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Fixed combination of a low/moderate-intensity statin + ezetimibe vs high-intensity statin monotherapy

A systematic review and meta-analysis of clinical effectiveness and safety: 15 studies, 251,450 patients with or at high risk of ASCVD.

15 studies6 RCTs + 9 observational251 450 patientsPROSPERO CRD42024545807

Search: 20 Feb 2024 (updated 17 May 2024)Review prepared: 29 June 2026

Key message

Summary

In patients with or at high risk of ASCVD, the fixed combination (FC) of a low/moderate-intensity statin with ezetimibe delivers a greater LDL-C reduction and markedly better tolerability than high-intensity statin monotherapy, with cardiovascular event rates that are comparable in RCTs and more favourable in observational (real-world) data. Better tolerability directly supports adherence and attainment of the LDL-C goal.

1.27×

more patients reach LDL-C < 70 mg/dL (RCT)

RR 1.27 [1.21, 1.34]

−48%

fewer muscle AEs on FC (RCT)

RR 0.52 [0.32, 0.85]

−20%

less new-onset diabetes on FC (obs.)

HR 0.80 [0.74, 0.87]

0.76

primary composite endpoint (obs.)

HR [0.73, 0.80]

Context

Introduction

Dyslipidaemia is a leading risk factor for atherosclerotic cardiovascular disease (ASCVD), still the number-one cause of death worldwide. Statins are the cornerstone of therapy: guidelines recommend intensively lowering LDL-C in patients with established ASCVD to reduce the risk of major adverse cardiovascular events (MACE).

Yet even on high-intensity statin monotherapy, reaching the LDL-C target and reducing MACE remains challenging, and high doses are limited by dose-dependent adverse events (chiefly muscle-related) that undermine adherence. Adding ezetimibe — a selective inhibitor of cholesterol absorption — to a low/moderate-intensity statin lowers LDL-C by a further 15–22%, offering an alternative to simply up-titrating the statin.

Objective

Aim and review question

PICO. P — patients with or at high risk of ASCVD · I — FC: low/moderate-intensity statin + ezetimibe · C — high-intensity statin monotherapy · O — MACE, lipids, safety, plaque regression.

Methodology

Methods

We searched PubMed, Scopus, Web of Science and Cochrane CENTRAL through February 2024 (updated May 2024). RCTs and prospective/retrospective observational studies comparing FC with high-intensity statin monotherapy in patients with or at high risk of ASCVD were eligible. The protocol was registered in PROSPERO (CRD42024545807).

A key methodological choice. RCTs and observational studies were analysed separately (per the 2023 Cochrane Handbook). This cleanly separates which FC advantages rest on randomised evidence (lipids, safety) from those based on observational data (hard clinical outcomes). Risk of bias was assessed with RoB 2 (RCTs) and the Newcastle–Ottawa Scale (NOS, observational); analysis used RevMan 5.4.1, random-effects model.

Selection

Study selection flow (PRISMA 2020)

Of 9,173 records identified, 15 studies entered the quantitative synthesis after duplicate removal and two-stage screening. The funnel is interactive — hover over a stage.

Evidence base

Characteristics of included studies

A total of 251,450 participants: 76,280 on FC (low/moderate-intensity statin + ezetimibe) and 175,170 on high-intensity statin monotherapy; about 65% male. All studies were conducted in Asia: 10 South Korea, 3 China, 2 Taiwan.

251 450

participants total

76 280

on FC

175 170

on monotherapy

~65%

male

Quality of the 6 RCTs (Cochrane RoB 2)

B. Kim et al. · low risk

Choi et al. · low risk

Oh et al. · some concerns

Tan et al. · some concerns

Ran et al. · high risk

+1 RCT

Observational studies (NOS): all rated “good” quality except one (“poor”, due to comparability and cohort follow-up).

FC advantage #1

Lipids and LDL-C goal attainment

This is the most robust (RCT-supported) block of FC advantages. Patients on FC were 1.27× more likely to reach LDL-C < 70 mg/dL — the threshold recommended for cardiovascular risk reduction — with significantly greater reductions in LDL-C and total cholesterol.

RR 1.27

patients with LDL-C < 70 mg/dL (RCT)

[1.21, 1.34] · I²=8%

-7.95

LDL-C, mg/dL (RCT)

[-10.02, -5.89]

-26.77

Total chol., mg/dL (RCT)

[-27.64, -25.89]

How to read. Each row is one outcome. The square is the effect estimate (HR/RR/MD), the horizontal line is the 95% confidence interval; the dashed vertical line marks “no difference”. If the whole line sits left of it, the difference favours FC and is statistically significant (green). Hover over a row for a plain-language explanation (e.g. “24% risk reduction”).

Change in lipids (mean difference, mg/dL) — pooled RCT analysis. Negative values favour FC. HDL-C and triglycerides did not differ significantly.

FC advantage #2

Safety and tolerability

Tolerability is the second RCT-supported argument for FC. On FC, muscle-related adverse events were halved (RR 0.52) and liver-enzyme elevations were nearly halved (RR 0.51); observational data showed 20% less new-onset diabetes (HR 0.80). For the remaining events (rhabdomyolysis, CK, GI, gallbladder, cancer) no difference was seen.

Safety: ratio measures (RR — RCT, HR — observational). Values < 1 with the whole interval left of 1 favour FC (green).

Cardiovascular outcomes

Hard clinical outcomes (MACE)

In observational studies (adjusted real-world HRs, RWD; >250k patients) FC is associated with significantly lower rates of the primary composite endpoint, cardiovascular and all-cause mortality, and non-fatal stroke. The pooled RCT analysis of hard outcomes is underpowered (few RCTs, small samples, short follow-up) and showed no significant difference — see the “RCT” tab.

Adjusted hazard ratios from observational studies. Values < 1 favour FC.

Pooled RCT analysis: no statistically significant difference for any clinical endpoint — intervals are wide because of the small number of events. This reflects insufficient power, not proven absence of benefit.

Clinical meaning

Adherence — the connecting link

The better tolerability of FC has a direct clinical consequence — adherence. Among patients hospitalised for myocardial infarction, only 58.9% adhered to high-intensity statin monotherapy at 6 months and 41.6% at 2 years. Adherence to a low/moderate-intensity statin + ezetimibe is higher, likely because of the lower risk of adverse events. Since lowering LDL-C is directly linked to better outcomes, the FC superiority in lipids and tolerability provides a biologically plausible mechanism for the observed clinical benefit.

RACING. The large RACING trial (n ≈ 3,780) demonstrated non-inferiority of rosuvastatin + ezetimibe vs a high-intensity statin with better tolerability — i.e. an adequately powered, longer RCT confirms the clinical validity of the FC approach that the smaller RCTs in this review could not show owing to limited power.

Adherence to high-intensity statin monotherapy in post-MI patients: 58.9% at 6 months and 41.6% at 2 years. For FC, exact figures are not reported in the source — adherence is described as higher (J. Kim et al.; RACING) owing to better tolerability.

Bottom line

Conclusions

Because of its greater LDL-C lowering and fewer adverse events, the fixed combination of a low/moderate-intensity statin with ezetimibe is a sound and potentially preferable option for patients who cannot tolerate high statin doses or need additional LDL-C lowering to reach target. Observational data point to a reduction in cardiovascular events; large, adequately powered RCTs with longer follow-up are needed for definitive confirmation.

Source

Sydhom P, Al-Quraishi B, El-Shawaf M, et al. The clinical effectiveness and safety of low/moderate-intensity statins & ezetimibe combination therapy vs. high-intensity statin monotherapy: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2024;24(1):660. PubMed 39567875 · DOI 10.1186/s12872-024-04144-y

All numeric estimates are reported from the publication above. The full list of the 15 included primary studies and supplements is in the original article.