Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues

Circulation

Volumn 140, Issue 25, 2019, Pages 2108-2118

  Butler, Javed ^a   Packer, Milton ^b   Greene, Stephen J ^c   Fiuzat, Mona ^c   Anker, Stefan D ^d,e   Anstrom, Kevin J ^c   Carson, Peter E ^f,g   Cooper, Lauren B ^h   Fonarow, Gregg C ⁱ   Hernandez, Adrian F ^c   Januzzi, James L ^j   Jessup, Mariell ^k   Kalyani, Rita R ^l   Kaul, Sanjay ^m   Kosiborod, Mikhail ^n,o   Lindenfeld, JoAnn ^p   McGuire, Darren K ^q   Sabatine, Marc S ^r   Solomon, Scott D ^r   Teerlink, John R ^s,t   Vaduganathan, Muthiah ^r   Yancy, Clyde W ^u   Stockbridge, Norman ^v   O'Connor, Christopher M ^h   more..

^a UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

^b BAYLOR UNIVERSITY MEDICAL CENTER   (United States)

^c DUKE CLINICAL RESEARCH INSTITUTE   (United States)

^d DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e Berlin Brandenburg Center for Regenerative Therapies   (Germany)

^f CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^g Washington Veterans Affairs Medical Center   (United States)

^h INOVA HEART AND VASCULAR INSTITUTE   (United States)

ⁱ UNIVERSITY OF CALIFORNIA   (United States)

^j MASSACHUSETTS GENERAL HOSPITAL   (United States)

^k AMERICAN HEART ASSOCIATION   (United States)

^l JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^m CEDARS SINAI MEDICAL CENTER   (United States)

ⁿ UNIVERSITY OF MISSOURI KANSAS CITY   (United States)

^o UNIVERSITY OF NEW SOUTH WALES   (Australia)

^p VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^q UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^r BRIGHAM AND WOMEN S HOSPITAL   (United States)

^s SAN FRANCISCO VETERANS AFFAIRS MEDICAL CENTER   (United States)

^t UNIVERSITY OF CALIFORNIA   (United States)

^u NORTHWESTERN UNIVERSITY   (United States)

^v CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

more..

Author keywords

biomarkers; clinical trial; diabetes mellitus, type 2; heart failure

Indexed keywords

SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SLC5A2 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 2;

CLINICAL TRIAL (TOPIC); HEART FAILURE; HOSPITALIZATION; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; REVIEW; RISK REDUCTION; BIOASSAY; BLOOD; CARDIOVASCULAR DISEASE; PHARMACOLOGY; PROCEDURES; RESEARCH; TREATMENT OUTCOME;

CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; DIABETES MELLITUS, TYPE 2; ENDPOINT DETERMINATION; HEART FAILURE; HUMANS; RESEARCH REPORT; SODIUM-GLUCOSE TRANSPORTER 2; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; TREATMENT OUTCOME;

EID: 85076716130     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.119.042155     Document Type: Review

References (63)

1. Food and Drug Administration Guidance for industry: Diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 mellitus. 2008. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed June 1, 2017
2. Nissen SE, Wolski K, Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007 356 2457 2471. doi: 10.1056/NEJMoa072761
3. Goldner MG, Knatterud GL, Prout TE, Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA 1971 218 1400 1410. doi: 10.1001/jama.1971.03190220020005
4. Lago RM, Singh PP, Nesto RW, Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: A meta-analysis of randomised clinical trials. Lancet 2007 370 1129 1136. doi: 10.1016/S0140-6736(07)61514-1
5. Nissen SE, Wolski K, Topol EJ, Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005 294 2581 2586. doi: 10.1001/jama.294.20.joc50147
6. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, EMPA-REG OUTCOME Investigators Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015 373 2117 2128. doi: 10.1056/NEJMoa1504720
7. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, LEADER Steering Committee; LEADER Trial Investigators Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016 375 311 322. doi: 10.1056/NEJMoa1603827
8. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, CANVAS Program Collaborative Group Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017 377 644 657. doi: 10.1056/NEJMoa1611925
9. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB, Management of hyperglycemia in type 2 diabetes, 2018: A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018 41 2669 2701. doi: 10.2337/dci18-0033
10. American Diabetes Association 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care 2019 42 suppl 1 S90 S102. doi: 10.2337/dc19-S009
11. Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu WT, Januzzi JL Jr, Kalyani RR, Kosiborod M, Magwire ML, Morris PB, 2018 ACC Expert Consensus Decision Pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2018 72 3200 3223. doi: 10.1016/j.jacc.2018.09.020
12. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, DECLARE-TIMI 58 Investigators Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019 380 347 357. doi: 10.1056/NEJMoa1812389
13. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ, RECORD Study Team Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, open-label trial. Lancet 2009 373 2125 2135. doi: 10.1016/S0140-6736(09)60953-3
14. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, SAVOR-TIMI 53 Steering Committee and Investigators Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013 369 1317 1326. doi: 10.1056/NEJMoa1307684
15. Butler J, Hamo CE, Filippatos G, Pocock SJ, Bernstein RA, Brueckmann M, Cheung AK, George JT, Green JB, Januzzi JL, EMPEROR Trials Program The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail 2017 19 1390 1400. doi: 10.1002/ejhf.933
16. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, Martinez FA, Bengtsson O, Ponikowski P, Sabatine MS, DAPA-HF Committees and Investigators A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail 2019 21 665 675. doi: 10.1002/ejhf.1432
17. Ziaeian B, Hernandez AF, DeVore AD, Wu J, Xu H, Heidenreich PA, Matsouaka RA, Bhatt DL, Yancy CW, Fonarow GC, Long-term outcomes for heart failure patients with and without diabetes: From the Get With The Guidelines-Heart Failure Registry. Am Heart J 2019 211 1 10. doi: 10.1016/j.ahj.2019.01.006
18. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr., Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care 2004 27 699 703. doi: 10.2337/diacare.27.3.699
19. Khan SS, Butler J, Gheorghiade M, Management of comorbid diabetes mellitus and worsening heart failure. JAMA 2014 311 2379 2380. doi: 10.1001/jama.2014.4115
20. Packer M, Heart failure: The most important, preventable, and treatable cardiovascular complication of type 2 diabetes. Diabetes Care 2018 41 11 13. doi: 10.2337/dci17-0052
21. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA, Heart failure: A cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol 2014 2 843 851. doi: 10.1016/S2213-8587(14)70031-2
22. Greene SJ, Vaduganathan M, Khan MS, Bakris GL, Weir MR, Seltzer JH, Sattar N, McGuire DK, Januzzi JL, Stockbridge N, Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes. J Am Coll Cardiol 2018 71 1379 1390. doi: 10.1016/j.jacc.2018.01.047
23. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019 139 2528 2536. doi: 10.1161/CIRCULATIONAHA.119.040130
24. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, EMPA-REG OUTCOME® trial investigators 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 1526 1534. doi: 10.1093/eurheartj/ehv728
25. Rådholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, Fulcher G, Barrett TD, Shaw W, Desai M, Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus. Circulation 2018 138 458 468. doi: 10.1161/CIRCULATIONAHA.118.034222
26. Packer M, Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications. Eur J Heart Fail 2018 20 1100 1105. doi: 10.1002/ejhf.1183
27. Greene SJ, Butler J, Primary prevention of heart failure in patients with type 2 diabetes mellitus. Circulation 2019 139 152 154. doi: 10.1161/CIRCULATIONAHA.118.037599
28. Vijayakumar S, Vaduganathan M, Butler J, Glucose-lowering therapies and heart failure in type 2 diabetes mellitus: Mechanistic links, clinical data, and future directions. Circulation 2018 137 1060 1073. doi: 10.1161/CIRCULATIONAHA.117.032099
29. Gerber Y, Weston SA, Redfield MM, Chamberlain AM, Manemann SM, Jiang R, Killian JM, Roger VL, A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med 2015 175 996 1004. doi: 10.1001/jamainternmed.2015.0924
30. Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, Devore AD, Yancy CW, Fonarow GC, Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol 2017 70 2476 2486. doi: 10.1016/j.jacc.2017.08.074
31. Greene SJ, O'Brien EC, Mentz RJ, Luo N, Hardy NC, Laskey WK, Heidenreich PA, Chang CL, Turner SJ, Yancy CW, Home-time after discharge among patients hospitalized with heart failure. J Am Coll Cardiol 2018 71 2643 2652. doi: 10.1016/j.jacc.2018.03.517
32. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler JR, Teerlink JR, Farb A, Standardized Data Collection for Cardiovascular Trials Initiative (SCTI) 2017 cardiovascular and stroke endpoint definitions for clinical trials. Circulation 2018 137 961 972. doi: 10.1161/CIRCULATIONAHA.117.033502
33. Figtree GA, Radholm K, Barrett TD, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Neal B, Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes: Results from the CANVAS program. Circulation 2019 139 2591 2593. doi:10.1161/CIRCULATIONAHA.119.040057
34. Greene SJ, Mentz RJ, Felker GM, Outpatient worsening heart failure as a target for therapy: A review. JAMA Cardiol 2018 3 252 259. doi: 10.1001/jamacardio.2017.5250
35. Greene SJ, Felker GM, Butler J, Outpatient versus inpatient worsening heart failure: Distinguishing biology and risk from location of care. Eur J Heart Fail 2019 21 121 124. doi: 10.1002/ejhf.1341
36. Skali H, Dwyer EM, Goldstein R, Haigney M, Krone R, Kukin M, Lichstein E, McNitt S, Moss AJ, Pfeffer MA, Prognosis and response to therapy of first inpatient and outpatient heart failure event in a heart failure clinical trial: MADIT-CRT. Eur J Heart Fail 2014 16 560 565. doi: 10.1002/ejhf.71
37. Okumura N, Jhund PS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Swedberg K, Zile MR, Solomon SD, PARADIGM-HF Investigators and Committees Importance of clinical worsening of heart failure treated in the outpatient setting: Evidence from the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF). Circulation 2016 133 2254 2262. doi: 10.1161/CIRCULATIONAHA.115.020729
38. Ferreira JP, Metra M, Mordi I, Gregson J, Ter Maaten JM, Tromp J, Anker SD, Dickstein K, Hillege HL, Ng LL, Heart failure in the outpatient versus inpatient setting: Findings from the BIOSTAT-CHF study. Eur J Heart Fail 2019 21 112 120. doi: 10.1002/ejhf.1323
39. Greene SJ, Wilson LE, Abbasi SA, Yusuf AA, Hammill BG, Outpatient intravenous diuretic therapy for heart failure in the United States. J Am Coll Cardiol 2019 73 1101 1103. doi: 10.1016/j.jacc.2018.12.034
40. Shen L, Jhund PS, Mogensen UM, Køber L, Claggett B, Rogers JK, McMurray JJV, Re-examination of the BEST trial using composite outcomes, including emergency department visits. JACC Heart Fail 2017 5 591 599. doi: 10.1016/j.jchf.2017.04.005
41. Yeung DF, Boom NK, Guo H, Lee DS, Schultz SE, Tu JV, Trends in the incidence and outcomes of heart failure in Ontario, Canada: 1997 to 2007. CMAJ 2012 184 E765 E773. doi: 10.1503/cmaj.111958
42. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, CREDENCE Trial Investigators Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019 380 2295 2306. doi: 10.1056/NEJMoa1811744
43. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019 393 31 39. doi: 10.1016/S0140-6736(18)32590-X
44. Verma S, Jüni P, Mazer CD, Pump, pipes, and filter: Do SGLT2 inhibitors cover it all? Lancet 2019 393 3 5. doi: 10.1016/S0140-6736(18)32824-1
45. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 2019 139 2022 2031. doi: 10.1161/CIRCULATIONAHA.118.038868
46. Furtado RHM, Bonaca MP, Raz I, Zelniker TA, Mosenzon O, Cahn A, Kuder J, Murphy SA, Bhatt DL, Leiter LA, Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction: Subanalysis from the DECLARE-TIMI 58 trial. Circulation 2019 139 2516 2527. doi: 10.1161/CIRCULATIONAHA.119.039996
47. Arnold SV, Echouffo-Tcheugui JB, Lam CSP, Inzucchi SE, Tang F, McGuire DK, Goyal A, Maddox TM, Sperling LS, Fonarow GC, Patterns of glucose-lowering medication use in patients with type 2 diabetes and heart failure. Insights from the Diabetes Collaborative Registry (DCR). Am Heart J 2018 203 25 29. doi: 10.1016/j.ahj.2018.05.016
48. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Bansilal S, Bhatt DL, Leiter LA, The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J 2018 200 83 89. doi: 10.1016/j.ahj.2018.01.012
49. Junod S, Davies M, Kermani F, FDA and clinical drug trials: A short history. In: A Quick Guide to Clinical Trials 2016 2nd ed Rockville, MD Bioplan Inc 25 55
50. D'Agostino RB, Heeren TC, Multiple comparisons in over-the-counter drug clinical trials with both positive and placebo controls. Stat Med 1991 10 1 6. discussion 7. doi: 10.1002/sim.4780100102
51. Dmitrienko A, D'Agostino RB Sr., Multiplicity considerations in clinical trials. N Engl J Med 2018 378 2115 2122. doi: 10.1056/NEJMra1709701
52. Food and Drug Administration Multiple endpoints in clinical trials: Guidance for industry. 2017. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm536750.pdf. Accessed April 8, 2019
53. European Medicines Agency Points to consider on multiplicity issues in clinical trials. 2002. https://www.ema.europa.eu/en/documents/scientific-guideline/points-consider-multiplicity-issues-clinical-trials-en.pdf. Accessed April 9, 2019
54. Digitalis Investigation Group The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997 336 525 533. doi: 10.1056/NEJM199702203360801
55. Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E, PIONEER-HF Investigators Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019 380 539 548. doi: 10.1056/NEJMoa1812851
56. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, Smith LK, Van Voorhees L, Gourley LA, Jolly MK, Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993 329 1 7. doi: 10.1056/NEJM199307013290101
57. Yusuf S, Pitt B, Davis CE, Hood WB Jr, Cohn JN, SOLVD Investigators Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992 327 685 691. doi: 10.1056/NEJM199209033271003
58. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN, SOLVD Investigators Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991 325 293 302. doi: 10.1056/NEJM199108013250501
59. Dargie HJ, Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001 357 1385 1390. doi: 10.1016/s0140-6736(00)04560-8
60. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992 327 669 677. doi: 10.1056/NEJM199209033271001
61. Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, African-American Heart Failure Trial Investigators Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004 351 2049 2057. doi: 10.1056/NEJMoa042934
62. Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L, Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: Analysis from the SHIFT study. Clin Res Cardiol 2013 102 11 22. doi: 10.1007/s00392-012-0467-8
63. Patel RB, Vaduganathan M, Greene SJ, Butler J, Nomenclature in heart failure: A call for objective, reproducible, and biologically-driven terminology. Eur J Heart Fail 2018 20 1379 1381. doi: 10.1002/ejhf.1231