The Journal of Clinical Endocrinology & Metabolism, 2024, 00, 1–8

https://doi.org/10.1210/clinem/dgad714
Advance access publication 4 January 2024

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Clinical Research Article

Comparison of the Efficacy of Ezetimibe Combination

Therapy and High-Intensity Statin Monotherapy in Type 2
Diabetes
So Young Park,1,2 Ji Eun Jun,2,3 In-Kyung Jeong,2,3 Kyu Jeung Ahn,2,3 Ho Yeon Chung,2,3
and You-Cheol Hwang2,3
1
Department of Endocrinology and Metabolism, Kyung Hee University Hospital, Seoul 02447, Republic of Korea
2
Department of Endocrinology & Metabolism, Kyung Hee University School of Medicine, Seoul 02453, Republic of Korea
3
Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea
Correspondence: You-Cheol Hwang, MD, PhD, Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, Kyung Hee
University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Republic of Korea. Email: khmcilyong@naver.com

Abstract
Context: Low-density lipoprotein cholesterol (LDL-C)-lowering therapy is considerably important in preventing cardiovascular disease (CVD)
among patients with diabetes. Studies comparing CVD, stroke, and mortality outcomes of low- or moderate-intensity statins with ezetimibe
combination therapy and high-intensity statin monotherapy in patients with diabetes remain lacking.
Objective: This study compared the primary prevention effect of myocardial infarction (MI), stroke, and all-cause death between combination
therapy of low- or moderate-intensity statins and ezetimibe and high-intensity statin monotherapy in patients with diabetes using the Korean
National Health Insurance claims database.
Methods: Patients aged ≥20 years with type 2 diabetes and dyslipidemia were enrolled. The combination therapy of low- or moderate-intensity
statin and ezetimibe was compared with high-intensity statin monotherapy after a propensity score–matched analysis. The incidence of
composite outcomes consisting of MI, stroke, and all-cause death and each component were analyzed.
Results: In moderate-intensity statin therapy with ezetimibe combination therapy, LDL-C (74 ± 37.9 mg/dL vs 80.8 ± 38.8 mg/dL, P < .001) and
the incidence of composite outcomes were lower (hazard ratio 0.85, 95% CI 0.74-0.98) than those in high-intensity statin monotherapy.
Meanwhile, no significant difference was observed in the LDL-C levels and composite outcomes between low-intensity statins with
ezetimibe combination therapy and high-intensity statin monotherapy.
Conclusion: Adding ezetimibe to a moderate-intensity statin in patients with type 2 diabetes has a greater LDL-C–lowering effect and greater
primary prevention of composite outcomes than that of high-intensity statin monotherapy.
Key Words: statin, ezetimibe, primary prevention, cardiovascular disease, diabetes mellitus
Abbreviations: ɤGTP, gamma-glutamyl peptidase; ACE, angiotensin-converting enzyme; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass
index; CKD, chronic kidney disease; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; H-S, high-intensity statin; KNHI, Korean
National Health Insurance; LDL-C, low-density lipoprotein cholesterol; L-S/E, low-intensity statins and ezetimibe; MI, myocardial infarction; M-S/E,
moderate-intensity statins and ezetimibe; PSM, propensity score matching; TG, triglyceride.

It is estimated that 30% to 60% of patients with diabetes
have dyslipidemia (1). Dyslipidemia in patients with diabetes
is characterized by elevated fasting and postprandial trigly-
cerides (TGs), low high-density lipoprotein cholesterol
(HDL-C), elevated low-density lipoprotein cholesterol
(LDL-C), and a predominance of small, dense LDL particles
(2). Furthermore dyslipidemia contributes to atherosclerotic
cardiovascular disease (ASCVD), which is the primary cause
of death in patients with diabetes (3). Statin therapy is the
most important primary and secondary prevention for redu-
cing the risk of mortality from ASCVD and coronary heart
disease in patients with diabetes (4, 5). Additionally, lower
LDL-C concentrations can lead to better clinical outcomes
(6). Therefore, recent guidelines aim to reduce LDL-C, and
recommend using moderate-intensity statins for the primary
prevention of ASCVD in patients with diabetes aged 40-75
years; high-intensity statins should be considered for mul-
tiple risk factors (7). However, despite LDL-C reduction us-
ing statins, there is a limit to sufficient LDL-C reduction, and
issues regarding the residual risk of recurrent cardiovascular
disease (CVD) remain (8). In addition, the usage of high-
intensity statins has raised concerns about several side effects
such as hepatotoxicity, myopathy, acute renal failure, and
cataracts (9). Therefore, guidelines recommend using ezeti-
mibe and PCSK9 inhibitors when additional LDL-
lowering treatments are required (10, 11).
However, all previous studies on the effectiveness of com-
bination therapy of statin and ezetimibe were secondary pre-
vention studies of CVD (12-14). There has been no
randomized controlled trial study comparing the primary

Received: 13 June 2023. Editorial Decision: 1 December 2023. Corrected and Typeset: 4 January 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
2 The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0

preventive effects of statin monotherapy and combination national health check-ups in 2015 were enrolled. The index

therapy of statin and ezetimibe on CVD. Moreover, there
are no studies on the primary prevention effect on CVD of eze-
timibe added to a statin in patients with diabetes. Therefore, in
this study, we aimed to compare the primary prevention effect
of myocardial infarction (MI), stroke, and all-cause death be-
tween combination therapy of low-intensity statins and ezeti-
mibe (L-S/E) or moderate-intensity statins and ezetimibe
(M-S/E) and high-intensity statin (H-S) monotherapy in
Korean patients with diabetes.
Materials and Methods
Data Sources
In this study, data were obtained from the Korean National
Health Insurance (KNHI) claims database and preventive
health check-ups in Korea between January 2014 and
December 2019. The KNHI covers 97% of the Korean popu-
lation, approximately 50 million people. The KNHI claims
database contains information on diagnostic and procedure
codes according to the 10th revision of the International
Classification of Diseases (ICD-10), prescriptions, dates of
hospital visits, and hospitalization. Meanwhile, preventive
health check-ups contain information on lifestyle factors
(smoking, drinking, and exercise), body measurements
(height, weight, body mass index [BMI], and waist circumfer-
ence), and laboratory results.
Study Participants and Design
This study was a retrospective cohort study. Patients aged ≥20
years with type 2 diabetes and dyslipidemia who underwent
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date was the date the health check-ups had been performed.
Those who had a history of MI or stroke before the index
date or who had been prescribed ezetimibe before the index
date were excluded. Additionally, those who had not been
prescribed statins within 1 year after the index date or statins
and ezetimibe for <90 days within 1 year after the index date
were excluded. Type 2 diabetes was defined as cases of disease
codes (ICD-10 codes: E11) or cases in which antidiabetic med-
ications were prescribed. Dyslipidemia was defined as cases in
which lipid-lowering medications were prescribed. A total of
412 245 patients were enrolled in this study (Fig. 1). The pa-
tients were classified according to whether ezetimibe was
used and the intensity of statin therapy (low, moderate, and
high-intensity statin therapy), based on the 2018 American
College of Cardiology/American Heart Association choles-
terol guidelines (15). All groups were followed up for MI,
stroke, and all-cause death occurrence, or until the last health
check-ups. In this study, we extracted the combination ther-
apy groups of L-S/E and M-S/E group, and compared the inci-
dence of MI, stroke, or all-cause death with H-S monotherapy
in each group.
Study Outcome
The primary outcome was the composite outcome of MI,
stroke, or all-cause death. The secondary outcome was the in-
cidence of each component of the composite outcome. MI was
defined as a diagnosis of ICD-10 code I21 or I22 with hospi-
talization. Stroke was defined as a case wherein a diagnosis
of ICD-10 code I63 or I64 was obtained on the basis of
brain magnetic resonance imaging or computed tomography

Patients with T2DM and dyslipidemia aged 20 years who

underwent national health check-ups in 2015
n = 811,046

Before index date,

MI=59,445
Stroke =106,956
Ezetimibe prescription = 53,259

Statin prescribers within 1 year after index date

n = 471,394

statin and ezetimibe prescription for

less than 90 days within 1 year after
index date, n = 42,821
Missig data, n= 11,454
1 year lag, n= 4,874

Ezetimibe users
n = 15,496
Ezetimibe non-users
n = 396,749

Low-intensity statin/ezetimibe High-intensity statin monotherapy Moderate-intensity statin/ezetimibe

n = 1,665 n = 12,312 n = 13,244
1:1 PSM 1:1 PSM

High-intensity statin monotherapy, n =1,665 High-intensity statin monotherapy, n = 10,013

Low-intensity statin/ezetimibe, n = 1,665 Moderate-intensity statin/ezetimibe, n = 10,013

Figure 1. Flow chart. T2DM, type 2 diabetes mellitus; MI, myocardial infarction; PSM, propensity score matching analysis.
The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0 3

Table 1. Baseline characteristics

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H-S group M-S/E group ASD H-S group L-S/E group ASD
(n = 10 013) (n = 10 013) (n = 1665) (n = 1665)

Age, years 57.6 ± 9.9 57.7 ± 9.9 0.01 57.4 ± 10.3 56.9 ± 10.4 0.047
(mean ± SD)
Sex, male (n, %) 5830 (58.2%) 5839 (58.3%) 0.002 949 (57%) 973 (58.4%) 0.03
Income, low 25% 2302 (23%) 2290 (22.9%) 0.003 360 (21.6%) 366 (22%) 0.009
(n, %)
BMI, kg/m2 26 ± 3.6 25.9 ± 3.5 0.008 25.5 ± 3.4 25.6 ± 3.4 0.023
(mean ± SD)
Waist circumference, cm (mean ± SD) 87.3 ± 9.1 87.2 ± 8.9 0.01 86.3 ± 9.1 86.7 ± 8.8 0.041
DM duration, years 5.7 ± 4.2 5.7 ± 4.3 0.006 4.6 ± 4.6 4.4 ± 4.7 0.042
(mean ± SD)
DM duration ≥5 years, (n, %) 4814 (48.1%) 4746 (47.4%) 0.014 663 (39.8%) 643 (38.6%) 0.025
Smoke (n, %)
nonsmoker 5358 (53.5%) 5388 (53.8%) 0.006 929 (55.8%) 893 (53.6%) 0.044
ex-smoker 2387 (23.8%) 2340 (23.4%) 0.011 394 (23.7%) 398 (23.9%) 0.006
current smoker 2268 (22.7%) 2285 (22.8%) 0.004 342 (20.5%) 374 (22.5%) 0.047
Drinker (n, %)
nondrinker 5720 (57.1%) 5720 (57.1%) 0 957 (57.5%) 954 (57.3%) 0.004
mild drinker 3440 (34.4%) 3445 (34.4%) 0.001 575 (34.5%) 538 (32.3%) 0.047
heavy drinker 853 (8.5%) 848 (8.5%) 0.002 133 (8%) 173 (10.4%) 0.083
Regular exercise 2137 (21.3%) 2140 (21.4%) 0.001 369 (22.2%) 358 (21.5%) 0.016
(n, %)
Hypertension (n, %) 6591 (65.8%) 6599 (65.9%) 0.002 936 (56.2%) 945 (56.8%) 0.011
CKD (n, %) 906 (9.1%) 949 (9.5%) 0.015 173 (10.4%) 170 (10.2%) 0.006
Medication (n, %)
Insulin 1098 (11.0%) 1089 (10.9%) 0.003 203 (12.2%) 207 (12.4%) 0.007
OHD ≥ 3, (n, %) 3741 (37.4%) 3671 (36.7%) 0.014 543 (32.6%) 539 (32.4%) 0.005
Aspirin, (n, %) 3669 (36.6%) 2739 (27.4%) 0.2 567 (34.1%) 412 (24.7%) 0.205
P2Y12 inhibitor, (n, %) 1749 (17.5%) 783 (7.8%) 0.293 275 (16.5%) 111 (6.7%) 0.311
Warfarin, (n, %) 76 (0.8%) 30 (0.3%) 0.063 15 (0.9%) 14 (0.8%) 0.006
NOAC, (n, %) 67 (0.7%) 57 (0.6%) 0.013 8 (0.5%) 8 (0.5%) 0
ACE inhibitor, (n, %) 456 (4.6%) 184 (1.8%) 0.155 75 (4.5%) 50 (3%) 0.079
ARB, (n, %) 5023 (50.2%) 5436 (54.3%) 0.083 704 (42.3%) 740 (44.4%) 0.044
Beta blocker, (n, %) 1387 (13.9%) 980 (9.8%) 0.126 199 (12%) 137 (8.2%) 0.124
CCB, (n, %) 3155 (31.5%) 3561 (35.6%) 0.086 457 (27.5%) 491 (29.5%) 0.045
Glucose, mg/dL 146.9 ± 50.8 147.1 ± 48.6 0.004 152.5 ± 56.3 154.1 ± 55.6 0.028
GFR 91.2 ± 65.6 89.6 ± 58.9 0.026 92.9 ± 84 88 ± 38.3 0.075
Total cholesterol, mg/dL 184.9 ± 56.8 189.5 ± 51.4 0.085 208.6 ± 59 213.9 ± 46.8 0.099
HDL-C, mg/dL 50.9 ± 12.9 50.9 ± 13.7 0.001 49.8 ± 12.2 49.94 ± 12.3 0.011
LDL-C, mg/dL 101.63 ± 49.29 102.63 ± 44.94 0.021 125.4 ± 51.2 125.9 ± 42 0.011
TG, mg/dL 143.6 159.5 0.183 149.8 171.4 0.228
(142–145.2) (157.7–161.4) (145.8–153.9) (166.4 -176.6)
AST, U/L 27.5 27.82 0.03 27.1 27 0.012
(27.2–27.7) (27.6–28.1) (26.5–27.7) (26.4–27.6)
ALT, U/L 28.7 29.1 0.02 28.1 28.5 0.024
(28.4–29.1) (28.7–29.4) (27.4–28.9) (27.7–29.3)
ɤGTP, U/L 38.6 39.9 0.045 38.8 40.7 0.06
(38–39.1) (39.3–40.6) (37.4–40.3) (39.2–42.2)

Mean ± SD, median (25th percentile—75th percentile), or n (%). Two-sample t test, propensity score matching.
Abbreviations: γGTP, gamma glutamyl peptidase; ACE inhibitor, angiotensin-converting enzyme inhibitor; ALT, alanine aminotransferase; ARB, angiotensin
receptor blockers; ASD, absolute standardized difference; AST, aspartate aminotransferase; CCB, calcium channel blocker; CKD, chronic kidney disease; DM,
diabetes mellitus; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; H-S group, high-intensity statin monotherapy group; LDL-C,
low-density lipoprotein cholesterol; L-S/E group, combination therapy group of low-intensity statin and ezetimibe BMI, body mass index; MI, myocardial
infarction; M-S/E group, combination therapy group of moderate-intensity statin and ezetimibe; NOAC, new oral anticoagulant; OHD, oral hypoglycemic
drug; TG, triglyceride.
4 The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0

performed during hospitalization. For all-cause deaths, death Table 2. Effect of adding ezetimibe to moderate-intensity statin

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certificates from the National Statistical Office were identified compared to high-intensity statin monotherapy on primary and
secondary outcome in patients with diabetes
via individual identification numbers assigned to citizens at
birth.
IR HR P
(per 1000 PY) (95% CI)
Other Covariates MI or stroke or all-cause death
Data on age, sex, low-income status, height, weight, BMI, H-S group 15.2 1 (ref.) .029
waist circumference, smoking, drinking, and regular exercise M-S/E group 10.1 0.85
were collected. Low-income status was defined as the lowest (0.74, 0.98)
20% of the population based on monthly household income. MI
Smoking history was classified as “nonsmoker,” “ex- H-S group 5.3 1 (ref.) .079
smoker,” or “current smoker.” The drinking history was clas-
M-S/E group 3.8 0.81
sified as “nondrinker,” “mild drinker,” or “heavy drinker.” (0.64, 1.03)
Participants who never drank alcohol were considered non-
Stroke
drinkers, whereas those with daily average alcohol intakes
of <30 and ≥30 g/day were defined as mild and heavy H-S group 4.1 1 (ref.) .014
drinkers, respectively. Regular exercise was defined as high- M-S/E group 2.1 0.7
intensity physical activity (physical activity causing extreme (0.52, 0.93)
shortness of breath) for >20 minutes per session or All-cause death
moderate-intensity physical activity (physical activity causing H-S group 7.3 1 (ref.) .637
substantial shortness of breath) for >30 minutes per session at M-S/E group 4.9 0.95
least once a week. Chronic kidney disease (CKD) was defined (0.77, 1.17)
as an estimated glomerular filtration rate of <60 mL/min/1.73
m2. Hypertension was defined by disease codes (ICD-10 By Cox proportional hazards model.
H-S group, high-intensity statin monotherapy group; HR, hazard ratio; IR,
codes: I10-12, I15) or cases in which antihypertensive incidence rate; MI, myocardial infarction; M-S/E group, combination
medications were prescribed. The prescription records of anti- therapy group of moderate-intensity statin and ezetimibe; PY, patient-years.
hypertensive drugs (angiotensin-converting enzyme [ACE]
inhibitors, angiotensin receptor blockers, beta-blockers, and
calcium channel blockers), anticoagulation or antiplatelet version 9.4 (SAS Institute Inc., Cary, NC, USA), and P < .05
drugs (aspirin, P2Y12 inhibitors, warfarin, and new oral an- was considered to be statistically significant.
ticoagulants), and antidiabetic drugs were examined. The
blood tests included lipid profiles (total cholesterol, Ethics Statement
HDL-C, LDL-C, and TGs), glucose, liver function tests (as-
partate aminotransferase, alanine aminotransferase, gam- This study was approved by the Institutional Review Board of
ma-glutamyl peptidase [ɤGTP], and glomerular filtration Kyung Hee University Hospital in Gangdong (number
rate. The duration of diabetes and prescription of statins or 2020-12-001). Informed consent was not required from the
ezetimibe were calculated. patients because of the nature of public data in the KNHI
claims database.

Statistical Analysis
Continuous variables with normal distributions were ex-
pressed as the means ± SD, and those without normal distri-
butions were expressed as the median (interquartile range).
Categorical variables were expressed as percentages. The inci-
dences of primary and secondary outcomes were calculated as
cases per 1000 person-years. The cumulative incidences of
MI, stroke, and all-cause death were analyzed using the
Kaplan–Meier log-rank test. For adjustment of confounding
factors, propensity score matching (PSM) was performed us-
ing a nearest-neighbor matching algorithm with a 1:1 match-
ing protocol without replacement and a caliper within the first
4 to 8 digits. An absolute standardized difference of <0.10 be-
fore and after matching implied a good balance between the
2 groups. The risks of the primary and secondary outcomes
were analyzed and compared using the Cox proportional
hazards model. Subgroup analyses were conducted according
to age (<40 vs 40–74 vs ≥75 years), sex, BMI (<25 vs
≥25 kg/m2), baseline LDL-C levels (<160 vs ≥160 mg/dL),
presence of hypertension or CKD, duration of diabetes (<5
years vs ≥5 years), duration of ezetimibe use (<180 vs ≥180
days) or statin use (<5 years vs ≥5 years), and antidiabetic
medications. Statistical analyses were performed using SAS
Results
Baseline Characteristics
Comparisons of the baseline characteristics between the M-S/
E group and the H-S group and between the L-S/E group and
the H-S group are summarized in Table 1. In the M-S/E group,
58.3% were men, with a mean age of 57.7 years, a mean BMI
of 25.9 kg/m2, and a mean diabetes duration of 5.7 years.
Additionally, 22.8% were current smokers, 65.9% had hyper-
tension, and 9.5% had CKD. After PSM, covariates were bal-
anced between the M-S/E group and the H-S group because
the absolute standardized difference after matching was
<0.10. However, the M-S/E group had more prescriptions
for aspirin, P2Y12 inhibitors, ACE inhibitors, and beta block-
ers, as well as a higher plasma TG level than the H-S group. In
the L-S/E group, 58.4% were men, with a mean age of 56.9
years, a mean BMI of 25.6 kg/m2, and a mean DM duration
of 4.4 years; of whom, 22.5% were current smokers, 56.8%
had hypertension, and 10.2% had CKD. There was no signifi-
cant difference between the L-S/E and the H-S groups for other
factors after PSM. However, compared with the H-S group,
the L-S/E group was prescribed more aspirin, a P2Y12 inhibi-
tor, and a beta blocker, and had higher plasma TG levels.
The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0
Figure 2. Kaplan–Meier curves showing the cumulative incidence of MI, stroke, and all-cause death in moderate-intensity statin with ezetimibe
combination therapy and high-intensity statin monotherapy group. (A) Composite outcomes, (B) MI, (C) stroke, (D) all-cause death. MI, myocardial
infarction.
Changes in Lipid Profiles
Adding ezetimibe to a moderate-intensity statin achieved lower
serum levels of total cholesterol and LDL-C than those in the
H-S group (P < .001). Conversely, the TG levels were lower in
the H-S group (P < .001) (Table S1 (16)). There was no signifi-
cant difference in the LDL-C level when ezetimibe was added
to a low-intensity statin compared with high-intensity statin
monotherapy, and the TG levels were lower in the H-S group
(Table S1 (16)).
Primary and Secondary Outcomes
The composite outcome of MI, stroke, or all-cause death was
lower in the M-S/E group than in the H-S group after PSM
(HR 0.85, 95% CI 0.74-0.98) (Table 2 and Fig. 2). As a result
of the secondary outcome, the risk of stroke was low in the
M-S/E group (HR 0.7, 95% CI 0.52-0.93). However, the risks
for MI and all-cause death were not significantly different be-
tween the 2 groups (MI, HR 0.81, 95% CI 0.64-1.03; all-
cause death, HR 0.95, 95% CI 0.77-1.17). Meanwhile, there
was no significant difference in the composite outcome be-
tween the L-S/E and H-S groups (Table 3 and Fig. 3).
5
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Subgroup Analyses
In the subgroup analyses, there was no significant difference
between the M-S/E and H-S groups in the composite outcome
based on age (<40 vs 40-74 vs ≥75 years), sex (female vs
male), BMI (<25 kg/m2 vs ≥25 kg/m2), baseline LDL-C level
(<160 mg/dL vs ≥160 mg/dL), presence of hypertension or
CKD, duration of statin use (<5 vs ≥5 years), duration of dia-
betes (<5 vs ≥5 years), insulin administration, and the number
of oral hypoglycemic drugs (<3 vs ≥3) (P for interaction
> .05). However, the composite outcome was better when eze-
timibe was used for >6 months in the M-S/E group than in the
H-S group (P for interaction = .028) (Table S2 (16)). In all
subgroup analyses, there was no significant difference in the
composite outcome between the L-S/E and H-S groups (P
for interaction > .05) (Table S3 (16)).
Discussion
In Korean patients with diabetes, adding ezetimibe to a
moderate-intensity statin has greater LDL-C lowering and pri-
mary prevention effects on the composite outcomes of MI,
6 The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0

Table 3. Effect of adding ezetimibe to low-intensity statin compared nonfatal stroke in patients with ASCVD (13), of whom a higher

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to high-intensity statin monotherapy on primary and secondary number of patients have an LDL-C concentration of <70 mg/dL.
outcome in patients with diabetes
After subgroup analysis, among patients with diabetes and
ASCVD, the 3-year outcome was comparable between the
IR HR P
(per 1000 PY) (95% CI)
moderate-intensity statin with ezetimibe combination therapy
and high-intensity statin monotherapy (22). Moderate-inten-
MI or stroke or all-cause death sity statins with ezetimibe combination therapy had a greater
H-S group 15.2 1 (ref.) .883 LDL-C lowering effect and a lower rate of drug discontinu-
L-S/E group 14.7 1.02 ation or dose reduction due to intolerance than high-intensity
(0.75, 1.39) statin monotherapy in patients with diabetes and ASCVD (22).
MI Moreover, a combination therapy of atorvastatin 40 mg and
H-S group 5.3 1 (ref.) .588
ezetimibe 10 mg/simvastatin 20 mg is reported to have a simi-
lar LDL-C–lowering effect (23, 24). In a cohort study using the
L-S/E group 6.3 1.14
(0.71, 1.85)
Taiwan National Health Insurance Research Database, the
composite outcome of cardiovascular death, non-fatal MI,
Stroke
and nonfatal stroke during a 2.4-year follow-up period was
H-S group 4.1 1 (ref.) .45 not significantly different between atorvastatin 40 mg and eze-
L-S/E group 4 1.27 timibe 10 mg/simvastatin 20 mg treatment in patients with
(0.68, 2.35) type 2 diabetes after acute coronary syndrome or acute ische-
All-cause death mic stroke (25). The RACING trial and Taiwan real-world co-
H-S group 7.3 1 (ref.) .677 hort study investigated the secondary prevention effect in
L-S/E group 7 0.91 high-risk patients with ASCVD, whereas our study analyzed
(0.59, 1.4) the primary prevention effect of MI or stroke. In addition,
our study compared low- and moderate-intensity statin and
By Cox proportional hazards model. ezetimibe combination therapy with high-intensity statin
H-S group, high-intensity statin monotherapy group; HR, hazard ratio; IR,
incidence rate; L-S/E group, combination therapy group of low-intensity monotherapy for the primary prevention effects of MI, stroke,
statin and ezetimibe; MI, myocardial infarction; PY, patient-years. or all-cause death in patients with diabetes. Compared with the
H-S group, the M-S/E group showed a better composite out-
come of MI, stroke, or all-cause death, whereas no significant
stroke, and all-cause death than high-intensity statin mono- difference was observed in the L-S/E group, which can be at-
therapy. Conversely, when ezetimibe was added to low- tributed to the smaller number of participants in the L-S/E
intensity statins, there was no significant difference in either group than in the M-S/E group (20 023 vs 6 948) or to the
LDL-C lowering or the primary prevention effects of the com- LDL-lowering effect. Considering the reduction in LDL-C
posite outcome, as compared to those observed with high- concentration was strongly associated with a reduction in
intensity statin monotherapy. the risk of major vascular events (26), the stronger LDL-C low-
Compared with other cholesterol-lowering agents, ezetimibe ering effect of the M-S/E group than that in the L-S/E group
selectively inhibits the intestinal absorption of cholesterol would have influenced the composite outcome. Therefore,
at the brush border of the small intestine, mediated by the sterol the preventive effect on CVD of ezetimibe in patients with dia-
transporter Niemann-Pick C1-Like-1 (NPC1L1) (17). Ezetimibe betes is most likely due to LDL-C reduction, and other pleio-
reduces total cholesterol, LDL-C, apolipoprotein B, and tropic effects of ezetimibe, such as plaque regression,
non-HDL-C levels. When added to statins, LDL-C concentra- anti-inflammatory or antioxidant action, inhibition of mono-
tion could be further reduced by 23% to 24% (18, 19). In add- cyte or macrophage differentiation, inhibition of smooth
ition to the LDL-C concentration-lowering effect, the CVD muscle cell proliferation, and inhibition of platelet aggregation
outcome was favorable when ezetimibe was added to the same (27-29), are considered to be relatively minimal. Our findings
dose of statin (12, 14). When ezetimibe was added to a are corroborated by the results of the Taiwan real-world co-
moderate-intensity statin, LDL-C concentration was reduced hort study (atorvastatin 40 mg vs ezetimibe 10 mg/simvastatin
more significantly than when it was added to high-intensity sta- 20 mg) (25). Moreover, our findings that additional use of eze-
tin monotherapy (20, 21). Additionally, subgroup analyses in timibe was beneficial when at least a moderate-intensity statin
previous studies showed a greater LDL-C reduction effect in pa- was used in patients with diabetes are consistent with the
tients with diabetes than in the general population. However, recommendation of at least a moderate-intensity statin for
these studies had short follow-up periods, a small number of pa- the primary prevention of ASCVD in diabetic patients aged
tients, and no information on clinical outcomes such as cardio- 40-75 years in the 2018 cholesterol guideline (10).
vascular death, MI, stroke, or arterial revascularization. In the In our study, the use of aspirin, P2Y12 inhibitor, ACE in-
IMPROVE-IT trial, the combination therapy of simvastatin hibitor, and beta blocker was higher in the H-S group than
40 mg and ezetimibe 10 mg improved cardiovascular outcomes in the M-S/E group. This may indicate that the H-S group
compared with simvastatin 40 mg alone in patients with acute may have underlying heart diseases such as angina, heart fail-
coronary syndrome (12). After subgroup analysis, CVD out- ure, and some heart rhythm disorders, or a higher risk of car-
comes were better when ezetimibe was added, even in patients diocerebrovascular disease. On the other hand, a higher
with diabetes. In the RACING trial, moderate-intensity statin prescription rate of aforementioned medications in H-S group
with ezetimibe combination therapy (rosuvastatin 10 mg may have beneficial effect on cardiovascular outcomes.
and ezetimibe 10 mg) was noninferior to high-intensity statin Collectively, this imbalance in prescription of some medications
monotherapy (rosuvastatin 20 mg) for the 3-year composite out- may reflect different cardiovascular risk at baseline and at the
comes of cardiovascular death, major cardiovascular events, or same time, may affect different future cardiovascular outcomes
The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0
Figure 3. Kaplan–Meier curves showing the cumulative incidence of MI, stroke, and all-cause death in low-intensity statin with ezetimibe combination
therapy and high-intensity statin monotherapy group. (A) Composite outcomes, (B) MI, (C) stroke, (D) all-cause death. MI, myocardial infarction.
between the 2 groups. Therefore, the caution is required when
interpreting our study results. Both baseline and achieved TG
levels were lower in H-S group than M-S/E group, but had little
effect on the composite outcome. Additionally, LDL-C reduction
had the strongest effect on the composite outcome.
Based on subgroup analyses, the duration of ezetimibe
treatment affected the outcome when ezetimibe was added
to a moderate-intensity statin rather than a low-intensity sta-
tin. The longer the use of ezetimibe, the better the composite
outcome. Additional large-scale studies with longer follow-up
periods are warranted to further understand the effects of
various factors on the primary outcome.
This study had some limitations. As this was an analysis of
real-world data and not a randomized controlled trial, certain
biases could not be avoided. Lifetime ASCVD risk, ASCVD
risk in those younger than 40 years, or death from cardiovas-
cular causes were not investigated. Moreover, other diabetes-
specific risk factors, such as the duration of diabetes for >10
years, the presence of microalbuminuria, diabetic nephrop-
athy, neuropathy, retinopathy, and peripheral arterial disease,
which could affect the occurrence of ASCVD (7) were not con-
sidered. In addition, the gender difference in alcohol thresh-
olds was not considered, and there were no diet data. Since
7
Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgad714/7510780 by ICDDR,B:Centre for Health and Population Reseasch user on 08 January 2024
the adverse effects caused by statins or statin/ezetimibe such
as elevated blood sugar levels, hepatotoxicity, and myopathy
could not be identified, the benefit of LDL-C lowering, and the
harm of high-dose drugs could not be considered together.
However, to the best of our knowledge, this is the first study to
analyze the primary prevention effect of MI, stroke, or all-cause
death by adding ezetimibe to a low- or moderate-intensity statin
in Korean patients with diabetes. Nevertheless, further research
across diverse races is required for more conclusive results.
In summary, adding ezetimibe to a moderate-intensity statin in
Korean patients with diabetes, a high-risk group for ASCVD, has
a greater LDL-lowering effect and a greater primary prevention
effect on the composite outcome of MI, stroke, and all-cause
death than that of high-intensity statin monotherapy.
Acknowledgments
The authors thank all study participants for contributing.
Funding
This work was supported by grants from Kyung Hee University
in 2022 (grant number KHU-20222246) and Celltrion.
8 The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0
Disclosure
The authors declare that they have no competing financial in-
terests or personal relationships that could influence the work
reported in this paper.
Data Availability
Y.H. is the guarantor of this work and, as such, had full access
to all the data in the study and takes responsibility for the integ-
rity of the data and the accuracy of the data analysis. The data-
sets generated during and/or analyzed in the current study are
available from the corresponding author upon reasonable
request.
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