Dyslipidaemia — Viva

Q1 — Definitions and lipoprotein physiology (2 min)

Examiner: Define dyslipidaemia and walk me through the apolipoproteins — which ones carry which lipoprotein, and what does each do? ^[15]

Model answer: Dyslipidaemia is any disturbance of circulating lipid or lipoprotein concentration — raised LDL-C, raised TG, low HDL-C, or raised Lp(a). Lipids travel in lipoproteins: an ApoB-48 tags chylomicrons (dietary fat from the gut), ApoB-100 tags VLDL, IDL, and LDL (endogenous hepatic lipids), and ApoA-I is the main apolipoprotein of HDL. Functionally: ApoB-100 is the ligand for the LDL receptor (hepatic clearance); ApoC-II activates lipoprotein lipase (LPL) on capillary endothelium, hydrolysing TG; ApoE is the ligand for the remnant receptor, clearing chylomicron and IDL remnants; ApoA-I activates LCAT and drives HDL's reverse cholesterol transport via ABCA1/ABCG1 and SR-B1. HMG-CoA reductase is the rate-limiting enzyme of hepatic cholesterol synthesis — the statin target. ^[15]

Examiner: And what is the mechanism by which LDL actually causes atherosclerosis? ^[15]

Model answer: The response-to-retention hypothesis. ApoB lipoproteins cross a dysfunctional endothelium and are retained in the intimal proteoglycans, where they undergo oxidative modification. Modified LDL is no longer recognised by the LDL receptor but is taken up, unregulated, by macrophage scavenger receptors (SR-A, CD36), converting macrophages into foam cells — the hallmark of the fatty streak. Foam cells release cytokines (TNF-α, IL-1, MCP-1) that upregulate endothelial adhesion molecules (VCAM-1, ICAM-1), recruit more monocytes and T-cells, and trigger smooth-muscle migration to form a fibrous cap. Inflammation-driven matrix metalloproteinases thin the cap, the plaque becomes vulnerable, and rupture exposes the thrombogenic core — platelets and coagulation activate, forming the occlusive thrombus of MI or ischaemic stroke. ^[15]

Q2 — Risk stratification and targets (3 min)

Examiner: A 60-year-old man, prior MI, now LDL 4.2 mmol/L. What is his risk category and what is the LDL target? Cite the guideline. ^[32]

Model answer: Post-MI / post-ACS is treated as very-high risk. European guideline LDL-C goals after ACS are under 1.4 mmol/L, and under 1.0 mmol/L for patients with a recurrent cardiovascular event within 2 years (Landmesser, citing 2019 ESC/EAS). Independently, the 2018 AHA/ACC guideline uses a maximally tolerated statin to lower LDL-C by ≥50% in clinical ASCVD, and a 70 mg/dL (1.8 mmol/L) threshold to add ezetimibe then a PCSK9 inhibitor in very-high-risk ASCVD. ^[32][15]

Examiner: Give me the other goals. ^[15]

Model answer: I would not quote the 2019 high/moderate/low absolute goals from memory here — the fetched European source used in this topic specifies under 1.4 mmol/L after ACS and under 1.0 mmol/L after recurrent events within 2 years. The fetched US source specifies ≥50% LDL-C reduction in clinical ASCVD and a 70 mg/dL add-on threshold in very-high-risk ASCVD. Intensity follows total risk, not the raw LDL number alone. ^[32][15]

Examiner: How do you estimate the total risk in primary prevention? ^[15]

Model answer: In the US, the 2018 AHA/ACC guideline uses a 10-year ASCVD risk discussion plus risk-enhancing factors; if the decision is uncertain, CAC is the tie-breaker — a score of zero can justify withholding or delaying a statin, while ≥100 Agatston units indicates one (unless deferred after discussion). In the UK, NICE NG238 uses QRISK3 for ages 25–84 without established CVD. ^[15][38]

Q3 — Management ladder (3 min)

Examiner: Take me through the drug ladder, with mechanism, dose, and a trial for each. ^[15]

Model answer:

• Statins (HMG-CoA reductase inhibitors) — first-line. High-intensity: atorvastatin 40–80 mg or rosuvastatin 20–40 mg once daily (≥50% LDL reduction). Trials: 4S (mortality, secondary prevention), WOSCOPS (primary prevention), HPS (across all risk strata).
• Ezetimibe 10 mg once daily — inhibits NPC1L1 at the jejunal brush border, blocking cholesterol absorption. Outcome benefit on top of statin: IMPROVE-IT (post-ACS).
• PCSK9 inhibitors — alirocumab 75–150 mg SC q2wk or evolocumab 140 mg SC q2wk (or 420 mg monthly); inhibits PCSK9, prolonging LDL-receptor life; adds 50–60% LDL reduction. Outcome benefit: FOURIER and ODYSSEY OUTCOMES.
• Bempedoic acid 180 mg daily — ATP-citrate lyase inhibitor; liver-only prodrug, so no myopathy — for statin-intolerant patients.
• Inclisiran 284 mg SC on day 1, day 90, then every 6 months — siRNA silencing hepatic PCSK9 mRNA; approximately 50% LDL-C reduction with twice-yearly maintenance (ORION-10/11).
• For raised TG: fenofibrate (never gemfibrozil with a statin) and icosapent ethyl 4 g/day (pure EPA) — REDUCE-IT reduced CV events in TG 1.5–5.6 mmol/L on a statin. ^{[15][9][10][16][17][12][35]}

Examiner: Why is gemfibrozil never combined with a statin? ^[15]

Model answer: Gemfibrozil inhibits the OATP2 hepatic transporter and glucuronidation of statins, markedly raising statin levels and causing a high incidence of rhabdomyolysis. Fenofibrate does not share this interaction and is the fibrate of choice when a fibrate-statin combination is needed. ^[35]

Q4 — Statin adverse effects and pitfalls (2 min)

Examiner: A patient on simvastatin develops muscle aches with CK 7× ULN. What do you do? ^[15]

Model answer: This is myositis (muscle symptoms with raised CK). Stop the statin, recheck CK until it normalises, then re-challenge with a different dose or regimen. Krishnamurthy: expectation-setting, dose and regimen adjustment, and re-challenge get many patients back on a statin; in SAMSON 50% successfully restarted. If genuinely intolerant, use bempedoic acid (CLEAR Outcomes, statin-intolerant population) plus ezetimibe or a PCSK9 inhibitor. I would not abandon the class. ^[34][16]

Examiner: What are the other adverse effects and the contraindications? ^[15]

Model answer: Other adverse effects: JUPITER showed a small rise in physician-reported diabetes without excess myopathy or cancer; TNT showed more persistent aminotransferase elevation on atorvastatin 80 mg than 10 mg (1.2% vs 0.2%). Pregnancy is a special population in the AHA statin-safety statement — do not quote an unsourced 1–3 month washout. CYP3A4-inhibiting macrolides (clarithromycin, erythromycin — not azithromycin) raise rhabdomyolysis and AKI risk when coprescribed with CYP3A4-metabolised statins; hold or switch the statin. ^[15][37]

Q5 — Special situations (2 min)

Examiner: Three rapid scenarios. One — a pregnant woman with known familial hypercholesterolaemia. Two — CKD with eGFR 25. Three — triglycerides 22 mmol/L with epigastric pain. ^[13]

Model answer:

• Pregnancy with FH: the AHA statin-safety statement reviews pregnancy as a special population. Severe FH in pregnancy belongs with a specialist lipid service; lipoprotein apheresis can be offered in homozygotes (EAS 2013). Do not quote an unsourced teratogenicity window.
• CKD, eGFR 25: SHARP (simvastatin 20 mg plus ezetimibe 10 mg vs placebo in 9270 patients with advanced CKD, about a third on dialysis) found a 17% proportional reduction in major atherosclerotic events (11.3 vs 13.4%; RR 0.83), and they were similar in patients on dialysis and those who were not. That is the fetched evidence base — do not overlay an unsourced dialysis-start ban.
• TG 22 mmol/L with epigastric pain is hypertriglyceridaemic pancreatitis — admit, NPO, aggressive IV fluids, opioid analgesia, insulin infusion (activates LPL), fenofibrate and omega-3 once enteral intake resumes, and therapeutic plasma exchange for refractory disease or pregnancy. Prevent recurrence with strict fat restriction, alcohol abstinence, glycaemic control, and chronic fibrate + omega-3. ^[13][19][15]

Q6 — ApoB, non-HDL-C and lipoprotein(a)

Examiner: A patient has LDL-C 2.4 mmol/L, but non-HDL-C is 4.0 mmol/L and apoB is high. What is happening, and why does it matter? ^[15]

Model answer: This is LDL-C–apoB discordance. In high-TG states such as diabetes and metabolic syndrome, LDL particles become small and cholesterol-depleted, so LDL-C underestimates the total number of atherogenic particles. Non-HDL-C (total cholesterol minus HDL-C) and apoB capture the cholesterol in all apoB-containing particles — LDL, IDL, VLDL, and Lp(a). This patient therefore has significant residual atherogenic risk despite a "normal" LDL-C, and management should focus on aggressive TG lowering, glycaemic control, and statin therapy. ^[15]

Examiner: When should we measure lipoprotein(a), and what do we do if it is elevated? ^[15]

Model answer: The 2010 EAS consensus advises that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk, with a desirable level below the 80th percentile (less than 50 mg/dL). Hepatic secretion of apo(a) accounts for 90% of plasma Lp(a). US 2018 guidance counts Lp(a) ≥50 mg/dL (125 nmol/L) as a risk-enhancing factor if measured in selected individuals. Because no Lp(a)-specific outcome drug is in the fetched sources here, management is aggressive control of other modifiable risks. ^[27][15]

References14ShowHide

1. [9]Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes N Engl J Med, 2015.PMID 26039521
2. [10]Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease N Engl J Med, 2017.PMID 28304224
3. [12]Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia N Engl J Med, 2019.PMID 30415628
4. [15]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC Guideline on the Management of Blood Cholesterol Circulation, 2019.PMID 30586774
5. [16]Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients N Engl J Med, 2023.PMID 36876740
6. [27]Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status Eur Heart J, 2010.PMID 20965889
7. [32]Landmesser U, McGinniss J, Steg PG, et al. Achievement of ESC/EAS LDL-C treatment goals after an acute coronary syndrome with statin and alirocumab Eur J Prev Cardiol, 2022.PMID 35708715
8. [34]Krishnamurthy A, Bradley C, Ascunce R, et al. SAMSON and the Nocebo Effect: Management of Statin Intolerance Curr Cardiol Rep, 2022.PMID 35759168
9. [35]Dalugama C, Pathirage M, Kularatne SAM Delayed presentation of severe rhabdomyolysis leading to acute kidney injury following atorvastatin-gemfibrozil combination therapy: a case report J Med Case Rep, 2018.PMID 29784023
10. [38]National Institute for Health and Care Excellence Cardiovascular disease: risk assessment and reduction, including lipid modification NICE NG238, 2023.Source
11. [13]Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial Lancet, 2011.PMID 21663949
12. [17]Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol N Engl J Med, 2020.PMID 32187462
13. [19]Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population Eur Heart J, 2013.PMID 23956253
14. [37]Patel AM, Shariff S, Bailey DG, et al. Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study Ann Intern Med, 2013.PMID 23778904