Hypercholesterolemia is characterized by elevated low-density lipoprotein cholesterol (LDL-C), which is the third leading risk factor for cardiovascular disease (CVD) worldwide. High LDL-C levels were responsible for 4.51 million deaths in 2020, and the same number, 3.81 million CVD deaths, were recorded in 2021 based on data from the Global Burden of Disease 2020 and the American Heart Association’s 2023 updates.
Patients with atherosclerotic cardiovascular disease (ASCVD) primarily benefit from statins as it is the primary medication to treat the hypercholesterolemia condition. Approximately 9% of patients develop statin intolerance, limiting their ability to benefit from treatment. Ezetimibe stands out as a promising, safe medication when combined with other cholesterol-lowering drugs to improve statin results in patients with high LDL-C. The research evaluates how combination lipid-lowering treatment using moderate- or high-intensity statins affects low-density lipoprotein cholesterol levels, heart disease risks, and associated side effects.
The study systematically reviewed literature from databases like PubMed, Embase, and ClinicalTrials.gov for randomized controlled trials (RCTs), prospective studies, and retrospective studies up to June 2024. Eligible participants were adults (≥18 years) diagnosed with both ASCVD and hypercholesterolemia. Among the examined research studies, the evaluation focused on the outcome differences between therapy with moderate to high-intensity statins in combination with ezetimibe and statin therapy alone. The research primarily evaluated LDL-C levels together with all-cause mortality rates and major adverse cardiovascular events (MACE) and stroke incidence, as well as therapy discontinuation rates. Fourteen studies in a total of 108,373 patients were included in the analysis that presented clinical outcomes as well as adverse event data.
Patients in the combination LLT group had an average age of 67.31 years, while the statin monotherapy group had an average age of 67.89 years. After pooled data analysis, the data researchers found that combination LLT succeeded better than statin monotherapy in lowering LDL-C levels. The analysis showed that combination LLT decreased LDL-C levels by -12.96 mg/dL (95% confidence interval (CI), -17.27 to -8.65; P < 0.001).
Additionally, combination LLT significantly reduced all-cause mortality (odds ratio [OR], 0.81; 95% CI, 0.67 to 0.97; P = 0.02), major adverse cardiovascular events (OR, 0.82; 95% CI, 0.69 to 0.97; P = 0.02), and stroke incidence (OR, 0.83; 95% CI, 0.75 to 0.91; P < 0.001).
The treatment showed no statistically significant effect on cardiovascular mortality rates based on the calculated OR of 0.86 with 95% CI, 0.65 to 1.12 while P=0.26. The rates of adverse events and treatment dropout were similar between the combination therapy group and the single therapy group, showing that the combination treatment caused no additional adverse effects.
This meta-analysis illustrates that combination LLT, which includes moderate- to high-intensity statins and ezetimibe, is more effective at lowering LDL-C levels and achieving cardiovascular outcomes than statin monotherapy. Combination therapy significantly lowers all-cause mortality, major adverse cardiovascular events, and stroke, with more substantial reductions in LDL-C. Markedly, the treatment was not associated with an increased rate of adverse events or therapy discontinuations compared to statin monotherapy, indicating its safety and effectiveness.
The treatment combination involving LLT should be prioritized as a first-line treatment for patients with ASCVD patients and hypercholesterolemic patients because it maximizes LDL-C goal achievement with concurrent reductions in cardiovascular event risks. Future healthcare guidelines should emphasize more strongly that implementing combination therapy from the beginning will improve treatment results for patients.
References: Banach M, Jaiswal V, Ang SP, et al. Impact of Lipid-Lowering Combination Therapy with Statins and Ezetimibe vs Statin Monotherapy on the Reduction of Cardiovascular Outcomes: A Meta-analysis. Mayo Clin Proc. 2025. Impact of Lipid-Lowering Combination Therapy with Statins and Ezetimibe vs Statin Monotherapy on the Reduction of Cardiovascular Outcomes: A Meta-analysis
