Empagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk

Empagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk Silvio E Inzucchi, Christoph Wanner, J...
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Empagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk Silvio E Inzucchi, Christoph Wanner, John M Lachin, David Fitchett, Stefan Hantel, Michaela Mattheus, Theresa Devins, Odd Erik Johansen, Hans J Woerle, Uli C Broedl, Bernard Zinman

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Disclosures: Silvio E Inzucchi • Professor of Medicine, Yale University School of Medicine, New Haven, CT, USA • Consultations and non-financial support – Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Poxel, Takeda, Eli Lilly

• CME funding to Yale University – Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbott, Merck and Sanofi

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Diabetes and heart failure • Heart failure is highly prevalent in patients with diabetes,1,2 occurring in >1 in 5 patients aged over 65 years.1 • Patients with both diabetes and heart failure have a poor prognosis, with a median survival ~4 years.3 • Glucose-lowering options for patients with type 2 diabetes and heart failure are limited. Meta-analysis of more vs. less intensive glucose control showed no benefit on heart failure hospitalization or death.4 • Specific glucose-lowering medications have not been shown to improve heart failure outcomes, and some may actually have deleterious effects.5-7 1. 2. 3. 4.

Bertoni AG et al. Diabetes Care 2004;27:699-703 Shah AD et al. Lancet Diabetes Endocrinol 2015;3:105-113 5. Lago RM et al. Lancet 2007;370:1129-1133. Cubbon RM et al. Diab Vasc Dis Res 2013;10:330-336 6. Scirica BM et al. Circulation 2014:130;1579-1588 Turnbull FM et al. Diabetologia 2009;52:288-2298 7. Smooke S et al. Am Heart J 2005;149:168-174

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Empagliflozin • Virtually all glucose filtered by the kidney is reclaimed in the proximal tubule.1 Sodium glucose cotransporter 2 (SGLT2) is responsible for 90% of this reabsorption. • Empagliflozin is a highly selective inhibitor of SGLT2.2 • By reducing renal glucose reabsorption, empagliflozin increases urinary glucose excretion.3 • In patients with type 2 diabetes, empagliflozin leads to:4 – Significant reductions in HbA1c – Weight loss – Reductions in BP without increases in heart rate 1. 2. 3. 4.

Abdul-Ghani et al. Curr Diab Rep. 2012;12:230-8. Grempler et al. Diabetes Obes Metab.2012 ;14:83-90. Heise T et al. Diabetes Obes Metab 2013;15:613-21. Liakos A et al. Diabetes Obes Metab 2014;16:984-93.

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EMPA-REG OUTCOME® Trial design Screening (n=11531)

Randomized and treated (n=7020)

Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342)

• Study medication was given in addition to standard of care. • The trial was to continue until ≥ 691 patients experienced an adjudicated primary outcome event. • Key inclusion criteria: – Adults with type 2 diabetes and established CVD – BMI ≤45 kg/m2; HbA1c 7–10%; eGFR ≥30 mL/min/1.73m2 (MDRD) CV, cardiovascular; BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease. Zinman B et al. N Engl J Med 2015 [Epub ahead of print].

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Planned outcomes and analyses • Primary outcome: 3-point MACE • Further outcomes included: heart failure hospitalization or CV death, hospitalization for heart failure, all-cause mortality • Analysis compared empagliflozin 10 mg and 25 mg (pooled) vs. placebo in patients treated with ≥1 dose of study drug (intent-to-treat population) • Secondary analyses included comparisons of individual empagliflozin doses vs. placebo • Subgroup analyses were based on baseline characteristics, including the presence/absence of investigator-reported heart failure 3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke. MACE, Major Adverse Cardiovascular Event; CV, cardiovascular; MI, myocardial infarction. Zinman B et al. N Engl J Med 2015 [Epub ahead of print].

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Baseline characteristics: Demographics & DM Placebo (n=2333)

Empagliflozin 10 mg (n=2345)

Empagliflozin 25 mg (n=2342)

Age, years

63.2 (8.8)

63.0 (8.6)

63.2 (8.6)

Body mass index, kg/m2

30.7 (5.2)

30.6 (5.2)

30.6 (5.3)

8.08 (0.84)

8.07 (0.86)

8.06 (0.84)

1339 (57.4)

1354 (57.7)

1318 (56.3)

1734 (74.3)

1729 (73.7)

1730 (73.9)

992 (42.5)

985 (42.0)

1029 (43.9)

101 (4.3)

96 (4.1)

102 (4.4)

1135 (48.6)

1132 (48.3)

1120 (47.8)

65 (50.6)

65 (47.9)

66 (48.9)

HbA1c, % >10 years of diabetes DM Meds Metformin Sulphonylurea Thiazolidinedione Insulin Mean daily dose, U** *Includes Australia and New Zealand

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Baseline characteristics: CV history Placebo (n=2333)

Empagliflozin 10 mg (n=2345)

Empagliflozin 25 mg (n=2342)

2307 (98.9%)

2333 (99.5%)

2324 (99.2%)

- MI

1083 (46.4%)

1107 (47.2%)

1083 (46.2%)

- CABG

563 (24.1%)

594 (25.3%)

581 (24.8%)

- Stroke

553 (23.7%)

535 (22.8%)

549 (23.4%)

244 (10.5%)

240 (10.2%)

222 (9.5%)

1773 (76.0%) 1927 (82.6%)

1827 (77.9%) 1939 (82.7%)

1803 (77.0%) 1937 (82.7%)

1868 (80.1%)

1896 (80.9%)

1902 (81.2%)

LDL-C

84.9 (35.3)

86.3 (36.7)

85.5 (35.2)

eGFR

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