Are We Using Ezetimibe As Much As We Should?

The usage of lipid-lowering treatment has been less than optimal, as about two-thirds of patients with atherosclerotic cardiovascular (CV) disease (CVD) do not attain optimal low-density lipoprotein cholesterol (LDL-C) levels, despite statin treatment.¹ The percentage of lipid goal attainment has been reported to be much lower in certain ethnic subgroups.² A recent (2022) retrospective United Kingdom study characterizing the adult primary care patient population (n = 279 221) with primary hypercholesterolemia (PH)/mixed dyslipidemia (MD), indicated that over a mean of 8.6 years, the basal prevalence (proportion of the population) of PH/MD almost doubled from 13.5% in 2009 to 23.5% by 2019.³ The incidence (number of new cases) was reduced from 176 to 49 per 100 000 population. Average age of the cohort was 58 years, baseline LDL-C was 4.32 mmol/L (167 mg/dL), approximately 20% had atherosclerotic CVD, 30% diabetes mellitus (DM), and 8.5% heterozygous familial hypercholesterolemia. Respective LDL-C decreases of 40% and 50% were attained in 2.6% and 2.3% of patients. Most were administered moderate-intensity statins as single therapy (62%); high-intensity statins were employed less often (24% as commencing therapy), while <10% of patients had ezetimibe together with statins of various intensities. Thus, a high percentage of patients with PH/MD who are at increased CV risk, are less than optimally managed regarding lipid reducing, and may have CV events with attendant important clinical and financial consequences. Therefore, despite recommendations for intensive LDL-C reduction, these are not applied in the clinical arena in the broader population.

Statins have been at the center stage of hypolipidemic therapies. Unfortunately, statins have been plagued by the occurrence, or fear of the occurrence, of several side-effects or adverse actions, which have partly hindered their more widespread use.⁴ Besides statins, 5 new lipid-lowering therapeutic modalities have been documented to further lower CVD risk comprising ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), icosapent ethyl (found effective in reducing triglycerides rather than cholesterol),^5,6 bempedoic acid, an ATP citrate lyase inhibitor (reduces LDL-C),⁷ and inclisiran, a new small interfering RNA treatment that blocks the generation of the PCSK9 protein.⁸ Of these, ezetimibe is an oral agent, in contrast to parenteral PCSK9i and inclisiran, and has been the most convenient and/or affordable regimen, with PCSK9i being the most expensive class of drugs and inclisiran the next most expensive agent.⁹ Importantly, the latter still remains untested; the outcome of a broad-scale trial of the influence of inclisiran on CV course is anticipated in 2026.⁹ Robust data also attest to the success of ezetimibe in decreasing CVD risk and events.^10,11 The recently added, bempedoic acid, an ATP citrate lyase inhibitor that reduces LDL-C concentrations with reported low incidence of muscle-related adverse events among statin-intolerant persons, has been recently found to decrease the occurrence of major adverse CV events (MACE).¹² However, this agent was also found, according to a recent meta-analysis, to increase the occurrence of gout, cholelithiasis, and renal impairment.¹³ Furthermore, the drug is still more expensive than statins, has no generic alternative and a 30-day supply can cost >$400.⁹

A recent study assessed the utility of hypolipidemic drugs in 728 423 persons with atherosclerotic CVD from 89 US health systems (2018-2021) employing electronic health records.¹ As of 2021, only 6% of atherosclerotic CVD individuals were receiving ezetimibe, 1.6% were on a PCSK9i, and 1.3% on icosapent ethyl, with use only slightly rising during the trial duration. The authors concluded that dealing with the underusage of non-statin lipid-reducing treatment for secondary prevention is a crucial point in closing the management hiatus of patients with remaining risk of atherosclerotic CVD. Non-statin lipid-lowering therapies do reduce residual atherosclerotic CVD risk. Thus, increasing use of these therapies is critical to improving this treatment gap. Furthermore, the benefits of LDL cholesterol lowering, even beyond current recommendations, are also apparent in patients at lower CV risk and younger age, indicating a need for earlier and effective intervention.¹⁴

For this narrative review, a comprehensive review of the literature was conducted and the outcome of trials examining the usage of ezetimibe, as mono- or combined treatment in patients with hyperlipidemia and/or CVD, including several subgroups, are discussed. Also, safety and cost-efficacy issues and current guidelines are detailed. A summary of the results of meta-analyses of studies employing ezetimibe is presented in Table 1.^15-27 The mechanisms of action of ezetimibe vis-a-vis those of statins are pictorially illustrated (Figure 1). Finally, a holistic lipid approach strategy is suggested.

Ezetimibe is a selective inhibitor of the Niemann-Pick C 1-Like 1 protein (NPC1L1P) transporter on enterocytes, leading to a reduction of the intestinal cholesterol absorption (Figure 1).^28,29 A meta-analysis of 8 short-term RCTs demonstrated that after 12 weeks of ezetimibe monotherapy, a significant LDL-C lowering of 15% to 22% was noted; the drug was well tolerated with a safety profile similar to placebo.¹⁸ Importantly, ezetimibe has low pharmacokinetic interactions with medications metabolized by cytochrome P450 with low incidence of muscle side-effects.

Ezetimibe also exhibits anti-inflammatory and immunomodulatory actions and affects the expression of specific antigens.^30-33 A recent meta-analysis indicated that ezetimibe significantly decreased C-reactive protein (CRP) levels by ~30%, independently of cholesterol reductions.³⁴ It is quickly absorbed from the gastrointestinal tract, then glucuronidated to produce the active metabolite; it also goes through substantial enterohepatic circulation.³⁰ Several genetic polymorphisms appear to affect the pharmacokinetics of ezetimibe. This agent also has an intricate influence on cytochrome P450 enzymes, as it is a metabolism-dependent inhibitor of cytochrome CYP3A4.³⁰ Ezetimibe does not have any clinically important interactions with fibrates, statins, or mipomersen.³⁰

There have been some concerns about a potential increase of intestine cancer and/or breast cancer by ezetimibe.³⁵ However, a recent meta-analysis confirmed ezetimibe’s safety in 28 444 participants over a median of 5 months (48 randomized controlled trials—RCTs) and in 1667 participants over a median of 40 months (4 observational studies), where the drug was not associated with cancer (relative risk—RR 1.01), fractures (RR 0.90), discontinuation due to adverse event (RR 0.87), gastrointestinal event (RR 1.34), myalgias (RR 0.82), neurocognitive events (RR 1.48), or new-onset DM (RR 0.88).³⁶ The authors concluded that ezetimibe does not differ much from placebo, standard care or other lipid-reducing agents in untoward effects or other adverse events.

As mentioned, non-statin lipid-lowering drugs are efficacious in lowering atherosclerotic CVD risk.⁶ However, usage of non-statin therapies is low for secondary prevention. Furthermore, there has been limited uptake of non-statin therapies over the last several years. Increasing use of these therapies is important to improve the treatment gap, as almost two-thirds of patients with atherosclerotic CVD do not attain target LDL-C despite statin treatment.

As also mentioned, a recent report evaluating the employment of hypolipidemic agents in 728 423 persons with atherosclerotic CVD in the US indicated that as of 2021, only 6% of atherosclerotic CVD patients were receiving ezetimibe, 1.6% were receiving a PCSK9i, and 1.3% were on icosapent ethyl, pointing to the suboptimal usage of non-statin lipid-reducing treatment.¹

Early data on use of ezetimibe with meta-analysis including only short-term studies in hypercholesterolemia, showed considerable potentially positive alterations in lipid and lipoprotein concentrations compared to baseline following ezetimibe single therapy.¹⁸ Ezetimibe alone and also combined with simvastatin has been demonstrated to lower the atherogenic small, dense LDL level in patients with DM.³⁷ Ezetimibe can also positively influence the spread of LDL subfractions, particularly in patients with high triglyceride levels.³⁸ Furthermore, combined therapies, such as those commonly employed in patients with acute myocardial infarction (MI), influence the quality of LDL particles.³⁹ Indeed, a link was shown of simvastatin/ezetimibe plus either clopidogrel or ticagrelor with less oxidized LDL, while simvastatin/ezetimibe with ticagrelor lowered the amount of cholesterol in the atherogenic subfractions of LDL, whereas rosuvastatin with ticagrelor was the only combined regimen linked with higher LDL size.³⁹

In clinical trials, single therapy with ezetimibe (10 mg/d) has been demonstrated to lower LDL-C in hypercholesterolemic patients by 15% to 22% with relatively increased interindividual fluctuation.^40,41 A meta-analysis of 8 RCTs (all 12 weeks duration, n = 2722) indicated that ezetimibe monotherapy conferred an important mean reduction in LDL-C (from baseline to endpoint) of −18.6%, (P < .00001) versus placebo.¹⁸ In addition, considerable (P < .00001) alterations were also detected in total cholesterol (−13.5%), high density lipoprotein cholesterol (HDL-C) (3%) and triglyceride concentrations (−8.1%). Single treatment with ezetimibe seemed to be tolerated well with a profile of safety which was akin to placebo. Of course, another setting where ezetimibe is used as monotherapy includes patients with intolerance to statins.^42,43

However, ezetimibe has been mostly employed as an adjunctive therapy added to standard statin treatment. Nevertheless, there may also be an occasional patient with familial hypercholesterolemia who has an excellent response to this agent.⁴⁴ As mentioned, NPC1L1 is the molecular goal of ezetimibe. Detailed analysis of the NPC1L1 gene and proteome from a super responder to ezetimibe regarding the role of NPC1L1 mutations pointed to an intricate series of events in which the joint mutations were demonstrated to influence cholesterol uptake when ezetimibe was present.⁴⁴ Proteomic analysis suggested that the super response may also be explained by the type of interactions with the proteins of the cytosol.

For patients needing a more aggressive lowering in cholesterol to aid in averting CVD, a statin can be combined with ezetimibe to enhance its efficacy.⁴⁵ Indeed, ezetimibe is often the initially added therapy to reach LDL-C goals. It decreases LDL-C by approximately an extra 20% and has a superb safety and tolerability profile. CV outcomes data indicate that such a combination therapy is a strong and by and large well-tolerated combination of drugs that increases the spectrum of choices at hand for the pharmacological treatment of hypercholesterolemia in adults, permitting more patients to attain their LDL-C target.^46-48 Combined therapy is also a choice to manage very-high-risk patients who cannot attain LDL-C goals with statin single therapy.⁴⁹

Data from RCTs indicate that all fixed-dose combinations of ezetimibe/statin considerably improve lipid patterns in patients with hypercholesterolemia versus statin monotherapy.⁵⁰ In all groups of patients managed with different doses of statin combined with a standard 10 mg-dose of ezetimibe, a reduction in mean LDL-C concentration of >50% has been noted. The safety and tolerability of ezetimibe/statin treatment seem to be equivalent with those of statin single therapy.

Among patients with atherosclerotic CVD, moderate-intensity statin with ezetimibe combination treatment was non-inferior to high-intensity statin single therapy for the 3-year composite results with a greater percentage of patients with LDL-C concentrations of <70 mg/dL and less intolerance-associated drug withdrawal or dose lowering.⁵¹ In this context, a multicenter Korean RCT randomized 3780 patients to take either moderate-intensity statin dose (rosuvastatin 10 mg) with ezetimibe (10 mg) combination treatment (n = 1894) or high-intensity statin single-therapy (rosuvastatin 20 mg; n = 1886).⁵¹ Over 2 years, the primary endpoint (3-year composite of CV death, major CV events, or non-fatal cerebrovascular accident) was noted in 172 patients (9.1%) in the combination treatment subset and 186 patients (9.9%) in the high-intensity statin single therapy subset (absolute difference −0.78%; 90% CI −2.39-0.83). LDL-C levels of <70 mg/dL at 1, 2, and 3 years were noted in 73%, 75%, and 72% of patients in the combined treatment subset, and 55%, 60%, and 58% of patients in the high-intensity statin single-therapy subset (all P < .0001). Withdrawal or dose lowering of the trial agent for reason of intolerance was encountered in 88 patients (4.8%) and 150 patients (8.2%), respectively (P < .0001).

In patients with acute coronary syndrome (ACS) (n = 18 144), ezetimibe, when added to statin treatment, produced an incremental reduction of LDL-C concentrations and ameliorated CV outcomes.⁵² Moreover, lowering LDL-C to concentrations below prior goals furnished extra advantage. Specifically, over a median of 6 years, the median time-weighted average LDL-C concentration during the trial was 53.7 mg/dL in the simvastatin-ezetimibe subset versus 69.5 mg/dL in the simvastatin-single therapy subset (P < .001). The Kaplan-Meier event rate for the primary end-point (composite of CV mortality, nonfatal MI, unstable angina needing rehospitalization, coronary revascularization at ⩾30 days after random allocation, or nonfatal cerebrovascular accident—CVA) at 7 years was 32.7% in the simvastatin-ezetimibe subset, versus 34.7% in the simvastatin-monotherapy subset (P = .016). Percentages of prespecified gallbladder, hepatic and muscle side-effects and cancer did not differ in the 2 subsets.

A post-hoc analysis of a subgroup of patients of the RACING (RAndomized Comparison of Efficacy and Safety of Lipid-lowerING With Statin Monotherapy vs Statin/Ezetimibe Combination for High-risk Cardiovascular Diseases) study comprising those who underwent percutaneous coronary intervention (PCI) (2497 patients, 67%, median 64 years, 79% men), who had increased rates of the primary endpoint (3-year composite of CV mortality, major CV events, and nonfatal cerebrovascular accident) (HR, 1.34; P = .014), indicated that moderate-intensity statin treatment combined with ezetimibe versus high-intensity statin treatment did not raise the occurrence of the primary endpoint (HR, 0.95; P = .781).⁵³ The proportion of patients with LDL-C <70 mg/dL at 1, 2, and 3 years was 74%, 76%, and 73%, respectively, in the combined treatment population, and was considerably greater than that in the high-intensity statin single-therapy subset (57%, 62%, and 59%, respectively, all P < .001). Withdrawal of lipid-reducing agents was noted less often in the combined therapy subset (4.2 vs 7.6%, P = .001). The authors concluded that the actions of ezetimibe combination treatment noted in the RACING trial were consistently maintained in patients with atherosclerotic CVD after PCI.

A meta-analysis was performed of 26 RCTs (n = 23 499) that compared ezetimibe versus placebo or ezetimibe plus other lipid-altering agents versus other lipid-altering agents alone in adults, with or without CVD, and who were followed-up for ⩾1 year.⁵⁴ The findings were driven by the largest study (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; IMPROVE-IT), which had weights ranging from 41.5% to 98.4% in the different meta-analyses. The authors concluded that ezetimibe with statins most likely mitigates the occurrence of major adverse CV events (MACE) versus statins alone (risk ratio—RR 0.94, 10 studies; moderate-quality evidence). Trials reporting on all-cause mortality with use of ezetimibe with statin or fenofibrate, found that these agents have little or no effect on this outcome (RR 0.98).⁵⁴ Combining ezetimibe with statins most likely lowers the occurrence of non-fatal myocardial infarction (MI) (RR 0.88, 21 145 participants; 6 studies; moderate-quality evidence) and non-fatal CVA (RR 0.83, 21 205 participants; 6 studies; moderate-quality evidence).⁵⁴ Trials reporting CV mortality with ezetimibe added to statin or fenofibrate, concluded that such regimen had little or no effect on this outcome (RR 1.00, 19 457 participants; 6 studies; moderate-quality evidence).⁵⁴ The need for coronary revascularisation might be decreased by combining ezetimibe with a statin (RR 0.94, 21 323 participating individuals; 7 studies); however, with no difference in coronary revascularisation rate noted when a sensitivity analysis was restricted to trials with a reduced risk of bias.⁵⁴ Regarding safety, ezetimibe added to statins may make little or no difference in the occurrence of liver disease (RR 1.14), while it is doubtful whether ezetimibe influences the incidence of myopathy (RR 1.31, 95% CI 0.72-2.38; 20 581 participants; 3 studies; very low-quality evidence) and rhabdomyolysis, granted the broad confidence intervals (CIs), and low event rate.⁵⁴ The authors concluded that moderate- to high-quality proof indicates that ezetimibe has modest advantageous influence on the occurrence of CVD endpoints, mainly led by a decrease in non-fatal MI and non-fatal CVA, but it has little or no influence on clinical fatal endpoints. The lowering of LDL-C, total cholesterol and triglycerides might account for the CV benefit of ezetimibe. The evidence is not sufficient to determine whether ezetimibe raises the risk of harmful events due to the low and very low quality of the evidence. The evidence for benefit was mainly acquired from patients with established atherosclerotic CVD (predominantly ACS) who were prescribed ezetimibe plus statins. However, the evidence is insufficient about the role of ezetimibe in primary prevention and the results of ezetimibe monotherapy in the prevention of CVD, and these topics thus need further investigation.

In summary, in patients with CVD, ezetimibe with a statin lowers MACE but has no influence on total and CV death rate, compared with a statin alone (strength of recommendation, A).⁵⁴ In adults with CVD, ezetimibe combined with a moderate-intensity statin (rosuvastatin 10 mg) was noninferior at lowering CV death, MACE, and nonfatal CVA, but was tolerated better, versus a high-intensity statin (rosuvastatin 20 mg) alone (strength of recommendation, B; 1 RCT).⁵⁴

Another meta-analysis of 8 RCTs (N = 19 558) of ezetimibe plus statin versus statin alone that monitored patients for a minimum of 6 months and provided information on ⩾1 end-points of total death rate, CV mortality, non-fatal MI, and non-fatal CVAs, indicated that ezetimibe added to moderate-dose statins can possibly lead to 17 fewer MIs and likely 6 fewer CVAs/1000 managed over 0.5 to 6 years but is not likely to lower total death rate or CV death.⁵⁵ The authors suggested that patients who value a small absolute decrease in MI and do not object to using an extra drug over a long period may choose ezetimibe besides statin therapy. In this analysis there were no increased specific harms conferred by ezetimibe added to statins. Importantly, in this review, the data from the IMPROVE-IT trial constituted the dominating evidence regarding sample size and number of events (responsible for >90%) among all pertinent trials comparing ezetimibe plus statin versus statin alone.

The extra action of ezetimibe to a high-potency statin regimen (eg, rosuvastatin) helps to attain cholesterol targets in a bigger number of high-risk patients,⁵⁶ while alleviating some safety concerns regarding high doses of statin treatment.⁵⁷ In addition, ezetimibe enhances rosuvastatin triglyceride-reducing and anti-inflammatory actions.⁵⁷

Finally, a recent meta-analysis of 17 articles compared the effects of statin-ezetimibe combined treatment and statin single therapy on lipid and glucose indices in patients with DM.⁵⁸ In the efficacy evaluation, the combined therapy led to a significantly larger decrease in LDL-C than did statin single therapy (standard difference in means 0.69). A larger ameliorating action was noted in the concentrations of total cholesterol, HDL-C, triglyceride, and apolipoprotein B, but not apolipoprotein A1, with combined treatment than with statin monotherapy. Furthermore, combined treatment decreased fasting blood glucose concentrations more so than did statin monotherapy. Regarding safety, there were no considerable differences in therapy-linked side-effects between the 2 therapies.

Taking into consideration the superb safety pattern and absence of clinically pertinent drug-drug interactions, the statin/ezetimibe combination is a useful alternate therapy to the up-titration of a statin dose.

Ezetimibe has also been used in combination with orlistat, an anti-obesity drug, which prevents the absorption of dietary fats by acting as a lipase inhibitor; the combined orlistat/ezetimibe regimen had a more advantageous influence on LDL-C and small dense LDL-C concentrations in overweight and obese patients with hypercholesterolemia than either agent alone.⁵⁹

Finally, ezetimibe has been suggested to be combined with bempedoic acid in an attempt to increase the proportion of patients attaining LDL cholesterol goals.⁶⁰ indeed, bempedoic acid has been heralded as a potent therapeutic ally, capable of significantly lowering LDL-C levels and curtailing CV events.⁶¹ Its favorable safety profile attests to its suitability, particularly among persons with statin intolerance or those belonging to a high-risk vascular group, pointing to a paradigm shift in our lipid management approaches.

A post-hoc analysis of the RACING study suggested that moderate-intensity statin combined with ezetimibe demonstrated similar CV advantages with those of high-intensity statin single therapy with reduced intolerance-linked drug withdrawal or dose lowering in elderly patients with atherosclerotic CVD who have an increased risk of intolerance, noncompliance, and withdrawal with high-intensity statin treatment.⁶² Thus, one can avoid the poor compliance with and worries concerning high-intensity statin treatment by using combined moderate-intensity statin and ezetimibe, at least for the elderly subpopulation. High-intensity statin therapy incurs a higher risk of intolerance, noncompliance, and drug withdrawal.⁶³

A recent meta-analysis of 11 trials (N = 20 291) indicated that the addition of ezetimibe to high-intensity statin therapy at the time of an ACS event leads to significantly enhanced cholesterol reduction at 1-week, 1-month, 3- months and 1-year of follow-up, which translates into a significantly lower recurrent CV events after an index event of ACS.¹⁹ Interestingly, a recent propensity-matched nationwide cohort study indicated that among individuals without pre-existing CVD, combined moderate-intensity statin and ezetimibe were superior to high-intensity statin monotherapy in preventing composite outcomes as well as each of MI and stroke, whereas low-intensity statin with ezetimibe combination reduced the risk of composite but not individual outcomes.⁶⁴

A most recent meta-analysis of 7 trials (N = 2337) employing rosuvastatin/ezetimibe (5/10 mg) versus rosuvastatin alone (20 mg) indicated that these 2 regimens had comparable lipid-lowering efficacy and tolerability.⁶⁵ The percentage of total cholesterol reduction was greater in the combination group (SMD 0.22; P = .02), whereas that of triglyceride reduction and HDL cholesterol elevation was similar between the 2 groups.

A systematic review and network meta-analysis comprised 14 trials evaluating ezetimibe and PCSK9 inhibitors among 83 660 adult patients receiving statins.⁶⁶ The addition of ezetimibe to statins decreased MI (RR 0.87) and stroke (RR 0.82) but not all-cause death rate (RR 0.99) or CV mortality (RR 0.97). Likewise, adding a PCSK9 inhibitor to statins decreased MI (RR 0.81) and stroke (RR 0.74) but not all-cause (RR 0.95) or CV death rate (RR 0.95). Among adult patients with very high CV risk, the addition of a PCSK9 inhibitor was possibly able to decrease MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); while with the addition of ezetimibe it was possible to decrease stroke (14 per 1000), but the decrease of MI (11 per 1000) (moderate certainty) did not succeed to attain the minimal important difference (MID) of 12 per 1000. The addition of ezetimibe to PCSK9 inhibitor and statin may decrease stroke (11 per 1000), but the lowering of MI (9 per 1000) (low certainty) did not attain MID. The addition of PCSK9 inhibitors to statins and ezetimibe may decrease MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with elevated CV risk, the addition of a PCSK9 inhibitor most likely lowered MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); the addition of ezetimibe likely decreased stroke (11 per 1000), but the decrease in MI did not reach MID (8 per 1000) (moderate certainty). The addition of ezetimibe to PCSK9 inhibitor and statins did not influence the results beyond MID, while the addition of a PCSK9 inhibitor to ezetimibe and statins may decrease stroke (13 per 1000). These influences were consistent in patients who could not tolerate statins. Among the groups of moderate and low CV risk, the addition of a PCSK9 inhibitor or ezetimibe to statins had little or no advantage for MI and stroke. The authors concluded that ezetimibe or PCSK9 inhibitors may lower non-fatal MI and stroke in adult patients who are at very high or high CV risk and are having maximally tolerated statin treatment or who do not tolerate statins, but not in those with moderate and low CV risk. Hence, one can consider adding first ezetimibe to statin, before thinking of resorting to more expensive therapies involving injections.

In keeping with the above results, an international panel recently made some recommendations, mostly weak recommendations, meaning that one has to trust and be guided by shared decision making when following these guidelines.⁶⁷ For adults already employing statins, the panel proposes the addition of a second lipid-lowering agent in individuals at very high and high CV risk but advises against adding it in individuals at low CV risk. For adults who do not tolerate statins, the panel suggests employing a lipid-reducing agent in people at very high and high CV risk but advises against its addition in those at reduced CV risk. When opting to include another lipid-reducing agent, the panel recommends ezetimibe in lieu of PCSK9 inhibitors. The panel proposes further the additional use of a PCSK9 inhibitor to ezetimibe for adults already receiving statins and who are at very high risk and also for those at very high and high risk who do not tolerate statins. The panel considered a strong recommendation for the addition of either ezetimibe or PCSK9 inhibitors in persons at high and very high CV risk as reflecting a definite advantage. The panel emphasized shared decision making and recognized that drug availability and costs will affect decisions when healthcare systems, clinicians, or persons decide on adding ezetimibe or PCSK9 inhibitors.

A recent systematic literature search examining the influence of ezetimibe on inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNFα) and Interleukin 6 (L-6), when administered in addition to statin therapy, indicated that overall ezetimibe curtails inflammation further to statin therapy. However, evidence was scant for CRP and also for TNFα and IL-6.⁹¹ A study evaluating the effectiveness of ezetimibe to influence coronary atherosclerotic plaque composition, indicated that compared with the control group, ezetimibe significantly reduced fibro-fatty plaque volume, but it had no significant effect on reduction of fibrous plaque, necrotic core, or change in dense calcification.⁹²

Importantly, ezetimibe enhances statin triglyceride-lowering and anti-inflammatory actions.⁵⁷ Furthermore, ezetimibe was shown to have a small (7%) but statistically significant decrease in the serum concentrations of lipoprotein Lp(a), an underrecognized causal risk factor for CVD,⁹³ in patients with primary hypercholesterolemia, albeit with unknown clinical significance.⁹⁴

Ezetimibe has also been found to effectively decrease phytosterol, besides cholesterol, absorption.⁹⁵ Phytosterol is a plant sterol, a molecule structurally akin to cholesterol, found only in dietary sources (eg, fruits, vegetables, cereals, nuts) since it cannot be generated in humans.⁹⁵ Sterol-enriched diets (⩾2 g/day) may lower total and LDL-C levels by 5% to 10%, either alone or when combined with statins, as they antagonize the absorption of dietary cholesterol in the gut. Importantly high serum phytosterol levels, such as those linked with sitosterolemia (a scarce genetic defect),⁹⁶ may confer a high atherosclerotic CV risk, albeit a threshold for such an action has not been determined.⁹⁷ Importantly, drugs such as ezetimibe may efficiently lower cholesterol and phytosterol absorption. It remains to be shown whether such therapy leading to reduced phytosterol absorption also results in CVD risk reduction.

A meta-analysis of 7 studies registering 31 048 patients (median follow-up 34.1 ± 26.3 months; 70% females; mean age 61 ± 8 years) indicated that compared with control treatment, ezetimibe considerably lowered the risk of MI by 13.5% (RR: 0.865, P < .001) and the risk of any CVA by 16% (RR: 0.840, P = .005), without any influence on total and CV death rate (RR: 1.003, P = .908; RR: 0.958, P = .330) and risk of new cancer (RR: 1.040, P = .303).⁹⁸ The authors concluded that ezetimibe significantly decreases the risk of MI and CVA without any influence on total and CV death rate and risk of cancer.

Ezetimibe, administered at a dose of 10 mg/d in the morning or the evening before or after food ingestion, is absorbed swiftly and metabolized extensively to pharmacologically active ezetimibe glucuronide.⁴¹ There is no clinically important influence of age, gender, or race on ezetimibe pharmacokinetics; no dose modification is required in patients with mild hepatic insufficiency or mild-to-severe renal function worsening. Ezetimibe added to statin does not seem to aggravate muscle toxicity (myositis) and creatine kinase (CK) concentrations beyond what is observed with statin therapy alone.

With regards to carcinogenicity of ezetimibe, a prospective analysis from IMPROVE-IT indicated that among 17 708 patients having simvastatin 40 mg daily, those allocated to ezetimibe 10 mg daily had a similar occurrence of malignancy and deaths due to malignancy versus those having placebo over a median of 6 years.⁹⁹ This study refuted the results of the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial which raised concerns about a possible elevated risk of malignancy incurred by ezetimibe (11.1%. versus 7.5%).¹⁰⁰

A recent review and meta-analysis of 48 RCTs (n = 28 444; median follow-up 34 weeks) and 4 observational trials (n = 1667; median follow-up 288 weeks) regarding the safety of ezetimibe, indicated moderate to high certainty that ezetimibe was not linked with cancer (relative risk—RR 1.01), fractures (RR 0.90), drug withdrawal due to any adverse event (RR 0.87), gastrointestinal side-effects leading to withdrawal (RR 1.34), myalgia or muscular pain necessitating withdrawal (RR 0.82), neurocognitive events (RR 0.48), or new-onset diabetes (RR 0.88).³⁶ Other reviews also indicate that ezetimibe does not elevate the risk of cancers; rather this agent could even tard the emergence and progression of cancer via various mechanisms (stem cell suppression, anti-angiogenesis, anti-inflammatory action, anti-proliferation, immune-enhancement).¹⁰¹ Nevertheless, more recent data suggest that ezetimibe may elevate the risk of intestinal cancer and has a trend of raising the risk of breast cancer, with no evidence about affecting the risk of other types of cancer.³⁵

As mentioned, a subanalysis of patients participating in the IMPROVE-IT study, detected no elevation in the risk of new-onset DM with the addition of ezetimibe to statin treatment.⁷⁴ Rather, ezetimibe therapy may be linked with ameliorated insulin sensitivity, ascribed, at least partly, to actions on adipocyte size in visceral fat, adipocyte inflammation, free fatty acid concentrations, and fatty acid oxidation.¹⁰² However, further trials are needed to establish these effects. Furthermore, the combination therapy has been established safe, and drug discontinuation rates have not been higher by adding ezetimibe.⁵⁶

Finally, concerns about cholelithiasis among patients treated with ezetimibe¹⁰³ may probably be put to rest as the data do not seem to support them.¹⁰⁴ Indeed, long-term therapy with ezetimibe ameliorates lipid metabolism without much affecting the tendency for gall bladder stones.¹⁰⁵ It has even been suggested that the specific inhibitory influence of ezetimibe on the intestinal NPC1L1 protein designates this drug as potential agent for averting gallstone production by decreasing bioavailability of intestine-derived cholesterol to the liver for biliary secretion and desaturating bile via the inhibition of intestinal absorption of cholesterol.¹⁰⁶

A cost-efficacy study conducted in China indicated that in patients receiving high-dose statins for the secondary prevention of CVDs, adding ezetimibe is cost-effective compared to adding PCSK9 inhibitors and adding both drugs.¹⁰⁷ A recent British study indicated that the most effective intervention is low/moderate-intensity statins and ezetimibe, and was projected to lead to a gain in quality-adjusted life-years of 0.067 per person initiated at 30 and 0.026 at age 60 years.¹⁰⁸ Finally, a systematic review and meta-analysis of cost-utility studies regarding cost-efficacy of ezetimibe plus statin lipid-lowering therapy indicated that ezetimibe plus statin therapy was significantly cost-effective versus other lipid-lowering therapeutic agents or placebo.¹⁰⁹ The pooled incremental net benefit (INB) (95% CI) was $4274, but there was large heterogeneity (I² = 84.21). On subgroup analysis, ezetimibe plus statin therapy was significantly cost-effective in high-income countries ($4356), for primary prevention ($4814), and for payers’ perspective ($3255), and from lifetime horizon ($4571). The evidence from lower-middle-income countries and the societal perspective remains inadequate.

Current American and European guidelines on cholesterol advised the addition of non-statins to statin treatment for high-risk secondary prevention patients above an LDL-C threshold of ⩾70 mg/dL (1.8 mmol/L) (Table 2).^41,63 A systematic review and meta-analysis of 11 RCTs (130 070 patients) (selected by follow-up ⩾6 months and sample size ⩾1000 patients) compared efficacy and safety of therapy to attain lower (<70) versus higher (⩾70 mg/dL) LDL-C among patients having intensive lipid-reducing treatment (statins alone or plus ezetimibe or PCSK-9i).⁶⁶ The median LDL-C concentrations reached in lower versus higher cholesterol subsets were 62 and 103 mg/dL, respectively. At median follow-up of 2 years, the lower versus higher LDL-C subset had significant diminution in all-cause death rate (absolute risk difference—ARD −1.56, RR 0.94) and in CV death rate (ARD −1.49; RR 0.90), and lower risk of MI, revascularization, CVAs, and MACE. These advantageous results were attained without raising the risk of cancer, DM, or bleeding CVA. The benefit of total death rate in the lower LDL-C subset was restricted to statin treatment and those with increased baseline LDL-C (⩾100 mg/dL). However, the RR decrease in ischemic and safety endpoints was not dependent on baseline LDL-C or drug treatment. The authors concluded that therapy to reach LDL-C concentrations <70 mg/dL employing intensive lipid-lowering treatment with current hypolipidemic therapies can safely lower the risk of death and MACE. Such guideline-directed reductions in LDL-C appear feasible with use of combined statin/ezetimibe regimens without the need to resort to more expensive or inconvenient (parenteral) regimens.

Following guideline-directed cholesterol-lowering treatment could avert a considerable number of recurrent CVD episodes. Simulations using data from 279 395 US patients with an MI hospitalization (2018-2019) (mean age 75 years, mean LDL-C 92 mg/dL), indicated that 27% were having guideline-directed cholesterol-lowering treatment.¹¹⁰ With current use of cholesterol-lowering treatment, 25% of patients had an atherosclerotic CVD episode over 3 years. If all patients were to avail themselves of guideline-directed treatment, ~20% were deemed to have a CVD episode over 3 years, representing a 21.6% relative risk reduction.

Current evidence indicates that attaining the guideline-directed LDL-C target rate is still suboptimal despite employing high-intensity statin treatment in a real-world scenario.¹¹¹ Hence, the need to add ezetimibe before one resorts to other more expensive and/or less convenient therapies. Unfortunately, the problem remains as the majority of adults with atherosclerotic CVD are not currently receiving guideline-recommended add-on lipid-lowering therapy.¹¹²

Indeed, a recent retrospective observational population study examined the rate of attainment of guideline-directed lipid levels employing associated health data in 10 071 patients submitted to PCI (2012-2017), of whom 48% had LDL-C <1.8 mmol/L (2016 goal) and (23%) <1.4 mmol/L (2019 goal).¹¹³ A total of 5340 patients had non-HDL cholesterol (non-HDL-C) measured with 57% <2.6 mmol/L (2016) and 37% <2.2 mmol/L (2019). In patients with vascular event recurrences, <6% of the patients attained the 2019 LDL-C goal of <1.0 mmol/L. Totally, 10 592 patients had triglyceride concentrations measured, of whom 14% were ⩾2.3 mmol/L and 41% ⩾1.5 mmol/L (2019). High-intensity statins were administered in 56.4% of the population, only 3% were given ezetimibe, fibrates or prescription-grade N-3 fatty acids. Females were more likely to have lipid concentrations above target. The authors concluded that there was a low rate of attainment of the new European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) lipid goals in this large post-PCI cohort and relatively low rates of intensive lipid-lowering drug prescriptions in those with elevated lipids. Thus, there is great potential to optimize lipid-reducing treatment further and 1 such way is by adding ezetimibe to statin therapy, especially in females.

A practical (real-world) guidance (2021) from the EAS Task Force indicates that statin-ezetimibe combined therapy is the first choice for dealing with high LDL-C and should be administered upfront in very-high-risk patients with high LDL-C less likely to attain target with a statin, and in primary prevention familial hypercholesterolemia patients.¹¹⁴ A PCSK9 inhibitor may be also prescribed if LDL-C concentrations are still elevated. In high and very-high-risk patients with mild to moderately high triglyceride concentrations (>2.3 and <5.6 mmol/L [>200 and <500 mg/dL) on a statin, management with either a fibrate or high-dose omega-3 fatty acids (icosapent ethyl) may be contemplated, balancing the advantages versus risks. Combined therapy with fenofibrate may be provided for both macro- and microvascular gains in patients with type 2 DM.

A recent meta-analysis confirmed that LDL-C-reducing therapies significantly mitigate death rate.¹¹⁵ However, the meta-regressions and meta-analyses by subsets indicated that LDL-C reduction may not be advantageous for total and CV death rate end-points in trials with >50% LDL-C lowering and in studies with low baseline LDL-C concentrations. Nevertheless, the decrease in MI risk was consistent across all analyses. Importantly, annual numbers-needed-to-treat were overall relatively increased, and studies including patients with high baseline LDL-C concentrations recorded the largest gain from LDL-C—reducing treatment particularly for MI. Attaining lower LDL-C targets did not further enhance risk reduction consistently. Defining subsets of patients who obtain the greatest gains from LDL-C level lowering is clinically important and necessary. Ezetimibe can be effective as monotherapy in certain groups, but is most apparently needed in combined therapies to achieve these goals.

Fixed combinations of a statin with ezetimibe have been available as a robust therapy of hypercholesterolemia which is more effective than statin therapy alone, even when the statin dose in the combination is low or moderate compared with a high-dose statin monotherapy regimen.⁴⁶ These combinations enable higher numbers of patients to meet the needs in LDL-C lowering¹¹⁶ and attain guideline-recommended LDL-C levels.⁴⁵ The safety profile of these combinations is preserved or enhanced by allowing the prescription of a decreased dose of statin which also mitigates or averts the occurrence of statin-intolerance.¹¹⁷ Furthermore, patient compliance seems to increase with use of single-pill regimens.¹¹⁸ Also, this approach has been reported to unexpectedly enhance triglyceride control.¹¹⁹ Additional CV outcomes data are needed to further confirm and establish their efficacy.

In this respect, a multicenter randomized, double-blind trial examined the safety and efficacy of a fixed-dose combined regimen of rosuvastatin 2.5 mg and ezetimibe 10 mg versus those of ezetimibe 10 mg single therapy, rosuvastatin 2.5 mg, and rosuvastatin 5 mg single therapy in 279 patients with hypercholesterolemia.¹²⁰ At the 8-week follow-up, a larger reduction in the LDL-C concentrations (primary endpoint) was demonstrated in the statin 2.5 mg plus ezetimibe 10 mg group (−45.7% ± 18.6%) than in the ezetimibe 10 mg group (−16.7% ± 14.7%, P < .0001), statin 2.5 mg group (−32.6% ± 15.1%, P < .0001), and statin 5 mg group (−38.9% ± 13.9%, P = .0003). Comparable results were noted with the lowering of total cholesterol, non-HDL-cholesterol, and apolipoprotein B protein. In patients with low and moderate risk, all patients attained the goal LDL-C concentrations in the statin 2.5 mg plus ezetimibe 10 group (100%) compared with 13% in the ezetimibe 10 mg group, 47.6% in the statin 2.5 mg group, and 65% in the statin 5 mg group. Untoward events were scarce and comparable in the 4 groups. The authors concluded that fixed-dose combined treatment with low-intensity rosuvastatin and ezetimibe was more efficacious in decreasing LDL-C and attaining LDL-C targets than moderate-intensity rosuvastatin single therapy.

A recent cost-effectiveness analysis using a Markov model indicated that ezetimibe increased quality-adjusted life years (QALYs) by 0.60 at cost lowering of −£2529 (incremental cost-effectiveness ratio—ICER = −£4231/QALY).¹²¹

Another recent cost-efficacy study spotted economic assessment studies reporting outcomes of ezetimibe plus statin treatment versus other lipid-reducing drugs or placebo.¹⁰⁹ The pooled incremental net benefit (INB) from 21 eligible trials indicated that the ezetimibe plus statin regimen was significantly cost-effective versus the other lipid-reducing drugs (statin monotherapy/PCSK9i plus ezetimibe and statins/PCSK9i with statin therapy), or placebo. The pooled INB (95% CI) was $4274 (621-7927), but there was high heterogeneity (I² = 84.21). On subgroup analysis ezetimibe plus statin treatment was significantly cost-effective in high-income countries [$4356 (621-8092)], for primary prevention [$4814 (2523-7106)], and for payers’ viewpoint [$3255 (571-5939)], and from lifetime horizon (survival extending over the entire lifespan) [$4571 (746-8395)]. There were limited data from lower-middle-income countries and the societal standpoint.

Finally, a more recent cost-efficacy analysis further confirmed ezetimibe plus statin (6 studies) to be a cost-effective strategy compared with statin monotherapy.¹²²

Statin intolerance deprives many patients from the standard hypolipidemic therapy. Current choices for such patients comprise the usage of a reduced but tolerated dose of a statin and adding or changing to ezetimibe or other non-statin regimens. Of course, PCSKi produce larger LDL-C decreases than ezetimibe in such patients, with fewer skeletal-muscle deleterious occurrences versus a statin.¹²² However, such therapy is costly and involves injections.

Another effective hypolipidemic approach to patients who cannot tolerate daily statin single treatment that has been suggested entails the combination of daily ezetimibe plus low-dose statin twice a week might be an alternative regimen for high-risk patients who are intolerant to daily statin regimen.¹²³

One important caveat regarding statin intolerance relates to the possibility that the prevalence of total statin intolerance might be frequently overestimated.¹²⁴ In this regard, a recent large meta-analysis of 176 trials (112 RCTs, 64 cohort studies) of >4 million (4 143 517) patients indicated that the prevalence of statin intolerance was low at 9.1% (95% confidence interval 8.0%-10%) when diagnosed by applying the international definitions.¹²⁴ The prevalence was not different when defined by employing criteria from various societies (5.9%-7%). The prevalence of statin intolerance in RCTs was considerably lower versus cohort trials (4.9% vs 17%). The prevalence of statin intolerance was much greater when primary or secondary prevention patients were examined separately rather than when grouped together (18%, 8.2%, 9.1%, respectively). Lipid solubility did not influence statin intolerance (4% vs 5%), but several other factors did, such as age, odds ratio—OR 1.33, P = .04; female sex, OR 1.47, P = .007; Asian and Black race, P < .05 for both; obesity, OR 1.30, P = .02; DM, OR 1.26, P = .02; hypothyroidism, OR 1.37, P = .01; chronic liver, and renal failure, P < .05 for both. Antiarrhythmic agents, calcium channel blockers, alcohol use, and increased statin dose also conferred an elevated risk of statin intolerance.¹²⁴

The usage of icosapent ethyl has been demonstrated to significantly lower triglyceride concentrations and decrease CV risks in patients having optimal statin or combined statin/ezetimibe therapy.^125,126 Icosapent ethyl is a highly purified eicosapentaenoic acid ethyl ester that decreases triglyceride concentrations without increasing LDL-C.¹²⁷ Icosapent ethyl was the first fish oil product which was granted approval by the US FDA to decrease the risk of atherosclerotic CVD in adults.¹²⁵ The results of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) trial where 8179 patients with proven CVD or with DM and other risk factors, who had been on statin treatment and who had a fasting triglyceride concentration of 135 to 499 mg/dL and a LDL-C concentration of 41 to 100 mg/dL, and were randomized to 2 g of icosapent ethyl bid (total daily dose, 4 g) or placebo, indicated that the likelihood of ischemic events, comprising CV death, was considerably decreased with icosapent ethyl versus placebo over a median of 4.9 years.⁶ The primary end point (CV death, nonfatal MI, nonfatal CVA, coronary revascularization, or unstable angina) was noted in 17% in the icosapent ethyl group versus 22% in the placebo group (hazard ratio—HR, 0.75; P < .001); the corresponding rates of the key secondary end point (composite of CV mortality, nonfatal stroke or MI) were 11.2% and 14.8% (HR, 0.74; P < .001). The rates of further ischemic end-points, as evaluated per a prespecified hierarchical protocol, were considerably reduced in the icosapent ethyl subset than in the placebo subset, including CV mortality (4.3% vs 5.2%; HR, 0.80; P = .03). More patients in the icosapent ethyl subset than in the placebo subset were hospitalized for atrial fibrillation or flutter (3.1% vs 2.1%, P = .004). Serious hemorrhagic episodes were noted in 2.7% of the patients in the icosapent ethyl subset and in 2.1% in the placebo subset (P = .06). Further analysis of this trial indicated that among statin-receiving patients with high triglycerides and CVD or DM, icosapent ethyl considerably decreases the load of first, subsequent, and total ischemic episodes.¹²⁸

Besides the REDUCE-IT trial and several subanalyses of this trial (in US patients, patients with a history of coronary artery bypass grafting, patients with CKD) where a consistent CV benefit was shown with use of icosapent ethyl,¹²⁵ additional trials have advocated the efficacy of icosapent ethyl in hypertriglyceridemia and CV risk lowering in patients receiving optimal hypolipidemic therapy with use of a statin and/or ezetimibe.¹²⁹

The position of the National Lipid Association (NLA) is that for patients 45 years of age or older with clinical atherosclerotic CVD, or 50 years or older with DM needing medical treatment plus ⩾ 1 extra risk factor, with fasting triglycerides 135 to 499 mg/dL on high-intensity or maximally tolerated statin treatment (±ezetimibe), addition of icosapent ethyl is advised for lowering the atherosclerotic CVD risk (evidence rating: class I; evidence level: B-R).¹³⁰

Finally, over a decade ago, an Expert Panel group put forth recommendations regarding triglycerides indicating that high non-fasting triglycerides is a risk factor for CVD; hence, they should be managed by aggressive lifestyle changes and/or triglyceride lowering agents, like statins, and fibrates.¹³¹ Importantly, as mentioned, ezetimibe enhances statin triglyceride-lowering and anti-inflammatory actions.⁵⁷

There are some limitations to this study. Women are under-represented in CV outcome trials and particularly in trials using ezetimibe.¹³² Importantly, women, older persons, and patients with noncardiac atherosclerotic CVD are specifically undertreated.¹³³ Available data are limited regarding the effect of ezetimibe on inflammatory markers. Cost efficacy data are limited to certain countries. High- and very high-risk patients are not achieving LDL-cholesterol level goal at high percentages despite use of high-intensity statin therapy for various reasons, 1 of which may be related to underuse of ezetimibe.¹¹¹ Studies of lipid management in the real-world setting indicate that LDL-cholesterol levels remains suboptimal, as currently available therapies are underutilized in high/very-high risk patients leading to suboptimal management of CV risk.¹³⁴ There are also ethnic group discrepancies that need to be addressed.¹³⁵ Importantly, prescription of the 1-pill combination of statin-ezetimibe exhibits better patient adherence.¹¹⁸

According with the National Health and Nutrition Examination Survey data from 2017 to 2020, eligibility and usage of statins, ezetimibe, PCSK9i, and icosapent ethyl among US adults were assessed per the American College of Cardiology/American Heart Association guidelines.¹³⁶ In this nationally representative US study, <50% fewer persons who had guideline-directed indications for lipid lowering with use of statins were actually receiving these drugs, with particular underuse among Black adults and younger adults 40 to 64 years of age. In addition, a considerable proportion of persons who appear to be candidates for PCSK9i and icosapent ethyl are on suboptimal treatment with statins and/or ezetimibe, and if optimally treated with these agents, significantly fewer persons would merit consideration for more expensive and injection-based hypolipidemic therapies. Fear of side-effects and cost of treatment seem to be a major barrier to optimal use of hypolipidemic therapies explaining such a degree of undertreatment with such therapies. Nevertheless, with maximal escalation of statins and even when ezetimibe has been added, 4.1% of adults or 6.1 million would still derive a gain from PCSK9i and 6.8% or 10.2 million from icosapent ethyl.¹³⁶

Statins remain the cornerstone of hypolipidemic therapy. Unfortunately, these agents have several side-effects, which have partly hindered their more widespread use. Ezetimibe is commonly the first added treatment to attain LDL-C targets. It reduces LDL-C by approximately an extra 20% and has an excellent safety and tolerability profile. When a statin is combined with ezetimibe, the dose of statin could be lower, thus averting or limiting the occurrence of adverse effects. Of course, such a combination does enhance the hypolipidemic effect. Ezetimibe could also serve as an alternative mode of treatment in certain cases of statin intolerance. Importantly, besides statins, among the lipid-lowering therapies, ezetimibe has also been proven by prospective studies and RCTs to further reduce CVD risk. Regarding possible pleiotropic effects which are inherent in statin therapies, there is a report of an anti-inflammatory effect of ezetimibe as well, which has been noted to occur on top of statin treatment. The percentage of patients with target level LDL-C (<70 mg/dL) can be much higher in a combined treatment group versus a high-intensity statin monotherapy group. This holds true also in patients with recent ischemic CVA, where moderate-intensity statin plus ezetimibe was shown to be superior to high-intensity statin alone for intensive LDL-C lowering. Also, withdrawal of lipid-lowering agents occurs less often in the combined therapy group. Importantly, in the pursuit of an escalation of hypolipidemic therapies, the use of non-statin therapies alone or in combination with statins, therapies that could also be affordable for the general public, the wider use of ezetimibe might help attain these goals.¹³⁷ In keeping with this view, a recent RCT comprising 150 patients with acute ischemic cerebrovascular disease randomly allocated to moderate-intensity statin with ezetimibe or high-intensity statin for 3 months indicated that the latter regimen further improved the attainment rate of LDL-C in these patients, with a higher reduction magnitude in LDL-C without compromising safety.¹³⁸ Finally, in a holistic lipid approach and strategy, adding icosapent ethyl might also decrease CV morbidity in patients who have reached LDL-C targets but have persistently high triglyceride concentrations considered an additional factor often contributing to residual CV risk in patients who are already at high risk. Indeed, most recent data from an RCT comprising 840 patients with a recent ACS (<1 year) indicated that this agent dramatically reduced the risk of ischemic events in high-risk statin-treated patients with no excess bleeding, suggesting the need for prompt use of this agent after ACS.¹³⁹

None