Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes.

Scheen, André

doi:10.1007/s40262-016-0498-9

Article (Scientific journals)

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes.

Scheen, André

2016 • In Clinical Pharmacokinetics

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/205970

DOI
10.1007/s40262-016-0498-9

PubMed
28039605

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Keywords :

Combined therapy; DPP-4 inhibitor; Fixed-dose combination; SGLT2 inhibitor; Type 2 diabetes

Abstract :

[en] Type 2 diabetes (T2D) generally requires a combination of several pharmacological approaches to control hyperglycaemia. Combining a sodium-glucose cotransporter type 2 inhibitor (SGLT2I, also known as gliflozin) and a dipeptidyl peptidase-4 inhibitor (DPP-4I, also known as gliptin) appears to be an attractive strategy because of complementary modes of action. This narrative review analyzes the pharmacokinetics and clinical efficacy of different combined therapies with an SGLT2I (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, tofogliflozin) and DPP-4I (linagliptin, saxagliptin, sitagliptin, teneligliptin). Drug-drug pharmacokinetic interaction studies do not show any significant changes in peak concentrations (C max) and total exposure (area under the curve of plasma concentrations [AUC]) of either drug when they were administered together orally compared with corresponding values when each of them was absorbed alone. Two fixed-dose combinations (FDCs) are already available (dapagliflozin-saxagliptin, empagliflozin-linagliptin) and others are in development (ertugliflozin-sitagliptin). Preliminary results show bioequivalence of the two medications administered as FDC tablets when compared with coadministration of the individual tablets. Dual therapy is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. SGLT2I and DPP-4I could be used as initial combination or in a stepwise approach. The additional glucose-lowering effect appears to be more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Combining the two pharmacological options is safe and does not induce hypoglycaemia.

Disciplines :

Pharmacy, pharmacology & toxicology
Endocrinology, metabolism & nutrition

Author, co-author :

Scheen, André ; Université de Liège > Département des sciences cliniques > Département des sciences cliniques

Language :

English

Title :

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes.

Publication date :

2016

Journal title :

Clinical Pharmacokinetics

ISSN :

0312-5963

eISSN :

1179-1926

Publisher :

Adis International, United Kingdom

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 26 January 2017

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Bibliography

Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429–42.
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22(1):84–113.
Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33–59.
Scheen AJ. SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Exp Opin Drug Safety. 2015;14(12):1879–904.
Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18(8):783–94.
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.
Scheen AJ. Diabetes: time for reconciliation between cardiologists and diabetologists. Nat Rev Cardiol. 2016;13(9):509–10.
Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016;42(2):71–6.
Sattar N, McLaren J, Kristensen SL, et al. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59(7):1333–9.
Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509–14.
Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.
Scheen AJ, Paquot N. Metabolic effects of SGLT2 inhibitors beyond increased glucosuria: a review of clinical evidence. Diabetes Metab. 2014;40(Suppl):S4–11.
Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849–52.
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38(9):1638–42.
Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37(19):1526–34.
Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Clin Pharmacokinet. 2015;54(7):691–708.
Scheen AJ. A review of gliptins for 2014. Exp Opin Pharmacother. 2015;16(1):43–62.
Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf. 2015;14(4):505–24.
Fiorentino TV, Sesti G. Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors. Endocrine. 2016;53(2):373–80.
Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2015;132(15):e198.
Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.
Standl E, Erbach M, Schnell O. Dipeptidyl-peptidase-4 inhibitors and heart failure: class effect, substance-specific effect, or chance effect? Curr Treat Options Cardiovasc Med. 2014;16(12):353.
Li L, Li S, Deng K, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610.
Paneni F. DPP-4 inhibitors, heart failure and type 2 diabetes: all eyes on safety. Cardiovasc Diag Ther. 2015;5(6):471–8.
Scheen AJ. Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes. Clin Pharmacokinet. 2015;54(1):1–21.
Scheen AJ. Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease. Expert Opin Drug Metab Toxicol. 2014;10(6):839–57.
Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010;12(8):648–58.
Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet. 2012;51(8):501–14.
Scheen AJ. DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol. 2016;12(12):1407–17.
Scheen AJ, Paquot N. Combinaison gliptine-gliflozine dans le traitement du diabète de type 2. Rev Med Suisse. 2016;12:1384–8.
Guthrie RM. Clinical use of dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in combination therapy for type 2 diabetes mellitus. Postgrad Med. 2015;127(5):463–79.
Sharma MD. Potential for combination of dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors for the treatment of type 2 diabetes. Diabetes Obes Metab. 2015;17(7):616–21.
Abdul-Ghani M. Where does combination therapy with an SGLT2 inhibitor plus a DPP-4 inhibitor fit in the management of type 2 diabetes? Diabetes Care. 2015;38(3):373–5.
Singh AK, Singh R. Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors combination therapy in type 2 diabetes: a systematic review of current evidence. Indian J Endocrinol Metab. 2016;20(2):245–53.
Aronson R. Single-pill combination therapy for type 2 diabetes mellitus: linagliptin plus empagliflozin. Curr Med Res Opin. 2015;31(5):901–11.
Woo V. Empagliflozin/linagliptin single-tablet combination: first-in-class treatment option. Int J Clin Pract. 2015;69(12):1427–37.
Scheen AJ. Drug–drug interactions with SGLT-2 inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes. Clin Pharmacokinet. 2014;53(4):295–304.
Scheen AJ. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol. 2014;10(5):647–63.
Scheen AJ. SGLT2 inhibitors: benefit/risk balance. Curr Diabetes Rep. 2016;16(10):92.
Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother. 2012;13(1):81–99.
Williams DM, Stephens JW. Combination therapy with saxagliptin and dapagliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2015;16(15):2373–9.
Vakkalagadda B, Vetter ML, Rana J, et al. Bioequivalence of saxagliptin/dapagliflozin fixed-dose combination tablets compared with coadministration of the individual tablets to healthy subjects. Pharmacol Res Perspect. 2015;3(6):e00201.
Boulton DW, Kasichayanula S, Keung CF, et al. Simultaneous oral therapeutic and intravenous (1)(4)C-microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin. Br J Clin Pharmacol. 2013;75(3):763–8.
Vakkalagadda B, Lubin S, Reynolds L, et al. Lack of a pharmacokinetic interaction between saxagliptin and dapagliflozin in healthy subjects: a randomized crossover study. Clin Ther. 2016;38(8):1890–9.
Hansen L, Iqbal N, Ekholm E, et al. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy. Endocr Pract. 2014;20(11):1187–97.
Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015;38(3):376–83.
Mathieu C, Ranetti AE, Li D, et al. Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38(11):2009–17.
Matthaei S, Catrinoiu D, Celinski A, et al. Randomized, double-blind trial of triple therapy with saxagliptin add-on to dapagliflozin plus metformin in patients with type 2 diabetes. Diabetes Care. 2015;38(11):2018–24.
Kim ES, Deeks ED. Empagliflozin/linagliptin: a review in type 2 diabetes. Drugs. 2015;75(13):1547–57.
Triplitt C, Solis-Herrera C, Cersosimo E, et al. Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus. Expert Opin Pharmacother. 2015;16(18):2819–33.
Tan X, Hu J. Empagliflozin/linagliptin: combination therapy in patients with type 2 diabetes. Ann Endocrinol (Paris). 2016;77(5):557–62.
Friedrich C, Metzmann K, Rose P, et al. A randomized, open-label, crossover study to evaluate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy male volunteers. Clin Ther. 2013;35(1):A33–42.
Lewin A, DeFronzo RA, Patel S, et al. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015;38(3):394–402.
DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38(3):384–93.
Tinahones FJ, Gallwitz B, Nordaby M, et al. Linagliptin (LINA) as add-on to empagliflozin (EMPA) and metformin in patients with type 2 diabetes (T2DM): two 24-week randomised, double-blind, parallel-group trials. Abstract presented at the 52nd annual meeting of the European Association for the Study of Diabetes; 12–16 September 2016, Munich.
Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74(7):807–24.
Kadowaki T, Marubayashi F, Yokota S, et al. Safety and efficacy of teneligliptin in Japanese patients with type 2 diabetes mellitus: a pooled analysis of two phase III clinical studies. Expert Opin Pharmacother. 2015;16(7):971–81.
Scott LJ. Teneligliptin: a review in type 2 diabetes. Clin Drug Investig. 2015;35(11):765–72.
Kinoshita S, Kondo K. Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin in Japanese healthy male volunteers. Expert Opin Drug Metab Toxicol. 2015;11(1):7–14.
Fulcher G, Matthews DR, Perkovic V, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82–91.
Plosker GL. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74(2):223–42.
Kasichayanula S, Liu X, Shyu WC, et al. Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects. Diabetes Obes Metab. 2011;13(1):47–54.
Jabbour SA, Hardy E, Sugg J, et al. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37(3):740–50.
Rodbard HW, Seufert J, Aggarwal N, et al. Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin. Diabetes Obes Metab. 2016;18(8):812–9.
Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: a 52-week open-label study. J Diabetes Investig. 2015;6(2):210–8.
Brand T, Macha S, Mattheus M, et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv Ther. 2012;29(10):889–99.
Kadokura T, Zhang W, Krauwinkel W, et al. Clinical pharmacokinetics and pharmacodynamics of the novel SGLT2 inhibitor ipragliflozin. Clin Pharmacokinet. 2014;53(11):975–88.
Smulders RA, Zhang W, Veltkamp SA, et al. No pharmacokinetic interaction between ipragliflozin and sitagliptin, pioglitazone, or glimepiride in healthy subjects. Diabetes Obes Metab. 2012;14(10):937–43.
Poole RM, Prossler JE. Tofogliflozin: first global approval. Drugs. 2014;74(8):939–44.
Kasahara N, Fukase H, Ohba Y, et al. A pharmacokinetic/pharmacodynamic drug–drug interaction study of tofogliflozin (a new SGLT2 inhibitor) and selected anti-type 2 diabetes mellitus drugs. Drug Res. 2016;66(2):74–81.
Tanizawa Y, Kaku K, Araki E, et al. Long-term safety and efficacy of tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, as monotherapy or in combination with other oral antidiabetic agents in Japanese patients with type 2 diabetes mellitus: multicenter, open-label, randomized controlled trials. Expert Opin Pharmacother. 2014;15(6):749–66.
Markham A, Elkinson S. Luseogliflozin: first global approval. Drugs. 2014;74(8):945–50.
Sasaki T, Seino Y, Fukatsu A, et al. Absence of drug–drug interactions between luseogliflozin, a sodium-glucose co-transporter-2 inhibitor, and various oral antidiabetic drugs in healthy Japanese males. Adv Ther. 2015;32(5):404–17.
Seino Y, Inagaki N, Haneda M, et al. Efficacy and safety of luseogliflozin added to various oral antidiabetic drugs in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2015;6(4):443–53.
Miao Z, Nucci G, Amin N, et al. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos. 2013;41(2):445–56.
Kumar V, Sahasrabudhe V, Matschke K, et al. Lack of a pharmacokinetic interaction between ertugliflozin and sitagliptin or metformin in healthy subjects [abstract]. Clin Pharmacol Ther. 2016;99:S47.
Eldor R, Pratley R, Golm G, et al. Effect of ertugliflozin plus sitagliptin on glycemic control vs. either treatment alone in subjects with T2DM inadequately controlled with metformin. Communication presented at the 76th scientific sessions of the American Diabetes Association Meeting [abstract no. 125-LB]; 10–14 June 2016, New Orleans.
Pratley R, Eldor R, Golm G, et al. Safety and efficacy of ertugliflozin plus sitagliptin versus either treatment alone in subjects with type 2 diabetes mellitus inadequately controlled with metformin: the VERTIS FACTORIAL trial. Communication presented at the 52nd meeting of the European Association for the Study of Diabetes [abstract 728]; 6–12 September 2016, Munich.
Lauring B, Eldor R, Liu J, et al. Efficacy and safety of ertugliflozin in subjects with type 2 diabetes mellitus inadequately controlled on the dual combination of metformin and sitagliptin: the VERTIS SITA2 trial. Oral presentation at the 52nd annual meeting of the European Association for the Study of Diabetes; 6–12 September 2016, Munich.