GRAPHICAL ABSTRACT

Highlights

• Starting ezetimibe-statin therapy reduced 3P-MACE risk more than statin monotherapy.

• Early ezetimibe-statin therapy more effectively reduces major events in high-risk individuals.

• Sustained ezetimibe enhances cardiovascular benefits.

INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide [1], with diabetes mellitus (DM) significantly increasing the risk of cardiovascular mortality due to its high global prevalence [2,3]. In lipid management, reducing low-density lipoprotein (LDL) cholesterol is crucial for lowering the risk of adverse cardiovascular events. Many international guidelines recommend 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) as the primary intervention for decreasing LDL-cholesterol, with treatment intensity determined by their LDL-cholesterol lowering efficacy [4,5]. In statin therapy, several caveats must be considered, including muscle-related symptoms, disturbances in glucose regulation, and liver function abnormalities [6,7]. Consequently, in some cases, statin dosage cannot be increased sufficiently to achieve LDL-cholesterol target goals due to these adverse events [8].

Ezetimibe, a dyslipidemic agent that inhibits the intestinal absorption of cholesterol by inhibiting the Niemann-Pick C1-Like 1 receptor, offers an alternative or adjunctive strategy. This is particularly relevant for patients who do not reach their lipid goals with statin therapy alone or who are intolerant to statins [9]. Several clinical trials have evaluated the efficacy of ezetimibe. The Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75) study demonstrated the efficacy of ezetimibe monotherapy, showing that it not only reduced LDL-cholesterol levels but also decreased cardiovascular events in elderly patients previously untreated with lipid-lowering therapy [10]. Two randomized controlled trials (RCTs), the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial and Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER) trial, investigated the additive effect of ezetimibe with moderate-intensity statin and proved the beneficial role of ezetimibe [11,12]. Recently, moderate-intensity statin combined with ezetimibe therapy showed noninferior cardiovascular outcomes, with better LDL-cholesterol reduction, compared to high-intensity statin monotherapy in Asians with atherosclerotic CVD, suggesting the beneficial role of ezetimibe in combination with statins [13]. However, this open-label study in patients with documented atherosclerotic CVD had limitations, including its non-inferiority design and relatively low event rates, which restricted comparison of individual clinical outcomes.

Based on these studies, we hypothesized that the combination of ezetimibe to lower-intensity statin might be an encouraging option in dyslipidemia management. Therefore, we aimed to investigate the effectiveness of initial lower-intensity statin-ezetimibe combination therapy versus higher-intensity statin monotherapy on major adverse cardiovascular events (MACE) and safety outcomes in patients with DM, using nationwide data from South Korea. By analyzing a nationwide database that includes a broad patient population, this study aims to offer insights into clinical decision-making by bridging the gap between the controlled settings of RCTs and the extensive scope of real-world, long-term data [14].

METHODS

Data source

We performed a nationwide, population-based, retrospective cohort study using data from the South Korean National Health Insurance Service (NHIS). The NHIS mandates public health insurance for all residents of South Korea. Mortality data, including dates and causes of death, were acquired from Statistics Korea [15]. Due to the anonymized nature of the data, which adheres to stringent confidentiality protocols, informed consent was waived. The methodologies employed in this study have been previously detailed and validated [16]. This investigation received the endorsement of the Seoul National University Bundang Hospital Institutional Review Board (IRB No. X-2203-744-902).

Study design and population

Eligibility for the study was determined by the following criteria: (1) age 19 years or older; (2) diagnosed with DM; and (3) naive to lipid-lowering treatments but commenced on statin monotherapy or a combination of statin and ezetimibe for a minimum duration of 180 days between the year from January 1, 2011, and December 31, 2019. Individuals prescribed other dyslipidemia treatments were excluded.

From this framework, we identified 2,487,802 individuals who initiated statin therapy after January 1, 2010, and were diagnosed with DM during the observation period. DM was defined based on International Classification of Diseases, 10th Revision (ICD-10) codes E10–E14 and the prescription of antidiabetic medications. We identified a subset of 1,454,287 patients, who persisted with statin therapy for at least 180 days within the initial year, was further narrowed down. Exclusions were made for patients whose statin dose intensity was indeterminable, those prescribed below a quarter of the lowest dosage, and those on more than double the highest available dosage, resulting in a refined cohort of 902,665. Further refinement to patients with baseline health examination data and those diagnosed with DM before starting statin therapy yielded 516,797 patients fit for analysis (Supplementary Fig. 1).

To compare the outcomes of initial statin monotherapy against combination therapy with statin and ezetimibe, we divided patients into primary prevention and secondary prevention cohorts based on the intensity of their statin regimen and their history of CVD. The secondary prevention cohort was defined as individuals diagnosed with ischemic heart disease, myocardial infarction (MI), stroke, or heart failure either at the initiation of statin therapy or prior to it. Recognizing the significant role of LDL-cholesterol reduction in mitigating cardiovascular events, matching was performed to compare high-intensity statin monotherapy with moderate-intensity statin plus ezetimibe, and moderate-intensity statin monotherapy with low-intensity statin plus ezetimibe, in accordance with the 2023 American College of Cardiology/American Heart Association (ACC/AHA) guidelines [4].

Outcomes

The primary endpoint of our study was the occurrence of a 3-points (3P) MACE, comprising a composite of non-fatal MI (I21–I22), non-fatal stroke (I60–I64), and cardiovascular death (recorded as a death with a diagnosis code starting with ‘I’). Stroke was defined more strictly using brain imaging procedures such as computed tomography and magnetic resonance imaging. Secondary endpoints included hospitalization for heart failure (I50), angina (I20) with coronary artery bypass graft or percutaneous coronary intervention, and all-cause mortality, along with the individual components of the 3P-MACE. Ischemic stroke (I63, I64) was also specifically identified. These outcomes, tracked until December 31, 2020, were defined using specific ICD-10 codes.

Our examination of safety outcomes involved identifying patients hospitalized for conditions potentially associated with statin or statin-ezetimibe therapy. These conditions covered liver-related abnormalities (K70–K77; R94.5), muscle-related disorders (M60–M63, and G72), renal diseases (N18, N19, Z49, Z99.2, and Z94.0), mental health issues (F06.7, G31.8, F00, F01, F03, F05.1, and G31.1), insomnia (G47), cancer (C), and elevated glucose levels (R73). The primary reason for hospitalization due to DM (E10–E14) were also observed. The specific diagnosis codes are detailed in Supplementary Table 1.

Propensity score matching analysis

To neutralize biases and confounders inherent in retrospective analyses, we used a 1:1 propensity score matching (PSM) method. This involved pairing the statin monotherapy group with the statin-ezetimibe combination cohort using a stratified multiple logistic regression model based on a comprehensive set of variables, including demographic data (age, sex), health examination results (body mass index [BMI], systolic blood pressure [SBP], LDL-cholesterol levels, alcohol consumption, smoking status, and exercise history), pre-existing conditions (MI, stroke, heart failure, atherosclerosis, thrombosis, vascular disease, Charlson comorbidity index [17]), medication use (antidiabetic agents, antithrombotic agents, and antihypertensive agents), and the start year of statin therapy. Patients with missing values for any baseline variables of interest were excluded during PSM.

Statistical analysis

Continuous variables were represented as mean±standard deviation and analyzed using the independent sample Student’s t-test, while categorical variables were presented as counts and percentages, assessed through the chi-square test or Fisher’s exact test, as appropriate based on the data distribution. Statistical significance for our analyses was established at a two-sided P value of <0.05. For PSM, a standardized mean difference (SMD) of <0.1 was considered indicative of adequate balance between the groups, ensuring comparability for robust analysis.

Post-PSM, we calculated both the absolute event rate and the event rate per 1,000 person-years for primary endpoints, individual events, and all-cause mortality to provide a comprehensive assessment of the impact of treatment modalities. To further refine risk analysis, Cox proportional hazards regression was applied, providing hazard ratios (HRs) and 95% confidence intervals (CIs) for a nuanced understanding of the relative risk. Kaplan-Meier curves were used for the visualization of endpoint incidence rates over time, with group differences assessed through the stratified log-rank test. We conducted subgroup analyses to examine the incidence of primary outcomes across varied clinical conditions and performed interaction analyses to explore potential heterogeneity in effects. The type of statin used at baseline was also considered in a separate subgroup analysis. Sensitivity analysis probed the relationship between 3P-MACE incidence and the impact of differing durations of statin or ezetimibe use. Changes in statin intensity during the observation period and comparisons of other intensity levels were also evaluated. Events occurring after the 30- or 90-day follow-up periods were also examined to capture delayed effects and assess the long-term impact of treatment. Statistical procedures were executed using SAS software version 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

Patients characteristics

From January 1, 2011, onward, our cohort comprised 408,747 patients receiving initial statin monotherapy and 108,050 patients treated with a statin-ezetimibe combination (Supplementary Table 2). Following 1:1 PSM, two balanced comparison groups were established, resulting in a total of 31,552 patients in two cohorts (21,458 in the primary prevention cohort and 10,094 in the secondary prevention cohort) (Supplementary Fig. 1). Baseline demographics and clinical characteristics, presented in Table 1, achieved equilibrium post-PSM, with a mean follow-up period of 5.5 years: 5.6 years in the primary prevention cohort (5.7±2.3 years for statin monotherapy vs. 5.5±2.4 years for statin-ezetimibe combination, SMD=0.053) and 5.2 years in the secondary prevention cohort (5.2±2.4 years for statin monotherapy vs. 5.1±2.5 years for statin-ezetimibe combination, SMD=0.026). Statin use at baseline is shown in Supplementary Table 3.

Among all trial participants, regardless of the treatment group, the primary composite outcome of 3P-MACE occurred at a rate of 4.1 per 1,000 person-years in patients without a history of CVD and 17.6 per 1,000 person-years in those with a history of CVD. The higher rate observed in the secondary prevention cohort was primarily driven by a higher incidence of cardiovascular death: 5.6 per 1,000 person-years compared to 1.0 per 1,000 person-years in the primary prevention cohort.

Initial statin monotherapy vs. statin and ezetimibe combination therapy

The composite primary outcome showed a significant reduction in the statin-ezetimibe combination group compared to the statin monotherapy group: 3.25 vs. 4.85 per 1,000 person-years (HR, 0.67; 95% CI, 0.56 to 0.81; P<0.001) in the primary prevention cohort, and 15.7 vs. 19.5 per 1,000 person-years (HR, 0.80; 95% CI, 0.70 to 0.91; P<0.001) in the secondary prevention cohort as shown in Table 2, Fig. 1. Specifically, the incidence of non-fatal MI was notably lower in the combination therapy group in both cohorts: 1.66 vs. 2.63 per 1,000 person-years (HR, 0.64; 95% CI, 0.46 to 0.82; P<0.001) in the primary prevention cohort; and 6.76 vs. 9.27 per 1,000 person-years (HR, 0.73; 95% CI, 0.60 to 0.89; P=0.002) in the secondary prevention cohort. Cardiovascular mortality trended lower in the combination group only in patients without a history of CVD, albeit with borderline statistical significance (0.80 vs. 1.13 per 1,000 person-years: HR, 0.72; 95% CI, 0.50 to 1.04; P=0.081).

No significant differences were observed in overall stroke incidence, while ischemic stroke was reduced with statin-ezetimibe combination therapy in the secondary prevention group (HR, 0.73; 95% CI, 0.56 to 0.96; P=0.025) (Supplementary Fig. 2). Hospitalization rates for angina requiring intervention were significantly reduced in patients receiving statin-ezetimibe combination therapy in both cohorts (HR, 0.68; 95% CI, 0.55 to 0.84; P<0.001, and HR, 0.83; 95% CI, 0.72 to 0.95; P=0.008). No significant differences were observed in hospitalization rates for heart failure in either cohort.

MACE occurrence by therapy duration

An analysis of the relationship between the duration of statinezetimibe combination therapy and the primary outcome revealed that treatment duration, segmented into quartiles, was associated with a declining trend in 3P-MACE incidence with longer usage of ezetimibe, showing similar effect sizes in both cohorts (HR, 0.82; 95% CI, 0.72 to 0.94, and HR, 0.83; 95% CI, 0.76 to 0.91, respectively) (Supplementary Fig. 3). The 3P-MACE risk was reduced by 44% in the primary prevention cohort when comparing the highest duration quartile (>97%, Q4) to the lowest duration quartile (≤27%, Q1). In the secondary prevention cohort, the risk was reduced by 38% in the third quartile (74% to 99%, Q3) and by 39% in the highest quartile (100%, Q4) compared to the lowest duration quartile (<31%, Q1).

Subgroup and sensitivity analysis

The advantage of initial statin-ezetimibe combination therapy was consistent across various demographic and clinical subsets, including age, sex, and pre-existing conditions (Fig. 2). Notably, a few subgroup differences were identified in the primary prevention cohort while no differences were shown in the secondary prevention cohort. In the subgroup with higher-intensity statin therapy, individuals with a BMI of 25 or over and an SBP of 130 or over showed better efficacy compared to the other subgroup (all P for interaction <0.05). The reduced sample size for the seven statin types led to the loss of statistical significance in assessing the effects on 3P-MACE for the three most frequently used statins (Supplementary Table 4). Excluding pitavastatin, which is available only as a moderate-intensity statin, did not affect the results (HR, 0.82; 95% CI, 0.72 to 0.94; P<0.001 for primary prevention, and HR, 0.83; 95% CI, 0.76 to 0.91; P=0.006 for secondary prevention). Changes in statin intensity for each group are presented in Supplementary Table 5. Preservation of the original statin intensity was highest for moderate-intensity statins, exceeding 90%, while high-intensity and low-intensity statin preservation rates were 65.7% and 69.2%, respectively. The adjusted HRs were 0.70 (95% CI, 0.58 to 0.84; P<0.001) for primary prevention, and 0.84 (95% CI, 0.74 to 0.96; P=0.012) for secondary prevention.

For high-intensity statin monotherapy versus low-intensity statin combined with ezetimibe, the combination therapy demonstrated superior preventive effects (Supplementary Table 6). In contrast, no significant differences were observed between moderate-dose statin monotherapy and moderate-dose statin combined with ezetimibe. Excluding patients with 30- and 90-day follow-ups weakened the observed differences but retained significance in the primary prevention cohort. However, in the secondary prevention cohort, no significant differences were observed after 30 days, suggesting early effectiveness in preventing 3P-MACE.

Safety concerns

Adverse events related to hospitalizations are detailed in Table 3. We found that patients receiving statin-ezetimibe combination therapy in the primary prevention cohort had a lower incidence of hospitalizations due to liver diseases, muscle-related diseases, and diabetes-related conditions compared to those on statin monotherapy (P<0.05). Abnormal liver function tests were significantly higher with statin monotherapy than with statin-ezetimibe combination therapy (P<0.05). The incidences of cognitive abnormalities, and cancer were comparable between both therapeutic approaches. No rhabdomyolysis was observed in our cohorts.

DISCUSSION

Our nationwide real-world investigation revealed that initiating therapy with a statin-ezetimibe combination conferred a marked reduction in 3P-MACE by 33% in those without CVD and 20% in those with CVD compared to statin monotherapy. Additionally, MI and hospitalizations for angina with intervention were reduced more with statin-ezetimibe combination therapy in both cohorts, showing its superior efficacy in managing cardiovascular risk among patients with DM. Notably, sustained administration of the statin-ezetimibe regimen was associated with enhanced MACE mitigation. Furthermore, this combination therapy was linked with a decreased incidence of adverse events, such as hospitalizations related to liver abnormalities.

Previous large-scale RCTs have struggled to conclusively ascertain the independent efficacy of ezetimibe across diverse treatment and patient demographics. The IMPROVE-IT study [11] proved that adding ezetimibe 10 mg to simvastatin 40 mg significantly reduced cardiovascular events compared to simvastatin 40 mg monotherapy (absolute risk difference=2.0%; HR, 0.936; 95% CI, 0.89 to 0.99; P=0.016) among 18,144 individuals presenting with acute coronary syndrome over a 6-year period, alongside a notable LDL-cholesterol reduction. The EWTOPIA 75 study [10] evidenced that among seniors ≥75 years without coronary artery disease, ezetimibe 10 mg therapy diminished the composite cardiac outcome, including 3P-MACE and coronary revascularization (HR, 0.66; 95% CI, 0.50 to 0.86; P=0.002). Yet, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study [18] reported that ezetimibe’s addition to simvastatin did not mitigate atherosclerosis progression, as measured by intima-media thickness, despite superior LDL-cholesterol reduction in familial hypercholesterolemia cases.

Many studies have consistently demonstrated that adding ezetimibe to statin therapy more effectively lowered LDL-cholesterol levels than statins alone [11,13]. The IMPROVE-IT [11] and EWTOPIA 75 [10] studies showed that ezetimibe therapy decreased LDL-cholesterol levels by 24% and 26%, respectively. In the Randomised Comparison of Efficacy and Safety of Lipid Lowering with Statin Monotherapy versus Statin–Ezetimibe Combination for high-risk Cardiovascular Disease (RACING) study [13], a combination of rosuvastatin 10 mg with ezetimibe 10 mg paralleled rosuvastatin 20 mg monotherapy in 3-year composite MACE occurrences in atherosclerotic CVD patients. Specifically, in individuals with diabetes within the RACING trial, the incident rate of the primary outcome was marginally lower in the moderate-intensity statin-ezetimibe group compared to the high-intensity statin monotherapy group (–1.27%; HR, 0.89; 95% CI, 0.64 to 1.22; P=0.460) [19]. Of note, the combination reduced both drug discontinuation rates and adverse events [13].

Crucially, our analysis highlighted that initial and prolonged use of statin-ezetimibe combination therapy is significantly more efficacious in preventing 3P-MACE than statin monotherapy in patients with DM. Previous research did not account for the duration of ezetimibe usage, including the RACING trial, which had participants using ezetimibe before enrollment in both groups. This effect was greater in patients without CVD than those with CVD. People with a more metabolically deteriorated status showed better efficacy with statin-ezetimibe combination therapy for the primary prevention of CVD. In secondary prevention, the effect size was similar across varied patient demographics, including age, sex, BMI, SBP, LDL-cholesterol levels, demonstrating favorable effects regardless of baseline characteristics. High-intensity statins, associated with better prognosis in patients with CVD [18], may be better compared with moderate-intensity statins combined with ezetimibe, as low-intensity combinations were less preferred.

Our results demonstrated robust and significant findings favoring the moderate-intensity statin-ezetimibe combination in preventing 3P-MACE (Fig. 2), particularly in the primary prevention cohort. In contrast, the comparison between low-intensity statin-ezetimibe and moderate-intensity statin monotherapy did not yield statistical significance. This outcome might be attributable to two primary factors. First, the lower event rate in this specific subgroup further diminished statistical power, potentially masking the true effect of the intervention. Second, subgroup analyses inherently result in smaller sample sizes, leading to wider CIs and a higher degree of uncertainty. For the secondary prevention cohort, no significant differences across subgroups were observed, likely to reflect the higher incidence of 3P-MACE events. Overall, these data highlight the potential benefit of combination therapy, though subgroup differences in the primary prevention cohort may be influenced by sample size and event rates.

Despite the wide application of statins in mitigating cardiovascular events and mortality across a diverse populations at risk or with CVD [20,21], attention to statin-associated adverse effects remains imperative [22]. Known complications, such as muscle symptoms leading to treatment discontinuation [23] and a modest elevation in blood glucose levels and diabetes onset risk [24], underscore the need for vigilant therapeutic management.

Our observation of increased diabetes-related hospitalizations in the primary prevention cohort with higher-intensity statin therapy aligns with existing literature, indicating that statins may impair glucose homeostasis by attenuating insulin secretion and impeding β-cell proliferation [25]. Often, people might not reach the desired LDL-cholesterol thresholds through statin monotherapy alone [26]. Therefore, while statins are the drug of choice in CVD prevention, the necessity for individualized statin therapy considering with a generally favorable safety profile is evident [27].

Ezetimibe, beyond its LDL-cholesterol-lowering capability, is recognized for its additional beneficial properties. It not only exhibits anti-inflammatory effects but also significantly reduces C-reactive protein levels alongside statins, providing a complementary approach to traditional lipid-lowering strategies [11,28]. Its mechanism, possibly including direct effects on macrophages and inhibiting oxidized LDL absorption [29], suggests a broader cardiovascular protective role, including attenuation of insulin resistance [30] and atherosclerosis progression [31,32]. We previously reported that the concentrations of small, dense LDL particles were significantly higher in individuals with impaired glucose regulation compared to those without [33]. Ezetimibe, both alone and in combination with simvastatin, has been shown to reduce the concentration of small, dense LDL in patients with type 2 DM [34]. Thus, ezetimibe may provide additional benefits in states of insulin resistance or metabolic syndrome [35].

This study has the advantage of identifying the exact starting point and duration of ezetimibe use. It is also worth noting that the study was conducted over a long period of time, up to 9 years. Current lipid management guidelines advocate for statin monotherapy to achieve LDL-cholesterol target goal and mitigate cardiovascular morbidity and mortality [4,5]. Nevertheless, our findings underscore the persistence of residual cardiovascular risk, thereby supporting the initiation of ezetimibe with statin therapy as an effective strategy to mitigate this risk [36-39]. Lastly, the research cohort, constructed using PSM with most of the available significant variables, ensures a well-balanced comparison between the two groups. However, the retrospective nature of the study and reliance on claims data bring potential biases and pose challenges in diagnostic validation and it would have been difficult to determine the exact reason for hospitalization. Nonetheless, the diagnoses were set based on reliable sources [40]. The duration of diabetes, which was not collected, could have influenced the outcomes and was not evaluated in our study. Among patients receiving moderate-intensity statin monotherapy versus moderate-dose statin combined with ezetimibe, no significant difference was observed between the two groups. This might reflect the inclusion of a diverse patient population, allowing for adjustments such as selecting statin intensity based on expected statin tolerability. Thus, the evidence supporting the efficacy of lower-intensity statins combined with ezetimibe requires further validation.

In conclusion, our study offers insights into the utilization of statin-ezetimibe combination therapy in East Asian patients with DM, demonstrating its superior efficacy in reducing 3P-MACE and MI rates, alongside enhanced safety profiles concerning liver disease and glucose regulation, compared to higher-intensity statins alone. These findings support the early consideration of ezetimibe combination therapy in the course of statin treatment, particularly for patients at higher risk of adverse effects or those with statin intolerance. The decision between monotherapy and combination therapy ought to be customized, reflecting the patient’s cardiovascular risk, LDL-cholesterol targets, medication tolerance, and potential for drug interactions. This calls for future prospective studies to refine and optimize CVD prevention strategies in this patient population.

SUPPLEMENTARY MATERIALS

NOTES

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: M.S., S.L.

Acquisition, analysis, or interpretation of data: M.S., Y.H.P.

Drafting the work or revising: M.S., S.L.

Final approval of the manuscript: all authors.

FUNDING

This project is funded by Seoul National University Bundang Hospital, Seongnam, South Korea. The funder had no role in the research.

ACKNOWLEDGMENTS

The authors extend their appreciation to the Department of Data Science at Hanmi Pharm. Co., Ltd., Seoul, South Korea, for their guidance on initiating the NHIS research.

Fig. 1.

Kaplan-Meier survival curves for cardiovascular events in patients initiating statin monotherapy vs. statin-ezetimibe combination therapy. This figure illustrates the survival probabilities for (A) 3-point major adverse cardiovascular events (3P-MACE), (B) myocardial infarction (MI), (C) stroke, and (D) cardiovascular death, comparing outcomes between statin monotherapy and statin-ezetimibe combination therapy in primary prevention (1st) and secondary prevention (2nd) cohorts. HR, hazard ratio; CI, confidence interval.

Fig. 2.

Subgroup analyses of 3-point major adverse cardiovascular events (3P-MACE) in (A) primary prevention and (B) secondary prevention cohort across diverse patient populations. HR, hazard ratio; CI, confidence interval; BMI, body mass index; SBP, systolic blood pressure; LDL, low-density lipoprotein; CKD, chronic kidney disease; SGLT2, sodium-glucose cotransporter-2.

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Sohn M, Park YH, Lim S. Comparative Efficacy of Initial Statin and Ezetimibe Combination versus Statin Monotherapy on Cardiovascular Outcomes in Diabetes Mellitus: A Nationwide Cohort Study. Diabetes Metab J. 2025 Jun 5. doi: 10.4093/dmj.2024.0482. Epub ahead of print.

Received: Aug 15, 2024; Accepted: Feb 06, 2025

DOI: https://doi.org/10.4093/dmj.2024.0482.

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