The effect of switching from statin-monotherapy to statin/ezetimibe
combination therapy on lipid profiles in patients with type 2
diabetes and dyslipidemia: a multicenter
open-label study (EUCLID)
Mitsuhide Takeshita, MD
1), Atsushi Tanaka, MD, PhD
1), Atsushi Kawaguchi, PhD
2), Keiko Sato, MSc
2),
Shigeru Toyoda, MD, PhD
3), Teruo Inoue, MD, PhD
3), Koichi Node, MD, PhD
1)and
On behalf of the EUCLID Study Investigators
Abstract:
Background: Combination therapy with a statin and ezetimibe is recognized as a useful therapeutic option for reducing the levels of low-density lipoprotein cholesterol (LDL-C). The aim of this study was to investigate the therapeutic effects of switching from statin-monotherapy to statin/ezetimibe combination therapy on lipid and metabolic profiles in patients with type 2 diabetes (T2D) and dyslipidemia. The study also assessed the clinical characteristics of patients who achieved or did not achieve their individual treatment target of low-density lipoprotein cholesterol (LDL-C) level after 12 months of combi-nation therapy. Methods: Patients with T2D and dyslipidemia received ezetimibe 10 mg per day for 12 months as an add-on to background statin treatment. The changes in lipid and inflammatory markers after initiatiadd-on of statin/ezetimibe combi-nation therapy were evaluated. In addition, we examined the clinical characteristics of participants who achieved or not achieve their target LDL-C level. Results: A total of 15 patients (mean age 65.7 ± 8.7 yr, 6 females) were included in the analyses. The levels of total cholesterol and LDL-C were decreased significantly at 3, 6, and 12 months compared to base-line values, whereas the levels of the other laboratory parameters remained unchanged at each time point. Six patients (40.0%) achieved their target LDL-C level, while 9 patients (60.0%) did not. The subgroup of patients who did not achieve their LDL-C targets had significantly higher baseline levels of total cholesterol (TC) and LDL-C compared to the subgroup who achieved their target. Conclusions: Switching from statin-monotherapy to statin/ezetimibe combination therapy was effective for reducing LDL-C levels. However, patients with higher baseline TC and LDL-C levels may require further in-tensive treatment to achieve their target level of LDL-C.
Key words:
Ezetimibe, Statin, Combination therapy, Type 2 diabetes, Dyslipidemia
Introduction
It is apparent that complicated dyslipidemia can further increase the risk of cardiovascular events in patients with diabetes. Patients with type 2 diabetes (T2D) are known to often have mixed dyslipidemia associated with insulin resis-tance that is seen as a shift to a more atherogenic lipid
pro-file, such as increased hepatic production of very low-density lipoprotein, decreased plasma concentration of high-density lipoprotein cholesterol (HDL-C), and elevated plasma concentration of postprandial triglyceride-rich lipo-proteins1,2). It has been reported that increased levels of
tri-glyceride (TG) and decreased levels of HDL-C are both in-dependent risk factors for progression of microvascular
com-1) Department of Cardiovascular Medicine, Saga University, Saga, Japan 2) Clinical Research Center, Saga University Hospital, Saga, Japan
3) Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Mibu, Japan Corresponding author: Atsushi Tanaka, MD, PhD, tanakaa2@cc.saga-u.ac.jp
Received: May 15, 2020, Accepted: June 2, 2020 CopyrightⒸ 2020 Japan Society for Vascular Failure
plications in patients with T2D3,4). There is also evidence in
the broad population of people with diabetes that an in-creased plasma concentration of low-density lipoprotein cho-lesterol (LDL-C) is the strongest risk factor for macrovascu-lar complications, including coronary artery disease5,6). A
re-duction in LDL-C level is associated with a decreased risk of cardiovascular events7,8)
, with therapeutic goals of LDL-C levels set individually according to the background risk of the patient. The Japanese guidelines for prevention of athe-rosclerotic cardiovascular disease (ASCVD)9), state that it is
necessary to strictly adhere to the guidelines in order to achieve these goals, especially in populations with a high cardiovascular event risk, including those with T2D.
In addition to lifestyle modification such as a healthy diet and exercise, treatment with a statin has been shown clearly to reduce cardiovascular events and mortality in a broad range of the population, irrespective of a history of diabetes or cardiovascular events. Statins are therefore recommended as an established first line medication for reducing LDL-C levels10-12)
. Furthermore, accumulated evidence in patients with T2D suggests that adding a combination of a statin and ezetimibe, a cholesterol absorption inhibitor that acts in the intestine, to basal statin therapy is more effective for im-proving lipid profiles than either statin monotherapy or in-creasing the statin dosage13-19)
. This strategy has also been re-ported to reduce atherosclerotic cardiovascular events20-23).
This combination therapy has therefore become more com-mon and is now recognized as a useful tool for gaining greater clinical benefits in patients with T2D and dyslipide-mia24)
.
Given this clinical evidence it is important to comprehen-sively evaluate the detailed changes in plasma lipid profile and clinically relevant markers, such as glucose metabolism and inflammatory activity in populations with specific dis-eases in which ezetimibe has been added to statin therapy. Moreover, it is necessary to determine whether or not the addition of ezetimibe to statin therapy contributes to achiev-ing lipid goals in routine clinical settachiev-ings. These investiga-tions may help to screen for patients in whom statin/ ezetimibe combination therapy is appropriate and assist in identifying patients who need additional or alternate treat-ment strategies to achieve their lipid targets. Clarifying these indicators is considered important for improving the quality of clinical management in specific disease populations. The aim of this study was therefore to investigate the therapeutic effects of switching from statin-monotherapy to statin/ ezetimibe combination therapy on lipid and metabolic pro-files in patients with T2D and dyslipidemia. The study also examined the clinical characteristics of patients who achieved or did not achieve their individual target LDL-C level after 12 months of statin-ezetimibe combined therapy.
Methods
Study Design and Population
TheEzetimibe add-on to statin for Usability Clinical trial on Lipid profile and Inflammation in hypercholesterolemia withDiabetes mellitus (EUCLID) study was an investigator-initiated, multicenter, prospective, open-label, single-arm pi-lot study undertaken at six hospitals in Japan. Prior to initia-tion, the study protocol was approved by local institutional review boards and independent ethics committees and the study was conducted in accordance with the Declaration of Helsinki. All participants provided written, informed consent prior to their participation in the study.
The inclusion and exclusion criteria for the study are shown in Supplementary Table 1. In brief, patients with T2D (HbA1c !9.0％) and dyslipidemia in spite of statin therapy of any dose for at least the previous three months were eligible for the study. Patients with either uncontrolled T2D or those receiving insulin treatment, familial or secon-dary hypercholesterolemia, recent cardiovascular events, or hepatic or renal dysfunction were not eligible for the study.
After informed consent had been obtained the patients had ezetimibe 10 mg per day added to their background sta-tin treatment for 12 months. Administration of lipid-lowering drugs other than the study drugs was not allowed during the study period. If possible, after taking into account the clinical condition of associated diseases, the background treatment of the patients, such as anti-diabetic agents re-mained unchanged during the study period.
Outcomes and Measurements
The following demographic variables were recorded at study entry: age, sex, body height and weight (calculated as body mass index, BMI), smoking status, previous medical history, and the use of medications. Liver and renal function and several lipid parameters [total cholesterol (TC), TG, LDL-C, HDL-C, and remnant-like particles-cholesterol (RLP-C)] were evaluated at baseline and 3, 6, and 12 months after intervention. Malondialdehyde-modified low-density lipoprotein (MDA-LDL) and high-sensitive C-reactive protein (hs-CRP) were measured at baseline and at three months by a central laboratory (SRL Inc., Tokyo, Ja-pan). Glycemic parameters (HbA1c and fasting plasma glu-cose) and other non-lipid biochemical parameters were measured at baseline and at 6 and 12 months.
Because this was a pilot study no specific primary and secondary endpoints were determined. We therefore explora-torily evaluated changes in the above mentioned laboratory markers after initiation of statin/ezetimibe combination ther-apy in the participants and also in subgroups stratified ac-cording to the baseline median LDL-C level. In addition, based on the recently published treatment guidelines for pre-vention of ASCVD in Japan9) we divided the participants
into two groups according to whether or not they achieved their individual treatment targets of LDL-C level.
Table 1. Baseline demographics and clinical characteristics of patients
Variables Overall Achieved Not-achieved p
(Achieved vs. Not-achieved)
(n=15) (n=6) (n=9)
Age, yr 65.7 ± 8.7 64.2 ± 9.8 66.7 ± 8.3 0.603
Females 6 (40.0) 4 (66.7) 2 (22.2) 0.136
Body mass index, kg/m2 27.4 ± 3.6 26.6 ± 3.7 27.9 ± 3.6 0.524
Currently smoking 0 (0) 0 (0) 0 (0)
Previous history
Hypertension 11 (73.3) 4 (66.7) 7 (77.8) 1.000
Atherosclerotic cardiovascular disease 11 (73.3) 3 (50.0) 8 (88.9) 0.235
Coronary artery disease 11 (73.3) 3 (50.0) 8 (88.9) 0.235
Percutaneous coronary intervention 6 (40.0) 1 (16.7) 5 (55.6) 0.287
Coronary artery bypass grafting 6 (40.0) 2 (33.3) 4 (44.4) 1.000
Cerebrovascular disease 2 (13.3) 2 (33.3) 0 (0) 0.143
Peripheral arterial disease 3 (20.0) 1 (16.7) 2 (22.2) 1.000
Medications Strong statin 14 (93.3) 6 (100) 8 (88.9) 1.000 D-glucosidase inhibitor 5 (33.3) 2 (33.3) 3 (33.3) 1.000 Sulfonylurea 6 (40.0) 3 (50.0) 3 (33.3) 0.622 Thiazolidinedione 5 (33.3) 2 (33.3) 3 (33.3) 1.000 Metformin 1 (6.7) 1 (16.7) 0 (0) 0.400
ACE inhibitor or ARB 13 (86.7) 4 (66.7) 9 (100) 0.143
Calcium channel blocker 8 (53.3) 4 (66.7) 4 (44.4) 0.608
Beta-blocker 6 (40.0) 3 (50.0) 3 (33.3) 0.622
Anti-platelet 13 (86.7) 4 (66.7) 9 (100) 0.143
Data are expressed as mean ± standard deviation, or n (%).
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker
Statistical Analysis
Categorical variables were expressed as numbers (percent-age) and compared using the Chi-square test or Fisher’s act test, where appropriate. Continuous variables were ex-pressed as mean ± standard deviation (SD) for normal dis-tributed data and compared using unpaired-t tests with the Levene test or F test and paired-t tests with the Bonferroni correction. All tests were two-tailed and P values < 0.05 considered statistically significant. All the analyses were car-ried using JMP Pro software (version 14.2.0, SAS Institute Inc., Cary, NC, USA).
Results
Between January 2010 and April 2014 a total of 24 pa-tients were registered in the study, with 9 papa-tients subse-quently excluded due to not meeting the exclusion criteria (n =4), withdrawal (n=3), or lost to follow-up (n=2). The re-maining 15 patients (female n=6, male n=9) were included in the analyses. The baseline demographics and clinical characteristics of these 15 patients are shown in Table 1. Mean age was 65.7 ± 8.7 years and mean BMI was 27.4 ± 3.6 kg/m2
. Eleven patients (73.3%) had a history of hyper-tension and 11 patients (73.3%) had at least a history of ASCVD. One patient had been receiving a low-potency sta-tin at baseline, while the remaining patients had been taking a high-potency statin.
Table 2 summarizes the values of the laboratory
parame-ters at baseline and at 3, 6, and 12 months and the corre-sponding changes from baseline for each time point. The levels of TC (Figure 1A) and LDL-C (Figure 1B) were reduced significantly from baseline levels at 3 (only LDL-C), 6, and 12 months. In contrast, the levels of the other lipid parameters, such as TG (Figure 1C), HDL-C (Figure 1D), and RLP-C (Figure 1E) did not appear to have changed at each time point. No changes in the levels of MDA-LDL (Figure 1F) and hs-CRP (Figure 1G) were ob-served at 3 months. In addition, the other laboratory pa-rameters measured including renal and liver function mark-ers did not change at each time point (Table 2).
When stratified according to the baseline median LDL-C level (96 mg/dL), the subgroup with a baseline LDL-C !96 mg/dL showed a significant decrease in the levels of TC (Figure 2A) and LDL-C (Figure 2B) at 3, 6, and 12 months, whereas the subgroup with a baseline LDL-C < 96 mg/dL showed no significant reduction in these parameters at any time point. No significant changes in the other pa-rameters were observed in either of these subgroups at each time point (Figure 2C-G, Supplementary Table 2).
Stratification into subgroups according to whether or not the therapeutic targets of LDL-C level had been achieved at 12 months showed 6 patients (40.0%) achieved their goal while 9 patients (60.0%) did not (Table 1). No significant difference in background medical characteristics was ob-served between the two subgroups. The levels of TC and LDL-C at baseline, 6, and 12 months in the subgroup who did not achieve their goal were significantly higher than
Table 2. Changes in laboratory parameters at 3, 6, and 12 months
Variables Time point Overall (n=15) Missing Variables Time point Overall (n=15) Missing
TC, mg/dL Baseline 178.7 ± 10.1 0 High-sensitivity
CRP, ng/mL
Baseline 1111.4 ± 408.1 1
3 months 163.2 ± 7.8 1 3 months 774.5 ± 237.5 0
Δ -19.1 ± 7.3 1 Δ -308.6 ± 338.9 1
6 months 156.0 ± 6.9 0 HbA1c, % Baseline 6.37 ± 0.16 0
Δ -22.7 ± 7.3* 0 6 months 6.37 ± 0.11 0
12 months 158.6 ± 9.4 0 Δ -0.01 ± 0.14 0
Δ -20.1 ± 6.5* 0 12 months 6.60 ± 0.17 0
LDL-C, mg/dL Baseline 100.9 ± 10.1 0 Δ 0.23 ± 0.18 0
3 months 83.7 ± 7.3 1 Fasting plasma
glucose, mg/dL Baseline 120.0 ± 4.8 1 Δ -19.8 ± 6.7* 1 6 months 117.7 ± 6.8 1 6 months 80.2 ± 6.4 0 Δ -1.9 ± 7.2 1 Δ -20.7 ± 5.9** 0 12 months 131.4 ± 8.7 0 12 months 79.4 ± 7.9 0 Δ 7.3 ± 9.5 1
Δ -21.5 ± 4.8** 0 eGFR, mL/min/1.73m2 Baseline 70.9 ± 3.1 0
TG, mg/dL Baseline 123.7 ± 11.8 0 6 months 72.6 ± 4.2 1 3 months 144.1 ± 17.0 1 Δ 1.1 ± 2.8 1 Δ 17.8 ± 10.7 1 12 months 68.5 ± 3.0 1 6 months 130.9 ± 11.3 0 Δ -3.0 ± 2.1 1 Δ 7.2 ± 11.4 0 Aspartate transaminase, U/L Baseline 24.3 ± 1.5 0 12 months 149.9 ± 31.2 0 6 months 24.9 ± 2.0 0 Δ 26.1 ± 26.4 0 Δ 0.6 ± 1.5 0 HDL-C, mg/dL Baseline 52.7 ± 3.0 0 12 months 24.8 ± 2.1 0 3 months 54.6 ± 4.0 1 Δ 0.5 ± 1.3 0
Δ 1.4 ± 2.0 1 Alanine transaminase, U/L Baseline 24.5 ± 2.8 0
6 months 53.3 ± 3.4 0 6 months 24.1 ± 3.2 0 Δ 0.6 ± 1.6 0 Δ -0.5 ± 1.7 0 12 months 53.3 ± 3.1 0 12 months 23.3 ± 2.6 0 Δ 0.6 ± 1.8 0 Δ -1.3 ± 1.5 0 RLP-C, mg/dL Baseline 6.6 ± 1.4 5 J-glutamyltranspeptidase, U/L (n=7) Baseline 33.6 ± 6.3 8 3 months 7.6 ± 1.9 5 6 months 31.0 ± 5.8 7 Δ 0.0± 0.7 6 Δ -2.2 ± 1.9 9 6 months 6.6 ± 2.3 5 12 months 30.1 ± 4.1 7 Δ -0.2 ± 1.0 6 Δ -6.5 ± 2.6 9
12 months 5.8 ± 1.7 5 Creatine
phosphoki-nase,U/L (n=14) Baseline 116.7 ± 15.0 1 Δ -1.1 ± 1.3 6 6 months 114.5 ± 15.9 2 MDA-LDL, mg/dL Baseline 112.8 ± 16.2 6 Δ 1.9 ± 20.1 3 3 months 100.6 ± 13.9 5 12 months 136.1 ± 16.3 2 Δ -15.1 ± 10.8 7 Δ 11.5 ± 19.7 3
Data are expressed as mean ± standard deviation.
* p<0.05 (from baseline to each time point), ** p<0.01 (from baseline to each time point).
CRP, C-reactive protein; eGFR, estimated glomerular fi ltration rate; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MDA-LDL, malondialdehyde-modifi ed low-density lipoprotein; RLP-C, remnant-like particle cholesterol; TC, total cholesterol; TG, triglyceride.
those in the subgroup who achieved their goal. In the non-achieving subgroup, the LDL-C levels were also signifi-cantly decreased at 6 and 12 months (Figure 3B). While no significant changes in the other lipid parameters were ob-served in both subgroups (Figure 3A, C-G) a borderline significant reduction in RLP-C levels was observed in the subgroup who achieved their goal at 6 and 12 months (p= 0.061 and 0.055, respectively) (Supplementary Table 3).
Finally, we summarized the achievement rate of individual therapeutic targets and specific values of LDL-C at 12 months according to baseline levels of LDL-C (Table 3). Interestingly, all patients who achieved the therapeutic tar-gets had lower baseline LDL-C level (< 120 mg/dL), while
patients with higher baseline LDL-C level (!160 mg/dL) failed to achieve their individual therapeutic targets and even specific LDL-C levels.
Discussion
The major findings of the EUCLID study were that: 1) switching from statin-monotherapy to statin/ezetimibe com-bination therapy was effective in patients with T2D and dyslipidemia for reducing LDL-C levels without having a negative impact on glucose parameters, 2) 12 months of combination therapy was more effective in patients with higher baseline LDL-C levels compared to that observed in
Figure 1. Individual changes in lipid and infl ammatory parameters
Total cholesterol (A), low-density lipoprotein cholesterol (B), triglyceride (C), high-density lipoprotein cholesterol (D), remnant-like particles-cholesterol (E), malondialdehyde-modifi ed low-density lipoprotein (F), and high-sensitive C-reactive protein (G).
0 0 0 0 0 0 0 0 PJG/ PJG/ $ % PJG/ PJG/ & ' 0 0 0 0 0 0 0 0 PJG/ ( 0 0 0 0 0 0 0 0 PJG/ QJG/ ) *
patients with lower levels, 3) however patients who did not achieve their treatment target LDL-C level had higher base-line TC and LDL-C levels compared to those in patients who achieved their target. These findings therefore suggest that ezetimibe treatment added to standard statin therapy was effective for reducing LDL-C levels, although patients with higher levels of baseline TC and LDL-C may require further intensive treatment to achieve their therapeutic target of LDL-C levels, especially in those with a high risk of car-diovascular events.
Ezetimibe is an established lipid-lowering agent that acts by inhibiting cholesterol absorption in the intestine. In addi-tion to its fundamental effect on lipid metabolism, ezetimibe is known to have beneficial effects on multiple pathophysi-ological conditions and settings, such as the development of carotid and coronary plaque, endothelial dysfunction, chronic kidney disease, and even post-acute coronary syn-drome, all of which are involved in the development of ASCVD20,25-28)
. Therefore, combination therapy with a statin
is recommended widely as an additional approach for achieving therapeutic goals of LDL-C level in a broad range of patient populations. To date, a large number of studies have shown clearly that relative to statin monotherapy, sta-tin/ezetimibe combination therapy has greater clinical bene-fits for improving lipid parameters and resultant cardiovas-cular outcomes in T2D patients with a broad range of car-diovascular risk13-17,21-23,29,30)
.
In the Japanese guidelines for prevention of ASCVD9)
, in-dividual goals for lipid parameters, particularly LDL-C, are required and need to be set strictly in order to achieve these goals and reduce the risk of cardiovascular events, especially in populations with a high cardiovascular risk, including those with T2D. In this therapeutic strategy combination therapy with underlying statin therapy is recognized as the central option to achieve the goals24)
. However, as shown in the present study, only 40% of patients achieved their LDL-C targets with statin/ezetimibe combination therapy, despite a substantial reduction in the LDL-C levels. In addition,
al-Figure 2. Changes in lipid and infl ammatory parameters in subgroups stratifi ed according to baseline median low-density
lipo-protein cholesterol level (96 mg/dL)
Total cholesterol (A), low-density lipoprotein cholesterol (B), triglyceride (C), high-density lipoprotein cholesterol (D), remnant-like particles-cholesterol (E), malondialdehyde-modifi ed low-density lipoprotein (F), and high-sensitive C-reactive protein (G). The blue line indicates the subgroup with a baseline low-density lipoprotein cholesterol level ≥ 96 mg/dL, and the red line indicates the subgroup with a baseline low-density lipoprotein cholesterol level < 96 mg/dL.
0 0 0 0 0 0 0 0 PJG/ PJG/ $ % PJG/ PJG/ & ' 0 0 0 0 0 0 0 0 PJG/ ( 0 0 0 0 0 0 0 0 PJG/ QJG/ ) *
though the combination therapy lowered LDL-C especially in a subgroup with a baseline LDL-C !96 mg/dL, the low-ering effect was limited in a higher baseline level of LDL-C (!160 mg/dL). These findings indicate an important clinical implication that physicians need to pay careful attention to routine lipid parameters especially in patients with higher levels of TC and LDL-C who need to achieve their lipid goals.
No apparent difference in demographics and clinical char-acteristics at baseline was observed in the present study be-tween subgroups who did or did not achieve their target C levels. However, the baseline levels of TC and LDL-C were significantly higher in patients who did not achieve their target LDL-C level at 12 months. This suggest that the simplest factor to predict the possibility of achieving a lipid goal with this combination therapy is the baseline levels of
TC and LDL-C. Shigematsu et al.31)also reported that
base-line LDL-C level (!140 mg/dL) was an independent predic-tor of marked TC reduction after 12 weeks of statin/ ezetimibe combination therapy. Although the mean baseline level of LDL-C in our study was lower than that reported by Shigematsu et al., a higher baseline level of baseline LDL-C appeared to be associated with non-achievement of treatment goals in spite of a relatively greater reduction in LDL-C level. Therefore, in the management of lipid profiles in pa-tients who failed to achieve their goals, some additional therapeutic strategies such as the use of a proprotein conver-tase subtilisin/kexin type 9 (PCSK9) inhibitor32) should be
further considered. However, a recent study reported that relative to a PCSK9 inhibitor, treatment with ezetimibe was a major cost-saving strategy for preventing cardiovascular events in patients with T2D, ASCVD, and dyslipidemia
in-Figure 3. Changes in lipid and infl ammatory parameters in subgroups stratifi ed according to whether or not they achieved
indi-vidual low-density lipoprotein cholesterol target levels at 12 months.
Total cholesterol (A), low-density lipoprotein cholesterol (B), triglyceride (C), high-density lipoprotein cholesterol (D), remnant-like particles-cholesterol (E), malondialdehyde-modifi ed low-density lipoprotein (F), and high-sensitive C-reactive protein (G). The blue line indicates the subgroup who achieved their low-density lipoprotein cholesterol target level at 12 months, while the red line indicates the subgroup who did not achieve this goal.
PJG/ PJG/ $ % PJG/ PJG/ & ' PJG/ ( 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 PJG/ QJG/ ) * 0 0 0 0
Table 3. Achievement rate of individual therapeutic targets and specifi c values of LDL-C at 12
months according to baseline levels of LDL-C
Baseline Number Individual therapeutic targets < 100 mg/dL < 120 mg/dL
< 120 mg/dL 11 6 (54.6%) 11 (100%) 11 (100%)
120 ≤ LDL-C < 140 mg/dL 1 0 (0%) 1 (100%) 1 (100%)
140 ≤ LDL-C < 160 mg/dL 1 0 (0%) 1 (100%) 1 (100%)
LDL-C ≥ 160 mg/dL 2 0 (0%) 0 (0%) 0 (0%)
N (%)
LDL-C, low-density lipoprotein cholesterol.
dependent of background statin therapy33). Therefore, in a
real-world clinical setting physicians need to select lipid-lowering medications taking into account the medical needs and the social background of patients.
Accumulated evidence suggests that intensive statin use is
associated with impairment of glucose metabolism and an increased incidence of new-onset T2D34-37)
. Although the im-pact of statin-induced benefits is often thought to be clini-cally acceptable beyond such glycemic harm, appropriate and careful statin use is needed especially in patients with
T2D. In contrast, previous studies have shown that ezetimibe treatment has beneficial or neutral effects on glucose me-tabolisms in patients with T2D38-40). In our study, the addition
of ezetimibe treatment for 12 months did not affect glyce-mic parameters, suggesting the clinical utility of statin/ ezetimibe combination therapy even in patients with T2D.
In the present study, the levels of RLP-C, an atherogenic lipid marker, tended to decrease during the follow-up inter-val in the subgroup who achieved their target LDL-C level at 12 months. This is partly consistent with a previous study in which the addition of ezetimibe to a high-potency statin improved atherogenic lipid profiles including RLP-C41)
. However, the reason why RLP-C levels did not change in the group who did not achieve their goals is uncertain. Fi-nally, in the current study no obvious effect of statin/ ezetimibe combination therapy was observed on inflamma-tory markers, MDA-LDL and hs-CRP over the short-term observation period of three months. This finding is similar to that of a previous study of 8 weeks’ duration that used low-dose simvastatin/ezetimibe combination therapy42)
. How-ever, it is possible longer intervention with statin/ezetimibe combination therapy may also improve these markers via beneficial modulations of lipid metabolism and atherogenic pathways.
Limitations
This study had several limitations. First, it was a single-arm, open-label, pilot study of a very small number of pa-tients. Furthermore, because the study was conducted during the early 2010s, some medical situations, such as available medications, differ from the current situation. Second, some laboratory markers were not measured at all time-points. Third, the type of background statin and dosages were not unified, with only three patients who had been taking the maximum tolerated dose of statin receiving additional ezetimibe treatment. In addition, no specific cutoff values for lipid parameters, including LDL-C, were used to select patients for the study. These issues may have partially af-fected the results of the study and their interpretation. Fur-ther research is Fur-therefore required to evaluate the clinical significance of ezetimibe in lipid management in the current era.
Conclusion
Switching from statin-monotherapy to statin/ezetimibe combination therapy was effective for reducing LDL-C lev-els in patients with T2D and dyslipidemia. However, pa-tients with higher baseline LDL-C levels may need further intensive treatment to achieve their target LDL-C level.
Conflicts of Interest
AT received modest honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Fukuda Denshi, Kowa, Mitsubishi Tanabe, Novo Nordisk, Ono, Taisho
Toyama, Takeda, and Teijin; a research funding from GlaxoSmithKline. TI received scholarship from Shionogi, Sumitomo Dainippon, Mitsubishi Tanabe, Terumo, and Dai-ichi Sankyo. KN received research grants from Asahi Kasei, Astellas, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe, Teijin, and Terumo; scholarship from Astellas, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Takeda, and Teijin; personal fees from Astellas, AstraZeneca, Boehringer Ingel-heim, Daiichi Sankyo, Eli Lilly, Mitsubishi Tanabe, MSD, Ono, Otsuka, and Takeda. All other authors declare no com-peting interests.
Acknowledgement
The authors would like to thank the study participants, staff, and investigators. We also thank Ms. Aya Yamada for her excellent study support. This work was partly supported by the Uehara Memorial Foundation.
References
1. Verges B. Pathophysiology of diabetic dyslipidaemia: where are we? Diabetologia 2015; 58: 886-99.
2. Taskinen MR, Boren J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015; 239: 483-95.
3. Sacks FM, Hermans MP, Fioretto P, Valensi P, Davis T, Horton E, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and ret-inopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation 2014; 129: 999-1008.
4. Toth PP, Simko RJ, Palli SR, Koselleck D, Quimbo RA, Cziraky MJ. The impact of serum lipids on risk for microangiopathy in pa-tients with type 2 diabetes mellitus. Cardiovasc Diabetol 2012; 11: 109.
5. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Mat-thews DR, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316: 823-8.
6. Wang Y, Lammi-Keefe CJ, Hou L, Hu G. Impact of low-density lipoprotein cholesterol on cardiovascular outcomes in people with type 2 diabetes: a meta-analysis of prospective cohort studies. Dia-betes Res Clin Pract 2013; 102: 65-75.
7. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing inten-sive versus moderate statin therapy. J Am Coll Cardiol 2006; 48: 438-45.
8. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376: 1670-81.
9. Kinoshita M, Yokote K, Arai H, Iida M, Ishigaki Y, Ishibashi S, et al. Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J Atheroscler Thromb 2018; 25: 846-984.
10. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371: 117-25.
11. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westen-dorp RG, et al. The benefits of statins in people without estab-lished cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009; 338: b
2376.
12. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients: a hierar-chical bayesian meta-analysis. J Am Coll Cardiol 2008; 51: 37-45. 13. Hwang YC, Jun JE, Jeong IK, Ahn KJ, Chung HY. Comparison of
the Efficacy of Rosuvastatin Monotherapy 20 mg with Rosuvasta-tin 5 mg and Ezetimibe 10 mg Combination Therapy on Lipid Pa-rameters in Patients with Type 2 Diabetes Mellitus. Diabetes Me-tab J 2019; 43: 582-9.
14. Le NA, Tomassini JE, Tershakovec AM, Neff DR, Wilson PW. Ef-fect of Switching From Statin Monotherapy to Ezetimibe/Simvas-tatin Combination Therapy Compared With Other Intensified Lipid-Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease. J Am Heart Assoc 2015; 4: e001675.
15. Ahmed O, Littmann K, Gustafsson U, Pramfalk C, Oorni K, Lars-son L, et al. Ezetimibe in Combination With Simvastatin Reduces Remnant Cholesterol Without Affecting Biliary Lipid Concentra-tions in Gallstone Patients. J Am Heart Assoc 2018; 7: e009876. 16. Sakamoto K, Kawamura M, Watanabe T, Ashidate K, Kohro T,
Tanaka A, et al. Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects. Lipids Health Dis 2017; 16: 122.
17. Winkler K, Jacob S, Muller-Schewe T, Hoffmann MM, Konrad T. Ezetimibe alone and in combination lowers the concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus. Atherosclerosis 2012; 220: 189-93.
18. Vaverkova H, Farnier M, Averna M, Missault L, Viigimaa M, Dong Q, et al. Lipid-altering efficacy of ezetimibe/simvastatin 10/ 20 mg compared to rosuvastatin 10 mg in high-risk patients with and without type 2 diabetes mellitus inadequately controlled de-spite prior statin monotherapy. Cardiovasc Ther 2012; 30: 61-74. 19. Leiter LA, Betteridge DJ, Farnier M, Guyton JR, Lin J, Shah A, et
al. Lipid-altering efficacy and safety profile of combination ther-apy with ezetimibe/statin vs. statin monotherther-apy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials. Diabetes Obes Metab 2011; 13: 615-28.
20. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372: 2387-97. 21. Chang SH, Wu LS, Lee CH, Kuo CT, Liu JR, Wen MS, et al.
Simvastatin-ezetimibe combination therapy is associated with a lower rate of major adverse cardiac events in type 2 diabetics than high potency statins alone: A population-based dynamic cohort study. Int J Cardiol 2015; 190: 20-5.
22. Miao XY, Liu HZ, Jin MM, Sun BR, Tian H, Li J, et al. A com-parative meta-analysis of the efficacy of statin-ezetimibe co-therapy versus statin monoco-therapy in reducing cardiovascular and cerebrovascular adverse events in patients with type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci 2019; 23: 2302-10. 23. Liu CH, Chen TH, Lin MS, Hung MJ, Chung CM, Cherng WJ, et
al. Ezetimibe-Simvastatin Therapy Reduce Recurrent Ischemic Stroke Risks in Type 2 Diabetic Patients. J Clin Endocrinol Metab 2016; 101: 2994-3001.
24. Handelsman Y, Fonseca V, Rosenstock J. Is combination therapy an effective way of reaching lipid goals in type 2 diabetes melli-tus? Expert Rev Clin Pharmacol 2012; 5: 43-54.
25. Wang J, Ai XB, Wang F, Zou YW, Li L, Yi XL. Efficacy of ezetimibe combined with atorvastatin in the treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease. Int Angiol 2017; 36: 467-73. 26. Sugiyama S, Jinnouchi H, Hieshima K, Kurinami N, Suzuki T,
Miyamoto F, et al. A pilot study of ezetimibe vs. atorvastatin for improving peripheral microvascular endothelial function in stable patients with type 2 diabetes mellitus. Lipids Health Dis 2015; 14: 37.
27. Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, et al. Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Pa-tients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial. J Am Coll Cardiol 2015; 66: 495-507.
28. Morita T, Morimoto S, Nakano C, Kubo R, Okuno Y, Seo M, et al. Renal and vascular protective effects of ezetimibe in chronic kidney disease. Intern Med 2014; 53: 307-14.
29. Huang Z, Li Q, Ye W, Zhang Q, Li X. Efficacy and Safety of Ezetimibe in Combination with Atorvastatin for Acute Coronary Syndrome Patients Accompanied with Type 2 Diabetes: A Single-Center, Non-randomized Cohort Study. Chem Pharm Bull 2019; 67: 419-25.
30. Jimenez JG, Rosen JB, Pirags V, Massaad R, Hanson ME, Brudi P, et al. The efficacy and safety of ezetimibe/simvastatin combina-tion compared with intensified lipid-lowering treatment strategies in diabetic subjects with and without metabolic syndrome. Diabe-tes Obes Metab 2013; 15: 513-22.
31. Shigematsu E, Yamakawa T, Taguri M, Morita S, Tokui M, Miya-moto K, et al. Efficacy of ezetimibe is associated with gender and baseline lipid levels in patients with type 2 diabetes. J Aheroscler Thromb 2012; 19: 846-53.
32. Ray KK, Leiter LA, Muller-Wieland D, Cariou B, Colhoun HM, Henry RR, et al. Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab 2018; 20: 1479-89.
33. Arbel R, Hammerman A, Azuri J. Usefulness of Ezetimibe Versus Evolocumab as Add-On Therapy for Secondary Prevention of Car-diovascular Events in Patients With Type 2 Diabetes Mellitus. Am J Cardiol 2019; 123: 1273-6.
34. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375: 735-42.
35. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305: 2556-64.
36. Cui JY, Zhou RR, Han S, Wang TS, Wang LQ, Xie XH. Statin therapy on glycemic control in type 2 diabetic patients: A network meta-analysis. J Clin Pharm Ther 2018; 43: 556-70.
37. Cai R, Yuan Y, Sun J, Xia W, Huang R, Tian S, et al. Statins worsen glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners: a meta- analysis. Expert Opin Pharmacother 2016; 17: 1839-49.
38. Saito I, Azuma K, Kakikawa T, Oshima N, Hanson ME, Tershak-ovec AM. A randomized, double-blind, placebo-controlled study of the effect of ezetimibe on glucose metabolism in subjects with type 2 diabetes mellitus and hypercholesterolemia. Lipids Health Dis 2015; 14: 40.
39. Ichimori S, Shimoda S, Goto R, Matsuo Y, Maeda T, Furukawa N, et al. Ezetimibe improves glucose metabolism by ameliorating he-patic function in Japanese patients with type 2 diabetes. J Diabetes Investig 2012; 3: 179-84.
40. Tsunoda T, Nozue T, Yamada M, Mizuguchi I, Sasaki M, Michishita I. Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose
intoler-ance. Diabetes Res Clin Pract 2013; 100: 46-52.
41. Sakamoto K, Kawamura M, Kohro T, Omura M, Watanabe T, Ashidate K, et al. Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins. PLoS One 2015; 10: e0138332.
42. Rudofsky G, Reismann P, Groener JB, Djuric Z, Fleming T, Metzner C, et al. Identical LDL-cholesterol lowering but non-identical effects on NF-kappaB activity: High dose simvastatin vs combination therapy with ezetimibe. Atherosclerosis 2012; 223: 190-6.
