Rationale for use of non-statins

The response to statins and the achievement of LDL-C goals in primary and secondary prevention patients have been the subject of several recent studies 4,1,2,3,4,5,6,7,8. The TERESA study revealed that only 31.1% of patients achieved the risk-based LDL-C goals, despite being on high-intensity statins, with nearly 70% of very high-risk patients failing to reach the recommended LDL-C goals 8. Statin hyporesponsiveness can be attributed to various factors, including rare genetic variants in lipoprotein-related or drug metabolism genes 9, 10. Before considering primary statin resistance, other potential causes such as analytical issues with LDL-C measurement and the presence of common lipid disorders [FH, elevated lipoprotein (a) (Lp(a)) and secondary dyslipidemias] should be ruled out. 13

Nonetheless, the most common reason for suboptimal response to statin therapy is the lack of compliance due to statin intolerance. The lipid management registry showed that over 50% of former statin users discontinued the medication due to perceived side effects, primarily muscle-related symptoms 11. Similarly, a recent meta-analysis estimated that between 5 and 17% of patients discontinue statins due to medication side effects, which is significantly higher than rates observed in clinical trials. 12

The SANTORINI study assessed lipid management in 9044 patients after the 2019 ESC/EAS guidelines update. It found that 80% of high- and very high-risk patients did not meet LDL-C goals. 27

In the DA VINCI study which involved 5888 patients, 54% of patients achieved the 2016 risk-based goal, while 33% achieved the 2019 goal. High-intensity statin monotherapy was used in 20% of very high-risk primary prevention patients and 38% of secondary prevention patients. Combination therapies, including ezetimibe (9%) or PCSK9-I (1%), were used less frequently. The corresponding 2016 and 2019 goal attainment was 53% and 20% for moderate–high-intensity statin combination with ezetimibe, and 67% and 58% for PCSK9-I combination. 28

Therefore, there are persistent gaps between clinical guidelines and clinical practice for lipid management across the world. To address these gaps, greater utilization of non-statin LLT even with optimized statins, especially for patients at the highest risk, is needed.

In recent years, clinical trials have demonstrated the efficacy of several non-statin agents in lowering LDL-C levels and reducing CV events in specific patient populations 29,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47. Landmark trials have established ezetimibe, PCSK9 monoclonal antibodies and bempedoic acid as non-statin agents that lower LDL-C levels and provide CV benefits. Additionally, a large-scale outcome trial is underway to evaluate the efficacy of inclisiran. 48

There is growing interest in early combination lipid-lowering management approaches 14, as they offer several benefits such as incremental LDL-C lowering, reduced risk for side effects and improved tolerability and adherence 15, 16. Combination therapies, especially including a PCSK9-I, have been shown to achieve the recommended LDL-C goals in a higher percentage of very high-risk patients compared to high-intensity monotherapy or statin/ezetimibe combination. 28

Cardiovascular risk stratification

Total CV risk is defined as the likelihood of a person to develop an atherosclerotic CV event within a given time period. It is determined by adding the risk contribution of various CV risk factors present in an individual. Some risk factors, such as a history of a previous atherosclerotic event, represent a very high total CV risk on their own, even in the absence of other risk factors.

There is no universal consensus on the definition of very high-risk patients, but it is recommended to intensify preventive approaches for these patients in all guidelines. The very high-risk patient category definition is different between guidelines. All guidelines base the intensity of their recommendations on the degree of risk. Guidelines differ in their risk calculation systems.

In the American Heart Association (AHA)/American College of Cardiology (ACC)/Multisociety (MS) guidelines, risk scores are calculated with pooled cohort equations (PCEs). PCEs calculate the 10-year risk of developing ASCVD by including non-fatal myocardial infarction (MI) or coronary artery disease (CAD) death and fatal or non-fatal stroke, among people free from ASCVD 1. In the ACC Expert Consensus Decision Pathway published in 2022 on the use of non-statins, patients with ASCVD were categorized into one of two groups: not at very high risk or at very high risk. Very high-risk patients have a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions. Major ASCVD events include ACS within 12 months, history of MI, ischemic stroke or symptomatic peripheral arterial disease (PAD). High-risk conditions include age ≥ 65 years, heterozygous FH (HeFH), history of prior coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) outside of the major ASCVD event(s), diabetes mellitus (DM), hypertension (HTN), chronic kidney disease (CKD) (eGFR 15–59 mL/min/1.73 m2), current smoking, persistently elevated LDL-C ≥ 100 mg/dL despite maximally tolerated statin therapy and ezetimibe or history of congestive heart failure (CHF). 2

The European Society of Cardiology (ESC) guidelines described low-, intermediate-, high- and very high-risk categories of ASCVD risk. People were sorted into one of these categories depending on the presence or absence of major risk factors and, in apparently healthy persons, depending mainly on their 10-year CV risk estimation. 49, 50

The ESC guidelines define patients with ASCVD, DM, CKD and individuals with specific risk factors as high- and very high-risk groups automatically. Individuals who do not have these characteristics are considered as apparently healthy people, and management is determined according to risk estimation by the SCORE2 and the SCORE2-Older Persons (SCORE2-OP) model for adults over the age of 69, which calculate the 10-year risk of total CV events. In diabetic patients, CV risk stratification is based on ASCVD, severe target organ damage (TOD) or SCORE2-Diabetes. Management is determined according to age, risk score and region. 49, 50

Ray et al. defined the extremely high-risk patient category as having one of the following characteristics: post-ACS and a history of other vascular event in the past 2 years, PAD, polyvascular disease, multivessel CAD and/or FH. 14

The American guidelines give recommendations for the possible use of the coronary artery calcium (CAC) score if the decision about statin treatment is uncertain in intermediate- and borderline-risk adults. If the CAC score is above 100, it is reasonable to initiate statin treatment. If the CAC score is 1–99, it is reasonable to use statins in individuals > 55 years. If the CAC score is zero, there is no need to use statins as long as higher-risk conditions are absent, but reassessment is suggested in 5–10 years 29. Similarly, the ESC guideline states that CAC scoring may be considered to improve risk classification around treatment decision thresholds, and they also consider plaque detection by carotid ultrasound an alternative when CAC scoring is unavailable or not feasible. 51

We endorse the CV risk stratification recommended by the latest ESC guidelines 49, 50. However, we recommend distinguishing patients who are at extremely high CV risk from the very high-risk category. We propose defining the extreme-risk patient category by the presence of at least one of the following criteria: (1) multiple major CV events, especially if recurrent within 2 years, (2) one major CV event and multiple high-risk conditions such as current smoking, DM, HTN and CKD, (3) polyvascular disease, (4) multivessel CAD and (5) recent ACS within the past 12 months (Fig. 1).

Fig. 1

Patient risk categories and recommended LDL-C goals

For patients in the low- to moderate- and high-risk conditions, it is advisable to check for risk modifiers. The presence of these risk modifiers upgrades the patient’s risk category and supports the use of LLT. Risk modifiers include family history of premature ASCVD (men aged < 55 years; and women aged < 65 years), familial dyslipidemia, metabolic syndrome, CKD, chronic immune-mediated inflammatory conditions, sex-specific conditions (history of premature menopause before age 40 years, pregnancy-related HTN and erectile dysfunction), psychosocial factors, left ventricular hypertrophy, atrial fibrillation, obstructive sleep apnea syndrome, non-alcoholic fatty liver disease, migraine with aura and if measured, CAC score > 0 Agatston units (AUs), elevated high-sensitivity C-reactive protein (> 2.0 mg/L), high Lp (a) > 50 mg/dL and ankle brachial index (ABI) < 0.9.

Lipid-lowering strategies

Statins, or hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are widely prescribed and effective in lowering cholesterol levels by inhibiting the enzyme responsible for cholesterol production. However, some patients experience side effects, such as muscle pain or liver abnormalities, leading to discontinuation or reduced adherence. 52

Non-statin options (Fig. 2)Fig. 2

Efficacy of different lipid-lowering medications as monotherapy or in combination

1.

Ezetimibe

Ezetimibe inhibits cholesterol absorption at the brush border of the small intestine by binding to the sterol transporter Niemann–Pick C1-Like-1 (NPC1L1). The reduction in cholesterol absorption, when combined with statins, offers a synergistic effect on LDL-C levels lowering. 53

Ezetimibe, given as a monotherapy in a single daily oral dose of 10 mg, reduces LDL-C levels by 15–22% compared to placebo. Adding ezetimibe to statin therapy reduces LDL-C by an additional 21–27%. Ezetimibe decreased triglyceride (TG) by about 8% and increased high-density lipoprotein cholesterol (HDL-C) by about 5%. 53

The IMPROVE-IT trial evaluated the effect of ezetimibe and simvastatin compared with simvastatin alone in patients with ACS. This study which included over 18,000 patients with ACS found that adding ezetimibe to statin therapy lowered LDL-C by 24% and the major adverse CV events (MACE) by 2% (absolute risk difference). 54

The US Food and Drug Administration (FDA) gave a category C mark to ezetimibe based on preclinical data from animal studies; however, no enough data is available to support the use of ezetimibe in pregnancy and lactation. The use of ezetimibe in children is not studied. 55

The most frequent side effects of ezetimibe are diarrhea (4%) and headache (2%) while liver injury is extremely rare. Ezetimibe use is contraindicated in moderate and severe liver impairment. There is no need for dose modification in renal impairment or mild hepatic impairment. 54

2.

PCSK9-targeted therapies

PCSK9 is a protease that degrades LDL receptors in the liver. Human monoclonal antibodies, alirocumab and evolocumab, administered through subcutaneous injections bind to PCSK9, preventing it from binding to LDL receptors. Inclisiran is a synthetic small interfering RNA (siRNA) that targets hepatic production of PCSK9. By preventing the destruction of the LDL receptors, these drugs enhance the ability of the liver to clear LDL-C from the bloodstream significantly reducing its level. 56

Multiple trials have demonstrated not only the potency of PCSK9-I in significantly lowering LDL-C levels 56, but also their efficacy in improving CV outcomes with reduction in MACE, including heart attacks and strokes.

In 2017, the FOURIER trial demonstrated that inhibition of PCSK9 with evolocumab on a background of statin therapy was efficacious in patients with stable ASCVD and additional high-risk features. The ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial demonstrating the benefits of PCSK9 inhibition with alirocumab on a background of statin therapy in patients with ACS. 31, 57

In a pooled patient-level analysis of 3660 patients in phase 3 trials of inclisiran (ORION-9, ORION-10 and ORION-11), the drug demonstrated a mean placebo-corrected change in LDL-C at day 510 of 50.7% (95% CI 52.9% to 48.4%; P < 0.0001). The corresponding time-adjusted mean change in LDL-C was 50.5% (95% CI 52.1% to 48.9%; P < 0.0001) 58. Inclisiran was FDA approved in December 2021 and is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or ASCVD who require additional lowering of LDL-C 59. The recommended dosage of inclisiran, in combination with maximally tolerated statin therapy, is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months thereafter. The effect of inclisiran on CV morbidity and mortality has not been determined. However, we are waiting the results of two important CV outcomes trials, ORION-4 (A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease) and VICTORION-2P (A Randomized, Double-blind, Placebo-controlled, Multicenter Trial, Assessing the Impact of Inclisiran on Major Adverse Cardiovascular Events in Participants With Established Cardiovascular Disease), which are currently in progress. 59

Generally, PCSK9-I has demonstrated a favorable safety profile. However, like any medication, they