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DC 172224
DC 172224
Dyslipidemia and impaired glucose me- we conducted a large-scale clinical study to achieve specific LDL-C targets by titrat-
tabolism in diseases such as diabetes are in patients with hypercholesterolemia and ing statin therapy.
known risk factors for cardiovascular dis- diabetic retinopathy (type 2 diabetes). Few
ease; patients with both conditions are at prospective clinical studies have evaluated RESEARCH DESIGN AND METHODS
even greater risk of cardiovascular (CV) the efficacy of intensive lipid-lowering ther- Study Design
events (1–3). Meta-analysis (4) has asso- apy specifically in primary prevention pa- The study used a multicenter, prospec-
ciated lower levels of LDL cholesterol tients with diabetes, particularly for reducing tive, randomized, open-label, blinded end
(LDL-C) with reduced risk of CV events in risk through lipid-lowering intervention in point (PROBE) design (9) and enrolled pa-
patients with type 2 diabetes, and the risk hypercholesterolemic patients with dia- tients at hospitals and family practice clin-
of CV events increases further in patients betic retinopathy. ics across Japan. The study was conducted
with diabetic retinopathy (5,6). However, The standard versus intEnsive statin under the Declaration of Helsinki and Jap-
little evidence is currently available on therapy for hypercholesteroleMic Patients anese ethical guidelines for clinical studies.
the efficacy of lipid therapy specifically in with diAbetic retinopaTHY (EMPATHY) The protocol was reviewed and approved
these very high-risk patients. study examined whether intensive lipid- by the institutional review board of each
13 26 39
Kusatsu General Hospital, Kusatsu, Japan Ideta Eye Clinic, Kumamoto, Japan Division of Cardiology, Department of Internal
14 27
Department of Ophthalmology, The University Department of Cardiovascular Surgery, Tokyo Medicine, The Jikei University School of Medi-
of Tokyo Graduate School of Medicine, Tokyo, Medical University Hachioji Medical Center, cine, Tokyo, Japan
40
Japan Hachioji, Japan Kitano Hospital, The Tazuke Kofukai Medical Re-
15 28
Department of Neurology, Tokyo Women’s Sugawara Medical Clinic, Tokyo, Japan search Institute, Osaka, Japan
29 41
Medical University School of Medicine, Tokyo, Department of Cardiology, Jinnouchi Hospital, Medical Innovation Center, Kyoto University Grad-
Japan Kumamoto, Japan uate School of Medicine, Kyoto, Japan
16 30 42
Division of Cardiology, National Cerebral and Department of Endocrinology and Metabo- Jichi Medical University, Shimotsuke, Japan
Cardiovascular Center, Suita, Japan lism, Yokohama City University School of Med- Corresponding author: Hiroshi Itoh, hiito@keio
17
Department of Medicine and Clinical Science, icine, Yokohama, Japan .jp.
31
Graduate School of Medical Sciences, Kyushu Department of Cardiovascular Medicine, Faculty
University, Fukuoka, Japan of Medical Sciences, Kyushu University, Fukuoka, Received 24 October 2017 and accepted 12
18
Department of Medicine and Biological Science, Japan March 2018.
32
Gunma University Graduate School of Medicine, Department of EBM Research, Institute for Ad- Clinical trial reg. no. UMIN000003486, www
Maebashi, Japan vancement of Clinical and Translational Science, .umin.ac.jp/ctr/.
19
Department of Cardiology, Graduate School of Kyoto University Hospital, Kyoto, Japan This article contains Supplementary Data online
33
Medicine Juntendo University, Tokyo, Japan Division of Diabetes, Metabolism and Endo- at http://care.diabetesjournals.org/lookup/suppl/
20
Department of Ophthalmology, Kyoto Univer- crinology, Department of Internal Medicine, The doi:10.2337/dc17-2224/-/DC1.
sity Graduate School of Medicine, Kyoto, Japan Jikei University School of Medicine, Tokyo, Japan
21
Department of Cardiology, Nagoya University 34
Department of Cardiovascular and Internal Med- © 2018 by the American Diabetes Association.
Graduate School of Medicine, Nagoya, Japan icine, Kanazawa University Graduate School of Readers may use this article as long as the work
22
Department of Cardiovascular Medicine, Saga Medicine, Kanazawa, Japan is properly cited, the use is educational and not
University, Saga, Japan 35
Clinical Research Support Center, The Univer- for profit, and the work is not altered. More infor-
23
Division of Nephrology, Endocrinology and Vas- sity of Tokyo Hospital, Tokyo, Japan mation is available at http://www.diabetesjournals
cular Medicine, Tohoku University Hospital, Sendai, 36
Yo Clinic, Kyoto, Japan .org/content/license.
37
Japan Department of Clinical Cell Biology and Med-
24
First Department of Internal Medicine, Nara icine, Chiba University Graduate School of Med-
Medical University, Kashihara, Japan icine, Chiba, Japan
25 38
Department of Cardiology, Nippon Medical School Sakakibara Heart Institute of Okayama, Okayama,
Chiba Hokuso Hospital, Inzai, Japan Japan
care.diabetesjournals.org Itoh and Associates 1277
This study was designed to evaluate the patient’s answers. No situations The full analysis set (FAS) was selected
the treat-to-target approach, so investiga- arose during the study that required as the main analysis set for efficacy. The
tors could not be blinded to statin types consideration of study discontinuation primary and secondary end points were
and doses. We thus selected a PROBE or suspension. analyzed in the same way in the FAS and
design rather than a double-blind design. the per protocol set, and results for the
To eliminate bias, defined end points Outcomes two sets were examined for consistency.
were evaluated by a blinded end point The primary and secondary outcomes The FAS comprised all randomly allocated
committee. of the EMPATHY study were previously subjects for whom efficacy data were
described (9) (Supplementary Data). The available. The per protocol set comprised
Procedures primary outcome was the composite in- all members of the FAS, except for sub-
As previously described (9), this PROBE cidence of CV events, including cardiac, jects who did not qualify or were not
study constituted a run-in period (4–8 cerebral, renal, and vascular events, or treated and cases of protocol violation or
weeks) and a treatment period (2–5.5 CV-associated death. The secondary out- noncompliance. All subjects who received
years). During run-in, patients received comes included death from any cause, the study treatment at least once and for
0.31–0.88]) (Fig. 1), as did the incidence creatinine (343.2%) and 86.5 mg/g creat- of patients experienced adverse drug re-
of cerebral infarction (HR 0.54 [95% inine (300.8%), and urine protein in- actions (ADRs) in the intensive group
CI 0.32–0.90]) (Fig. 2). The incidence of creased 10.7 mg/dL (1,503.1%) and (10.1%) than the standard group (6.7%)
stroke (cerebral infarction, cerebral hem- 11.0 mg/dL (236.1%) in the intensive (P , 0.001), but most of those ADRs were
orrhage, and subarachnoid hemorrhage), and standard groups, respectively. None mild. The proportion of serious ADRs was
cerebral hemorrhage, and subarachnoid of these parameters differed significantly similar between groups (1.3% vs. 0.9%;
hemorrhage did not differ between the between the intensive and standard groups P = 0.22).
groups (HR 0.64 [95% CI 0.40–1.01], HR (Supplementary Table 4).
1.34 [95% CI 0.46–3.86], and HR NA [not As part of an exploratory analysis, we
applicable], respectively). No other sig- performed subgroup analysis of the pri- CONCLUSIONS
nificant differences were noted. The HR mary end point for both treatment The EMPATHY study assessed the bene-
for cardiac events was 0.93 (95% CI 0.65– groups based on various demographic fits of intensive statin monotherapy for
1.33), for renal events 1.07 (95% CI 0.72– factors (Supplementary Fig. 4). No sig- lipid management in patients with hyper-
1.58), and for vascular events 1.00 (95% nificant heterogeneity of treatment ef- cholesterolemia and diabetic retinopathy
CI 0.38–2.67) (Supplementary Table 3). fects was seen in any of the factors in a primary prevention setting. The study
Change and percent change from examined. also evaluated the appropriateness of the
baseline to 36 months in the parameters treat-to-target approach in this patient
for CKD were evaluated as a secondary Safety population. Results indicated that lipid-
end point. Estimated glomerular filtration Overall, a similar percentage of patients lowering therapy targeting LDL-C ,70 mg/dL
rate decreased by 5.9 mL/min/1.73 m2 in both groups experienced AEs (inten- had no more beneficial effect on the primary
(7.8%) in the intensive group and 6.5 sive 75.3%; standard 75.2%) and serious end point than therapy targeting LDL-C of
mL/min/1.73 m2 (8.3%) in the standard AEs (intensive 21.3%; standard 22.0%) 100–120 mg/dL. In exploratory findings, the
group. Urine albumin increased by 85.3 mg/g (Table 2). A significantly higher proportion secondary end points of cerebral events and
1280 Intensive Statin Therapy in High-Risk Patients Diabetes Care Volume 41, June 2018
Figure 2—Cumulative event curve for secondary end points in the intensive and standard therapy groups: death from any cause (A), stroke (B), cerebral
infarction (C), cerebral hemorrhage (D), and subarachnoid hemorrhage (E). P value was calculated using a stratified log-rank test with sex (male or
female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP %]) as stratification factors. HR (95% CI) was estimated using a stratified Cox
proportional hazards model with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP %]) as stratification factors;
P values for secondary end points are nominal.
cerebral infarction were reduced significantly (IMPROVE-IT) (17) demonstrated the use- on primary prevention to expand the
in the intensive group. No major safety fulness of intensive lipid therapy for the evidence regarding intensive lipid man-
concerns were noted. secondary prevention of CV events, using agement using statin monotherapy. How-
The Improved Reduction of Out- statin and ezetimibe to achieve LDL-C ever, our results differed from those
comes: Vytorin Efficacy International Trial as low as 50 mg/dL. Our study focused previous studies using statins.
care.diabetesjournals.org Itoh and Associates 1281
Why did our study fail to show superior between-group difference in LDL-C was would be predicted by Supplementary
results for intensive therapy? EMPATHY ;40 mg/dL (,70 mg/dL for the intensive Fig. 6, given the observed 23.6 mg/dL
included some soft end points that re- group vs. ;110 mg/dL for the standard reduction in LDL-C (after 1 year). In other
quired subjective assessment, such as re- group), and the HR was predicted to be words, the primary results of the EMPATHY
vascularization, and renal events that 0.65. However, after 3 years of treatment, study, despite not being significant, are
were attributable to arteriosclerosis. To the actual LDL-C difference was 27.7 mg/dL consistent with previous findings. We hy-
evaluate these effects on the study results, (76.5 vs. 104.1 mg/dL). pothesize that if we had achieved the
we compared the groups using three- In exploratory findings, we compared predicted difference of 40 mg/dL LDL-C
point major CV events (CV death, nonfatal our results to the Cholesterol Treatment between two treatment groups, the pri-
myocardial infarction, and nonfatal stroke) Trialists’ (CTT) meta-analysis (18) and mary end point would have reached sta-
and the primary end point after excluding three primary prevention studies in pa- tistical significance. This suggests that
renal events. We found no significant tients with diabetes (13–15). We graphed aggressive LDL-C management may further
differences (HR 0.82 [95% CI 0.58–1.14] the relationship between changes in reduce risk in patients with conditions such
and HR 0.76 [95% CI 0.57–1.01], respec- LDL-C and proportional reduction in event as hyperlipidemia and diabetic retinopathy.
tively) (Supplementary Fig. 5), suggesting rate (major CV events including major To further clarify the reasons for the
that our study findings were unaffected coronary events [coronary death or non- failure to demonstrate the efficacy of in-
by either soft end points or renal events. fatal myocardial infarction], stroke of tensive therapy, we performed post hoc
Primary end point incidence was 20.41/ any type, and coronary revascularization analysis, classifying patient data into four
1,000 person-years in the standard group [angioplasty or bypass grafting]). Inter- subcategories (mean LDL-C ,70, 70 to
and 17.27/1,000 person-years in the in- estingly, the slope of the line for the di- ,100, 100 to ,120, and $120 mg/dL
tensive group. The cumulative incidence abetes studies seems to be steeper than during the study). Our exploratory find-
at 3 years was 5.8% and 5.4%, respec- the original CTT line (Supplementary Fig. ings tended to show event prevention at
tively, exceeding our earlier estimates of 6). Next, we plotted the findings of the lower LDL-C values in both the intensive
4.1% and 2.7%. The statistical power of EMPATHY study. In our study, the predic- and standard groups (Supplementary
the study was thus sufficient to detect ted between-group difference in LDL-C of Fig. 7). We plan additional exploratory
significant differences in CV events be- ;40 mg/dL should have provided a re- analysis of between-group comparison,
tween the two groups. duction of ;30% in major CV events, limited to patients in each group with
We believe that this study failed to close to this data line and to the originally LDL-C levels within the targeted range.
find a significant reduction in the primary predicted primary event reduction rate We obtained preliminary results show-
end point because of the smaller-than- (HR 0.65). The observed 20% reduction in ing that the event rate for the primary
predicted difference in LDL-C between major CV events (HR 0.80 [95% CI 0.59– end point was significantly lower in the
the two treatment groups. Our planned 1.07]) is quite similar to the reduction that intensive group than in the standard group.
1282 Intensive Statin Therapy in High-Risk Patients Diabetes Care Volume 41, June 2018
Our findings from that subanalysis will be groups. This suggested low potential risk more significantly than the standard therapy
published separately. for excessive LDL-C reduction by statin targeting LDL-C $100 and ,120 mg/dL.
In an intervention study where the monotherapy. Aggressive LDL-C lowering However, based on previous studies in
control group also receives statin ther- might be associated with increased levels patients with diabetes in a primary pre-
apy, the duration of follow-up is of of cerebral hemorrhage, since cerebral vention setting, the event reduction rate
considerable importance. Non-Japanese hemorrhage increased with intensive ther- in this study is consistent with expect-
studies with a relative difference in LDL-C of apy in the SPARCL study (21). However, ations regarding the LDL-C difference that
40–50% between two groups required subsequent investigation of SPARCL was achieved and might be clinically mean-
2 years to show significance in incidence showed that on-treatment LDL-C did ingful. Exploratory results suggest that in-
between groups (19,20). EMPATHY follow- not predict cerebral hemorrhage (23). tensive therapy reduces cerebral events,
up time was 3 years, but the between- EMPATHY findings showed no intergroup especially cerebral infarction, with no in-
group difference in LDL-C was lower than differences in cerebral hemorrhage, po- crease in AEs in this population.
anticipated; longer follow-up might have tentially eliminating concerns of in-
shown greater between-group difference. creased cerebral hemorrhage risk due to
Tanabe Pharma Corp., MSD K.K., and GlaxoS- Pharma Inc., Sunstar Group Ltd., Eli Lilly and Shionogi & Co., Ltd. during the conducting of the
mithKline K.K., grants from Eisai Co., Ltd., Teijin Company Japan K.K., Sanofi K.K., AstraZeneca study and grants and personal fees from Otsuka
Pharma Ltd., Nippon Shinyaku Co., Ltd., VitalAire K.K., Takeda Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. and Nippon Boehringer
Japan K.K., Fujifilm RI Pharma Co., Ltd., Boston Toyama Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. and grants from Mitsubishi
Scientific Corp., Fuji Chemical Industries Co., Ingelheim Co., Ltd., Kowa Pharmaceutical Co., Tanabe Pharma Corp., Fujifilm RI Pharma Co.,
Ltd., Fukuda Denshi Co., Ltd., and Actelion Phar- Ltd., and Sanwa Kagaku Kenkyusho Co., Ltd. out- Ltd., Roche Diagnostics K.K., MSD K.K., Pfizer
maceuticals Japan Ltd., and personal fees from side the submitted work. S.K. reports grants from Japan Inc., Bayer Yakuhin, Ltd., and Shionogi &
ASKA Pharmaceutical Co., Ltd., Chugai Pharma- Shionogi & Co., Ltd. during the conducting of the Co., Ltd. outside the submitted work. T.S. reports
ceutical Co., Ltd., Taisho Toyama Pharmaceutical study. K.K. reports grants and personal fees from personal fees and nonfinancial support from
Co., Ltd., Toa Eiyo Ltd., Ono Pharmaceutical Co., Shionogi & Co., Ltd. during the conducting of the Shionogi & Co., Ltd. during the conducting of
Ltd., Medtronic Japan Co., Ltd., and Mochida study. M.Ki. reports grants and personal fees the study. S.Sh. reports personal fees and non-
Pharmaceutical Co., Ltd. outside the submitted from Shionogi & Co., Ltd. during the conducting financial support from Shionogi & Co., Ltd. during
work. Y.E. reports nonfinancial support from of the study and grants and personal fees from the conducting of the study. M.S. reports per-
Shionogi & Co., Ltd. during the conducting of Astellas Pharma Inc., Sanofi K.K., Pfizer Japan Inc., sonal fees and nonfinancial support from
the study. H.F. reports other fees (consultant) Ono Pharmaceutical Co., Ltd., Novartis Pharma Shionogi & Co., Ltd. during the conducting of
from Mehergen Group Holdings, Inc. outside the K.K., Mitsubishi Tanabe Pharma Corp., Kyowa the study. S.Su. reports personal fees from Shio-
submitted work. J.H. reports grants and personal Hakko Kirin Co., Ltd., Abbott Japan Co., Ltd.,
Boehringer lngelheim Co., Ltd., Ono Pharmaceu- 2. Sone H, Tanaka S, Tanaka S, et al.; Japan 13. Colhoun HM, Betteridge DJ, Durrington PN,
tical Co., Ltd., Pfizer Japan Inc., Shionogi & Co., Diabetes Complications Study Group. Serum level et al.; CARDS investigators. Primary prevention
Ltd., Taisho Toyama Pharmaceutical Co., Ltd., of triglycerides is a potent risk factor comparable of cardiovascular disease with atorvastatin in
Takeda Pharmaceutical Company Ltd., and Mitsubishi to LDL cholesterol for coronary heart disease in type 2 diabetes in the Collaborative Atorvastatin
Tanabe Pharma Corp., grants from Bristol-Myers Japanese patients with type 2 diabetes: subanal- Diabetes Study (CARDS): multicentre randomised
Squibb, Eli Lilly and Company Japan K.K., Teijin ysis of the Japan Diabetes Complications Study placebo-controlled trial. Lancet 2004;364:685–696
Pharma Ltd., and Toyama Chemical Co., Ltd., and (JDCS). J Clin Endocrinol Metab 2011;96:3448– 14. Sever PS, Poulter NR, Dahlöf B, et al. Re-
personal fees from AstraZeneca K.K., Eisai Co., 3456 duction in cardiovascular events with atorvas-
Ltd., Kowa Company, Ltd., Kowa Pharmaceutical 3. Gaede P, Pedersen O. Intensive integrated ther- tatin in 2,532 patients with type 2 diabetes:
Co., Ltd., Sanofi K.K., and Sanwa Kagaku Ken- apy of type 2 diabetes: implications for long-term Anglo-Scandinavian Cardiac Outcomes Trial–
kyusho Co., Ltd. outside the submitted work. K. prognosis. Diabetes 2004;53(Suppl. 3):S39–S47 lipid-lowering arm (ASCOT-LLA). Diabetes Care
Yos. reports personal fees and nonfinancial sup- 4. Kearney PM, Blackwell L, Collins R, et al.; 2005;28:1151–1157
port from Shionogi & Co., Ltd. during the con- Cholesterol Treatment Trialists’ (CTT) Collaborators. 15. Collins R, Armitage J, Parish S, Sleigh P, Peto
ducting of the study. M.Yo. reports grants and Efficacy of cholesterol-lowering therapy in 18,686 R; Heart Protection Study Collaborative Group.
personal fees from Shionogi & Co., Ltd. outside people with diabetes in 14 randomised trials of
MRC/BHF Heart Protection Study of cholesterol-
the submitted work. N.Y. reports personal fees statins: a meta-analysis. Lancet 2008;371:117–125
lowering with simvastatin in 5963 people with
5. Kramer CK, Rodrigues TC, Canani LH, Gross JL,