1

avigating the Canadian Lipid Guidelines

Rob Hegele MD, FRCPC, FACPSchulich School of Medicine & Dentistry

University of Western OntarioLondon, Ontario, Canada

Disclosure: Speaker and advisory board member forAbbott, Aegerion, Amgen, AstraZeneca, Genzyme,

Merck, Pfizer, Roche, Sunovion

N

E

S

W

Non-HDL

Evidence base

Secondary markers

Whom to screen?

Non-HDL

Evidence base

Secondary markers

Whom to screen?

Non-HDL

Evidence base

Secondary markers

Whom to screen?

Whom to screen?

23-04-19 7

Whom to screenMen ≥40 years of age, and women ≥50 years of age or postmenopausal

All patients with the following conditions, regardless of age o Current cigarette smoking o Diabetes o Arterial hypertension o Family history of premature CVD (<55 years in men and 65 years in

women) o Family history of hyperlipidemia o Erectile dysfunction o Moderate renal function impairment (eGFR <60 mL/min/1.73 m2) or

urinary albumin:creatinine >3 mg/mmol (micro-albuminuria) o Inflammatory disease (rheumatoid arthritis, systemic lupus erythematosus,

psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease) o HIV infection o Chronic obstructive pulmonary disease o Abdominal aneurysm o Evidence of atherosclerosis o Clinical manifestation of hyperlipidemia (xanthomas, xanthelasmas,

premature arcus cornealis) o Obesity (metabolic syndrome, pre-diabetes, polycystic ovarian syndrome,

body mass index > 30 kg/m2)

8

Risk ratio & 95% CIPlaceboEze/simv

Eze/simv better

Placebo better

(n=4620)(n=4650)

Non-dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=3023) 230 (15.0%) 246 (16.5%)

Any patient 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022)

0.6 0.8 1.0 1.2 1.4

SHARP: Major atherosclerotic eventsby renal status at randomization

No significant heterogeneity between non-dialysis and dialysis patients (p=0.25)

23

23-04-19 9

Risk assessment: recommendationsCV risk assessment using the “10 year risk” from the Framingham model modified (% risk doubled) when family early CVD history is positive (i.e. 10 relative <55 years for men; <65 years for women).

Every 3 to 5 years for men 40 -75 y and women 50 – 70 y.

Assess risk whenever a patient’s expected risk status changes.

Younger individuals with > 1 risk factor may also benefit from a risk assessment to motivate them to improve their lifestyle.

(Strong/Moderate)

23-04-19 10

Limitations of 10 year risk estimates• Sensitive to the patient’s age• Majority of individuals are “low risk”• More accurate among younger individuals• Competing risk increases with age (i.e. cancer)• Risk categories (low, intermediate, high) are arbitrary;

by consensus• Sub-optimal understanding and use

Despite the limitations assessing total CVD risk improves management of blood pressure and blood lipids

23-04-19 11

High risk recommendations1. Defined as clinical atherosclerosis, or DM > 15 years

duration, or DM with age > 40 years, or adjusted FRS > 20%. (Strong/High).

2. Now AAA, COPD, high risk CKD and high risk hypertension are included. (Strong/High).

3. Primary target LDL-C < 2.0 mmol/L or > 50% reduction. Alternative targets: apo B < 0.80 g/L or non-HDL-C < 2.6 mmol/L. (Strong/Moderate).

23-04-19 12

Risk assessment: values and preferences

1. The primary evaluation is the modified 10 year Framingham Risk Score (FRS).

2. Simultaneous evaluation of cardiometabolic risk for diabetes may motivate lifestyle changes.

3. 10 year FRS is limited in younger individuals, in whom calculation of “cardiovascular age” can motivate subjects to achieve risk factor targets.

Non-HDL

23-04-19 14

Non-HDL-C as an alternate target

23-04-19 15

Non-HDL-C as an alternate target

non-HDL-C = TC – HDL-C

23-04-19 16

Non-HDL-C: values and preferences

• Adding non-HDL-C: ? simplifying the guidelines.

• However, apo B is not available in some jurisdictions, while non-HDL-C is available with no extra cost or testing.

• Also, increasing data demonstrate its potential advantages over LDL-C: superior risk predictor, fasting not required.

• Therefore, it was decided to increase its profile in the guidelines. Non-HDL-C is particularly useful when apo B is unavailable and TG > 1.5 mmol/L.

23-04-19 17

Practical tips

• LDL-C remains the primary target in the guidelines. Clinicians would be encouraged to be familiar with the use of LDL-C and one of the two alternate targets.

• We do not advocate using all 3 indices regularly or testing for LDL-C, non-HDL-C and apo B concurrently in subjects.

• For those who have apo B available and are comfortable with using it, there are advantages that were previously addressed.

Evidence base

19

LDL-C lowering: major CV eventsA prospective meta-analysis of data from 129,526 individuals from 26 trials of statins

Prop

ortio

nal r

educ

tion

inat

hero

scle

rotic

eve

nt ra

te (9

5% C

I)

0%

5%

10%

15%

20%

25%

30% Statin vs control(21 trials)

More vs Less(5 trials)

0 0.50 1.00.25 0.75

Cholesterol treatment trialists’ (CTT) collaborators. Lancet 2010 Nov 13;376:1670-81

Mean LDL-C difference between treatment groups (mmol/L)

20

LDL-C lowering in low-risk people

Cholesterol treatment trialists’ (CTT) collaborators. Lancet 2012 Aug 11; 380:581-90.

A prospective meta-analysis of data from 174,149 individuals from 27 trials of statins

23-04-19 21

Low risk recommendations1. Pharmacotherapy with LDL-C ≥ 5.0 mmol/L, or

evidence of genetic dyslipidemia (e.g. familial hypercholesterolemia) (Strong/Moderate Evidence).

2. >50% reduction of LDL-C after treatment is initiated (Strong/Moderate Evidence)

23-04-19 22

Low risk: values and preferences

General procedure: unchanged.

Less clinical trial evidence, so practice will vary and depend on patient wishes and clinical evaluation.

For subjects with 5-9% risk:

- more frequent monitoring of risk- discuss risks/benefits of statin therapy- judicious use of secondary testing

Secondary markers

23-04-19 24

Secondary testing

Biochemical: hsCRP, Lp(a), HbA1c and ACR

Imaging: IMT, ABI, GXT, CAC

Choose selectively to help clarify risk when FRS and lipid levels are not definitive

23-04-19 25

Choose a test appropriate for the patient (not multiple tests)• Lp(a) 30-70 mg/dL: 1.3 X increased CVD risk Lp(a) > 80 mg/dL: 1.5 X increased CVD risk

• hsCRP > 2 mg/dL: ~ 1.5 - 2.0 X increased CVD risk

• HbA1c 6.0 – 6.5 %: ~ 1.5 - 1.8 X increased CVD risk

• Microalbuminuria (ACR): ~ 1.5 X increased CVD risk

23-04-19 26

Secondary testing recommendations 1. Perform to further assess risk in “intermediate risk”

subjects who are not candidates for lipid treatment based on conventional risk factors or when treatment is uncertain. (Strong/Moderate Evidence).

2. Consider for a selected subset of “low to intermediate risk” (5-9% FRS) subjects for whom further risk assessment is indicated, e.g. strong FHx of premature CAD, abdominal obesity, South Asian ancestry or IGT. (Weak/Low Evidence).

Non-HDL

Evidence base

Secondary markers

Whom to screen?

23-04-19 28

Summary of 2012 lipid guideline targetsRisk Level Initiate therapy if: Primary Target

LDL-CAlternate Targets

High Consider treating all(Strong/High)

≤ 2 mmol/L or 50% decrease (Strong/High)

Apo B ≤ 0.8 g/LNon HDL-C ≤ 2.6 mmol/L(Strong/Moderate)

Intermediate LDL-C ≥ 3.5 mmol/L (Strong/Moderate)Consider ifapo B ≥ 1.2 g/L ornon-HDL-C ≥ 4.3 mmol/L(Conditional, Moderate)

≤ 2 mmol/L or 50% decrease (Strong/High)

Apo B ≤ 0.8 g/LNon-HDL-C ≤ 2.6 mmol/L(Conditional/Moderate)

Low * LDL-C ≥ 5.0 mmol/L (Familial hypercholesterolemia)(Strong/Moderate)

50% decrease(Strong/Moderate)

* For 5-9% group, consider yearly FRS and discuss risk-benefit of Rx at lower LDL-C

23-04-19 29

Summary of 2012 lipid guideline targetsRisk Level Initiate therapy if: Primary Target

LDL-CAlternate Targets

High Consider treating all(Strong/High)

≤ 2 mmol/L or 50% decrease (Strong/High)

Apo B ≤ 0.8 g/LNon HDL-C ≤ 2.6 mmol/L(Strong/Moderate)

Intermediate LDL-C ≥ 3.5 mmol/L (Strong/Moderate)Consider ifapo B ≥ 1.2 g/L ornon-HDL-C ≥ 4.3 mmol/L(Conditional, Moderate)

≤ 2 mmol/L or 50% decrease (Strong/High)

Apo B ≤ 0.8 g/LNon-HDL-C ≤ 2.6 mmol/L(Conditional/Moderate)

Low * LDL-C ≥ 5.0 mmol/L (Familial hypercholesterolemia)(Strong/Moderate)

50% decrease(Strong/Moderate)

* For 5-9% group, consider yearly FRS and discuss risk-benefit of Rx at lower LDL-C

30

Framingham risk score adjusted (doubled) for family history

Secondary and high-risk prevention:• RCT evidence for CKD (SHARP study)• include AAA, COPD and high-risk hypertension (ASCOT study)

Primary prevention:• Intermediate risk defined as FRS 10-19% ten-year risk • Low risk: more frequent monitoring at 5-9% risk• Secondary tests to stratify risk when LDL-C does not trigger Rx

Targets:• primary: LDL-C < 2.0 mmol/L or > 50% reduction• alternate: non-HDL-C < 2.6 mmol/L

or apo B < 0.8 g/L

Changes since 2009

Non-HDL

Evidence base

Secondary markers

Whom to screen?

32

http://www.ccs.ca/guidelines/index

23-04-19 33

Statin intolerance1) statins not be withheld on the basis of a potential,

small risk of new-onset DM (Strong/Very Low).2) evaluate all purported statin-associated symptoms

systematically, observe during cessation, re-initiation (same or switch), altered dosing frequency to find a tolerated, statin-based therapy. (Strong/Very Low).

3) we do not recommend vitamins, minerals or supplements for symptoms of myalgia perceived to be statin-associated. (Strong/Very Low).

34

Take home points1. FRS doubled with positive family history2. Primary target: - absolute LDL-C < 2 mmol/L

- relative decrease in LDL-C >50%

3. Alternates: - non-HDL-C < 2.6 mmol/L - apo B < 0.8 g/L

4. 5-9% risk: - monitor yearly5. Secondary markers:

- biochemical: hsCRP, Lp(a), A1c, ACR- non-invasive: GXT, ABI, IMT, CAC

6. Lifestyle recommendations7. Statin intolerance recommendations

23-04-19 35

Lifestyle advice

• Health behaviour interventions are the cornerstone of CVD management and prevention– Diets– Exercise– Alcohol intake– Cigarette smoking– Stress and mental health issues

23-04-19 36

Lifestyle recommendationsEncourage all to adopt healthy eating habits to lower CVD risk: 1)Moderate energy (caloric) intake to achieve/maintain a healthy body weight.2)Emphasize a diet rich in vegetables, fruit, whole-grain cereals, poly- and mono-unsaturated, including omega-3 fatty acids particularly from fish. 3)Avoid trans fats, limit saturated and total fats to < 7% and < 30% of daily total energy (caloric) intake, respectively.4)Increase daily fibre intake to > 30 g.5)Limit cholesterol intake < 200 mg daily for individuals with dyslipidemia or at increased CVD risk. (Conditional/Moderate Evidence)

23-04-19 37

Lifestyle recommendations• Adults should accumulate > 150 minutes of

moderate-to-vigorous-intensity aerobic physical activity per week, in bouts of 10 min or more to reduce CVD risk. (Strong/High)

• We recommend smoking cessation (Strong/Moderate)

• Limit alcohol intake to < 30 g per day (1-2 drinks) (Strong/High)