Teneligliptin: a review on cardio-renal safety
Keywords:Teneligliptin, Dipeptidyl peptidase-4 (DPP4) inhibitors, cardiovascular safety, Renal safety, Type 2 diabetes mellitus
Type 2 diabetes mellitus (T2DM) is a well-known risk factor for cardiovascular disease and chronic kidney disease (CKD). Various drugs including DPP4 inhibitors with different pharmacologic profile are being used in patients with type 2 diabetes for improving glycaemic control. Cardiovascular (CV) safety is one of the important aspects while selecting the glucose lowering therapies. In addition, DPP-4 inhibitors differ in their mode of excretion and degree of accumulation, which require dose/frequency modification in patients with impaired renal function. Therefore, understanding the cardio-renal safety profile of DPP4 inhibitors is of great importance. Teneligliptin is a DPP4 inhibitor, approved recently for the management of type 2 diabetes mellitus. The purpose of the present review is to integrate published literature and evaluate the cardio-renal safety of teneligliptin in type 2 diabetic patients. As per the available evidence, teneligliptin has apparently positive effects on CV safety markers like no QT prolongation at clinically relevant dose, small but significant improvement in left ventricular (LV) function, improvement in adiponectin levels and improvement in endothelial dysfunction. These findings support the cardiovascular safety of teneligliptin in T2DM patients. Dual route of excretion makes teneligliptin suitable (no dose adjustment required) for T2DM patients with renal failure. Available clinical evidence suggests that teneligliptin exerts cardiovascular safety in T2DM patients. This drug can be used in T2DM patients with CKD including end stage renal disease patients without any major safety concern.
International diabetes federation. IDF Diabetes Atlas, 7th edn. Brussels, Belgium: international diabetes federation, 2015.
Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes. 2008;26(2):77-82.
Mak KH, Moliterno DJ, Granger CB, Miller DP, White HD, Wilcox RG et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries. J Am Coll Cardiol. 1997;30(1):171-9.
Lind M, Garcia-Rodriguez LA, Booth GL, Cea-Soriano L, Shah BR, Ekeroth G et al. Mortality trends in patients with and without diabetes in Ontario, Canada and the UK from 1996 to 2009: a population-based study. Diabetologia. 2013;56(12):2601-8.
Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-12.
Guidance for industry diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed on 24 Dec 2015.
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.
Goda M, Kadowaki T. Teneligliptin for the treatment of type 2 diabetes. Drugs Today Barc Spain, 1998. 2013;49(10):615-29.
List of approved drug from 01-01-2015 to 31-01-2015, central drugs standard control organization. http://www.cdsco.nic.in/forms/list.aspx?lid=2034&Id=11. Accessed on 24 Dec 2015.
Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology. 1996;137(7):2968-78.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26.
Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in examine: a multicentre, randomized, double-blind trial. Lancet Lond Engl. 2015;385(9982):2067-76.
Costante R, Stefanucci A, Carradori S, Novellino E, Mollica A. DPP-4 inhibitors: a patent review (2012 - 2014). Expert Opin Ther Pat. 2015;25(2):209-36.
Davis TME. Dipeptidyl peptidase-4 inhibitors: pharmacokinetics, efficacy, tolerability and safety in renal impairment. Diabetes Obes Metab. 2014;16(10):891-9.
Cosson S, Kevorkian JP. Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab. 2003;29(5):455-66.
Monji A, Mitsui T, Bando YK, Aoyama M, Shigeta T, Murohara T. Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol Heart Circ Physiol. 2013;305(3):H295-304.
Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the life link database. Diabetes Care. 2011;34(1):90-5.
Hashikata T, Yamaoka-Tojo M, Kakizaki R, Nemoto T, Fujiyoshi K, Namba S et al. Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes. Heart Vessels. 2015 Aug 13. DOI 10.1007/s00380-015-0724-7.
Kutoh E, Hirate M, Ikeno Y. Teneligliptin as an initial therapy for newly diagnosed, drug naive subjects with type 2 diabetes. J Clin Med Res. 2014; 6(4):287-94.
Eto T, Inoue S, Kadowaki T. Effects of once-daily teneligliptin on 24-h blood glucose control and safety in Japanese patients with type 2 diabetes mellitus: a 4-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2012;14(11):1040-6.
Kim MK, Rhee EJ, Han KA, Woo AC, Lee M-K, Ku BJ, et al. Efficacy and safety of teneligliptin, a dipeptidyl peptidase-4 inhibitor, combined with metformin in Korean patients with type 2 diabetes mellitus: a 16-week, randomized, double-blind, placebo-controlled phase III trial. Diabetes Obes Metab. 2015;17(3):309-12.
Kadowaki T, Kondo K. Efficacy and safety of teneligliptin added to glimepiride in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study with an open-label, long-term extension. Diabetes Obes Metab. 2014;16(5):418-25.
Kadowaki T, Kondo K. Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2013;4(6):576-84.
Tanaka S, Suzuki K, Aoki C, Niitani M, Kato K, Tomotsune T et al. Add-on treatment with teneligliptin ameliorates glucose fluctuations and improves glycemic control index in Japanese patients with type 2 diabetes on insulin therapy. Diabetes Technol Ther. 2014;16(12):840-5.
van Noord C, Eijgelsheim M, Stricker BHC. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010;70(1):16-23.
Bloomfield DM, Krishna R, Hreniuk D, Hickey L, Ghosh K, Bergman AJ et al. A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects. J Clin Pharmacol. 2009;49(8):937-46.
Shubrook J, Colucci R, Guo A, Schwartz F. Saxagliptin: a selective dpp-4 inhibitor for the treatment of type 2 diabetes mellitus. Clin Med Insights Endocrinol Diabetes. 2011;4:1-12.
Ring A, Port A, Graefe-Mody EU, Revollo I, Iovino M, Dugi KA. The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses. Br J Clin Pharmacol. 2011;72(1):39-50.
He Y-L, Zhang Y, Serra D, Wang Y, Ligueros-Saylan M, Dole WP. Thorough QT study of the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor, on cardiac repolarization and conduction in healthy volunteers. Curr Med Res Opin. 2011;27(7):1453-63.
PMDA report on the deliberation results on tenalia (Teneligliptin): English version;2012. Available at https://www.pmda.go.jp/files/000153594.pdf Accessed on 24 Dec 2015.
Kishimoto M. Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes. Diabetes Metab Syndr Obes Targets Ther. 2013;6:187-95.
National cerebral and cardiovascular center. Teneligliptin on the progressive left ventricular diastolic dysfunction with type 2 diabetes mellitus study - clinicaltrials.gov NCT02449330. https://clinicaltrials.gov/ct2/show/NCT02449330?term=TOPLEVEL&rank=1. Accessed on 24 Dec 2015.
Abe M, Okada K. DPP-4 inhibitors in diabetic patients with chronic kidney disease and end-stage kidney disease on dialysis in clinical practice. Contrib Nephrol. 2015;185:98-115.
Nakamaru Y, Hayashi Y, Ikegawa R, Kinoshita S, Perez Madera B, Gunput D et al. Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans. Xenobiotica Fate Foreign Compd Biol Syst. 2014;44(3):242-53.
Halabi A, Maatouk H, Siegler KE, Faisst N, Lufft V, Klause N. Pharmacokinetics of teneligliptin in subjects with renal impairment: clinical pharmacology in drug development. Clin Pharmacol Drug Dev. 2013;2(3):246-54.
Graefe-Mody U, Friedrich C, Port A, Ring A, Retlich S, Heise T et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab. 2011;13(10):939-46.
Otsuki H, Kosaka T, Nakamura K, Shimomura F, Kuwahara Y, Tsukamoto T. Safety and efficacy of teneligliptin: a novel DPP-4 inhibitor for hemodialysis patients with type 2 diabetes. Int Urol Nephrol. 2014;46(2):427-32.