New Guidelines Supported by Lipid-Lowering Therapy Studies, Indicating Benefit of PCSK9 Inhibitors

New European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines were presented over the weekend in Paris, France, that highlighted an increased focus on low-density lipoprotein (LDL) cholesterol level reduction through statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The updated guidelines were simultaneously published in the European Heart Journal.¹

Retention of LDL cholesterol has been linked with atherosclerotic cardiovascular disease (ASCVD), with evidence confirming its significance in atherogenesis, the accumulation of fatty plaques in the arteries. Colin Baigent, chairperson of the guidelines task force and director of the Medical Research Council population health research unit at the University of Oxford, emphasized the importance of lowering LDL cholesterol amid correlating risk. “There is now overwhelming evidence from experimental, epidemiological, genetic studies, and randomized clinical trials, that higher LDL cholesterol is a potent cause of heart attack and stroke,” said Baigent.

The guidelines aim to ensure that available drugs like PCSK9 inhibitors evolocumab, sold by Amgen as Repatha, and alirocumab, sold by Sanofi-Regeneron as Praluent, are used as effectively as possible to lower elevated LDL cholesterol levels in high-risk patients. The new version of the ESC/EAS guidelines reflects research published since they were last updated in 2016. Additional studies on the effectiveness of these PCSK9 inhibitors for lipid control were presented at the 2019 ESC Congress in Paris, France, this past weekend.

Key changes included in the 2019 guidelines include:

• ApoB is now the recommended lipid analysis for cardiovascular disease risk assessment as opposed to an available alternative, especially for people with high triglycerides, diabetes, obesity/metabolic syndrome, or very low LDL cholesterol
• For treatment of dyslipidemias, type 2 diabetes (T2D) patients at very high risk are recommended to have an LDL cholesterol reduction of ≥ 50% from baseline and an LDL cholesterol goal of <1.4 mmol/L (55mg/dL), T2D patients at high risk recommended to have an LDL cholesterol reduction of ≥ 50% from baseline and an LDL cholesterol goal of <1.8 mmol/L (70mg/dL), and type 1 diabetes patients at very high risk or high risk are recommended to receive statins
• For treatment of dyslipidemias in older patients ≤ 75, statins are recommended for primary prevention according to the level or risk, in which statin initiation in this group may be considered if at high risk or above
• For treatment of dyslipidemias in premenopausal women, statin therapy is not recommended for those with diabetes, who are considering pregnancy or not using contraception

Achieving Targets Across Racial Groups

During the Congress, Amgen presented data on evolocumab’s effectiveness toward different races/ethnicities through an analysis of global phase 2 and 3 double-blind and open-label extension studies.² As cardiovascular risk factors and clinical outcomes of ASCVD vary amongst each race and ethnic group, researchers sought to examine the drug’s efficacy on LDL cholesterol levels of each population.

Target goals of LDL cholesterol <1.8 mmol/L (<70 mg/dL), and a 50% reduction of LDL cholesterol were prioritized in the studies; the new ESC/EAS guidelines recommend the 50% reduction goal for high-risk patients with T2D and say it should be considered for those with familial hypercholesterolemia Trial parameters included:

• 4375 patients with at least 12 weeks of treatment Patient results were analyzed by elements such as self-identified race (white, black/African American, and Asian) and self-identified ethnicity (Hispanic/Latino)
• Elements such as stain intolerance, T2D, heterozygous familial hypercholesterolaemia (HeFH), and hypercholesterolemia/mixed dyslipidemia were analyzed as well

Effectiveness of evolocumab was found significantly in white and non-white race groups as the mean percent change in LDL cholesterol from baseline ranged from -52% to -59% for white patients and -49% to -67% for non-white patients, which was relative to the target goal of a 50% reduction. Also, 63% to 78% of white patients and 58% to 86% of non-white patients achieved at least the 50% reduction goal. The other target goal of achieving an LDL cholesterol level less than 1.8 mmol/L was achieved in 43% to 84% of white patients and 62% to 94% of non-white patients receiving evolocumab.

Patients with T2D were the only group to differ by race/ethnicity for evolocumab efficacy as Asians achieved a more significant reduction in LDL cholesterol, which the authors attributed to the reduced number of Asian patients in the study. Including evolocumab in treatment practices showed a definite reduction in LDL cholesterol levels, which supports ESC/EAS guidelines.

Use of a PCSK9 in Patients With ACS

The use of these lipid-lowering therapies, however, should not be perceived as singular in its application. When paired with high intensity statin therapy, evolocumab showcased a substantial reduction in LDL cholesterol levels for patients in the early phase of acute coronary syndrome (ACS).

In a study published by the Journal of the American College of Cardiology, called EVOPACS (EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes), researchers assessed evolocumab efficacy in lowering LDL cholesterol during the in-hospital phase of ACS.³ Prior guidelines recommended the use of high-intensity statin therapy for initial treatment in patients with ACS, but often when patients use high-intensity statin therapy, they do not achieve LDL cholesterol target levels below 1.8 mmol/L.

Researchers studied 308 patients hospitalized for ACS with heightened levels of LDL cholesterol (≥ 1.8 mmol/L on high-intensity statin for at least 4 weeks; ≥ 2.3 mmol/L on low or moderate intensity statin; or ≥ 3.2 mmol/L on no stable dose of statin):

• Patients randomly assigned at 1 to 1 to receive treatment in-hospital of 420mg of evolocumab or placebo
• After 4 weeks, assigned treatment was provided in addition to 40 mg of atorvastatin
• Percentage change in LDL cholesterol calculated from baseline to 8 weeks

Results of the study revealed that 78.2% of patients had not been on previous statin treatment. A significant decrease in mean LDL cholesterol levels through evolocumab was shown at week 8 as compared to placebo (3.61 mmol/L to 0.79 mmol/L vs 3.42 mmol/L to 2.06 mmol/L) with an additional definite difference in mean percentage change from baseline of -40.7% (95% CI, -45.2 to -36.2; P < .001). Target levels of less than 1.8 mmol/L were achieved at week 8 by 95.7% of evolocumab recipients as opposed to 37.6% of placebo recipients.

The study signifies the PCSK9 inhibitor’s efficacy in substantially lowering LDL cholesterol in high-risk patients when added to high-intensity statin therapy.

The considerable evidence correlating PCSK9 inhibitors to LDL cholesterol reduction warrants the new guidelines’ focus on these treatments. As cardiovascular disease is responsible for more than 4 million deaths in Europe alone each year, the use of PCSK9 inhibitors are vital for reduced risk.

“Lowering LDL cholesterol reduces risk irrespective of the baseline concentration. It means that in people at very high risk of heart attack or stroke, reducing LDL cholesterol is effective even if they have below average starting levels,” said Baigent.

References

1. Mach F, Baigent C ,Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) [published online August 31, 2019]. Eur Heart J. doi/10.1093/eurheartj/ehz455/5556353.

2. Rodriguez CJ, Daviglus ML, Lopez JAG, et al. Effects of evolocumab on LDL-C by race and ethnicity: an analysis of double-blind and open-label extension studies.

3. Koskinas KC, Windecker S, Pedrazzini G, et al. Evolocumab for early reduction of LDL-cholesterol levels in patients with acute coronary syndromes (EVOPACS). [published online August 31, 2019]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2019.08.010.