Lipid reporting Stephen du Toit

The bad news is…

Current report

• Primary prevention viewpoint

• Lipids - one component of CVD risk assessment

• “Lipid reporting” focus of this presentation

• Reporting – historic “targets” from pre 2003

• MOH guidelines released November 2013

Combined CVD risk >20% 2013

• For people with known cardiovascular disease and those with a combined cardiovascular risk >20 percent, statin treatment is strongly recommended.

• For people with known CVD or combined CVD risk >20 percent, start with 20–40 mg of atorvastatin.

• There is no evidence that outcomes are improved by adding other cholesterol-lowering drugs to a statin.

• Targets not mentioned!

Combined CVD risk 10 – 20% 2013

• For patients with combined CVD risk between about 10 percent and 20 percent, discuss the benefits (and risks) of initiating statins.

• Following lifestyle management, repeat lipid profile (non-fasting) to recalculate risk and use the results to inform shared treatment decision-making in 6–12 months.

• The aim is to achieve a moderate reduction in LDL-C; no target is required for those with a combined risk ratio under 20 percent.

• Re-measurement can wait until the next formal combined risk assessment.

Combined CVD risk < 10%

• Most patients can be managed without drug treatment

• All patients benefit from lifestyle interventions • Diet

• Physical activity

• Weight

• Smoking cessation

Replacing this:

Total cholesterol < 8

A combined CVD risk, of which lipids is one component, should be estimated to guide CVD risk management decisions. If lipid modifying medication is considered, suggest checking for treatable secondary causes of dyslipidaemia.

Total cholesterol ≥ 8

Lipid lowering treatment is usually recommended when Total Cholesterol or TC:HDL ratio is > 8. Treatable secondary causes of dyslipidaemia should be considered and excluded before starting lipid medication. Hereditary causes of dyslipidaemia should be considered.

Triclycerides ≥ 10 mmol/L

Triglyceride levels above 10 mmol/L are associated with increased risk of pancreatitis. Secondary causes such as obesity, high alcohol intake and impaired glucose tolerance/diabetes should be considered.

HDL ≥ 2.5 mmol/L

An elevated HDL is not always associated with decreased CVD risk.

Why?

• Targets have been used for > 15 years and “served us well”

• Lower (LDL) is better!

• Why discard targets ?

• 2013 Guidelines focus on statins

Gaps in evidence for targets (2013)

• No trial with titration of dose to achieve LDL target in all participants

• Ideal targets unknown

• “Better” response to statin does not predict better outcome

• Higher dose improves outcome

• Adding some non-statins does not reduce risk

• Adding non statins may cause harm

• Increased dose of statin causes harm

• Undertreat patients with “lowish” baseline levels

Heart Protection Study

• 320145 entered pre-randomisation run in phase:

4 – 6 weeks of simvastatin to limits randomisation to those likely to take statin for 5 years.

• LDL response was measured.

• 20 536 High risk patients, randomised to 40 mg Simvastatin daily

• Even rate = first major vascular event

Response Simvastatin Placebo < 38 % 19.9 25.6

Average 20 25.1 > 48% 19.5 24.8

Lancet 2002; 360: 7–22

Treat to new Targets

• 3rd NCEP recommended LDL < 2.5 in high risk CHD patients

• 18 000 patients with clinically evident CHD screened

• LDL 3.4 – 6.5 given Atorvastatin 10 mg

• 10 000 patients with mean LDL of < 3.4 mmol/L while on 10 mg Atorvastatin randomised to 10 or 80 mg Atorvastatin

• Primary outcome: Major Cardiovascular event

• Follow-up median of 4.9 years

LaRosa JC et al. N Engl J Med 2005;352:1425-1435.

Mean Lipid Levels during the Study.

2.6 2.0

LaRosa JC et al. N Engl J Med 2005;352:1425-1435.

Cumulative Incidence of a First Major Cardiovascular Event (Panel A), a First Major Coronary Event (Panel B), Nonfatal Myocardial Infarction (MI) or Death

from CHD (Panel C), and a First Fatal or Nonfatal Stroke (Panel D).

Total major CVD

event

10.9 vs 8.7

Any cardiovascular

33.5 vs 28.1

Adverse effects

8.1 vs 5.8%

Rubins HB et al. N Engl J Med 1999;341:410-418.

Kaplan–Meier Estimates of the Incidence of Death from Coronary Heart Disease and Nonfatal Myocardial Infarction in the Gemfibrozil and Placebo

Groups. VA HIT trial

Recruited 1991 – 1993

2531 men

CVD disease

Low HDL and LDL,

moderate ↑trigs

No effect on LDL

HDL increased by 0.1

mmol/L

Trigs decreased by 31%

22 % reduction in CVD

death, AMI

The ACCORD Study Group. N Engl J Med 2010;362:1563-1574.

Kaplan–Meier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death.

ACCORD study

5518 Diabetic

patients

Outcome = 1st CVD

event

36% CVD disease

Simvastatin +

fenofibrate/placebo

Mean followup 4.7

years

The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203-212.

First Major Vascular Event during Follow-up.

HPS2-THRIVE study 25 500 with CVD disease All on “effective statin” Niacin-laropiprant arm: LDL decreased by 0.25 mmol/L HDL increased by 0.16 mmol/L Trigs decreased by 0.37 mmol/L No benefit

The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203-212.

Effects of Niacin–Laropiprant on Selected Serious Adverse Events and Diabetes.

Barter PJ et al. N Engl J Med 2007;357:2109-2122.

Kaplan–Meier Curves for Death from Any Cause and for the Primary Composite Outcome.

Illuminate trial CETP inhibitor Torcetrapid or placebo 15 000 with CVD disease. Atorvastatin HDL increased by 70% LDL decreased by 25% Systolic increased by 4.5 mmHg HR for CVD = 1.25 HR for death = 1.58 – trial stopped!

6.Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–742

2013 MOH guidelines

Principle: Intensity of treatment is proportional to estimated CVD risk.

Goal is to reduce CVD risk.

• Easier to modify very abnormal than moderately abnormal risk factor

• Often appropriate to treat risk factors simultaneously

• BP/statins work independently to reduce CVD risk

• Lipids - Statin focussed.

- no drugs with additional benefit when combined with statin

BUT

Since 2013….

Ezetimibe and PCSK-9

Cannon CP et al. N Engl J Med 2015;372:2387-2397.

Kaplan–Meier Curves for the Primary Efficacy End Point.

IMPROVE-IT 18 000 post ACS on 40 mg Simvastatin randomised to Ezetimibe/placebo 7 years followup Mean LDL 1.8 vs 1.4 Endpoint 34% vs 32% = same as predicted for statins for same LDL reduction

Figure. After undergoing autocleavage in the endoplasmic reticulum (ER), the prodomain of

PCSK9 remains associated with the catalytic domain in the Golgi, and the complex is secreted

into the plasma.

Omar N. Akram et al. Arterioscler Thromb Vasc Biol.

2010;30:1279-1281

Copyright © American Heart Association, Inc. All rights reserved.

PCSK9 2003- gain of function causes FH 2005- Loss of function in 2% of African American Low LDL levels 88% reduction in CVD risk

Serine protease Binds to LDL receptor Co-internalised with LDL receptor in lysosome LDL receptor degraded rather than recycled

Sabatine MS et al. N Engl J Med 2015;372:1500-1509.

Low-Density Lipoprotein (LDL) Cholesterol Levels.

Sabatine MS et al. N Engl J Med 2015;372:1500-1509.

Cumulative Incidence of Cardiovascular Events.

Open label randomised trial 11 months median followup Once a month evolocumab subcut or 2 weekly No placebo Primary endpoint adverse effects Fourier trial 27 500 high risk patients, expected to be reported in 2017 27 August 2015 FDA approval in patients with FH or Clinical CVD !

New guidelines in development

Gerry Devlin member

So… • Lower probably be better but how you get there

is important

• New calculator using NZ data • New guidelines under development Expected in about 12 months Expect NZ population based risk calculator and revised “CVD risk levels” Treat to reduce the risk.

Thanks for your attention