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

Hiroshi Itoh, Issei Komuro, Masahiro Takeuchi, Kenji Ueshima, Masakazu Yamagishi, Tsutomu Yamazaki, Nagahisa Yoshimura, Kazuwa Nakao, Ryozo Nagai, for the EMPATHY Investigators

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

• leMi

Mic Patien ents with h DiAbe betic ic Retino inopa paTH THY

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

Patients with diabetic retinopathy are at higher risk for

CV events than patients with diabetes but no retinopathy

Eur Heart J 2007;28:88 / Diabetes Care 2008;31:811 / JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2007 Diabetes Care 2011;34:1238

Europe US US Japan Primary ↓30-40% (if TC > 135 mg/dL) < 100 mg/dL (no risk factor) < 70 mg/dL (≥ 1 risk factor) < 120 mg/dL Secondary < 70-77 mg/dL < 70 mg/dL < 100 mg/dL

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

6 12 18 24 30 36 42 48 54 60

0.10 0.08 0.06 0.04 0.02 0.00

Event t rate

2524 2458 2390 2312 2101 1571 1285 917 501 225 43 Number at risk Standard Intensive 2518 2445 2369 2292 2119 1572 1274 910 500 235 33

Months hs since ce randomis

• misation

Standard ndard Inten ensi sive ve

HR 0.84 84 (95% % CI 0.67-1. 1.07 07) ) log log-ran ank p p = 0.15 15

0.0 Intensi nsive ve better Standard dard better 0.5 1.0 1.5 2.0 2.5 3.0 Primar mary

Components (Secondary endpoint)

0.84 (0.67-1.07) 07)

0.93 (0.65-1.33) 0.52 (0.31-0.88) 1.07 (0.72-1.58) 1.00 (0.38-2.67) 57 62 22 42 52 49 8 8

129 129 153 153

Cardiac events Cerebral events Renal events Vascular events

HR (95% CI) p-val alue ue 0.15

0.69 0.01 0.73 1.00

Standard dard Intensi nsive ve

Primary Endpoint and Components

n = 2518 n = 2524 n of events

endpoint

• int

Deat ath from

• m any caus

use Strok roke Cereb rebral al infar arctio ion Cereb rebral al hemor

• rrh

rhage age

0.00 0.01 0.02 0.03 0.04 2524 2482 2434 2373 2171 1638 1346 976 539 246 45 Number at risk Standard Intensive 2518 2461 2399 2344 2181 1635 1339 957 526 247 37

HR HR 1.21 1 (95% % CI 0.77 77-1. 1.91 91) log-ran ank k p = 0.40

6 12 18 24 30 36 42 48 54 60 0.00 0.01 0.02 0.03 0.04 0.00 0.01 0.02 0.03 0.04 2524 2476 2419 2355 2154 1617 1325 961 529 240 45 Number at risk Standard Intensive 2518 2456 2389 2332 2168 1625 1330 951 524 247 37

0.54 54 (0.32 32-0. 0.90 90), p = 0.02

6 12 18 24 30 36 42 48 54 60 0.000 0.005 0.010 0.015 0.020 2524 2481 2433 2371 2167 1635 1342 972 536 245 44 2518 2460 2399 2344 2180 1632 1335 954 522 246 36

1.34 34 (0.46 46-3. 3.86 86), p = 0.59

Month ths s since randomisa sation Month ths s since randomisa sation 6 12 18 24 30 36 42 48 54 60

Subar barac achn hnoid

• id hemor
• rrh

rhag age

0.000 0.002 0.004 0.006 0.010 0.008 2524 2482 2434 2373 2171 1638 1346 976 539 246 45 2518 2461 2399 2344 2181 1635 1338 956 526 247 37

HR NA, p = 0.33

Month ths s since randomisa sation 6 12 18 24 30 36 42 48 54 60 2524 2475 2418 2353 2150 1614 1321 957 526 239 44 2518 2455 2389 2332 2167 1622 1325 947 521 246 36

0.64 64 (0.40 40-1. 1.01 01), p = 0.05

6 12 18 24 30 36 42 48 54 60

Standar ndard Intensi nsive

Secondary Endpoints

Event t rate Event t rate Stroke: cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage

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) 0.50 Serious 1 1 (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]

1206 1152 1057 677 269 23 Standard Intensive 703 1201 699 680 1180 689 641 795 466 378 154 492 270 8 122 75

0.00 0.02 0.04 0.06 0.10 0.08 6 12 18 24 36 42 48 54 30 60

852 797 732 442 165 11 988 847 984 966 826 974 916 549 678 558 223 306 384 15 64 106

6 12 18 24 36 42 48 54 30 60

Mont nths hs sinc nce random ndomis isatio ion

Event t rate

Mont nths hs sinc nce random ndomis isatio ion HR 0.48 48 (95% % CI 0.28 28-0. 0.82 82) p = 0.007 007 HR HR 0.43 43 (95% % CI 0.27 27-0. 0.68 68) p < 0.001 001

Patient ents s who reache hed d LDL-C C target range ge (average) rage)

Number at risk

Patien ents s who reache hed d LDL-C C target range ge (at last visi sit)

Standar ndard Intens nsive Standar ndard Intensi nsive

0.00 0.02 0.04 0.06 0.10 0.08

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