COST-EFFECTIVENESS OF CANAGLIFLOZIN VERSUS SITAGLIPTIN WHEN ADDED TO METFORMIN AND SULFONYLUREA IN TYPE 2 DIABETES IN CANADA
Main Article Content
Keywords
C anagliflozin, cost-effectiveness analysis, sitagliptin, third-line therapy, type 2 diabetes
Abstract
Background
Canagliflozin, an agent that inhibits sodium glucose co -transporter 2, is approved as add- on to metformin plus sulfonylurea for the treatment of type 2 diabetes in Canada . Canagliflozin offers greater glycemic control , as well as important additional benefits such as weight loss and blood pressure reductions , versus dipeptidyl peptidase -4 inhibitors such as sitagliptin .
Objective
This analysis evaluated the cost -effectiveness of canagliflozin 300 mg and canagliflozin 100 mg versus sitagliptin 100 mg in patients with type 2 diabetes inadequately controlled on metformin plus sulfonylurea from the perspective of the Canadian Agency for Drugs and Technologies in Health.
Methods
A 40- year cost -effectiveness analysis was performed using the validated Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (E CHO- T2DM) . Patient characteristics, treatment effects, and rates of hypoglycemia and adverse events were sourced from the canagliflozin clinical program . Canada -specific costs and utilities were applied . Sensitivity analyses were conducted using alternative values for key model inputs.
Results
Both canagliflozin 300 and 100 mg dominated sitagliptin 100 mg over 40 years , providing quality - adjusted life -year gains of 0.31 and 0.28, and cost offsets of $2,217 and $2,5 60, respectively . Both canagliflozin doses dominated sitagliptin in each of the sensitivity analyses.
Conclusions
Simulation results suggested that c anagliflozin 300 and 100 mg provided better health outcomes and lower costs than sitagliptin 100 mg as a third -line therapy added -on to metformin and sulfonylurea in patients with type 2 diabetes in Canada .
References
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18. Schernthaner G, Mogensen CE, Schernthaner GH. The effects of GLP -1 analogues, DPP -4 inhibitors and SGLT2 inhibitors on the renal system. Diab Vasc Dis Res 2014;11(5) :306- 23.
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24. Willis M, Asseburg C, He J. Validation of economic and health outcomes simulation model of type 2 diabetes mellitus (ECHO -T2DM). J Med Econ 2013;16(8):1007- 21.
25. Asseburg C, Willis M, Johansen P, Nilsson A, Neslusan C, Schroeder M. Update of t he model validation of the Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO - T2DM). Poster presented at: 21st Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR); May 21 -25 2016; Washington, DC .
26. Mount Hood 4 Modeling Group. Computer modeling of diabetes and its complications: a report on the f ourth Mount Hood Challenge meeting. Diabetes Care 2007;30(6):1638- 46.
27. Brown JB, Palmer AJ, Bisgaard P, Chan W, Pedula K, Russell A. The Mt. Hood C hallenge : cross -testing two diabetes simulation models. Diabetes Res Clin Pract 2000;50(s uppl 3) :S57 -64.
28. Neslusan C, Teschemaker A, Johansen P, Willis M, Valencia -Mendoza A, Puig A. Cost - effectiveness of canagliflozin versus sitagliptin as add -on to metformin in patients with type 2 diabetes mellitus in Mexico. Value Health Regional Issues 2015;8:8- 19.
29. Brown JB, Russell A, Chan W, Pedula K, Aickin M. The global diabetes model: user friendly version 3.0. Diabetes Res Clin Pract 2000;50(s uppl 3) :S15 -46.
30. UK Prospectiv e Diabetes Study (UKPDS) Group. Intensive blood- glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837- 53.
31. Eastman RC, Javitt JC, Herman WH, et al. Model of complications of NIDDM. II. Analysis of the health benefits and cost -effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 1997;20(5):735- 44.
32. Bagust A, Beale S. Modelling EuroQol health - related utility val ues for diabetic complications from CODE -2 data. Health Econ 2005;14(3):217- 30.
33. Hoerger TJ, Wittenborn JS, Segel JE, et al. A health policy model of CKD: 1. model construction, assumptions, and validation of health consequences. Am J Kidney Dis 2010;55(3):452- 62.
34. Hayes AJ, Leal J, Gray AM, Holman RR, Clarke PM. UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabe tes Study: UKPDS 82. Diabetologia 2013;56(9):1925- 33.
35. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355(23):2427- 43.
36. Boulware LE, Jaar BG, Tarver -Carr ME, Brancati FL, Pow e NR. Screening for proteinuria in US adults: a cost -effectiveness analysis. JAMA 2003;290(23):3101- 14.
37. Nyirjesy P, Sobel JD, Fung A, et al. Genital mycotic infections with canagliflozin, a sodium glucose co -transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin 2014;30(6):1109- 19.
38. Nicolle LE, Capuano G, Fung A, Usiskin K. Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co - transporter 2 inhibitor . Postgrad Med 2014;126(1):7- 17.
39. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52 -week, randomized tria l. Diabetes Care 2013;36(9):2508- 15.
40. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Prac t 2013;67(12):1267- 82.
41. INVOKANA ® (canagliflozin) tablets, for oral use [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2014.
42. Janssen Research & Development. Integrated summary of e fficacy. Canagliflozin as an adjunctive treatment to diet and exercise alone or co-administered with other antihyperglycemic agents to i mprove glycemic control in a dults with type 2 d iabetes mellitus. 2012.
43. Yamout HM, Perkovic V, Davies M, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am J Nephrol 2014;40(1):64- 74.
44. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52 - week, treat -to-target trial comparing insulin detemir with insulin glargine when administered as add -on to glucose -low ering drugs in insulin- naive people with type 2 diabetes. Diabetologia 2008;51( 3):408- 16.
45. Riddle MC, Vlajnic A, Zhou R, Rosenstock J. Baseline HbA1c predicts attainment of 7.0% HbA1c target with structured titration of insulin glargine in type 2 diabetes: a patient -level analysis of 12 studies. Diabetes Obes Metab 2013;15(9):819- 25.
46. Fonseca V, Gill J, Zhou R, Leahy J. An analysis of early insulin glargine added to metformin with or without sulfonylurea: impact on glycaemic control and hypoglycaemia. Diabetes Obes Metab 2011;13(9):814- 22.
47. Clarke PM, Glasziou P, Patel A, et al. Event rates, hospital utilization, and costs associated with major complications of diabetes: a multicountry comparative analysis. PLoS Med 2010;7(2):e1000236.
48. Tarride JE, Gordon A, Vera -Llonch M, Dukes E, Rousseau C. Cost -effectiveness of pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia: a Canadian perspective. Clin Ther 2006;28(11):1922- 34.
49. Sibbald RG, Torran ce G, Hux M, Attard C, Milkovich N. Cost -effectiveness of becaplermin for nonhealing neuropathic diabetic foot ulcers. Ostomy Wound Manage 2003;49(11):76- 84.
50. O'Brien JA, Patrick AR, Caro J. Estimates of direct medical costs for microvascular and macrovascu lar complications resulting from type 2 diabetes mellitus in the United States in 2000. Clin Ther 2003;25(3):1017- 38.
51. O'Reilly D, Hopkins R, Blackhouse G, et al. Long -term cost -utility analysis of a multidisciplinary primary care diabetes management program in Ontario. Can J Diabetes 2007;31(3):205- 14.
52. Regie de l'assurance maladie du Quebec. Liste des médicaments. Règlement concernant la liste des médicaments couverts par le régime général d'assurance médicaments. http://www.ramq.gouv.qc.ca/fr/publications/citoy ens/publications -legales/Pages/liste - medicaments.aspx . Accessed March 2 , 2016.
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54. Evans M, Khunti K, Mamdani M, et al. Health - related quality of life associated with daytime and nocturnal hypoglycaemic events: a time trade -off survey in five countries. Health Qual Life Outcomes 2013;11:90.
55. Shingler S, Fordham B, Evans M, et al. Utilities for treatment -related adverse events in type 2 diabetes. J Med Econ 2015;18(1):45- 55.
56. Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double -blind, phase 3 study. Diabetes Care 2015;38(3):355- 64.
57. National Institute for Health and Clinical Excellence. Obesity prevention: NICE guidelines [Clinical guideline 43]. http://ww w.nice.org.uk/guidance/CG43/ . Accessed December 3, 2015.
58. Macran S. The relationship between body mass index and health -related quality of life (Discussion paper 190). http://www.york.ac.uk/che/pdf/DP1 90.pdf . Accessed March 2 , 2016.
59. 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.
60. Kansal A, Zheng Y, Proskorovsky I, Krotneva S, Kandaswamy P, Ruffolo A. Modeling cardiovascular outcomes of treatment with empagliflozin in type 2 diabetes based on hard outcomes data. Poster presented at: 21st Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR); May 21 -25 2016; Wash ington, DC.
61. O'Reilly D, Burke N, Blackhouse G, Tsoi B, Campbell K, Jegathisawaran J. Review of the cost and health -related quality of life associated with diabetes and diabetes -related complications. 2012;TEMMP -D045- 2012.REP.
62. Sullivan PW, Lawrence WF, Ghu shchyan V. A national catalog of preference- based scores for chronic conditions in the United States. Med Care 2005;43(7):736- 49.
63. Morgan CL, McEwan P, Morrissey M, Peters JR, Poole C, Currie CJ. Characterization and comparison of health -related utility in people with diabetes with various single and multiple vascular complications. Diabet Med 2006;23(10):1100- 5.
64. Clarke P, Gray A, Holman R. Estimating utility values for health states of type 2 diabetic patients using the EQ -5D (UKPDS 62). Med Decis Making 2002;22(4):340- 9.
2. International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium: International Diabetes Federation; 2013.
3. Public Health Agency of Canada. Diabetes in Canada. Facts and figures from a public health perspective, 2 011. http://www.phac - aspc.gc.ca/cd -mc/publications/diabetes - diabete/facts -figures -faits -chiffres -2011/ pdf/facts - figures -faits -chiffres -eng.pdf . Accessed March 2 , 2016.
4. Dawson KG, Gomes D, Gerstein H, Blanchard JF, Kahler KH. The economic cost of diabetes in Canada, 1998. Diabetes Care 2002;25(8):1303- 7.
5. Canadian Diabetes Association. An economic tsunami: the costs of diabetes in Canada, December 2009. http://www.diabetes.ca/CDA/media/documents/p ubli cations -and -newsletters/advocacy - reports/economic -tsunami -cost -of-diabetes -in- canada -english.pdf . Accessed March 2, 2016.
6. Canadian Diabetes Association. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Associat ion 2013 c linical practice guidelines for the prevention and management of d iabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1 -212.
7. Leiter LA, Berard L, Bowering CK, et al. Type 2 diabetes mellitus management in Canada: is it improving? Can J Diabetes 2013;37(2):82- 9.
8. Canadian Agency for Drugs and Technologies in Health. CADTH Optimal Use Report. Second - line pharmacotherapy for type 2 diabetes – update. http://www.cadth.ca/media/pdf/OP0512_Diabetes Update_Second -line_e.pdf .
9. Canadian Agency for Drugs and Technologies in Health. CADTH Optimal Use Report. Third -line pharmacotherapy for type 2 d iabetes – update. http://www.cadth.ca/media/pdf/OP0512_Diabetes %20Update_Third -line_e.pdf . Accessed March 2 , 2016.
10. Morgan S, Smolina K, Mooney D, et al. The Canadian Rx Atlas. 3rd ed. UBC Centre for Health Services and Policy Research ; 2013.
11. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient -centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes . Diabetes Care 2015;38(1):140- 9.
12. Jabbour SA. SGLT2 inhibitors to control glycemia in type 2 diabetes mellitus: a new approach to an old problem. Postgrad Med 2014;126(1):111- 7.
13. Canadian Drug Expert Committee. Common drug review: CDEC final recommendation, canagliflozin (Invokana, Janssen Inc.). http://www.cadth.ca/media/cdr/complete/cdr_co mplete_SR0370_Invokana_Jan- 19_15.pdf . Accessed March 2 , 2016.
14. Rosenthal N, Meininger G, Ways K, et al. Canagliflozin: a sodium glucose co -transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. Ann N Y Acad Sci 2015;1358:28- 43.
15. Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in t ype 2 diabetes mellitus. Curr Med Res Opin 2015;31(12):2219- 31.
16. Weir MR. The kidney and type 2 diabetes mellitus: therapeutic implications of SGLT2 inhibitors. Postgrad Med 2016;128(3):290- 8.
17. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progr ession of kidney disease in t ype 2 d iabetes . N Engl J Med 2016; doi:10.1056/NEJMoa1515920 .
18. Schernthaner G, Mogensen CE, Schernthaner GH. The effects of GLP -1 analogues, DPP -4 inhibitors and SGLT2 inhibitors on the renal system. Diab Vasc Dis Res 2014;11(5) :306- 23.
19. Green JB, Bethel MA, Armstrong PW, et al. Effect of s itagliptin on c ardiovascular outcomes in type 2 d iabetes. N Engl J Med 2015;373(3):232- 42.
20. Canadian Agency for Drugs and Technologies in Health. New d rugs for type 2 d iabetes: a therapeutic revi ew update. https://www.cadth.ca/new -drugs -type -2-diabetes - therapeutic -review -update . Accessed February 25, 2016.
21. Palmer AJ ; The Mount Hood 5 Modeling Group. Computer modeling of diabetes and its complications: a report on the fifth Mount Hood Challenge meeting. Value Health 2013;16(4):670- 85.
22. American Diabetes Association. Guidelines for computer modeling of diabetes and its complications. Diabetes Care 2004;27(9):2262- 5.
23. Canadian Agency for Drugs and Technologies in Health. Guidelines for the Economic Evaluation of Health Technologies: Canada. 3rd ed 2006. https://www.cadth.ca/media/pdf/186_EconomicG uidelines_e.pdf. Accessed March 2 , 2016.
24. Willis M, Asseburg C, He J. Validation of economic and health outcomes simulation model of type 2 diabetes mellitus (ECHO -T2DM). J Med Econ 2013;16(8):1007- 21.
25. Asseburg C, Willis M, Johansen P, Nilsson A, Neslusan C, Schroeder M. Update of t he model validation of the Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO - T2DM). Poster presented at: 21st Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR); May 21 -25 2016; Washington, DC .
26. Mount Hood 4 Modeling Group. Computer modeling of diabetes and its complications: a report on the f ourth Mount Hood Challenge meeting. Diabetes Care 2007;30(6):1638- 46.
27. Brown JB, Palmer AJ, Bisgaard P, Chan W, Pedula K, Russell A. The Mt. Hood C hallenge : cross -testing two diabetes simulation models. Diabetes Res Clin Pract 2000;50(s uppl 3) :S57 -64.
28. Neslusan C, Teschemaker A, Johansen P, Willis M, Valencia -Mendoza A, Puig A. Cost - effectiveness of canagliflozin versus sitagliptin as add -on to metformin in patients with type 2 diabetes mellitus in Mexico. Value Health Regional Issues 2015;8:8- 19.
29. Brown JB, Russell A, Chan W, Pedula K, Aickin M. The global diabetes model: user friendly version 3.0. Diabetes Res Clin Pract 2000;50(s uppl 3) :S15 -46.
30. UK Prospectiv e Diabetes Study (UKPDS) Group. Intensive blood- glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837- 53.
31. Eastman RC, Javitt JC, Herman WH, et al. Model of complications of NIDDM. II. Analysis of the health benefits and cost -effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 1997;20(5):735- 44.
32. Bagust A, Beale S. Modelling EuroQol health - related utility val ues for diabetic complications from CODE -2 data. Health Econ 2005;14(3):217- 30.
33. Hoerger TJ, Wittenborn JS, Segel JE, et al. A health policy model of CKD: 1. model construction, assumptions, and validation of health consequences. Am J Kidney Dis 2010;55(3):452- 62.
34. Hayes AJ, Leal J, Gray AM, Holman RR, Clarke PM. UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabe tes Study: UKPDS 82. Diabetologia 2013;56(9):1925- 33.
35. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355(23):2427- 43.
36. Boulware LE, Jaar BG, Tarver -Carr ME, Brancati FL, Pow e NR. Screening for proteinuria in US adults: a cost -effectiveness analysis. JAMA 2003;290(23):3101- 14.
37. Nyirjesy P, Sobel JD, Fung A, et al. Genital mycotic infections with canagliflozin, a sodium glucose co -transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin 2014;30(6):1109- 19.
38. Nicolle LE, Capuano G, Fung A, Usiskin K. Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co - transporter 2 inhibitor . Postgrad Med 2014;126(1):7- 17.
39. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52 -week, randomized tria l. Diabetes Care 2013;36(9):2508- 15.
40. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Prac t 2013;67(12):1267- 82.
41. INVOKANA ® (canagliflozin) tablets, for oral use [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2014.
42. Janssen Research & Development. Integrated summary of e fficacy. Canagliflozin as an adjunctive treatment to diet and exercise alone or co-administered with other antihyperglycemic agents to i mprove glycemic control in a dults with type 2 d iabetes mellitus. 2012.
43. Yamout HM, Perkovic V, Davies M, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am J Nephrol 2014;40(1):64- 74.
44. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52 - week, treat -to-target trial comparing insulin detemir with insulin glargine when administered as add -on to glucose -low ering drugs in insulin- naive people with type 2 diabetes. Diabetologia 2008;51( 3):408- 16.
45. Riddle MC, Vlajnic A, Zhou R, Rosenstock J. Baseline HbA1c predicts attainment of 7.0% HbA1c target with structured titration of insulin glargine in type 2 diabetes: a patient -level analysis of 12 studies. Diabetes Obes Metab 2013;15(9):819- 25.
46. Fonseca V, Gill J, Zhou R, Leahy J. An analysis of early insulin glargine added to metformin with or without sulfonylurea: impact on glycaemic control and hypoglycaemia. Diabetes Obes Metab 2011;13(9):814- 22.
47. Clarke PM, Glasziou P, Patel A, et al. Event rates, hospital utilization, and costs associated with major complications of diabetes: a multicountry comparative analysis. PLoS Med 2010;7(2):e1000236.
48. Tarride JE, Gordon A, Vera -Llonch M, Dukes E, Rousseau C. Cost -effectiveness of pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia: a Canadian perspective. Clin Ther 2006;28(11):1922- 34.
49. Sibbald RG, Torran ce G, Hux M, Attard C, Milkovich N. Cost -effectiveness of becaplermin for nonhealing neuropathic diabetic foot ulcers. Ostomy Wound Manage 2003;49(11):76- 84.
50. O'Brien JA, Patrick AR, Caro J. Estimates of direct medical costs for microvascular and macrovascu lar complications resulting from type 2 diabetes mellitus in the United States in 2000. Clin Ther 2003;25(3):1017- 38.
51. O'Reilly D, Hopkins R, Blackhouse G, et al. Long -term cost -utility analysis of a multidisciplinary primary care diabetes management program in Ontario. Can J Diabetes 2007;31(3):205- 14.
52. Regie de l'assurance maladie du Quebec. Liste des médicaments. Règlement concernant la liste des médicaments couverts par le régime général d'assurance médicaments. http://www.ramq.gouv.qc.ca/fr/publications/citoy ens/publications -legales/Pages/liste - medicaments.aspx . Accessed March 2 , 2016.
53. Ontario Ministry of Health and Long -term Care. Drugs funded by Ontario Drug Benefit (ODB) program. http://www.health.gov.on.ca/en/pro/programs/dru gs/odbf_eformulary.aspx . Accessed March 2 , 2016.
54. Evans M, Khunti K, Mamdani M, et al. Health - related quality of life associated with daytime and nocturnal hypoglycaemic events: a time trade -off survey in five countries. Health Qual Life Outcomes 2013;11:90.
55. Shingler S, Fordham B, Evans M, et al. Utilities for treatment -related adverse events in type 2 diabetes. J Med Econ 2015;18(1):45- 55.
56. Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double -blind, phase 3 study. Diabetes Care 2015;38(3):355- 64.
57. National Institute for Health and Clinical Excellence. Obesity prevention: NICE guidelines [Clinical guideline 43]. http://ww w.nice.org.uk/guidance/CG43/ . Accessed December 3, 2015.
58. Macran S. The relationship between body mass index and health -related quality of life (Discussion paper 190). http://www.york.ac.uk/che/pdf/DP1 90.pdf . Accessed March 2 , 2016.
59. 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.
60. Kansal A, Zheng Y, Proskorovsky I, Krotneva S, Kandaswamy P, Ruffolo A. Modeling cardiovascular outcomes of treatment with empagliflozin in type 2 diabetes based on hard outcomes data. Poster presented at: 21st Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR); May 21 -25 2016; Wash ington, DC.
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