High low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk of cardiovascular (CV) events. The cornerstone of secondary prevention is treatment with LDL lowering agents.1

LDL-C targets

To lower the risk of CV events in very high-risk patients, the ESC/European Atherosclerosis Society (EAS) dyslipidaemia guideline sets lower and more challenging LDL-C goals:2

  • In primary prevention for individuals at very-high risk but without familial hypocholesteraemia (FH), an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.4mmol/L
  • In primary prevention for individuals with FH at very-high risk, an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.4mmol/L
  • For patients with atherosclerotic CVD (ASCVD) who experience a second vascular event within two years (not necessarily of the same type as the first event) while taking maximally tolerated statin-based therapy, an LDL-C goal of <1mmol/L may be considered.

Guidelines recommend a sequential management approach

The latest international guidelines recommend a sequential management approach.2,3,4

The ESC/EAS guideline recommends:2

  • A high-intensity statin up to the highest tolerated dose to reach the goals set for the specific level of risk
  • If the goals are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended
  • For primary prevention patients at very high risk, but without FH, if the LDL-C goal is not achieved on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor may be considered
  • For secondary prevention, patients at very high risk of not achieving their goal on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended
  • For very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goal on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended
  • If a statin-based regimen is not tolerated at any dosage (even after re-challenge), ezetimibe should be considered
  • If a statin-based regimen is not tolerated at any dosage (even after re-challenge), a PCSK9 inhibitor added to ezetimibe may also be considered
  • If the goal is not achieved, statin combination with a bile acid sequestrant may be considered.

Why do guidelines recommend a sequential approach?

The recently published Da Vinci study showed that among patients receiving high-intensity statins as monotherapy, LDL-C goals were achieved in 22% of very high-risk patients and 45% in patients with established ASCVD.5

So why then do guidelines recommend a sequential approach and not early initiation of combination therapy? According to Prof Liberopoulos, all the evidence that supports a sequential approach comes from statin trials. The majority of these trials compared CVD risk reduction with high- or moderate-intensity statin therapy versus placebo. These trials all show the superiority of statin therapy versus placebo.1

A second reason may be because of the variability in LDL-C lowering with a statin. For example, a 2015 Cochrane Review showed that atorvastatin consistently lowered LDL-C over the dose range of 2.5mg/d to 80mg/d. The effect was greater with higher doses than with lower doses. For example, doses of 10mg/d to 80 mg/day resulted in 36% to 53% decreases in risk reduction.7

The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin, showed that the agent (20mg) was associated with a 50% reduction in CV events.8

However, stressed Prof Liberopoulos, these findings do not take into consideration that some patients may be hyper-responders and achieve 70%-80% reductions in LDL-C, which influence mean reported reduction rates.1

The greater the LDL-C reduction, the lower the incidence of CV events during follow up, he added. Therefore, it made sense that guidelines support the use of a high-intensity statin and a wait and see approach to how it affects LDL-C lowering, he added.1

Furthermore, studies showed that not all patients need the addition of a second agent, he said. For example, Sachdeva et al analysed admission lipid levels in 136 905 patients hospitalised with coronary artery disease between 2000 and 2006. About 50% had admission LDL levels <2.5mmol/L and high-density lipoprotein (HDL) levels <1.03mmol/L, while <10% had HDL ≥1.5mmol/L. Before admission, only 21.1% of patients were receiving lipid-lowering medications.9

The remaining patients were started on statin therapy and half achieved a 50% LDL-C reduction, and therefore did not need a second agent, said Prof Liberopoulos.1

How effective is sequential treatment in clinical practice?

The efficacy of statins to lower LDL-C is not questioned. However, in clinical practice, following the sequential approach has not been that successful, because the majority of very-high risk patients do not reach recommended LDL-C targets (<1.4mmol/L) despite guideline-recommended treatment as shown in the Da Vinci study.1,5

In addition, the sequential approach does not address therapeutic inertia. Many primary care physicians will not intensify (or even de-intensify) treatment at follow-up, noted Prof Liberopoulos.1

The approach is also not in line with the current concept of the lower the better, the earlier the better and the longer the better for LDL-C lowering.1

Guidelines for hypertension recommend monotherapy for patients at low risk of CVD and combination therapy in a single pill for high-risk patients. Triple combination therapy is recommended for those patients who do not reach blood pressure targets and the addition of spironolactone or other agents inpatient with treatment-resistant hypertension. The time has come for a paradigm shift in the approach to dyslipidaemia management in patients at very high risk of CVD, said Prof Liberopoulous.1

This approach incorporates:

Step 1: Dual combination therapy ideally in a single pill of a high-intensity statin and ezetimibe

Step 2: Triple combination ideally with a single pill high-intensity statin and ezetimibe and the addition of a PCSK9i

Step 3: Triple combination with a single pill high-intensity statin and ezetimibe and the addition of a PCSK9i and bebedoic acid or other agents.