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Pharmacokinetics and Clinical Use of Incretin-Based Therapies in Patients with Chronic Kidney Disease and Type 2 Diabetes

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Abstract

The prevalence of chronic kidney disease (CKD) of stages 3–5 (glomerular filtration rate [GFR] <60 mL/min) is about 25–30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population.

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References

  1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1–266.

  2. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007; 49(2 Suppl 2):S12–154.

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

  4. Detournay B, Simon D, Guillausseau PJ, et al. Chronic kidney disease in type 2 diabetes patients in France: prevalence, influence of glycaemic control and implications for the pharmacological management of diabetes. Diabetes Metab. 2012;38(2):102–12.

    CAS  PubMed  Google Scholar 

  5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577–96.

    CAS  PubMed  Google Scholar 

  6. Ritz E. Limitations and future treatment options in type 2 diabetes with renal impairment. Diabetes Care. 2011;34(Suppl 2):S330–4.

    PubMed Central  PubMed  Google Scholar 

  7. 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.

    CAS  PubMed  Google Scholar 

  8. Ahmed Z, Simon B, Choudhury D. Management of diabetes in patients with chronic kidney disease. Postgrad Med. 2009;121(3):52–60.

    PubMed  Google Scholar 

  9. Scheen AJ. Medications in the kidney. Acta Clinica Belgica. 2008;63(2):76–80.

    CAS  PubMed  Google Scholar 

  10. Lubowsky ND, Siegel R, Pittas AG. Management of glycemia in patients with diabetes mellitus and CKD. Am J Kidney Dis. 2007;50(5):865–79.

    CAS  PubMed  Google Scholar 

  11. Haneda M, Morikawa A. Which hypoglycaemic agents to use in type 2 diabetic subjects with CKD and how? Nephrol Dial Transplant. 2009;24(2):338–41.

    PubMed  Google Scholar 

  12. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab. 2000;26(Suppl 4):73–85.

    CAS  PubMed  Google Scholar 

  13. Reilly JB, Berns JS. Selection and dosing of medications for management of diabetes in patients with advanced kidney disease. Semin Dial. 2010;23(2):163–8.

    PubMed  Google Scholar 

  14. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–705.

    CAS  PubMed  Google Scholar 

  15. Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother. 2012;13(1):81–99.

    CAS  PubMed  Google Scholar 

  16. Owens DR, Monnier L, Bolli GB. Differential effects of GLP-1 receptor agonists on components of dysglycaemia in individuals with type 2 diabetes mellitus. Diabetes Metab. 2013;39(6):485–96.

    CAS  PubMed  Google Scholar 

  17. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728–42.

    CAS  PubMed  Google Scholar 

  18. Scheen AJ. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol. 2013;9(5):529–50.

    CAS  PubMed  Google Scholar 

  19. Ramirez G, Morrison AD, Bittle PA. 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.

    PubMed  Google Scholar 

  20. Giorda CB, Nada E, Tartaglino B. Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature. Endocrine. 2014;46(3):406–19.

    CAS  PubMed  Google Scholar 

  21. Mikhail N. Use of dipeptidyl peptidase-4 inhibitors for the treatment of patients with type 2 diabetes mellitus and chronic kidney disease. Postgrad Med. 2012;124(4):138–44.

    PubMed  Google Scholar 

  22. Davis TM. Dipeptidyl peptidase-4 inhibitors: pharmacokinetics, efficacy, tolerability and safety in renal impairment. Diabetes Obes Metab. 2014;16(10):891–9.

  23. von Websky K, Reichetzeder C, Hocher B. Physiology and pathophysiology of incretins in the kidney. Curr Opin Nephrol Hypertens. 2014;23(1):54–60.

    Google Scholar 

  24. Skov J. Effects of GLP-1 in the kidney. Rev Endocr Metab Disord. 2014;15(3):197–207.

    CAS  PubMed  Google Scholar 

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

  26. Fujita H, Morii T, Fujishima H, et al. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int. 2014;85(3):579–89.

    CAS  PubMed  Google Scholar 

  27. Filippatos TD, Elisaf MS. Effects of glucagon-like peptide-1 receptor agonists on renal function. World J Diabetes. 2013;4(5):190–201.

    PubMed Central  PubMed  Google Scholar 

  28. Meier JJ, Nauck MA, Kranz D, et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53(3):654–62.

    CAS  PubMed  Google Scholar 

  29. Idorn T, Knop FK, Jorgensen MB, et al. Elimination and degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with end-stage renal disease. J Clin Endocrinol Metab. 2014;99(7):2457–66.

    CAS  PubMed  Google Scholar 

  30. Scheen AJ. A review of gliptins for 2014. Exp Opin Pharmacother. 2014; in press.

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

    CAS  PubMed  Google Scholar 

  32. Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet. 2012;51(8):501–14.

    CAS  PubMed  Google Scholar 

  33. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007;30(7):1862–4.

    CAS  PubMed  Google Scholar 

  34. He YL. Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clin Pharmacokinet. 2012;51(3):147–62.

    CAS  PubMed  Google Scholar 

  35. He YL, Kulmatycki K, Zhang Y, et al. Pharmacokinetics of vildagliptin in patients with varying degrees of renal impairment. Int J Clin Pharmacol Ther. 2013;51(9):693–703.

    CAS  PubMed  Google Scholar 

  36. Boulton DW, Li L, Frevert EU, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet. 2011;50(4):253–65.

    CAS  PubMed  Google Scholar 

  37. Karim A, Fleck P, Hetman L, et al. Single-dose pharmacokinetics of the dipeptidyl peptidase-4 inhibitor alogliptin in subjects with renal impairment. Diabetes. 2008;57(Suppl 1):A160, 538.

  38. European Medicines Agency. Vipidia (alogliptin): CHMP assessment report. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002182/WC500152273pdf. Last accessed 8 Sep 2014.

  39. Food and Drug Administration. Center for Drug Evaluation and Research. Nesina (alogliptin): application number 002227Orig1s000. Clinical pharmacology and biopharmaceutics review(s). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000ClinPharmR.pdf. Last accessed 8 Sep 2014.

  40. Scheen AJ. Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation). Exp Opin Drug Metab Toxicol. 2011;7(12):1561–76.

    CAS  Google Scholar 

  41. Graefe-Mody U, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab. 2011;13(10):939–46.

    CAS  PubMed  Google Scholar 

  42. Plosker GL. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74(2):223–42.

    CAS  PubMed  Google Scholar 

  43. Chan JC, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab. 2008;10(7):545–55.

    CAS  PubMed  Google Scholar 

  44. Eligar VS, Bain SC. A review of sitagliptin with special emphasis on its use in moderate to severe renal impairment. Drug Des Devel Ther. 2013;7:893–903.

    PubMed Central  PubMed  Google Scholar 

  45. Arjona Ferreira JC, Marre M, Barzilai N, et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care. 2013;36(5):1067–73.

    PubMed Central  PubMed  Google Scholar 

  46. Keller F, Hartmann B, Czock D. Time of effect duration and administration interval for sitagliptin in patients with kidney failure. Eur J Drug Metab Pharmacokinet. 2014;39(2):77–85.

    CAS  PubMed  Google Scholar 

  47. Arjona Ferreira JC, Corry D, Mogensen CE, et al. Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial. Am J Kidney Dis. 2013;61(4):579–87.

    PubMed  Google Scholar 

  48. St Peter WL, Weinhandl ED, Flessner MF. Sitagliptin—another option for managing type 2 diabetes in dialysis patients? Am J Kidney Dis. 2013;61(4):532–5.

    PubMed  Google Scholar 

  49. Boerner BP, Miles CD, Shivaswamy V. Efficacy and safety of sitagliptin for the treatment of new-onset diabetes after renal transplantation. Int J Endocrinol. 2014;2014:617638.

    PubMed Central  PubMed  Google Scholar 

  50. Strom Halden TA, Asberg A, Vik K, et al. Short-term efficacy and safety of sitagliptin treatment in long-term stable renal recipients with new-onset diabetes after transplantation. Nephrol Dial Transplant. 2014;29(4):926–33.

    CAS  PubMed  Google Scholar 

  51. Lestner JM, Baburaj R, Edwards CM. Renal impairment with sitagliptin: is there a need for active monitoring of potential renal toxicity? Br J Hosp Med (Lond). 2011;72(7):412–3.

    CAS  Google Scholar 

  52. Keating GM. Vildagliptin: a review of its use in type 2 diabetes mellitus. Drugs. 2014;74(5):587–610.

    CAS  PubMed  Google Scholar 

  53. Russo E, Penno G, Del Prato S. Managing diabetic patients with moderate or severe renal impairment using DPP-4 inhibitors: focus on vildagliptin. Diabetes Metab Syndr Obes. 2013;6:161–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Ahren B, Schweizer A, Dejager S, et al. Mechanisms of action of the DPP-4 inhibitor vildagliptin in humans. Diabetes Obes Metab. 2011;13(9):775–83.

    CAS  PubMed  Google Scholar 

  55. Lukashevich V, Schweizer A, Shao Q, et al. 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.

    CAS  PubMed  Google Scholar 

  56. Kothny W, Shao Q, Groop PH, et al. One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal insufficiency. Diabetes Obes Metab. 2012;14(11):1032–9.

  57. Banerji MA, Purkayastha D, Francis BH. Safety and tolerability of vildagliptin vs. thiazolidinedione as add-on to metformin in type 2 diabetic patients with and without mild renal impairment: a retrospective analysis of the GALIANT study. Diabetes Res Clin Pract. 2010;90(2):182–90.

    CAS  PubMed  Google Scholar 

  58. Ligueros-Saylan M, Foley JE, Schweizer A, et al. An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of phase II and III clinical trials. Diabetes Obes Metab. 2010;12(6):495–509.

    CAS  PubMed  Google Scholar 

  59. Ito M, Abe M, Okada K, et al. The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis. Endocr J. 2011;58(11):979–87.

    CAS  PubMed  Google Scholar 

  60. Ito H, Mifune M, Matsuyama E, et al. Vildagliptin is effective for glycemic control in diabetic patients undergoing either hemodialysis or peritoneal dialysis. Diabetes Ther. 2013;4(2):321–9.

    PubMed Central  PubMed  Google Scholar 

  61. Lukashevich V, Schweizer A, Foley JE, et al. Efficacy of vildagliptin in combination with insulin in patients with type 2 diabetes and severe renal impairment. Vasc Health Risk Manag. 2013;9:21–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Werzowa J, Hecking M, Haidinger M, et al. Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation: a randomized, placebo-controlled clinical trial. Transplantation. 2013;95(3):456–62.

    CAS  PubMed  Google Scholar 

  63. Haidinger M, Werzowa J, Hecking M, et al. Efficacy and safety of vildagliptin in new-onset diabetes after kidney transplantation—a randomized, double-blind, placebo-controlled trial. Am J Transplant. 2014;14(1):115–23.

    CAS  PubMed  Google Scholar 

  64. Ali S, Fonseca V. Saxagliptin overview: special focus on safety and adverse effects. Expert Opin Drug Saf. 2013;12(1):103–9.

    CAS  PubMed  Google Scholar 

  65. Zhang L, Boulton DW, Pfister M. A pharmacometric approach to quantify the impact of chronic kidney disease and hemodialysis on systemic drug exposure: application to saxagliptin. J Clin Pharmacol. 2012;52(1 Suppl):126S–33S.

    CAS  PubMed  Google Scholar 

  66. Nowicki M, Rychlik I, Haller H, et al. 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.

    CAS  PubMed  Google Scholar 

  67. Nowicki M, Rychlik I, Haller H, et al. 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.

    CAS  PubMed  Google Scholar 

  68. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.

    CAS  PubMed  Google Scholar 

  69. Scott LJ. Alogliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs. 2010;70(15):2051–72.

    CAS  PubMed  Google Scholar 

  70. Sakai Y, Suzuki A, Mugishima K, et al. Effects of alogliptin in chronic kidney disease patients with type 2 diabetes. Intern Med. 2014;53(3):195–203.

    PubMed  Google Scholar 

  71. Ohashi N, Tsuji N, Naito Y, et al. Alogliptin improves steroid-induced hyperglycemia in treatment-naive Japanese patients with chronic kidney disease by decrease of plasma glucagon levels. Med Sci Monit. 2014;20:587–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Fujii Y, Abe M, Higuchi T, et al. The dipeptidyl peptidase-4 inhibitor alogliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis. Expert Opin Pharmacother. 2013;14(3):259–67.

    CAS  PubMed  Google Scholar 

  73. Nakamura Y, Inagaki M, Shimizu T, et al. Long-term effects of alogliptin benzoate in hemodialysis patients with diabetes: a 2-year study. Nephron Clin Pract. 2013;123(1–2):46–51.

    CAS  PubMed  Google Scholar 

  74. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.

    CAS  PubMed  Google Scholar 

  75. Scheen AJ. Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation). Expert Opin Drug Metab Toxicol. 2011;7(12):1561–76.

    CAS  PubMed  Google Scholar 

  76. Gallwitz B. Safety and efficacy of linagliptin in type 2 diabetes patients with common renal and cardiovascular risk factors. Ther Adv Endocrinol Metab. 2013;4(3):95–105.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Friedrich C, Emser A, Woerle HJ, et al. Renal impairment has no clinically relevant effect on the long-term exposure of linagliptin in patients with type 2 diabetes. Am J Ther. 2013;20(6):618–21.

    PubMed  Google Scholar 

  78. Groop PH, Del Prato S, Taskinen MR, et al. Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment. Diabetes Obes Metab. 2014;16(6):560–8.

    CAS  PubMed  Google Scholar 

  79. McGill JB, Sloan L, Newman J, et al. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Scott D. Treatment of type 2 diabetes in chronic kidney disease: a case for linagliptin in the treatment of diabetes in severe renal impairment. Diabetes Metab Syndr Obes. 2013;6:359–63.

    PubMed Central  PubMed  Google Scholar 

  81. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013;36(11):3460–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Kim SH, Lee SH, Yim HJ. Gemigliptin, a novel dipeptidyl peptidase 4 inhibitor: first new anti-diabetic drug in the history of Korean pharmaceutical industry. Arch Pharm Res. 2013;36(10):1185–8.

    CAS  PubMed  Google Scholar 

  83. Lim KS, Kim JR, Choi YJ, et al. Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, phase I study. Clin Ther. 2008;30(10):1817–30.

    CAS  PubMed  Google Scholar 

  84. Lim KS, Cho JY, Kim BH, et al. Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers. Br J Clin Pharmacol. 2009;68(6):883–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Shon JH, Kim N, Park SJ, et al. Effect of renal impairment and haemodialysis on the pharmacokinetics of gemigliptin (LC15-0444). Diabetes Obes Metab. 2014;16(10):1028–31.

  86. Gallwitz B. Glucagon-like peptide-1 analogues for type 2 diabetes mellitus: current and emerging agents. Drugs. 2011;71(13):1675–88.

    CAS  PubMed  Google Scholar 

  87. Scott LJ. Exenatide extended-release: a review of its use in type 2 diabetes mellitus. Drugs. 2012;72(12):1679–707.

    CAS  PubMed  Google Scholar 

  88. Scheen AJ. Which incretin-based therapy for type 2 diabetes? Lancet. 2014;384(9951):1325–7.

    PubMed  Google Scholar 

  89. Copley K, McCowen K, Hiles R, et al. Investigation of exenatide elimination and its in vivo and in vitro degradation. Curr Drug Metab. 2006;7(4):367–74.

    CAS  PubMed  Google Scholar 

  90. McCormack PL. Exenatide twice daily: a review of its use in the management of patients with type 2 diabetes mellitus. Drugs. 2014;74(3):325–51.

    CAS  PubMed  Google Scholar 

  91. Perry CM. Liraglutide: a review of its use in the management of type 2 diabetes mellitus. Drugs. 2011;71(17):2347–73.

    CAS  PubMed  Google Scholar 

  92. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. 2007;64(3):317–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Food and Drug Administration. Center for Drug Evaluation and Research. Exenatide LAR, Bydureon. Clinical pharmacology and biopharmaceutical review(s). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000ClinPharmR.pdf. Accessed 15 July 2014.

  94. Pawaskar M, Tuttle KR, Li Q, et al. Observational study of kidney function and albuminuria in patients with type 2 diabetes treated with exenatide BID versus insulin glargine. Ann Pharmacother. 2014;48(5):571–6.

    CAS  PubMed  Google Scholar 

  95. Jacobsen LV, Hindsberger C, Robson R, et al. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol. 2009;68(6):898–905.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Davidson JA, Brett J, Falahati A, et al. Mild renal impairment and the efficacy and safety of liraglutide. Endocr Pract. 2011;17(3):345–55.

    PubMed  Google Scholar 

  97. Imamura S, Hirai K, Hirai A. The glucagon-like peptide-1 receptor agonist, liraglutide, attenuates the progression of overt diabetic nephropathy in type 2 diabetic patients. Tohoku J Exp Med. 2013;231(1):57–61.

    CAS  PubMed  Google Scholar 

  98. Forst T, Pfutzner A. Pharmacological profile, efficacy and safety of lixisenatide in type 2 diabetes mellitus. Expert Opin Pharmacother. 2013;14(16):2281–96.

    CAS  PubMed  Google Scholar 

  99. Schmidt LJ, Habacher W, Augustin T, et al. A systematic review and meta-analysis of the efficacy of lixisenatide in the treatment of patients with type 2 diabetes. Diabetes Obes Metab. 2014;16(9):769–79.

    CAS  PubMed  Google Scholar 

  100. Liu YH, Ruus P. Pharmacokinetics and safety of the GLP-1 agonist AVE0010 in patients with renal impairment. Diabetes. 2009; 58(Suppl 1):Abstract 557.

  101. Gómez-Huelgas R, Ambos A, Arteaga JM, et al. Lixisenatide is effective and well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes. 2014;63(Suppl 1):992.

    Google Scholar 

  102. Poole RM, Nowlan ML. Albiglutide: first global approval. Drugs. 2014;74(8):929–38.

    CAS  PubMed  Google Scholar 

  103. Young MA, Wald JA, Matthews JE, et al. Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide. Postgrad Med. 2014;126(3):35–46.

    PubMed  Google Scholar 

  104. Meyers JL, Candrilli SD, Kovacs B. Type 2 diabetes mellitus and renal impairment in a large outpatient electronic medical records database: rates of diagnosis and antihyperglycemic medication dose adjustment. Postgrad Med. 2011;123(3):133–43.

    PubMed  Google Scholar 

  105. McFarland MS, Markley BM, Zhang P, et al. Evaluation of modification of diet in renal disease study and Cockcroft–Gault equations for sitagliptin dosing. J Nephrol. 2012;25(4):515–22.

    CAS  PubMed  Google Scholar 

  106. Scheen AJ, Radermecker RP. Addition of incretin therapy to metformin in type 2 diabetes. Lancet. 2010;375(9724):1410–2.

    PubMed  Google Scholar 

  107. Fass AD, Gershman JA. Efficacy and safety of dipeptidyl peptidase-4 inhibitors in combination with metformin. Adv Ther. 2013;30(4):337–53.

    CAS  PubMed  Google Scholar 

  108. Scheen AJ. Pharmacokinetic and pharmacodynamic evaluation of sitagliptin plus metformin. Expert Opin Drug Metab Toxicol. 2010;6(10):1265–76.

    CAS  PubMed  Google Scholar 

  109. Halimi S, Schweizer A, Minic B, et al. Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet. Vasc Health Risk Manag. 2008;4(3):481–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Scheen AJ. Metformin + saxagliptin for type 2 diabetes. Expert Opin Pharmacother. 2012;13(1):139–46.

    CAS  PubMed  Google Scholar 

  111. Scheen AJ. Efficacy and safety of Jentadueto(R) (linagliptin plus metformin). Expert Opin Drug Saf. 2013;12(2):275–89.

    CAS  PubMed  Google Scholar 

  112. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34(6):1431–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Scheen AJ, Paquot N. Metformin revisited: a critical review of the benefit-risk balance in at-risk patients with type 2 diabetes. Diabetes Metab. 2013;39(3):179–90.

    CAS  PubMed  Google Scholar 

  114. 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.

    CAS  PubMed  Google Scholar 

  115. Van Gaal LF, Gutkin SW, Nauck MA. Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control? Eur J Endocrinol. 2008;158(6):773–84.

    PubMed  Google Scholar 

  116. Weise WJ, Sivanandy MS, Block CA, et al. Exenatide-associated ischemic renal failure. Diabetes Care. 2009;32(2):e22–3.

    PubMed  Google Scholar 

  117. Lopez-Ruiz A, del Peso-Gilsanz C, Meoro-Aviles A, et al. Acute renal failure when exenatide is co-administered with diuretics and angiotensin II blockers. Pharm World Sci. 2010;32(5):559–61.

    PubMed  Google Scholar 

  118. Johansen OE, Whitfield R. Exenatide may aggravate moderate diabetic renal impairment: a case report. Br J Clin Pharmacol. 2008;66(4):568–9.

    PubMed Central  PubMed  Google Scholar 

  119. Ferrer-Garcia JC, Martinez-Chanza N, Tolosa-Torrens M, et al. Exenatide and renal failure. Diabet Med. 2010;27(6):728–9.

    CAS  PubMed  Google Scholar 

  120. Nandakoban H, Furlong TJ, Flack JR. Acute tubulointerstitial nephritis following treatment with exenatide. Diabet Med. 2013;30(1):123–5.

    CAS  PubMed  Google Scholar 

  121. Dubois-Laforgue D, Boutboul D, Levy DJ, et al. Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists. Diabetes Res Clin Pract. 2014;103(3):e53–5.

    CAS  PubMed  Google Scholar 

  122. Kaakeh Y, Kanjee S, Boone K, et al. Liraglutide-induced acute kidney injury. Pharmacotherapy. 2012;32(1):e7–11.

    PubMed  Google Scholar 

  123. Gariani K, de Seigneux S, Moll S. Acute interstitial nephritis after treatment with liraglutide. Am J Kidney Dis. 2014;63(2):347.

    PubMed  Google Scholar 

  124. Pendergrass M, Fenton C, Haffner SM, et al. Exenatide and sitagliptin are not associated with increased risk of acute renal failure: a retrospective claims analysis. Diabetes Obes Metab. 2012;14(7):596–600.

    CAS  PubMed  Google Scholar 

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Funding and conflict of interest

No sources of funding were used to assist in the preparation of this manuscript. No conflicts of interest are directly relevant to the content of this manuscript.

A. J. Scheen has received lecture/advisor/clinical investigator fees from AstraZeneca/BMS, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Novartis, NovoNordisk, Sanofi-Aventis and Takeda.

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  1. Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium

    André J. Scheen

  2. Division of Diabetes Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman (B35), University of Liège, 4000, Liège, Belgium

    André J. Scheen

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  1. André J. Scheen
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Scheen, A.J. Pharmacokinetics and Clinical Use of Incretin-Based Therapies in Patients with Chronic Kidney Disease and Type 2 Diabetes. Clin Pharmacokinet 54, 1–21 (2015). https://doi.org/10.1007/s40262-014-0198-2

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