Moderate Intensity Statin and Ezetimibe Combination Therapy vs.
High Intensity Statin Monotherapy for Cardiac Risk Reduction
Kassidy Hitt PA-S, Wilson Crone, MD, PhD
Center for Physician Assistant Studies
Clinical Question
• "In patients with atherosclerotic cardiovascular disease,
what is the efficacy of statin with ezetimibe combination
therapy on cardiac risk reduction and side-effect profile,
when compared with high-intensity statin monotherapy?“
Search Strategy
• Harrison’s Principles of Internal Medicine, 21e and Current Medical Diagnosis and Treatment, 2022 were inconsistent in their
therapy.
• A search of the PubMed database using keywords ezetimibe AND cardi* AND statin yielded three pertinent articles comparing
as well as differences in safety and effectiveness between the treatments.
Case Scenario
• 47 year old African American female presents with
increasing fatigue and dizziness over the past 6 months
and recent chest pain on exertion.
• History: 19 pack-years (cigarettes), moderate drinking
(with current AUDIT score of 7= risky)
• Family history: various cardiovascular events,
hypertension and dyslipidemia
• BMI of 43 kg/m2
• BP of 144/92 mmHg
o LDL of 152 mg/dL
o HDL of 33 mg/dL
o triglycerides of 280 mg/dL
o thyroid panel was unremarkable
• 10-year ASCVD risk score = 8.1%
Conclusions
• This combination presents patients and clinicians with a progressive treatment option.
• Ezetimibe and moderate intensity statin therapy boasts modest, compounding lipid-reduction and a lower side effect profile, making it a
high-intensity statin regimen. This is especially true for patients with known ASCVD who are otherwise intolerant to statins.
Background
• Statins:
o First line lipid-lowering agents that slow hepatic
cholesterol production
o Effectively reduce atherosclerotic cardiovascular
disease (ASCVD) risk, cardiac events, and mortality
o High intensity titrations can cause significant sideeffects for intolerant patients
• Ezetimibe:
o Newer drug that inhibits reabsorption of cholesterol in
the intestine, increasing its clearance from the blood
by up to 20%
o Potential for complementary cholesterol and adverse
event reduction when combined with a moderate
intensity statin
o Typically well-tolerated, with few drug interactions
• 2020 American College of Cardiology/American Heart
Association (ACC/AHA) recommendations for lipid therapy
included the use of ezetimibe as an add-on to moderateintensity statins. However, guidelines still lack consistency
across various sources and populations.
Table 1. Patient outcomes with statin vs. statin/ezetimibe therapies
Citation
Reference
LOE
Zhan
et al.
(2018)
1
Population,
Patients with,
high risk for
Adverse cardiac
outcomes
Intervention
Treatment
High-intensity
monotherapy
High-intensity
ezetimibe
N
(cardiac
outcome %)
21,727
(10 studies)
Ratio
(95% CI)
RR: 0.94
(0.90,
ARD
(95% CI)
Discontinuation of treatment
N (%)
Discontinued
𝑏
Treatment
NNTh
(95% CI)
ARD
(95% CI)
Future Directions
• Larger, more regulated studies, would need to be
conducted on diversified populations to fully
understand the promise that this treatment
combination has to offer.
• Once the medical literature is conclusive and
consistent, ezetimibe and moderate-intensity statin
therapy could be considered to formally replace highintensity statins as the principal lipid-lowering therapy.
1.7%
(0.06%,
This Photo by Unknown Author is licensed under CC BY-SA
Kim
et al.
(2022)
3
Patients with
ASCVD,
South Korea
High-intensity
monotherapy
186/1886
(9.9%)
Moderatestatin +
172/1894
(9.1%)
HR: 0.92
(0.75,
0.8%
(-2.39,
150/1886
(8.2%)
88/1894
(4.8%)
Application to Patient
• According to the ACC/AHA guidelines, the patient in this
scenario would benefit from high intensity statin
therapy, alongside intensive lifestyle modifications.
• However, these studies suggest that ezetimibe with
moderate intensity statin therapy would be an
appropriate combination to trial before initiating high
intensity statins with this patient.
• Given the major role that LDL-C plays in reducing
cardiovascular risk, the primary goal would be to
maintain LDL cholesterol below 130 mg/dL, with
triglycerides and ASCVD risk trending downward.
• Any side effects should be noted and managed,
including myalgias, gastrointestinal upset, heartburn,
diarrhea, headache, dizziness, etc.
• ALT, AST and CK labs should be routinely drawn to track
liver function and related adverse effects associated
with the regimen.
3.3%
(1.8%, 4.9%)
31
(21,
Notes. ARD: absolute difference. ASCVD: atherosclerotic cardiovascular disease. HR: hazard ratio. LOE: level of evidence. NNTh: number needed to
Table 2. Lipid and liver outcomes with statin vs. statin/ezetimibe therapies
Citation
Intervention
Hepatopathy
Reference Population,
Ratio
Treatment
N
(95% CI)
LOE
Setting
Zhan
et al.
(2018)
1
Citation
LOE
Patients
at high risk
ASCVD
High-intensity
monotherapy
High-intensity
ezetimibe
Treatment Comparison,
Population
20,687
(4 studies)
High-intensity statin
vs. moderate-intensity statin +
for patients with high ASCVD
RR: 1.14
(0.96, 1.35)
References
This Photo by Unknown Author is licensed under CC BY-SA
Category
ALT
Ah
et al.
(2022)
1
Lipid outcomes
AST
CK
SE
(95% CI)
0.22
(0.10, 0.34)
0.20
(0.09, 0.32)
0.08
(-0.04, 0.20)
SE
Category
(95% CI)
0.31
LDL-C
(0.15, 0.46)
0.22
Total
(0.10, 0.34)
0.20
Triglycerides
(0.09,
0.08
HDL-C
(-0.04,
Favors
Combination
therapy
Combination
Combination
NS
Notes. ALT: alanine aminotransferase. ARD: absolute difference. ASCVD: atherosclerotic cardiovascular disease. AST: aspartate aminotransferase. CI:
high density lipoprotein cholesterol. HR: hazard ratio. LDL-C: low density lipoprotein cholesterol. LOE: level of evidence. NNTh: number needed to treat
standard error.
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