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Lipidology update: targets and timing of well-established therapies

05 Mar 2024
Guasti

Assoc. Prof Luigina Guasti , FESC

Lupi

Dr. Alessandro Lupi

Summary

Low-density lipoprotein cholesterol (LDL-C) is the primary target in lipid-lowering strategies.  The goal of treatment depends on the level of individual risk in each patient, the goal of which is going to be lower in higher risk patients. The latest European Society of Cardiology (ESC) Guidelines and other recent literature underline that the maximum achievable reduction of LDL-C leads to the maximum attainable reduction in vascular events. This leads towards intensification of LDL-C-lowering therapy, particularly in the higher risk categories of patients, with the challenging targets of <55 mg/dl and <40 mg/dl in selected patients in the very high-risk population. As a combination therapy, a healthy lifestyle is essential, and statins are the initial drug therapy for all patients including the elderly. The addition of ezetimibe and of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) help reach target levels according to severity or risk. New evidence demonstrates that pursuing target levels in patients with acute vascular events should begin as early as possible.

Lipids

Take-home messages

  1. Lowering LDL-C is a primary target in the whole population.
  2. There are no known adverse events linked to very low LDL-C levels; patients with high very/high risk have lower LDL-C goals.
  3. Statins are the first-line recommended drug treatment to reduce cardiovascular risk reducing Apo-B-containing lipoprotein and true statin intolerance, though documented, is rare.

 

Impact on practice statement

  • Since true statin intolerance is rare, it is worth to consider maintaining this drug treatment in patients who report statin-associated muscle symptoms as adverse effect.
  • Since no known adverse events have been linked to very low LDL-C levels, we have to avoid the fear of overtreatment and treat according to target levels.
  • Older adults with atherosclerotic vascular disease should be treated as younger patients.
  • Initiating lipid-lowering therapies using high-dose statins, or high-dose statins plus ezetimibe and/or PCSK9i in acute vascular events appears to be beneficial.

 

(For “New drugs treatments”: see the article of Dr Dimitri Richter in this series.)

Lipidology update: targets and timing of well-established therapies 

The latest guidelines on dyslipidaemias and cardiovascular disease prevention, such as the 2018 American Heart Association/American College of Cardiology (AHA/ACC)/Multisociety Guideline on the Management of Blood Cholesterol, the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines for the management of dyslipidaemias, the 2021 ESC Guidelines on cardiovascular disease prevention in clinical and the 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia, underline the causal role of low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B-containing lipoproteins in determining atherosclerotic cardiovascular disease (ASCVD) [1-4].

All the current guidelines emphasise the need for a lifelong healthy lifestyle and focus on individual cardiovascular (CV) risk in order to set specific recommendations including drug treatment initiation and LDL-C targets to be obtained. They also identify risk-modifying and risk-enhancing factors to be considered in decision-making about therapy. LDL-C goals in the European guidelines are more stringent, particularly for patients at high risk or above compared to other guidelines [1-5].

The lipid goals are the same in the 2019 ESC/EAS Guidelines for the management of dyslipidaemias 2019 ESC/EAS dyslipidaemia Guidelines and in the 2021 ESC Prevention of CV Disease Guidelines, though the latter suggests a stepwise approach to treatment goals except for very high-risk patients. The ESC guidelines reinforce the idea that the absolute benefit from LDL-C reduction depends on both the absolute risk of ASCVD and the absolute reduction in LDL-C especially since there is no known adverse events have been linked to very low LDL-C levels.

Risk categories

Table 1 shows the definitions of patient risk, according to the the 2019 ESC/EAS Guidelines for the management of dyslipidaemias [2]. An individual’s global risk can be reclassified by the presence of certain risk modifying factors such as social deprivation, immune/inflammatory diseases, atrial fibrillation, or a family history of premature cardiovascular disease. A computed tomography (CT) calcium score may be useful in treatment strategies when the LCL-C goal cannot be achieved by lifestyle intervention. It is particularly relevant to consider risk modifier factors in subjects at low/moderate risk to avoid underestimating the actual risk.

A lipoprotein(a) [Lp(a)] measurement – one of the so-called “risk-modifying and enhancing factors”- should be considered at least once in the life of every adult to identify those with very high inherited Lp(a) levels (>180 mg/dL). In select patients at moderate risk with high Lp(a) values, this measurement may be used to reclassify their risk level to a higher level.

 

Table 1. Risk categories and LDL-C targets. 

Risk categories

Clinical data

LDL-C Target

Very high-risk

ASCVD, either clinical or unequivocal on imaging (CT scan included in these guidelines)

Diabetes mellitus with target organ damage, long standing duration (>20 years), or associated with other risk factors

eGFR <30 mL/min/1.73 m2

Familial hypercholesterolemia (FH) with ASCVD or with another major risk factor

SCORE >10%

<55 mg/dL both in primary and secondary prevention

<40 mg/dL in selected patients with recurrent ASCVD

High-risk

Markedly elevated single risk factors, including total cholesterol >310 mg/dL, LDL-C >190 mg/dL or blood pressure >180/110 mmHg

FH without other risk factors

Diabetes with a duration >10 years or with another risk factor

eGFR 30-59 mL/min/1.73 m2

Calculated SCORE >5% and <10%		 <70 mg/dL
Moderate-risk  

Younger patients (Type 1 diabetes mellitus <35 years; Type 2 diabetes mellitus <50 years) with diabetes mellitus duration <10 years, without other risk factors

Calculated SCORE >1 % and <5%;

<100 mg/dL should be considered
Low-risk Low-risk calculated SCORE <1% fatal cardiovascular disease <116 mg/dL may be considered

(Summary reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology from reference [2] Mach F, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455. https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Dyslipidaemias-Management-of

ASCVD: atherosclerotic cardiovascular disease; CT: computed tomography; eGFR: estimated glomerular filtration rate; FH: familial hypercholesterolaemia; LDL-C: low-density lipoprotein cholesterol

 

Targets

The goal of treatment is to obtain the lowest possible LDL-C level by intensifying treatment appropriately, remembering the precept that there is no “too low threshold” for lowering LDL-C levels) while, at the same time, taking into consideration risk categories, especially in patients at high or very high CV risk (Table 1).

Reaching you goals using well proven drug therapies

The well proven therapies recommended to reach the target level goals in the different risk categories of patients (Central Figure) are 1) the maximum tolerated dose of statins, and, if the targets are not achieved, 2) the addition of ezetimibe and then 3) proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i).

According to the concept that demonstrates ApoB-containing lipoproteins have a causal role in ASCVD, statins are the first choice for reducing triglycerides (TG) in patients at high risk with hypertriglyceridaemia >200mg/dL;  n-3 PUFAs and fibrates other potential pharmacological interventions can also be considered. For very high TG levels (associated with genetic causes and carrying an risk of acute pancreatitis), caloric and fat restriction, alcohol abstinence, and initiation of fibrate therapy, possibly in association with n-3 fatty acids, should be put in place.

 

Central Figure. The basics in the management of dyslipidaemia and the different parameters affecting the decision.

337_Guasti_FINAL FOR PUBLICATION_Central illustration.jpg 

Statin intolerance

Statin intolerance is a public health challenge, leading to statin discontinuation, underdosing and subsequent increases in CV events [6,7]. Statin-associated muscle symptoms are by far the most frequently reported adverse effects, with other possible statin-related adverse effects including hepatotoxicity, renal toxicity, potential impact on neurocognitive aspects, and haemorrhagic stroke [6-9]. A recent meta-analysis analysing more than 4 million patients confirms that the overall prevalence of statin intolerance is relatively low [6] with the prevalence being 9.1%, irrespective of the definition applied. However, when diagnosis was based on the approved definitions, the prevalence was less than 7% and less than 5% in randomised clinical trials (RCTs) [6].

Advanced age, hepatic or renal impairment, previous muscular, hepatic or other side effects, or a potential for interaction with concomitant therapies may be risk factors for statin intolerance.

Because of the catastrophic effects of statin withdrawal or suboptimal lipid-lowering therapy, meticulous evaluation of patients with so-called “statin intolerance,” mainly related to statin-induced muscle symptoms, and encouragement of adherence to statin therapy is necessary in order to reduce the risk of unnecessary discontinuation of these drugs.

Special populations: the elderly

Lipid-lowering therapies should be used in older patients with ASCVD as in younger people. This is a strong recommendation from the ESC guidelines. The 2019 ESC Guidelines on dyslipidaemias recommend treating older patients with ASCVD to target levels similar to those for younger patients. This is further supported by a systematic review and meta-analysis showing that lipid-lowering was as effective in patients >75 years old in reducing CV events as it was in patients <75 years [10]. These data were obtained in 21,492 (8.8% of the total population of 244,090 patients from 29 trials) aged at least 75 years, 11,750 (54·7%) of whom were from statin trials, 6,209 (28.9%) from ezetimibe trials, and 3,533 (16.4%) from PCSK9i trials [10].

Moreover, lipid-lowering treatment had a relative clinical benefit in the primary prevention of major vascular events in individuals aged ≥70 years, similarly as in individuals aged <70 years [11] as well as in reducing overall mortality [12].

Although frailty is considered as a potential cause of statin intolerance and is a potential challenge in initiating lipid-lowering treatments, new statin use in the elderly was associated with a lower risk of mortality and major adverse CV events, independent of frailty in a large population of 710,313 veterans (mean age [±standard deviation] 75.3 [±6.5], 98% male, 89% white) of whom, 86,327 (12.1%) were frail [13].

According to ESC guidelines, in primary prevention, people ≤75 years old should be treated according to their level of risk whereas older subjects may be considered for initiation of statin treatment if at high or very high risk. The recommendation is to start with lower doses based on comorbidities - in particular renal impairment - altering pharmacokinetics, with potential accumulation and drug-drug interactions, and then titrate to target levels with caution [2].

Special populations: early lipid-lowering treatment in acute coronary syndrome

The benefits of statins in secondary prevention are well established [14], and numerous RCTs have shown the benefits granted by early and intensive statin therapy in patients with acute coronary syndromes (ACS) [15,16]. RCTs have consistently demonstrated that lower LDL-C levels after ACS are unequivocally associated with lower CV event rates [17]. A meta-analysis of trials comparing more intensive vs less intensive LDL-C lowering with statins indicated that more intensive statin therapy was associated with more significant CV risk reduction [18]. For every 1.0 mmol/L reduction in LDL-C, further reduction in risk was similar to the proportional reductions in the trials of statins vs control. Consequently, statins are recommended in all patients with ACS, irrespective of LDL-C concentration at hospitalisation.

ACS present a “time-dependent” pattern of complication rates, with the highest risk for thrombotic complications and cardiac death in the first weeks/months following hospital admission [19-23]. Thus lipid-lowering treatment should be started as early as possible, to tackle LDL-C in the moment of maximum risk [19-21,23] and to enhance patient adherence after discharge. Moreover, lipid-lowering treatment should be given as high-intensity treatment, as this is associated with early and sustained clinical benefits [24]. Thus, it is recommended that a high-intensity statin (e.g. atorvastatin or rosuvastatin) is initiated as early as possible after hospital admission, preferably before planned percutaneous coronary intervention, and prescribed up to the highest tolerated dose in order to reach the LDL-C goals [2,23,25].

The intensity of statin therapy should be higher in those receiving a low- or moderate-intensity statin treatment at presentation unless they have a history of intolerance to high-intensity statin therapy or other characteristics that may influence safety [18,26,27]. The current treatment goal for secondary prevention is to lower LDL-C to <55 mg/dL and to achieve a ≥50% LDL-C reduction from baseline. For patients who experience a second adverse CV event (not necessarily of the same type) within two years, an LDL-C goal of <40 mg/dL appears to confer additional benefit [2,28-30]. Lower-intensity statin therapy might be appropriate in patients with risk factors for statin intolerance [2].

Following ACS and especially within the first 24 hours after myocardial infarction with ST elevation (STEMI), the lipid profile exhibits phasic changes characterised by small reductions in total cholesterol, LDL-C, and high-density lipoprotein cholesterol (HDL-C), and increases in TG [31,32]. Thus, a lipid profile should be obtained as early as possible after admission for STEMI (even non-fasting) to represent the baseline patient lipidic metabolism realistically, as total cholesterol and HDL-C show slight diurnal variation and LDL-C’s variation is within 10% [33]. Blood lipids and creatine-kinase levels should be reassessed 4–6 weeks after the ACS to determine whether the recommended LDL target levels have been reached and to exclude safety issues. The lipid-lowering therapy can then be titrated accordingly, and, if the LDL-C goal is not achieved despite the maximum tolerated dose of a statin used, adding ezetimibe is recommended [2,34]. Initiation of PCSK9i treatment is recommended in patients failing to reach their LDL-C goal despite maximum tolerated statin and ezetimibe therapy [2, 23, 28, 29]. Finally, icosapentethyl, at a dose of 2g b.i.d., might be added to statins in patients with TG levels of 1.5–5.6 mmol/L (135–499 mg/dL) despite statin treatment [2,23,35].

 

Trial results with high doses of atorvastatin and simvastatin [18,36,37] favour a high-intensity statin treatment for ACS patients. In statin intolerants, treatment with ezetimibe should be considered. Ezetimibe could also be used in combination with statins as an initial therapeutic strategy, based upon the results of the “Improved Reduction of Outcomes: Vytorin Efficacy International Trial” (IMPROVE-IT) [34]. In this study, 18,144 patients with a recent ACS (29% with STEMI) were randomised to either ezetimibe 10 mg/simvastatin 40mg or simvastatin 40mg alone. Over a 7-year follow up, the combined treatment arm compared with the statin-only arm showed significantly lower rates of the composite primary endpoint of cardiovascular death, myocardial infarction, hospital readmission for unstable angina, coronary revascularisation, or stroke (32.7% vs 34.7%, hazard ratio [HR] 0.94, 95% confidence interval [CI]: 0.89–0.99). Adding ezetimibe to statins was safe and provided long-term benefits for CV outcomes.

Thus, if ACS patients have baseline LDL-C levels which indicate that it is unlikely that target levels will be reached with statin therapy alone, initiating ezetimibe in addition to a statin (or a statin-plus-ezetimibe combination treatment) should be considered during the ACS hospitalisation [2,23,34].

Recent data from PCSK9i phase 1-3 trials demonstrated that PCSK9i decrease LDL-C up to 60%, either as monotherapy or in addition to a statin dose, with additional beneficial effects over TG and HDL-C levels [38-41]. Meta-analyses of trials enrolling more than 10,000 patients indicated a significant mortality benefit (HR 0.45, 95% CI: 0.23–0.86) but focused upon relatively few endpoints [39,42].

In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial consisting of more than 27,000 patients with ASCVD, additional risk factors, and LDL 70 mg/dL, who were already receiving moderate or high-intensity statin therapy as compared to placebo, evolocumab reduced the primary composite endpoint of CV death, myocardial infarction, stroke, hospitalisation for unstable angina, or coronary revascularisation by 15% at the relative rate and by 1.5% at the absolute rate. There were no differences in all-cause or CV mortality or significant differences in adverse events [28]. Based on this relatively limited body of evidence, clinicians should consider adding a non-statin pharmacological treatment to high-risk patients failing to reach LDL-C targets after ACS despite the maximum tolerated dose of statin.

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Notes to editor


Authors:

Luigina Guasti 1, MD, PhD, FAHA, FESC; Alessandro Lupi 2, MD

1. Department of Medicine and Surgery, University of Insubria, Varese, Italy;  

2. Cardiology Department, Hospital San Biagio (Ospedale San Biagio), Domodossola VB, Italy

 

Address for correspondence:

Assoc. Prof Guasti, Via Guicciardini 5 Varese, Italy

E-mail: luigina.guasti@uninsubria.it

 

Author disclosures:

The authors have no conflicts of interest to declare in relation to this article.

 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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