dept. of clinical biochemistry royal free campus

LDL. HDL and CVDD P Mikhailidis

BSc MSc MD FCPP FGHA FCP FRSPH FFPM FRCP FRCPath

Dept. of Clinical Biochemistry Royal Free campus

University College London (UCL)

DECLARATION OF INTEREST

• Attended conferences and gave talks sponsored by Novo Nordisk, Amgen and Libytec


• Lead for Guidelines on the Management of Carotid Artery Stenosis (Eur Soc Vasc Surg)

• Chair European Expert Panel on Small Dense Low Density Lipoprotein

• Co-chair Expert Panel on Post-Prandial Lipaemia


Editor-in-Chief of: • Curr Med Res Opin• Expert Opin Pharmacother• Angiology• Curr Vasc Pharmacol • Open Cardiovasc Med J • Expert Rev Cardiovasc Ther• Journal of Drug Assessment

Low Density Lipoprotein (LDL)

What are the LDL-C levels in neonates?

What are the LDL-C levels in hunter-gatherers (e.g. living in the Amazon)?

What are the LDL-C levels in people with proprotein convertase subtilisin/kexin 9 (PCSK9) loss of function mutations?

Martin SS, Blumenthal RS, Miller M. LDL cholesterol: the lower the better. MedClin North Am 2012; 96: 13 - 26

What are the LDL-C levels in neonates? 50-70 mg/dl (1.3 - 1.8 mmol/l)

What are the LDL-C levels in hunter gatherers (e.g. living in the Amazon)? Similar to above

What are the LDL-C levels in people with proprotein convertase subtilisin/kexin 9 (PCSK9) loss of function mutations? Similar to above but 1 case down to 15 mg/dl and is healthy.


• What are the new LDL-C targets?

GUIDELINE LDL TARGETS

USA (2001) ≤ 2.6 mmol/l (100 mg/dl)UK (2004) ≤ 2.0 mmol/l (80 mg/dl)USA (2004) ≤ 1.8 mmol/l (70 mg/dl)(optional) very high risk patientsUK JBS2 (2005) ≤ 2.0 mmol/l (80 mg/dl) (total cholesterol 4.0 mmol/l; 160 mg/dl)European (2007) ≤ 2.5 mmol/l (96 mg/dl)Canada (2009) ≤ 2.0 mmol/l (80 mg/dl) ESC/EAS (2011) ≤ 1.8 mmol/l (70 mg/dl)

American College of Cardiology/American Heart Association – 2018

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 139: e1046 - e1081

and,

Circulation 2019; 139: e1082 - e1143

Statin treatment groups: (1) Clinical ASCVD (2) 40-75 age years, diabetes mellitus with LDL-C ≥ 70 mg/dL (1.8 mmol/l). Multiple risk factors = possible high dose statins.(3) 40-75 age years + LDL-C 70-189 mg/dL (1.8-4.8 mmol/l) + 10-year ASCVD risk ≥ 7.5% (4) Severe hypercholesterolemia (LDL-C ≥ 190 mg/dL; 4.9 mmol/l)

ASCVD on maximal statin therapy:Ezetimibe for clinical ASCVD and LDL-C ≥ 70 mg/dL (Class IIb; weak; Level of Evidence C); ezetimibe and PCSK9 inhibitor as add-on therapy for very high-risk ASCVD and LDL-C ≥ 70 mg/dL (Class of recommendation IIa: moderate)

Pooled Cohort Equations:Low risk (<5%), borderline risk (5% - < 7.5%), intermediate risk (7.5% – < 20%), and high risk (≥ 20%) (Class of recommendation I; strong Level of Evidence B-NR; moderate evidence)

NR = non-randomised trials

2016 Joint European Society of Cardiology (ESC) Guidelines

• Statins: main drugs (even for combined hyperlipidaemia)• Ezetimibe: not for monotherapy unless statins not tolerated• Resins: not for monotherapy unless statins not tolerated. Poorly tolerated and raise

triglycerides. Cost. • Fibrates and niacin: primarily for triglyceride lowering and increasing HDL-C.

Limited evidence regarding CV events; niacin no longer available in many countries. • Fish oils (ω-3 fatty acids): 2 - 4 g/day for triglyceride lowering. Limited evidence

regarding CV events. Recent REDUCE-IT trial more positive but AF/atrial flutter is increased.

• PCSK9 inhibitors: Limited evidence regarding CV events (evidence now available for evolocumab and alirocumab). Cost.

• Apheresis: not mentioned!

2016 Joint European Society of Cardiology (ESC) Guidelines

Knowledge gaps:

• Triglyceride or HDL-C values as targets for therapy?

• Can Lp(a) lowering against background statin therapy reduce the risk of CVD?

• How to increase adoption of non-HDL-C and non-fasting samples in clinical practice.

• Whether functional foods and food supplements with a lipid-lowering effect can safely reduce the risk of CVD.

Goal for Extreme Risk =

55 mg/dl (1.4. mmol/l)

Jellinger PS, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocr Pract 2017; 23(Suppl 2): 1 – 87

Extreme risk = Progressive ASCVD including unstable angina after achieving an LDL-C <70 mg/dL (1.8 mmol/l)Established clinical cardiovascular disease in patients with DM, CKD 3/4, or HeFHPremature ASCVD (<55 male, <65 female)

Lower target of LDL-C <55 mg/dl (1.4 mmol/l) can beconsidered in ACS patients with DM.

Li YH, Ueng KC, Jeng JS, Charng MJ, Lin TH, Chien KL, Wang CY, Chao TH, Liu PY, Su CH, Chien SC, Liou CW, Tang SC, Lee CC, Yu TY, Chen JW, Wu CC, Yeh HI; Writing Group of 2017 Taiwan Lipid Guidelines for High Risk Patients. 2017 Taiwan lipid guidelines for high risk patients. J Formosa Med Assoc 2017; 116: 217 - 48

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)

Authors/Task Force Members: Francois Mach (Chairperson) (Switzerland), Colin Baigent (Chairperson) (UK), Alberico L Catapano (Chairperson) (Italy), Konstantinos C Koskinas (Switzerland), Manuela Casula (Italy), Lina Badimon(Spain), M John Chapman (France), Guy G De Backer (Belgium), Victoria Delgado (Netherlands), Brian A Ference (UK), Ian M Graham (Ireland), Alison Halliday (UK), Ulf Landmesser (Germany), Borislava Mihaylova (UK), Terje R Pedersen (Norway), Gabriele Riccardi (Italy), Dimitrios J. Richter (Greece), Marc S Sabatine (USA), Marja-Riitta Taskinen (Finland), Lale Tokgozoglu(Turkey), Olov Wiklund (Sweden)

Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41: 111 - 188

Table 4: Cardiovascular risk categories• VERY-HIGH RISK

Documented ASCVD, either clinical or unequivocal on imaging. Documented ASCVD includes previous ACS (MI or unstable angina), stable angina, coronary revascularization (PCI, CABG, and other arterial revascularization procedures), stroke and TIA, and peripheral arterial disease.

Unequivocally documented ASCVD on imaging includes those findings that are known to be predictive of clinical events, such as significant plaque on coronary angiography or CT scan (multivessel coronary disease with two major epicardial arteries having > 50% stenosis), or on carotid ultrasound.

DM with target organ damage, or at least 3 major risk factors, or early onset of T1DM of long duration (> 20 years).

Severe CKD (eGFR < 30 mL/min/1.73m2).

A calculated SCORE ≥ 10% for 10-year risk of fatal CVD.

FH with ASCVD or with another major risk factor.

• HIGH-RISK

• Markedly elevated single risk factors, in particular TC > 8 mmol/L (> 310 mg/dL), LDL-C > 4.9 mmol/L (> 190 mg/dL) or BP ≥ 180/110 mmHg.

• Patients with FH without other major risk factors.

• Patients with DM without target organ damage with DM duration ≥ 10 years or another additional risk factor.

• Moderate CKD (eGFR 30 - 59 mL/min/1.73 m2).

• A calculated SCORE ≥ 5% and < 10% for 10-year risk of fatal CVD.

• MODERATE RISK

Young patients (T1DM < 35 years; T2DM < 50 years) with DM duration < 10 years, without other risk factors.Calculated SCORE ≥ 1 % and < 5% for 10-year risk of fatal CVD.

• LOW RISK• Calculated SCORE < 1% for 10-year risk of fatal CVD.

New/revised concepts

More intensive reduction of LDL-C across CV risk categories• For secondary prevention in very-high-risk patients, an LDL-C reduction of ≥ 50% from baseline and an LDL-C goal of < 1.4 mmol/L (< 55 mg/dL) are recommended.For patients with ASCVD who experience a second vascular event within 2 years (not necessarily of the same type as the first event) while taking maximally tolerated statin therapy, an LDL-C goal of < 1.0 mmol/L (< 40 mg/dL) may be considered.

• In primary prevention, for individuals at very-high risk but without FH, an LDL-C reduction of ≥ 50% from baseline and an LDL-C goal of < 1.4 mmol/L (< 55 mg/dL) are recommended. For individuals at very-high risk (that is, with another risk factor but without ASCVD), in primary prevention the same goals for LDL-C lowering should be considered.

• For patients at high risk, an LDL-C reduction of ≥ 50% from baseline and an LDL-C goal of < 1.8 mmol/L (< 70 mg/dL) are recommended.

• For individuals at moderate risk, an LDL-C goal of < 2.6 mmol/L (< 100 mg/dL) should

be considered.

• For individuals at low risk, an LDL-C goal of <3.0 mmol/L (< 116 mg/dL) may be

considered.


• What are the new LDL-C targets?• Even lower is even better (1 mmol/l; 40 mg/dl)• Also, remember lower for longer is better

OK using statins but what about other drugs?

High dose high intensity statin → add ezetimibe → add PCSK9 inhibitor

SOME OTHER INTERESTING POINTS

In 3.5 years the PCSK9i class moved from class IIb to class Ia

If a statin-based regimen is not tolerated for primary prevention at any dosage (even after re-challenge), a PCSK9i added to ezetimibe may be considered (Class C, Level IIb). But what is there any other alternative option?

Non-HDL-C

Lp(a)

Drugs other than those mentioned here

TGs AND STATINS

The effect of statins on TG levels depends on 2 factors:1] the baseline TG level – the higher the greater the fall in TG level,2] the greater the fall in LDL-C (or statin dose) –the greater the fall in TG.

TNT: Baseline and final LDL cholesterol levels (mmol/l)

(duration: 4.9 years)LaRosa JC et al. N Engl J Med 2005; 352: 1425 - 35

LDL-C Atorvastatin 10 mg(n = 5006)

Atorvastatin 80mg (n = 4995)

Baseline LDL-C 2.5 (96 mg/dl) 2.5 (96 mg/dl)

Final LDL-C 2.6 (100 mg/dl) 2.0 (77 mg/dl)

TNT: Primary efficacy outcomes

LaRosa JC et al. N Engl J Med 2005; 352: 1425 - 35

Outcome Atorvastatin 10 mg (n = 5006)

Atorvastatin 80 mg (n = 4995)

Hazard ratio(95% CI)

p

Total major cardiovascular events (%)

10.9 8.7 0.78(0.69-0.89)

<0.001

Death from CHD (%)

2.5 2.0 0.80(0.61-1.03)

0.09

Nonfatal MI (%) 6.2 4.9 0.78(0.66-0.93)

0.004

Fatal or nonfatal stroke (%)

3.1 2.3 0.75(0.59-0.96)

0.02

IDEAL studySimvastatin 20 (n = 4449)* vs atorvastatin 80 mg (n = 4439). Previous MI; 4.8 years follow-up.• No difference in primary end point. However, there were significant differences

in secondary endpoints favouring more aggressive treatment.

Myalgia 51 vs 97 P < 0.001Diarrhoea 9 vs 38 P < 0.001Abdominal pain 10 vs 37 P < 0.001Nausea 6 vs 32 P< 0.004AST 2 vs 18 >3X ULN P < 0.001ALT 5 vs 43 >3X ULN P < 0.001Adverse event leading to permanent discontinuation 186 vs 426 P < 0.001

*23% were on simvastatin 40 mg and 13% had atorvastatin 40 mg

Pedersen TR et al. JAMA 2005; 294: 2437-45

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial

A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome

Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372: 2387 - 97

Patients stabilized post ACS ≤ 10 days:LDL-C 50 - 125* mg/dL (or 50 - 100** mg/dL if prior lipid-lowering Rx)

Standard Medical & Interventional Therapy

Ezetimibe / Simvastatin 10 / 40 mg

Simvastatin 40 mg

Follow-up Visit Day 30, every 4 months

Duration: Minimum 2 ½-year follow-up (at least 5250 events)

Primary Endpoint: CV death, MI, hospital admission for UA,coronary revascularization (≥ 30 days after randomization), or stroke

n = 18,144

Uptitrated to Simva 80 mg if LDL-C > 79(adapted per

FDA label 2011)

Study Design

*3.2 mM

**2.6 mM

Cannon CP AHJ 2008; 156: 826 - 32; Califf RM NEJM 2009; 361: 712 - 7; Blazing MA AHJ 2014; 168: 205 - 12

90% power to detect

~9% difference

LDL-C and Lipid Changes

Median Time averaged:

1.80 vs 1.39 mmol/L

70 vs 54 mg/dL

Primary Endpoint — ITT

Simva — 34.7% 2742 events

EZ/Simva — 32.7% 2572 events

HR 0.936 CI (0.887, 0.988)p = 0.016

Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

7-year event rates

NNT = 50

Simva — 22.2% 1704 events

EZ/Simva — 20.4% 1544 events

HR 0.90 CI (0.84, 0.97)P = 0.003NNT = 56

CV Death, Non-fatal MI, or Non-fatal Stroke

7-year event rates

IMPROVE-IT added to CTT: Ezetimibe vs. Statin Benefit

CTT Collaboration: Lancet 2005; 366:1267-78 Lancet 2010;376:1670-81

IMPROVE-IT

Conclusions

First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy:

YES: Non-statin lowering LDL-C with ezetimibereduces cardiovascular events

YES: Even Lower is Even Better(mean LDL-C 1.40 vs 1.81 mmol/L at 1 year; 55 vs 70 mg/dl)YES: Confirms ezetimibe safety

Meta-Analysis: Ezetimibe Added to a Statin

• n = 5, 039

• LDL fall = 23.6% p< 0.0001• HDL increase = 1.7% p< 0.0001• TG fall = 10.7% p< 0.0001

Mikhailidis DP et al. Curr Med Res Opin 2007; 23: 2009 - 26

IMPROVE-IT

LDL-C difference = 69.9 vs 53.2 mg/dli.e. 16.7 mg/dl or 23.9%

Our meta-analysis = 23.6%

COMBINATION THERAPY META-ANALYSIS

• 11 RCTs: 109,244 patients • Overall, the incidences of major adverse cardiovascular events (MACEs) were

9.70% in the statin combination groups and 9.92% in the statin monotherapy groups • No significant difference observed in the risk of MACEs either in subgroup analysis

(CETP inhibitor: RR 1.07, 95% CI 0.93-1.23, p = 0.37; niacin: RR 1.03, 95% CI 0.85-1.25, p = 0.79; n-3 fatty acid: RR 0.98, 95% CI 0.88-1.09, p = 0.70; fenofibrate: RR 0.93, 95% CI 0.80-1.09, p = 0.38), with the exception of the statin/ezetimibe combination subgroup (RR 0.92, 95% CI 0.87-0.97, p = 0.004)

• Adding lipid-modifying agent to statin significantly increased liver injury risk Adding ezetimibe to statin did not alter side effect profile

• Ip CK, et al. Int J Cardiol 2015; 191: 138 - 48

A Naturally Randomized IMPROVE-IT Trial

Brian A Ference, MD, MPhil, MSc, FACC

Division of Translational Research and Clinical Epidemiology (TRaCE)Division of Cardiovascular MedicineWayne State University School of Medicine

Ference, BA et al. J Am Coll Cardiol 2015; 65: 1552 - 61

http://content.onlinejacc.org/issue.aspx?journalid=101&issueid=933571&direction=P

GroupLDL-C

Effect Size (mg/dl) ORCHD (95%CI)

Both NPC1L1 & HMGCR LDL-C Scores above median

-5.8 0.892 (0.839-0.948)p = 2.4x10-4

HMGCR LDL-C Score above median

-2.9 0.947 (0.914-0.982)p = 3.3x10-3

NPC1L1 LDL-C Score above median

-2.4 0.952 (0.923-0.983)p = 2.6x10-3

| | | | 0.85 0.90 0.95 1.0

2x2 Factorial Mendelian Randomization

Ference, BA et al. J Am Coll Cardiol 2015; 65: 1552 - 61

“IMPROVE-IT”

Concepts:

1] Even lower is even better

2] A lower LDL-C for even longer is even better

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

FOURIERFurther cardiovascular OUtcomes Research with PCSK9 Inhibition in

subjects with Elevated Risk

MS Sabatine, RP Giugliano, AC Keech, N Honarpour,SM Wasserman, PS Sever, and TR Pedersen,

for the FOURIER Steering Committee & Investigators

American College of Cardiology – 66th Annual Scientific SessionLate-Breaking Clinical Trial

March 17, 2017


Trial Design

Evolocumab SC 140 mg Q2W or 420 mg QM

Placebo SCQ2W or QM

LDL-C ≥70 mg/dL ornon-HDL-C ≥100 mg/dL

Follow-up Q 12 weeks

Screening, Lipid Stabilization, and Placebo Run-in

High or moderate intensity statin therapy (± ezetimibe)

27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

RANDOMIZEDDOUBLE BLIND

Sabatine MS et al. Am Heart J 2016;173:94 - 101


Randomized 27,564 patients

Evolocumab(N=13,784)

Placebo(N=13,780)

Premature perm.drug discontinuation 5.6%/yr 5.8%/yr

Withdrew consent 0.29%/yr 0.35%/yr

Lost to follow-up 5 patients 13 patients

Follow-up median 26 months (IQR 22-30)

Ascertainment for primary endpoint was complete for99.5% of potential patient-years of follow up

Follow-up

2907 patients experienced primary endpoint1829 experienced key secondary endpoint


Baseline Characteristics

Characteristic ValueAge, years, mean (SD) 63 (9)Male sex (%) 75Type of cardiovascular disease (%)

Myocardial infarction 81Stroke (non-hemorrhagic) 19Symptomatic PAD 13

Cardiovascular risk factor (%)Hypertension 80Diabetes mellitus 37Current cigarette use 28

Pooled data; no differences between treatment arms

Median time from most

recent event ~3 yrs


Lipid Lowering Therapy& Lipid Levels at Baseline

Characteristic ValueStatin use (%)*

High-intensity 69Moderate-intensity 30

Ezetimibe use (%) 5Median lipid measures (IQR) – mg/dL

LDL-C 92 (80-109)Total cholesterol 168 (151-189)HDL-C 44 (37-53)Triglycerides 133 (100-182)

Pooled data; no differences between treatment arms

*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.

1% were on low intensity or intensity data were missing.

Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines.


0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

LDL

Cho

lest

erol

(mg/

dl)

Weeks

LDL Cholesterol

Evolocumab(median 30 mg/dl, IQR 19-46 mg/dl)

Placebo

59% mean reduction (95%CI 58-60), P<0.00001

Absolute reduction: 56 mg/dl (95%CI 55-57)


0%

2%

4%

6%

8%

10%

12%

14%

16%

Primary Endpoint

Evolocumab

Placebo

Months from Randomization

CV

Dea

th, M

I, St

roke

,H

osp

for U

A, o

r Cor

Rev

asc

0 6 12 18 24 30 36

Hazard ratio 0.85(95% CI, 0.79-0.92)

P<0.0001 12.6%

14.6%


Types of CV Outcomes

EndpointEvolocumab(n = 13,784)

Placebo(n = 13,780) HR (95% CI)

3-yr Kaplan-Meier rate

CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)

Death due to acute MI 0.26 0.32 0.84 (0.49-1.42)Death due to stroke 0.29 0.30 0.94 (0.58-1.54)Other CV death 1.9 1.8 1.10 (0.90-1.35)

MI 4.4 6.3 0.73 (0.65-0.82)Stroke 2.2 2.6 0.79 (0.66-0.95)


Types of CV Outcomes

EndpointEvolocumab(n = 13,784)

Placebo(n = 13,780) HR (95% CI)

3-yr Kaplan-Meier rate

CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92)CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)MI 4.4 6.3 0.73 (0.65-0.82)Stroke 2.2 2.6 0.79 (0.66-0.95)Hosp for unstable angina 2.2 2.3 0.99 (0.82-1.18)Coronary revasc 7.0 9.2 0.78 (0.71-0.86)

Urgent 3.7 5.4 0.73 (0.64-0.83)Elective 3.9 4.6 0.83 (0.73-0.95)

Death from any cause 4.8 4.3 1.04 (0.91-1.19)


Comparison to Cholesterol

Treatment Trialists Collaboration

Major Coronary Events

Stroke

Coronary revascularizationUrgent

Elective

Major Vascular Events

0.78 (0.70-0.86)

0.80 (0.71-0.90)

0.77 (0.66-0.91)

0.77 (0.63-0.94)

0.75 (0.67-0.84)

0.73 (0.62-0.86)

0.84 (0.73-0.98)

0.77 (0.73-0.82)

0.83 (0.76-0.90)

Lipid-lowering therapy better Lipid-lowering therapy worse

Hazard Ratio (95% CI) per 1 mmol/L reduction in LDL-C

2.01.0

CTTC Meta-analysis Year 2

FOURIER Year 2

CTTC data: Lancet 2010; 376: 1670 - 81

0.5


Summary

• LDL-C by 59%– Consistent throughout duration of trial– Median achieved LDL-C of 30 mg/dl (IQR 19-46 mg/dl)

• CV outcomes in patients already on statin therapy– 15% broad primary endpoint; 20% CV death, MI, or stroke– Consistent benefit, incl. in those on high-intensity statin, low LDL-C– 25% reduction in CV death, MI, or stroke after 1st year– Long-term benefits consistent w/ statins per mmol/L LDL-C

• Safe and well-tolerated – Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo– Rates of EvoMab discontinuation low and no greater than pbo– No neutralizing antibodies developed

LaRosa JC et al. N Engl J Med 2005; 352: 1425 - 35

Event Rates vs LDL Cholesterol during Statin Therapy in Secondary-Prevention Studies

Landmark Statin Trials: LDL-C vs Events

Perc

enta

ge w

ith C

HD

eve

nt

Primary preventionPravastatinLovastatin

Modified from Kastelein JJP. Atherosclerosis 1999; 143(suppl 1): S17 - S21

Atorvastatin

10

5.4 (210)2.3 (90) 2.8 (110) 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190)

WOSCOPS-S WOSCOPS-P

0

5 AFCAPS-S AFCAPS-P

9876

4321

ASCOT-P

ASCOT-S

LDL-C, mmol/L (mg/dL)

S = statin treated; P = placebo treated

Low Density Lipoprotein (LDL)• Small dense LDL (sdLDL)

• Difficult to prove causality on trial based evidence but experimental evidence is strong.

• How to measure sdLDL?• “Clinical” sign: high TG levels: > 150 mg/dl (1.7 mmol/l). Also,

low HDL-C levels

Mikhailidis DP, Elisaf M, Rizzo M, Berneis K, Griffin B, Zambon A, Athyros V, de Graaf J, März W, ParhoferKG, Rini GB, Spinas GA, Tomkin GH, Tselepis AD, Wierzbicki AS, Winkler K, Florentin M, Liberopoulos E. European panel on low density lipoprotein (LDL) subclasses: a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses: executive summary. Curr Vasc Pharmacol 2011; 9: 531 - 2 (open access)•Mikhailidis DP, Elisaf M, Rizzo M, Berneis K, Griffin B, Zambon A, Athyros V, de Graaf J, März W, ParhoferKG, Rini GB, Spinas GA, Tomkin GH, Tselepis AD, Wierzbicki AS, Winkler K, Florentin M, Liberopoulos E. European panel on low density lipoprotein (LDL) subclasses: a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr Vasc Pharmacol 2011; 9: 533 - 71


• Friedewald formula

LDL-C = Total cholesterol – HDL – TG/5 (mg/dl)LDL-C = Total cholesterol – HDL – TG/2.2 (mmol/l)

1] Fasting2] TG levels > 400 mg/dl (4.5 mmol/l)

High Density Lipoprotein (HDL)

Consider Quantity and Quality

Harmful (torcetrapib) or neutral trials (evacetrapib and dalcetrapib) with CETP inhibitors. REVEAL was positive but anacetrapib will not be developed further; why? Role of other lipid changes?

Remember: epidemiology/genetics vs an individual case.

HDL Milano: low levels but long life

High HDL-C may be harmful. How to tell?

HDL-like infusions for ACS?

Jafri H, Alsheikh-Ali AA, Karas RH. Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk. Ann Intern Med 2010 21; 153: 800 - 8

20 RCTs: 543 210 person-years of follow-up; 7 838 MIs

Adjustment for on-treatment LDL-C levels, age, hypertension, diabetes, and tobacco use.

In Poisson meta-regressions, every 0.26 mmol/l (10 mg/dl) decrease in HDL-C was associated with 7.1 (95% CI 6.8 - 7.3) and 8.3 (8.1 - 8.5) more MIs per 1000 person-years in statin-treated patients and control participants, respectively.

High Density Lipoprotein (HDL)

Madsen CM, Varbo A, Tybjærg-Hansen A, Frikke-Schmidt R, Nordestgaard BG. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. Eur Heart J 2017: 39: 1181 - 90

Vitali C, Khetarpal SA, Rader DJ. HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics. Curr Cardiol Rep 2017; 19: 132

RISK FACTOR ANALYSIS IN SPARCL

• Optimal control: LDL-C <70 mg/dl, HDL-C >50 mg/dl, TG <150 mg/dl and SBP/DBP <120/80 mmHg.

• Risk of stroke decreased as control increased (HR [95% CI] 0.98 [0.76 to 1.27], 0.78 [0.61 to 0.99], 0.62[0.46 to 0.84], and 0.35 [0.13 to 0.96]) for those achieving control of 1, 2, 3, or 4 factors as compared with none, respectively.

Amarenco P et al. Stroke 2009; 40: 2486 - 92

STATINS AND OPERATIVE CARDIAC MORTALITY

• Decreased operative mortality associated with general and vascular surgery

• Benefit evident even after short-term use of statins

Paraskevas KI, Liapis CD, Hamilton G, Mikhailidis DP. Eur J VascEndovasc Surg 2006;32:286 - 93 Paraskevas KI, Veith FJ, Liapis CD, Mikhailidis DP. Curr Vasc Pharmacol2013;11:112 - 20

STATINS AND OPERATIVE CARDIAC MORTALITY

• Pre-interventional use of statins has a protective effect against peri-interventional stroke, MI, or death in patients with internal carotid artery stenosis treated with stent-angioplasty (n = 344)

• Reiff T, et al. Eur J Vasc Endovasc Surg 2014; 48: 626 - 32

• Pre-interventional use of statins not only reduce CV events and mortality but may also have an important effect on the anatomic durability of CEA.

• Avgerinos ED, et al. Curr Vasc Pharmacol 2015; 13: 239 - 47

NEW ONSET DIABETES (NOD)

• Do not look at general percentages – there are high risk populations. However, there is benefit in terms of risk reduction overall. Important to discuss weight gain etc with patients. Ezetimibe?

• PCSK-9 inhibitors?

EZETIMIBE AND DIABETESGiugliano RP, et al. Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With vs. Without Diabetes: Results from IMPROVE-IT. Circulation 2018; 137: 1571 - 82.

Baseline LDL-C was significantly lower in diabetic’s vs non-diabetics; 89 vs 97 mg/dl (2.3 vs 2.5 mmol/l) (p<0.001).

Diabetic post ACS patients, using E+S achieved a 5.5% absolute risk reduction; HR 0.85 (0.78-0.94); In the non-DM patients the absolute event rates were reduced by 0.7%; HR 0.98 (0.91-1.04).

Perhaps the favourable effects of ezetimibe on glucose metabolism, including reductions in fasting plasma glucose, insulin levels, and insulin resistance, may have contributed to the enhanced benefit observed in diabetic patients (stated by the authors).

Clearly,• Lower is better for LDL-C• Lower for longer is better for LDL-C

The question is how much lower and for whom?

Non-HDL-C should receive greater use/recognition

The future:HDL-C?TG? Fasting or non-fasting?Lp(a)?

dept. of clinical biochemistry royal free campus

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