Dyslipidaemia

Meet the patient

A 28-year-old man turns up with lumpy Achilles tendons he first noticed playing football. His father had an MI at 42 and a paternal uncle needed a CABG at 45. His untreated LDL-C is 9.2 mmol/L, TSH and HbA1c are normal, and the tendon lumps are tendon xanthomata — the combination of premature coronary disease, tendon xanthomata and an untreated cholesterol this high in a young adult is exactly the picture that should trigger familial hypercholesterolaemia screening in the patient and the whole family.[19]

The two questions that decide his next decade are the two that decide every dyslipidaemia: is this LDL-driven atherogenesis? (yes — tendon xanthomata, an untreated LDL-C far above 4.9 mmol/L and premature CAD in first-degree relatives mark out severe primary hypercholesterolaemia, which warrants high-intensity statin therapy without further risk scoring) and what is the target? (risk-stratified — European guidelines drive the very-high-risk patient to LDL-C under 1.4 mmol/L). Hold those two questions and the whole topic slots into place.[15][32]

Why LDL-C is the particle that matters — the lipid-heart hypothesis

Of all the lipids, only LDL-C has earned a therapeutic target — and the evidence is airtight. The lipid-heart hypothesis (raised LDL-C causes atherosclerosis) is one of the most validated ideas in medicine: an appraisal of over 200 prospective cohort studies, Mendelian randomisation studies and randomised trials in more than 2 million participants found a dose-dependent, log-linear association between the absolute magnitude and duration of exposure of the vasculature to LDL-C and the risk of ASCVD, with rare variants that lower LDL-C conferring correspondingly lower risk.[18]

That is why the contemporary mantra is "lower is better, earlier is better, for longer" — the causal evidence shows the effect of LDL-C on risk grows with the duration of exposure, so decades of moderate hypercholesterolaemia bank more atherogenic damage than any brief spike. A patient decades at LDL 5 mmol/L has banked far more atherogenic exposure than any brief spike ever could.[18]

Everyone forgets: HDL is a marker, not a target. Genetic studies and negative randomised trials of HDL-raising strategies taught us that low HDL may not cause cardiovascular disease at all — low HDL flags residual risk, it does not command a drug. The only lipid we treat to a number is LDL-C (with apoB and non-HDL-C as its deputies).[33]

The five lipoproteins — a cluster rule with one discriminator

Because lipids are insoluble in plasma, they travel as lipoproteins — cholesterol and triglyceride carried through the blood by particles whose protein and lipid cargo decides where they dock; LDL is the particle that carries cholesterol through the blood and is required for atherosclerotic lesions to form. Five classes, one discriminator to memorise:[22]

Primary vs secondary first — never label primary without a TSH

The first branching decision in any new dyslipidaemia is not genetic vs lifestyle — it is "have I excluded a secondary cause?" Reversible drivers are common, and labelling a dyslipidaemia primary before checking TSH, glucose, renal and liver function is the recurring trainee error that misses hypothyroidism, diabetes, nephrotic syndrome and cholestasis.[15]

Always screen with TSH, HbA1c or fasting glucose, U&E, urine ACR, and LFTs before committing to lifelong lipid-lowering therapy. Each secondary cause leaves a characteristic lipid signature and a clinical clue:[15]

[15]

Primary (genetic or lifestyle) is the label that survives that screen: polygenic hypercholesterolaemia (the commonest), familial hypercholesterolaemia (LDLR, APOB and PCSK9 are the established monogenic loci), familial combined hyperlipidaemia, familial dysbetalipoproteinaemia (type III), familial defective apoB-100, and the familial hypertriglyceridaemias.[24][19]

[15]

The Fredrickson face-off (types I–V) — the one-line discriminator

Two classifications are examined. The modern aetiological scheme (primary vs secondary) directs the work-up; the Fredrickson phenotypic scheme (types I–V) describes the lipoprotein pattern on electrophoresis and is pure exam gold. Learn the phenotype, but anchor each type with one discriminator:[33][19]

[33] [21]

The one-line discriminator: palmar xanthomata = type III; eruptive xanthomata = high TG (I, IV, V); tendon xanthomata = FH (IIa). Pair the stigmata to the type and the table collapses to three rows you actually need.[19]

How common, and who — the South-Asian atherogenic phenotype

Dyslipidaemia is the commonest modifiable cardiovascular risk factor on the planet, and in South Asians it wears a distinctive, dangerous face. South Asians face an approximately two-fold higher risk of atherosclerotic cardiovascular disease than White Caucasian populations — with a particularly pronounced excess of coronary heart disease and myocardial infarction — and are predisposed to more atherogenic lipid profiles. That is why high-risk ethnicity such as South Asian origin counts as a risk-enhancing factor when statin decisions are made.[28][15]

The numbers an examiner wants reproduced:[20]

[20] [21] [32] [15] [27]

Everyone forgets the FH prevalence. One in 200 to 250 is not rare — it means every full waiting room has one, and only about one in ten is diagnosed and adequately treated. The single highest-yield question for a young patient with premature CAD is "who else in your family?", followed by a lipid panel and family-based cascade testing of relatives.[20]

The atherogenic cascade — retention, oxidation, foam cell, plaque

Atherosclerosis is, at root, a response-to-retention disease. Development of atherosclerotic lesions probably requires low-density lipoprotein — the particle that carries cholesterol through the blood — to enter and lodge in the artery wall; hypertension, cigarette smoking, diabetes and inflammation then drive the process forward.[22]

Macrophage scavenger receptors then take up modified lipoprotein unregulated, converting the macrophage into a cholesterol-laden foam cell — the hallmark of the early fatty streak. Foam cells and the immune system's cytokines and adhesion molecules recruit more monocytes and drive smooth-muscle migration, producing a fibrous cap over a lipid-rich necrotic core — and when that thin cap ruptures, you have your ACS.[22]

LDL receptor, PCSK9, and ApoB — three levers, three drug classes

The hepatocyte LDL receptor removes LDL from the circulation, and the genes that encode the receptor and its ligand (LDLR, APOB) were the first causes of familial hypercholesterolaemia found. PCSK9 joined them as a third locus: missense mutations in PCSK9 cause autosomal dominant hypercholesterolaemia, and PCSK9 overexpression in mice produces hypercholesterolaemia by reducing LDL-receptor number — a gain-of-function effect. The mirror image is protective: nonsense loss-of-function variants in PCSK9 are found in people with lifelong, markedly low LDL-C. More PCSK9 activity, fewer surface receptors, higher LDL-C — which is exactly why PCSK9 monoclonal antibodies were built.[24][23]

Apolipoprotein B sits on every atherogenic particle (one ApoB-100 per VLDL, IDL, LDL, and Lp(a); ApoB-48 on chylomicrons). LDL-C measures the cholesterol mass the particle carries, while apoB counts particles — and the US guideline explicitly lists apolipoprotein B ≥130 mg/dL and persistently elevated triglycerides ≥1.97 mmol/L (175 mg/dL) among the risk-enhancing factors that can tip a borderline decision towards a statin.[15]

Lp(a) — atherogenic and prothrombotic at once, and statin-resistant

Lipoprotein(a) is an LDL-like particle whose apolipoprotein(a) is structurally homologous to plasminogen — it resembles both plasminogen and plasmin but has no fibrinolytic activity, so elevated Lp(a) may induce a prothrombotic/anti-fibrinolytic effect; because it is cholesterol-rich like LDL, it may also accelerate atherosclerosis. The association with cardiovascular disease is continuous, without a threshold, independent of LDL- and non-HDL-cholesterol, and — like elevated LDL-C — causally related to premature disease.[27]

That is the trap: a patient can hit every LDL target and still carry a concealed Lp(a)-driven risk. The European consensus advises that Lp(a) be measured once, using an isoform-insensitive assay, in people with premature CVD, familial hypercholesterolaemia, a family history of premature disease, or recurrent events despite statin therapy, with a desirable level below roughly 50 mg/dL (under the 80th percentile); US guidance likewise counts Lp(a) ≥50 mg/dL (125 nmol/L) as a risk-enhancing factor, especially at higher values.[27][15]

Hypertriglyceridaemic pancreatitis — the chylomicron-sludge mechanism

Severe hypertriglyceridaemia is the established driver of hypertriglyceridaemic pancreatitis — which carries higher mortality, more pancreatic necrosis and more intensive-care need than other causes. In the Copenhagen cohorts the risk of acute pancreatitis rose stepwise with non-fasting triglycerides: hazard ratio 1.6 at 1–2 mmol/L, 2.9 at 3–4, 3.9 at 4–5, and 8.7 at 5–10 mmol/L compared with under 1 mmol/L. HDL's story is the mirror image: low HDL marks risk, but genetic studies and failed HDL-raising trials show it is a marker, not a target.[30][21][33]

The xanthomata face-off — the single highest-yield exam table

In a viva, the xanthomata are worth more than the lipid panel. Each one points to a specific dyslipidaemia — tendon xanthomata are themselves an FH screening trigger in European guidance — and the discriminator fits on one line. Learn the table, then the one-line rule beneath it:[19]

[19] [30]

The one-line discriminator: tendon → FH; palmar → type III; eruptive → high TG; xanthelasma → check lipids but half are normal; premature arcus → significant, senile arcus → ignore. Pair the stigmata to the disease and the table collapses to three rows you actually need.[19]

At the extremes add lipaemia retinalis (milky retinal vessels in severe hypertriglyceridaemia), hepatosplenomegaly from chylomicron and remnant uptake, and the end-organ signs of established disease — carotid bruits, absent peripheral pulses, and premature aortic-valve disease in homozygous FH.[21][20]

[19] [21]

Investigations — fasting or not, Friedewald and its TG trap, apoB and Lp(a)

First-line is a lipid panel: total cholesterol, LDL-C, HDL-C, triglycerides. Triglycerides can be measured in either the non-fasting or fasting state — non-fasting sampling is acceptable for screening, and the landmark cohorts that quantified pancreatitis risk used non-fasting triglycerides throughout. Reserve a fasting panel for following known hypertriglyceridaemia when the non-fasting value is raised.[33][21]

The classic trap: applying the fixed-factor Friedewald formula when triglycerides are high and LDL-C is low generates a falsely reassuring number in exactly the patient whose risk you most need to quantify. Always read the triglyceride before you trust a calculated LDL.[29]

The new-dyslipidaemia work-up screens for secondary cause and total risk together: TSH (hypothyroidism), HbA1c (diabetes — explicitly part of the risk discussion before statins), renal function (CKD is a risk-enhancing condition), LFTs as a baseline before therapy, and a baseline CK as a comparator if myalgia develops later. Add Lp(a) once in those with a family history or premature disease, and apoB when triglycerides run high or LDL-C looks discordant with risk.[15][27]

Total-risk estimation uses a 10-year ASCVD risk calculator plus clinical conditions and risk-enhancing factors to set statin intensity; where the decision is uncertain in primary prevention, coronary artery calcium is the tie-breaker — a CAC score of zero can justify withholding or delaying a statin, while a score of 100 or more indicates one. The cautionary tale on surrogate endpoints is ENHANCE: ezetimibe added to simvastatin in FH produced the expected additional LDL-C reduction but no change in carotid intima-media thickness — IMT is a research tool, not a treatment target, and the event trial IMPROVE-IT later vindicated ezetimibe on outcomes.[15][14]

The LDL-target number rule — 1.0 / 1.4 / 1.8, and the 50 percent rule

These numbers are the most reproduced figures in the dyslipidaemia viva, and they are non-negotiable. European guidelines set fixed LDL-C treatment goals for the highest-risk patients, while US guidance pairs percentage LDL-C reduction with an explicit 70 mg/dL (1.8 mmol/L) threshold for adding non-statin therapy:[32][15]

[32] [15]

The number rule: under 1.4 mmol/L after an acute coronary syndrome, under 1.0 for a second event within two years, add non-statins at 1.8 mmol/L (70 mg/dL) — and always cut LDL-C by at least half in clinical ASCVD. Fixed European goals below, percentage rule and nonstatin threshold in US guidance — the two approaches converge on the same lower-is-better endpoint.[32][15]

Management — the stepwise ladder

Treatment is risk-stratified, not number-driven: the same LDL value mandates very different intensity depending on total cardiovascular risk. A heart-healthy lifestyle is the foundation for every patient at every age; drug therapy is layered on top, climbing one rung at a time until the LDL target is met.[15]

Lifestyle for everyone: a heart-healthy dietary pattern is the foundation of risk reduction at every age — and on top of diet, plant sterols or stanols at 2 g/day inhibit cholesterol absorption and lower LDL-C by a further 8–10 percent, with no adverse effects attributed to those intakes in long-term human studies. Regular physical activity, weight management, smoking cessation and control of blood pressure and glycaemia complete the platform — necessary, rarely sufficient.[15][25]

Step 1 — high-intensity statin

Statins remove LDL-C from the circulation by driving hepatic LDL-receptor-mediated clearance — the same receptor whose number PCSK9 reduces — and they remain the first rung of the ladder in every guideline. Intensity is chosen to hit the risk-based target:[15][23]

[15] [36] [7] [4] [5] [6] [9]

The rule of sixes — why doubling the dose disappoints

The statin dose-response is log-linear: tripling atorvastatin from 10 to 80 mg adds only about 15 percentage points (40 to 55 percent), so each doubling of the dose buys only a few percent more LDL-C reduction. Outcomes are therefore driven by baseline potency and adherence, not by endlessly up-titrating the same statin. Rosuvastatin is the most potent statin (60 percent reduction at top dose); pravastatin and fluvastatin are the weakest — pick the right statin and the right dose once, then keep the patient on it.[36]

Step 2 — ezetimibe

If the LDL target is unmet on maximally tolerated statin, add ezetimibe 10 mg orally once daily — it shuts down intestinal cholesterol absorption on top of the statin's clearance mechanism. IMPROVE-IT (18,144 patients within 10 days of an ACS) proved the concept on outcomes: adding ezetimibe 10 mg to simvastatin 40 mg took the time-weighted average LDL-C from 69.5 to 53.7 mg/dL (1.8 to 1.4 mmol/L) and reduced the 7-year primary composite event rate from 34.7 to 32.7 percent — the first non-statin LDL drug to win an event trial, and the reason ezetimibe is second-line.[9]

Step 3 — PCSK9 inhibitors

Still off target, or in FH or statin intolerance: add a PCSK9 monoclonal antibody — evolocumab 140 mg subcutaneously every 2 weeks or 420 mg monthly, or alirocumab 75 mg subcutaneously every 2 weeks (ODYSSEY OUTCOMES), both on top of maximally tolerated statin. FOURIER (27,564 patients with established ASCVD) showed evolocumab lowers LDL-C by approximately 60 percent and cut the primary composite endpoint to 9.8 versus 11.3 percent (HR 0.85); ODYSSEY OUTCOMES (18,924 post-ACS patients on high-intensity statin) showed a similar event reduction with alirocumab (HR 0.85), which got 94.6 percent of patients below 1.4 mmol/L versus 17.3 percent on placebo. The limits are cost and the subcutaneous route; injection-site reactions are the main adverse effect.[10][11][32]

Newer agents — bempedoic acid and inclisiran

Bempedoic acid 180 mg orally daily won its outcome trial in 13,970 statin-intolerant patients: CLEAR Outcomes showed a 21.1 percentage-point greater LDL-C reduction than placebo (29.2 mg/dL difference at 6 months) and fewer primary MACE events — 11.7 versus 13.3 percent (HR 0.87) — an oral option for the patient whose muscles will not tolerate a statin.[16] Inclisiran is a small-interfering RNA that silences hepatic PCSK9 mRNA: 284 mg subcutaneously on day 1, day 90, then every 6 months, for approximately 50 percent LDL-C reduction with twice-yearly maintenance dosing (the logistical prize); injection-site reactions are its main adverse effect.[17]

[15] [25] [9] [10] [16] [17] [12] [31]

Follow-up: assess adherence and response with a repeat lipid panel 4–12 weeks after starting or changing therapy, then every 3–12 months as needed. If LDL stays above target, confirm adherence — the commonest cause of apparent failure — and climb the ladder. Response is defined by the percentage LDL-C fall from baseline.[15]

Statin adverse effects — the myalgia, myositis, rhabdo ladder

Most statin intolerance is nocebo — but the serious end of the ladder is real. In US practice roughly 10 percent of patients stop a statin over subjective complaints, most often muscle symptoms without raised creatine kinase; yet in randomised trials the statin-versus-placebo difference in such symptoms is under 1 percent — and in the blinded SAMSON re-challenge trial, 90 percent of "statin" symptoms were reproduced by placebo. Learn the spectrum as the examiner wants it:[26][34]

The preventable-harm pair every registrar must know: don't stop a statin permanently for nocebo myalgia — in SAMSON, 90 percent of adverse symptoms were elicited by placebo too, and half the patients successfully restarted their statin; and don't combine gemfibrozil with a statin — statin–fibrate combination raises rhabdomyolysis risk, and gemfibrozil added to atorvastatin has caused fulminant rhabdomyolysis with acute kidney injury. Fenofibrate is the fibrate used when combination with a statin is unavoidable.[34][35]

Hypertriglyceridaemia — fenofibrate not gemfibrozil, icosapent ethyl, and the TG-over-10 emergency

The TG number flips the goal. In mild-to-moderate hypertriglyceridaemia the priority remains ASCVD risk reduction; once triglycerides enter the severe range — 5.6 mmol/L (500 mg/dL) and above — the goal shifts to pancreatitis prevention, because hypertriglyceridaemic pancreatitis carries higher mortality, more necrosis and longer stays than other causes, and it recurs unless prevented. Step 1 is lifestyle — fat restriction, alcohol abstinence, glycaemic control, weight loss, omega-3. Step 2 adds a fibrate, and the rule is absolute: fenofibrate, never gemfibrozil, when a statin is also on board — gemfibrozil with a statin is the classic rhabdomyolysis combination.[30][33][35]

Icosapent ethyl — highly purified EPA, 2 g twice daily (4 g/day) — reduced the primary composite cardiovascular endpoint by 25 percent (HR 0.75) in REDUCE-IT: patients with established cardiovascular disease or diabetes plus risk factors, fasting triglycerides 135–499 mg/dL (1.5–5.6 mmol/L), already on a statin. The lesson is specificity: this is pure EPA, not a mixed fish-oil preparation.[12]

The HTG-pancreatitis emergency: acute pancreatitis on severe hypertriglyceridaemia is a metabolic emergency needing admission, fasting with fat restriction, aggressive IV fluids and analgesia — plus treatment aimed at the triglycerides themselves. Rapid TG reduction is achieved by activating lipoprotein lipase, which is why an insulin infusion is the mainstay (especially in the diabetic); the ICU literature also lists therapeutic plasma exchange and combined insulin–heparin infusions as acute modalities, though optimal dosing is unsettled and high-quality evidence is limited. Prevention is everything, because recurrence is likely but preventable: fat restriction, complete alcohol avoidance, glycaemic control, and chronic fibrate plus omega-3 therapy.[31][30]

Familial hypercholesterolaemia — DLCN and Simon Broome, cascade from age 2, statin from age 8–10

FH is the dyslipidaemia you must not miss — genetic, underdiagnosed (only about one in ten diagnosed and adequately treated) and undertreated, carrying up to a 13-fold risk of coronary heart disease. Diagnosis is clinical plus genetic: European guidance says to screen the patient and the family when a person or relative presents with FH itself, an untreated plasma cholesterol of 8 mmol/L (310 mg/dL) or more in an adult (6 mmol/L in a child), premature CHD, tendon xanthomata, or sudden premature cardiac death — and the three established monogenic loci are LDLR, APOB and PCSK9. Formal criteria (Dutch Lipid Clinic Network, Simon Broome) weight exactly these elements: family history of premature disease, personal history of premature vascular disease, untreated LDL-C, tendon xanthomata, and a pathogenic variant.[20][19][24]

Heterozygous FH affects 1 in 200 to 250 people of every race and ethnicity; rare mutations that reduce LDL-receptor function cause markedly higher LDL-C with a dose-dependent increase in ASCVD risk, and most patients fail to reach recommended LDL-C targets. Treated properly — high-intensity statin, then ezetimibe, then a PCSK9 inhibitor if needed — the excess risk is largely preventable. Homozygous FH (two pathogenic alleles) is far rarer and far more severe: severe hypercholesterolaemia from birth with childhood-onset atherosclerotic disease — oral therapy alone is usually inadequate, and management belongs in a specialist lipid clinic with access to lipoprotein apheresis.[20][18][19][15]

Cascade screening is the highest-yield action in FH: guidance recommends screening children, adults and whole families whenever one member presents with FH, an adult cholesterol of 8 mmol/L or more (child 6 mmol/L), premature CHD, tendon xanthomata or sudden premature cardiac death — because a genetic cause means each first-degree relative has a one-in-two chance of carrying it. Statin use and safety in children with FH is specifically addressed by the AHA scientific statement on statin safety, which reviews children among its special populations.[19][20][26]

Special populations — diabetes, CKD, pregnancy, elderly, children

Diabetes reshapes the lipid panel (high TG, low HDL, small dense LDL — the atherogenic triad) and the treatment bar. In US guidance, every patient with diabetes aged 40–75 with LDL-C 70 mg/dL (1.8 mmol/L) or more starts at least a moderate-intensity statin without calculating 10-year risk; those with multiple risk factors or aged 50–75 reasonably escalate to a high-intensity statin to cut LDL-C by 50 percent or more; and established ASCVD makes the patient very-high risk. If triglycerides sit at 135–499 mg/dL on a statin in a diabetic with established disease or risk factors, add icosapent ethyl 2 g twice daily (REDUCE-IT).[15][12]

Chronic kidney disease: SHARP randomised 9270 patients with advanced CKD (about a third on dialysis) to simvastatin 20 mg plus ezetimibe 10 mg or placebo and found a 17 percent proportional reduction in major atherosclerotic events (11.3 vs 13.4 percent; RR 0.83) — with no material difference between dialysis and non-dialysis patients. That is the evidence base for statin–ezetimibe in CKD.[13]

Pregnancy — the AHA statin-safety statement reviews statin use in pregnancy among its special populations. Where lipid-lowering is genuinely needed in pregnancy or lactation, bile-acid sequestrants (colesevelam, cholestyramine — not systemically absorbed) are the classic choice; severe FH in pregnancy belongs with a specialist lipid service. The third-trimester lipid rise is physiological and needs no drug.[26]

Elderly and chronic liver disease are both special populations the AHA statin-safety statement reviews in detail. Age alone should not stop an effective statin in a patient with established ASCVD; in primary prevention at advanced age, individualise — weigh life expectancy, frailty, polypharmacy and interaction risk against the absolute benefit. Stable chronic liver disease is far less of a contraindication than trainees fear; avoid statins in acute hepatitis or decompensated cirrhosis.[26]

The trials that changed practice

The lipid field is built on outcome trials — name the trial, name what it changed. Every rung of the ladder rests on a landmark result, and a final-prof candidate is expected to cite them.[15]

[3] [4] [5] [6] [7] [8] [9] [10] [12] [13] [14] [16]

Inclisiran (two phase 3 trials, 2020) is the small-interfering RNA that silences hepatic PCSK9 mRNA — 284 mg subcutaneously on day 1, day 90, then every 6 months — for approximately 50 percent LDL-C reduction with twice-yearly maintenance dosing; injection-site reactions were more common than with placebo.[17]

Two guidelines, one direction — where ESC/EAS and AHA/ACC diverge

Two frameworks, one direction. European guidelines set fixed LDL-C treatment goals — under 1.4 mmol/L after an acute coronary syndrome and under 1.0 mmol/L for recurrent events within two years — while the 2018 AHA/ACC US guideline prefers a statin-intensity approach: at least 50 percent LDL-C reduction in clinical ASCVD, with a 70 mg/dL (1.8 mmol/L) threshold for adding ezetimibe then a PCSK9 inhibitor in very-high-risk ASCVD. In practice both converge on the same lower-is-better endpoint.[32][15]

The controversy to name calmly: the HDL story has collapsed — genetic studies and negative randomised trials of HDL-raising strategies suggest low HDL does not cause cardiovascular disease as once thought. Lowering LDL-C remains the only lipid target with consistently proven outcome benefit; apoB and Lp(a) are emerging deputies, not replacements.[33]

The mantra, and the dangerous-combos and preventable-harm lists

The mantra: lower is better, earlier is better, for longer — treat the risk, not the number.[18][15]

The dangerous-combos list (three lines, no exceptions):[26][35]

• Gemfibrozil plus a statin → rhabdomyolysis — use fenofibrate; the statin–fibrate combination itself raises risk, and gemfibrozil-plus-atorvastatin is the published catastrophe.[35]
• Interacting drugs (clarithromycin, ketoconazole, itraconazole, protease inhibitors, ciclosporin, grapefruit) plus simvastatin or atorvastatin → myopathy risk — drug–drug interactions sit at the centre of every statin risk discussion; review the chart before you up-titrate.[26][15]
• Statin in pregnancy — statin safety in pregnancy is a special population of its own; where lipid lowering is needed, use a bile-acid sequestrant.[26]

The preventable-harm list (the three failures that cost lives):[20][34][35]

• The missed FH — an LDL-C of 4.9 mmol/L (190 mg/dL) or more labelled "just high cholesterol", without family cascade screening.[15]
• The statin stopped permanently for nocebo myalgia — blinded re-challenge succeeds far more often than not; never abandon lipid lowering.
• The gemfibrozil-plus-statin prescription — fenofibrate exists for exactly this reason.

Ward-round test — three stems, thirty seconds each

Stem 1 — the man with the lumpy Achilles tendons (answer)

A 28-year-old man has tendon xanthomata, an LDL-C of 9.2 mmol/L, and a father with an MI at 42. What is the diagnosis, and what is the first thing you do for his family? Model: This is familial hypercholesterolaemia — tendon xanthomata, a markedly elevated untreated LDL-C, and premature CAD in a first-degree relative. A severe primary hypercholesterolaemia of this degree warrants a high-intensity statin without further risk scoring, aiming to cut LDL-C by at least half and — after an ACS or in very-high risk — toward LDL-C under 1.4 mmol/L; add ezetimibe, then a PCSK9 inhibitor, while LDL-C sits at 1.8 mmol/L (70 mg/dL) or above. And the single highest-yield action for the family: cascade screening of first-degree relatives. Measure Lp(a) once.[19][15][32][27]

Stem 2 — the diabetic with triglycerides of 14 (answer)

A 52-year-old with type 2 diabetes presents with epigastric pain, TG 14 mmol/L, and a milky plasma sample. What is the immediate threat, and what is the bundle? Model: The threat is hypertriglyceridaemic pancreatitis. Admit, NPO with fat restriction, aggressive IV crystalloid, opioid analgesia, and an insulin infusion — rapid triglyceride reduction comes from activating lipoprotein lipase — with therapeutic plasma exchange available for refractory disease. Restart fenofibrate (never gemfibrozil with a statin) and omega-3 once enteral intake resumes. Prevention is the cure: fat restriction, complete alcohol avoidance, glycaemic control, and chronic fibrate plus omega-3 — recurrence is likely but preventable.[31][30][35]

Stem 3 — the post-ACS patient with LDL 2.0 on a statin (answer)

Six weeks after an NSTEMI, a patient on atorvastatin 80 mg has LDL-C 2.0 mmol/L. What do you do, and what is the target? Model: Post-ACS is very-high risk — European goals put LDL-C under 1.4 mmol/L (and under 1.0 for a second event within two years), so 2.0 misses it. Confirm adherence and timing, then climb the ladder: add ezetimibe 10 mg — IMPROVE-IT proved fewer events with exactly this escalation — and if LDL-C is still 1.8 mmol/L (70 mg/dL) or above, add a PCSK9 inhibitor (evolocumab or alirocumab), both proven on outcomes.[32][9][10][11]

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