Journal Club 2015年9月24日 8:30-8:55 ８階 医局 Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. September 17, 2015DOI: 10.1056/NEJMoa1504720 2015年9月24日　8:30-8:55 ８階　医局 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文　 Matsuda, Masafumi

Meta-analysis of intensive glucose control in T2DM: major CV events including heart failure Number of events More intensive Less intensive Difference in HbA1c (%) HR (95% CI) Stroke 378 370 -0.88 0.96 (0.83, 1.10) Myocardial infarction 730 745 0.85 (0.76, 0.94) Hospitalisation for or death from heart failure 459 446 1.00 (0.86, 1.16) Favours more intensive Favours less intensive Meta-analysis of 27,049 participants and 2370 major vascular events from: ADVANCE UKPDS ACCORD VADT HR, hazard ratio; CV, cardiovascular Turnbull FM et al. Diabetologia 2009;52:2288–2298

Meta-analysis of intensive glucose control in T2DM: mortality Number of events More intensive Less intensive Difference in HbA1c (%) HR (95% CI) All-cause mortality 980 884 -0.88 1.04 (0.90,1.20) CV death 497 441 1.10 (0.84,1.42) Non-CV death 476 432 1.02 (0.89,1.18) Favours more intensive Favours less intensive Meta-analysis of 27,049 participants and 2370 major vascular events from ADVANCE UKPDS ACCORD VADT HR, hazard ratio; CV, cardiovascular Turnbull FM et al. Diabetologia 2009;52:2288–2298

DPP4阻害薬、GLP-1受容体作動薬、SGLT2阻害薬の心血管障害への影響 Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; 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. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–1335. European Heart Journal doi:10.1093/eurheartj/ehv239

Press Release Archive: Diabetes 20 August 2015 Jardiance® demonstrated cardiovascular (CV) risk reduction in people with type 2 diabetes at high risk for CV events Ingelheim, Germany and Indianapolis, US, 20 August, 2015 – Boehringer Ingelheim and Eli Lilly and Company today announced positive top-line results from EMPA-REG OUTCOME®. This is a long-term clinical trial investigating cardiovascular (CV) outcomes for Jardiance® (empagliflozin) in more than 7,000 adults with type 2 diabetes (T2D) at high risk for CV events. EMPA-REG OUTCOME® met its primary endpoint and demonstrated superiority of Jardiance®, when added to standard of care, in CV risk reduction. The primary endpoint was defined as time to first occurrence of either CV death, or non-fatal myocardial infarction or non-fatal stroke. Jardiance® is the only glucose-lowering agent to have demonstrated CV risk reduction in a dedicated cardiovascular outcomes trial. 51st EASD Annual Meeting, Stockholm, Sweden, 14-18 September 2015 http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/20_august_2015_diabetes.html

埼玉医科大学総合医療センター　内分泌・糖尿病内科

N Engl J Med. September 17, 2015DOI: 10.1056/NEJMoa1504720 From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) and the Divisions of Endocrinology (B.Z.) and Cardiology (D.F.), University of Toronto — all in Toronto; the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), Boehringer Ingelheim Pharma, Biberach (E.B., S.H.), and Boehringer Ingelheim Pharma, Ingelheim (M.M., H.J.W., U.C.B.) — all in Germany; the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (T.D.); Boehringer Ingelheim Norway, Asker, Norway (O.E.J.); and the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.). N Engl J Med. September 17, 2015DOI: 10.1056/NEJMoa1504720

Background The effects of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.

Methods We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.

Participating countries 590 sites in 42 countries Participating countries (42): Argentina Australia Austria Belgium Brazil Canada Colombia Croatia Czech Republic Denmark Estonia France Georgia Greece Hong Kong Hungary India Indonesia Israel Italy Japan Korea Malaysia Mexico Netherlands New Zealand Norway Peru Philippines Poland Portugal Romania Russia Singapore South Africa Spain Sri Lanka Taiwan Thailand Ukraine United Kingdom United States North America, Australia, New Zealand Latin America Asia Africa Europe

Randomised and treated Trial design Placebo (n=2333) Screening (n=11531) Randomised and treated (n=7020) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Study medication was given in addition to standard of care Glucose-lowering therapy was to remain unchanged for first 12 weeks Treatment assignment double masked The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event

Key inclusion and exclusion criteria Key inclusion criteria Adults with type 2 diabetes BMI ≤45 kg/m2 HbA1c 7–10%* Established cardiovascular disease Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease Key exclusion criteria eGFR <30 mL/min/1.73m2 (MDRD) BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease *No glucose-lowering therapy for ≥12 weeks prior to randomisation or no change in dose for ≥12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation

Pre-specified primary and key secondary outcomes Primary outcome 3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke Key secondary outcome 4-point MACE: Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event

Baseline characteristics 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) Male 1680 (72.0) 1653 (70.5) 1683 (71.9) Region Europe 959 (41.1) 966 (41.2) 960 (41.0) North America* 462 (19.8) 466 (19.9) Asia 450 (19.3) 447 (19.1) 450 (19.2) Latin America 360 (15.4) 359 (15.3) 362 (15.5) Africa 102 (4.4) 107 (4.6) 104 (4.4) tlr-1245_0025final—01-1501. Table 15.1.4.1: 1 Demographic data − treated set. Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug *Includes Australia and New Zealand

Baseline characteristics: type 2 diabetes Placebo (n=2333) Empagliflozin 10 mg (n=2345) 25 mg (n=2342) HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84) Time since diagnosis of type 2 diabetes, years ≤5 423 (18.1) 406 (17.3) 434 (18.6) >5 to 10 571 (24.5) 585 (24.9) 590 (25.2) >10 1339 (57.4) 1354 (57.7) 1318 (56.3) Glucose-lowering medication* Metformin 1734 (74.3) 1729 (73.7) 1730 (73.9) Sulphonylurea 992 (42.5) 985 (42.0) 1029 (43.9) Thiazolidinedione 101 (4.3) 96 (4.1) 102 (4.4) Insulin 1135 (48.6) 1132 (48.3) 1120 (47.8) Mean daily dose, U** 65 (50.6) 65 (47.9) 66 (48.9) Table 15.1.4.1: 1 Table 15.2.4.3.8: 5 but updated by MM (awaiting final PDF). Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug *Medication taken alone or in combination **Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg, n=1120

Baseline characteristics: CV risk factors LDL cholesterol, mg/dL 84.9 (35.3) 86.3 (36.7) 85.5 (35.2) HDL cholesterol, mg/dL 44.0 (11.3) 44.7 (12.0) 44.5 (11.8) eGFR, mL/min/1.73m2 (MDRD) 73.8 (21.1) 74.3 (21.8) 74.0 (21.4) ≥90 mL/min/1.73m2 488 (20.9%) 519 (22.1%) 531 (22.7%) 60 to <90 mL/min/1.73m2 1238 (53.1%) 1221 (52.1%) 1204 (51.4%) <60 mL/min/1.73m2 607 (26.0%) 605 (25.8%) 607 (25.9%) Systolic blood pressure, mmHg 135.8 (17.2) 134.9 (16.8) 135.6 (17.0) Diastolic blood pressure, mmHg 76.8 (10.1) 76.6 (9.8) 76.6 (9.7) Heart rate, bpm* 70.7 (0.2) 71.0 (0.2) 70.5 (0.2) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Body mass index, kg/m2 30.7 (5.2) 30.6 (5.2) 30.6 (5.3) Weight, kg 86.6 (19.1) 85.9 (18.8) 86.5 (19.0) Waist circumference, cm 105.0 (14.0) 104.7 (13.7) 104.8 (13.7) tlr-1245_0025final—01-1501. Table 15.1.4.1: 1 Demographic data − treated set; Table 15.1.4.2: 4 Baseline efficacy and other variables − treated set. tlr-1245_0025final—01-1502. Table 15.2.4.3.5.1: 3 Descriptive statistics for SBP (mmHg) over time up to week 94 − treated set; Table 15.2.4.3.6.1: 3 Descriptive statistics for DBP (mmHg) over time up to week 94 − treated set. Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug *Mean (SE). LDL, low density lipoprotein; HDL, high density lipoprotein; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease equation

Baseline characteristics: CV complications Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Any CV risk factor 2307 (98.9%) 2333 (99.5%) 2324 (99.2%) Coronary artery disease 1763 (75.6%) 1782 (76.0%) 1763 (75.3%) Multi-vessel coronary artery disease 1100 (47.1%) 1078 (46.0%) 1101 (47.0%) History of MI 1083 (46.4%) 1107 (47.2%) 1083 (46.2%) Coronary artery bypass graft 563 (24.1%) 594 (25.3%) 581 (24.8%) History of stroke 553 (23.7%) 535 (22.8%) 549 (23.4%) Peripheral artery disease 479 (20.5%) 465 (19.8%) 517 (22.1%) Single vessel coronary artery disease 238 (10.2%) 258 (11.0%) 240 (10.2%) Cardiac failure* 244 (10.5%) 222 (9.5%) tlr-1245_0025final—01-1501. Table 15.1.4.2: 1 Baseline cardiovascular high risk factors − treated set 1245_0025final—01-1501. Table 15.1.4.2: 3 Cardiac failure (narrow SMQ 20000004) diagnosis at baseline − treated set CAD defined as any of the components of history of MI, CABG, multivessel CAD, or single vessel CAD. Information on single vessel coronary artery disease was not available for one patient in the placebo group. Cardiac failure: based on narrow standardised MedDRA query ‘cardiac failure’. Data are n (%) in patients treated with ≥1 dose of study drug *Based on narrow standardised MedDRA query “cardiac failure”

Baseline characteristics: CV medication (1) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Anti-hypertensive therapy 2221 (95.2%) 2227 (95.0%) 2219 (94.7%) ACE inhibitors/ARBs 1868 (80.1%) 1896 (80.9%) 1902 (81.2%) Beta-blockers 1498 (64.2%) 1530 (65.2%) 1526 (65.2%) Diuretics 988 (42.3%) 1036 (44.2%) 1011 (43.2%) Calcium channel blockers 788 (33.8%) 781 (33.3%) 748 (31.9%) Mineralocorticoid receptor antagonists 136 (5.8%) 157 (6.7%) 148 (6.3%) Renin inhibitors 19 (0.8%) 16 (0.7%) 11 (0.5%) Other 191 (8.2%) 193 (8.2%) 190 (8.1%) 1245_0025final—01-1501. Table 15.1.4.3: 1 Anti−coagulants, lipid−lowering, antihypertensive and heart failure drugs at baseline − treated set Data are n (%) in patients treated with ≥1 dose of study drug ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers

Baseline characteristics: CV medication (2) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Lipid-lowering drugs 1864 (79.9%) 1926 (82.1%) 1894 (80.9%) Statins 1773 (76.0%) 1827 (77.9%) 1803 (77.0%) Fibrates 199 (8.5%) 214 (9.1%) 217 (9.3%) Ezetimibe 81 (3.5%) 95 (4.1%) 94 (4.0%) Niacin 35 (1.5%) 56 (2.4%) Other 175 (7.5%) 172 (7.3%) 193 (8.2%) Anti-coagulants and anti-platelets 2090 (89.6%) 2098 (89.5%) 2064 (88.1%) Acetylsalicylic acid 1927 (82.6%) 1939 (82.7%) 1937 (82.7%) Clopidogrel 249 (10.7%) 253 (10.8%) 241 (10.3%) Vitamin K antagonists 156 (6.7%) 141 (6.0%) 125 (5.3%) 1245_0025final—01-1501. Table 15.1.4.3: 1 Anti−coagulants, lipid−lowering, antihypertensive and heart failure drugs at baseline − treated set Data are n (%) in patients treated with ≥1 dose of study drug

Exposure Placebo (n=2333) Empagliflozin 10 mg (n=2345) Treatment duration, years 2.6 (1.8-3.4) 2.6 (1.9-3.4) 2.6 (2.0-3.4) Observation time, years 3.1 (2.2-3.5) 3.2 (2.2-3.6) Data are median (interquartile range) in patients treated with ≥1 dose of study drug 1245_0025final—01-1501. Table 15.1.5: 1 Exposure to study drug − treated set; Table 15.1.5: 2 Overall observational period − treated set

HbA1c 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.1.3: 1 HbA1c (%) change from baseline MMRM results over time − FAS (OC−AD) 12 28 40 52 66 80 94 108 122 136 150 164 178 192 206 Placebo 2294 2272 2188 2133 2113 2063 2008 1967 1741 1456 1241 1109 962 705 420 151 Empagliflozin 10 mg 2296 2272 2218 2150 2155 2108 2072 2058 1805 1520 1297 1164 1006 749 488 170 Empagliflozin 25 mg 2296 2280 2212 2152 2150 2115 2080 2044 1842 1540 1327 1190 1043 795 498 195 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

Weight Placebo Empagliflozin 10 mg 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.3.3: 1 Weight (kg) change from baseline MMRM results over time − treated set (OC−AD) Empagliflozin 25 mg 12 28 52 108 164 220 Placebo 2285 1915 2215 2138 1598 1239 425 Empagliflozin 10 mg 2290 1893 2238 2174 1673 1298 483 Empagliflozin 25 mg 2283 1891 2226 2178 1678 1335 489 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

Waist circumference Placebo Empagliflozin 10 mg 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.4.3: 1 Waist circumference (cm) change from baseline MMRM results over time − treated set (OC−AD) Empagliflozin 25 mg 12 28 52 108 164 220 Placebo 2259 1869 2183 2110 1562 1220 418 Empagliflozin 10 mg 2272 1836 2219 2155 1644 1285 475 Empagliflozin 25 mg 2273 1857 2209 2157 1648 1329 486 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

Systolic blood pressure Placebo Empagliflozin 25 mg 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.5.3: 1 SBP (mmHg) change from baseline MMRM results over time − treated set (OC−AD) Empagliflozin 10 mg 16 28 40 52 66 80 94 108 122 136 150 164 178 192 206 Placebo 2322 2235 2203 2161 2133 2073 2024 1974 1771 1492 1274 1126 981 735 450 171 Empagliflozin 10 mg 2322 2250 2235 2193 2174 2125 2095 2072 1853 1556 1327 1189 1034 790 518 199 Empagliflozin 25 mg 2323 2247 2221 2197 2169 2129 2102 2066 1878 1571 1351 1212 1070 842 528 216 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

Diastolic blood pressure Placebo Empagliflozin 25 mg 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.6.3: 1 DBP (mmHg) change from baseline MMRM results over time − treated set (OC−AD) Empagliflozin 10 mg 16 28 40 52 66 80 94 108 122 136 150 164 178 192 206 Placebo 2322 2235 2203 2161 2133 2073 2024 1974 1771 1492 1274 1126 981 735 450 171 Empagliflozin 10 mg 2322 2250 2235 2193 2174 2125 2095 2072 1853 1556 1327 1189 1034 790 518 199 Empagliflozin 25 mg 2323 2247 2221 2197 2169 2129 2102 2066 1878 1571 1351 1212 1070 842 528 216 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

Heart rate (ECG) Empagliflozin 10 mg 1245_0025final--01-1503--study-report-body (1). Table 15.3.3.2.3: 1 Heart rate (bpm) change from baseline MMRM results over time - treated set (OC-AD) Placebo Empagliflozin 25 mg 28 52 80 108 136 164 192 Placebo 2174 2127 2032 1928 1796 1300 1002 552 Empagliflozin 10 mg 2205 2137 2064 2006 1877 1366 1045 597 Empagliflozin 25 mg 2192 2127 2066 2006 1907 1383 1086 633 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

Low-density lipoprotein cholesterol Placebo 1245_0025final--01-1503--study-report-body (1). Table 15.3.2.4.3.3: 1 LDL cholesterol (mg/dL) change from baseline MMRM results over time − treated set (OC−AD) Empagliflozin 25 mg Empagliflozin 10 mg 4 28 52 80 108 136 164 192 Placebo 2297 2273 2179 2104 2006 1932 1419 1086 694 Empagliflozin 10 mg 2294 2269 2205 2143 2072 1998 1474 1133 740 Empagliflozin 25 mg 2287 2256 2188 2132 2060 2020 1503 1169 779 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

High-density lipoprotein cholesterol Empagliflozin 25 mg Empagliflozin 10 mg Placebo 1245_0025final--01-1503--study-report-body (1). Table 15.3.2.4.2.3: 1 HDL cholesterol (mg/dL) change from baseline MMRM results over time − treated set (OC−AD) 4 28 52 80 108 136 164 192 Placebo 2297 2273 2181 2104 2007 1932 1419 1087 694 Empagliflozin 10 mg 2295 2270 2209 2144 2074 2001 1475 1134 741 Empagliflozin 25 mg 2289 2259 2191 2135 2064 2022 1507 1170 779 All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

Cardiovascular outcomes Silvio E Inzucchi Professor of Medicine, Yale University School of Medicine, New Haven, CT, USA

Primary outcome: 3-point MACE HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

3-point MACE Empagliflozin 10 mg HR 0.85 (95% CI 0.72, 1.01) p=0.0668 Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio

3-point MACE: sensitivity analyses On-treatment analysis** 407/4607 227/2308 0.87 (0.74, 1.02) 0.0839 Per protocol analysis*** 487/4654 278/2316 0.86 (0.75, 1.00) 0.0519 Patients with event/ analysed Empagliflozin Placebo HR (95% CI) p-value Intent-to-treat population 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 ITT: Table 15.2.1.1: 2 OS: Table 15.2.1.2: 1 PPS: Table 15.2.1.2: 3 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. *95.02% CI. **Excluding events >30 days after last intake of study drug and patients who received study drug for <30 days (cumulative). ***Patients treated with ≥1 dose of study drug who did not have important protocol violations.

Patients with event/ analysed CV death, MI and stroke Patients with event/ analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death Table 15.2.4.1.1: 1 Table 15.2.4.1.2: 1 Table 15.2.4.1.3: 1 Table 15.2.4.1.5: 1 Table 15.2.4.1.8: 1 Table 15.2.4.1.9: 1 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

CV death HR 0.62 (95% CI 0.49, 0.77) p<0.0001 Cumulative incidence function. HR, hazard ratio

CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p=0.0016 Cumulative incidence function. HR, hazard ratio

Patients with event/analysed CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Table 15.2.4.1.1: 1 Table 15.2.4.1.2: 1 Table 15.2.4.1.3: 1 Table 15.2.4.1.5: 1 Table 15.2.4.1.8: 1 Table 15.2.4.1.9: 1 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

Fatal and non-fatal stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value Intent-to-treat population 164/4687 69/2333 1.18 (0.89, 1.56) 0.2567 Numerical difference largely driven by events occurring >30 days after treatment stop Favours empagliflozin Favours placebo Table 15.2.1.1: 2 On-treatment per protocol analysis (OS): Table 15.2.4.1.3: 3 On-treatment set (up to treat. stop + 30 days/indiv. trial compl): Table 15.2.4.1.3: 5 On-treatment analysis* 141/4607 66/2308 1.04 (0.78, 1.40) 0.7849 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; *Excluding events >30 days after last intake of study drug and patients who received study drug for <30 days (cumulative)

3-point MACE and 4-point MACE Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 4-point MACE Table 15.2.4.1.1: 1 Table 15.2.4.1.2: 1 Table 15.2.4.1.3: 1 Table 15.2.4.1.5: 1 Table 15.2.4.1.8: 1 Table 15.2.4.1.9: 1 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

3-point MACE and 4-point MACE Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 4-point MACE 599/4687 333/2333 0.89 (0.78, 1.01)* 0.0795 Table 15.2.4.1.1: 1 Table 15.2.4.1.2: 1 Table 15.2.4.1.3: 1 Table 15.2.4.1.5: 1 Table 15.2.4.1.8: 1 Table 15.2.4.1.9: 1 Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

3-point MACE: subgroup analysis HR (95% CI) Empagliflozin Placebo All patients 4687 2333 Age, years 0.01 <65 2596 1297 ≥65 2091 1036 Sex 0.81 Male 3336 1680 Female 1351 653 Race 0.09 White 3403 1678 Asian 1006 511 Black/African-American 237 120 HbA1c, % <8.5 3212 1607 ≥8.5 1475 726 Body mass index, kg/m2 0.06 <30 2279 1120 ≥30 2408 1213 eGFR, mL/min/1.73m2 0.20 ≥90 1050 488 60 to <90 2425 1238 <60 1212 607 p-value for interaction Favours empagliflozin Favours placebo For the test of homogeneity of the treatment group difference among subgroups with no adjustment for multiple tests. eGFR, estimated glomerular filtration rate (according to Modification of Diet in Renal Disease equation)

CV death: subgroup analyses HR (95% CI) Empagliflozin Placebo All patients 4687 2333 Age, years 0.21 <65 2596 1297 ≥65 2091 1036 Sex 0.32 Male 3336 1680 Female 1351 653 Race 0.43 White 3403 1678 Asian 1006 511 Black/African-American 237 120 HbA1c, % 0.51 <8.5 3212 1607 ≥8.5 1475 726 Body mass index, kg/m2 0.05 <30 2279 1120 ≥30 2408 1213 eGFR, mL/min/1.73m2 0.15 ≥90 1050 488 60 to <90 2425 1238 <60 1212 607 p-value for interaction Favours empagliflozin Favours placebo For the test of homogeneity of the treatment group difference among subgroups with no adjustment for multiple tests. eGFR, estimated glomerular filtration rate (according to Modification of Diet in Renal Disease equation)

Heart failure

Hospitalisation for heart failure HR 0.65 (95% CI 0.50, 0.85) p=0.0017 Cumulative incidence function. HR, hazard ratio

Hospitalisation for heart failure Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86) p=0.0044 Empagliflozin 25 mg HR 0.68 (95% CI 0.50, 0.93) p=0.0166 Cumulative incidence function. HR, hazard ratio

All-cause mortality

All-cause mortality HR 0.68 (95% CI 0.57, 0.82) p<0.0001 Kaplan-Meier estimate. HR, hazard ratio

All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) Kaplan-Meier estimate. HR, hazard ratio

All-cause mortality, CV death and non-CV death Patients with event/analysed Empagliflozin Placebo HR 95% CI p-value All-cause mortality 269/4687 194/2333 0.68 (0.57, 0.82) <0.0001 CV death 172/4687 137/2333 0.62 (0.49, 0.77) Non-CV death 97/4687 57/2333 0.84 (0.60, 1.16) 0.2852 ACM: Table 15.2.4.1.5: 1 CV death: Table 15.2.4.1.1: 1 Non-CV death: Table 15.2.4.1.1: 3 Favours empagliflozin Favours placebo Cox regression analysis. CV, cardiovascular; HR, hazard ratio

Safety and tolerability David Fitchett, MD Cardiologist, St Michael’s Hospital Associate Professor of Medicine, University of Toronto, Toronto, Canada

Adverse events Placebo (n=2333) Empagliflozin 10 mg (n=2345) Rate One or more AEs 2139 (91.7%) 178.67 2112 (90.1%) 150.34 2118 (90.4%) 148.36 One or more drug-related* AEs 549 (23.5%) 11.33 666 (28.4%) 14.15 643 (27.5%) 13.38 One or more AEs leading to discontinuation 453 (19.4%) 8.26 416 (17.7%) 7.28 397 (17.0%) 6.89 One or more serious AEs 988 (42.3%) 22.34 876 (37.4%) 18.20 913 (39.0%) 19.39 tlr-1245_0025final—01-1501. Table 15.1.4.1: 1 Demographic data − treated set. Rate = per100 patient-years *As reported by the investigator Patients treated with ≥1 dose of study drug

Adverse events consistent with urinary tract infection Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate Events consistent with UTI 423 (18.1%) 8.21 426 (18.2%) 8.02 416 (17.8%) 7.75 Events leading to discontinuation 10 (0.4%) 0.17 22 (0.9%) 0.37 19 (0.8%) 0.31 By sex Male 158 (9.4%) 3.96 180 (10.9%) 4.49 170 (10.1%) 4.09 Female 265 (40.6%) 22.81 246 (35.5%) 18.83 246 (37.3%) 20.38 Total: Table 15.3.1.6: 1 Rate = per100 patient-years Patients treated with ≥1 dose of study drug Based on 79 MedDRA preferred terms

Complicated urinary tract infection Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate Complicated urinary tract infection* 41 (1.8%) 0.71 34 (1.4%) 0.57 48 (2.0%) 0.80 Urinary tract infection 16 (0.7%) 0.28 13 (0.6%) 0.22 0.27 Pyelonephritis† 22 (0.9%) 0.38 15 (0.6%) 0.25 20 (0.9%) 0.33 Urosepsis 3 (0.1%) 0.05 6 (0.3%) 0.10 11 (0.5%) 0.18 Rate = per100 patient-years Patients treated with ≥1 dose of study drug Events reported in >0.1% of patients in any group are shown *Pyelonephritis, urosepsis or serious adverse event consistent with urinary tract infection †Based on 15 MedDRA preferred terms

Adverse events consistent with genital infection Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate Events consistent with genital infection 42 (1.8%) 0.73 153 (6.5%) 2.66 148 (6.3%) 2.55 Serious events 3 (0.1%) 0.05 5 (0.2%) 0.08 4 (0.2%) 0.07 Events leading to discontinuation 2 (0.1%) 0.03 19 (0.8%) 0.32 14 (0.6%) 0.23 By sex Male 25 (1.5%) 0.60 89 (5.4%) 2.16 77 (4.6%) 1.78 Female 17 (2.6%) 1.09 64 (9.2%) 3.93 71 (10.8%) 4.81 Overall: table 15.3.1.8: 1 Serious: table 15.3.1.8: 4 Leading to discontinuation: table 15.3.1.8: 5 Rate = per100 patient-years Patients treated with ≥1 dose of study drug Based on 88 MedDRA preferred terms

Confirmed hypoglycaemic adverse events Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Confirmed hypoglycaemic adverse events 650 (27.9%) 656 (28.0%) 647 (27.6%) Events requiring assistance 36 (1.5%) 33 (1.4%) 30 (1.3%) Patients taking insulin at baseline Total 483 (42.6%) 494 (43.6%) 464 (41.4%) 28 (2.5%) 27 (2.4%) 25 (2.2%) Overall n(%): table 15.3.1.4: 4 Requiring assistance n (%): table 15.3.1.4: 4 Patients treated with ≥1 dose of study drug Plasma glucose <3.9 mmol/L (70 mg/dL) and/or requiring assistance

Other adverse events (1) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate Diabetic ketoacidosis* 1 (<0.1%) 0.02 3 (0.1%) 0.05 Acute kidney injury† 155 (6.6%) 2.77 121 (5.2%) 2.07 125 (5.3%) 2.12 Events consistent with volume depletion§ 115 (4.9%) 2.04 1.97 124 2.11 Serious events 24 (1.0%) 0.42 19 (0.8%) 0.32 26 (1.1%) 0.43 Events leading to discontinuation 7 (0.3%) 0.12 4 (0.2%) 0.07 Venous thrombotic events** 20 (0.9%) 0.35 9 (0.4%) 0.15 21 Table 15.3.1.1: 1 (tir), n(%) Rate = per100 patient-years Patients treated with ≥1 dose of study drug *Based on 4 MedDRA preferred terms. †Based on 1 standardised MedDRA query §Based on 8 MedDRA preferred terms. **Based on 1 standardised MedDRA query

Other adverse events (2) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate Hepatic injury* 108 (4.6%) 1.91 80 (3.4%) 1.35 88 (3.8%) 1.48 Hypersensitivity* 197 (8.4%) 3.59 158 (6.7%) 2.75 181 (7.7%) 3.14 Bone fractures† 91 (3.9%) 1.61 92 1.57 87 (3.7%) 1.46 Table 15.3.1.1: 1 (tir), n(%) Rate = per100 patient-years Patients treated with ≥1 dose of study drug *Based on standardised MedDRA queries †Based on 62 MedDRA preferred terms

Changes in clinical laboratory parameters Electrolytes  Sodium, mEq/L 141 (2) 0 (2) Potassium, mEq/L 4.3 (0.4) 0.0 (0.4) Calcium, mg/dL 9.7 (0.5) 0.0 (0.5) 9.7 (0.4) Magnesium, mEq/L 1.7 (0.2) 0.0 (0.2) 0.1 (0.2) Phosphate, mg/dL 3.7 (0.3) 0.0 (0.3) 0.1 (0.3) Serum creatinine, mg/dL 1.04 (0.24) 0.07 (0.25) 1.03 (0.23) 0.04 (0.2) 1.04 (0.25) 0.04 (0.19) eGFR mL/min/1.73m2   74.8 (20.6) -4.5 (12.9) 75.2 (21.1) -2.5 (13.1) 75.0 (21.4) -2.8 (13.4)   Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Baseline Change from baseline Haematocrit, % 41.1 (5.7) 0.9 (4.7) 41.2 (5.6) 4.8 (5.5) 41.3 (5.7) 5.0 (5.3) Haemoglobin, g/dL 13.4 (1.5) -0.1 (1.2) 0.8 (1.3) 13.5 (1.5) Data are mean (SD) in patients treated with ≥1 dose of study drug Changes from baseline are at last value on treatment, defined as the last measurement ≤3 days after the last intake of study drug

Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk 56 High CV risk 38% diabetes, 46% hypertension Ramipril2 for 5 years Empagliflozin for 3 years 39 T2DM with high CV risk 92% hypertension Simvastatin1 for 5.4 years 30 High CV risk 5% diabetes, 26% hypertension All cause death Simva: 182 / 2221 (8,2%), placebo :256 / 2223 (11,5%) HR= 0,71[0,59;0,85] pooled empa : 269 (5.7%)/2333, placebo : 194 (8.3%)/4687 HR= 0.68 (0.57,0.82) Ramipril: 482 / 4645 (10,4%), placebo : 569 / 4652 (12,2%) HR=0,85[0,76;0,95] Pre-ACEi/ARB era <29% statin >80% ACEi/ARB >75% statin Pre-statin era 1994 2000 2015 1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm; 2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm

Results A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.

Conclusions Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)

抄録 http://drmagician.exblog.jp/23687444/ 【背 景】 【背　景】 心血管リスクの高い2型糖尿病患者での心血管罹患および死亡において，ナトリウム-グルコース 共役輸送体-2阻害薬（SGLT2阻害薬）のエンパグリフロジンの標準治療への上乗せ効果は知られて いない． 【方　法】 患者は1日1回のエンパグリフロジンの10mg，25mgまたはプラセボに無作為に割り付けられた．主 要複合評価項目は，エンパグリフロジン群対プラセボ群でプールされた解析としての心血管死， 非致死的心筋梗塞，非致死的脳卒中とした．副次複合評価項目は，主要評価項目に不安定狭心症 による入院を追加したものとした． 【結　果】 計7020例の患者が治療を受けた（観察期間中央値3.1年）．主要評価項目はエンパグリフロジン群 で4687例中490例（10.5%），プラセボ群で2333例中282例（12.1%）であった（HR 0.86; 95.02%CI 0.74-0.99; p=0.04）．心筋梗塞や脳卒中の発生率は両群間で有意差はみられなかったが，エンパ グリフロジン群で，心血管死亡率（3.7% vs 5.9%; 38%の相対リスク減少），心不全による入院率 （2.7% vs 4.1%; 35%の相対リスク減少），全死亡率（5.7% vs 8.3%; 32%の相対リスク減少）が 有意に低かった．両群間で副次評価項目に有意差はみられなかった（p=0.08）．エンパグリフロ ジンを投与された患者において，生殖器感染症発生率の増加がみられたが，他の有害事象につい ては有意差がみられなかった． 【結　論】 標準治療に試験薬を追加する設定において，エンパグリフロジンの投与を受けた，心血管イベン トリスクの高い2型糖尿病患者は，プラセボ群と比較して，主要複合心血管評価項目と全死亡率が 低かった． http://drmagician.exblog.jp/23687444/

Message サブグループ解析で服薬でベネフィットのある集団は BMIは30未満 年齢は65歳以上 HbA1cは8.5%未満 他の薬物(insulin, pioglitazone, DPP4阻害薬,metformin) は用いていない 蛋白尿は出ている これまでよく言われている患者像とはかなり異なると感じる。 副作用関連では 腎障害が減る 尿路感染は特に女性で減る！　（性器感染は増えるが） 書いていないが、インスリンの減量効果、悪性腫瘍、脳梗塞既往のサブ解 析　はどうか気にはかかるが？