Combination therapy with a moderate-intensity statin and ezetimibe is comparable to high-intensity statin monotherapy regarding rates of 3-year cardiovascular events, and there is lower intolerance-related discontinuation or dose reduction in patients with diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD), according to a study in the European Heart Journal.
Researchers reported findings from the stratified subgroup analysis of the randomized, open-label, noninferiority Randomized Comparison of Efficacy and Safety of Lipid-lowering with Statin Monotherapy Vs Statin/ezetimibe Combination for High-risk Cardiovascular Disease (RACING) trial, which was conducted at 26 centers in South Korea.
Participants were randomly assigned in a 1:1 ratio to receive ezetimibe combination therapy (rosuvastatin 10-mg with ezetimibe 10-mg) or high-intensity statin monotherapy (rosuvastatin 20-mg). Follow-up visits were conducted at 2 and 6 months and at 1, 2, and 3 years.
The primary outcome was a composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years.
A total of 3780 patients were enrolled from February 2017 to December 2018, and 37.0% of patients had DM at baseline. In the DM group, 701 patients (mean age, 64±9 years; 77.7% men) received combination therapy and 697 patients (mean age, 65±9 years; 73.9% men) received monotherapy. Among the 2382 nonDM patients, 1193 (mean age, 63±10 years; 73.3% men) received combination therapy and 1189 (mean age, 63±10 years; 74.9% men) received monotherapy.
In the patients with DM, the rate of the primary outcome was 10.0% in the combination therapy group and 11.3% in the monotherapy group (hazard ratio [HR], 0.89; 95% CI, 0.64-1.22; P =.460). The combination therapy group had a lower rate of discontinuation or dose reduction of study drug owing to intolerance vs the high-intensity statin monotherapy group (5.2 vs 8.7%; P =.014).
In patients without DM, the primary outcome rate was 8.9% in the combination therapy group and 9.4% in the monotherapy group (HR, 0.94; 95% CI, 0.72-1.23; P =.674). The rate of discontinuation or dose reduction owing to intolerance was lower in the combination therapy group compared with the monotherapy group (4.5 vs 7.9%; P =.001).
In participants with DM, the median low-density lipoprotein cholesterol (LDL-C) level was 53 mg/dL throughout in the combination therapy group vs 61 mg/dL in the monotherapy group (P <.001). The proportion of participants who had LDL-C levels of less than 70 mg/dL was consistently higher in the combination therapy group at 1 (81.0% vs 64.1%), 2 (83.1% vs 70.2%), and 3 years (79.9% vs 66.8%; all P <.001).
In a post hoc analysis, the proportion of patients with LDL-C levels of less than 55 mg/dL was consistently increased in the combination therapy group compared with the monotherapy group, regardless of DM status. In addition, the rate of new-onset DM was not different between the 2 groups in patients without DM (safety population, 17.1% vs 16.7%; P =.833).
In subgroup analyses with patients with DM, the effect of ezetimibe combination therapy vs high-intensity statin monotherapy was consistent for the primary outcome across subgroups, including in patients with baseline LDL cholesterol levels of less than 100 mg/dL.
Study limitations include the open-label design and small number of events, and the number of patients in the DM subgroup may have limited statistical power for the effect of ezetimibe combination therapy. In addition, participants may have had a lower risk vs those in general clinical practice.
“These findings directly support the use of moderate-intensity statin with ezetimibe combination therapy as a suitable alternative to high-intensity monotherapy if high-intensity statins cannot be tolerated or further reduction in LDL cholesterol levels is required, as recommended by the current guidelines for managing dyslipidemia among patients with DM and ASCVD,” wrote the investigators.
Disclosure: This research was funded by grants from Hanmi Pharmaceutical (Seoul, Korea). Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Lee Y-J, Young Cho J, You SC, et al. Moderate-intensity statin with ezetimibe vs. high-intensity statin in patients with diabetes and atherosclerotic cardiovascular disease in the RACING trial. Eur Heart J. Published online December 19, 2022. doi: 10.1093/eurheartj/ehac709