Tues 07 Anderson Dyslipidemia0.5 0.75 1 1.25 1.5 Statin/more better Control/less better

Contemporary management of Dyslipidemia

Todd Anderson Feb 2018

www.ccs.ca Dyslipidemia Guidelines

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your presentation

Within the past two years:

Approach to Risk Management

Who, how when to screen

How to evaluate risk

When to initiate what treatment

Monitoring and surveillance

• Target levels of LDL-C

• Role of Combination therapy

• Risk assessment strategies

Areas to consider guideline change

Category Consider Initiating pharmaco-therapy if

Target NNT

Primary preventionHigh FRS (≥20%) all LDL-C < 2.0 mmol/L or

> 50% ↓

Or

Apo B < 0.8 g/L

Or

non-HDL-C < 2.6

mmol/L

35

Intermediate FRS (10-19%) LDL-C ≥ 3.5 mmol/L or Non-HDL ≥ 4.3 mmol/L or Apo B ≥ 1.2 g/L or Men ≥ 50 and women ≥ 60 yrs and one additional CVD RF

40

Statin indicated conditions

Clinical atherosclerosis*

20Abdominal aortic aneurysmDiabetes mellitus>40 yrs15 yrs duration for age >30 yrs (DM 1)Microvascular diseaseChronic kidney disease (age ≥ 50 y)eGFR < 60 mL/min/1.73 m2 orACR > 3 mg/mmolLDL-C ≥ 5. 0 mmol/L >50% ↓ in LDL-C

FRS – modified Framingham Risk Score; ACR – albumin:creatinine ratio; * consider LDL-‐C < 1.8 mmol/L for subjects with ACS within last 3 months


The Case for Lower is Better• Biological plausibility – Apo B lipoproteins linked to atherogenesis

• Epidemiology data – Mendelian randomization

• On Rx LDL-‐C related to events

• CTT meta-‐analysis – 22% reduction per 1 mmol/L ↓

• IVUS trials

• Emerging randomized trial data with new meds


Biological Plausibility

Labos et al. ATVB 2018;; ahead of press

Statin effect is mediated entirely by change in LDL-C


CHD Reduction from Earlier LDL-C Lowering: Lifetime low LDL

Ferrence BA, et al. J Am Coll Cardiol. 2012;60(25):2631-‐9.

Association between 1mmol/L lower LDL-C and risk of CHD

Lifetime lower LDL-C due to genetics resulted in a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life

0.5 0.75 1 1.25 1.5

Statin/more better Control/less better

<2.0³2,<2.5

³2.5,<3.0

³3,<3.5

³3.5

Total

910 (14.7%)

1528 (14.0%)

1866 (12.4%)

2007 (12.3%)

4508 (13.0%)

10973 (13.0%)

1012 (16.4%)

1729 (15.9%)

2225 (14.7%)

2454 (15.2%)

5736 (16.5%)

13350 (15.8%)

0.78 (0.61 - 0.99)

0.77 (0.67 - 0.89)

0.77 (0.70 - 0.85)

0.76 (0.70 - 0.82)

0.80 (0.76 - 0.83)

0.78 (0.76 - 0.80)

No. of events (% pa)

Statin/more Control/less

<2.0³2,<2.5

³2.5,<3.0

³3,<3.5

³3.5

Total

704 (17.9%)

1189 (18.4%)

1065 (20.1%)

517 (20.4%)

303 (23.9%)

3837 (19.4%)

795 (20.2%)

1317 (20.8%)

1203 (22.2%)

633 (25.8%)

398 (31.2%)

4416 (22.3%)

0.71 (0.52 - 0.98)

0.77 (0.64 - 0.94)

0.81 (0.67 - 0.97)

0.61 (0.46 - 0.81)

0.64 (0.47 - 0.86)

0.72 (0.66 - 0.78)

<2.0

³2,<2.5

³2.5,<3.0

³3,<3.5

³3.5

Total

206 (9.0%)

339 (7.7%)

801 (8.2%)

1490 (10.8%)

4205 (12.6%)

7136 (11.0%)

217 (9.7%)

412 (9.1%)

1022 (10.5%)

1821 (13.3%)

5338 (15.9%)

8934 (13.8%)

0.87 (0.60 - 1.28)

0.77 (0.62 - 0.97)

0.76 (0.67 - 0.86)

0.77 (0.71 - 0.84)

0.80 (0.77 - 0.84)

0.79 (0.77 - 0.81)

More vs less statin

Statin vs control

All trials

Relative risk (CI) permmol/L LDL-C reduction

99% or 95% CI

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction, by baseline LDL-C

Primary Endpoint — ITT (2014)

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

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

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 Cholesterol (m

g/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)

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

0%

2%

4%

6%

8%

10%

12%

14%

16%

Primary Endpoint

Evolocumab

Placebo

Months from Randomization

CV Death, MI, Stroke,

Hosp for UA, or CorRevasc

0 6 12 18 24 30 36

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

P<0.0001 12.6%

14.6%


PCSK9 Inhibition and Very low LDL-‐C

Giugliano et al. Lancet Aug 28, 2017

25,982 Fourier patients – 4 week LDL-CPositive outcomes down to 0.2 mmol/L


PCSK9 Inhibition and Very low LDL-‐C

Giugliano et al. Lancet Aug 28, 2017

25,982 Fourier patients – 4 week LDL-CPositive outcomes down to 0.2 mmol/LPrimary EP – death, MI, revasc, hospitalization for UA


Ongoing Outcome Trials with PCSK9 Inhibitors

ACS: acute coronary syndrome; CAD: coronary artery disease; CHD: coronary heart disease; CVD: coronary vascular disease; EZE: ezetimibe; FH:Familial Hypercholesterolemia; HeFH: Heterozygous Familial Hypercholesterolemia; PAD: peripheral-‐artery disease; T2DM: type 2 diabetes mellitus.clinicaltrials.gov accessed August 25, 2015.

Study FOURIER ODYSSEY OUTCOMES SPIRE-‐1/ SPIRE-‐2

Treatment

Evolocumab: 420 mg QM or 140 mg Q2W

Background: optimal lipid lowering therapy

Alirocumab: 75 mg Q2W (up titrated to 150 mg Q2W if LDL >1.3 mmol/L;; down titrated

if LDL <0.65 mmol/L)Background: optimized lipid

lowering therapy

Bococizumab: 150 mg Q2W

Background: lipid lowering therapy

PopulationMI or stroke (≥ last 4 weeks)

OR PAD(plus Risk factors for CVD)

Patients hospitalized for ACS(<12 months before randomization)

Patients at high risk of a CV event

# patients 27,500 18,000 SPIRE-1: 17,000SPIRE-2: 9,000

LDL-C for eligibility

LDL-C ≥ 1.8 mmol/L (or non-HDL-C ≥ 2.6 mmol/L) after 4 week stabilization with optimal

lipid lowering therapy

≥ 1.8 mol/L or non-HDL-C ≥ 2.6 mmol/L

SPIRE-1: LDL-C ≥1.8 and <2.6 mmol/L SPIRE-2: LDL-C ≥2.6 mmol/L or non-HDL-C ≥3.4 mmol/L

Estimated study completion 2017 December 2017 SPIRE-1:June 2018

SPIRE-2: March 2018


CETP Inhibition in CV disease

Landry et al. NEJM;; Aug 24, 201730449 in TIMI 55/Reveal Study



Targets – ACC/AHA

Lloyd-Jones JACC 2017


When to Consider Pharmacological Treatment in Risk Management – Statin Indicated conditions


Targets – American Association of Clinical Endocrinologists

Jellinger et al. Endocrine Practice 2017;;23:supplement


Quantitative approach to non-statins

Robinson et al. JACC 2016;;68:2412

Defined risk based on trialsUsed % reduction in LDL-C for various drugs to determine NNT in different scenariosCTT estimate of event reduction based on 22% per 1 mmol/L

Very high risk – CVD plus DM or CKD or FH, or recent ACS

High risk – CVD alone, or FH in primary prevention


PCSK9 Inhibition – cost effectiveness

Fonarow et al, JAMA Cardiology, August 2017

Annual event rate of 6.4%/yr


• Target levels of LDL-C• Lower target of 1.8 for ASCVD• Elimination of target – use indications for combination therapy

• > 50 % reduction and target of < 1.8 for ASCVD

• Role of Combination therapy• Change in status of PCSK9 inhibitors

• Risk assessment strategies• More categories of risk • Different algorithms to determine risk instead of just FRS or statin indicated conditions

Areas to consider guideline change

Documents

Tues 07 Anderson Dyslipidemia0.5 0.75 1 1.25 1.5 Statin/more better Control/less better