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What's New With the Treatments of High-Risk Dyslipidemia?

Authors: Stephen J. Nicholls, MBBS, PhDFaculty and Disclosures


Posted: 25/3/2017

This educational activity is intended for an international audience of Asia-Pacific healthcare professionals, specifically cardiologists, diabetologists & endocrinologists, and primary-care physicians involved in the management of patients with high-risk dyslipidemia.

Upon completion of this activity, participants will:

Have increased knowledge regarding the:

  • Optimal management of patients with high-risk dyslipidemia
  • Impact of new therapies on the risk of CV events
  • What's New With the Treatments for High-Risk Dyslipidemia?

  • Slide 1.

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  • Risk of MI Associated With ApoB/ApoA1 Ratio[1]

    • Dyslipidemia is an important risk factor of cardiovascular (CV) disease
    • Throughout all the countries of Asia and the world, the apolipoprotein (Apo)B/ApoA1 ratio is an important risk factor for myocardial infarction (MI)

  • Slide 2.

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  • Statins: Approximate LDL-C-Lowering Efficacy[2-5]

    • Multiple trials demonstrated that lipid lowering with statins is associated with a significant reduction of LDL low-density lipoprotein cholesterol (LDL-C)

  • Slide 3.

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  • Effect of Statins vs Placebo on CV Events[6]

    • Multiple trials demonstrated that lipid lowering with statins effectively reduces the risk of MI and stroke

  • Slide 4.

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  • Lipid Goal Attainment in Asian Patients With ACS[7]

    • Many high-risk patients with established acute coronary syndromes (ACS) fail to achieve effective LDL-C lowering
    • According to guidelines, almost 50% of patients with established CV disease may not achieve the ideal treatment targets

  • Slide 5.

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  • PCSK9 Inhibition in Patients With Hypercholesterolemia Receiving Statin Therapy[8-10]

    • PCSK9 is an important factor that regulates the expression of the LDL receptor on the liver surface
    • Genetic studies showed that increased activity of PCSK9 is associated with a decrease of the number of LDL receptors and with high levels of LDL-C
    • Conversely there are polymorphisms associated with less PCSK9 activity, in which patients have acceptably higher levels of LDL receptor expression, lower levels of LDL-C and a much lower risk of CV events on long-term follow-up
    • PCSK9 inhibitors are highly effective in lowering LDL-C when administered as monotherapy, as well as in combination with statins

  • Slide 6.

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  • PCSK9 CV Outcomes Trials[11-14]

    • There are 4 large CV outcome trials that have been evaluating the impact of PCSK9 inhibitors on CV events

  • Slide 7.

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  • FOURIER Trial Design[15]

    • The FOURIER study included more than 27,000 patients with high CV risk
    • Patients had a history of prior MI, stroke, or symptomatic peripheral artery disease (PAD)
    • Patients were required to have either a LDL-C ≥ 1.8 mmol/L (70 mg/dL) or a non-high-density lipoprotein cholesterol (HDL-C) ≥ 2.6 mmol/L (100 mg/dL)
    • Patients were randomly assigned to receive evolocumab or placebo, administered by a subcutaneous (SC) injection, every 2 or 4 weeks

  • Slide 8.

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  • FOURIER Endpoints[15]

    • The primary efficacy endpoint was the combination of CV death, MI, stroke, hospitalization for unstable angina (UA), or coronary revascularization
    • A key important secondary endpoint was the combination of CV death, MI, and stroke
    • The investigators looked carefully at all adverse events (AEs) and serious adverse events (SAEs), including those related to the muscles, new onset diabetes, and neurocognitive events

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  • FOURIER Follow-Up[16,17]

    • Patients were followed for a median of 26 months
    • The great majority of patients completed the follow-up

  • Slide 10.

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  • FOURIER: Baseline Characteristics[16]

    • The mean age of patients was 63 years
    • Of those enrolled, 81% of patients had a history of previous MI, 19% a history of nonhemorrhagic stroke, and 13% a history of symptomatic peripheral artery disease (PAD)
    • For those patients who had a previous MI or stroke, the median time from their recent event was about 3 years
    • There was a high rate of concomitant risk factors for atherosclerotic CV disease
    • These risk factors are very relevant to the patients who are seen in Asia

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  • FOURIER: Lipid-Lowering Therapy and Lipid Levels at Baseline[16]

    • More than two-thirds of patients were treated with high-intensity statin therapy
    • The remaining patients were treated with moderate-intensity statin therapy
    • 5% of patients received ezetimibe
    • The mean baseline LDL-C was 2.4 mmol/L (92 mg/dL)

  • Slide 12.

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  • FOURIER: Effect on LDL-C[16]

    • A significant 59% reduction in LDL-C was observed in the evolocumab group
    • The evolocumab-treated patients had a median LDL-C of 1 mmol/L (39 mg/dL) (on treatment)

  • Slide 13.

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  • FOURIER: Main CV Outcomes[16]

    • There was a highly robust and significant reduction of major CV events
    • The primary endpoint of CV death, MI, stroke, hospitalization for UA, or coronary vascularization was reduced by 15%
    • The main secondary efficacy endpoint of CV death, MI, and stroke was reduced by 20%

  • Slide 14.

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  • FOURIER: Main CV Outcomes (cont)[16]

    • There was a 27% reduction of MI and a 21% reduction of stroke
    • It is very important and relevant for patients in Asia
    • The 22% reduction in coronary revascularization reinforces the findings from prior studies suggesting potential benefits of PCSK9 inhibitors on coronary atherosclerosis
    • No significant effect on death was observed and that is perhaps not that surprising, given the relatively short exposure to treatment in this study

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  • FOURIER: Lower LDL-C Is Better[17]

    • There is a very clear direct relationship between the achieved on-treatment LDL-C and the rate of CV death, MI, and stroke
    • This reinforces the message: The lower the LDL-C, the lower the CV risk
    • At least down to a level of 0.5 mmol/L (20 mg/dL), we observe no flattening of that relationship
    • The lower is the better is very much reaffirmed by this study

  • Slide 16.

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  • FOURIER: Safety[16]

    • It was quite reassuring that evolocumab was very well tolerated with no safety concerns
    • There was no excess of risk in any reported AES
    • There was no excess of risk in terms of either allergic or injection site reactions
    • There was no excess of risk in terms of AEs related to muscle, emergence of cataracts, diagnosis of new onset diabetes or neurocognitive AEs

  • Slide 17.

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  • Summary of FOURIER[16]

    • Evolocumab reduced LDL-C by 59%, with a median achieved LDL-C level of 39 mg/dL, consistent with the duration of the trial
    • This was translated to a profound reduction in CV outcomes in patients who were already treated with a statin
    • We saw a 15% reduction in the broad primary endpoint, as well as a 20% reduction in the important triple ischemic endpoint of CV death, MI, or stroke
    • The treatment was safe and well tolerated with similar rates of AEs, including diabetes, neurocognitive events with evolocumab, and placebo

  • Slide 18.

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  • EBBINGHAUS: Trial Design[18,19]

    • The EBBINGHAUS study is a substudy of FOURIER that enrolled 1974 patients who did not have a history of dementia, cognitive impairment, or other symptoms that might interfere with the ability to evaluate their cognitive function

  • Slide 19.

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  • Cognition and PCSK9 Inhibitors[20]

    • Brain synthesizes its own cholesterol locally and it's unlikely that any of the monoclonal antibodies that we use in clinical practice -- including evolocumab -- cross an intact blood-brain barrier purely because of their size
    • There had been a meta-analysis suggesting a potential increased risk with PCSK9 inhibitors for neurocognitive events
    • Despite the event rates being low -- less than 1% -- they were unadjudicated and represented a diverse range of AE items that were reported, and they were not correlated with achieved levels of LDL cholesterol

  • Slide 20.

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  • EBBINGHAUS Primary Endpoint: Spatial Working Memory Strategy Index[19]

    • The EBBINGHAUS study prospectively evaluated neurocognitive function with a range of neuropsychological assessments to evaluate executive function

  • Slide 21.

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  • EBBINGHAUS: Cognitive Assessments by Nadir Achieved LDL-C and Treatment[19]

    • They demonstrated noninferiority between evolocumab and placebo in terms of cognitive function
    • Just as reassuringly, noninferiority was demonstrated at all levels of LDL-C, even at very low levels of LDL-C (below 25 mg/dL)

  • Slide 22.

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  • The SPIRE-1 and SPIRE-2 CV Outcome Trials[21]

    • The SPIRE-1 and SPIRE-2 studies enrolled patients at high risk who either had established atherosclerotic CV disease or who were at high risk in primary prevention
    • The SPIRE-1 study required patients to have an LDL-C ≥ 1.8 mmol/L (70 mg/dL) or a non-HDL-C ≥ 2.6 mmol/L (100 mg/dL)
    • The SPIRE-2 study required patients to have an LDL-C ≥ 2.6 mmol/L (100 mg/dL) or a non-HDL-C ≥ 3.4 mmol/L (130 mg/dL)
    • Patients were treated every 2 weeks with the monoclonal antibody bococizumab or placebo in addition to maximal tolerated statin therapy

  • Slide 23.

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  • SPIRE-1 and SPIRE-2: Baseline Clinical Characteristics[21]

    • Patients in SPIRE-2 study had a much higher LDL-C level -- 134 mg/dL -- compared with 94 mg/dL in SPIRE-1 study
    • As a consequence, the absolute risk of major CV adverse events was substantially higher in the SPIRE-2 study

  • Slide 24.

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  • SPIRE-1 and SPIRE-2: Confirmation of Attenuation in LDL-C Reduction Over Time[21]

    • The reason why the SPIRE studies were stopped early is that it became apparent throughout the course of these studies that there was a high rate of development of neutralizing antibodies against bococizumab with a consequent lack of effective lipid lowering
    • The lipid-lowering efficacy reduced over time

  • Slide 25.

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  • SPIRE-1 and SPIRE-2 Primary Prespecified Endpoint[21]

    • These studies were stopped early and the rates of events were very low
    • The SPIRE-1 study was highly underpowered in its ability to look at the effects on CV events because of low levels of LDL-C and the shorter duration of follow-up
    • A benefit was observed in the SPIRE-2 study
    • A significant 21% reduction of the primary endpoint was observed in the bococizumab group

  • Slide 26.

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  • SPIRE-1 and SPIRE-2: Incidence Rates AEs per 100 P-Y of Exposure[21]

    • There are differences between the PCSK9 inhibitors
    • Bococizumab is a humanized monoclonal antibody
    • Evolocumab and alirocumab are fully human monoclonal antibodies
    • In addition to the emergence of neutralizing antibodies to bococizumab, observed in the SPIRE studies, there was a greater rate of SAEs leading to drug discontinuation and much higher rates of injection site reactions and immunogenic response to use of this agent compared with placebo

  • Slide 27.

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  • ODYSSEY Outcomes: Phase 3 Post-ACS With Alirocumab[12]

    • The ODYSSEY outcome study is a phase 3 study comparing alirocumab to placebo in patients with a history of ACS
    • Patients were required to have an LDL-C > 70mg/dL

  • Slide 28.

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  • Conclusion

    • PCSK9 inhibitors demonstrated a significant reduction of LDL-C levels
    • The FOURIER and SPIRE-2 studies demonstrated a significant effect on CV events
    • The Asian population presents a high CV risk and particularly a high risk of stroke
    • PCSK9 inhibitors offer the opportunity to reduce the CV risk of these patients

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  • This content has been condensed for improved clarity.


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