- Top tips in lipid lowering - Issues & Answers 2019...Declaration of interests • I have received honoraria for participation in advisory boards for Genzyme, Roche, Aegerion, Sanofi

Dyslipidaemia

- Top tips in lipid lowering

Dr RDG Neely

Head of Lipid Clinic, Royal Victoria Infirmary,

Newcastle upon Tyne

Trustee, HEART UK

Declaration of interests

• I have received honoraria for participation in advisory boards for Genzyme, Roche, Aegerion, Sanofi and Amgen.

• I have received sponsorship from MSD to attend an educational meeting.

• I have been Newcastle upon Tyne hospital NHS Foundation Trust site investigator for clinical trials sponsored by KaraBio, MSD, Sanofi, Amgen and ISIS.

• I am a Trustee and board member of the Heart UK the Cholesterol Charity and Co-Chairman of the Familial Hypercholesterolemia Guideline implementation group.

• I am a member of Newcastle FATS guideline group on lipid modifiying treatment.

D1

Dyslipidaemia – the latest NICE Guideline

National Clinical Guideline Centre July 2014

CG181 Lipid modification: Cardiovascular risk assessment and the

modification of blood lipids for the primary and secondary prevention

of cardiovascular disease

10 Everyday Dilemmas in Dyslipidaemia

1. Full fasting lipid profile or non-fasting test? 2. To QRisk or not to QRisk? 3. Is it FH? Who to treat and who to refer? 4. Treat now or try lifestyle intervention? 5. What statin, what dose? 6. Statin switching – out with the old? 7. When should I worry about liver enzymes? 8. Who needs combination lipid lowering therapy? 9. What about the triglycerides? 10.Statin intolerance – fact or fiction?

D1



D1

Lp(a)

Fasting

Non-Fasting

Fasting – does it matter?

Lipid Measurements Total cholesterol includes both atherogenic (LDL-C, IDL-C

and VLDL-C) and anti-atherogenic fractions (HDL-C). Method calibration varies between laboratories

HDL-Cholesterol anti-atherogenic fraction, essential for risk assessment, but newer automated methods are prone to positive bias

Triglycerides not considered directly atherogenic but is a risk modifier, a component of the “Metabolic syndrome”, sentinel marker of secondary hyperlipidaemias, risk factor for pancreatitis, 12h fasting triglycerides <4.5 required for calculation of LDL-C.

Calculated Lipid Variables LDL-Cholesterol considered the most important class of

atherogenic lipoproteins; calculated using the Friedewald equation:

(LDL-C = TC – (HDL-C + TG/2.2)

Non-HDL-C Total atherogenic lipoproteins, alternative to LDL-C recommended by NCEP when TG are elevated or patient is non-fasting, simpler to calculate than LDL-C:

(Non-HDL-C = TC – HDL-C) Non-HDL-C is a more reliable measurement for monitoring treatment LDL-C is required for diagnosis of Familial Hypercholesterolaemia

Calculated Lipid Variables LDL-Cholesterol considered the most important class of

atherogenic lipoproteins; calculated using the Friedewald equation:

(LDL-C = TC – (HDL-C + TG/2.2)

Non-HDL-C Total atherogenic lipoproteins, alternative to LDL-C recommended by NCEP when TG are elevated or patient is non-fasting, simpler to calculate than LDL-C:

(Non-HDL-C = TC – HDL-C) Non-HDL-C is a more reliable measurement for monitoring treatment LDL-C is required for diagnosis of Familial Hypercholesterolaemia BUT Calculation of LDL-C assumes a constant Cholesterol /TG ratio in VLDL, which requires fasting to ensure absence of postprandial lipoproteins, including chylomicrons and chylomicron remnants

Lp(a)

HDL-C Non-HDL-C

GOOD BAD

What’s in non-HDL-cholesterol?

Chylomicron remnants

(RLP)

Major Atherogenic Lipoproteins

LDL

Lp(a)

IDL

Lp(a) Lp(a)

HDL-C Non-HDL-C

GOOD BAD

NICE CG181 Recommendations 2014

Lipid measurement and referral

• Before starting lipid modification therapy for the primary prevention of CVD, take at least 1 lipid sample to measure a full lipid profile. This should include measurement of total cholesterol, HDL cholesterol, non-HDL cholesterol and triglyceride concentrations. A fasting sample is not needed. [new 2014] [1.3.4]



D1

Identifying and assessing cardiovascular disease (CVD) risk

• Use the QRISK2 risk assessment tool to assess CVD risk for the primary prevention of CVD in people up to and including age 84 years. [new 2014] [1.1.8]


When should the QRISK2-2014 NOT be used ?

1. High cardiovascular risk conditions i

people with pre-existing CVD

ii Chronic Kidney Disease with estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 and/or albuminuria

iii Type 1 Diabetes

iv People aged 85 or older who are at increased risk of CVD because of age alone, particularly those who smoke or have raised blood pressure

individual management as per NICE Clinical Guideline CG181

When should the QRISK2-2014 NOT be used ?

2. People at high CVD risk because of familial hypercholesterolaemia (FH) or other inherited disorders of lipid metabolism.

After exclusion of secondary hyperlipidaemias, clinical suspicion of FH or FCH if:

Total Cholesterol >7.5 mmol/l with a family history of premature CVD AND LDL-C > 4.9 mmol/l

OR Total Cholesterol >9.0 mmol/l With no family history of premature CVD OR Non-HDL-Cholesterol > 7.5

OR Triglycerides > 10 mmol/l (12 hour fasting) + additional risk of pancreatitiis

BUT Use the clinical findings, lipid profile and family history to judge the likelihood of a familial lipid disorder rather than the use of strict lipid cut-off values alone (NICE CG71)

When might QRISK2-2014 underestimate risk?

additional risk with underlying medical conditions or treatments:

i People already taking antihypertensive or lipid modification therapy, or who have recently stopped smoking.

ii people treated for HIV iii people with serious mental health problems

iv people taking medicines that can cause dyslipidaemia (e.g. antipsychotics, corticosteroids or immunosuppressants)

v people with autoimmune and other systemic inflammatory disorders such as systemic lupus erythematosus, psoriasis

vi Severe obesity (body mass index greater than 40 kg/m2)

vii Triglycerides > 4.5 mmol/l (12 hour fasting) http://www.nice.org.uk/guidance/cg181



D1

Is it FH?

Tendon Xanthomas


• Use the clinical findings, lipid profile and family history to judge the likelihood of a familial lipid disorder rather than the use of strict lipid cut-off values alone. [new 2014] [1.3.5]

• Exclude possible common secondary causes of dyslipidaemia (such as excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease and nephrotic syndrome) before referring for specialist review. [new 2014] [1.3.6]


Condition / drug treatment

Lipid change Lipoprotein elevated Cholesterol Triglycerides HDL-C

Diabetes mellitus ++/+ - VLDL Untreated hypothyroidism ++ LDL Alcohol excess ++/+ + VLDL Obesity + - VLDL Chronic renal failure + ++ - VLDL/ LDL Nephrotic syndrome ++ + VLDL/ LDL Cholestasis ++ LDL/LP-X Gout + VLDL Pregnancy +/- +/++ VLDL Anorexia nervosa + LDL Hypopituitarism +/+++ ++/+ - VLDL/ LDL/ IDL/ RLP Long term drug treatment Anticonvulsants +/++ HDL Androgens -/-- Lowers HDL Atypical antipsychotics +/+++ +/+++ - VLDL/LDL Beta blockers + VLDL Corticosteroids + + - VLDL/ LDL Ciclosporin + + - LDL/ VLDL HIV/anti-retroviral drugs +/++ VLDL Oral oestrogens + + VLDL Retinoids ++/+ - VLDL

Secondary Dyslipidaemias

Exclusion of Secondary Hyperlipidaemias Key Investigations

Tests Exclude Renal profile (Na+,K+,Creatinine, eGFR) Renal failure

Liver profile (TProt, Alb, ALP, ALT, GGT) Cholestasis, M protein

Thyroid profile (TSH, FT4) Hypothyroidism

HbA1c (or Fasting Glucose) Diabetes

Dipstick urinalysis (protein) Nephrotic Syndrome

Also consider

Creatine Kinase (CK) High Baseline


• Consider the possibility of familial hypercholesterolaemia and investigate as described in Familial hypercholesterolaemia (NICE clinical guideline 71) if they have:

• a total cholesterol concentration more than 7.5 mmol/litre and

• a family history of premature coronary heart disease. [new 2014] [1.3.7]


Familial Hypercholesterolaemia Mechanism: Reduction in receptor mediated clearance of LDL

Due to mutation of LDLR, APOB or PCSK9 gene

Prevalence: 1 in 500

Lipid Profile: Elevated LDL-cholesterol, TC 9-12mmol/L

Inheritance: Autosomal dominant

Physical Signs: Tendon Xanthomas, corneal arcus Homozygotes – planar cutaneous xanthomas, aortic stenosis

CHD risk: Very high (affects 50% of males by age 50, 50% of females by age 60)

NB 80% of primary hypercholesterolaemia is polygenic

Prevalence of Primary Hyperlipidaemias Hypercholesterolaemia approx. frequency

Familial 1 in 500 Polygenic 1 in 50

Hypertriglyceridaemia

Familial lipoprotein lipase deficiency 1 in 1,000,000

Familial apolipoprotein CII deficiency 1 in 1,000,000

Familial Hypertriglyceridaemia 1 in 100

Combined Hyperlipidaemia

Familial combined hyperlipidaemia 1 in 100

Familial Type III (Remnant) Hyperlipidaemia

1 in 5,000


• Arrange for specialist assessment of people with a total cholesterol concentration of more than 9.0 mmol/litre or a non-HDL cholesterol concentration of more than 7.5 mmol/litre even in the absence of a first-degree family history of premature coronary heart disease. [new 2014] [1.3.8]




D1

Lifestyle modifications for the primary and secondary prevention of CVD [1.2]

To encourage the person to participate in reducing their

CVD risk: • find out what, if anything, the person has already been told

about their CVD risk and how they feel about it • explore their beliefs about what determines future health • assess their confidence in making changes to their lifestyle,

undergoing investigations and taking medication • inform them of potential future management based on

current evidence and best practice • involve them in developing a shared management plan • check with them that they have understood what has been

discussed. [new 2014] [1.1.27]




D1

Lipid modification therapy for the primary and secondary prevention of CVD

• Offer atorvastatin 20 mg for the primary

prevention of CVD to people who have a 10% or greater 10-year risk of developing CVD. Estimate the level of risk using the QRISK2 assessment tool. [new 2014] [1.3.18]


31%–40%: medium intensity

Statins are grouped into intensity categories Reduction in LDL cholesterol

Dose (mg/day) 5 10 20 40 80 Fluvastatin – – 21% 27% 33% Pravastatin – 20% 24% 29% – Simvastatin – 27% 32% 37% 42%*

Atorvastatin – 37% 43% 49% 55% Rosuvastatin 38% 43% 48% 53% –

LDL=low-density lipoprotein. *MHRA advice: there is an increased risk of myopathy with high-dose (80 mg) simvastatin. This dose should be considered only in people with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when benefits are expected to outweigh potential risks.

20%–30%: low intensity

Above 40%: high intensity

D10

Lipid modification therapy for the primary and secondary prevention of CVD

• Start statin treatment in people with CVD with

atorvastatin 80 mg. Use a lower dose of atorvastatin if any of the following apply:

• potential drug interactions • high risk of adverse effects • patient preference.

[new 2014][1.3.20]

NICE CG181 Key Priority 2014

Follow-up of people started on statin treatment

• Measure total cholesterol, HDL cholesterol and

non-HDL cholesterol in all people who have been started on high-intensity statin treatment at 3 months of treatment and aim for a greater than 40% reduction in non-HDL cholesterol. [new 2014] [1.3.28]


Follow-up of people started on statin treatment

If a greater than 40% reduction in non-HDL cholesterol

is not achieved: • discuss adherence and timing of dose • optimise adherence to diet and lifestyle

measures • consider increasing dose if started on less

than atorvastatin 80 mg and the person is judged to be at higher risk because of comorbidities, risk score or using clinical judgement. [new 2014] [1.3.28]




D1

31%–40%: medium intensity

Statins are grouped into intensity categories Reduction in LDL cholesterol

Dose (mg/day) 5 10 20 40 80 Fluvastatin – – 21% 27% 33% Pravastatin – 20% 24% 29% – Simvastatin – 27% 32% 37% 42%*

Atorvastatin – 37% 43% 49% 55% Rosuvastatin 38% 43% 48% 53% –

LDL=low-density lipoprotein. *MHRA advice: there is an increased risk of myopathy with high-dose (80 mg) simvastatin. This dose should be considered only in people with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when benefits are expected to outweigh potential risks.

20%–30%: low intensity

Above 40%: high intensity

D10



D1

>3 x ULN

<3 x ULN

Increase from baseline liver enzymes

Managing Liver Enzyme Abnormalities

Consider other causes of liver damage (e.g. alcohol,

hepatitis, drug interaction)

Change to alternative statin with different metabolism or consider other options

NO

Stop statin Recheck liver enzymes

in 4 – 6 weeks

Recheck within 6 weeks

Persistently elevated

Resolved within 6 weeks

NO



D1

Combination Therapy for Preventing CVD

• Do not offer the combination of a bile acid sequestrant (anion exchange resin), fibrate, nicotinic acid or omega-3 fatty acid compound with a statin for the primary or secondary prevention of CVD [new 2014] [1.3.50]


Ezetimibe

• People with primary hypercholesterolaemia should be considered for ezetimibe treatment in line with Ezetimibe for the treatment of primary (heterozygousfamilial and non-familial) hypercholesterolaemia (NICE technology appraisal guidance 132) [2008] [1.3.51]


NICE TA132 – ezetimibe

Ezetimibe is recommended as an option for the treatment of adults with primary HC • who are intolerant to statin therapy or • when serum total or LDL-cholesterol is not

appropriately controlled either after appropriate dose titration of initial statin therapy or

• when dose titration is limited by intolerance to the initial statin therapy and consideration is being given to changing from initial statin therapy to an alternative statin.



D1

Triglycerides

• Refer for urgent specialist review if a person has a triglyceride concentration of more than 20 mmol/litre that is not a result of excess alcohol or poor glycaemic control. [new 2014] [1.3.9]

• In people with a triglyceride concentration between 10 and 20 mmol/litre:

• repeat the triglyceride measurement with a fasting test (after an interval of 5 days, but within 2 weeks) and

• review for potential secondary causes and • seek specialist advice if the triglyceride concentration

remains above 10 mmol/litre. [new 2014] [1.3.10]


Triglycerides

• In people with a triglyceride concentration between 4.5 and 9.9 mmol/litre:

• be aware that the CVD risk may be underestimated by risk assessment tools and

• optimise the management of other CVD risk factors present and

• seek specialist advice if non-HDL cholesterol concentration is more than 7.5 mmol/ litre.

[new 2014] [1.3.11]




D1

Statin intolerance - frequency of adverse effects

% of total

Muscle symptoms 70%

Elevated CK 12%

Liver enzyme abnormalities 14%

Gastrointestinal upset 8%

Other (skin, sleep disturbance, neuropathies) 8%

Minor muscle symptoms are commonest, reported by 10-15% of patients

Ruisinger JF et al., Am J Cardiol (2009) 103: 393

SEARCH – the demise of simvastatin 80mg

Link E et al, NEJM (2007) 359: 789

Is it a statin related myopathy (SRM)?

Fernandez G et al., Cleve Clin J Med (2011) 78: 393

Features of typical statin related myopathy Symmetrical pain or weakness in large proximal muscles Symptoms worsened by exercise Symptoms resolve within 2 weeks off statin Symptoms recur within 2 weeks of rechallenge Normal thyroid function, Vitamin D and CRP/ESR Feature suggesting alternative diagnosis Asymmetrical or distal muscle pain or weakness Symptoms are continuous Symptoms continue 2 weeks after statin cessation Symptoms do not return with statin rechallenge Evidence of hypothyroidism, low Vitamin D or high CRP

Statin-related myotoxicity (SRM) phenotype classification

Alfirevic A Clin Ther Pharmacol (2014)

Advice and monitoring for adverse effects

• Before offering a statin, ask the person if they have had persistent generalised unexplained muscle pain, whether associated or not with previous lipid-lowering therapy. If they have, measure creatine kinase levels (CK).

• If creatine kinase levels are more than 5 times the upper limit of normal, re-measure creatine kinase after 7 days. If creatine kinase levels are still 5 times the upper limit of normal, do not start statin treatment.

• If creatine kinase levels are raised but less than 5 times the upper limit of normal, start statin treatment at a lower dose.

[new 2014] [1.3.33]


Advice and monitoring for adverse effects

• Advise people who are being treated with a statin to seek medical advice if they develop muscle symptoms (pain, tenderness or weakness). If this occurs, measure creatine kinase. [new 2014] [1.3.34]

• If people report muscle pain or weakness while taking a statin, explore other possible causes of muscle pain or weakness and raised creatine kinase if they have previously tolerated statin therapy for more than 3 months. [new 2014] [1.3.35]


Statin Intolerance – specialist referral

• Seek specialist advice about options for treating people at high risk of CVD such as those with CKD, type 1 diabetes, type 2 diabetes or genetic dyslipidaemias, and those with CVD, who are intolerant to 3 different statins. Advice can be sought for example, by telephone, virtual clinic or referral. [new 2014] [1.3.43]


Statin Intolerance

• If a person is not able to tolerate a high-intensity statin aim to treat with the maximum tolerated dose. [new 2014] [1.3.41]

• Tell the person that any statin at any dose reduces CVD risk. If someone reports adverse effects when taking high-intensity statins discuss the following possible strategies with them:

• stopping the statin and trying again when the symptoms have resolved to check if the symptoms are statin related

• reducing the dose within the same intensity group • changing the statin to a lower intensity group.

[new 2014] [1.3.42]


Take Home Messages Use QRISK2 risk assessment tool to assess CVD risk for primary prevention

Make sure that secondary dyslipidaemias have been excluded

Do not use QRisk2 to assess CVD risk for secondary prevention OR in primary prevention in patients with CKD, Type 1 Diabetes or FH Risk threshold for the consideration of statin therapy for primary prevention lowered to 10% or greater 10 year risk of developing CVD

High intensity statin therapy is recommended for both primary and secondary prevention of CVD Non-fasting non-HDL-cholesterol replaces fasting LDL-cholesterol for monitoring and assessment of adequacy of response to therapy

Seek specialist advice about options for treating people at high risk of CVD who are intolerant to 3 different statins

Documents

- Top tips in lipid lowering - Issues & Answers 2019...Declaration of interests • I have received honoraria for participation in advisory boards for Genzyme, Roche, Aegerion, Sanofi