lowering therapy using statin in patients of diabetic retinopathy - PowerPoint PPT Presentation

Does intensive treat-to to-target LDL-C C lowering therapy using statin in patients of diabetic retinopathy reduce cardiovascular events? ? The EM EMPATHY study Standa andard rd vers rsus IntEns nsiv ive e Statin in Ther erapy py for Hype percho rcholes lester erole oleMi Mic Patien ents with h DiAbe betic ic Retino inopa paTH THY Hiroshi Itoh, Issei Komuro, Masahiro Takeuchi, Kenji Ueshima, Masakazu Yamagishi, Tsutomu Yamazaki, Nagahisa Yoshimura, Kazuwa Nakao, Ryozo Nagai, for the EMPATHY Investigators

Conflicts of Interest Professor Itoh has research contracts at Takeda Pharmaceutical Company Limited, Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Company, Limited, MSD K.K., Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd., Taisho Toyama Pharm.Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., Kyowa Hakko Kirin Co., Ltd., Teijin Pharma Limited, Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and consulting fee from Nipro Corporation., SBI Pharmaceuticals Co., Ltd. Funding: Shionogi & Co., Ltd. Registration ID: UMIN000003486

Background: Statin Therapy When this study was being planned (2010), there was much evidence on statin therapy, but…  Evidence from 5 studies of more vs. less statin therapy in CTT: ‒ All secondary prevention ‒ Relatively few patients with diabetes (11% to 24%) ‒ Not treat-to-target trial (comparison of different statins or of fixed statin doses) Lancet 2010;376:1670  CARDS was the only one study that focused exclusively on patients with diabetes, but was vs. placebo Diabetologia 2009;52:218

Background: Lipid Management in Diabetes Mellitus Patients with diabetes are at high risk for CV events  LDL-C target in guidelines for lipid management in patients with diabetes Europe US US Japan ↓ 30-40% < 100 mg/dL (no risk factor) Primary < 70 mg/dL (≥ 1 risk factor) < 120 mg/dL (if TC > 135 mg/dL) Secondary < 70-77 mg/dL < 70 mg/dL < 100 mg/dL Eur Heart J 2007;28:88 / Diabetes Care 2008;31:811 / JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2007  Patients with diabetic retinopathy are at higher risk for CV events than patients with diabetes but no retinopathy Diabetes Care 2011;34:1238

Purpose To compare the efficacy of intensive vs. standard treatment for CVD primary prevention in patients with diabetic retinopathy Using a two-tiered treat-to-target strategy: LDL-C target < 70 mg/dL vs. < 120 mg/dL (ADA/ACC 2008) (JAS 2007) ⇒ First evidence focusing on patients with diabetic retinopathy ⇒ First evidence using a treat-to-target strategy

Primary Endpoint 0.10 HR 0.84 84 (95% % CI 0.67-1. 1.07 07) ) Standard ndard log-ran log ank p p = 0.15 15 0.08 Inten ensi sive ve t rate 0.06 Event 0.04 0.02 0.00 0 6 12 18 24 30 36 42 48 54 60 Months hs since ce randomis omisation Number at risk Standard 2524 2458 2390 2312 2101 1571 1285 917 501 225 43 Intensive 2518 2445 2369 2292 2119 1572 1274 910 500 235 33

Primary Endpoint and Components Intensi nsive ve Standard dard HR (95% CI) p-val alue ue n = 2518 n = 2524 n of events Primar mary endpoint oint 129 129 153 153 0.84 (0.67-1.07) 07) 0.15 Components (Secondary endpoint) Cardiac events 57 62 0.93 (0.65-1.33) 0.69 Cerebral events 22 42 0.52 (0.31-0.88) 0.01 Renal events 52 49 1.07 (0.72-1.58) 0.73 Vascular events 8 8 1.00 (0.38-2.67) 1.00 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Intensi nsive ve better Standard dard better

Secondary Endpoints Deat ath from om any caus use Strok roke Standar ndard 0.04 0.04 HR 1.21 HR 1 (95% % CI 0.77 77-1. 1.91 91) 0.64 64 (0.40 40-1. 1.01 01), p = 0.05 Intensi nsive log-ran ank k p = 0.40 0.03 0.03 t rate Event 0.02 0.02 Stroke: cerebral infarction, cerebral hemorrhage, 0.01 0.01 subarachnoid hemorrhage 0.00 0.00 Number at risk 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 Standard 2524 2482 2434 2373 2171 1638 1346 976 539 246 45 2524 2475 2418 2353 2150 1614 1321 957 526 239 44 Intensive 2518 2461 2399 2344 2181 1635 1339 957 526 247 37 2518 2455 2389 2332 2167 1622 1325 947 521 246 36 Cereb rebral al infar arctio ion Cereb rebral al hemor orrh rhage age Subar barac achn hnoid oid hemor orrh rhag age 0.010 0.04 0.020 0.54 54 (0.32 32-0. 0.90 90), p = 0.02 1.34 34 (0.46 46-3. 3.86 86), p = 0.59 HR NA, p = 0.33 0.008 t rate 0.03 0.015 0.006 Event 0.02 0.010 0.004 0.005 0.01 0.002 0.000 0.00 0.000 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 Month ths s since randomisa sation Month ths s since randomisa sation Month ths s since randomisa sation Number at risk Standard 2524 2476 2419 2355 2154 1617 1325 961 529 240 45 2524 2481 2433 2371 2167 1635 1342 972 536 245 44 2524 2482 2434 2373 2171 1638 1346 976 539 246 45 Intensive 2518 2456 2389 2332 2168 1625 1330 951 524 247 37 2518 2460 2399 2344 2180 1632 1335 954 522 246 36 2518 2461 2399 2344 2181 1635 1338 956 526 247 37

Safety Intensiv sive (n = 2511) Standar ard (n = 2518) p-value lue n of events n of patients (%) n of events n of patients (%) Adverse events Total 7832 1890 (75.3) 8189 1894 (75.2) 0.97 Serious 815 535 (21.3) 901 554 (22.0) 0.55 Adverse drug reactions Total 368 253 (10.1) 218 168 (6.7) <0.001 Serious 41 32 (1.3) 28 23 (0.9) 0.22 Main adverse events Hepatobiliary disorders Total 82 71 (2.8) 52 48 (1.9) 0.03 Serious 29 22 (0.9) 14 13 (0.5) 0.13 Renal and urinary disorders Total 200 166 (6.6) 250 215 (8.5) 0.01 Serious 26 21 (0.8) 28 28 (1.1) 0.39 Rhabdomyolysis Total 3 3 (0.1) 4 4 (0.2) 1.00 Serious 1 1 (0.0) 1 1 (0.0) 1.00 Myopathy Total 1 1 (0.0) 0 0 0.50 Serious 1 1 (0.0) 0 0 0.50 Cancer* Total 132 114 (4.5) 107 120 (4.2) 0.63 Serious 94 81 (3.2) 91 80 (3.2) 0.94 *: neoplasms benign, malignant and unspecified (including cysts and polyps)

Primary Endpoint Limited to Patients Who Reached LDL-C Target Range [Post-hoc Analysis] Patient ents s who reache hed d LDL-C C target Patien ents s who reache hed d LDL-C C target range ge (average) rage) range ge (at last visi sit) 0.10 0.10 HR 0.48 48 (95% % CI 0.28 28-0. 0.82 82) HR 0.43 HR 43 (95% % CI 0.27 27-0. 0.68 68) 0.08 0.08 p = 0.007 007 p < 0.001 001 Standar ndard t rate Standar ndard 0.06 0.06 Event 0.04 0.04 Intensi nsive Intens nsive 0.02 0.02 0.00 0.00 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 Mont nths hs sinc nce random ndomis isatio ion Mont nths hs sinc nce random ndomis isatio ion Number at risk Standard 1206 1201 1180 1152 1057 795 677 492 269 122 23 852 847 826 797 732 549 442 306 165 64 11 Intensive 703 699 689 680 641 466 378 270 154 75 8 988 984 974 966 916 678 558 384 223 106 15

Conclusion  Achieving LDL-C < 70 mg/dL in a treat-to-target strategy in high-risk patients with hypercholesterolaemia and diabetic retinopathy may have benefit  This potential benefit deserves further investigation