Linagliptin – nový zástupce farmak s inkretinovým účinkem

Číslo: 4 / 2011 (Obsah)
Rubrika: Nová léčiva / Nové indikace
Obor: Diabetologie
Autoři: Prof. MUDr. Terezie Pelikánová, DrSc.
Autoři - působiště: Centrum diabetologie, Institut klinické a experimentální medicíny, Praha
Klíčová slova: linagliptin, gliptiny, diabetes mellitus, renální insuficience
Citace: 1 Pelikánová T, Bartoš V. Praktická diabetologie. 5th ed. Praha: Maxdorf, 2011. 2 Gallwitz B. Small molecule dipeptidylpeptidase IV inhibitors under investigation for diabetes mellitus therapy. Expert Opin Investig Drugs 2011;20:723–32. 3 Scott LJ. Linagliptin: in type 2 diabetes mellitus. Drugs 2011;71:611–24. 4 Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther 2011;28:447–59. 5 Thomas L, Eckhardt M, Langkopf E, et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazoli n-2-ylmethyl)-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 2008;325:175–82. 6 Retlich S, Duval V, Ring A, et al. Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg–10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects. Clin Pharmacokinet 2010;49:829–40. 7 Huttner S, Graefe-Mody EU, Withopf B, et al. 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 2008;48:1171–8. 8 Fuchs H, Tillement JP, Urien S, et al. 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 2009;61:55–62. 9 Retlich S, Duval V, Graefe-Mody U, et al. Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients. J Clin Pharmacol 2010;50:873–85. 10 Heise T, Graefe-Mody EU, Huttner S, et al. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab 2009;11:786–94. 11 Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, et al. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 2010;38:667–78. 12 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 Jun 15. [Epub ahead of print] 13 Del Prato S, Taskinen M-R, Owens D, et al. Efficacy and safety of linagliptin in patients with type 2 diabetes and poor glycemic control. Diabetes 2011;60:1067-P. 14 Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomised controlled trial. Diabetes Obes Metab 2011;13:258–67. 15 Taskinen MR, Rosenstock J, Tamminen I, et al. 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 2010;13:65–74. 16 Forst T, Uhlig-Laske B, Ring A, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet Med 2010;27:1409–19. 17 Haak T, Meinicke T, Jones R, et al. Combination of linagliptin and metformin improves glycemic control in type 2 diabetes: a randomized trial with an open-label arm in patients with poor glycemic control. Diabetes 2011;60:279-OR. 18 Lewin A, Arvay L, Liu D, et.al. Safety and efficacy of linagliptin as add-on therapy to sulphonylurea in inadequately coltrolled type 2 diabetes. Diabetologia 2010;53:821-P. 19 Gomis R, Espadero RM, Jones R, et al. 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 2011;13:653–61. 20 Owens D, Swallow R, Woerle HJ. Linagliptin improves glycaemic control in type 2 diabetes patients inadequately controlled by metformin and sulpholnylurea without weight gain and low risk of hypoglycaemia. Diabetes 2010;59:548-P. 21 Gallwitz B, Uhlig-Laske B, Bhattacharaya S, et al. Linagliptin has similar efficacy to glimepiride but improved cardiovascular safety over 2 years in patients with type 2 diabetes inadequately controlled on metformin. Diabetes 2011;60:39–LB. 22 Jelsing J, Vrang N, Mark M, et al. The DPP-4 inhibitor linagliptin delays onset of diabetes and preserves beta-cell function in non-obese diabetic NOD mice. Diabetes 2011;60:1123-P. 23 Cooper M, Eynatten MV, Emser A, et al. Efficacy and safety of linagliptin in patients with type 2 diabetes with or without renal impairment: results from a global phase 3 program. Diabetes 2011;60:1068-P. 24 Sloan L, Newman J, Sauce C, et al. Safety and efficacy of linagliptin in type 2 diabetes patients with severe renal impairment. Diabetes 2011;60:413-P. 25 Groop PH, Eynatten Mv, Emser A, et al. Efficacy and safety of linagliptin in type 2 diabetes patients at high risk of renal complications: results from a large phase 3 program. Diabetes 2011;60:2274-PO. 26 Friedrich C, Emser A, Woerle HJ, et al. Renal impairment has no relevant effect on long-term exposure of linagliptin in patients with type 2 diabetes mellitus. Diabetes 2011;60:1105-P. 27 Barnett AH, Tahrani AA, Eynatten MV, et al. The novel dpp-4 inhibitor linagliptin is associated with a very low risk of hypoglycemia: results from a large phase III program. Diabetes 2011;60:2346-PO. 28 Johansen O-E, Neubacher D, Eynatten M, et al. Cardiovascular risk with linagliptin in patients with type 2 diabetes: a prespecified, prospective, and adjudicated meta-analysis from a large phase III program. Diabetes 2011;60:30-LB. 29 Rosenstock J, Marx N, Kahn SE, et al. Rationale and design of the CAROLINA trial: an active comparator CARdiovascular Outcome study of the DPP-4 Inhibitor LINAgliptin in patients with type 2 diabetes at high cardiovascular risk. Diabetes 2011;60:1103-P. 30 ČDS. Česká diabetologická společnost. Doporučený postup péče o diabetes mellitus 2. typu – 2011 (www.diab.cz). 31 Standards of medical care in diabetes – 2011. Diabetes Care 2011;34(Suppl 1):S11–61. 32 Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203. 33 Bouček P, Kvapil M, Monhart V, et al. Doporučené postupy při diabetickém onemocnění ledvin 2011. Společná doporučení České diabetologické společnosti ČLS JEP a České nefrologické společnosti. 2011: www.diab.cz.

Souhrn

Linagliptin je novým zástupcem farmak ze skupiny gliptinů – látek s antidiabetickým účinkem, jejichž mechanismus účinku spočívá v blokádě dipeptidylpeptidázy-4 (DPP-4). Chemickým složením se liší od ostatních registrovaných gliptinů, a tato odlišnost má i farmakologické dopady. Jeho molekula je odvozena od molekuly xantinu a je eliminován převážně jinou cestou než ledvinami. Má příznivý farmakologický profil. Je vysoce selektivním inhibitorem DPP-4 s vysokou účinností a více než 80% inhibicí enzymu v trvání 24 hodin po perorálním podání. Linagliptin zvyšuje sekreci inzulinu a potlačuje sekreci glukagonu v závislosti na výši glykemie. V současné době byly ukončeny studie III. fáze klinického hodnocení, v nichž byl linagliptin podáván více než 6 000 nemocných. V nich byl doložen jeho příznivý účinek na zlepšení kompenzace diabetu (pokles HbA1c o cca 0,5–0,8 %, snížení glykemie nalačno i postprandiálně), srovnatelný s účinkem dalších registrovaných gliptinů, a příznivý bezpečnostní profil, srovnatelný s placebem. Linagliptin neovlivňuje hmotnost a – stejně jako je tomu u ostatních gliptinů – není spojen s rizikem hypoglykemie, pokud je podáván v monoterapii nebo v kombinaci s metforminem či pioglitazonem. Účinnost a bezpečnost linagliptinu byla ověřena v klinických studiích, v nichž byl linagliptin použit v monoterapii nebo byl přidán (add-on) do kombinace k léčbě metforminem, deriváty sulfonylurey (DSU) či pioglitazonem nebo ke dvojkombinaci metformin a DSU či metformin a pioglitazon. Unikátní vlastností linagliptinu je převážně extrarenální cesta jeho vylučování, která umožňuje podávat jej bez snížení dávky nemocným ve všech fázích renální insuficience, včetně terminálního stadia s glomerulární filtrací pod 0,25 ml/s. „

Literatura

1 Pelikánová T, Bartoš V. Praktická diabetologie. 5th ed. Praha: Maxdorf, 2011. 2 Gallwitz B. Small molecule dipeptidylpeptidase IV inhibitors under investigation for diabetes mellitus therapy. Expert Opin Investig Drugs 2011;20:723–32. 3 Scott LJ. Linagliptin: in type 2 diabetes mellitus. Drugs 2011;71:611–24. 4 Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther 2011;28:447–59. 5 Thomas L, Eckhardt M, Langkopf E, et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazoli n-2-ylmethyl)-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 2008;325:175–82. 6 Retlich S, Duval V, Ring A, et al. Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg–10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects. Clin Pharmacokinet 2010;49:829–40. 7 Huttner S, Graefe-Mody EU, Withopf B, et al. 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 2008;48:1171–8. 8 Fuchs H, Tillement JP, Urien S, et al. 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 2009;61:55–62. 9 Retlich S, Duval V, Graefe-Mody U, et al. Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients. J Clin Pharmacol 2010;50:873–85.
10
Heise T, Graefe-Mody EU, Huttner S, et al. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab 2009;11:786–94.
11
Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, et al. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 2010;38:667–78.
12
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 Jun 15. [Epub ahead of print]
13
Del Prato S, Taskinen M-R, Owens D, et al. Efficacy and safety of linagliptin in patients with type 2 diabetes and poor glycemic control. Diabetes 2011;60:1067-P.
14
Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomised controlled trial. Diabetes Obes Metab 2011;13:258–67.
15
Taskinen MR, Rosenstock J, Tamminen I, et al. 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 2010;13:65–74.
16
Forst T, Uhlig-Laske B, Ring A, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet Med 2010;27:1409–19.
17
Haak T, Meinicke T, Jones R, et al. Combination of linagliptin and metformin improves glycemic control in type 2 diabetes: a randomized trial with an open-label arm in patients with poor glycemic control. Diabetes 2011;60:279-OR.
18
Lewin A, Arvay L, Liu D, et.al. Safety and efficacy of linagliptin as add-on therapy to sulphonylurea in inadequately coltrolled type 2 diabetes. Diabetologia 2010;53:821-P.
19
Gomis R, Espadero RM, Jones R, et al. 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 2011;13:653–61.
20
Owens D, Swallow R, Woerle HJ. Linagliptin improves glycaemic control in type 2 diabetes patients inadequately controlled by metformin and sulpholnylurea without weight gain and low risk of hypoglycaemia. Diabetes 2010;59:548-P.
21
Gallwitz B, Uhlig-Laske B, Bhattacharaya S, et al. Linagliptin has similar efficacy to glimepiride but improved cardiovascular safety over 2 years in patients with type 2 diabetes inadequately controlled on metformin. Diabetes 2011;60:39–LB.
22
Jelsing J, Vrang N, Mark M, et al. The DPP-4 inhibitor linagliptin delays onset of diabetes and preserves beta-cell function in non-obese diabetic NOD mice. Diabetes 2011;60:1123-P.
23
Cooper M, Eynatten MV, Emser A, et al. Efficacy and safety of linagliptin in patients with type 2 diabetes with or without renal impairment: results from a global phase 3 program. Diabetes 2011;60:1068-P.
24
Sloan L, Newman J, Sauce C, et al. Safety and efficacy of linagliptin in type 2 diabetes patients with severe renal impairment. Diabetes 2011;60:413-P.
25
Groop PH, Eynatten Mv, Emser A, et al. Efficacy and safety of linagliptin in type 2 diabetes patients at high risk of renal complications: results from a large phase 3 program. Diabetes 2011;60:2274-PO.
26
Friedrich C, Emser A, Woerle HJ, et al. Renal impairment has no relevant effect on long-term exposure of linagliptin in patients with type 2 diabetes mellitus. Diabetes 2011;60:1105-P.
27
Barnett AH, Tahrani AA, Eynatten MV, et al. The novel dpp-4 inhibitor linagliptin is associated with a very low risk of hypoglycemia: results from a large phase III program. Diabetes 2011;60:2346-PO.
28
Johansen O-E, Neubacher D, Eynatten M, et al. Cardiovascular risk with linagliptin in patients with type 2 diabetes: a prespecified, prospective, and adjudicated meta-analysis from a large phase III program. Diabetes 2011;60:30-LB.
29
Rosenstock J, Marx N, Kahn SE, et al. Rationale and design of the CAROLINA trial: an active comparator CARdiovascular Outcome study of the DPP-4 Inhibitor LINAgliptin in patients with type 2 diabetes at high cardiovascular risk. Diabetes 2011;60:1103-P.
30
ČDS. Česká diabetologická společnost. Doporučený postup péče o diabetes mellitus 2. typu – 2011 (www.diab.cz).
31
Standards of medical care in diabetes – 2011. Diabetes Care 2011;34(Suppl 1):S11–61.
32
Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203.
33
Bouček P, Kvapil M, Monhart V, et al. Doporučené postupy při diabetickém onemocnění ledvin 2011. Společná doporučení České diabetologické společnosti ČLS JEP a České nefrologické společnosti. 2011: www.diab.cz.

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