Lipid Modification to Reduce Cardiovascular Risk: Are We Achieving Our Goals?

Alberico L. Catapano, PhD, MDhc University of Milan Bassini Hospital Milan, Italy

Alberico L. Catapano, PhD, MDhc, has a financial interest/relationship or affiliation in the form of: Consultant for Akcea Therapeutics; Inc.; Daiichi Sankyo Company, Limited; Esperion Therapeutics, Inc.; Ionis Pharmaceuticals, Inc.; Kowa Company, Ltd.; Merck KGaA; N.V.; AG; Recordati Rare Diseases Inc; Regeneron Pharmaceuticals, Inc.; Sandoz AG; and . Grant/Research Support from Amgen Inc.; ; Menarini Silicon Biosystems S.p.A.; Mylan N.V.; Regeneron Pharmaceuticals, Inc.; and Sanofi. Speakers Bureau participant with Akcea Therapeutics; Amgen Inc.; Amryt Pharma; AstraZeneca; Daiichi Sankyo Company, Limited; Esperion Therapeutics, Inc.; Ionis Pharmaceuticals, Inc.; Kowa Company, Ltd.; Merck KGaA; Mylan N.V.; Novartis AG; Recordati Rare Diseases Inc; Regeneron Pharmaceuticals, Inc.; Sandoz AG; and Sanofi. Honoraria from Akcea Therapeutics; Amgen Inc.; Amryt Pharma; AstraZeneca; Daiichi Sankyo Company, Limited; Esperion Therapeutics, Inc.; Ionis Pharmaceuticals, Inc.; Kowa Company, Ltd.; Merck KGaA; Mylan N.V.; Novartis AG; Recordati Rare Diseases Inc; Regeneron Pharmaceuticals, Inc.; Sandoz AG; and Sanofi. Advisory Board for Aegerion Pharmaceuticals, Inc.; Akcea Therapeutics; Amgen Inc.; Daiichi Sankyo Company, Limited; Esperion Therapeutics, Inc.; Ionis Pharmaceuticals, Inc.; Kowa Company, Ltd.; Menarini Silicon Biosystems S.p.A.; Merck KGaA; Mylan N.V.; Novartis AG; Recordati Rare Diseases Inc; Regeneron Pharmaceuticals, Inc.; Sandoz AG; and Sanofi.

Learning Objectives • Establish optimal LDL-C levels for patients at high cardiovascular risk • Summarise the strengths and limitations of the latest data on lipid-lowering therapy • Describe how combination therapy can help patients achieve their LDL-C goals

Test your knowledge, share your thoughts, and download activity materials at: www.peervoice.com/GED900 Lipid Modification to Reduce Cardiovascular Risk: Are We Achieving Our Goals?

Introduction terms, the better the gain that we can achieve in terms of The standard of care for managing dyslipidaemia in high- events the patient avoids in the future. risk individuals, along with the definition of optimal low- density lipoprotein cholesterol (LDL-C) levels, has evolved Having said that, our goals are very demanding; I do considerably over the past few years. What is the rationale for appreciate that. We are asking for LDL-C below 50 mg/dL in these changing standards of care? Here, Alberico L. Catapano, very-high-risk individuals, which is roughly 1.4 mmol/L. We PhD, MDhc, explains why a more intensive reduction of LDL-C also have the goal of ≥50% reduction—and I warn people not may be needed for patients at risk for cardiovascular disease to be fooled by the percentage reduction; 100% of nothing is (CVD). nothing, and 10% of a lot still is a lot. For an individual starting from an LDL-C of 80 mg/dL (roughly 2.2 mmol/L), even if Why Is There an Urgent Need to Prevent CVD? we just reduce by 1-mmol, that would mean a benefit that Cardiovascular disease is the leading cause of disease is roughly a 23% relative risk reduction. Setting these LDL-C burden in the world. What is particularly alarming, beyond goals means promoting the understanding that the more you just the continued rise of CVD for almost all countries outside and the patient collaboratively work to get closer to the goal, the high-income world, is that age-standardised CVD rates the more benefit the patient would gain. have begun to rise in many locations where they had been previously declining. In fact, in 2019, 6.2 million individuals aged between 30 and 70 years died due to CVD (Roth GA et al; Figure 2. ESC/EAS Recommendations for LDL-C GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Reduction Goals Across CV Risk Categories For Patients at: LDL-C Goal: Writing Group. J Am Coll Cardiol. 2020;76:2982-3021). High risk Reduction of ≥50% from baseline and goal of <1.8 mmol/L (<70 mg/dL) Moderate risk Goal of <2.6 mmol/L (<100 mg/dL) Low risk Goal of <3.0 mmol/L (<116 mg/dL) Obviously, CVD encompasses of vast array of conditions, For Patients at: LDL-C Goal: Primary but many are related to atherosclerotic CVD (ASCVD), Prevention Very-high risk, without FH Reduction of ≥50% from baseline and goal of <1.4 or without ASVD but with another risk factor mmol/L (<55 mg/dL) especially ischaemic events—of which elevated LDL-C is a Reduction of ≥50% from baseline and goal of <1.4 Very-high risk mmol/L (<55 mg/dL) causative atherogenic factor (Figure 1). As people’s lifestyles Secondary Prevention Very-high risk with ASCVD who experience second vascular event within 2 y while taking Goal of <1.0 mmol/L (<40 mg/dL) are changing, their ASCVD risk factors are evolving and maximally tolerated statin therapy increasing as well, especially during this COVID-19 pandemic. EAS: European Atherosclerosis Society; ESC: European Society of Cardiology; FH: familial hypercholesterolaemia. Access is becoming yet another risk factor—people with Mach F et al; ESC Scientific Document Group. Eur Heart J. 2020;41:111-188. Correction: Eur Heart J. 2020;41:4255. established CVD are reluctant to maintain regular healthcare appointments, let alone those who may be at risk for As part of this activity, we conducted a survey among ASCVD. This is a call to action for us to improve our primary international cardiologists (N = 33), asking about the optimal prevention efforts. LDL-C level for the following patient scenario: • 61-year-old male with a current LDL-C of 172 mg/dL (4.5 mmol/L) Figure 1. Proportion of CVD Deaths by Cause (2019) • Elevated triglycerides at 240 mg/dL (2.7 mmol/L) • Slightly elevated blood pressure at 148/85 mm Hg • His mother had a fatal MI at age 65 years

Most of the respondents selected ≤70 mg/dL (1.8 mmol/L) as the optimal LDL-C level to try to achieve reduce CV risk; 12% selected ≤55 mg/dL (1.4 mmol/L). The patient in this scenario is at high CV risk (not at very high risk), so I think the response pattern is encouraging that my colleagues are striving for that

AA: aortic aneurysm; AF: atrial fibrillation; CVD: cardiovascular disease; HD: heart disease; ICH: intracerebral haemorrhage; PAD: goal of ≥50% reduction. peripheral artery disease. Roth GA et al; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. J Am Coll Cardiol. 2020;76:2982-3021. What Challenges Do We Face in Reducing LDL-C Levels?

What LDL-C Levels Should We Aim For? Now, why may patients have difficulty in achieving their LDL-C Given the unmet needs in ASCVD prevention, the most recent goal? We do need to acknowledge that for some patients,

guidelines from the European Society of Cardiology (ESC) such as those with a baseline LDL-C of 300 mg/dL, getting to and European Atherosclerosis Society (EAS) now recommend <55 mg/dL may be near impossible. But, as I explained, we more intensive reduction of LDL-C across CV risk categories would still strive for that goal in order to achieve the maximum

(Figure 2). This is because the evidence shows us that the possible reduction and hence largest benefit possible. more we can reduce ApoB-containing lipoprotein in absolute

www.peervoice.com/GED900 2 Lipid Modification to Reduce Cardiovascular Risk: Are We Achieving Our Goals?

Another challenge is treatment inertia, a tendency to use low or average doses of statins that are not high-intensity statin. Some patients truly cannot tolerate high-dose statins, although my experience is that out of 3,000 patients, only 10 patients are truly intolerant. The other patients who report intolerability may only be intolerant in their mind, given the perception that the statins are associated with side effects. Myalgia is not as frequent as has been historically reported, but we cannot clinically judge if muscle pain reported by a patient is truly related to treatment. So this remains a challenge and if a patient is deemed intolerant to high-dose statin therapy, then you should address reaching the goal with a lower dose of a statin, or changing the statin itself, and associating that with ezetimibe and/or a PCSK9 inhibitor if needed.

My suggestion would be, for those patients who are at high or very high CVD risk, where the goals are demanding, consider where you start from with the LDL-C. If you are >50% away from the goal, why not consider starting with a combination, such as a high-intensity statin plus ezetimibe? This will give you a 65% to 70% LDL-C reduction, the patient may be at better odds of actually reaching goal, and in fact, may require fewer visits to attain that goal.

So I think combination therapy is an opportunity, and that will set the stage for the remaining population who may need an even more intensive approach, such as with PCSK9 inhibition. In the future it can be other emerging agents, such as bempedoic acid or inclisiran, which is not a direct PCSK9 inhibitor, but rather a moderator of PCSK9 biosynthesis. My colleague Kausik Ray, BSc (Hons), MBChB, FRCP, MD, MPhil (Cantab), FACC, FESC, FAHA will illustrate his lipid-lowering strategy with a patient scenario in a future activity.

In summary, there still remains a significant gap between identifying CVD as a problem, identifying the best course of action, and then consistently executing the intense treatment plans so many of our patients need. But, I am encouraged that as more agents are added to the treatment paradigm, the benefit can only increase as we fine-tune a treatment course for each individual patient.

This has been an activity published by PeerVoice.

www.peervoice.com/GED900 3 Test your knowledge, share your thoughts, and download activity materials at: www.peervoice.com/GED900

Lipid Modification to Reduce Cardiovascular Risk: Are We Achieving Our Goals?

Content developed in concert with the faculty. Release Date: 19 April 2021

This activity is supported by an educational grant from Daiichi Sankyo Europe GmbH.

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