Pharmacoeconomic analysis of modern oral hypoglycemic agents with inadequate glycemic control on metformin

The aim. Based on a pharmacoeconomic analysis (PHe) of the use of sodium-glucose cotransporter-2 inhibitors (iSGLT2) and dipeptidyl peptidase-4 (iDPP-4) inhibitors to determine the optimal treatment strategy in patients with type 2 diabetes mellitus (T2DM) with inadequate glycemic control in metformin. Methodology. PE based on the clinical data obtained in the Russian multicenter observational epidemiological study FORSIGHT-T2DM and data obtained by analyzing and synthesizing previously published results of randomized controlled trials. Based on the obtained by Markov modeling outcomes we conduct a cost-eff ectiveness analysis with a calculation of cost-eff ectiveness ratio (CER). The time horizon was 7 years. Results. The highest survival rate observed in patients taking alogliptin and empaglifl ozin. The lowest total direct medical costs was on linagliptin (511,830 rubles) and canaglifl ozin (663,571 rubles). The highest utility index according to the EQ-5D questionnaire in iDPP-4 group was on vildagliptin (0.496), in iSGLT2 group on dapaglifl ozin (0.489) and canaglifl ozin (0.489). The highest life years gained (LYG) in iDPP-4 group was on alogliptin (0.65 years); in iSGLT2 group on empaglifl ozin (0.51 year). The highest quality adjusted life years (QALY) was on alogliptin (0.32) and empaglifl ozin (0.25). The results of PHe showed that the lowest discounted CЕR_LYG was on alogliptin (937 921 rubles) and empaglifl ozin (1 645 559 rubles). The lowest discounted CЕR_QALY was on alogliptin (1 918 522 rubles) and empaglifl ozin (3 369 349 rubles). The sensitivity analysis confi rmed that increasing the price of empaglifl ozin and alogliptin by 25 % and / or reducing the proportion of patients who reached the target of HbA1c level by 25 % when taking empaglifl ozin or alogliptin did not change the most cost-eff ectiveness strategy. Conclusion. The results of this PE showed that alogliptin and empaglifl ozin have the lowest CЕR_LYG and CЕR_QALY. In patients with inadequate glycemic control on metformin add-on empaglifl ozin or alogliptin is the most cost-eff ective treatment strategies.

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42. Govan L, Wu O, Lindsay R, Briggs A. How Do Diabetes Models Measure Up? A Review Of Diabetes Economic Models and ADA Guidelines. JHEOR. 2015;3(2):132-52.

43. Neal B, Perkovic V, Mahaff ey KW, et al. Canaglifl ozin and Cardiovascular and Renal Events in Type 2 Diabetes for the CANVAS Program Collaborative Group. N. Engl. J. Med. 2017;377: 644-657. DOI: 10.1056/NEJMoa1611925.

44. Kalashnikova M, Gerasimov A, Belousov D, et al. Analysis of healthrelated quality of life in patients with type 2 diabetes mellitus: results of an epidemiological study FORSIGHT-T2DM. Presented at 20th European Congress of Endocrinology. Barcelona, Spain. 19-22 May 2018. Endocrine Abstracts (2018) 56 GP91 | DOI: 10.1530/endoabs.56.GP91.

45. Mahaff ey KW, Neal B, Perkovic V. Canaglifl ozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canaglifl ozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-334.

46. Kontsevaya AV, Shalnova SA, Balanova YuA. Life quality of the Russian population by the data from ESSE-RF study. Kardiovaskulyarnaya terapiya i profi laktika. 2016;15(5):84-90. (In Russ). http://dx.doi.org/10.15829/1728-8800-2016-5-84-90.

47. Häring HU, Merker L, Seewaldt-Becker E, et al. EMPA-REG MET Trial Investigators. Empaglifl ozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014 Jun;37(6):1650-9. DOI: 10.2337/dc13-2105.

48. Sullivan PW, Ghushchyan VH. EQ-5D Scores for Diabetes-Related Comorbidities. Value in health. 2016;19(8):1002-1008. https://doi.org/10.1016/j.jval.2016.05.018.

49. Søft eland E, Meier JJ, Vangen B, et al. Empaglifl ozin as Add-on Th erapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, DoubleBlind, Parallel-Group Trial. Diabetes Care. 2017;40:201-209. DOI: 10.2337/dc16-1347.

50. Currie CJ, Morgan CL, Poole CD, et al. Multivariate models of healthrelated utility and the fear of hypoglycaemia in people with diabetes. Curr Med Res Opin. 2006;22:1523-34. https://doi.org/10.1185/030079906X115757.

51. DeFronzo RA, Lewin A, Patel S, et al. Combination of empaglifl ozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384—93.

52. Sundh J, Johansson G, Larsson K, et al. Comorbidity and health-related quality of life in patients with severe chronic obstructive pulmonary disease attending Swedish secondary care units. International Journal of Chronic Obstructive Pulmonary Disease. 2015;10:173-183. DOI:10.2147/COPD.S74645.

53. Zinman B, Wanner C, Lachin JM, et al. Empaglifl ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373:2117-2128. DOI: 10.1056/NEJMoa1504720.

54. Postanovlenie Pravitel’stva Moskvy ot 23 dekabrya 2016 g. №935-PP «O Territorial’noj programme gosudarstvennyh garantij besplatnogo okazaniya grazhdanam medicinskoj pomoshchi v gorode Moskve na 2018 god i na planovyj period 2019 i 2020 godov» (In Russ). http://www.mgfoms.ru/medicinskieorganizacii/tarifi

55. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. For the Alogliptin Study 008 Group. Effi cacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract, January. 2009;63(1):46-55. DOI: 10.1111/j.1742-1241.2008.01933.x.

56. Yagudina R, Kulikov A, Serpik V. Discounting for pharmacoeconomic evaluation. Farmakoekonomika. 2009;2(4):10-13. (In Russ).

57. Kaku K, Sumino S, Katou M, Nishiyama Y, Kinugawa Y. Randomized, double-blind, phase III study to evaluate the effi cacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. DOI: 10.1111/dom.12837.

58. Mearns ES, Sobieraj DM, White CM, et al. Comparative Effi cacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis. PLoS One. 2015 Apr 28;10(4):e0125879. DOI: 10.1371/journal.pone.0125879. eCollection 2015.

59. Seino Y, Miyata Y, Hiroi S, et al. Effi cacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36. DOI: 10.1111/j.1463-1326.2012.01620.x.

60. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Eff ect of dapaglifl ozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Jun 26;375(9733):2223-33. DOI: 10.1016/S0140-6736(10)60407-2.

61. White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin aft er Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013;369:1327-1335. DOI: 10.1056/NEJMoa1305889.

62. Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E. Durability and tolerability of dapaglifl ozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015 Nov;17(11):1075-84. DOI: 10.1111/dom.12543.

63. Goodman M, Th urston H, Penman J. Effi cacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009 May;41(5):368-73. DOI: 10.1055/s-0028-1104604.

64. Wiviott SD, Raz I, Bonaca MP, et al. Dapaglifl ozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 2018. DOI: 10.1056/NEJMoa1812389.

65. Ferrannini E, Fonseca V, Zinman B, et al. Fift y-two-week effi cacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism. 2009;11:157-166.

66. Lavalle-González FJ, Januszewicz A, Davidson J, et al. Effi cacy and safety of canaglifl ozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56:2582-92.

67. Filozof C, Gautier JF. A comparison of effi cacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet. Med. 2010;27:318-326.

68. Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, Meininger G. Effi cacy and safety of canaglifl ozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013 Dec;67(12):1267-82. DOI: 10.1111/ijcp.12322.

69. McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profi le of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015 Nov;17(11):1085-92. DOI: 10.1111/dom.12548. Epu.b 2015 Sep. 10.

70. Cefalu WT, Leiter LA, Yoon KH, et al. Effi cacy and safety of canaglifl ozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941-50.

71. Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. DOI: 10.1111/j.1463-1326.2010.01326.x.

72. Neal B, Perkovic V, Mahaff ey KW, et al. Canaglifl ozin and Cardiovascular and Renal Events in Type 2 Diabetes for the CANVAS Program Collaborative Group. N. Engl. J. Med. 2017;377: 644-657. DOI: 10.1056/NEJMoa1611925.

73. Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovascular Diabetology. 2018;17-39 DOI:HYPERLINK «https://doi.org/10.1186/s12933-018-0682-3»10.1186/s12933-018-0682-3.

74. Mahaff ey KW, Neal B, Perkovic V. Canaglifl ozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canaglifl ozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-334.

75. DeFronzo RA, Hissa MN, Garber AJ, et al. Saxagliptin 014 Study Group. The Effi cacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone. Diabetes Care. 2009 Sep;32(9):1649-55. doi: 10.2337/dc08-1984.

76. Häring HU, Merker L, Seewaldt-Becker E, et al. EMPA-REG MET Trial Investigators. Empaglifl ozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014 Jun;37(6):1650-9. DOI: 10.2337/dc13-2105.

77. Göke B, Gallwitz B, Eriksson J, Hellqvist Å, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type-2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619-1631.

78. Søft eland E, Meier JJ, Vangen B, et al. Empaglifl ozin as Add-on Th erapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, DoubleBlind, Parallel-Group Trial. Diabetes Care. 2017;40:201-209. DOI: 10.2337/dc16-1347.

79. Scirica BM. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus / BM Scirica, DL Bhatt, E Braunwald, et al. N. Engl. J. Med. 2013;369:1317-1326. DOI: 10.1056/NEJMoa1307684.

80. DeFronzo RA, Lewin A, Patel S, et al. Combination of empaglifl ozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384—93.

81. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Sitagliptin Study 020 Group. Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43. DOI: 10.2337/dc06-0706.

82. Zinman B, Wanner C, Lachin JM, et al. Empaglifl ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015;373:2117-2128. DOI: 10.1056/NEJMoa1504720.

83. Arechavaleta R, Seck T, Chen Y, et al. Effi cacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011 Feb;13(2):160-8. DOI: 10.1111/j.1463-1326.2010.01334.x.

84. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. For the Alogliptin Study 008 Group. Effi cacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract, January. 2009;63(1):46-55. DOI: 10.1111/j.1742-1241.2008.01933.x.

85. Green JB, Bethel MA, Armstrong PW, et al., For the TECOS Study Group. Eff ect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015; 373:232-242 DOI: 10.1056/NEJMoa1501352.

86. Kaku K, Sumino S, Katou M, Nishiyama Y, Kinugawa Y. Randomized, double-blind, phase III study to evaluate the effi cacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. DOI: 10.1111/dom.12837.

87. Davies MJ, et al. European Association for the Study of Diabetes. ADA, American Diabetes Association. Diabetes Care. 2018. Sep. — https://doi.org/10.2337/dci18-0033.

88. Seino Y, Miyata Y, Hiroi S, et al. Effi cacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36. DOI: 10.1111/j.1463-1326.2012.01620.x.

89. White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin aft er Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013;369:1327-1335. DOI: 10.1056/NEJMoa1305889.

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