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Professor FJ RaalFRCP, FCP(SA), Cert Endo, MMed, PhDDirector: Carbohydrate & Lipid Metabolism Research Unit ProfessorHead: Division of Endocrinology & MetabolismFaculty of Health SciencesUniversity of the Witwatersrand

Professor Dirk BlomFCP(SA), PhDHead: Division of LipidologyDepartment of MedicineUniversity of Cape Town

Dyslipidaemia – getting to lower LDL targets safely

Learning objectivesYou will learn:

• New South African guidelines on lipid-lowering are recommending lower LDL-cholesterol levels: <1.4mmol/l in very high-risk patients and 1.8mmol/l in high-risk patients

• To interpret these guidelines effectively in daily clinical practice

• To introduce PCSK9 inhibitors safely and appropriately in your daily practice.

Introduction

Cholesterol, particularly LDL-cholesterol, is the pivotal risk factor for the development of atherosclerosis. As a small particle, LDL-cholesterol results in extensive adverse outcomes in terms of vascular morbidity and mortality.

ApoB-containing lipoproteins are central to the pathogenesis of atherosclerosis. LDL is the most abundant and important apoB-containing lipoprotein in humans and increased levels of LDL-cholesterol are responsible for much vascular morbidity and mortality. One might ask whether LDL-cholesterol is more benign than COVID/SARS-CoV-2, which is currently dominating the world. In terms of mortality, LDL-cholesterol as related to atherosclerosis results in one in every 2.4 deaths worldwide, with more than 17 million deaths globally each year; this certainly dwarfs COVID-19’s current 1.2 million deaths and we should therefore not neglect non-communicable diseases such as atherosclerotic cardiovascular disease (ASCVD).

The other co-causative risk factors of atherosclerotic cardiovascular disease, such as hypertension, smoking, obesity and diabetes mellitus must also be addressed; but without accompanying dyslipidaemia, their adverse effects on the vasculature are reduced. Therefore cholesterol, particularly LDL-cholesterol, as a risk factor remains pivotal. Lowering LDL-cholesterol is important to reduce cardiovascular morbidity and mortality.

This report was made possible by an unrestricted educational sponsorship from Sanofi. The content of the report is independent of the sponsor. The expert participated voluntarily.

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Dyslipidaemia – getting to lower LDL targets safely

“In the future, I believe the LDL-cholesterol target for very high-risk patients will be further reduced to ≤1mmol/l” Professor Raal

Evidence of LDL-cholesterol’s pivotal role in atherosclerosisProfessor Derick Raal

The Cholesterol Treatment Trials collabora-tion (CTT) evaluated the results of 26 statin trials involving more than 170 000 patients over more than a decade and showed the

relationship between reduction in LDL-cholesterol levels and the annual incidence of major coronary artery disease (CAD) and vascular events (Table 1).1,2

Table 1. Every 1mmol/l reduction in LDL-cholesterol leads to:

• An annual 21-24% reduction in major CAD or vascular events• 12% annual reduction in overall mortality.

Latest cholesterol-lowering guidelinesThe South African Dyslipidaemia Guideline Consensus Statement of 2018 set LDL-cholesterol targets for patients at very high

cardiovascular risk (Table 2).3 These have now been updated in accordance with the lat-est evidence.4

Table 2. South African guidelines: Patients at very high cardiovascular risk require immediate intensive lipid management4

• Established atherosclerotic disease: – CAD – Cerebrovascular disease – Peripheral vascular disease

• Type 2 diabetes mellitus plus one or more cardiovascular disease risk factors or age >40 years• Type 1 diabetes mellitus with microalbuminuria/proteinuria• Chronic kidney disease:

– eGFR <30ml/min/1.73m2

• Genetic dyslipidaemia, e.g. familial hypercholesterolaemia (FH)• Asymptomatic individuals with arterial plaque demonstrated on imaging.

Recommended target: LDL-cholesterol target <1.8mmol/l and a reduction of at least 50% of the baseline LDL-cholesterol levels.4

In 2019, the ESC/EAS guidelines were revised. The South African Heart Association and the Lipid and Atherosclerosis Society of South Africa (LASSA) have now also revised their guidance on new targets, recommending a lower LDL-cholesterol level of <1.4mmol/l for primary and secondary prevention in very

high-risk patients. Interestingly, even greater prominence has been given in all the latest guidance to the first goal of LDL-cholesterol lowering, which is to achieve a ≥50% reduc-tion from baseline and a target of <1.4mmol/l in these patients (Tables 3 and 4).4

Table 3. New South African LDL-cholesterol targets4

Primary and secondary prevention: Very high-risk patients <1.4mmol/l and ≥50% reduction<1.0mmol/l*

Patients at high risk ≥50% reduction and <1.8mmol/l

Patients at low and moderate risk <3mmol/l and <2.6mmol/l (moderate risk)

Patients with ACS not at goal on statin and ezetimibe Add PCSK9 to reach appropriate goal

*For patients who experience a second event within two years while on maximum statin therapy

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Dyslipidaemia – getting to lower LDL targets safely

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Table 4. Definition of high- and very high-risk patients4

High-risk: • Framingham 10-year risk of >15% is high-risk and >30% very high-risk • Markedly elevated single risk factors – TC >8mmol/l or LDL-C >4.9mmol/l or BP

≥180/110mmHg• FH without other major risk factors• Moderate CKD (eGFR 30-59ml/min/1.73m2)• DM with target organ damage.

Very high-risk • ASCVD (clinical/imaging)• FH with ASCVD or another major risk factors• Severe CKD (eGFR <30ml/min/1.73m2)• DM and target organ damage ≥3 major risk factors or early onset of type 1 diabetes

mellitus of long duration/>20 years.

Clinical strategy: How to get to these lower LDL-cholesterol targets?The principle in daily clinical practice of getting to this lower target is: firstly, to use only high-intensity statins; secondly, con-sider combination therapy using agents that have different mechanisms of action, such as ezetimibe; and thirdly, use the newly available (in South Africa) PCSK9 inhibitors.

“In my clinical practice, I only use high-intensity statins such as atorvastatin and rosuvastatin at maximal doses. Simvastatin very rarely forms part of my therapeutic approach,” said Professor Raal.

It is important to note that doubling of the statin dose only results in a further 6% reduction in LDL-cholesterol and that the residual risk associated with statin-only use can be reduced by further lowering of LDL-cholesterol using either ezetimibe or a PCSK9 inhibitor or both.

Using ezetimibe plus statin to reach a lower LDL-cholesterol target achieves better results as was shown by the lower LDL-cholesterol levels achieved in the IMPROVE-IT study, which showed an additional 16.4% reduction in cardiovascular events and death when this combination was used.5

The clinical expectation when using a com-bination of a high-intensity statin and ezetimibe is a 55-65% reduction in LDL-cholesterol levels. This is sufficient for many patients with established ASCVD. However, it is important in the South African context to remember that less than 10% of FH patients were shown in the South African cohort of the SAFEHEART study to reach these new recommended lower LDL-cholesterol target levels prior to the introduction of the PCSK9 inhibitors.

The essential role of PCSK9 inhibitors in achieving ‘optimal’ LDL-cholesterol levels

While PCSK9 inhibitors have been available globally for four years or longer, South Africa is one of the last countries in the world to get these agents (alirocumab and evolocumab) for cholesterol lowering. PCSK9 inhibitors are monoclonal antibodies and, in essence, the inhibition of PCSK9 rescues LDL-receptors from degradation and increases the presence and role of these receptors in removing LDL-cholesterol from the circulation (Figure 1).6

Lipidologists in South Africa have been involved in the clinical trials of PCSK9 inhibitors since the initial proof of concept

study7 in 2012 showed that alirocumab mono-therapy can achieve a 60% reduction in LDL-cholesterol and that the effect lasts for 2-3 weeks following a single dose; levels return to baseline within 2-4 weeks.

“In a study of homozygotes and heterozygous FH patients whom I was involved with some five years ago,8 treatment with PCSK9 inhibi-tors on top of statin and ezetimibe therapy achieved LDL-cholesterol target levels in these patients that I had never seen before – truly remarkable drugs,” Professor Raal explained (Table 5).

...less than 10% of FH patients were shown in the South African cohort of the SAFEHEART study to reach these new recommended lower LDL-cholesterol target levels prior to the introduction of the PCSK9 inhibitors

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Dyslipidaemia – getting to lower LDL targets safely

“The most deserving patients for the use of PCSK9 inhibitors are those furthest from their recommended LDL-cholesterol target”

Table 5. Clinical guide to medications and their lipid-lowering intensity

Treatment Average LDL-cholesterol reduction

Moderate-intensity statinHigh-intensity statinHigh-intensity statin and ezetimibePCSK9 inhibitorPCSK9 inhibitor and high-intensity statinPCSK9 inhibitor and high-intensity statin and ezetimibe

≈ 30%≈ 50%≈ 65%≈ 60%≈ 75%≈ 85%

PCSK9 inhibitors – for which patients are they indicated?“The most deserving patients for the use of PCSK9 inhibitors are those furthest from their recommended LDL-cholesterol target,” Professor Raal noted.

In order to address some concern that all patients in the high-risk category not at their LDL-cholesterol target of 1.8mmol/l would require PCSK9 inhibitors, analyses were done which showed that only 10-15% of these high-risk patients with ASCVD would require PCSK9 inhibitor therapy.

The current global and South African guid-ance is to use PCSK9 inhibitors in patients at very high risk not achieving their target goal of <1.4mmol/l on a maximum tolerated dose

of statin and ezetimibe.4

Also, PCSK9 inhibitors should be consid-ered in primary prevention for individuals with heterozygous FH at very high-risk, who require a ≥50% reduction from baseline and have an LDL-cholesterol goal of <1.4mmol/l. Treatment with a PCSK9 inhibitor is clearly recommended for very high-risk FH patients not at goal; also, research has shown that these agents are effective, regardless of which LDL-receptor mutation is present, so genetic testing is not essential.

Finally, these agents will be very useful in patients unable to tolerate statins or effective doses of statins.

Figure 1. Effects on LDL-cholesterol with and without PCSK9 inhibition6

Without PCSK-inhibition With PCSK-inhibition

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Dyslipidaemia – getting to lower LDL targets safely

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PCSK9 is clearly not needed for human life and survival to old age

What is the long-term safety of and experience with PCSK9 inhibitors?Professor Dirk Blom, University of Cape Town

A reassurance as to safety with regard to the concept of PCSK9 inhibition is seen in natural-occurring human genetic mutations resulting in loss of PCSK9 function; this is similar to the knock-out effect obtained with a PCSK9 inhibitor. These mutations do not lead to any adverse effects over the lifetime of these patients. This cohort of patients has, in effect, experienced low LDL-cholesterol levels from birth with no adverse effects.7 Of interest is a UCT student’s recent study of

lipid levels in pregnant Zimbabwean women which identified a woman with extremely low levels of LDL-cholesterol: <0.3mmol/l. This woman was subsequently found to be homozygous for a loss of function muta-tion in PCSK9. Both the mother and her newborn are well despite their extremely low level of LDL-cholesterol. “PCSK9 is clearly not needed for human life and survival to old age,” Professor Blom noted.

Alirocumab and evolocumab are fully human antibodies8

It is important to note that the registered PCSK9 inhibitors, alirocumab and evo-locumab, are ‘fully human’ antibodies with no residual mouse protein fragments. Other ‘humanised’ monoclonal antibodies were not successful and were not brought to market as

they induced neutralising antibodies in some patients (antidrug antibodies), thereby reduc-ing the drug’s effectiveness and also causing higher rates of immunological reactions, such as injection site reactions.

Safety of PCSK9 inhibitors in clinical trialsData drawn from the double-blind clini-cal trial environment have shown in both the Fourier (evolocumab)9 and ODYSSEY Outcomes trials (alirocumab)10 that PCSK9 inhibitors generally had an adverse event profile similar to placebo. The only excep-tion to this is an increase in mild site injection reactions (3.8 vs 2.1 in the ODYSSEY trial)

causing redness and local tenderness, which was insufficient as a troublesome side-effect to cause discontinuation of treatment with the PCSK9 inhibitor.

“In general, we are not seeing any adverse events, greater than placebo, when a PCSK9 inhibitor is prescribed,” said Professor Blom.

Any adverse reactions due to very low LDL-cholesterol levels?

Even at the very low LDL-cholesterol levels (<0.5mmol/l) achieved in some patients with PCSK9 therapy the adverse event profile

does not differ significantly from that seen in patients with higher LDL-cholesterol values (Table 6).

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Dyslipidaemia – getting to lower LDL targets safely

Table 6. Adverse events by LDL-cholesterol level11

<0.5mmol/l (n=2 669)

0.5 to <1.3mmol/l (n=8 003)

1.3 to <1.8mmol/l (n=3 444)

1.8 to <2.6mmol/l (n=7 471)

≥2.6mmol/l (n=4 395)

P value

Serious adverse events 614 (23%) 1 948 (24%) 838 (24%) 1 684 (23%) 1 022 (23%) 0.13

Adjusted OR (95% CI) 0.97 (0.86–1.10)

1.01 (0.92–1.11)

1.01 (0.90–1.13)

0.93 (0.84–1.02)

1 (ref) 0.30

Adverse events* leading to discontinuation of study drug

98 (4%) 295 (4%) 124 (4%) 234 (3%) 149 (3%) 0.11

Adjusted OR (95% CI) 1.08 (0.82–1.43)

1.07 (0.86–1.33)

1.07 (0.83–1.39)

0.91 (0.73–1.14)

1 (ref) 0.13

AST or ALT elevation (>3 times ULN)

41 (2%) 120 (1%) 76 (2%) 119 (2%) 83 (2%) 0.19

Adjusted OR (95% CI) 0.96 (0.64–1.43)

0.87 (0.64–1.17)

1.25 (0.90–1.74)

0.91 (0.68–1.24)

1 (ref) 0.64

Neurocognitive events are not increased11

There had been some concern about a possi-ble increase in neurocognitive events as LDL-cholesterol levels dropped below 1mmol/l. This was not seen in the data from the Fourier trial, which included patients treated for 2.5 years and longer (Table 7). “One

should note that there were very low numbers of events in both arms resulting in wide con-fidence levels,” Professor Blom noted. Other studies have shown that the adrenal glands are also unaffected by low LDL-cholesterol levels.

Table 7. Adverse events by LDL-cholesterol11

<0.5mmol/l (n=2 669)

0.5 to <1.3mmol/l (n=8 003)

1.3 to <1.8mmol/l (n=3 444)

1.8 to <2.6mmol/l (n=7 471)

≥2.6mmol/l (n=4 395)

P value

Neurocognitive events 49 (2%) 122 (2%) 51 (1%) 100 (1%) 52 (1%) 0.019

Adjusted OR (95% CI) 1.28 (0.84–1.96)

1.10 (0.78–1.55)

1.10 (0.73–1.65)

0.97 (0.68–1.39)

1 (ref) 0.15

New-onset diabetes mellitus† 135/1 655 (8%) 389/4 863 (8%) 162/1 886 (9%) 356/4 603 (8%) 220/2 778 (8%) 0.63

Adjusted OR (95% CI) 1.06 (0.83–1.35)

1.00 (0.83–1.20)

1.03 (0.83–1.30)

0.95 (0.78–1.14)

1 (ref) 0.48

“It is clear that all cells are able to synthesise the cholesterol they need rather than relying exclusively on importing cholesterol; very low LDL-cholesterol is thus not associated with

increased neurocognitive events, haemor-rhagic stroke or non-cardiovascular causes of mortality,” Professor Blom said.

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Dyslipidaemia – getting to lower LDL targets safely

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“It is clear that all cells are able to synthesise the cholesterol they need rather than relying exclusively on importing cholesterol; very low LDL-cholesterol is thus not associated with increased neurocognitive events, haemorrhagic stroke or non-cardiovascular causes of mortality” Professor Blom

Efficacy and dosing of PCSK9 inhibitorsThe dose of alirocumab used in the clinical tri-als was 75mg once every two weeks; if the LDL-cholesterol target was not reached, this was up-titrated to 150mg once every two weeks.12

“I will, however, predict that we are going to see wider use of the 150mg dose of alirocumab in clinical practice, which would also be my preference, to get maximal LDL-cholesterol lowering quickly,” Professor Blom noted.

In the ODYSSEY trial of heterozygous FH patients, the approach of starting at 75mg and up-titrating at week 8 resulted in a drop of 51%-58% (on higher dose) in LDL-cholesterol. (Figure 2).

Patients with homozygous FH respond less well to PCSK9 inhibitors as they have

mutations in both LDL-receptor alleles. In patients with homozygous FH the response to treatment is determined by the residual LDL receptor function.13 Some patients with no residual receptor function do not respond at all. Patients with homozygous FH should ideally be referred to a specialist lipid clinic for review and evaluation as they may benefit from the addition of novel therapies that do not require LDL receptors to act.

The results of an open-label extension study of patients in South Africa treated with alirocumab in the ODYSSEY clinical trial programme and whose therapy continued showed that over a further three years, these low levels of LDL-cholesterol were main-tained; South African patients responded just as well as those in the rest of the world.10,14

Figure 2. ODYSSEY extension trial results10

ALI: alirocumab; PBO: placebo

No. patients analysed

Placebo + statin therapy at maximum tolerated

dose ± other LLT

Alirocumab + statin therapy at maximum tolerated dose

± other LLT

LDL-

C, L

S m

ean

(±S

E), m

mo

l/l

mg

/dl

0 4 8 12 16 24 52 64 7836

FH IALI 322 304 290 277 279PBO 163 152 149 146 145

FH IIALI 166 152 157 158 154PBO 81 76 78 78 71

4.5

4

3.5

3

2.5

2

1.5

1

174

155

135

116

97

77

58

39

Week

FH I

FH II

FH I

FH II

DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

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Dyslipidaemia – getting to lower LDL targets safely

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Long-term extension studies over five years with evolocumab treatment in the Fourier study of post-ACS patients also showed that the initial change in LDL-cholesterol levels from baseline was maintained with ongoing therapy.

“Both the alirocumab14 and evolocumab10

studies, despite including different patient populations, achieved an absolute risk reduc-tion of 1% in cardiovascular and non-fatal myocardial infarction events. Patient accept-ance of PCSK9 inhibitor therapy is high; this class of medication is highly effective and very safe,” Professor Blom concluded.

Key learnings

• It is important to realise that the maximum benefit occurs in patients at the highest risk and that accurately stratifying risk is essential in determining the benefit of PCSK9 inhibitor therapy

• It is important in clinical practice to understand that many patients will benefit from PCSK9 inhibitor therapy, but that it is important initially to select those who will receive the highest benefit from this particular lipid-lowering therapy.

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ReferencesClick on reference to access the scientific article1. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety

of cholesterol lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-1278.

2. The Cholesterol Treatment Trialists (CTT) collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376(9753): 1670-1681.

3. Klug EQ, Raal FJ, Marais AD, et al. South African Dyslipidaemia Guidelines Consensus Statement: 2018 update. A joint statement from the South African Heart Association (SA Heart) and the Lipid and Atherosclerosis Society of Southern Africa (LASSA). S Afr Med J 2018; 108(11b): 973-1000.

4. Klug EQ, Raal FJ. New cholesterol targets for patients at high or very high cardiovascular risk and the indications for PCSK9 inhibitors (Letter to the editor). S Afr Med J 2020; 110(11): 1059.

5. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372(25): 2387-2397.

6. Hovingh G K, Davidson MH, Kastelein JJP, et al. Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J 2013; 34(13): 962-971.

7. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012; 366: 1108-1118.

8. Ridker PM, Tardif J-C, Amarenco P, et al. Lipid-reduction

variability and antidrug-antibody formation with bococizumab. N Engl J Med 2017; 376: 1517-1526.

9. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-1722.

10. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015; 36(43): 2996-3003.

11. Giugliano RP, Pedersen TR, Park J-G, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017; 390(10106): 1962-1971.

12. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379: 2097-2107. DOI: 10.1056/NEJMoa1801174

13. Hooper AJ, Marais AD, Tanyanyiwa DM, et al. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007; 193: 445-448.

14. Blom DJ, Breedt J, Burgess LJ, et al. Long-term safety and efficacy of alirocumab in South African patients with heterozygous familial hypercholesterolaemia: the ODYSSEY Open-Label Extension study. Cardiovasc J Afr 2019; 30(5): 279-284.