Felix Vallotton Ball (1899) LDL-C management in Asian diabetes: moderate vs. high intensity statin --- a lesson from EMPATHY study

Felix Vallotton Ball (1899) LDL-C management in Asian diabetes: moderate vs. high intensity statin --- a lesson from EMPATHY study

Conflict of interest disclosure None Committee of Scientific Affairs Committee of Scientific Affairs

(Itoh H 2003)

Prevalence of cardiac events in diabetic patients (%) 15 1) J-ACCESS: Japanese Initial MI Recurrent MI 2) Finnish Study: Europeans (%) Initial MI Recurrent MI 50 45.0% Cardiac event * rate 10 5 2.2% 5.7% 5.1% 11.7% Incidence of MI 40 30 20 10 3.5% 20.2% 18.8% 0 Non DM DM Non DM DM 4,031 patients with suspected or confirmed ischemic heart diseases were followed up for 3 years. *Cardiac event: cardiac death, non fatal MI, severe heart failure Adapted from 1)Nishimura T, et al.: Eur J Nucl Med Mol Imaging 2008;35;319 0 Non DM DM Non DM DM Incidence of MI was compared between non DM (n = 1,373) and type 2 DM (n = 1,059). Follow up period was 7 years. 2)Haffner S.M, et al.: N Engl J Med 1998;339;229

Incidence of coronary artery diseases stratified by risk factors (in the Japan Lipid Intervention Trial) (/1000 patients 6 years) Male Female (55 years, LDL-C 150 mg/dl) (Secondary prevention: < 64 years) Incidence of CAD Secondary prevention Primary prevention Secondary prevention Primary prevention DM HT Smoking Mabuchi H.The Lipid 18: 63-72, 2007

Risk factors for ischemic heart diseases in type 2 DM UK vs. Japan UKPDS23 2009 report of JDCS 2011 report of JDCS Ranking Risk factor p Risk factor p Risk factor p 1 LDL-C <0.0001 LDL-C 0.000 TG <0.01 2 HDL-C 0.0001 TG 0.005 LDL-C <0.01 3 HbA1c 0.0022 HbA1c 0.027 HbA1c 0.05 4 SBP 0.0065 CPR 0.041 SBP 0.09 5 Smoking 0.056 Smoking 0.064 Smoking 0.12 Adapted from BMJ 1998; 316: 823 ー 8,Vasc Med 2007; 3:125 ー 34, J Clin Endocrin Metab 2011; 96: 3488-3456

Felix Vallotton chaste of Suzanne (1922)

Comparison of lipid management guidelines (Korea,Japan,Europe,USA) Indication of treatment target Indications of statin dose Korean guideline 2015 JAS2017 EAS/ESC2016 ACC/AHA2013 + + + - - - - + Target for secondary prevention LDL-C<70 Non-HDL-C<100 or 50% reduction of the baseline LDL-C value LDL-C<100 Non-HDL-C<130 ACS, FH, DM with risk factor(s) LDL-C<70 Non-HDL-C<100 LDL-C<70 Non-HDL-C<100 High-Intensity Statin Target for T2DM Primary prevention Secondary prevention LDL-C<100 Non-HDL-C<130 LDL-C<70 Non-HDL-C<100 or 50% reduction of the baseline LDL-C value LDL-C<120 Non-HDL-C<100 LDL-C<100 Non-HDL-C<130 ACS, FH, DM with risk LDL-C<70 Non-HDL-C<100 CKD, 40 years, risk factor(s) for CAD, organ complication LDL-C<70 Non-HDL-C<100 In other cases LDL-C<100 Non-HDL-C<130 LDL-C<70 Non-HDL-C<100 10 year ASCVD risk 7.5% High-intensity Statin In other cases Moderateintensity statin High- intensity statin

(Itoh H 2003)

Cumulative incidence of cardiovascular events according to the retinopathy severity level (Type 1 diabetes, 20 years of follow-up) Without retinopathy Early non proliferative moderate to severe non proliferative Proliferative 30 26.9 28.5 26.9 25 20 15 17.1 12.5 21.0 13.3 14.7 10 6.0 6.0 5 3.5 0.8 0 Cardiovascular event rate (% )Angina Myocardial infarction Stroke Klein BE, et al. Arch Intern Med; 164, 1917-24 (2004)

Incidence of occult coronary artery diseases in patients with diabetic retinopathy LMT disease 8 Pts(14.5%) Negative results of diagnostic tests 159 Pts (74.3%) Coronary disease 55 Pts (25.7%) Non-LMT Proximal LAD 18 Pts (32.7%) Non-LMT Non-proximal LAD 29 Pts LMT:Left main trunk, LAD:Left anterior descending coronary artery Referred to the diabetic retinopathy clinic in Tokyo university (Ohno, T et al:j Thorac Cardiovasc Surg.,2009, 139, 92)

Does intensive treat-to-target LDL-C lowering therapy using statin in patients of diabetic retinopathy reduce cardiovascular events? The EMPATHY study Standard versus IntEnsive Statin Therapy for HypercholesteroleMic Patients with DiAbetic RetinopaTHY Hiroshi Itoh, Issei Komuro, Masahiro Takeuchi, Kenji Ueshima, Masakazu Yamagishi, Tsutomu Yamazaki, Nagahisa Yoshimura, Kazuwa Nakao, Ryozo Nagai, for the EMPATHY Investigators (H Itoh et. al. Diabetes Care. 2018 Jun;41(6):1275-1284)

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 Primary Europe US Japan 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 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

Patient Population Inclusion criteria: Age 30 y, outpatient Existing hypercholesterolemia: LDL-C 120 mg/dl in previously untreated patients LDL-C 100 mg/dl in patients previously treated with any single statin or lipid-lowering drug Type 2 diabetes No history of CAD (MI, angina, coronary revascularization) Documented diabetic retinopathy Exclusion criteria: History of CAD or stroke Existing symptomatic PAD, renal transplant recipient or dialysis patient Existing familial hypercholesterolemia Presently undergoing treatment with 2 lipid-lowering drugs

Design Multicenter, open-label, randomized, parallel-group, comparison study Type 2 diabetes with hypercholesterolemia with diabetic retinopathy Observation period (4-8 w) Intensive group (LDL-C <70 mg/dl) Blood glucose and blood pressure controlled according to Japanese guidelines Standard group (LDL-C 100 and <120 mg/dl) Treatment period (minimum 2 y; mean 37±13 mo) Screening Informed consent Provisional enrollment (Ophthalmologic examination) Actual enrollment Randomization Observations and tests every 6 mo

Endpoints Primary endpoint Occurrence of CV diseases, or death due to CV diseases cardiac events / cerebral events* / renal events / vascular events *: cerebral infarction, cerebral revascularization Secondary endpoints Death from any cause Occurrence of each component of primary endpoint Occurrence of stroke (cerebral infarction / cerebral hemorrhage / subarachnoid hemorrhage) Occurrence of each component of stroke Changes in CKD-related indices Safety Evaluated by Event Evaluation Committee under masked conditions

Patient Flowchart 5995 screened 5144 randomization 851 excluded 390 did not meet inclusion criteria 452 declined to participate 9 other reasons 53 excluded 46 did not have investigator s signature 1 not properly registered 6 lack of efficacy data 2571 intensive therapy 2518 analyzed (FAS) 2573 standard therapy 2524 analyzed (FAS) 49 excluded 44 did not have investigator s signature 3 not properly registered 2 lack of efficacy data

Baseline Characteristics Characteristics Intensive % (n = 2518) Standard % (n = 2524) Male 47.7 47.7 Age (years) 63.0 63.2 Body-mass index (kg/m 2 ) 25.7 25.6 Statin, none 47.7 45.8 Duration of diabetes (years) 12.8 13.0 Diabetic complications Neuropathy 30.9 30.9 Nephropathy 53.9 51.1 Peripheral artery disease [Fontaine class I] 5.0 4.4 Current smoking 18.3 19.0 Hypertension 70.6 71.2 HbA1c (%) 7.8 7.8 LDL-C (mg/dl) 106.2 106.1 Systolic / Diastolic blood pressure (mmhg) 134.6 / 74.9 134.6 / 74.8 egfr (ml/min/1.73m 2 ) 74.0 74.6

Changes in LDL-C Mean LDL-C (mg/dl) 200 LDL-C (mg/dl) 12-month 36-month Standard 105.2 104.1 Intensive 81.7 76.5 Difference 23.6 27.7 100 * * * * * * * * * * 0 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation * : p < 0.001 Standard Intensive

Primary Endpoint 0.10 0.08 HR 0.84 (95% CI 0.67-1.07) log-rank p = 0.15 Standard Event rate 0.06 0.04 0.02 Intensive 0.00 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation 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 Primary endpoint Intensive Standard n = 2518 n = 2524 n of events 129 153 HR (95% CI) p-value 0.84 (0.67-1.07) 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 Intensive better Standard better

Secondary Endpoints Death from any cause Event rate 0.04 0.03 0.02 0.01 HR 1.21 (95% CI 0.77-1.91) log-rank p = 0.40 0.00 Number at risk 0 6 12 18 24 30 36 42 48 54 60 Standard 2524 2482 2434 2373 2171 1638 1346 976 539 246 45 Intensive 2518 2461 2399 2344 2181 1635 1339 957 526 247 37 Cerebral infarction Event rate 0.04 0.03 0.02 0.01 0.54 (0.32-0.90), p = 0.02 Stroke 0.04 0.03 0.02 0.01 0.00 0 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 Cerebral hemorrhage 0.020 0.015 0.010 0.005 0.64 (0.40-1.01), p = 0.05 1.34 (0.46-3.86), p = 0.59 Subarachnoid hemorrhage 0.010 0.008 0.006 0.004 0.002 HR NA, p = 0.33 Standard Intensive Stroke: cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage 0.00 0 6 12 18 24 30 36 42 48 54 60 Number at risk Months since randomisation Standard 2524 2476 2419 2355 2154 1617 1325 961 529 240 45 Intensive 2518 2456 2389 2332 2168 1625 1330 951 524 247 37 0.000 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation 2524 2481 2433 2371 2167 1635 1342 972 536 245 44 2518 2460 2399 2344 2180 1632 1335 954 522 246 36 0.000 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation 2524 2482 2434 2373 2171 1638 1346 976 539 246 45 2518 2461 2399 2344 2181 1635 1338 956 526 247 37

Safety Intensive (n = 2511) Standard (n = 2518) p- value 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)

Relationship Between Changes in LDL-C and Proportional Reduction in Event Rate in Diabetes Mellitus In Comparison with CTT Meta-analysis 50 Proportional reduction in event rate (%) 40 30 20 10 0 HPS-DM/primary EMPATHY Observed 23.6mg/dL CARDS Predicted 40mg/dL ASCOT-LLA-DM -10 0 0.5 1.0 1.5 2.0 Reduction in LDL-C at 1 year (mmol/l) CTT (Cholesterol Treatment Trialists) Major vascular events: major coronary event, coronary revascularisation, stroke 40mg/dL =110mg/dL - 70mg/dL (Standard) (Intensive)

Primary Endpoint Limited to Patients Who Reached LDL-C Target Range [Post-hoc Analysis] 0.10 Patients who reached LDL-C target range (average) 0.10 Patients who reached LDL-C target range (at last visit) Event rate 0.08 0.06 0.04 0.02 HR 0.48 (95% CI 0.28-0.82) p = 0.007 Standard Intensive 0.08 0.06 0.04 0.02 HR 0.43 (95% CI 0.27-0.68) p < 0.001 Standard Intensive 0.00 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation Number at risk Standard 1206 1201 1180 1152 1057 795 677 492 269 122 23 Intensive 703 699 689 680 641 466 378 270 154 75 8 0.00 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation 852 847 826 797 732 549 442 306 165 64 11 988 984 974 966 916 678 558 384 223 106 15

Summary In this study, intensive lipid-lowering therapy using a treat-to-target strategy did not significantly reduce primary endpoint events Related to the smaller difference in LDL-C than expected between the two groups? reduced cerebral events significantly, but not cardiac events, in secondary endpoints In cerebral events, mainly reduction in cerebral infarction Related to the higher ratio of stroke to cardiac events in Japan, compared to Europe and US? reduced CV events significantly in patients achieving LDL- C target [post-hoc analysis] Potential importance of achieving LDL-C < 70 mg/dl in high-risk patients Further research needed

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

Diabetes is associated with a twofold increase in the risk of cardiovascular disease both in Asian and Australasian populations. Sex-, study-, and age-adjusted hazard ratios (on a log scale) for major cardiovascular diseases (diabetic versus nondiabetic), overall and by geographic area. ANZ: Australia and New Zealand DM vs. non DM (Asia Pacific Cohort Studies Collaboration Diabetes Care 2003;26:360)

Comparison of LDL cholesterol - lowering effects of statins between Koreans and Western people Korean Circ J 46: 275-306, 2016, J Lipid Atheroscler 3; 21-28, 2014

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