Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy
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The dipeptidyl peptidase 4 (DPP-4) inhibitors comprise a promising new class of agent for the management of type 2 diabetes. They possess a range of physiological effects associated with improved glycemic control including stimulation of glucose-dependent insulin secretion and suppression of glucagon secretion, and lower blood glucose levels through different, but potentially complementary, mechanisms to standard oral therapies. Linagliptin is the latest DPP-4 inhibitor to complete pivotal phase 3 trials. The data show that linagliptin provides significant, clinically meaningful and sustained improvements in glycemic control, with an incidence of adverse events similar to placebo and an excellent tolerability profile. In addition, linagliptin has been shown to be weight neutral and, importantly, there was no increased risk of hypoglycemia attributed to linagliptin use in monotherapy or combination therapy with metformin or pioglitazone. A unique characteristic of linagliptin that differentiates it from other members of the class is its primarily nonrenal route of excretion. The linagliptin phase 3 program included several hundred patients with type 2 diabetes and different stages of renal disease and the data suggest that the drug would not need dose adjustment, regardless of the degree of renal impairment. There is a particular need for safe and effective therapeutic agents that can be used when renal function declines. Linagliptin has recently been approved by the US Food and Drug Administration and may find a place in therapy as a treatment option for the significant number of patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.
KeywordsDPP-4 inhibitor glycemic control linagliptin renal impairment type 2 diabetes
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- 1.International Diabetes Federation. Diabetes Atlas. 4th edition. Available at: www.diabetesatlas.org. Accessed November 1, 2010.
- 2.Yorkshire & Humber Public Health Observatory. APHO diabetes prevalence model. Available at: www.yhpho.org.uk/resource/view.aspx?RID=81090. Accessed November, 2010.
- 5.Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-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 Experimental Therapeut. 2008;325:175–182.CrossRefGoogle Scholar
- 8.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;49:829–840.PubMedCrossRefGoogle Scholar
- 10.Graefe-Mody U, Friedrich C, Port A, et al. Linagliptin, a novel DPP-4 inhibitor: no need for dose adjustment in patients with renal impairment. Poster 822-P, European Association for the Study of Diabetes Annual Meeting, 20–24 September 2010, Stockholm, Sweden.Google Scholar
- 11.Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of MK-0431 (sitagliptin), a selective dipeptidyl-peptidase-IV (DPP-IV) inhibitor. Clin Pharmacol Therapeut. 2006;38:PII–46.Google Scholar
- 16.Owens DR, Swallow R, Woerle HJ, et al. Linagliptin improves glycaemic control in type 2 diabetes patients inadequately controlled by metformin and sulfonylurea without weight gain and low risk of hypoglycaemia. Poster 548-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.Google Scholar
- 17.Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, placebo controlled study. Diabetes Obes Metab. 2011;doi: 10.1111/j.1463-1326.2011.01391.x.Google Scholar
- 18.Lewin AJ, Arvay L, Liu D, et al. Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Poster 821-P, European Association for the Study of Diabetes Annual Meeting, 20–24 September 2010, Stockholm, Sweden.Google Scholar
- 19.Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy improves glycemic control in Japanese patients with T2DM over 12 weeks. Poster 696-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.Google Scholar
- 20.Kawamori R, Inagaki N, Araki E, et al. Linagliptin provides superior glycemic control compared to voglibose as monotherapy in Japanese patients with type 2 diabetes. Poster 632-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.Google Scholar
- 26.Shah P, Schumann DM, Ardestani A, et al. The DPP-4 inhibitor linagliptin restores β-cell function in human isolated islets. Poster 1742-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.Google Scholar
- 29.National Kidney Foundation. Diabetes and Chronic Kidney Disease; Stages 1–4. Available at: www.kidney.org/atoz/pdf/diabetes.pdf. Accessed November, 2010.
- 30.Tayside Diabetes MCN Handbook. Pharmalogical management of glycaemic control in people with type 2 diabetes. Available at: www.diabetes-healthnet.ac.uk/HandBook/TreatementsWithHypoAgents2.aspx. Accessed November 1, 2010.
- 31.US Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009.Google Scholar
- 36.National Institute for Health and Clinical Excellence (NICE). CG87 type 2 diabetes — newer agents (May 2009). Available at: www.nice.org.uk/nicemedia/live/12165/44318/44318.pdf. Accessed November 1, 2010.