Hyperlipidaemia

• It’s undertreated nationally
  • • Only 50% of people with a Q risk 3 score > 10% (the risk of MI or CVA over next 10 years) are prescribed lipid lowering therapy
    • 83% of people with established CV disease are on lipid lowering therapy
    • Only 33% of people with CVD are achieving their lipid targets
• Physiology
  • • Atherosclerosis is caused by the progressive deposition of LDL-C and other apolipoprotein-B (ApoB)-containing lipoproteins within the artery wall
    • This causes a cascade of inflammatory reactions leading to the formation and progression of atherosclerotic plaque.
    • Over time, atherosclerotic plaques can enlarge and the risk of having an acute atherosclerotic CV event increases
    • HDL scavenges excess cholesterol and delivers to the liver for deposal
• Treatment considerations
  • • For every 1 mmol reduction in LDL there’s a nearly 25% reduction in atherosclerotic cardiovascular disease
    • Even better correlation between risk and non-HDL cholesterol
    • The intensity of the recommended LDL lowering is determined by a person’s level of risk
    • Lipid lowering therapy in primary prevention is not restricted to persons at very high risk, but depends on both the estimated CV risk and the baseline (untreated) LDL levels
    • This interactive lipid management tool can help aid in treatment decisions

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Investigation

• Lipid panel – can usually do as non-fasting (unless high triglycerides)
  • • Involves measuring total cholesterol (TC), HDL and triglycerides
    • Everything else is calculated incl LDL
    • Non-HDL cholesterol (Also known as ApoB) = total cholesterol minus HDL (better for assessing CV risk than LDL). High non-HDL = higher CV risk
    • LDL and triglycerides may not be reliable if non-fasting sample
    • If triglycerides raised (esp if >9), LDL may be falsely low.
    • Total cholesterol includes both atherogenic (LDL, IDL, VLDL, Lp(a)) and antiatherogenic fractions (HDL)
    • Consider a diagnosis of familial hypercholesterolaemia if TC > 7.5, or LDL > 4.9, or non-HDL > 5.9
    • Refer to lipid clinic if TC >9, LDL >6.5 and /or HDL >7.5 or triglycerides > 10
• Triglycerides
  • • Triglycerides are not directly atherogenic but considered a risk modifier
    • Associated with CV risk independent of LDL levels
    • To accurately measure triglycerides, patient must have fasted (normal < 1.7)
    • If triglycerides > 20 – refer to specialist urgently (and consider if due to poor diabetic control or ETOH). Often admitted and given insulin to reduce the risk of pancreatitis.
    • If triglycerides 10-20, repeat fasting sample at 1-2 weeks. If remains > 10, refer to specialist
    • If triglycerides > 4.5, repeat fasting test
    • See hypertriglyceridaemia section below for more detailed management
• Lipoprotein (a)
  • • An LDL-like particle, 90% genetically determined (autosomal co-dominant)
    • Measure once in a lifetime only (esp if familial hyperlipidaemia, or premature CV disease)
    • Stable throughout life, not lowered by statins or lifestyle
    • Proatherogenic and prothrombotic. Also increases risk of Aortic Stenosis
    • Can hugely increase CV risk and not included in Qrisk 3 score
    • Risk correlates to level (sometimes measured in mg/dL, but nmol/L quoted below)
      • • Risk increases slightly if >62 nmol/L
        • Levels >100 nmol/L increase CV risk substantially
        • If >250 nmol/L, doubles CV risk.
        • If >430 nmol/L, same CV risk as untreated FH
• Remnant cholesterol
  • • Cholesterol rich in triglyceride-rich lipoproteins
    • Elevated in DM and obesity
    • Crude measurement: RC = TC – HDL – LDL
    • Increases CV risk independently of LDL
• Extra tests
  • • ApoB100 – useful for CV risk estimation
    • ApoA1 – low in metabolic syndrome, very low in LCAT, Fish Eye, Tangiers
• Other bloods – TFT, LFTs, HbA1c, U&Es and CK if muscle pain and planning to start statin
• BMI and BP
• Can assess previous coronary or peripheral artery imaging (and calcium score) if performed
  • • Subclinical atherosclerosis by imaging or increased CAC score is a risk modifier in individuals at moderate risk (or individuals around treatment decision thresholds)
    • Statin therapy may lead to a decrease in lipid-rich plaque and an increase in calcification, indicating plaque stabilization so interpret with caution if statin-treated

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Check CV risk (and ‘heart age’)

• Check the Q Risk 3 score
• Need to know: Cholesterol/HDL ratio, systolic BP, height and weight, medications, medical hx, family hx of CVD, smoking status, postcode
• Do not use in T1DM, HIV, or if previous diagnosis of coronary disease or previous CVA/TIA, severe hyperlipidaemia / FH (clinically)
• Not needed if CKD eGFR <60 or proteinuria (can use Q risk 3 but you would treat the patient with statins anyway), or if aged >85 (you can assume CV risk based on age alone)

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Secondary causes of hyperlipidaemia to consider

• Drugs
  • • Anabolic steroid use (may not be volunteered, ask specifically)
    • Anti-psychotics, especially olanzapine, clozapine and quetiapine
    • Steroids, thiazides, betablockers all increase TG
    • Oestrogens, antipsychotics, ciclosporin, retinoids – can cause a mixed dyslipidaemia
• Hypothyroidism (elevated LDL)
• Nephrotic syndrome (elevated LDL and TG)
• Anorexia
• Obstructive liver disease eg PBC, and chronic liver disease
• Obesity (increases tryglycerides and reduces HDL)
• DM (elevates triglycerides, low HDL)
• Pregnancy (avoid measuring lipids during pregnancy, everything is a bit increased)
• Acute hepatitis
• SLE
• HIV (protease inhibitors)
• CKD (elevated TG)
• Alcohol (increase triglycerides and HDL)

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Targets and treatment thresholds

• Primary prevention (often with 20mg atorvastatin initially)
  • • Treat if:
      • • Age < 84 and QRISK score >10% over next 10 years
        • T1DM and >40 yrs or duration of DM > 10 years or established nephropathy or other CV risk
        • CKD (eGFR <60)
    • Consider if:
      • • Aged > 85 (consider frailty, life expectancy etc)
        • Additional risk factors – HIV treatment, severe mental illness, taking meds that cause dyslipidaemia, chronic inflammatory disorder, severe obesity
    • Aim for >40% reduction in non-HDL
• Secondary prevention
  • • Treat all patients who have had a CV event (incl angina and PVD)
    • Take baseline lipids first, start on atorvastatin 80mg OD, then recheck in 3 months
    • For patients admitted with ACS who are already taking a statin, therapy should be intensified during the same admission to reduce LDL to <1.4 mmol/L
    • Targets
      • • LDL < 1.8 or 2.0 (the latter according to latest NICE, but some controversy. ESC advice LDL <1.4 in high risk patients)
        • Non-HDL < 2.6 (or >40% reduction, >50% in FH, or <2.6 according to NICE)
        • But the lower the better! To get proper plaque regression you need LDL < 1.8

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Treatment

• Treat risk, not lipids! The more you lower LDL, the more you reduce CV risk
• Lifestyle measures (limited effect, absolute best effect is 15% reduction)
  • • To reduce LDL – Avoid trans fats, reduce saturated fats, increase fibre, eat food enriched with phytosterols, red yeast rice nutraceuticals, weight loss
    • To reduce triglycerides – Reduce ETOH (biggest effect), then increasing exercise, reducing carbs, supplement with n-3 polyunsaturated fats
    • To increase HDL – Increase exercise (best), avoid trans fats, weight loss, reduce carbs
    • No compelling evidence that supplements can reduce CV risk
• Statins
  • • 20mg atorvastatin for primary prevention (higher does in this scenario give some but not much more benefit).
    • 20mg atorvastatin will reduce LDL by 43% on average, 80mg will reduce by 55%
    • 80mg atorvastatin for secondary prevention
    • If CKD – might start at 20mg atorvastatin
    • Pregnancy – stop statins 3 months before attempting to conceive. Restart once breastfeeding finished
• Recheck lipids along with LFTs in 3 months (non-fasting)
  • • If non-HDL hasn’t fallen by 40% –  check adherence and consider uptitrating if other CV risk factors (to max 80mg atorvastatin)
    • Some patients with high LDL have suboptimal reductions of lipids on statins – no specific additional treatments, manage risk factors
    • Only check CK if symptomatic, or muscle pain pre-statin
    • If ALT or AST > 3x upper limit of normal, don’t start statin (or stop it and consider restarting in one month)
• If side effects on high dose statin – offer lower dose or alternative statin (rosuvastatin best alternative by far). See ‘statin side effects’ below
• If still no control – add ezetimibe 10mg OD
  • • This combo reduces LDL by 61% on average
    • Can cause headache or GI distress
    • Combination therapy should be used more often, as you would for HTN
• If statins not tolerated / contraindicated
  • • Consider ezetimibe monotherapy – this reduces GI cholesterol absorption. Reduces LDL by 24% when used alone.
    • If still no control, consider ezetimibe / bempedoic acid 180mg combination (bempedoic acid can cause gout). This combination reduces LDL by 38%
• If still no control, refer to specialist (and ensure fasting LDL levels have been checked). Injectables can be considered

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Other options

• PCSK9 inhibitor (Monoclonals called alirocumab and evolocumab)
  • • Self-administered s/c injections, every 2-4 weeks. Initiated in specialist clinics. Reduces LDL by 55%.
    • Eligibility:
      • • FH if LDL-C is >5
        • FH and CVD with LDL-C > 3.5
        • CVD and high risk, with LDL-C >4
        • CVD and v high risk with LDL-C >3.5
    • Therefore: Not used in people without FH or CVD
    • Evolocumab 140mg every 2 weeks
    • Alirocumab 75-150mg every 2 weeks
    • Side effects – can cause myopathy, cold-like symptoms, injection site reactions, nausea, arthralgia, angioedema (rare).
• Inclisiran
  • • siRNA inhibits translation on PCSK9.
    • s/c injection every 6 months (after two initial doses at 1 and 3 months)
    • Used for secondary prevention if max dose statin doesn’t do the job.
    • 50% reduction of LDL (however data lacking on its impact on CV events, research ongoing)
    • LDL must be > 2.6 to initiate, and on max dose of statin
    • Good evidence, but very under-prescribed
    • Some estimate that by treating 300,000 patients annually with inclisiran, 55,000 heart attacks and strokes can be prevented over 10 years in the UK
    • Available from GPs
    • Costs £45 per injection so not expensive
• Bempedoic acid
  • • Decreases cholesterol synthesis
    • Reduces LDL by around 20% (at 180mg daily)
    • Can cause URTI, increased risk of gout, myalgia (although muscle-related adverse events reportedly similar to placebo)
    • Bempedoic acid monotherapy is not cost effective (so avoid)
• Lomitapide (MTTP inhibitor)
  • • Can cause hepatotoxicity. Named patient basis. For homozygous FH
• Volanesorsen (Antisense oligonucleotide)
  • • Reduces triglycerides
    • Can cause low plts and hepatotoxicity
    • Named patient basis
    • Useful for resistant hypertriglyceridemia
• Fish oils (Vazkepa)
  • • Reduces triglycerides.
    • Associated with AF and hepatotoxicity.
    • Useful in secondary prevention if on statin, elevated fasting triglycerides and LDL-C from 1.04-2.6 (if over, qualifies for Inclisiran)
• Fenofibrate (and other fibrates)
  • • Used for hypertriglyceridemia
    • Can cause hepatotoxicity
    • Shouldn’t be used routinely to reduce CV risk except in FH.
    • Useful in severe hypertriglyceridaemia to reduce risk of pancreatitis
• Icosapent ethyl
  • • Used for hypertriglyceridaemia (if fasting triglycerides >1.7 and LDL 1-2.6)
    • Useful in secondary prevention.
• Evinacumab
  • • A monoclonal used for homogenous FH (costs around £6500 per infusion, and given every 4 weeks)
• Future therapies may include cholesterol ester transfer protein inhibitors, oral PCSK9 inhibitors, and gene editing therapy targeting ANGPTL3 and PCSK9
• When to consider referral to lipid service
  • • All genetic hyperlipidaemias (or suspected cases)
    • Intolerance to statins – including abnormal LFTs or raised CK
    • Marked hypertriglyceridemia
    • If on PCSK9 inhibitors or Vazkepa

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Statin side effects

• Intolerance prevalence is 9% but often incorrectly labelled.
• 90% of side effects attributed to statins are due to nocebo effect (giving patients a placebo and telling them it’s a statin does cause side effects at almost the same rate as a statin). Consider switching statins or using lower doses
• HIV drugs can interact – generally opt for lower doses of statins, or avoid, and especially avoid simvastatin
• Myalgia
  • • Consider other causes unrelated to statin (eg PMR, vitamin D deficiency. Check CRP, bone profile, vitamin D, CK)
    • Risk of rhabdo – 1 in every 10,000.
    • If CK < 10x upper limit, can break from statin for 6 weeks and rechallenge at a lower dose if CK normalises
    • Raised CK often resolves within 6 weeks
    • If does not normalise and progressive muscle weakness consider Statin-induced necrotising autoimmune myopathy (Very rare. Check HMGCR antibodies and treat by immunosuppression)
    • If CK 10-50x ULN and normal renal function – can also stop for 6 weeks and rechallenge but maybe avoid
    • If CK > 50x normal or 10-50x normal and AKI, stop statin permanently
    • More often seen in patients with multiple comorbidities
    • Try not to check serial CK on statins (other things increase it, including exercise). But baseline CK may be helpful
    • Co-enzyme Q10 sometimes used to treat statin-related myalgia, but not NICE approved currently
• Deranged LFTs
  • • Risk is 4 in 1000 people (ALT >3x ULN)
    • Measure every 3 months after dose change, then annually
    • If ALT or AST > 3 x ULN, then stop statin and recheck in one month
    • If < 3 x ULN, continue statin and repeat in one month. If still elevated but < 3xULN then continue statin and repeat in 6 months
    • Unclear if statins ever cause serious liver injury, and if they do, it’s extremely rare.
• Neurological symptoms
  • • Insomnia, headache, amnesia, nightmares, dizziness
    • Can try pravastatin (less crosses the blood brain barrier)
• DM
  • • Statins increase your HbA1C and can therefore cause DM in prone patients – the risk is one extra case of DM in 200 people over a 5-year period of statin use
    • Benefit usually outweighs risk – continue statin
• GI
  • • Usually transient. Could be unrelated.
    • Includes diarrhoea, flatulence, constipation, nausea
• Statin-induced acute lung injury is rare
• Statin-induced dermatitis
• Thrombocytopenia
• Other uncommon side effects include alopecia, memory loss, pancreatitis, paraesthesia, sexual dysfunction

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Family hypercholesterolaemia (FH)

• Inherited AD, common (1:300)
• 90% undiagnosed
• Mutations can be found in APOB, LDLR, PCSK9 and APOE
• Homozygous FH is more severe (prevalence 1 in 300,000)
• Usually due to defect in LDL receptor
• Cholesterol levels 7-14
• Often family hx of premature CV disease (CV disease < 55yrs in men and < 60yrs in women)
• 50% of men with FH will have MI by the age of 50
• Clinical features
  • • Can be arcus (esp if < 40 yrs)
    • Xanthelasma (around eyes) – less specific
    • Tendon xanthomata virtually diagnostic of heterozygotic FH (and occurs in 70% overall)
• Use The Simon Broome Criteria to diagnose
  • • Based on TC > 7.5mmol/L or LDL-C > 4.9mmol/L, presence of tendon xanthomas and family history
    • Tells you if they have definite or possible FH
    • Definite diagnosis if meets lipid criteria plus either tendon xanthoma or genetic mutation
• Often normal triglycerides, if elevated think of other things
• Genetic testing should be done but does not impact decision on whether to treat
• Other tests
  • • Rule out secondary causes of hypercholesterolaemia – TFTs, LFTs, renal function, hba1c, urine ACR
    • Check urate, CK (as may start certain drugs)
    • Check lipoprotein (a), apolipoproteins, and consider coronary calcium scoring if no previous CV event
• Treatment
  • • Can use the following (in order): Statins, ezetimibe, bile acid sequestrants, PCSK-9 inhibitors, monoclonal antibodies.
    • Often need combo therapy because of ‘missed years’ – atherosclerosis accumulating pre-diagnosis
    • Aim for at least 50% reduction in LDL or non-HDL from baseline
• Do NOT use CV risk calculators for these patients (will underestimate risk)

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Hypertriglyceridemia

• Causes
  • • ETOH
    • Poorly controlled DM (common)
    • Obesity/diet
    • Drugs
    • Renal disease (mildly up if uraemic)
    • Pregnancy
    • Paraproteins
    • Autoimmune disorders eg SLE (can get antibodies to LPL)
    • Glycogen storage disorders
    • Genetics conditions
• If cholesterol elevated too – mostly due to familial combined hyperlipidaemia (or familial dysbetalipoproteinaemia)
• If just triglycerides up and normal cholesterol – can be due to familial chylomicronaemia syndrome or familial hypertriglyceridemia
• Levels
  • • Mild-moderate is defined as 2.3-10mmol/L
    • Severe > 10
    • If triglycerides 10-20, repeat a fasting test after > 5 days but < 2 weeks. Refer to lipid clinic if results remains > 10
    • If triglycerides > 20, refer to lipid clinic
• Occasionally can lead to
  • • Pancreatitis – Risk of pancreatitis rises in proportion to degree of hypertriglyceridemia
    • Eruptive xanthomata (often on the back and thighs, can mimic acne, itchy, often resolve once triglycerides decrease)
    • Lipaemia retinalis
• Always exclude secondary causes
• More common in pregnancy, when risk of pancreatitis is increased
• Acute treatment
  • • Insulin fixed rate even in non-diabetics
    • Often start fibrate too. Renally excreted so adjust dose in CKD.
    • Heparin
    • Occasionally plasma exchange
    • Avoid propofol if patient on ICU
    • Restrict dietary fat (<10g daily for first 3 days)
• Chronic treatment
  • • Very low-fat diet, low carbs, weight loss
    • Optimise glycaemic control
    • Fibrates – better than statins, but they can cause dyspepsia, gallstones, myopathy. Don’t impact on mortality.
    • Often start statin as well if mild to moderate
    • Omega 3 fatty acids (reduces synthesis and secretion of VLDL and increases expression of LPL in adipose tissue)
    • Consider Icosapent ethyl
    • Consider volanesorsen

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Other lipid disorders

• Dysbetalipoproteinaemia
  • • Affects 1 in 10,000. Genetic.
    • Genetic prevalence is 1%, but usually requires second hit, eg DM/ETOH and only 1 in 50 of those genetically susceptible will develop it
    • Results in apo E2 (a defective form of apoE)
    • Excess IDL and chylomicron remnants. High triglycerides.
    • The normal type is ApoE3. However, sometimes testing picks up ApoE4 which is associated with early onset dementia
    • Increased risk of atherosclerosis and PVD
    • Can be tuberous xanthomas and striae palmaris
    • Responds well with diet and fibrates
• Familial combined hyperlipidaemia / mixed dyslipidaemia
  • • AD inherited
    • May be high non-HDL to Apo B level
    • Increased VLDLs
    • Linear, tuberous and palmar xanthomata
    • Treated in similar way to FH
• Familial chylomicronaemia syndrome
  • • Presents in kids mostly, but can present in adults with recurrent pancreatitis and triglycerides >10 without secondary causes.
    • Do an FCS score to calculate likelihood