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2型糖尿病治療薬SGLT2阻害薬の薬理作用メカニズムに関するモデリング＆シミュレーションを用いた定量的研究

穴井, 和美 筑波大学 DOI:10.15068/0002000848

2021.08.02

概要

世界の糖尿病人口は増加の一途をたどっており、国際糖尿病連合（IDF）の報告によると、2019年現在で約 4億6300 万人と推定されている[1].糖尿病とは、インスリン作用不足による慢性の高血糖状態を主徴とする代謝疾患群であり、その成因により1型、2型、その他の特定の機序・疾患によるもの、妊娠糖尿病に分類される[2].その中で、全糖尿病患者の90%以上を占める2型糖尿病は、インスリン分泌低下やインスリン抵抗性をきたす遺伝的素因に、過食、運動不足、肥満など種々の環境因子や後天的身体要因が加わって発症すると考えられている.インスリン非依存状態の2型糖尿病では、まず食事・運動療法による治療が行われるが、それでも代謝コントロールが不十分な場合には、薬物療法が開始される.

糖尿病治療薬には注射薬から経口薬まで様々な種類が存在する.糖尿病の治療薬として最初に登場したのはインスリン注射であるが、その後は使いやすさ等から、インスリン分泌促進薬（スルホニル尿素薬やグリニド薬）、インスリン抵抗性改善薬（ビグアナイド薬、チアゾリジン薬）、小腸糖吸収抑制薬（α-グルコシダーゼ薬）といった経口血糖降下薬が次々に開発された.近年では、インスリン分泌を促進する消化管ホルモンであるインクレチン（グルカゴン様ペプチド（GLP）-1、グルコース依存性インスリン分泌刺激ポリペプチド（GIP））の分解を抑制するdipeptidyl peptidase (DPP) IV 阻害薬やGLP-1受容体作動薬が使用可能となり、従来薬と比べて低血糖を起こしにくいため広く使用されている.そして2014年に、腎臓をターゲットとした新規作用機序を有する、インスリン非依存性の経口糖尿病治療薬 Sodium-dependent glucose cotransporter (SGLT) 2 阻害薬がわが国で上市された.

経口摂取された炭水化物は、主にグルコースに消化され、小腸で吸収されて血液中に移行し、脳や筋肉などの末梢組織に取り込まれてエネルギー源として利用される.血液循環により腎臓に運ばれてきたグルコースは、糸球体で100%ろ過されるが、ろ過後、ほぼすべてのグルコースが近位尿細管で再吸収され、健康成人では尿糖は認められない.グルコースはほぼすべての細胞にとって必須なエネルギー源であるが、親水性化合物であるために、細胞への取り込みや輸送にはトランスポーターを必要とする[3, 4].SGLTは糖輸送を担う重要なトランスポーターであり、Na+の細胞内外の濃度差を駆動力として、濃度勾配に逆らい糖を輸送することが出来る.SGLTにはSGLT1‒SGLT6のサブタイプが存在するが[3, 4]、中でもSGLT2及びSGLT1の研究が数多くなされ、その生理的な役割が明らかとなっている.SGLT2は腎の近位尿細管 segment 1（S-1）およびsegment 2（S-2）の管腔側刷子縁膜に局在しており[5]、グルコースに対し低親和性であるが高い輸送能力を持ち、健康成人においては、糸球体でろ過されたグルコースの約 90%を再吸収して血液中に戻す役割を担っている[5, 6].一方、SGLT1は近位尿細管 segment 3（S-3）の管腔側に発現し、輸送能力は低いが高親和性であるため、健康成人においては上流に存在するSGLT2で再吸収されなかった原尿中の約 10%の尿糖再吸収を担っている.SGLT1は他にも小腸上皮細胞、気管、心臓などに発現しており、小腸ではグルコース吸収において重要な役割を担うことが良く知られている[5-7].

SGLT2 阻害薬は、SGLT2を阻害して糖の再吸収を抑制し、尿糖排泄を促進することにより、高血糖を改善する（Figure 1）[8].SGLT2 阻害薬以外の全ての抗糖尿病薬による治療では、血糖値を低下させた結果、尿糖は減少することを考えると、SGLT2 阻害薬の薬理作用は画期的であるといえる.現在、わが国では6成分7 製剤のSGLT2 阻害薬が上市されており、薬剤によりSGLTsに対する選択性や薬物動態等が異なる（Table 1）.また、インスリンに依存しないメカニズムであるため、低血糖を起こしにくく、他の糖尿病治療薬と併用される場面も多い.このような状況下で、薬剤の特徴や薬効メカニズムの理解につながる情報を広く提供し共有することは、薬剤の適正使用のために重要である.

近年はコンピューターの発達に伴いモデリング&シミュレーション（M&S）手法の発達が目覚ましく、複雑な生体内の現象を数理学的モデルで記述し、シミュレーションすることが可能となってきた.医薬品の開発過程においても、in vitro試験や非臨床・臨床試験等で取得される様々な情報やデータに基づいてモデルを構築することにより、例えば単回投与から反復投与、健康成人から患者の薬物動態あるいは薬理作用の予測が可能となる.ヒト生体内の生理学的現象や薬剤等のエビデンスに対する説明や理解のために、生理学的因子を加味した薬物動態及び薬理学的モデルを適切に構築し、必要な情報を取得していくことは、病態の新たな理解や薬効メカニズムの解明、適切な薬剤の種類・用法用量の選択等を可能にし、薬剤の適正使用推進につながる.

本研究では、SGLT2 阻害薬の一つであるカナグリフロジンに対して、臨床現場から挙がってきた複数のクリニカルクエスチョン（CQ）について、薬物動態及び薬理学的モデルを駆使した定量的解析による回答を得ることにより、SGLT2阻害薬の薬理メカニズムの理解ならびに薬剤の適正使用につなげることを目的とし、第 2 章でSGLT2 阻害薬の腎における薬理作用メカニズムについて、第 3章でSGLT2 阻害薬の主に小腸における薬理作用メカニズムについて、M&Sの手法を用いた検討を行った.

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参考文献

1. IDF diabetes atlas 9th edition [Internet]. International Diabetes Federation. Available from: https://www.diabetesatlas.org/.

2. 日本糖尿病学会編．糖尿病治療ガイド 2020-2021．文光堂.

3. Mather A, Pollock C. Glucose handling by the kidney. Kidney Int. Suppl. 2011(120):S1-6.

4. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol. Rev. 2011;91(2):733-794.

5. Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radovic N, Jadrijevic S, Aleksic I, Walles T, Sauvant C, Sabolic I, Koepsell H. Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch. 2015;467(9):1881-1898.

6. Chen LH, Leung PS. Inhibition of the sodium glucose co-transporter-2: Its beneficial action and potential combination therapy for type 2 diabetes mellitus. Diabetes Obes. Metab. 2013;15(5):392-402.

7. Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, Veyhl-Wichmann M, Srinivasan A, Balen D, Breljak D, Rexhepaj R, Parker HE, Gribble FM, Reimann F, Lang F, Wiese S, Sabolic I, Sendtner M, Koepsell H. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61(1):187-196.

8. Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: Effects on renal and intestinal glucose transport: From bench to bedside. Diabetes Care. 2015;38(12):2344-2353.

9. カナグル総合製品情報概要 [Internet]. Available from: https://medical.mt- pharma.co.jp/intro/can/pdf/mtpc-can-all.pdf.

10. Interview form of canagliflozin [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. [cited 3 September 2014]. Available from: https://www.info.pmda.go.jp/go/interview/1/400315_3969022F1029_1_090_1F.

11. Interview form of dapagliflozin [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. [cited 24 April 2015]. Available from: https://www.info.pmda.go.jp/go/interview/2/670227_3969019F1027_2_091_1F. pdf.

12. Interview form of ipragliflozin [Internet]. [cited 14 Novemver 2017]. Available from: https://www.info.pmda.go.jp/go/interview/1/800126_3969018F1022_1_011_1F. pdf.

13. Interview form of empagliflozin [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. [cited 14 Novemver 2017]. Available from: https://www.info.pmda.go.jp/go/interview/1/650168_3969023F1023_1_207_1F. pdf.

14. Interview form of tofogliflozin [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. [cited 10 Novemver 2020]. Available from: https://www.info.pmda.go.jp/go/interview/2/270072_3969021F1024_2_002_1F. pdf.

15. Interview form of luceogliflozin [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. [cited 10 Novemver 2020]. Available from: https://www.info.pmda.go.jp/go/interview/2/400059_3969020F1020_2_012_1F. pdf.

16. Ohgaki R, Wei L, Yamada K, Hara T, Kuriyama C, Okuda S, Ueta K, Shiotani M, Nagamori S, Kanai Y. Interaction of the sodium/glucose cotransporter (SGLT) 2 inhibitor canagliflozin with SGLT1 and SGLT2. J. Pharmacol. Exp. Ther. 2016;358(1):94-102.

17. Cangoz S, Chang YY, Chempakaseril SJ, Guduru RC, Huynh LM, John JS, John ST, Joseph ME, Judge R, Kimmey R, Kudratov K, Lee PJ, Madhani IC, Shim PJ, Singh S, Singh S, Ruchalski C, Raffa RB. The kidney as a new target for antidiabetic drugs: SGLT2 inhibitors. J. Clin. Pharm. Ther. 2013;38(5):350-359.

18. Lu Y, Griffen SC, Boulton DW, Leil TA. Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans. Front. Pharmacol. 2014;5:274.

19. New drugs approved in FY 2014 [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. 2014 [cited 17 December 2014]. Available from: https://www.pmda.go.jp/drugs/2014/P201400070/index.html.

20. New drugs approved in FY2013 [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. 2013 [cited 24 April 2015]. Available from: https://www.pmda.go.jp/drugs/2014/P201400016/index.html.

21. Jamei M, Turner D, Yang J, Neuhoff S, Polak S, Rostami-Hodjegan A, Tucker G. Population-based mechanistic prediction of oral drug absorption. AAPS J. 2009;11(2):225-237.

22. Hsu V, de LTVM, Zhao P, Zhang L, Zheng JH, Nordmark A, Berglund EG, Giacomini KM, Huang SM. Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations. Clin. Pharmacokinet. 2014;53(3):283-293.

23. Neuhoff S, Gaohua L, Burt H, Jamei M, Li L, Tucker G, Rostami-Hodjegan A. Accounting for transporters in renal clearance: Towards a mechanistic kidney model (Mech KiM). Sugiyama Y, Steffansen B, editors: Springer New York; 2013. 155-177 p.

24. Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: Predicting the tissue distribution of moderate-to-strong bases. J. Pharm. Sci. 2005;94(6):1259-1276.

25. Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J. Pharm. Sci. 2006;95(6):1238-1257.

26. Kuriyama C, Xu JZ, Lee SP, Qi J, Kimata H, Kakimoto T, Nakayama K, Watanabe Y, Taniuchi N, Hikida K, Matsushita Y, Arakawa K, Saito A, Ueta K, Shiotani M. Analysis of the effect of canagliflozin on renal glucose reabsorption and progression of hyperglycemia in Zucker diabetic fatty rats. J. Pharmacol. Exp. Ther. 2014;351(2):423-431.

27. Hummel CS, Lu C, Loo DD, Hirayama BA, Voss AA, Wright EM. Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am. J. Physiol. Cell Physiol. 2011;300(1):C14-21.

28. Polidori D, Sha S, Ghosh A, Plum-Morschel L, Heise T, Rothenberg P. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 2013;98(5):E867-871.

29. DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, Morrow LA, Leslie BR, Boulton DW, Ching A, LaCreta FP, Griffen SC. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013;36(10):3169-3176.

30. Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 1973;22(23):3099-3108.

31. Sarai N, Matsuoka S, Noma A. Simbio: A java package for the development of detailed cell models. Prog. Biophys. Mol. Biol. 2006;90(1-3):360-377.

32. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata diabetes study. Diabetes Care. 1999;22(6):920-924.

33. Nakagami T, Group DS. Hyperglycaemia and mortality from all causes and from cardiovascular disease in five populations of Asian origin. Diabetologia. 2004;47(3):385-394.

34. Polidori D, Sha S, Mudaliar S, Ciaraldi TP, Ghosh A, Vaccaro N, Farrell K, Rothenberg P, Henry RR. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: Results of a randomized, placebo-controlled study. Diabetes Care. 2013;36(8):2154-2161.

35. Noda T, Ebihara E, Ueno H, Sadohara K, Tanaka Y, Nagatomo Y, Murakami Y, Yonamine S, Tsuchimochi W, Sakoda H, Yamaguchi H, Nakazato M. Concurrent use of teneligliptin and canagliflozin improves glycemic control with beneficial effects on plasma glucagon and glucagon-like peptide-1: A single-arm study. Diabetes Ther. 2019;10(5):1835-1846.

36. Sha S, Polidori D, Farrell K, Ghosh A, Natarajan J, Vaccaro N, Pinheiro J, Rothenberg P, Plum-Morschel L. Pharmacodynamic differences between canagliflozin and dapagliflozin: Results of a randomized, double-blind, crossover study. Diabetes Obes. Metab. 2015;17(2):188-197.

37. Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, Dietrich B, Golor G, Schrodter A, Keymeulen B, Lasseter KC, Kipnes MS, Snyder K, Hilliard D, Tanen M, Cilissen C, De Smet M, de Lepeleire I, Van Dyck K, Wang AQ, Zeng W, Davies MJ, Tanaka W, Holst JJ, Deacon CF, Gottesdiener KM, Wagner JA. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 2006;91(11):4612-4619.

38. Takebayashi K, Hara K, Terasawa T, Naruse R, Suetsugu M, Tsuchiya T, Inukai T. Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: A randomized trial. Endocr. J. 2017;64(9):923-931.

39. Yoshikawa T, Inoue R, Matsumoto M, Yajima T, Ushida K, Iwanaga T. Comparative expression of hexose transporters (SGLT1, GLUT1, GLUT2 and GLUT5) throughout the mouse gastrointestinal tract. Histochem. Cell Biol. 2011;135(2):183-194.

40. Fukuda-Tsuru S, Anabuki J, Abe Y, Yoshida K, Ishii S. A novel, potent, and long- lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. Eur. J. Pharmacol. 2012;696(1-3):194-202.

41. Hsueh CH, Hsu V, Zhao P, Zhang L, Giacomini KM, Huang SM. PBPK modeling of the effect of reduced kidney function on the pharmacokinetics of drugs excreted renally by organic anion transporters. Clin. Pharmacol. Ther. 2018;103(3):485- 492.

42. Nakamaru Y, Emoto C, Shimizu M, Yamazaki H. Human pharmacokinetic profiling of the dipeptidyl peptidase-IV inhibitor teneligliptin using physiologically based pharmacokinetic modeling. Biopharm. Drug Dispos. 2015;36(3):148-162.

43. Mori K, Saito R, Nakamaru Y, Shimizu M, Yamazaki H. Physiologically based pharmacokinetic-pharmacodynamic modeling to predict concentrations and actions of sodium-dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules. Biopharm. Drug Dispos. 2016;37(8):491-506.

44. New drugs approved in FY2013. [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. 2013 [cited 24 April 2015]. Available from: https://www.pmda.go.jp/drugs/2013/P201300172/index.html.

45. Suzuki M, Honda K, Fukazawa M, Ozawa K, Hagita H, Kawai T, Takeda M, Yata T, Kawai M, Fukuzawa T, Kobayashi T, Sato T, Kawabe Y, Ikeda S. Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice. J. Pharmacol. Exp. Ther. 2012;341(3):692-701.

46. Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, Takasu T, Imamura M, Qun L, Tomiyama H, Kobayashi Y, Noda A, Sasamata M, Shibasaki M. Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo. Naunyn Schmiedebergs Arch. Pharmacol. 2012;385(4):423-436.

47. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: Characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes. Metab. 2012;14(1):83-90.

48. Interview form of sitagliptin [Internet]. PMDA (Pharmaceutical and Medical Devices Agency) Japan. [cited 8 May 2018].

49. Yamamoto-Noguchi CC, Furutani E, Sumi S. Mathematical model of glucose- insulin metabolism in type 1 diabetes including digestion and absorption of carbohydrates. Frontiers in Life Engineering. 2014;7(6):314-320.

50. Moller JB, Jusko WJ, Gao W, Hansen T, Pedersen O, Holst JJ, Overgaard RV, Madsen H, Ingwersen SH. Mechanism-based population modelling for assessment of l-cell function based on total GLP-1 response following an oral glucose tolerance test. J. Pharmacokinet. Pharmacodyn. 2011;38(6):713-725.

51. Dalla Man C, Micheletto F, Sathananthan M, Vella A, Cobelli C. Model-based quantification of glucagon-like peptide-1-induced potentiation of insulin secretion in response to a mixed meal challenge. Diabetes Technol. Ther. 2016;18(1):39-46.

52. Pacini G, Bergman RN. Minmod: A computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput. Methods Programs Biomed. 1986;23(2):113-122.

53. Toffolo G, Campioni M, Basu R, Rizza RA, Cobelli C. A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction. Am. J. Physiol. Endocrinol. Metab. 2006;290(1):E169-E176.

54. Ohkura T, Fujioka Y, Sumi K, Nakanishi R, Shiochi H, Yamamoto N, Matsuzawa K, Izawa S, Ohkura H, Kato M, Taniguchi S, Yamamoto K. Sitagliptin improves the impaired acute insulin response during a meal tolerance test in Japanese patients with type 2 diabetes mellitus: A small-scale real-world study. Diabetes Ther. 2014;5(1):285-297.

55. Tsuchimochi W, Ueno H, Yamashita E, Tsubouchi C, Sakoda H, Nakamura S, Nakazato M. Teneligliptin improves glycemic control with the reduction of postprandial insulin requirement in Japanese diabetic patients. Endocr. J. 2015;62(1):13-20.

56. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia. 2014;57(5):891-901.

57. Okamoto A, Yokokawa H, Sanada H, Naito T. Changes in levels of biomarkers associated with adipocyte function and insulin and glucagon kinetics during treatment with dapagliflozin among obese type 2 diabetes mellitus patients. Drugs R D. 2016;16(3):255-261.

58. Nagai Y, Ohta A, Sada Y, Kato H, Tanaka Y. Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes. Expert Opin. Pharmacother. 2017;18(1):13-17.

59. Meier JJ, Nauck MA, Kranz D, Holst JJ, Deacon CF, Gaeckler D, Schmidt WE, Gallwitz B. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53(3):654-662.

60. Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, Karrison T, Frank B. Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type i diabetic patients. J. Clin. Invest. 1986;77(1):98-105.

61. van Riel N. Minimal models for glucose and insulin kinetics; a matlab implementation. Eindhoven University of Technology; 2004; Retrieved from https://www.researchgate.net/publication/273122307.

62. Cobelli C, Caumo A, Omenetto M. Minimal model Sg overestimation and Si underestimation: Improved accuracy by a bayesian two-compartment model. Am. J. Physiol. 1999;277(3):E481-488.

63. Sjostrand F, Edsberg L, Hahn RG. Volume kinetics of glucose solutions given by intravenous infusion. Br. J. Anaesth. 2001;87(6):834-843.

64. Englyst KN, Vinoy S, Englyst HN, Lang V. Glycaemic index of cereal products explained by their content of rapidly and slowly available glucose. Br. J. Nutr. 2003;89(3):329-340.

65. 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):1040-1046.

66. Balazki P, Schaller S, Eissing T, Lehr T. A quantitative systems pharmacology kidney model of diabetes associated renal hyperfiltration and the effects of SGLT inhibitors. CPT: pharmacometrics & systems pharmacology. 2018;7(12):788-797.

67. Schaller S, Willmann S, Lippert J, Schaupp L, Pieber TR, Schuppert A, Eissing T. A generic integrated physiologically based whole-body model of the glucose- insulin-glucagon regulatory system. CPT: pharmacometrics & systems pharmacology. 2013;2:e65.

68. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11-26.

69. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest. 2014;124(2):509-514.

70. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, Investigators E-RO. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373(22):2117-2128.

71. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, Group CPC. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 2017;377(7):644-657.

72. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357.

73. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.

74. Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Belohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett J, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Vinh PN, Schou M, Tereshchenko S, Køber L, Kosiborod MN, Langkilde AM, Martinez FA, Ponikowski P, Sabatine MS, Sjöstrand M, Solomon SD, Johanson P, Greasley PJ, Boulton D, Bengtsson O, Jhund PS, McMurray JJV. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. Jama. 2020;323(14):1353- 1368.

75. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi D-J, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca H-P, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde M-F, Spinar J, Squire I, Taddei S, Wanner C, Zannad F. Cardiovascular and renal outcomes with empagliflozin in heart failure. New England Journal of Medicine. 2020;383(15):1413-1424.

76. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F- F, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde A-M, Wheeler DC. Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine. 2020;383(15):1436-1446.

77. Marshall SF, Burghaus R, Cosson V, Cheung SY, Chenel M, DellaPasqua O, Frey N, Hamrén B, Harnisch L, Ivanow F, Kerbusch T, Lippert J, Milligan PA, Rohou S, Staab A, Steimer JL, Tornøe C, Visser SA. Good practices in model-informed drug discovery and development: Practice, application, and documentation. CPT: pharmacometrics & systems pharmacology. 2016;5(3):93-122.

78. Bradshaw EL, Spilker ME, Zang R, Bansal L, He H, Jones RDO, Le K, Penney M, Schuck E, Topp B, Tsai A, Xu C, Nijsen M, Chan JR. Applications of quantitative systems pharmacology in model-informed drug discovery: Perspective on impact and opportunities. CPT: pharmacometrics & systems pharmacology. 2019;8(11):777-791.

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