How low should we go for

cholesterol and with which drugs

D P Mikhailidis BSc MSc MD FCPP FCP FRSPH FFPM

FRCP FRCPath

Dept. of Clinical Biochemistry

(Vascular Disease Prevention Clinics)

Royal Free Hospital

University College London (UCL)

DECLARATION OF INTEREST

• Attended conferences and gave talks sponsored

by MSD, AstraZeneca and Libytec

DECLARATION OF INTEREST

• Lead: Guidelines for Medical Management of Carotid Artery

Stenosis (Eur Soc Vasc Surg)

• Chair: Expert Panel on Small Dense Low Density Lipoprotein

• Co-chair: Expert Panel on Post-Prandial Hypertriglyceridaemia

• Executive Board member of the International Atherosclerosis

Society (IAS), 2016-18

DECLARATION OF INTEREST

Editor-in-Chief of several journals, including:

• Curr Med Res Opin

• Expert Opin Pharmacother

• Angiology

• Curr Vasc Pharmacol

• Open Cardiovasc Med J

LECTURE PLAN

• Targets according to guidelines

• IMPROVE-IT in the context of current evidence

• PCSK-9 inhibitors

• Several meta-analyses

2016 Joint European Society of

Cardiology Guidelines

• LDL-C 1.8 mmol/L (70 mg/dL) appears to be a reasonable

goal for prevention of recurrent CV events and in very-high-

risk subjects.

• A goal of LDL-C reduction of at least 50% is also

recommended if the baseline LDL-C level is 1.8 - 3.5 mmol/L

(70 - 135 mg/dL).

• Non-HDL-C target values may be an alternate target if non-

fasting samples are obtained, and goals should be <2.6, <3.3

and <3.8 mmol/L (<100, <130 and <145 mg/dL) with very

high, high and low to moderate CV risk, respectively.

Piepoli MF et al. Euro Heart J doi:10.1093/eurheartj/ehw106

2016 Joint European Society of

Cardiology Guidelines

• No differences in the relative reduction between men and

women and between younger and older age or between those

with and without DM.

Piepoli MF et al. Euro Heart J doi:10.1093/eurheartj/ehw106

2016 Joint European Society of

Cardiology Guidelines

• Statins: main drugs (even for combined hyperlipidaemia)

• Ezetimibe: not for monotherapy unless statins not tolerated

• Resins: 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 (n-3 fatty acids): 2 - 4 g/day for triglyceride lowering.

Limited evidence regarding CV events.

• PCSK9 inhibitors: Limited evidence regarding CV events.

Cost.

• Apheresis: not mentioned!

2016 Joint European Society of

Cardiology Guidelines

• Combination therapy:

Statin +ezetimibe

Fenofibrate + statin: decrease TG and LDL-C and raise HDL-C.

Limited evidence for CVD events reduction.

Drugs metabolized through cytochrome P450 should be avoided.

Fibrates should preferably be taken in the morning and statins

in the evening to minimize peak dose concentrations.

Patients have to be instructed about warning symptoms

(myalgia), even though such adverse effects are very rare.

Gemfibrozil should not be added to a statin, because of the high

potential for interactions.

2016 Joint European Society of

Cardiology Guidelines

Knowledge gaps:

• Triglyceride or HDL-C values as a target for therapy.

• Whether Lp(a) lowering against background statin therapy

can 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.

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

Goals

IMPROVE-IT: First large trial evaluating clinical

efficacy of combination EZ/Simva vs simvastatin

(i.e. the addition of ezetimibe to statin therapy):

➢Does lowering LDL-C with the non-statin agent

ezetimibe reduce cardiac events?

➢“Is (Even) Lower (Even) Better?”

(estimated mean LDL-C ~50 vs 65 mg/dL)

➢Safety of ezetimibe

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

Patient Population

Inclusion Criteria:

➢ Hospitalization for STEMI, NSTEMI/UA < 10 days

➢ Age ≥ 50 years, and ≥ 1 high-risk feature:

– New ST chg, + troponin, DM, prior MI, PAD, cerebrovasc,

prior CABG > 3 years, multivessel CAD

➢ LDL-C 50-125 mg/dL (50-100 mg/dL if prior lipid-lowering Rx)

[1.3 – 3.2 and 1.3 – 2.6 mmol/l)

Major Exclusion Criteria:

➢ CABG for treatment of qualifying ACS

➢ Current statin Rx more potent than simva 40 mg

➢ Creat Cl < 30 mL/min, active liver disease

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

Baseline Characteristics

Simvastatin

(n = 9077)

%

EZ/Simva

(n = 9067)

%

Age (years) 64 64

Female 24 25

Diabetes 27 27

MI prior to index ACS 21 21

STEMI / NSTEMI / UA 29 / 47 / 24 29 / 47 / 24

Days post ACS to rand (IQR) 5 (3, 8) 5 (3, 8)

Cath / PCI for ACS event 88 / 70 88 / 70

Prior lipid therapy 35 36

LDL-C at ACS event (mmol/L, IQR) 2.46 (2.04, 2.85) 2.46 (2.05,2.85)

LDL-C and Lipid Changes

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 1.89 3.76 1.55 1.25 3.8

EZ/Simva 1.39 3.26 1.36 1.26 3.3

Δ in

mmol/L

-0.43 -0.50 -0.19 +0.02 -0.5

Median Time averaged

1.80 vs 1.39 mmol/L

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* EZ/Simva* p-value

Primary 34.7 32.7 0.016

CVD/MI/UA/Cor Revasc/CVA

Secondary #1 40.3 38.7 0.034

All D/MI/UA/Cor Revasc/CVA

Secondary #2 18.9 17.5 0.016

CHD/MI/Urgent Cor Revasc

Secondary #3 36.2 34.5 0.035

CVD/MI/UA/All Revasc/CVA

0.936

Ezetimibe/Simva

Better

Simva

Better

UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization

(≥30 days after randomization); All D, all-cause death; CHD, coronary heart disease death;

All Revasc, coronary and non-coronary revascularization (≥30 days)

*7-year

event rates (%)

Primary and 3 Prespecified Secondary Endpoints — ITT

0.8 1.0 1.1

0.948

0.912

0.945

HR Simva* EZ/Simva* p-value

All-cause death 0.99 15.3 15.4 0.782

CVD 1.00 6.8 6.9 0.997

CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002

Stroke 0.86 4.8 4.2 0.052

Ischemic stroke 0.79 4.1 3.4 0.008

Cor revasc ≥ 30d 0.95 23.4 21.8 0.107

UA 1.06 1.9 2.1 0.618

CVD/MI/stroke 0.90 22.2 20.4 0.003

Ezetimibe/Simva

Better

Simva

Better

Individual Cardiovascular Endpoints and CVD/MI/Stroke

0.6 1.0 1.4 *7-year

event rates (%)

Simva — 22.2%

1704 events

EZ/Simva — 20.4%

1544 events

HR 0.90 CI (0.84, 0.97)

P = 0.003

NNT = 56

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

7-year event rates

Simva† EZ/Simva†

Male 34.9 33.3

Female 34.0 31.0

Age < 65 years 30.8 29.9

Age ≥ 65 years 39.9 36.4

No diabetes 30.8 30.2

Diabetes 45.5 40.0

Prior LLT 43.4 40.7

No prior LLT 30.0 28.6

LDL-C > 2.75 mM 31.2 29.6

LDL-C ≤ 2.75 mM

38.4 36.0

Major Pre-specified Subgroups

Ezetimibe/Simva

Better

Simva

Better

0.7 1.0 1.3 †7-year

event rates

*

*p-interaction = 0.023, otherwise > 0.05

IMPROVE-IT added to CTT: Ezetimibe vs Statin Benefit

CTT Collaboration:

Lancet 2005; 366:1267-78

Lancet 2010;376:1670-81

IMPROVE-IT

Safety — ITT

No statistically significant differences in cancer or muscle- or gallbladder-related events

Simva

n = 9077

%

EZ/Simva

n = 9067

%

p

ALT and/or AST ≥3x ULN 2.3 2.5 0.43

Cholecystectomy 1.5 1.5 0.96

Gallbladder-related AEs 3.5 3.1 0.10

Rhabdomyolysis* 0.2 0.1 0.37

Myopathy* 0.1 0.2 0.32

Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64

Cancer* 10.2 10.2 0.57

* Adjudicated by Clinical Events Committee % = n/N for the trial duration

Mean LDL-C at 1 Year OT & ITT

Simva OT LDLC 69.5 mg/dL Simva ITT LDLC 69.9 mg/dL

LDLC values at 1 year

ITT

OT

ITT

OT

EZ/Simva OT LDLC 52.5 mg/dL EZ/Simva ITT LDLC 53.2 mg/dL

OT LDLC 17.0 mg/dL ITT LDLC 16.7 mg/dL

EZ/Simva

Simva

Primary Endpoint On Treatment

Simva — 32.4%

2079 events

EZ/Simva — 29.8%

1932 events

HR 0.924 CI (0.868, 0.983)

P = 0.012

Primary Endpoint: CV death, MI, hospital admission for UA,

coronary revascularization (> 30 days after randomization), or stroke

19% greater treatment effect than ITT

NNT = 38

7 year event rates

Simva* EZ/Simva* HR

Major vascular 37.4 35.3 0.866 events (MCE+ CR+ stroke)

35.4 32.7 0.860

Major coronary 18.4 17.0 0.794 events (nfMI+CHD) 15.8 13.8 0.723 Non-fatal MI 14.4 12.8 0.726

13.5 11.6 0.714

CHD death (coronary 5.8 5.7 0.901 death)

3.1 3.1 0.894

Coronary revasc. 27.7 26.1 0.897 27.4 25.3 0.913

Any stroke 4.8 4.2 0.700 4.5 3.7 0.594

Ischemic stroke 4.1 3.4 0.586

3.9 3.2 0.582

CTT Collaboration.

Lancet 2010

*7-year

event rates

HR per 1 mM LDLC reduction IMPROVE-IT ITT vs OT

Ezetimibe/Simva

Better

Simva

Better

0.2 1.0 1.4

Line denoting ~20% benefit

Conclusions

IMPROVE-IT: First trial demonstrating incremental

clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy:

YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events

YES: Even Lower is Even Better (achieved mean LDL-C 1.40 vs 1.81 mmol/L at 1 year)

YES: Confirms ezetimibe safety profile

Reaffirms the LDL hypothesis: reducing LDL-C levels prevents cardiovascular events

Results could be considered for future guidelines (% or absolute value?)

Simva† EZ/Simva†

Male 34.9 33.3

Female 34.0 31.0

Age < 65 years 30.8 29.9

Age ≥ 65 years 39.9 36.4

No diabetes 30.8 30.2

Diabetes 45.5 40.0

Prior LLT 43.4 40.7

No prior LLT 30.0 28.6

LDL-C > 2.75 mM 31.2 29.6

LDL-C ≤ 2.75 mM

38.4 36.0

Major Pre-specified Subgroups

Ezetimibe/Simva

Better

Simva

Better

0.7 1.0 1.3 †7-year

event rates

*

*p-interaction = 0.023, otherwise > 0.05

All Events Analysis

9,545 total primary endpoint (PEP) events (5,314 (56%) first events + 4,231 (44%)

subsequent events).

Total PEP events reduced by 9% with ezet/simva vs placebo/simva (incidence-

rate ratio: 0.91; 95% CI 0.85 to 0.97; p = 0.007).

Total PEP events: 70.7% of the participants had no events, 16.6% had 1 event,

7.3% had 2 events and 5.4% had ≥ 3 events. The greatest number of events was

14 events in 2 patients; 13% of the 18,144 subjects had >1 PEP event.

1-month LDL-C levels were lowest in those without a subsequent PEP event and

highest in those with >1 PEP event (mean 58.3 mg/dl for no event, 59.6 mg/dl for

1 event and 60.1 mg/dl for >1 event; p < 0.001 for 3-way comparison).

An LDL-C of < 70 mg/dl at 1 month was most common among subjects without

a PEP event during the trial compared with subjects with 1 or > 1 event (p <

0.001 for 3-way comparison).

Murphy SA, et al. J Am Coll Cardiol 2016: 67: 353 - 61

Meta-analysis of trials comparing

aggressive vs conventional

treatment with statins

PROVE-IT, TNT, A to Z and IDEAL

Combined analysis: 16% odds reduction

in coronary death or MI (p < 0.00001), and a

16% odds reduction in coronary death or any

cardiovascular event (p < 0.00001). n = 27,548

J Am Coll Cardiol 2006;48:438-45

Meta-analysis of trials comparing

aggressive vs conventional

treatment with statins

PROVE-IT, TNT, A to Z and IDEAL

Trend toward decreased cardiovascular

mortality (odds reduction 12%, p = 0.054)

Pooled LDL-C 101 vs 75 mg/dl (2.6 vs 1.9 mmol/l)

J Am Coll Cardiol 2006;48:438-45

IDEAL study

Simvastatin 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 < 0.001

Diarrhoea 9 vs 38 P < 0.001

Abdominal pain 10 vs 37 P < 0.001

Nausea 6 vs 32 P< 0.004

AST 2 vs 18 >3X ULN P < 0.001

ALT 5 vs 43 >3X ULN P < 0.001

Adverse 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

IDEAL study

During treatment, mean LDL-C levels were 104 mg/dL (2.7 mmol/l) in the

simvastatin group and 81 mg/dL (2.1 mmol/l) in the atorvastatin group.

A major coronary event occurred in 463 simvastatin patients (10.4%) and in

411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78 -

1.01; P = 0.07).

Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71 - 0.98; P = 0.02).

PROVE-IT Pravastatin or Atorvastatin Evaluation and

Infection Therapy – Thrombolysis in Myocardial

Infarction 22

• n = 4162

• Hospitalized for ACS – 10 days

• Pravastatin 40 mg vs atorvastatin 80 mg

• 24 months

• Primary end points: death, MI, unstable angina,

revascularization, stroke

PROVE-IT: Final LDL

cholesterol level

<0.001

2.7 (104)

1.6 (62)

2.7 (104)

2.5 (96)

Baseline LDL-C

Final LDL-C

(mg/dl)

p Atorvastatin 80

mg (n = 2003)

Pravastatin 40

mg (n = 1973)

Cannon CP, et al. N Engl J Med 2004;350:1495-504

PROVE-IT: Primary composite

end point

16

Relative risk

reduction (%)

0.005

22.4

26.3

All-cause

mortality/

MI/unstable

angina/

revascularization

(PCI or CABG)/

stroke (%)

p Atorvastatin

80 mg

(n=2003)

Pravastatin

40 mg

(n=1973)

Primary end point

PROVE-IT: Secondary end points

0.04 14 16.3 18.8 Revascularization

(%)

0.02 29 3.8 5.1 Unstable angina (%)

0.06 18 8.3 10.0 Death/nonfatal MI

(%)

0.07 28 2.2 3.2 All-cause mortality

(%)

0.029 14 19.7 22.3 CHD death, nonfatal

MI, or

revascularization

(%)

p Relative risk

reduction, %

Atorvastatin

80 mg

(n=2003)

Pravastatin

40 mg

(n=1973)

Secondary end points

TNT: Baseline and final LDL

cholesterol levels (mmol/l)

LDL-C Atorvastatin 10 mg

(n = 5006)

Atorvastatin 80

mg (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

Niemann-Pick C1-Like 1

(NPC1L1) Genes, LDL-C Levels

and Risk

Ference BA, et al. J Am Coll Cardiol 2015 Mar 6. pii: S0735-1097(15)00607-5.

doi: 10.1016/j.jacc.2015.02.020. [Epub ahead of print]

Myocardial Infarction Genetics Consortium Investigators. N Engl J Med

2014;371:2072-82

A Naturally Randomized IMPROVE-IT Trial

Brian A. Ference, M.D., M.Phil., M.Sc., F.A.C.C. Division of Translational Research and Clinical Epidemiology (TRaCE)

Division of Cardiovascular Medicine Wayne State University School of Medicine

ONLINE FIRST 11 March 2015

Group

LDL-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;doi:10.1016/j.jacc.2015.02.020).

Conclusions from Naturally Randomized Data

• Lower LDL-C mediated by polymorphisms in the NPC1L1 gene is casually associated with lower risk of CHD

• The effect of lower LDL-C on risk of CHD mediated by polymorphisms in NPC1L1 and HMGCR is approximately the same per unit lower LDL-C

• Combined polymorphisms in NPC1L1 and HMGCR have independent linearly additive effects on LDL-C and a log-linearly additive effects on risk of CHD

Naturally randomized genetic evidence agrees very closely with randomized IMPROVE-IT trial evidence

Implications for Treatment with Ezetimibe

• No biological difference in effect of lower LDL-C on risk of CHD mediated by inhibition of NPC1L1 or HMGCR

• Lowering LDL-C by inhibiting NPC1L1 with ezetimibe, inhibiting HMGCR with a statin or both should reduce risk of CHD proportional to absolute achieved reduction in LDL-C regardless of which treatment is used

• Combination ezetimibe and low dose statin should be as effective as high dose statin at reducing CV events with potential for fewer dose-dependent statin side-effects

Ezetimibe + simvastatin vs statin monotherapy in patients with diabetes

Chang SH, et al. Int J Cardiol 2015;190:20-5

4,099 patients on simva-ezet and 16,396 on statin monotherapy. Mean age: 59.1 years. 37,388 person-years. The annual incidence rate of new-onset MACE was lower in the simva-ezet group (2.61%) than in the statin monotherapy group (3.02%) (p = 0.0476). Cox regression analysis: simva-ezet use was independently associated with a lower risk of MACE (HR, 0.77; 95%CI 0.66-0.90).

Ezetimibe and glycaemic control

Reports of improved insulin sensitivity with ezet. This is the reverse of New Onset Diabetes (NOD) with statins. Also, ezet improving Non-Alcoholic Fatty Liver Disease (NAFLD). Interesting concept. Zafrir B, Jain M. Cardiovasc Drugs Ther 2014: 361-77

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/dl

i.e. 16.7 mg/dl or 23.9%

Our meta-analysis = 23.6%

PCSK-9 (proprotein convertase

subtilisin kexin type 9)

• Loss-of-function PCSK9 mutations associated

with decreased cholesterol levels

– Agents could be used in combination with statins

and ezetimibe to increase lipid-lowering efficacy

– Ongoing research: antibodies, antisense

oligonucleotides, RNA interference and small

molecules

PCSK-9 (proprotein convertase

subtilisin kexin type 9)

• mAbs (monoclonal antibodies):

Bind to PCSK-9 near its catalytic site.

Evolocumab (Amgen), Alirocumab (Aventis/Regeneron) and Bococizumab

(Pfizer)

• Peptide mimics:

Look like the LDL receptor and bind PCSK-9

• Gene silencing:

PCSK-9 antisense oligonucleotide

PCSK-9

Sabatine MS, et al.; Open-Label Study of Long-Term Evaluation against

LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab

in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9

• Compared with standard therapy, evolocumab reduced the

LDL-C level by 61% (median: 120 to 48 mg/dl; P < 0.001)

• CV events at 1 year were reduced from 2.18% in the

standard-therapy group to 0.95% in the evolocumab group

(hazard ratio: 0.47; 95% CI, 0.28 to 0.78; P = 0.003)

• 4465 patients who had completed 1 of 12 phase 2 or 3

evolocumab studies ("parent trials."). Mixed risk patients.

PCSK-9

Robinson JG et al. ODYSSEY LONG TERM Investigators.

Efficacy and safety of alirocumab in reducing lipids and

cardiovascular events. N Engl J Med 2015;372:1489-99

• 2341 patients at high risk for CV events who had LDL-C

levels ≥70 mg/dl (1.8 mmol/l) and were receiving statins at

the maximum tolerated dose

• LDL-C decreased by -62% (P < 0.001)

• major adverse CV events (death from CHD, nonfatal MI,

fatal or nonfatal ischemic stroke or unstable angina

requiring hospitalization) was lower with alirocumab than

with placebo (1.7 vs 3.3%; hazard ratio, 0.52; 95% CI, 0.31

to 0.90; P = 0.02)

PCSK-9

Can be administered with statins or ezetimibe.

Statins and fibrates raise PCSK-9 levels

PCSK-9 inhibitors can lower Lp(a) levels

Homozygous familial hypercholesterolaemia (LDL-C ↓ by ≈

30%)

Heterozygous familial hypercholesterolaemia (LDL-C ↓ by ≈

60%)

Adverse effects: nasopharyngitis, muscle-related and

neurocognitive effects

PCSK-9

Several other trials:

For example,

LAPLACE

GAUSS

TESLA

DESCARTES

FOURIER

SPIRE-1 AND -2

RUTHERFORD-2

“New” drugs just starting to be

investigated

microRNAs (miRS)

Athyros VG, Katsiki N, Karagiannis A. Is targeting microRNAs the

philosopher's stone for vascular disease? Curr Vasc Pharmacol 2015 Mar 31.

[Epub ahead of print].

Mikhailidis DP, Athyros VG. Dyslipidaemia in 2013: New statin guidelines and

promising novel therapeutics. Nat Rev Cardiol. 2014;11:72-4.

“New” drugs that are just starting

to be investigated

microRNAs (miRs):

• Mimic miRs, inhibit their synthesis, block their actions.

• “Good” miRs and “Bad” miRs concept.

• Some drugs (e.g. statins) that are currently available affect miRs. Does this

influence how effective they may be? Pleiotropic actions.

Gene repair:

PCSK9 META-ANALYSIS

• 13 083 patients randomized to PCSK9 inhibitors (n = 8250), placebo (n

= 3957), ezetimibe (n = 846), or PCSK9 inhibitors and ezetimibe (n =

30).

• PCSK9 inhibitors significantly reduced LDL-C by 57% relative to

placebo (p < 0.001) and 36.1% relative to ezetimibe (p < 0.001).

• PCSK9 inhibitors reduced the incidence of all-cause mortality [OR 0.43

(95% CI 0.22-0.82), p = 0.01] but was associated with an increased

incidence of neurocognitive adverse events [OR 2.34 (95% CI 1.11-4.93),

I2 = 4%, p = 0.02] compared with placebo.

Lipinski MJ, et al. Eur Heart J 2015 Nov 17 [Epub ahead of print]

EZETIMIBE META-ANALYSIS

• 7 trials enrolling 31,048 patients (median follow-up 34.1 ± 26.3 months;

70% women; mean age 61 ± 8 years).

• Compared with control therapy, adding ezetimibe significantly reduced

the risk of MI by 13.5% (RR: 0.865, 95% CI: 0.801 to 0.934, p < 0.001)

and the risk of any stroke by 16.0% (RR: 0.840, 95% CI: 0.744 to 0.949,

p = 0.005), without any effect on all-cause and CV mortality (RR: 1.003,

95% CI: 0.954 to 1.055, p = 0.908; RR: 0.958, 95% CI: 0.879 to 1.044, p

= 0.330; respectively) and risk of new cancer (RR: 1.040, 95% CI: 0.965

to 1.120, p = 0.303).

Savarese G, et al. Safety and efficacy of ezetimibe: A meta-analysis. Int J

Cardiol 2015; 201: 247-52

EZETIMIBE META-ANALYSIS

• 5 ezetimibe/simvastatin RCTs (30,051 individuals), 2 comparing

ezetimibe/simvastatin vs placebo and 3 vs less intensive treatment.

Outcomes reduced almost to the same extent were stroke (RR: -13%,

95% CI: -21% to -3%), CHD (RR: -12%, 95% CI: -19% to -5%), and

composite of stroke and CHD (RR: -14%, 95% CI: -20% to -8%).

• Logarithmic risk ratios were not associated with LDL-C lowering. Our

meta-analysis provides evidence that, in patients with different CV

disease burden, major CV events are safely reduced by LDL-C lowering

with ezetimibe/simvastatin, while raising the hypothesis that the extent of

LDL-C lowering might not be accompanied by incremental clinical-event

reduction.

Thomopoulos C, et al. Clin Cardiol 2015 Aug 18. [Epub ahead of print]

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 was 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

Do not forget?

• Apheresis (wider availability of centres?

Will become less useful after the PCSK9

drugs)

• Liver transplantation (?distant future)

Question 1

For very high risk patients what is the LDL-C

goal according to the guidelines?

1. 100 mg/dl

2. 80 mg/dl

3. 70 mg/dl

4. 50 mg/dl

Question 2

In IMPROVE-IT the number of combined

events was?

1. > 9,000

2. > 8,000

3. > 7,000

4. > 6,000

Question 3

PCSK9 inhibitors act by:

1. Increasing the number of hepatic LDL-C

receptors

2. Decreasing the number of hepatic LDL-C

receptors