Safety and efficacy of linagliptin in type 2 diabetes patients with common renal and cardiovascular risk factors

Therapeutic Advances in Endocrinology and Metabolism

Volumn 4, Issue 3, 2013, Pages 95-105

  Gallwitz, Baptist ^a  

^a UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

cardiovascular risk; DPPP 4 inhibitors; incretin based therapies; linagliptin; oral antidiabetic drugs; renal impairment; type 2 diabetes

Indexed keywords

ALOGLIPTIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLIMEPIRIDE; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; HEMOGLOBIN A1C; INSULIN; LINAGLIPTIN; LINAGLIPTIN PLUS METFORMIN; METFORMIN; PIOGLITAZONE; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; SULFONYLUREA; VILDAGLIPTIN; VOGLIBOSE;

ADD ON THERAPY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CEREBROVASCULAR ACCIDENT; CHRONIC KIDNEY DISEASE; DIABETIC PATIENT; DRUG CONTRAINDICATION; DRUG EFFICACY; DRUG ELIMINATION; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG TREATMENT FAILURE; GLOMERULUS FILTRATION RATE; GLUCAGON RELEASE; HEPATOBILIARY SYSTEM; HUMAN; HYPOGLYCEMIA; INSULIN RELEASE; KIDNEY; KIDNEY FUNCTION; META ANALYSIS; MONOTHERAPY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; WEIGHT GAIN;

EID: 84878388020     PISSN: 20420188     EISSN: 20420196     Source Type: Journal    
DOI: 10.1177/2042018813486165     Document Type: Article

References (72)

1. Ahren B. Simonsson E. Larsson H. Landin-Olsson M. Torgeirsson H. Jansson P. et al (2002) Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 25: 869–875.
2. Amiel S. Dixon T. Mann R. Jameson K. (2008) Hypoglycaemia in type 2 diabetes. Diabetic Med 25, 245–254.
3. Ansar S. Koska J. Reaven P. (2011) Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovasc Diabetol 10: 61. DOI: 10.1186/1475-2840-10-61.
4. Bakris G. (2011) Recognition, pathogenesis and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc 86: 444–456.
5. Ban K. Hui S. Drucker D. Husain M. (2009) Cardiovascular consequences of drugs used for the treatment of diabetes: potential promise of incretin-based therapies. J Am Soc Hypertens 3: 245–259.
6. Ban K. Noyan-Ashraf M. Hoefer J. Bolz S. Drucker D. Husain M. (2008) Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117: 2340–2350.
7. Blech S. Ludwig-Schwellinger E. Grafe-Mody E. Withopf B. Wagner K. (2010) The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 38: 667–678.
8. Brownlee M. (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615–1625.
9. Chapelsky M. Thompson-Culkin K. Miller A. Sack M. Blum R. Freed M. (2003) Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin Pharmacol 43: 252–259.
10. Deacon C. Holst J. (2010) Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes. Expert Opin Investig Drugs 19: 133–140.
11. Deacon C. Hughes T. Holst J. (1998) Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes 47: 764–769.
12. Del Prato S. Barnett A. Huisman H. Neubacher D. Woerle H. Dugi K. (2011) Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab 13: 258–267.
13. Dicker D. (2011) DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care 34(Suppl. 2): S276–S278.
14. Dore D. Seeger J. Arnold C. (2009) Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin 25: 1019–1027.
15. Drucker D. Goldfine A. (2011) Cardiovascular safety and diabetes drug development. Lancet 377: 977–979.
16. Drucker D. Nauck M. (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368: 1696–1705.
17. Eckhardt M. Hauel N. Himmelsbach F. Langkopf E. Nar H. Mark M. et al (2008) 3,5-Dihydro-imidazo[4,5-d]pyridazin-4-ones: a class of potent DPP-4 inhibitors. Bioorg Med Chem Lett 18: 3158–3162.
18. Eeg-Olofsson K. Cederholm J. Nilsson P. Zethelius B. Nunez L. Gudbjornsdottir S. et al (2009) Risk of cardiovascular disease and mortality in overweight and obese patients with type 2 diabetes: an observational study in 13,087 patients. Diabetologia 52: 65–73.
19. Elashoff M. Matveyenko A. Gier B. Elashoff R. Butler P. (2011) Pancreatitis, pancreatic and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 141: 150–156.
20. Engel S. Williams-Herman D. Golm G. Clay R. Machotka S. Kaufman K. et al (2010) Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. Int J Clin Pract 64: 984–990.
21. Fadini G. Avogaro A. (2011) Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vascul Pharmacol 55: 10–16.
22. Frederich R. Alexander J. Fiedorek F. Donovan M. Berglind N. Harris S. et al (2010) A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 122: 16–27.
23. Friedrich C. Emser A. Woerle H. Graefe-Mody U. (2013) Renal impairment has no clinically relevant effect on the long-term exposure of linagliptin in patients with type 2 diabetes. Am J Ther. Epub ahead of print 13 February.
24. Fuchs H. Tillement J. Urien S. Greischel A. Roth W. (2009) Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans. J Pharm Pharmacol 61: 55–62.
25. Gallwitz B. (2007) Sitagliptin: profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes. Drugs Today 43: 13–25.
26. Gallwitz B. (2011) Small molecule dipeptidylpeptidase IV inhibitors under investigation for diabetes mellitus therapy. Expert Opin Investig Drugs 20:723–732.
27. Gallwitz B. (2013) Emerging DPP-4 inhibitors: focus on linagliptin for type 2 diabetes. Diabetes Metab Syndr Obes 6: 1–9.
28. Gallwitz B. Rosenstock J. Emser A. von Eynatten M. Woerle H. (2013) Linagliptin is more effective than glimepiride at achieving a composite outcome of target HbA1c < 7% with no hypoglycaemia and no weight gain over 2 years. Int J Clin Pract 67: 317–321.
29. Gallwitz B. Rosenstock J. Rauch T. Bhattacharya S. Patel S. von Eynatten M. et al (2012) 2-Year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet 380: 475–483.
30. Garg R. Chen W. Pendergrass M. (2010) Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care 33: 2349–2354.
31. Gomis R. Espadero R. Jones R. Woerle H. Dugi K. (2011) Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 13: 653–661.
32. Graefe-Mody E. Jungnik A. Ring A. Woerle H. Dugi K. (2010) Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers. Int J Clin Pharmacol Ther 48: 652–661.
33. Graefe-Mody U. Friedrich C. Port A. Ring A. Retlich S. Heise T. et al (2011) Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab 13: 939–946.
34. Haak T. Meinicke T. Jones R. Weber S. von Eynatten M. Woerle H. (2012) Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 14: 565–574.
35. Heise T. Graefe-Mody E. Huttner S. Ring A. Trommeshauser D. Dugi K. (2009) Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab 11: 786–794.
36. Hocher B. Sharkovska Y. Mark M. Klein T. Pfab T. (2012) The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats. Int J Cardiol. Epub ahead of print 2 January.
37. Huttner S. Graefe-Mody E. Withopf B. Ring A. Dugi K. (2008) Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J Clin Pharmacol 48: 1171–1178.
38. International Diabetes Federation (IDF) (2011) The global burden. In: Diabetes Atlas, 5th ed. Brussels: IDF. Available at http://www.idf.org/diabetesatlas/5e/the-global-burden.
39. Inzucchi S. Bergenstal R. Buse J. Diamant M. Ferrannini E. Nauck M. et al (2012) 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 55: 1577–1596.
40. Johansen O. Neubacher D. von Eynatten M. Patel S. Woerle H. (2012) Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol 11: 3. DOI: 10.1186/1475-2840-11-3.
41. Kawamori R. Inagaki N. Araki E. Watada H. Hayashi N. Horie Y. et al (2012) Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab 14: 348–357.
42. Kothny W. Shao Q. Groop P. Lukashevich V. (2012) One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment. Diabetes Obes Metab 14: 1032–1039.
43. Kroller-Schon S. Knorr M. Hausding M. Oelze M. Schuff A. Schell R. et al (2012) Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition. Cardiovasc Res 96: 140–149.
44. McGill J. Sloan L. Newman J. Patel S. Sauce C. von Eynatten M. et al (2013). 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 36: 237–244.
45. Meier J. (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 8: 728–742.
46. Mentlein R. (1999) Dipeptidyl-peptidase IV (CD26) – role in the inactivation of regulatory peptides. Regul Pept 85: 9–24.
47. Mentlein R. Gallwitz B. Schmidt W. (1993) Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214: 829–835.
48. Meyers J. Candrilli S. Kovacs B. (2011) 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 123: 133–143.
49. Monnier L. Lapinski H. Colette C. (2003) Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26: 881–885.
50. National Kidney Foundation (2012) KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 60: 850–886. Available at http://www.kidney.org/professionals/KDOQI/guidelines_diabetesUp/diabetes-ckd-update-2012.pdf (accessed 19 March 2013).
51. Nauck M. Heimesaat M. Orskov C. Holst J. Ebert R. Creutzfeldt W. (1993) Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91: 301–307.
52. Nikolaidis L. Mankad S. Sokos G. Miske G. Shah A. Elahi D. et al (2004) Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109: 962–965.
53. Nowicki M. Rychlik I. Haller H. Warren M. Suchower L. Gause-Nilsson I. et al (2011 a) 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 65: 1230–1239.
54. Nowicki M. Rychlik I. Haller H. Warren M. Suchower L. Gause-Nilsson I. (2011 b) Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes Obes Metab 13: 523–532.
55. Ohkubo Y. Kishikawa H. Araki E. Miyata T. Isami S. Motoyoshi S. et al (1995) Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 28: 103–117.
56. Owens D. Swallow R. Dugi K. Woerle H. (2011) Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabetic Med 28: 1352–1361.
57. Ritz E. (2011) Limitations and future treatment options in type 2 diabetes with renal impairment. Diabetes Care 34(Suppl. 2): S330–S334.
58. Schweizer A. Dejager S. Foley J. Couturier A. Ligueros-Saylan M. Kothny W. (2010) Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large phase III type 2 diabetes population. Diabetes Obes Metab 12: 485–494.
59. Selvin E. Bolen S. Yeh H. Wiley C. Wilson L. Marinopoulos S. et al (2008) Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 168: 2070–2080.
60. Shrishrimal K. Hart P. Michota F. (2009) Managing diabetes in hemodialysis patients: observations and recommendations. Cleveland Clin J Med 76: 649–655.
61. Singh S. Chang H. Richards T. Weiner J. Clark J. Segal J. (2013) Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med 173: 534–539.
62. Sokos G. Nikolaidis L. Mankad S. Elahi D. Shannon R. (2006) Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Failure 12: 694–699.
63. Taskinen M. Rosenstock J. Tamminen I. Kubiak R. Patel S. Dugi K. et al (2011) Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 13: 65–74.
64. Thomas L. Eckhardt M. Langkopf E. Tadayyon M. Himmelsbach F. Mark M. (2008) (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylm ethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 325: 175–182.
65. Tzoulaki I. Molokhia M. Curcin V. Little M. Millett C. Ng A. et al (2009) Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. Br Med J 339: b4731. DOI: 10.1136/bmj.b4731.
66. UK Prospective Diabetes Study (UKPDS) Group (1998 a) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352: 854–865.
67. UK Prospective Diabetes Study (UKPDS) Group (1998 b) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–853.
68. US Renal Data System (USRDS) (2009) Chapter 1. Chronic kidney disease in the adult NHANES population. In: USRDS 2009 Annual Data Report. Volume 1: Atlas of Chronic Kidney Disease in the United States. Bethesda MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, pp. 35–48. Available at http://www.usrds.org/atlas09.aspx (accessed 4 April 2013).
69. Ussher J. Drucker D. (2012) Cardiovascular biology of the incretin system. Endocr Rev 33: 187–215.
70. Verge D. Lopez X. (2010) Impact of GLP-1 and GLP-1 receptor agonists on cardiovascular risk factors in type 2 diabetes. Curr Diabetes Rev 6: 191–200.
71. Williams-Herman D. Engel S. Round E. Johnson J. Golm G. Guo H. et al (2010) Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord 10: 7.
72. Williams R. van Gaal L. Lucioni C. (2002) Assessing the impact of complications on the costs of type II diabetes. Diabetologia 45: S13–S17.