markedly elevated TAGS preclude estimation of HDL = unreliable

  • TC >8 or a TC:HDL-C ratio >8

    • Lipid lowerging treatment usually recommended regardless of combined CVD risk

Secondary causes of lipid abnormalities

  • diet

  • etoh

  • hypothyroidism

  • DM

  • liver disease

  • nephrotic syndrome

  • steroid treatment

  • pregnancy

  • consider genetic lipid disorder if:

    • TC ≥ 8mmol/L

    • premature fhx of coronary artery disease

Lipid lowering for people with combined CVD risk between 10-20%

  • Discuss benefits (and risks) of statins

  • Lifestyle

  • Repeat lipid profile 6-12 months

  • Aim: achieve moderate reduction in LDL-C

    • no target for those with combined risk \<20%

    • remeasure @ next CVRA

  • Consider treatable primary cause for a dyslipidaemia

    • High saturated fat diet

    • excessive EtOH

    • hypothyroidism

    • diabetes

    • liver disease

    • nephrotic syndrome

    • steroid treatment

  • consider lower dose statin

    • simvastatin 40mg or atorvastatin 20mg

Lipid lowering for people with combined CVD risk >20%

  • statin treatment strongly recommended

    • Atorvastatin: 20-40mg

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

Speicific lipid profiles:

  • predominant hypercholesterolaemia

    • statins = first line

    • can be used in combination with ezetimibe, nicotinic acid or resins

      • lower TC and LDL-C

      • Nicotinic acid / fibrates may be considered if low HDL \<1

      • very low HDL \<0.7 may require specialist review

  • predominant hypertriglyceridaemia

    • identify lifestyle

    • or any primary cause

    • correctin these factors may make drug treatment unecessary

    • Nicotinic acid, acipimox or fibrates most appropriate

    • statins usually not effective if TAG >5

  • combined

    • lifestyle

    • statin and nicotinic or gibrate

Statin:

  • Simvastatin

  • Atorvastatin

  • Pravastatin

  • Rosuvstatin (NS)

  • CYP 3A4

  • in those taking statin for 5yrs

    • NNT to prevent one non fatal MI = 39

    • NNT to prevent one death = 83

Monitoring

  • non fasting lipids q3-6/12 until person stable then once/year

    • moderate reduction in LDL-C

      • no specific target 20%

      • higher reduction if risk >20%

Adverse effects:

  • Muscle symptoms

  • medicine interactions

  • Major organ effects

    • hepatic/renal

  • metabolism

    • risk of T2DM

  • Memory

Hepatotoxicity

  • highly unsuual

    • “negligible”

  • routine monitoring unnecessary

  • UK/USA guidelines recommend baseline

    • ALT unlikley provide useful information unless suspect liver dysfunction

  • elevated ALT/AST less than 3%

    • not significantly differnet from those taking placebo

    • often return to normal wihtout pt. needing to stop taking statin

  • if ALT markedly elevated

    • risk v benefit should be revisitied

    • used in caution if 3x upper limit of N

    • lower dose may be appropriate if choose to start

    • NAFLD = mild-moderate rise

      • Atrovastatin = reduce aminotransferase levels in thi sgroup

      • mildly abnormal levels in NAFLD = not contraindication for statin therapy

  • reasonable to monitor if suspected liver dysfunction and elevated baseline or symptoms

    • unexplained fatigue

    • weakness

    • loss of appetite

    • abdominal pain

    • dark-coloured urine

    • yellowing of skin or sclera

  • request ALT only rather than LFTs

Acute kidney injury

  • risk slightly increased

    • (muscle protein entering blood stream)

    • aged >40 and first 120days of ≥ 40mg simvastatin for hospitilisation for AKI

      • relative risk increase by 1/3

      • NNH = 1700

      • those with CKD and statin not at increased risk

Type 2 DM

  • increase risk of developing diabetes

    • increases according to teratment intensity

      • 20-40mg simvastatin (moderate)

        • NNH = 1000

      • high ≥ 40mg

        • NNH = 250

    • risk outweighed by reduced risk of cardiovascualr events

      • except

        • \<40yo

        • >75yo

        • low LDL - C

  • in adults with DM

    • statin treatment decrease relative risk by 2-%

    • those most at risk of DM

      • most to gain

  • if develop T2DM then conitnue statin

Memory

  • no clear evidence that adverse effect

    • observational data = link between memory loss and confusion

    • heart protection study and PROSPER:

      • no significant difference in rate of cognitive decline

  • strategies if patient concerned re statin:

    • swtiching stating,

    • taking low dose

    • trialing alterante day dosing

  • reassured that any cognitive symptoms due to statin use:

    • likely to resolve within 3-4 weeks of stopping treatment

Myalgia

  • with or without muscle weakness = most common adverse effect associated with statin use

    • 10% of people prescribed statins

    • not necesarily cause in all these people

  • may be described as:

    • muscle ache

    • heaviness

    • stiffness

    • cramping

    • tendon pain

    • nocturnal leg cramps may also occur

  • weakness may occur wihtout discomfort

    • inability to open jars

    • difficulty snapping their fingers / difficulty getting out of chair

  • Statin - associated myalgia characterised by:

    • symmetrical involvmenet of large and proximal muscel groups

      • especially legs

    • typically within 6mo of initiating statin

  • when associated with muscle inflammation = myositis

    • usually with increase CK

    • Rhabdomyolysis

      • inflammation -> muscle fibre breakdown -> myoglobin into bloodstream

      • criteria

        • CK > 10x ULN

        • evidence of myoglobinaemia

      • death due to Rhabdo in patients taking statin = extremely rare

      • NNH 8000 (taking statin for ≥ 40 years for 1 extra death)

      • immediately withdraw statin if:

        • unexplained brownish-red coloured urine

          • myoglobinuria (“tea brown”)

        • decrease urine output

        • fatigue

        • muscle weakness

      • tests;

        • CK

        • Cr

        • electrolytes (Ca/PO4)

        • urine dipstick - haem

  • increase CK not necessarily diagnostic of pathology

    • transient increase healthy people

      • vigorous exercise

  • serious muscle cell damage

    • co-morbid

    • dehydration

    • pre-existing renal impairment

    • insufficient evidecne to recommend coadministration of CoQ10 for prevention of statin-associated myalgia

      • precursor of cholesterol

      • reductions thought to interfere with cellular respiration and result in muscle toxicity

      • muscle CoQ10 levels don’t correlate well with histological changes

  • risk factors

    • patient characteristics:

      • Age >80

      • F

      • Ethnicity

        • African/caribbean

        • asian - rosuvastatin

      • small body size and frailty

      • excessive physical activity

      • Drinking >1L of grapefruit juice / day

      • personal / fhx or muscle symptoms

      • history of elevated CK

      • unexplained muscle cramps

    • comorbidities

      • hypothyroidism

      • CKD

      • DM - Type 1/2

      • Alcoholism

      • history of major surgery / recent procedure

      • infections

    • medicines:

      • high dose statins (simvastatin ≥ 80mg /day

        • no longer recommended

      • medicines that interact with statins

      • concurrent use of oral corticosteroids

        • increase risk of developing muscles ysmtpoms

          • 3xF

          • 2xM

      • substance use (missuse)

    • Genetics

      • inherited muscle disease

      • polymorphisms in CYP

      • drug transporter genes

  • stop simvastatin (and to a lesser degree atorvastatin)

    • erythromycin and clarithromycin

      • case reports with azithromycin/roxithromycin + atorvastatin but no clincially significant interactions are known to occur between these antibiotics and atorvastatin

    • azole antifungals

    • Protease inhibitors

      • anitvirals

    • Gembibrozil

    • ciclosporin

    • Danazol

  • Pravastatin mainly cleared by kidneys and fully subsidised alternative for those taking CYP active drugs

    • pravastatin + fibrates = increase risk of muscle damage

  • Rosuvastatin largely metabolised by antoher enxzye systems

    • different interactions

  • Genetic test

    • SLCO1b1 on chromosone 12

      • presence/absence single nucleotide polymorphism

    • prevallence of 15%

    • 1 copy:

      • 4.5x increase risk of myalgia

    • 2 copies

      • 17 x increase risk

    • unsubsidised = 120$

  • before initiating

    • ask about history of muscle symptoms

    • possible adverse effects discussed

  • baseline CK if;

    • personal / fhx of statin intolerance

    • personal / fhx of muscle disease

    • concurrent medicines that may increase risk of myalgia

    • risk factors for statin associated muscle damage

management of statin myalgia

  • commonly reported

    • avoid unnecessary discontinuation of treatment

  • differential

    • myalgia associated with phsyical activity likely to be self-limiting

    • acute onset with URTI = viral infectin

    • swelling/warmth = localised inflammation/infection

    • with poor sleep wuality + stress: Fibromyalgia

    • with mornign stiffness

      • PMR

    • slow onset

      • hypothyroidism

      • hypercalcaemia

      • severe vit D deficiency

  • request CK/Cr

    • CK doens’t prove statin induced myalgisa

  • symptom based approach

    • muscle pain but no increase CK

      • reduce statin/discontinuation

      • don’t monitor CK

    • with CK 3-10x noral

      • reduce/discontinue

      • symptoms and CK regularly monitored if treatment continued

        • weekly

    • CK >10x ULN

      • discontinued immediately

  • rechallenge at original/lower dose

    • sensitivity/specificity of w/d and retrial unkown

    • STOMP trial = 4.6% experienced myalgia during controlled withdrawal and rechallenge

  • if causal relationship found

    • discuss benefit/risks

    • trial of pravastatin

  • most ldl-c lowering benefit of statin occurs at lower doses

  • consider alternate day

  • may benefit from non-statin lipid-lowering medicines

    • gembibrozil

    • nicotinic acid

Interacting medication and max. simvastatin dose

  • potent CYP3a4 inhibitors

    • macrolide abx erythyromycin/clarithromycin

    • azole

    • protease inhibitor

    • contraindicated

      • use alternative / stop simvastatin

      • use with caution and monitor closely atorvasstatin

  • moderate

    • Amiodarone

    • verapamil

    • diltiazem

    • amlodipine

    • nicotinic acid (>1g/day)

    • don’t exceed 20mg simvastatin

    • use with caution

  • minor

    • azithromycin

    • roxithromycin

      • case reports

      • use with caution simvastatin

      • ok with atorvastatin

  • INDUCERS

    • carbamazepine

    • phenytoin

    • rifampicin

    • st. john’s wort

    • probable reduction in plasma concentration of statin

      • monitor closley

  • consider a simvastatin dose reduction (max = 10mg) with:

    • fibrates,

    • systemic fusidic acid,

    • colchicine,

    • renal impairment

Statin safety monitoring

  • generally safe

  • Monitoring LFT not necesasry --> risk of liver toxicity negligible

  • Monitoring CK not required in those asymptomatic

  • CK for unexplained muscle pain, tenderness or weakness

    • Risk of myopathy usually dose related; increased in

      • elderly;

      • combination treatments

      • pre-existing muscle, liver or kidney

      • high dose

      • intercurrent illness

      • frailty

    • For muscle pain without CK rise: dose reduciton/discontinuation may be required

  • CK rise 3-10x normal with symptoms: dose reduction/discontinuation with regular weekly monitoring of symptoms and CK is appropriate

  • CK risk >10x normal with symptoms; discontinue immediately

= no longer necessary to monitor Liver unless speicic risk factors or signs of liver dyfunction/misle prolnes

  • used with caution ALT 3x noraml

  • discontinued CK10x > ULN

Nicotinic acid

  • adjunct to statin or used alone

  • CI - bleeding

  • initially 100mg tds - increase to 1g tds

Ezetimibe

  • adjunct to dietary and statin

  • 10mg od

Fibrates

  • decrease serum TAGs

  • variable effects on LDL

  • first line on ly in those whose serum TAG concentration > 10 or in those who cannot tolerate a statin

  • bezafibrate

    • 200mg tds normal release

    • 500mg od modified release

    • 400mg daily if eGFR 40-60

    • 200mg q1-2d if eGFR 15-40

    • avoid if \< eGFR \<15

    • avoid with statin - increase myalgia

  • gemfibrozil

    • 600mg bd