Comparative Efficacy of Initial Statin and Ezetimibe Combination versus Statin Monotherapy on Cardiovascular Outcomes in Diabetes Mellitus: A Nationwide Cohort Study

Abstract

Backgruound: This study aimed to assess the efficacy of an initial combination therapy of statin and ezetimibe compared with statin monotherapy on major cardiovascular outcomes in individuals with diabetes.

Methods: In this population-based cohort study using National Health Insurance Service data (2010-2020), we included adults with diabetes who had not previously used any lipid-lowering medications. Those initiating statin monotherapy were matched 1:1 using propensity scores with patients starting combination therapy with a lower-potency statin and ezetimibe. This matching process resulted in 21,458 individuals in the primary prevention cohort and 10,094 in the secondary prevention cohort, respectively. The primary endpoint was a composite of myocardial infarction, stroke, and cardiovascular death. Hospitalizations for heart failure, angina, and all-cause mortality were analyzed. The impact of ezetimibe maintenance on the primary endpoint was analyzed, and other hospitalizations were categorized as adverse events.

Results: Compared with statin monotherapy, statin-ezetimibe combination significantly reduced the incidence of the primary endpoint (4.85 vs. 3.25 per 1,000 person-years: hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.56 to 0.81 in the primary cohort; and 19.5 vs. 15.7 per 1,000 person-years: HR, 0.80; 95% CI, 0.70 to 0.91 in the secondary cohort) and myocardial infarction (HR, 0.64; 95% CI, 0.46 to 0.82 in the primary cohort; and HR, 0.73; 95% CI, 0.60 to 0.89 in the secondary cohort). A longer maintenance period of ezetimibe was significantly related to better efficacy in the composite cardiovascular outcomes. High-intensity statin monotherapy was associated with an elevated risk of liver, muscle, and diabetes-related hospitalization in the primary prevention cohort.

Conclusion: Initial therapy with a statin-ezetimibe combination is associated with a reduced risk of cardiovascular events and fewer adverse events compared to statin monotherapy in individuals with diabetes, over a mean follow-up of 5.5 years (up to 9 years).

Keywords: Cardiovascular diseases; Diabetes mellitus; Ezetimibe; Hydroxymethylglutaryl-CoA reductase inhibitors.

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.