Endocrinol Metab.  2016 Mar;31(1):161-167. 10.3803/EnM.2016.31.1.161.

Effects of Dipeptidyl Peptidase-4 Inhibitors on Hyperglycemia and Blood Cyclosporine Levels in Renal Transplant Patients with Diabetes: A Pilot Study

• Bae J
• Lee MJ
• Choe EY
• Jung CH
• Wang HJ
• Kim MS
• Kim YS
• Park JY
• Kang ES

• KMID: 2169708
• DOI: http://doi.org/10.3803/EnM.2016.31.1.161

Abstract

BACKGROUND
The use of dipeptidyl peptidase-4 (DPP-4) inhibitors is increasing among renal transplant patients with diabetes. However, the glucose-lowering efficacies of various DPP-4 inhibitors and their effects on blood cyclosporine levels have not been fully investigated. We compared the glucose-lowering efficacies of DPP 4 inhibitors and evaluate their effects on the blood levels of cyclosporine in renal transplant recipients with diabetes.
METHODS
Sixty-five renal allograft recipients who received treatment with DPP-4 inhibitors (vildagliptin, sitagliptin, or linagliptin) following kidney transplant were enrolled. The glucose-lowering efficacies of the DPP-4 inhibitors were compared according to the changes in the hemoglobin A1c (HbA1c) levels after 3 months of treatment. Changes in the trough levels of the cyclosporine were also assessed 2 months after treatment with each DPP-4 inhibitor.
RESULTS
HbA1c significantly decreased in the linagliptin group in comparison with other DPP-4 inhibitors (vildagliptin -0.38%±1.03%, sitagliptin -0.53%±0.95%, and linagliptin -1.40±1.34; P=0.016). Cyclosporine trough levels were significantly increased in the sitagliptin group compared with vildagliptin group (30.62±81.70 ng/mL vs. -24.22±53.54 ng/mL, P=0.036). Cyclosporine trough levels were minimally changed in patients with linagliptin.
CONCLUSION
Linagliptin demonstrates superior glucose-lowering efficacy and minimal effect on cyclosporine trough levels in comparison with other DPP-4 inhibitors in kidney transplant patients with diabetes.

Keyword

Dipeptidyl-peptidase IV inhibitors; Sitagliptin phosphate; Vildagliptin; Linagliptin; Cyclosporine; Kidney transplantation; Diabetes mellitus

MeSH Terms

Allografts
Cyclosporine*
Diabetes Mellitus
Dipeptidyl-Peptidase IV Inhibitors
Humans
Hyperglycemia*
Kidney
Kidney Transplantation
Pilot Projects*
Transplantation
Cyclosporine
Dipeptidyl-Peptidase IV Inhibitors

Figure

• 

  Fig. 1 Change in cyclosporine trough level. aVildagliptin vs. sitagliptin, P=0.036; vildagliptin vs. linagliptin, P=0.780; sitagliptin vs. linagliptin, P=0.149.

Reference

1. Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med. 1994; 331:365–376.

2. Schiel R, Heinrich S, Steiner T, Ott U, Stein G. Long-term prognosis of patients after kidney transplantation: a comparison of those with or without diabetes mellitus. Nephrol Dial Transplant. 2005; 20:611–617.

3. Neumiller JJ, Wood L, Campbell RK. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus. Pharmacotherapy. 2010; 30:463–484.

4. Davidson JA. Advances in therapy for type 2 diabetes: GLP-1 receptor agonists and DPP-4 inhibitors. Cleve Clin J Med. 2009; 76:Suppl 5. S28–S38.

5. Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011; 34:Suppl 2. S276–S278.

6. Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010; 12:648–658.

7. Fuchs H, Runge F, Held HD. Excretion of the dipeptidyl peptidase-4 inhibitor linagliptin in rats is primarily by biliary excretion and P-gp-mediated efflux. Eur J Pharm Sci. 2012; 45:533–538.

8. Cohen DJ, Loertscher R, Rubin MF, Tilney NL, Carpenter CB, Strom TB. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med. 1984; 101:667–682.

9. Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol. 2007; 2:374–384.

10. Oellerich M, Armstrong VW, Schutz E, Shaw LM. Therapeutic drug monitoring of cyclosporine and tacrolimus. Update on Lake Louise Consensus Conference on cyclosporin and tacrolimus. Clin Biochem. 1998; 31:309–316.

11. Lin JH. Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin Drug Metab Toxicol. 2007; 3:81–92.

12. Christians U, Sewing KF. Alternative cyclosporine metabolic pathways and toxicity. Clin Biochem. 1995; 28:547–559.

13. Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther. 1997; 62:248–260.

14. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130:461–470.

15. Valderhaug TG, Hjelmesæth J, Hartmann A, Roislien J, Bergrem HA, Leivestad T, et al. The association of early post-transplant glucose levels with long-term mortality. Diabetologia. 2011; 54:1341–1349.

16. Thomas MC, Mathew TH, Russ GR. Glycaemic control and graft loss following renal transplantation. Nephrol Dial Transplant. 2001; 16:1978–1982.

17. Wiesbauer F, Heinze G, Regele H, Horl WH, Schernthaner GH, Schwarz C, et al. Glucose control is associated with patient survival in diabetic patients after renal transplantation. Transplantation. 2010; 89:612–619.

18. Hecking M, Kainz A, Werzowa J, Haidinger M, Doller D, Tura A, et al. Glucose metabolism after renal transplantation. Diabetes Care. 2013; 36:2763–2771.

19. Hamamoto S, Kanda Y, Shimoda M, Tatsumi F, Kohara K, Tawaramoto K, et al. Vildagliptin preserves the mass and function of pancreatic β cells via the developmental regulation and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetes Obes Metab. 2013; 15:153–163.

20. Jelsing J, Vrang N, van Witteloostuijn SB, Mark M, Klein T. The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves β-cell mass in non-obese diabetic mice. J Endocrinol. 2012; 214:381–387.

21. Mikhail N. Safety of dipeptidyl peptidase 4 inhibitors for treatment of type 2 diabetes. Curr Drug Saf. 2011; 6:304–309.

22. Chu XY, Bleasby K, Yabut J, Cai X, Chan GH, Hafey MJ, et al. Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther. 2007; 321:673–683.

23. Scheen AJ. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet. 2010; 49:573–588.

24. He YL, Sabo R, Sunkara G, Bizot MN, Riviere GJ, Leon S, et al. Evaluation of pharmacokinetic interactions between vildagliptin and digoxin in healthy volunteers. J Clin Pharmacol. 2007; 47:998–1004.

25. Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos. 2010; 38:667–678.

26. Koziolek MJ, Riess R, Geiger H, Thevenod F, Hauser IA. Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients. Kidney Int. 2001; 60:156–166.

27. Krishna R, Bergman A, Larson P, Cote J, Lasseter K, Dilzer S, et al. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol. 2007; 47:165–174.

28. Anglicheau D, Pallet N, Rabant M, Marquet P, Cassinat B, Meria P, et al. Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction. Kidney Int. 2006; 70:1019–1025.