failure, and hemodialysis. As regard to diabetes, authors and collaborators have developed research concerning the comparisons of low carbohydrate diet (LCD), calorie restriction (CR), meal tolerance test (MTT), increased ketone bodies, continuous glucose monitoring (CGM), and so on [9,10]. Furthermore, we established the Japan LCD Promotion Association (JLCDPA) and have continued various activities through JLCDPA such as seminars for LCD, medical societies, textbooks, journals, and newsletters through the internet [11,12].
Furthermore, for CKD and hemodialysis, we reported several studies concerning nerve conduction velocity (NCV), diabetic kidney disease (DKD), carnitine, and others for patients with chronic renal failure and hemodialysis [13,14,15]. Through our clinical practice, there was a case with beneficial efficacy with the treatment of Xultophy [16]. Successively, our hemodialysis team has studied the effect of Xultophy for hemodialysis patients, and the results and discussion would be described in this study.

Subjects:
Subjects in this study included ten patients with T2DM and chronic renal failure (CRF) who have been treated by hemodialysis three times a week. The basic data of the subjects are shown in Table-1.

Methods:
The purpose of the study was to administer Xultophy, evaluate the results, and to discuss the clinical significance. The patients were treated before by Dulaglutide or Degludec with stable diabetic state and stable HbA1c values. The changes in HbA1c values were shown in Fig-1. In this figure, #1 -#10 with colored numbers mean case 1 -10 at the right side, and #5 -#12 with black numbers mean the starting doses of Xultophy at 0 months at the left side. The doses of them were the same or increased 1-4 doses for 6 months. The changes in HbA1c on 0, 2, 4, 6 months are summarized in Fig-1.
The Xultophy ® pen has been prevalent, which is prefilled by 300 units of Xultophy ® 100/3.6 (300 unit's insulin degludec/10.8 mg liraglutide). As for the safety mechanism, it does not have a push-button extension, or the dose button does not move while dialing the doses [17]. The method is a once-daily regimen, and it usually has less weight gain or hypoglycemia associated with increased insulin regimens. In addition, Xultophy shows the benefit of reduced gastrointestinal (GI) side effects in comparison with those of GLP-1 RA alone [17,18].

Results
In the current study, the results for 10 cases of hemodialysis are shown in Table-1. The values of mean ± standard deviation (SD) were as follows: ages 74.5 ± 5.9 years, M/F=6/4, BMI 21.1± 3.8kg/m 2 , hemodialysis duration 8.1 ± 5.7 years. The average value of serum creatinine before hemodialysis at 0 months was 8.2 ± 1.9 mg/dL. By the administration of Xultophy, the changes in HbA1c values in 0, 2, 4, 6 months for 10 cases were described in Fig-1. At 6 months, 7 out of 10 showed a decreasing tendency of HbA1c, 2 showed no changes, and 1 showed an increasing tendency.

Discussion
The treatment of diabetes has changed in recent years. Efficient insulin preparations have emerged, and GLP-1 RA preparations have been introduced to clinical practice. Subsequently, a combination of long-acting insulin and GLP-1 RA has been developed.
Insulin Degludec and liraglutide are combined and it was approved for T2DM patients by the regulatory agency [19]. It was IDegLira, which is called Xultophy 100/3.6, by Novo Nordisk, Denmark. It has been combined as Fixed-Ratio Combinations (FRC) of basal insulin and long-acting GLP-1 analog for once-daily subcutaneous injection for T2DM [20][21][22]. Its efficacy and safety of IDegLira have been evaluated by the DUAL I-IX series of randomized clinical trials (RCTs). They compared the new agent IDegLira use to other long-acting new generation basal insulin and longacting GLP-1 RA analog [23][24][25].
From these results, IDegLira was recognized to be superior to other agents provided alone for reducing HbA1c values. Furthermore, IDegLira has shown weight reduction rather than weight increase, reduced episodes of hypoglycemia, reduced insulin-dose requirement, and higher rates of achieving less than 7% as HbA1c target [19][20][21][22][23][24][25]. These benefits were revealed in DUAL RCTs studies, and the beneficial potential of IDegLira FRC was expected for increasing adherence to diabetic treatment. IDegLira has been produced as a fixed-ratio combination (FRC) of the basal degludec and liraglutide, GLP-1 agonist [26]. The beneficial points of combined agents are described [27]. From several data of DUAL results and post hoc analyses, some cases have shown remarkable efficacy for IDegLira [28]. Refraining from more complex injectable treatments, patients with renal insufficiency are one of the most adequate and effective cases, for whom therapeutic options are rather limited [28]. There is another research group of IDegLira, which is the European Xultophy Treatment Retrospective Audit (EXTRA) [29]. From the data of EXTRA real-world evidence study, better clinical outcomes and cost-effectiveness were observed. In detail, IDegLira vs multiple daily insulin injections (MDI) showed EUR 3013 vs. 6890 per quality-adjusted life-year (QALY) gained, respectively.
In this study, we have tried the administration of IDegLira (Xultophy) in 10 hemodialysis patients and examined the changes in HbA1c at 0, 2, 4, and 6 months. The protocol was successful with no particular problems, unexpected symptoms, or signs. Conventionally, it is said that no remarkable adverse effects are observed in the administration of Xultophy [26]. At 0 month, there are 5 cases with lower HbA1c (5.6%-6.1%), for which 5-6 doses of Xultophy were administered. In contrast, there are 5 cases with higher HbA1c (6.3%-8.1%), for which 8-12 doses of Xultophy were administered. At 6 months, 7 out of 10 showed a decreasing tendency of HbA1c, 2 showed no changes, and 1 showed an increasing tendency. Among them, the two cases with higher HbA1c at 0 months (cases 6 and 7) showed a remarkable reduction. It was reported that the decrease of HbA1c was larger in the cases where the pre-level of HbA1c was rather higher.
As to the characteristics of the subjects in the current study, they are diabetic and undergoing hemodialysis due to chronic renal failure (CRF). Consequently, the relationship between renal dysfunction and GLP-1 RA is important. There are several kinds of GLP-1 Ras so far. Among them, lixisenatide and exenatide are predominantly cleared through the kidney [30]. The dose of exenatide is not recommended to be increased in the diabetic case with eGFR of 30-60 mL/min/1.73 m2. In contrast, dulaglutide and liraglutide have predominantly hepatic clearance. GLP-1 RAs have been recognized to show direct and indirect renal protective effects and some hepatic health benefits (Grade A; EL 1). When these are given to diabetic cases with renal impairment, it is necessary to consider the caution of gastrointestinal adverse effects, which is Grade D; EL 4 [30]. Liraglutide has shown potential vascular protective effects through some mechanism incompletely understood. From the study of T2DM rats, liraglutide may ameliorate vascular endothelial dysfunction via anti-oxidative and activated endothelial oxide synthase (eNOS) [31].
This study has limitations. The subjects are patients undergoing hemodialysis due to diabetic renal failure, and their background seems to be highly heterogeneous. The number of cases was small, including mild to severe cases, and the value of HbA1c was distributed widely. The initial dose of Xultophy is reported to be 16 doses in Europe and North American countries, and 10 doses in Japan. In the current study, Xultophy was started with 5-12 doses, which were remarkably lower doses than usual doses with stable clinical course. One of the reasons may be from the characteristic of the patients, who were diabetic with undergoing hemodialysis. The provided doses of Xultophy were not so increased for 6 months. The doses will be increased according to the patient's situation for better glucose variability after 6 months. For further investigation of the effect of IDegLira in hemodialysis patients, detailed studies will be required including adequate protocols with some groups and applicable biomarkers.
In summary, this pilot study showed the efficacy of IDegLira for diabetic patients with hemodialysis. Authors expect that this report would become some fundamental and reference data for clinical research in the future.

Ethical Considerations
The current study was basically conducted in compliance with the ethical principles. It was along with the Declaration of Helsinki. In addition, some commentary was present for the Ethical Guidelines for Research in the medical research for the human and in the conduction of the Good Clinical Practice (GCP). Regarding the protection of human rights, some ongoing consideration was present. Further, there was "Ethical Guidelines for Epidemiology Research" applied for the related guideline. Those principles were from Japan by the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports, Science, and Technology.
As to this study, authors have taken the written informed consent from all subjects. Moreover, we established the ethical committee in Kanaiso hospital for clinical research. The ethical committee includes the president of the hospital, the director of the Pharmacology Department, the directors of the nursing and administration departments, and some experts in the legal, medical, and pharmaceutical specialties. The members discussed satisfactory about the research content and agreed that this study would be adequate without any problems.