Strategies to achieve low-density lipoprotein cholesterol targets in high-risk patients

Abstract

Several options exist in very-high risk patients who do not achieve low-density lipoprotein cholesterol (LDL-C) targets despite treatment with atorvastatin 80 mg, including switching to rosuvastatin 40 mg, adding ezetimibe or adding a proprotein convertase subtilisin/kexin type 9 inhibitor. Taking into account the safety, LDL-C lowering capacity, effect on cardiovascular events and cost of these available options, switching to rosuvastatin 40 mg appears to represent the most attractive strategy. Nevertheless, more studies are needed to confirm the effects of this strategy on LDL-C levels given the limited available data.

Keywords:

• Atorvastatin
• rosuvastatin
• ezetimibe
• PCSK9 inhibitors
• low-density lipoprotein cholesterol targets

This article refers to:

LDL cholesterol levels after switch from atorvastatin to rosuvastatin

Elevated low-density lipoprotein cholesterol (LDL-C) levels represent a major modifiable risk factor for cardiovascular disease (CVD)¹, which is the leading cause of death worldwide². Accordingly, current guidelines state that LDL-C is the primary target in the management of dyslipidemias³. However, a considerable proportion of patients do not reach LDL-C targets⁴. In many cases, the use of low-intensity statin treatment is a major contributor to the failure to achieve these targets⁴. Indeed, in the EUROASPIRE-IV survey, more than 90% of patients who were hospitalized for an acute coronary syndrome (ACS) received a statin at discharge but only 37.6% were prescribed a high-intensity statin⁴.

In patients with very high cardiovascular risk (i.e. those with established CVD, type 2 diabetes mellitus (T2DM) with additional cardiovascular risk factors or target-organ damage, stage 4–5 chronic kidney disease (CKD) or Systemic Coronary Risk Evaluation (SCORE) ≥10%), current guidelines recommend a LDL-C goal of <70 mg/dl or a reduction of at least 50% if the baseline LDL-C is between 70 and 135 mg/dl³. In patients with high cardiovascular risk (i.e. those with T2DM without other risk factors or target-organ damage, stage 3 CKD, a markedly elevated single risk factor or SCORE 5–9%), a LDL-C goal of <100 mg/dl or a reduction of at least 50% if the baseline LDL-C is between 100 and 200 mg/dl is recommended³. The only statins that can achieve this reduction in LDL-C levels are atorvastatin 40–80 mg and rosuvastatin 20–40 mg^5,6. However, other strategies may be sufficient in some patients^5,6. Moreover, the response to a given dose of a statin may vary a lot from patient to patient⁷. Atorvastatin has documented benefits in high-risk patients with and without established CVD^8–11 and is the most frequently prescribed statin in these patients¹². However, atorvastatin 80 mg reduces LDL-C levels by up to 49–53% approximately^10,11. Therefore, patients with very high cardiovascular risk and very high baseline LDL-C levels might not be able to reach the LDL-C target (i.e. <70 mg/dl) despite treatment with the maximal recommended dose of atorvastatin. In these patients, several options exist, including switch to rosuvastatin or adding a second lipid-lowering agent.

Previous studies that compared different doses of atorvastatin and rosuvastatin in very-high-risk patients showed that rosuvastatin 40 mg reduces LDL-C levels by 4–7% more than atorvastatin 80 mg and was equally well tolerated^13,14. In contrast, in a retrospective cohort study recently published in Current Medical Research and Opinion by Lewis et al., patients who switched from atorvastatin 80 mg to rosuvastatin 40 mg showed a median 18% reduction in LDL-C levels¹⁵. Moreover, in patients who switched from atorvastatin 40 mg to rosuvastatin 20 or 40 mg, LDL-C levels decreased by a median of 21 and 26%, respectively¹⁵. Notably, it is well established that doubling the dose of any statin reduces LDL-C levels by approximately 6%⁵. Therefore, in patients receiving atorvastatin 40 mg, doubling the dose of atorvastatin appears to be substantially less effective than switching to rosuvastatin 20 or 40 mg.

In patients who do not achieve LDL-C targets despite treatment with atorvastatin 80 mg, another option is to add ezetimibe³. Moreover, a certain number of high-risk patients have resistance or intolerance to statins and therefore require other lipid-lowering treatment¹⁶. Adding ezetimibe to a statin reduces LDL-C levels by approximately 24% and is well tolerated¹⁷. Even though this reduction is marginally higher than the reduction reported in the study by Lewis et al. when switching from atorvastatin 80 mg to rosuvastatin 40 mg (i.e. 18%), it should be noted that there is only one study that compared the effects of statin monotherapy with ezetimibe/statin combination on cardiovascular events and this study was performed in a selected population, i.e. in patients with a recent ACS¹⁸. Accordingly, current guidelines mention that statins should be prescribed up to the highest recommended dose or highest tolerable dose to reach LDL-C goals before adding a second lipid-lowering agent³.

Another option in patients who do not achieve LDL-C targets despite treatment with atorvastatin 80 mg is to add a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor¹⁹. These agents yield considerable reductions in serum LDL-C levels when added to a statin (by up to 60%) and appear to be safe, except for an increased risk for injection-site reactions^20,21. Moreover, the addition of evolocumab to statin treatment reduced cardiovascular events in patients with established CVD and preliminary results suggest that alirocumab might also reduce cardiovascular morbidity^20,21. Nevertheless, these agents are expensive and their cost-effectiveness has been questioned²². Accordingly, they represent a second-line treatment option in patients who do not achieve LDL-C targets despite treatment with the maximal tolerated dose of a potent statin^23,24.

In conclusion, several options exist in very-high-risk patients who do not achieve LDL-C targets despite treatment with atorvastatin 80 mg, including switching to rosuvastatin 40 mg, adding ezetimibe or adding a PCSK9 inhibitor. Taking into account the safety, LDL-C lowering capacity, effect on cardiovascular events and cost of these available options, switching to rosuvastatin 40 mg appears to represent the most attractive strategy. Nevertheless, more studies are needed to confirm the effects of this strategy on LDL-C levels given the limited available data. Indeed, the only study on this topic¹⁵ was not a controlled randomized trial but strictly observational. Moreover, patient compliance with treatment should be evaluated before up-titrating the hypolipidemic therapy.

Transparency

Declaration of funding

The contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication.

Declaration of financial/other relationships

C.M. and K.T. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

None reported.