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Efficacy of Saxagliptin versus Mitiglinid in patients with type 2 diabetes and end-stage renal disease

Renal Replacement Therapy volume 3, Article number: 15 (2017) Cite this article

Abstract

Background

There are very few oral antidiabetic drugs recommended for patients on dialysis. Saxagliptin is known for its potent effect and long duration of action. In this study, we compared the efficacy of Saxagliptin with Mitiglinid for diabetes control and renal anemia in hemodialysis patients with type 2 diabetes mellitus.

Methods

We performed a 6-month prospective, open-label, parallel group study of 41 patients with type 2 diabetes mellitus undergoing hemodialysis who took alpha-glucosidase inhibitors or meglitinides and did not use insulin. Saxagliptin and Mitiglinid were administered at 2.5 and 5 mg/day, respectively. The primary outcomes were changes in hemoglobin A1c (HbA1c) and glycated albumin (GA). Other efficacy assessments included changes in Hb, darbepoetin alpha (DA) dose, and erythropoietin responsiveness index (ERI).

Results

No patient required an increase in Saxagliptin or Mitiglinid dose, and there were no cases of hypoglycemia with symptoms. HbA1c and GA values were not significantly different between both groups. For HbA1c, the gradient of the regression line of the Saxagliptin and Mitiglinid groups were Y = −7.144e-005*X + 6.023 and Y = −0.02604*X + 6.292, respectively, and no significant difference was found (p = 0.3281). However, for GA, the regression line of the Saxagliptin group significantly decreased (Y = −0.5036*X + 19.34 and Y = −0.2346*X + 18.79, p = 0.0371). Both groups did not have a significant change in the DA dose through the observation period. However, the DA dose of the Saxagliptin group significantly decreased when we compared the regression lines (Y = −0.8304*X + 21.06 and Y = 0.6286*X + 16.12, p = 0.0019) of both groups. Furthermore, ERI did not change significantly but showed a significant difference when regression lines were compared (Y = −0.2030*X + 6.654 and Y = 0.1116*X + 5.288, p = 0.0082).

Conclusions

The present study showed that Saxagliptin was not inferior to Mitiglinid in the glycemic control of ESRD patients with type 2 diabetes mellitus, and it is well tolerated and safe. Saxagliptin may also improve bioavailability of iron compared to Mitiglinid, but long-term follow-up in a large scale study with more precise ferrokinetic marker measurements are necessary to confirm these results.

Background

Type 2 diabetes mellitus is on a rapid increase globally, especially in Asia [1, 2]. In Japan, the number of hemodialysis patients where diabetic nephropathy is a primary disease is increasing. Currently, diabetic nephropathy is the primary disease for approximately 40% of all patients on dialysis [3].

The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines recommend standard hemoglobin A1c (HbA1c) targets for patients with type 2 diabetes mellitus and end-stage renal disease (ESRD) to potentially reduce the risk of other microvascular complications (neuropathy and retinopathy) [4, 5]. However, treatment options available for these patients are limited due to safety and tolerability issues [6]. Oral medications recommended in the Japanese guidelines include only alpha-glucosidase inhibitors, meglitinides, and dipeptidyl peptidase-4 (DPP-4) inhibitors [7]. These three drug types in combination and insulin preparation are used in treatment. However, there is no evidence indicating which drug is ideal.

The DPP-4 inhibitor has few hypoglycemic side effects [8]. Also, it is hard to cause the weight gain too [9]. It has been reported to exert a kidney protection effect and is expected as the new drug of choice in diabetes treatment where there is decreased renal function [10,11,12,13,14,15,16]. Recently, DPP-4 inhibits hemopoietic factors such as granulocyte-colony stimulating factor (G-CSF) or erythropoietin, and it is reported that the antagonism is inhibited by DPP-4 inhibitors [17,18,19]. However, the clinical effect on renal anemia treatment is unknown. Meglitinides are a class of oral hypoglycaemic agents that increase insulin secretion in the pancreas. Their effect is to produce a rapid, short-lived insulin output [20].

Saxagliptin is a selective DPP-4 inhibitor specifically designed for extended inhibition of the DPP-4 enzyme that is primarily metabolized by cytochrome P450 (CYP) 3A4/5 to form an active metabolite, 5-hydroxy Saxagliptin, which is cleared by the kidney [21, 22]. Saxagliptin is eliminated by both renal and hepatic routes [23, 24]. Recent studies have shown that Saxagliptin is a well-tolerated treatment option for patients with type 2 diabetes mellitus and renal impairment [13,26,, 25–27].

To further characterize the use of Saxagliptin in patients with kidney disease, the present study compared the efficacy of Saxagliptin with that of Mitiglinid monotherapy for diabetes control and renal anemia administered over 6 months in patients with type 2 diabetes mellitus and ESRD requiring hemodialysis.

Methods

Patients

The inclusion criteria was intended for patients who took alpha-glucosidase inhibitors or meglitinides, among patients who were on hemodialysis in an outpatient setting for chronic renal failure due to type 2 diabetes mellitus and who were not on insulin.

Patients were on hemodialysis therapy for at least 6 months and were 20 years or older at the screening visit. Exclusion criteria were as follows: (1) age <20 years; (2) a history of severe heart failure, angina, myocardial infarction, or stroke within the past 6 months; (3) the presence of infectious disease, liver dysfunction, thyroid disease, malignant tumors, or treatment with steroids or immunosuppressants; and (4) treatment with any DPP-4 inhibitor within the past 6 months.

Hemodialysis

All patients underwent dialysis for 4 or 5 h. Blood flow rate was 200 mL/min and a dialysate flow rate was 500 mL/min. All centers used the high-flux membrane, and the size of the dialyzer was decided according to the physique of the patient. The ultrafiltration-rate was decided according to the dry weight. The glucose concentration of the dialysate was 125 mg/dL. Heparin was administered at a dose of 2500–6000 U per dialysis session for anticoagulation.

Study design

This was a 6-month, prospective, open-label, parallel-group, bi-center study and was conducted between May 2014 and April 2015. Before randomization, patients stopped alpha-glucosidase inhibitors or meglitinides intake and entered a 1-month drug washout.

The patients were subsequently randomly assigned to the Saxagliptin or Mitiglinid group (open-label random assignment). For the randomization method, we performed simple randomization with alternate assignment. In the Saxagliptin group, patients received 2.5 mg of Saxagliptin once a day. In the mitiglinide group, patients received 5 mg of mitiglinide three times a day.

Downtitration, including interruption of treatment, could occur if a patient had unexplained hypoglycemia or at the clinical judgment of the investigator, to reduce the risk of hypoglycemia. Treatment adherence was assessed by patient query at prespecified visits throughout the study.

Blood samples were obtained before the first hemodialysis session of the week. Postprandial plasma glucose, complete blood cell counts, and other biochemical measurements were performed every month. All patients received Darbepoetin alpha (DA) and DA dose was adjusted according to the severity of anemia. The erythropoietin responsiveness index (ERI) was defined as the mean weekly erythropoiesis stimulating agents (ESA) dose divided by the clinical dry weight and mean blood hemoglobin [i.e., ERI = weekly ESA dose (units)/dry weight (kg)/hemoglobin (g/dL), DA (μg): ESA (units) = 1: 200] [28].

Efficacy endpoints

The primary efficacy endpoint was changes in HbA1c and GA values and comparison between the two groups. Other efficacy assessments included changes in Hb, DA dose, and ERI. Patients could be withdrawn from the study in the event of drug intolerance, if either the serum transaminase concentration or creatine kinase concentration increased to more than two times the upper limit of the normal range or other adverse events, based on the investigator’s judgment.

Statistical analyses

Measurement values are shown as mean +/− standard deviation (mean +/− SD). Continuous variables were compared using the Student’s t test, and one-way ANOVA was performed on the longitudinal data to address its multiplicity. Tukey’s multiple comparison test was used as the post-hoc test. P values less than 0.05 were regarded as statistically significant. Regression lines were separately determined for the data collected during the 6-month period and compared. All analyses were performed using Prism software version 6 (GraphPad Software, Inc., La Jolla, CA, USA).

Results

Patient characteristics

A total of 94 patients were initially screened, and 41 patients were randomly assigned to the Saxagliptin (n = 21) or Mitiglinid (n = 20) group. Colorectal cancer was detected during an observation period, and one case in the Saxagliptin group was excluded. There was a final of 20 subjects in each group. For the premedication in both groups, there were 6 acarbose, 6 voglibose, and 8 mitiglinide in the Saxagliptin group and 8 acarbose, 5 voglibose, and 6 mitiglinide in the mitiglinide group. There was also one Glimepiride recipient in the mitiglinide group. The patient profiles are shown in Table 1. There were no significant differences in the baseline age, anthropometric variables, and laboratory data between the two groups except for serum Ca concentration.

Table 1 Patients’ baseline profiles (N = 40)
Full size table

Glycemic control

No parameter showed any significant changes during the period of examination. There were no changes in the doses of Saxagliptin and Mitiglinid.

No significant change was found in postprandial plasma glucose values over the study duration. Mean postprandial plasma glucose value 6 months after Saxagliptin administration was 152.4 +/− 74.71 mg/dL (ANOVA; p = 0.0938), and the regression line gradient was Y = −0.5571*X + 150.6 (Fig. 1), while mean postprandial plasma glucose value 6 months after Mitiglinid administration was 138.1 +/− 71.77 mg/dL (ANOVA; p = 0.9357), and the regression line gradient was Y = −2.404*X + 149.3. No significant difference was found when the regression line gradient of Saxagliptin and Mitiglinid was compared (p = 0.5252).

Fig. 1
figure 1

Comparison of regression line gradients of postprandial plasma glucose between Saxagliptin and Mitiglinid groups. Saxagliptin group Y = −0.5571*X + 150.6, Mitiglinid group Y = −2.404*X + 149.3. PPG postprandial plasma glucose

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No significant change was found in HbA1c values over the study duration. Mean HbA1c value 6 months after Saxagliptin administration was 5.905 +/− 0.9770% (ANOVA; p = 0.9099), and the gradient of the regression line was Y = −7.144e-005*X + 6.023 (Fig. 2), while mean HbA1c value of the Mitiglinid group was 6.145 +/− 1.1540 (ANOVA; p = 0.9994), and the gradient of the regression line was Y = −0.02604*X + 6.292. No significant difference was found when the slope of regression lines of Saxagliptin and Mitiglinid was compared (p = 0.3281).

Fig. 2
figure 2

Comparison of regression line gradients of HbA1c between Saxagliptin and Mitiglinid groups. Saxagliptin group Y = −7.144e-005*X + 6.023, Mitiglinid group Y = −0.02604*X + 6.292, p = 0.3281

Full size image

Mean GA value 6 months after Saxagliptin administration was 16.45 +/− 2.981% (ANOVA; p = 0.0883), and the gradient of the regression line was Y = −0.5036*X + 19.34, while mean GA value of the Mitiglinid group was 17.12 +/− 4.383% (ANOVA; p = 0.9552), and the gradient of the regression line was Y = −0.2346*X + 18.79. There was a significant difference in the slope of regression lines between the two groups (p = 0.0371) (Fig. 3).

Fig. 3
figure 3

Comparison of regression line gradients of GA between Saxagliptin and Mitiglinid groups. Saxagliptin group:Y = −0.5036*X + 19.34, Mitiglinid group Y = −0.2346*X + 18.79, p = 0.0371

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ESA dose and laboratory variables

Renal anemia was well controlled in both groups. After 6 months, in Saxagliptin group mean DA dose was 16.75 +/− 22.08 μg/w, and in Mitiglinid group was 19.50 +/− 11.46 μg/w. Both groups did not have a significant change through the observation period (Saxagliptin group, ANOVA p = 0.4333; Mitiglinid group, ANOVA, p = 0.3768). However, the slope of the regression lines of both groups had a significant difference (Saxagliptin group, Y = −0.8304*X + 21.06; Mitiglinid group, Y = 0.6286*X + 16.12, p = 0.0019) (Fig. 4).

Fig. 4
figure 4

Comparison of regression line gradients of DA dose between Saxagliptin and Mitiglinid groups. Saxagliptin group Y = −0.8304*X + 21.06, Mitiglinid group Y = 0.6286*X + 16.12, p = 0.0019

Full size image

Both groups also did not have a significant change in ERI over the study duration (Saxagliptin group, from 6.891 +/− 6.958 to 5.561 +/− 8.330, ANOVA p = 0.5856; Mitiglinid group, from 4.982 +/− 4.107 to 5.842 +/− 3.766, ANOVA p = 0.9910), but a significant difference was observed when the slope of regression lines were compared between the two groups (Saxagliptin group, Y = −0.2030*X + 6.654; Mitiglinid group, Y = 0.1116*X + 5.288, p = 0.0082) (Fig. 5).

Fig. 5
figure 5

Comparison of regression line gradients of ERI between Saxagliptin and Mitiglinid groups. Saxagliptin group:Y = −0.2030*X + 6.654, Mitiglinid group Y = 0.1116*X + 5.288, p = 0.0082

Full size image

Baseline parameters were not different between the two groups (Table 1), but subjects administered Saxagliptin showed a significant increase in transferrin saturation (TSAT) (p = 0.0148) and serum Fe level (p = 0.0085) when these were compared during the observation period. Ferritin showed a tendency to decrease. These trends observed in subjects in the Saxagliptin group were reversed in the Mitiglinid group, but significant changes in parameters such as the serum Fe level were not found (Table 2).

Table 2 Effect on renal anemia during study period and changes in nutritional status and CRP
Full size table

Also, during the observation period, the Mitiglinid group received saccharated ferric oxide more than the Saxagliptin group (188.6 +/− 117.1 mg versus 131.4 +/− 79.04 mg), but there was no significant difference (p = 0.3056) (Fig. 5).

No significant changes were found between both groups for the nutrition index-related marker and inflammatory reaction marker (e.g., CRP) (Table 2).

Adverse event

In this study, no patients experienced liver dysfunction. No cases required an increase in Saxagliptin or Mitiglinid dose over the study duration. There were also no recognized cases of hypoglycemia with symptoms or abnormal liver function. There were no patients who stopped medicine. During the study period, neoplasm was reported for one patient in the Saxagliptin group and none in the Mitiglinid group. However, as it was a colorectal cancer detected during the early phase of this study, the relationship with the drug is thought to be low.

Discussion

Patients with type 2 diabetes mellitus and ESRD have limited therapeutic options to manage hyperglycemia [7, 29]. Furthermore, few randomized controlled trials have compared antihyperglycemic agents in these patients [30].

In this study, we demonstrate that Saxagliptin can be used safely in diabetic patients undergoing hemodialysis, but cannot significantly reduce HbA1c and GA levels during a 6-month treatment period. Analysis of this study’s results demonstrated that Saxagliptin was not inferior to Mitiglinid in the glycemic control of ESRD patients with type 2 diabetes mellitus.

The usefulness of Mitiglinid in dialysis patients is usually reported as a meglitinide preparation with accommodation to a patient on dialysis, and it has become the drug of choice in glycemic control for patients on dialysis who have few treatment options [31,32,33]. Saxagliptin, in contrast, has been reported for use in patients with moderate CKD with type 2 diabetes mellitus and ESRD [13, 27, 30]. In particular, the SAVOR-TIMI53 study, which included large-scale clinical trials that followed approximately 16,000 patients for an average of 2.1 years, reported that the safety of Saxagliptin is not significantly different from placebo in chronic kidney disease (CKD) patients not on dialysis [34].

No changes in HbA1c in comparison with GA were found in this study. This may be due to our target population where patients having difficulty in glycemic control and using insulin were excluded from this study, and only patients who could control blood glucose with oral medication only were included. Therefore, the baseline GA and HbA1c values were low, and it seems that there was no difference in value at the end of the study. Based on a report using a different DPP-4 inhibitor, the rate of HbA1c decline may depend on the baseline value [9, 35]. GA is recognized as a more reliable marker than HbA1c for monitoring glycemic control in ESRD patients with diabetes [36, 37]. In this study, there was a significant difference in the regression line gradient in GA but not HbA1c in the Saxagliptin group. Our data also suggest that GA is a better marker for glycemic control in diabetic patients with ESRD compared to HbA1c.

Meglitinides and DPP-4 inhibitors are both medicines classified as insulin secretagogue, but their duration of action is different [29, 38]. Meglitinide is a drug aimed at primarily correcting postprandial hyperglycemia to avoid a delay in insulin secretion and the concomitant protraction of the hyperglycemic state and therefore has a relatively short duration of action [33, 39]. However, DPP-4 inhibitors exert a hypoglycemic effect through incretin effects that lasts for 24 h [23]. This difference in duration of action may explain the difference in glycemic control profile, and the likelihood that GA is decreased more in the Saxagliptin group has been considered.

In this study, increase in serum iron concentrations and transferrin saturation (TSAT) were significant in the Saxagliptin but not the Mitiglinid group. The ferritin was not significantly altered in both group, but a decrease trend was found in the Saxagliptin group, adversely an upward trend was found in the Mitiglinid group. For Hb, no significant alteration was found in both groups, but a decrease in the DA dose and improvement of the ERI was found in the Saxagliptin group. Though there was less consumption of saccharated ferric oxide in the Saxagliptin group, thus, bioavailability of the iron might be improved in the Saxagliptin group. However, it is necessary to measure a more precise ferrokinetic marker such as hepciden 25 or ferroportin [40,41,42,43,44].

DPP-4 inhibits hemopoietic factors such as G-CSF or erythropoietin, and it has been reported that the antagonism is inhibited by a DPP-4 inhibitor [16,17,18]. Several reports suggest that DPP-4 inhibitors have antiinflammatory effects and can improve bone marrow function [45, 46]. The possibility of scission protection by DPP-4 with antiinflammatory agents such as BNP/ANP (brain natriuretic peptide/atrial natriuretic peptide) or NPY (neuropeptide), which are substrates of DPP-4, is suggested, and an intracorporeal inflammation condition is therefore thought to be ameliorated by DPP-4 inhibitor [47,48,49,50]. This may explain the improved iron bioavailability.

No significant alteration was found in the marker used to indicate inflammatory status in this study during the study period. We used C-reactive protein (CRP), a common laboratory examination item, as the inflammatory associated marker. A difference between both groups might be detected if a high-precision inflammatory marker, such as high-sensitivity CRP or interleukin-6 (IL-6), was used instead. These possibilities need to be addressed in future studies.

Limitations

There are some limitations to this study. First, it was conducted at just two centers; therefore, subject numbers were limited. This trial also did not have a double-blind design, and results might have been biased. While this study was too small to allow robust statistical analysis, it demonstrated obvious contrasts between the two groups in renal anemia and Fe movement parameters at each evaluation.

Conclusions

The present study showed that Saxagliptin was not inferior to Mitiglinid in the glycemic control of ESRD patients with type 2 diabetes mellitus, and it is well tolerated and safe. Furthermore, Saxagliptin may improve iron bioavailability compared to Mitiglinid. However, long-term follow-up in a larger scale study with more precise ferrokinetic markers is necessary to confirm its efficacy and safety.

References

  1. Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol. 2015;12(2):73–81.

    Article  PubMed  Google Scholar 

  2. NCD-RisC NRFC. Articles: worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4•4 million participants. Lancet. 2016;387(10027):1513–30.

    Article  Google Scholar 

  3. Masakane I, Nakai S, Ogata S, Kimata N, Hanafusa N, Hamano T, Wakai K, Wada A, Nitta K. An overview of regular dialysis treatment in Japan (as of 31 December 2013). Ther Apher Dial. 2015;19(6):540–74.

    Article  CAS  PubMed  Google Scholar 

  4. Slinin Y, Ishani A, Rector T, Fitzgerald P, MacDonald R, Tacklind J, Rutks I, Wilt TJ. Management of hyperglycemia, dyslipidemia, and albuminuria in patients with diabetes and CKD: a systematic review for a KDOQI clinical practice guideline. Am J Kidney Dis. 2012;60(5):747–69.

    Article  PubMed  Google Scholar 

  5. Foundation NK. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60(5):850–86.

    Article  Google Scholar 

  6. Rossing P, de Zeeuw D. Need for better diabetes treatment for improved renal outcome. Kidney Int. 2011;79(S120):S28–32.

    Article  Google Scholar 

  7. Nakao T, Inaba M, Abe M, Kaizu K, Shima K, Babazono T, Tomo T, Hirakata H, Akizawa T, Therapy JSfD. Best practice for diabetic patients on hemodialysis 2012. Ther Apher Dial. 2015;19:40–66.

    Article  PubMed  Google Scholar 

  8. Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2012;15(2):112–20.

    Article  PubMed  Google Scholar 

  9. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA 1cwithout causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11(12):1145–52.

    Article  CAS  PubMed  Google Scholar 

  10. Sakai Y, Suzuki A, Mugishima K, Sumi Y, Otsuka Y, Otsuka T, Ohno D, Murasawa T, Tsuruoka S. Effects of alogliptin in chronic kidney disease patients with type 2 diabetes. Intern Med. 2014;53(3):195–203.

    Article  PubMed  Google Scholar 

  11. McGill JB, Sloan L, Newman J, Patel S, Sauce C, von Eynatten M, Woerle H-J. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care. 2013;36(2):237–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ramirez G, Morrison A, Bittle P. Clinical practice considerations and review of the literature for the use of DPP-4 inhibitors in patients with type 2 diabetes and chronic kidney disease. Endocr Pract. 2013;19(6):1025–34.

    Article  PubMed  Google Scholar 

  13. Nowicki M, Rychlik I, Haller H, Warren ML, Suchower L, Gause-Nilsson I. Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes Obes Metab. 2011;13(6):523–32.

    Article  CAS  PubMed  Google Scholar 

  14. Graefe-Mody U, Friedrich C, Port A, Ring A, Retlich S, Heise T, Halabi A, Woerle HJ. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab. 2011;13(10):939–46.

    Article  CAS  PubMed  Google Scholar 

  15. Lukashevich V, Schweizer A, Shao Q, Groop PH, Kothny W. Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24‐week randomized placebo‐controlled trial. Diabetes Obes Metab. 2011;13(10):947–54.

    Article  CAS  PubMed  Google Scholar 

  16. Tanaka T, Higashijima Y, Wada T, Nangaku M. The potential for renoprotection with incretin-based drugs. Kidney Int. 2014;86(4):701–11.

    Article  CAS  PubMed  Google Scholar 

  17. Broxmeyer HE, Hoggatt J, O’Leary HA, Mantel C, Chitteti BR, Cooper S, Messina-Graham S, Hangoc G, Farag S, Rohrabaugh SL, et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med. 2012;18(12):1786–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. O’Leary H, Ou X, Broxmeyer HE. The role of dipeptidyl peptidase 4 in hematopoiesis and transplantation. Curr Opin Hematol. 2013;20(4):314–9.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ou X, O’Leary HA, Broxmeyer HE. Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Blood. 2013;122(2):161–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Abe M, Okada K, Soma M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr Drug Metab. 2011;12(1):57–69.

    Article  CAS  PubMed  Google Scholar 

  21. Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010;12(8):648–58.

    Article  CAS  PubMed  Google Scholar 

  22. Neumiller JJ, Campbell RK. Saxagliptin: a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus. Am J Health Syst Pharm. 2010;67(18):1515–25.

    Article  CAS  PubMed  Google Scholar 

  23. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs. 2011;71(11):1441–67.

    Article  CAS  PubMed  Google Scholar 

  24. Yang LPH. Saxagliptin: a review of its use as combination therapy in the management of type 2 diabetes mellitus in the EU. Drugs. 2012;72(2):229–48.

    Article  CAS  PubMed  Google Scholar 

  25. Scheen AJ. Saxagliptin plus metformin combination in patients with type 2 diabetes and renal impairment. Expert Opin Drug Metab Toxicol. 2012;8(3):383–94.

    Article  CAS  PubMed  Google Scholar 

  26. Aschner PJ. The role for saxagliptin within the management of type 2 diabetes mellitus: an update from the 2010 European Association for the Study of Diabetes (EASD) 46th annual meeting and the American Diabetes Association (ADA) 70th scientific session. Diabetol Metab Syndr. 2010;2:69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nowicki M, Rychlik I, Haller H, Warren M, Suchower L, Gause-Nilsson I, Schützer K-M. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J Clin Pract. 2011;65(12):1230–9.

    Article  CAS  PubMed  Google Scholar 

  28. Marcelli D, Bayh I, Merello JI, Ponce P, Heaton A, Kircelli F, Chazot C, Di Benedetto A, Marelli C, Ladanyi E, et al. Dynamics of the erythropoiesis stimulating agent resistance index in incident hemodiafiltration and high-flux hemodialysis patients. Kidney Int. 2016;90(1):192–202.

    Article  CAS  PubMed  Google Scholar 

  29. Nakamura Y. Diabetes therapies in hemodialysis patients: dipeptidase-4 inhibitors. World J Diabetes. 2015;6(6):840–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Abe M, Higuchi T, Moriuchi M, Okamura M, Tei R, Nagura C, Takashima H, Kikuchi F, Tomita H, Okada K. Efficacy and safety of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in hemodialysis patients with diabetic nephropathy: a randomized open-label prospective trial. Diabetes Res Clin Pract. 2016;116(C):244–52.

    Article  CAS  PubMed  Google Scholar 

  31. Abe M, Okada K, Maruyama T, Maruyama N, Matsumoto K. Efficacy and safety of mitiglinide in diabetic patients on maintenance hemodialysis. Endocr J. 2010;57(7):579–86.

    Article  CAS  PubMed  Google Scholar 

  32. Abe M, Okada K, Maruyama T, Maruyama N, Matsumoto K. Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis. Expert Opin Pharmacother. 2010;11(2):169–76.

    Article  CAS  PubMed  Google Scholar 

  33. Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;2:CD004654.

    Google Scholar 

  34. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.

    Article  CAS  PubMed  Google Scholar 

  35. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q, Group AS. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009;11(2):167–76.

    Article  CAS  PubMed  Google Scholar 

  36. Inaba M, Okuno S, Kumeda Y, Yamada S, Imanishi Y, Tabata T, Okamura M, Okada S, Yamakawa T, Ishimura E, et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol. 2007;18(3):896–903.

    Article  CAS  PubMed  Google Scholar 

  37. Peacock TP, Shihabi ZK, Bleyer AJ, Dolbare EL, Byers JR, Knovich MA, Calles-Escandon J, Russell GB, Freedman BI. Comparison of glycated albumin and hemoglobin A1c levels in diabetic subjects on hemodialysis. Kidney Int. 2008;73(9):1062–8.

    Article  CAS  PubMed  Google Scholar 

  38. Guardado-Mendoza R, Prioletta A, Jimenez-Ceja LM, Sosale A, Folli F. The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus. Arch Med Sci. 2013;9(5):936–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Phillippe HM, Wargo KA. Mitiglinide: a novel agent for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2010;44(10):1615–23.

    Article  PubMed  Google Scholar 

  40. Vermeulen E, Vermeersch P. Hepcidin as a biomarker for the diagnosis of iron metabolism disorders: a review. Acta Clin Belg. 2012;67(3):190–7.

    CAS  PubMed  Google Scholar 

  41. Poggiali E, Migone De Amicis M, Motta I. Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. Eur J Intern Med. 2014;25(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  42. Konz T, Montes-Bayon M, Vaulont S. Hepcidin quantification: methods and utility in diagnosis. Metallomics. 2014;6(9):1583–90.

    Article  CAS  PubMed  Google Scholar 

  43. Ganz T, Nemeth E. Iron balance and the role of hepcidin in chronic kidney disease. Semin Nephrol. 2016;36(2):87–93.

    Article  CAS  PubMed  Google Scholar 

  44. Sebastiani G, Wilkinson N, Pantopoulos K. Pharmacological targeting of the hepcidin/ferroportin axis. Front Pharmacol. 2016;7:160.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care. 2014;37(10):2884–94.

    Article  CAS  PubMed  Google Scholar 

  46. Satoh-Asahara N, Sasaki Y, Wada H, Tochiya M, Iguchi A, Nakagawachi R, Odori S, Kono S, Hasegawa K, Shimatsu A. A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients. Metab Clin Exp. 2013;62(3):347–51.

    Article  CAS  PubMed  Google Scholar 

  47. Mima A, Hiraoka-Yamomoto J, Li Q, Kitada M, Li C, Geraldes P, Matsumoto M, Mizutani K, Park K, Cahill C. Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes. Diabetes. 2012;61(11):2967–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hocher B, Reichetzeder C, Alter ML. Renal and cardiac effects of DPP4 inhibitors—from preclinical development to clinical research. Kidney Blood Press Res. 2012;36(1):65–84.

    Article  CAS  PubMed  Google Scholar 

  49. Muskiet MHA, Smits MM, Morsink LM, Diamant M. The gut-renal axis: do incretin-based agents confer renoprotection in diabetes? Nat Rev Nephrol. 2014;10(2):88–103.

    Article  CAS  PubMed  Google Scholar 

  50. Panchapakesan U, Mather A, Pollock C. Role of GLP-1 and DPP-4 in diabetic nephropathy and cardiovascular disease. Clin Sci. 2013;124(1):17–26.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank all the participants and the dialysis staffs.

Funding

The authors have received no research funds.

Availability of data and materials

Please contact author for data requests.

Authors’ contributions

Y Sakai designed and performed the study, analyzed the data, and wrote the paper. SS, KM, AK, Y Sumi, YO, and TO performed the study and acquired the laboratory data with Y Sakai. ST supervised the study. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable

Ethics approval and consent to participate

All patients provided informed consent to participate in the study after the study protocol, and associated risks were explained to each patient individually. The present study protocol was approved by the Ethical Committee of Nippon Medical School Musashikosugi Hospital (246-25-14) and was designed in accordance with the Declaration of Helsinki.

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Authors and Affiliations

  1. Department of Nephrology, Nippon Medical School Musashikosugi Hospital, 1-396 kosugi-cho, Nakahara-ku, Kawasaki, Japan

    Yukinao Sakai, Koji Mugishima, Anna Katayama, Yuichiro Sumi, Yusuke Otsuka & Tomoyuki Otsuka

  2. Department of Internal Medicine, Zenjinkai Maruko-Clinic, 1-840 Shinmaruko-higashi, Nakahara-ku, Kawasaki, Japan

    Saori Sakai

  3. Department of Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan

    Yukinao Sakai & Shuichi Tsuruoka

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  1. Yukinao Sakai
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  2. Saori Sakai
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Correspondence to Yukinao Sakai.

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Sakai, Y., Sakai, S., Mugishima, K. et al. Efficacy of Saxagliptin versus Mitiglinid in patients with type 2 diabetes and end-stage renal disease. Ren Replace Ther 3, 15 (2017). https://doi.org/10.1186/s41100-017-0098-7

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  • DOI: https://doi.org/10.1186/s41100-017-0098-7

Keywords

Renal Replacement Therapy

ISSN: 2059-1381

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