Ezetimibe Lipid-Lowering Therapy Beyond Statins

1. Mortality and Cardiovascular Outcomes:

Meta-analysis of 15 randomized controlled trials including 123,785 patients showed that intensified lipid-lowering therapy (ezetimibe, bempedoic acid, or PCSK-9 inhibitors) combined with statins reduced cardiovascular events by 19% (OR 0.81 [0.75-0.86]) compared to statin monotherapy
Risk reductions were observed for:

Myocardial infarction: OR 0.81 [0.74-0.89]
Ischemic stroke: OR 0.77 [0.70-0.84]

However, all-cause mortality was not improved (OR 0.99 [0.93-1.04]), even in studies with ≥3 years follow-up

2. Combination Therapy vs High-Intensity Statin Monotherapy:

Analysis of 13 studies with 8,592 patients showed moderate-intensity statin plus ezetimibe (MIS+EZT) achieved:

Higher rates of LDL <70 mg/dL (OR 1.76 [1.26-2.45])
Greater LDL reduction (-5.05 mg/dL [-9.02 to -1.07])
Greater total cholesterol reduction (-7.91 mg/dL [-14.90 to -0.91])
Greater triglyceride reduction (-8.20 mg/dL [-13.05 to -3.35])

No significant differences in adverse events between groups

3. Real-World Effectiveness (Finnish Registry Study):

Among 57,505 post-MI patients:

Cumulative ezetimibe use: 3.7% at 90 days, 13.4% at 5 years, 19.8% at 10 years
Early ezetimibe use associated with lower all-cause mortality (adj. HR 0.77 [0.69-0.86])
Ongoing ezetimibe therapy showed even greater mortality benefit (adj. HR 0.53 [0.48-0.59])
43.6% discontinued ezetimibe during follow-up

4. Primary Prevention Outcomes:

Canadian study of 67,884 primary prevention patients showed:

Combination therapy vs high-intensity statin resulted in:

Lower 10-year cumulative incidence of primary outcome (32.7% vs 36.1%)
Reduced all-cause death (HR 0.85 [0.80-0.91])
Reduced stroke (HR 0.86 [0.74-0.99])
No difference in MI or revascularization

5. Secondary Prevention and Target Achievement:

Study of 264 STEMI patients showed:

Rosuvastatin 40mg + ezetimibe 10mg achieved LDL target (<55 mg/dL) in 90% of patients
Rosuvastatin 40mg alone achieved target in only 47.92%
Combination therapy provided greater LDL reduction (-59.65% vs -37.54%, p<0.0001)

6. Special Populations - Elevated Lipoprotein(a):

Study of 520 IHD patients showed:

High-intensity statin + ezetimibe reduced:

All-cause mortality (HR 0.44 [0.21-0.89])
MACE (HR 0.71 [0.52-0.95])

Benefits more pronounced in patients with elevated Lp(a):

MACE reduction with Lp(a) ≥70 nmol/L: HR 0.51
MACE reduction with Lp(a) ≥100 nmol/L: HR 0.36

7. Triple Therapy Results:

Study of 299 ACS patients compared:

High-intensity statin (HIS) alone
Rosuvastatin + ezetimibe (RE)
Rosuvastatin + ezetimibe + bempedoic acid (REB)

LDL-C reduction at 4 weeks:

HIS: 44.4%
RE: 55.5%
REB: 62.2%

Target achievement (<70 mg/dL):

HIS: 81.6%
RE: 88.7%
REB: 95.2%

8. Meta-analysis of Combination LLT vs Statin Monotherapy:

Analysis of 11 studies (106,358 patients) showed combination therapy achieved:

Greater LDL-C reduction (-12.13 mg/dL [-18.26 to -5.99])
Lower all-cause mortality (OR 0.75 [0.62-0.92])
Lower cardiovascular mortality (OR 0.75 [0.66-0.84])
Lower MACE (OR 0.72 [0.63-0.82])
Comparable safety profile

9. Systematic Review of Secondary Prevention:

Analysis of 8 studies (40,236 patients) showed MIS+EZE vs HIS achieved:

Lower cardiovascular mortality (RR 0.83 [0.73-0.94])
Lower all-cause mortality (RR 0.90 [0.82-0.98])
Lower non-fatal stroke (RR 0.83 [0.73-0.93])
Higher LDL-C target achievement (RR 1.26 [1.19-1.34])
Lower adverse events (RR 0.84 [0.74-0.95])
Lower muscle-related adverse events (RR 0.67 [0.49-0.92])

Key Conclusions:

1. Efficacy:

Combination therapy consistently shows superior LDL-C lowering compared to statin monotherapy
Better achievement of target LDL-C levels across multiple studies
Cardiovascular event reduction demonstrated in both primary and secondary prevention
Particular benefit in high-risk populations (e.g., elevated Lp(a))

2. Safety:

Similar or better safety profile compared to high-intensity statin monotherapy
Lower rates of muscle-related adverse events with combination therapy
Comparable rates of liver-related adverse events and new malignancies
No increase in treatment discontinuation rates

3. Clinical Implementation:

Despite proven benefits, real-world utilization remains suboptimal
High discontinuation rates in clinical practice
Younger patients more likely to receive combination therapy
Cost considerations may influence therapy choice, particularly regarding PCSK9 inhibitors

4. Specific Populations:

Benefits observed across various subgroups including:

Primary prevention
Secondary prevention
Acute coronary syndrome
Elevated Lp(a)
Diabetic patients

These findings suggest that combination lipid-lowering therapy, particularly moderate-intensity statin plus ezetimibe, offers an effective and well-tolerated alternative to high-intensity statin monotherapy. The evidence supports its use in both primary and secondary prevention, with particular benefits in high-risk populations. However, real-world implementation remains suboptimal, suggesting a need for improved clinical adoption strategies and patient education to maximize therapeutic benefits.

Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events (2024)

Background

Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe, bempedoic acic, and proprotein convertase subtilisin/kexin type 9 (PCSK-9) (synthase-) inhibitors allow for the reduction in LDL-cholesterol in addition to statin therapy.

Purpose

We aimed to perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. In specific, we evaluated the potential influence of duration of follow-up on the association with mortality endpoints.

Methods

We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe, bempedoic acid, Bococizumab, Alirocumab, Evolocumab, Inclisiran in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of August 2023, were included. We made our search specific and sensitive using Medical Subject

Headings terms and free text and considered studies published in English language. Search terms used were : "Bempedoic Acid" or "Bococizumab" or "Alirocumab" or "Evolocumab" or "Ezetimibe" or "Inclisiran" and "statin" and "cardiovascular events".

Results

A total of 123,785 patients from 15 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, ODYSSEY LONG TERM, EWTOPIA 75, PACMAN-AMI, RACING, SIPRE I, SPIRE II, OSLER-1 and OSLER-2, CLEAR HARMONY, CLEAR OUTCOMES, CLEAR SERENITY, CLEAR WISDOM) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 19% risk reduction in cardiovascular events (OR [95%CI]: 0.81 [0.75; 0.86]). Effect sizes were similar for myocardial infarction (0.81 [0.74; 0.89]) and even more pronounced for ischemic stroke (0.77 [0.70; 0.84]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.99 [0.93; 1.04]). Stratifying by follow-up duration of < vs. ≥ 3 years, no improvement in all-cause mortality was observed in both groups (<3 years: 1.04 [0.93; 1.17]; ≥3 years: 0.97 (0.88; 1.06). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown).

Conclusion

Intensified LDL-lowering therapy with ezetimibe, bempedoic acic or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. A potential survival benefit was also not observed in studies with follow-up duration of ≥ 3 years.

Safety and Efficacy of Moderate-intensity statin plus ezetimibe versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease: a meta-analysis (2024)

Background

Atherosclerotic cardiovascular disease (ASCVD), affects approximately 18.6 million individuals worldwide, poses an important healthcare challenge. Despite the established efficacy of both high-intensity statin monotherapy (HIS) and moderate-intensity statin plus ezetimibe (MIS+EZT) in ASCVD management, the optimal treatment strategy remains unclear.

Purpose

This meta-analysis seeks to assess the impact of moderate-intensity statin plus ezetimibe (MIS+EZT) versus high-intensity statin monotherapy (HIS) on LDL < 70mg/dl; Total Cholesterol; LDL; High Density Cholesterol (HDL) and triglycerides levels. Our goal is to synthesize the existing evidence and pinpoint areas that warrant further investigation.

Methods

A thorough literature search was conducted across PubMed, Scopus, Web of Science, and the Cochrane databases, focusing on studies that compared the effects of moderate-intensity statins plus ezetimibe with high-intensity statin monotherapy in ASCVD patients.

Results

In the 13 included studies, involving 8,592 patients, of which 4,525 (52.67%) received moderate-intensity statin plus ezetimibe treatment. The follow-up period ranged from 12 to 219 weeks, with participant ages varying from 66 to 76.5 years in the MIS+EZT group and from 67 to 75.9 years in the HIS group. Analysis revealed significant MIS+EZT-associated with greater percentages in Low Density Lipoprotein (LDL) < 70 (Odds Ratio (OR) 1.76; 95% CI [1.26; 2.45]; p=0.001; I²=73%), LDL reduction (Mean Difference (MD) -5.05 mg/dL; 95% CI [-9.02;-1.07]; p<0.013; I²=56%;); Total Cholesterol reduction (MD -7.91 mg/ dL; 95% CI [-14.90; -0.91]; p<0.027; I²=60%); Triglycerides reduction (MD -8.20 mg/ dL; 95% CI [-13.05; -3.35]; p<0.001; I²=2%;); There was no statistical difference between groups in Drug Adverse reaction (Risk Ratio (RR) 1.19; 95% CI [0.79; 1.78]; p=0.404; I²=0%); and Drug intolerance (RR 0.78 ; 95% CI [0.32; 1.92]; p=0.584; I²=35%).

Conclusions

This meta-analysis underscores the effectiveness of MIS+EZT in enhancing significant clinical outcomes for ASCVD patients, as evidenced by improvements in a greater percentage of patients achieved the LDL <70 target, LDL, Total Cholesterol and Triglycerides levels . Importantly, there were no significant differences in the occurrence of overall adverse events and adverse drug reactions between the two groups.

The upfront lipid-lowering combination therapy of statins and ezetimibe vs statin monotherapy in the reduction of cardiovascular outcomes. A meta-analysis (2024)

Background

Despite some data in last few years, there is still some inconsistency concerning the effectiveness and safety of the upfront intensive lipid lowering combination therapy (LLT; of moderate to high intensity statin therapy and ezetimibe) in comparison to high intensity statin therapy and recommended by some guidelines stepwise therapy approach.

Purpose

We sought to evaluate the efficacy of combination LLT compared with statin monotherapy for cardiovascular outcomes, LDL-C reduction, and associated adverse events.

Methods

A systematic literature search was conducted using PubMed, Embase, and ClinicalTrial.gov to identify relevant articles published from inception until 29th December 2023. The outcomes were assessed using pooled odds ratio (OR) for categorical data and mean difference (MD) for continuous data, with corresponding 95% confidence intervals (95% CI).

Results

A total of 11 studies (8 randomized controlled trials and 3 cohort studies) with 106,358 were involved in the analysis. The mean age of the patients in the combination LLT and statin monotherapy group was 65.3 and 65.7 years, respectively. Pooled analysis shows that combination LLT significantly reduces the LDL-C level from the baseline (MD, -12.13 mg/dl [0.31 mmol/l] (95%CI: -18.26 to -5.99 mg/dl), p<0.001), all-cause mortality (ACM) (OR, 0.75, 95%CI: 0.62 to 0.92, p=0.01), cardiovascular mortality (CVM) (OR 0.75, 95%CI: 0.66 to 0.84, p<0.001), major adverse cardiovascular events (MACE) (OR, 0.72 95%CI: 0.63 to 0.82, p<0.001), non-significant reduction in the incidence of stroke (OR 0.82, 95%CI: 0.66 to 1.01, p=0.06) when compared with statin monotherapy alone. Similarly, the therapy discontinuation rate was comparable between combination LLT and statin monotherapy groups (OR, 0.87 (95%CI: 0.53 to 1.40), p=0.56). The risk of adverse events related to the gastrointestinal tract (OR, 1.12 (95%CI: 0.93 to 1.36), p=0.23) and musculoskeletal system (OR, 0.88 (95%CI: 0.52 to 1.50), p=0.65) was comparable between both the groups of patients.

Conclusion

Combination LLT was associated with an overall greater reduction in LDL-C, a lower risk of ACM, MACE, and CVM compared to statin monotherapy alone.

Ezetimibe use and mortality after myocardial infarction: a nationwide cohort study (2024)

Background

Inhibition of intestinal cholesterol absorption by ezetimibe improves outcomes after myocardial infarction (MI), yet real-world data on ezetimibe is lacking.

Purpose

To study usage and outcome impact of ezetimibe after MI.

Methods

Consecutive MI patients in Finland (2010-2018) were retrospectively studied (N=57,505; 65% men; mean age 69 years). Study data were combined from national registries. The median follow-up was 4.5 (IQR 2.8-7.1) years. Differences between groups were adjusted with multivariable regression. Ezetimibe use was studied with competing risk analyses. Median follow-up was 4.5 (IQR 2.8-7.1) years.

Results

The cumulative incidence of ezetimibe use was 3.7% at 90-days, 13.4% at 5-years and 19.8% at 10-years. Younger age was the strongest predictor for ezetimibe use (adj. sHR 6.67; CI 5.88-7.69 for patients aged <60 vs. ≥80 years). Women were more likely to use ezetimibe during follow-up than men. The average proportion of patients using ezetimibe during follow-up was 6.8%. (11.7% at 10-years). Ezetimibe was discontinued by 43.6% of patients during the follow-up. Patients with early ezetimibe after MI had lower all-cause mortality during follow-up (33.6% vs. 45.1%; adj. HR 0.77; CI 0.69-0.86; p<0.0001). Early ezetimibe use was associated with lower mortality irrespective of sex, age, atrial fibrillation, diabetes, heart failure, malignancy, revascularization, or statin use. Ongoing ezetimibe therapy during follow-up was associated with lower mortality in time-dependent analysis (adj. HR 0.53; CI 0.48-0.59; p<0.0001).

Conclusion

Ezetimibe is associated with lower risk of death after MI, but therapy use is limited and discontinuity is frequent.

Efficacy of combination lipid lowering therapy in achieving low density lipoprotein cholesterol targets after one month of event in patients with acute coronary syndrome (2024)

Introduction

Rapid reduction in low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of recurrent events in patients with acute coronary syndrome (ACS) with benefits proportional to LDL-C reduction. Early use of combination lipid-lowering therapy (LLT) is therefore recommended. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-intensity statins (HIS) improve LDL-C goal attainment but are unaffordable for many patients in India and worldwide.

Purpose

We share our experience with the use of dual RE (rosuvastatin plus ezetimibe) and triple REB (rosuvastatin plus ezetimibe and bempedoic acid) combination LLT in patients admitted with ACS.

Methods

All ACS patients admitted to our institute over one year (January 2023 to December 2023) were considered in this retrospective analysis. Those with unavailable lipid profile reports, either at the time of ACS or at 1-month follow-up, were excluded. Clinical and laboratory details were obtained from hospital records. The primary objective was to assess the percentage change in LDL-C levels from index event to 4 weeks follow-up.

Results

A total of 299 patients were included, out of which 60 were on HIS alone, 71 were on RE, and 168 were on REB (Figure). The majority (99%) of patients in the REB group were statin naïve, compared to the other two groups. The baseline mean LDL-C levels at the time of the index event were 95.3+30.5, 103.2+39.6, and 115.6+32.9 mg/dl, respectively (p<0.001) (Table). The mean LDL-C levels at four weeks post-ACS reduced to 52.9+21.2, 45.9+20.5, and 43.7+15.4 mg/dl, respectively (p<0.01). The percentage reduction in LDL-C level was 44.4%, 55.5%, and 62.2%, respectively (p<0.001). REB enabled 70.8% and 95.2% of patients to achieve the Lipid Association of India, and American College of Cardiology recommended LDL-C targets of <50 mg/dl and <70 mg/dl within 4 weeks. These target levels were achieved in 67.6% and 88.7% of patients on the dual RE therapy and 50% and 81.6% of patients, respectively, on HIS alone.

Conclusion

Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen compared to costly PCSK9i therapy.

Efficacy of combination therapy with statin and ezetimibe versus high dose statin monotherapy in secondary prevention in high-risk patients (2024)

Background

Secondary prevention in patients with acute coronary syndrome focuses on lowering low-density lipoprotein (LDL) cholesterol below 55 mg/dL. In all statin-naïve patients at high risk (LDL-cholesterol target <55 mg/dL), initiation of high-intensity statin monotherapy is recommended by ESC guidelines. Nonetheless, at one month, a significant proportion of patients do not reach their LDL-cholesterol target.

Purpose

The aim of this study was to compare lipid-lowering therapy with statin monotherapy versus statin with ezetimibe in secondary prevention in patients at high risk.

Methods

The current prospective study included 264 consecutive patients admitted with acute ST elevation myocardial infarction who underwent percutaneous coronary intervention. None of the patients had taken lipid-lowering drugs in the previous 12 months. Patients were randomly assigned to one of two treatment groups: Group 1 - rosuvastatin 40 mg (n= 144) and Group 2 - rosuvastatin 40 mg and ezetimibe 10 mg (n= 120). All patients' lipid profiles were assessed upon admission and after one month of lipid-lowering treatment.

Results

At baseline, no patient had LDL cholesterol level lower than 55 mg/dL. There was no significant difference in lipid profile at baseline between the two groups (all p > 0.05). No differences were observed between the two groups in terms of baseline LDL-cholesterol deviation from the target (103.4% versus 99.70%; p= 0.66). As expected, the combination therapy reduced LDL-cholesterol at one month significantly higher compared to high-dose statin monotherapy (-59.65% versus -37.54%; p< 0.0001). After one month of treatment, only 47.92% of patients in Group 1 reached the LDL-cholesterol target (<55 mg/dL) compared to 90.00% of the patients in Group 2 (p<0.0001; R.R.= 0.53).

Conclusion(s)

Our findings show that statin and ezetimibe combination therapy is more effective in reduction in LDL-cholesterol levels and reaching targets compared to statin monotherapy alone. In statin-naïve patients at high risk, early initiation of the statin and ezetimibe combination instead of statin monotherapy should be taken into account in secondary prevention, for an earlier reach of the LDL-cholesterol target and to reduce the overall cardiovascular risk.

High intensity statin-ezetimibe combination therapy reduces mortality in patients with ischaemic heart disease and elevated Lipoprotein(a) (2024)

Background

Early and prompt reduction of low-density lipoprotein cholesterol concentrations (LDL-C) using combination lipid-lowering therapy (LLT) is recommended to lower cardiovascular risk in patients with ischaemic heart disease (IHD) and elevated LDL-C. Lowering LDL-C is also an important cardiovascular risk mitigation strategy in patients with elevated lipoprotein(a) [Lp(a)]. However, it is unknown if combination LLT reduces mortality in patients with elevated Lp(a).

Aim

To undertake an observational study to investigate the effect of combination LLT using high intensity statin with ezetimibe on cardiovascular outcomes in patients with and without elevated Lp(a).

Methods

Serum Lp(a) concentrations were measured in 520 consecutively recruited patients with IHD admitted to hospital, half of whom were admitted for acute myocardial infarction. Patients treated with high intensity statin and ezetimibe within the 1st year from admission to hospital (‘HI statin-ezetimibe group’, n=157) were compared with the rest of patients who had less intensive lipid lowering regimen (‘Others group’, n=363) for cardiovascular outcomes.

Results

During the 2-year follow-up period, 14.6%, 6.5%, and 53.1% of patients had all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) respectively. Median age was 63.5 years and 82.3% were male. Multivariable Cox regression showed that baseline Lp(a) ≥70 nmol/L was associated with increased risk of all-cause mortality (HR 1.97, 95% CI 1.20-3.22, P=0.007). Compared with a less intensive regimen, HI statin-ezetimibe was associated with reduced risk of all-cause mortality (HR 0.44 [0.21-0.89], P=0.023) and MACE (HR 0.71 [0.52-0.95], P=0.027), with no statistically significant effect on cardiovascular mortality (HR 0.43, P=0.142). Notably, the cardiovascular benefits of HI statin-ezetimibe were more pronounced in patients with elevated Lp(a); a greater reduction in risk of MACE was seen for patients with Lp(a) ≥70 nmol/L (HR 0.51, P=0.007) or Lp(a) ≥100 nmol/L (HR 0.36, P=0.009), and in all-cause mortality risk for those with Lp(a) ≥70 nmol/L (HR 0.24, P=0.025). Although LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe use in patients with or without elevated Lp(a).

Conclusion

Intensification of lipid-lowering therapy with high-intensity statin and ezetimibe improves cardiovascular outcomes in patients at very high cardiovascular risk, particularly those with elevated Lp(a). Larger studies are required to confirm our findings that this cardiovascular benefit is partially independent of LDL-C lowering.

Combination of moderate-intensity statins and ezetimibe versus high-intensity statins alone for primary prevention of cardiovascular events (2024)

Abstract

Background

Combination of a moderate-intensity statin with ezetimibe can lead to similar reductions in cardiovascular events as monotherapy with a high-intensity statin in patients with established atherosclerotic cardiovascular disease (ASCVD). The comparative effectiveness of these two cholesterol-lowering strategies in the primary prevention setting is unknown.

Purpose

To compare incident ASCVD events associated with a combination of moderate-intensity statin and ezetimibe versus monotherapy with a high-intensity statin in adults without prior history of cardiovascular disease.

Methods

We conducted a new-user active comparator retrospective population-based cohort study in Canada. We included all adults aged ≥ 67 years (eligible for drug coverage) with a first prescription of either a combination of moderate-intensity statin with ezetimibe ("combination therapy") or high-intensity statin alone between January 2010 and December 2022. Patients were excluded if they had not received any prior lipid lowering therapies or had a history of myocardial infarction (MI), stroke, heart failure, peripheral vascular disease or prior coronary revascularisation at any time before or within 3 months of treatment initiation. The primary outcome was a composite of all-cause death, hospitalization for MI or stroke, or coronary revascularization. An inverse probability of treatment weighting propensity score was used to account for confounding (demographics, comorbidities, laboratory tests, other medications).

Results

Among 67,884 patients (mean age: 74.0±5.5y; 53% females), 8,798 (13%) initiated combination therapy and 59,086 (87%) initiated a high-intensity statin. At 1 year, after weighting, the mean achieved LDL-C was ~1.9 mmol/L in both groups. The median follow-up was 6.5 years. The cumulative incidence of the primary outcome at 10 years in the weighted cohort was 32.7% in the combination therapy group and 36.1% in the high-intensity statin group (HR: 0.87; 95% CI: 0.82 to 0.92; p<0.001; absolute risk reduction: 3.5%; 95% CI: 0.8 to 6.1; Figure 1). This result was primarily driven by a lower risk of all-cause death (HR: 0.85; 95% CI: 0.80 to 0.91; p<0.001; Figure 2) and stroke (cause-specific [cs] HR: 0.86; 95% CI 0.74 to 0.99; p=0.04), whereas no differences were observed in the risk of MI (csHR: 0.97; 95% CI: 0.82 to 1.15) or coronary revascularization (csHR: 0.97; 95% CI 0.85 to 1.11).

Conclusion

The combination of moderate-intensity statins with ezetimibe was associated with a lower risk of incident ASCVD compared with high-intensity statins alone among primary prevention patients in a real-world setting. These results were driven by a lower risk of all-cause death and stroke, but not coronary events. The influence of statin intolerance on the allocated strategy and adherence to therapy cannot be addressed in this analysis, which, along with verifying these estimates, may be best determined in a prospective randomized trial.

Moderate-intensity statin combined with ezetimibe versus high-intensity statin monotherapy for secondary cardiovascular risk reduction: a systematic review and meta-analysis (2024)

Introduction

Intensive lowering of LDL cholesterol levels is recommended for patients with atherosclerotic cardiovascular disease (ASCVD) [1]. Statins are the first-line therapy for secondary prevention [1]. Recent studies such as the RACING trial suggest that the combination of moderate-intensity statins and ezetimibe (MIS+EZE) may achieve a greater LDL cholesterol reduction and a lower adverse event rate than high-intensity statins alone (HIS) [2].

Purpose

The aim of this systematic review and meta-analysis is to assess cardiovascular outcomes and clinical safety of MIS+EZE versus HIS in patients with ASCVD.

Methods

We searched PubMed, Cochrane and Embase for studies that compared MIS+EZE to HIS in patients with ASCVD and included studies reporting cardiovascular mortality, all cause mortality, non-fatal stroke, non-fatal myocardial infarction, unstable angina, coronary revascularization, heart failure, and LDL-C ≤ 70mg/dL. Studies with the same statin dose in both treatment groups and studies with overlapping populations were excluded. Treatment effects for binary endpoints were compared using pooled risk-ratios (RR) with 95% confidence intervals.

Results

Out of 6238 studies, we included 6 RCTs and 2 retrospective cohort studies with 40,236 patients of whom 10,254 were treated with MIS+EZE (25,5%). Mean follow-up ranged from 90 days to 3 years.

Cardiovascular mortality (RR 0.83; CI95% 0.73-0.94; p=0.003), all-cause mortality (RR 0.90; CI95% 0.82-0.98; p=0.02) and non-fatal stroke (RR 0.83; CI95% 0.73-0.93; p=0.002) were significantly lower in patients treated with MIS+EZE compared to those treated with HIS. A significantly higher proportion of patients in the MIS+EZE group reached an LDL-C ≤ 70mg/dL (RR 1.26; CI95% 1.19-1.34; p<0.00001). No statistically significant difference was found for non-fatal myocardial infarction (RR 0.87; CI95% 0.64-1.17; p=0.36), coronary revascularization (RR 1.03; CI95% 0.78-1.35; p=0.83), heart failure (RR 0.95; CI95% 0.86-1.06; p=0.38) and unstable angina (RR 1.52; CI95% 0.62-3.75; p=0.36). A RCT sub-analysis was feasible for cardiovascular mortality and showed no statistically significant difference between the two groups (RR 1.01; CI95% 0.42-2.42; p=0.98).

Regarding safety endpoints, the risk of adverse events (RR 0.84; CI95% 0.74-0.95; p=0.004) and the risk of muscle-related adverse events (RR 0.67; CI95% 0.49-0.92; p=0.01) were significantly lower in MIS+EZE group. The significant reduction in muscle-related adverse events was maintained in the RCT sub-analysis (RR 0.61; CI95% 0.41-0.91; p=0.02). There was no difference between groups in the risk of liver-related adverse events (RR 0.63; CI95% 0.29-1.41; p=0.26) or new-onset malignancy (RR 0.99; CI95% 0.87-1.12; p=0.85).

Conclusion

The combination of moderate-intensity statins and ezetimibe may be considered as an alternative therapeutic strategy to reduce secondary cardiovascular risk with lower rates of drug intolerance.

Efficacy and safety of double-dose statin monotherapy versus moderate-intensity statin combined with ezetimibe dual therapy in diabetic patients: a systematic review and meta-analysis of randomized controlled trials (2024)

Cardiovascular disease is a leading cause of mortality, especially in individuals with type 2 diabetes mellitus and dyslipidemia. Despite adequate statin therapy, some patients fail to achieve the target low-density lipoprotein-cholesterol levels. Trials have compared doubling the statin dose with the addition of ezetimibe. A systematic literature search was performed using various databases. Forest plots were constructed for pooled analysis with statistical significance set at P < 0.05. Seven trials were included. Monotherapy showed no significant difference compared with dual therapy for low-density lipoprotein-cholesterol levels [mean difference (MD): −5.03; P = 0.37], high-density lipoprotein-cholesterol levels (MD: 0.01; P = 0.95), total cholesterol (MD: −2.38; P = 0.66), and triglycerides (MD: 5.37; P = 0.67) at follow-up compared to baseline. Monotherapy significantly reduced serious clinical adverse events (risk ratio: 0.21; P = 0.04), with no difference in treatment-related adverse effects, discontinuation due to treatment-related or overall adverse events.

Safety and Efficacy of Moderate-intensity statin plus ezetimibe versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease: a meta-analysis (2024)

Purpose

Methods

Results

Conclusions

My Longevity Journey

Ezetimibe Lipid-Lowering Therapy Beyond Statins

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