Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™)

Bernard Zinman, Silvio E Inzucchi, John M Lachin, Christoph Wanner, Roberto Ferrari, David Fitchett, Erich Bluhmki, Stefan Hantel, Joan Kempthorne-Rawson, Jennifer Newman, Odd Erik Johansen, Hans-Juergen Woerle, Uli C Broedl, Bernard Zinman, Silvio E Inzucchi, John M Lachin, Christoph Wanner, Roberto Ferrari, David Fitchett, Erich Bluhmki, Stefan Hantel, Joan Kempthorne-Rawson, Jennifer Newman, Odd Erik Johansen, Hans-Juergen Woerle, Uli C Broedl

Abstract

Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.

Methods: Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.

Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m2, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m2. The study is expected to report in 2015.

Discussion: EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.

Trial registration: Clinicaltrials.gov NCT01131676.

Figures

Figure 1
Figure 1
Study design.

References

    1. American Diabetes Association. Standards of medical care in diabetes–2013. Diabetes Care. 2013;36(Suppl 1):S11–S66.
    1. Collaboration ERF, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingrlsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–2222.
    1. Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal TP, Hemmingsen C, Wetterlev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;11 CD008143.
    1. Ninomiya T, Perkovic V, De Galan BE, Zoungas S, Pillai A, Jardine M, Patel A, Cass A, Neal B, Poulter N, Mogensen CE, Cooper M, Marre M, Williams B, Hamet P, Mancia G, Woodward M, Machmahon S, Chalmers J. ADVANCE Collaborative Group. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813–1821.
    1. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, Marinopoulos SS, Puhan MA, Ranasingher P, Block L, Nicholson WK, Hutfless S, Bass EB, Bolen S. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602–613.
    1. Rosenstock J, Marx N, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Bluhmki E, Patel S, Johansen OE, Woerle HJ. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res. 2013;10:289–301.
    1. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J. 1991;121:1244–1263.
    1. Lee SJ, Leipzig RM. Incorporating lag time to benefit into prevention decisions for older adults. JAMA. 2013;310:2609–2610.
    1. Food and Drug Administration (Center for Drug Evaluation and Research) Guidance for Industry: Diabetes Mellitus - Eevaluating Cardiovascular risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. . (accessed November 15, 2013)
    1. European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products in the Treatment or Prevention of Diabetes Mellitus. 2012. . (accessed November 15, 2013)
    1. Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32:515–531.
    1. 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;14:83–90.
    1. Häring H-U, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, Broedl UC. EMPA-REG METSU Trial Investigators. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396–3404.
    1. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC. EMPA-REG PIO™ Trial Investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16:147–158.
    1. Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, Broedl UC. EMPA-REG MONO Trial Investigators. Empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a randomised, 24-week, double-blind, placebo-controlled, parallel group, trial with sitagliptin as active comparator. Lancet Diabetes Endocrinol. 2013;1:208–219.
    1. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ. Empagliflozin improves blood pressure in patients with type 2 diabetes (T2DM) and hypertension. Diabetologia. 2013;56(suppl 1):S377 [942].
    1. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC. EMPA-REG RENAL Trial Investigators. Efficacy and safety of empagliflozin added to existing anti-diabetes therapy in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:369–384.
    1. Cherney DZI, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, Woerle HJ, Von Eynatten M, Broedl UC. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.
    1. Cherney DZI, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan N, Woerle HJ, Johansen OE, Broedl UC, Von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–597.
    1. Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, Sugg J, Parikh S. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16:159–169.
    1. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin 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;382:941–950.
    1. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15:463–473.
    1. Fleming T, Sharples K, McCall J, Moore A, Rodgers A, Stewart R. Maintaining confidentiality of interim data to enhance trial integrity and credibility. Clinical Trials. 2008;5:157–167.
    1. Neal B, Perkovic V, De Zeeuw D, Mahaffey KW, Fulcher G, Stein P, Desai M, Shaw W, Jiang J, Vercruysse F, Meininger G, Matthews D. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)–a randomized placebo-controlled trial. Am Heart J. 2013;166:217–223.
    1. Burns KD, Perkins BA, Soleymanlou N, Xiao F, Zimpelmann J, Woerle HJ, Johansen OE, Broedl UC, Von Eynatten M, Cherney DZI. Sodium glucose cotransport-2 inhibition increases urinary ACE2 levels in patients with type 1 diabetes. Diabetes. 2014;S1:543-P.
    1. Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306:F194–F204.
    1. Hach T, Gerich J, Salsali A, Kim G, Hantel S, Woerle HJ, Broedl UC. Empagliflozin improves glycemic parameters and cardiovascular risk factors in patients with type 2 diabetes (T2DM): pooled data from four pivotal Phase III trials. Diabetes. 2013;62(suppl 1A):LB19 [69-LB].
    1. Gilbert RE. Sodium-glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering? Kidney Int. 2013. doi:10.1038/ki.2013.451 [Epub ahead of print]

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi