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

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

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)

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)

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

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

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

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

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

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

FOURIER Follow-Up^[16,17]

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

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

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)

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)

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%

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

Thank You

This content has been condensed for improved clarity.