|Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review
|Aaron Y. Kluger1, 2, *(), Kristen M. Tecson1, 2, 3, Clay M. Barbin4, 5, Andy Y. Lee4, 5, Edgar V. Lerma6, Zachary P. Rosol4, 5, Janani Rangaswami7, 8, Norman E. Lepor9, 10, Michael E. Cobble11, Peter A. McCullough1, 3, 4, 5
|1 Baylor Heart and Vascular Institute, Dallas, TX, 75226
2 Baylor Scott & White Research Institute, Dallas, TX, 75226
3 Texas A & M College of Medicine Health Science Center, Dallas, TX, 75226
4 Baylor University Medical Center, Dallas, TX, 75226
5 Baylor Heart and Vascular Hospital, Dallas, TX, 75226
6 UIC/Advocate Christ Medical Center, Oak Lawn, IL, 60453
7 Einstein Medical Center, Philadelphia, PA, 19141
8 Sidney Kimmel College of Thomas Jefferson University, Philadelphia, PA, 19107
9 David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095
10 Cedars-Sinai Medical Center, Los Angeles, CA, 90048
11 University of Utah School of Medicine, Salt Lake City, UT, 84132
In this systematic review, we sought to summarize the 3 recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials (Dapagliflozin Effect on CardiovasculAR Events (DECLARE-TIMI 58), Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, and Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)) and to explore the potential causes for their different results. We found that the major adverse cardiovascular event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14% for DECLARE-TIMI 58, CANVAS, and EMPA-REG OUTCOME, respectively. DECLARETIMI 58 had the fewest cardiorenal events (across treatment and control arms) and EMPA-REG OUTCOME the most. DECLARE-TIMI 58 used alternative inclusion criterion for baseline renal function (creatinine clearance ≧ 60 mL/min) compared to the other trials (estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 bodysurface area). Therefore, the DECLARE-TIMI 58 study cohort had higher eGFR (mean eGFR 85.2 mL/min/1.73 m2 compared to 76.5 and 74 in CANVAS and EMPAREG OUTCOME, respectively); this may have caused the difference in results. Additionally contributing to the high event rate in EMPA-REG OUTCOME was the requirement of prior confirmed cardiovascular disease (CVD), resulting in 99.2% of patients with CVD compared to only 65.6% and 40.6% in CANVAS and DECLARE-TIMI 58, respectively (which did not require CVD). In conclusion, there is a need for large-scale studies of SGLT2i with matching inclusion/exclusion criteria and appropriate endpoints to ensure a truly direct comparison of the drugs.
Published: 30 June 2018
Aaron Y. Kluger, E-mail: firstname.lastname@example.org
Cite this article:
Aaron Y. Kluger, Kristen M. Tecson, Clay M. Barbin, Andy Y. Lee, Edgar V. Lerma, Zachary P. Rosol, Janani Rangaswami, Norman E. Lepor, Michael E. Cobble, Peter A. McCullough. Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review. Reviews in Cardiovascular Medicine, 2018, 19(2): 41-49.
https://rcm.imrpress.com/EN/10.31083/j.rcm.2018.02.907 OR https://rcm.imrpress.com/EN/Y2018/V19/I2/41
|  Altman DG, Bland JM. How to obtain the P value from a confidence interval. BMJ. 2011;343:d2304.
 Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017;376:2367-2375.
 Becker BN; Vassalotti JA. A software upgrade: CKD testing in 2010. Am J Kidney Dis. 2010;55:8-10.
 Birkeland KI, Bodegard J, Norhammar A, et al. How Representative are the Patients Included in the CV outcome Trials with SGLT2 Inhibitors of a General Type 2 Diabetes Population? A Large European Observational study. Diabetes Obes Metab. 2018.
 Cannon CP, McGuire DK, Pratley R, et al. VERTIS-CV Investigators. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J. 2018;206:11-23.
 Cavallari I; Maddaloni E. Cardiovascular effects of SGLT-2 inhibitors: What we have learned from cardiovascular outcome trials and what we still need to understand. Diabetes Metab Res Rev. 2019:e3124.
 Chang TI, Li S, Chen SC, et al. KEEP Investigators. Risk factors for ESRD in individuals with preserved estimated GFR with and without albuminuria: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis. 2013;61:S4-S11.
 Clinical Trials.gov [Internet]. Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004) . C2018.
 Douros A, Dell'Aniello S, Yu OHY, et al. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ. 2018;362:k2693.
 Drugs.com: Know More. Be Sure [Internet]. Steglatro. 2018. Available from: https://www.drugs.com/pro/steglatro.html#S5.3.
 Drugs.com: Know More. Be Sure [Internet]. Jardiance. c2018. Available from: https://www.drugs.com/pro/jardiance.html.
 Drugs.com: Know More. Be Sure [Internet]. Invokana. c2018. Available from: https://www.drugs.com/pro/invokana.html.
 Drugs.com: Know More. Be Sure [Internet]. Farxiga. 2018. Available from: https://www.drugs.com/pro/farxiga.html.
 Fitchett DH, Udell JA and Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2017;19:43-53.
 Gilbert MP, Pratley RE. The impact of diabetes and diabetes medications on bone health. Endocr Rev. 2015;36:194-213.
 Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125-35.
 Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013 Jul 20;382(9888):260-72. doi: 10.1016/S0140-6736(13)60687- X. Epub 2013 May 31. Review. Erratum in: Lancet. 2013;382:208.
 Kastarinen M, Juutilainen A, Kastarinen H, et al. Risk factors for endstage renal disease in a community-based population: 26-year follow-up of 25,821 men and women in eastern Finland. J Intern Med. 2010;267:612-20.
 Kaneko M, Narukawa M. Assessment of the Risk of Hospitalization for Heart Failure With Dipeptidyl Peptidase-4 Inhibitors, Saxagliptin, Alogliptin, and Sitagliptin in Patients With Type 2 Diabetes, Using an Alternative Measure to the Hazard Ratio. Ann Pharmacother. 2017;51:570-576.
 American Heart Association; American College Of Cardiology Foundation. Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College Of Cardiology Foundation. J Am Coll Cardiol. 2010;55:1885-94.
 Kosiborod M, Cavender MA, Fu AZ, et al. CVD-REAL Investigators and Study Group*. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249-259.
 Kosiborod M, Lam CSP, Kohsaka S, et al. CVD-REAL Investigators and Study Group. Cardiovascular Events Associated With SGLT- 2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018;71:2628-2639.
 Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604-612.
Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ. 2014;348:g2366.
 Lincoff AM, Wolski K, Nicholls SJ et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Jama. 2007;298:1180-8.
 Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068-72.
 McCullough PA, Patanker G, Stoler RC. Estimating Renal Filtration, Drug Dosing, and Clinical Outcomes. J Am Coll Cardiol. 2015;65:2724-5.
 McMurray JJ, Gerstein HC, Holman RR, et al. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2:843-51.
 Mitchell M, Muftakhidinov B, Winchen T [Internet]. Engauge Digitizer Software. c2018.
 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-269.
 Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133:e38-360.
 Neal B, Perkovic V, Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin cardiovascular assessment study (CANVAS)–a randomized placebo-controlled trial. Am Heart J. 2013;166:217-223.
 Neal B, Perkovic V, Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin cardiovascular assessment study (CANVAS)-a randomized placebo-controlled trial. Am Heart J. 2013;166:217-223.
 Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function. Circulation. 2018;138:1537-1550.
 O’Brien MJ, Karam SL, Wallia A, et al. Association of Secondline Antidiabetic Medications With Cardiovascular Events Among Insured Adults With Type 2 Diabetes. JAMA Netw Open. 2018;1:e186125.
 Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. The New England journal of medicine. 2006;355:251-9
 Penman A, Hancock H, Papavasileiou E, et al. Risk Factors for Proliferative Diabetic Retinopathy in African Americans with Type 2 Diabetes. Ophthalmic Epidemiol. 2016;23:88-93.
 Powell WR, Christiansen CL, Miller DR. Meta-Analysis of Sulfonylurea Therapy on Long-Term Risk of Mortality and Cardiovascular Events Compared to Other Oral Glucose-Lowering Treatments. Diabetes Ther. 2018;9:1431-1440.
 Sarnak MJ, Levey AS, Schoolwerth AC, et al. American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension. 2003;42:1050-65.
 Scheen AJ. Pharmacodynamics, efficacy and safety of sodiumglucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33-59.
 Scheen AJ. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease. Clin Pharmacokinet. 2015;54:691-708.  Scirica BM, Bhatt DL, Braunwald E, et al. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-26.
 Stevens LA, Li S, Kurella Tamura M, et al. Comparison of the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) study equations: risk factors for and complications of CKD and mortality in the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis. 2011;57:S9-16.
 Thomas MC, Tsalamandris C, MacIsaac RJ, et al. The epidemiology of hemoglobin levels in patients with type 2 diabetes. Am J Kidney Dis. 2006;48:537-45.
 Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108-2117.
 Wanner C, Inzucchi SE, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375:323-34.
 Wattanakit K, Folsom AR, Chambless LE, et al. Risk factors for cardiovascular event recurrence in the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J. 2005;149:606-12.
 Werner K, Christensson A, Legrand H, et al. Cystatin C and creatinine-based eGFR levels and their correlation to long-term morbidity and mortality in older adults. Aging Clin Exp Res. 2018.
 Wittbrodt ET, Eudicone JM, Bell KF, et al. Eligibility varies among the 4 sodium-glucose cotransporter-2 inhibitor cardiovascular outcomes trials: implications for the general type 2 diabetes US population. Am J Manag Care. 2018;24:S138-S145.
 Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Bansilal S, Bhatt DL, Leiter LA, McGuire DK, Wilding JP, Gause-Nilsson IA, Langkilde AM, Johansson PA, Sabatine MS. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J. 2018;200:83-89.
 Wiviott SD, Raz I, Bonaca MP, et al. DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2018;380:4.
 World Health Organization. Global Report on Diabetes [Internet]. c2016. Available from http://apps.who.int/iris/bitstream/10665/204871/1/978924 1565257_eng.pdf?ua=1.
 Writing Committee, Das SR, Everett BM, et al. 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;3200-23.
 Zannad F, Stough WG, Lipicky RJ, et al. Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion. Eur Heart J Cardiovasc Pharmacother. 2016;2:200-5.
 Zelniker TA, Braunwald E. Cardiac and Renal Effects of Sodium- Glucose Co-Transporter 2 Inhibitors in Diabetes: JACC State-ofthe- Art Review. J Am Coll Cardiol. 2018;72:1845-1855.
 Zelniker TA, Wiviott SD, Raz I, et al. 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.
 Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOMETM). Cardiovasc Diabetol. 2014;13:102.
 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. The New England journal of medicine. 2015;373:2117-28.
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