Preventive Cardiology & Endocrinology & Internal Medicine & Family Medicine
LDL cholesterol («bad cholesterol»)
LDL cholesterol (Low-Density Lipoprotein) is the fraction of cholesterol carried by LDL lipoproteins in the bloodstream to peripheral tissues. Nicknamed the «bad cholesterol», it is the main modifiable biomarker of atheromatous cardiovascular risk - a direct and continuous causal relationship between LDL-C and the risk of myocardial infarction, ischemic stroke and cardiovascular death has been established by decades of epidemiological data, Mendelian randomizations and randomized clinical trials (RCTs). The relationship is dose-dependent and linear over a wide range of concentrations: each 1 mmol/L reduction in LDL-C is associated with a reduction of around 22 % in major cardiovascular events (MACE) - an estimate from the Cholesterol Treatment Trialists' (CTT) Collaboration 2010 and 2019 meta-analysis, involving over 170,000 participants in 26 RCTs. LDL-C, however, is only one component of the complete lipid profile, which also includes total cholesterol, triglycerides, HDL-C, non-HDL-C (calculated as total cholesterol - HDL-C - reflects all atherogenic lipoproteins) and apolipoprotein B (ApoB - a direct marker of atherogenic particle concentration). In Canada, the Lipid Guidelines 2021 (Pearson - Canadian Journal of Cardiology) stratify cardiovascular risk into categories (very high + high + intermediate + low) to define therapeutic targets for LDL-C and indications for pharmacological treatment, with non-HDL-C and ApoB as complementary follow-up markers.
Physiology of LDL, risk assessment, and target values
- Metabolism of LDL and mechanisms of atherosclerosis: lipoprotein and LDL metabolism: the liver synthesizes and secretes VLDL (Very Low Density Lipoprotein) loaded with endogenous triglycerides → VLDL releases its triglycerides into the peripheral capillaries (action of lipoprotein lipase - LPL) → VLDL becomes enriched with in cholesterol and lose triglycerides → transformation into IDL (Intermediate Density Lipoprotein) → then into LDL (Low Density Lipoprotein) → LDL contains mainly esterified cholesterol + a molecule of apolipoprotein B-100 (ApoB-100) → LDL binds to LDL receptors (LDLr - hepatocyte and peripheral receptors) → endocytosis + lysosomalial degradation → cholesterol release → regulation by the LDLR gene and PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) → PCSK9 degrades LDL receptors on the hepatocyte surface → fewer receptors → less LDL uptake → LDL-C → statins increase LDLR gene expression → more receptors → increased LDL uptake → reduced LDL-C → mechanism of atherosclerosis : oxidation of LDL (oxLDL) → phagocytosis by macrophages → foam cells → accumulation in arterial wall → atheromatous plaque → plaque rupture → platelet activation → thrombus → MI + stroke; calculation of LDL-C - Friedewald formula: LDL-C = total cholesterol - HDL-C - (triglycerides / 2.2) [in mmol/L] → or (triglycerides / 5) [in mg/dL] → valid if TG <4,5 mmol/L → si TG >4.5 mmol/L → imprecise formula → use directly measured LDL-C (ultracentrifugation or homogenous method) → ApoB: direct marker of LDL particle number (1 ApoB per LDL particle) → normal adult value: 1.0–1.05 g/L → target after treatment in secondary prevention: 0.7–0.8 g/L + Lp(a) — lipoprotein(a): LDL particle with apolipoprotein(a) → independent genetic risk factor → not influenced by statins + ezetimibe → reduced by PCSK9 inhibitors (30–40 %) + messenger RNA inhibitors (olpasiran + pelacarsen — approval pending); cardiovascular risk stratification in Canada (Canadian lipid guidelines 2021 — Pearson): very high risk: established CVD (MI + stroke + angina + peripheral artery disease + coronary revascularization) + or T1DM + T2DM with target organ damage + LDL-C target: <1.8 mmol/L AND reduction ≥50% % vs. baseline → target non-HDL-C: 2.4 mmol/L → target ApoB: <0.7 g/L → high risk: 10-year ASCVD score ≥20 % or LDL-C ≥5 mmol/L or FH (familial hypercholesterolemia) or LDL-C target: <2.0 mmol/L → intermediate risk: FRS 10–19.9 % → risk score modified by aggravating factors (high Lp(a) + coronary calcifications + high CAC + low ABI + uncontrolled HTN) → LDL-C target: ≥50% reduction % → low risk: FRS <10 % → traitement si ldl-c très élevé (>5 mmol/L) or additional factors
- Comprehensive lipid panel, screening indications, and secondary causes complete lipid panel (fasting or non-fasting depending on indications): total cholesterol + LDL-C + HDL-C + triglycerides + calculation of non-HDL-C (TC - HDL-C) → ApoB if available → Canadian guidelines 2021 allow non-fasting panel for initial screening → if TG >4.5 mmol/L in non-fasting → repeat fasting → Lp(a): measure at least once in any adult → adjusts risk stratification → screening frequency (Pearson 2021): men ≥40 years + women ≥50 years or postmenopausal → screening every 3-5 years → T2DM + hypertension + obesity + smoking + early family cardiovascular ATCD → earlier + more frequent screening + secondary causes of hypercholesterolemia (elevated LDL-C) to be excluded before attributing elevation to genetics or lifestyle: hypothyroidism : TSH → most frequent and treatable cause (normalization of LDL with LT4 therapy) + nephrotic syndrome: hypoalbuminemia → compensatory hepatic synthesis of lipoproteins → elevated LDL + CKD → reduced lipoprotein catabolism → cholestasis → reduced biliary excretion of cholesterol → elevated LDL + drugs: corticosteroids + antiretrovirals (PI) + cyclosporine + retinoids + atypical antipsychotics + some beta-blockers + progestogens → obesity + diet rich in saturated fats + trans → unbalanced diabetes → pregnancy (LDL increased physiologically) + familial hypercholesterolemia (FH) : LDLR gene mutation (80 % of HF) + ApoB + PCSK9 gain-of-function → LDL-C often >5 mmol/L from childhood → tendinous xanthomas (Achilles tendons + finger extensors) + corneal arc before age 40 → risk of MI before age 55 + cascade family screening
Pharmacological Treatment and Therapeutic Objectives
| Treatment / medication | Data, mechanisms, and outcomes | Key studies and recommendations |
|---|---|---|
| Statins: A pillar of lipid-lowering therapy Atorvastatin — Rosuvastatin — High intensity — Moderate intensity — LDLR mechanism — Myopathy — Rhabdomyolysis — CK — Interactions — Statin intolerance — Primary prevention — Secondary prevention |
Statins - 1st-line treatment to reduce LDL-C: mechanism: competitive inhibition of HMG-CoA reductase (key enzyme in hepatic cholesterol biosynthesis) → reduction of intracellular cholesterol synthesis → compensatory upregulation of hepatocyte LDL receptors → increased uptake of circulating LDL → reduction of LDL-C + classification according to intensity: high intensity (LDL-C reduction ≥50 %): atorvastatin 40-80 mg/d + rosuvastatin 20-40 mg/d → moderate intensity (LDL-C reduction 30-49 %): atorvastatin 10-20 mg + rosuvastatin 5-10 mg + simvastatin 20-40 mg + pravastatin 40-80 mg → results of major reference studies: 4S (Scandinavian Simvastatin Survival Study - Lancet 1994): simvastatin + secondary prevention → reduction in total mortality -30 % + LIPID (Lancet 1998) + CARE (NEJM 1996) + HPS (Heart Protection Study - Lancet 2002): simvastatin 40 mg + DCV established → 25 % reduction in MACE → benefit regardless of baseline LDL-C level → CTT Collaboration 2010 - Lancet (meta-analysis 26 RCT n=170,000): each 1 mmol/L reduction in LDL-C → 22 % reduction in MACE → linear relationship + JUPITER (Ridker 2008 - NEJM n=17,802): rosuvastatin 20 mg + primary prevention + CRP ≥2 mg/L → 44 % MACE reduction + TNT (LaRosa 2005 - NEJM): atorvastatin 80 mg vs 10 mg → the greater the LDL reduction → the greater the benefit → «the lower the better» → statin adverse effects: myopathy (myalgia + CK elevation): 5-10 % of patients report myalgia on statin → but in double-blind RCTs → similar incidence to placebo (Cohen 2020 - European Heart Journal - nocebo effect) → rhabdomyolysis: rare (1/10,000 patient-years) → if CK >10× normal + symptoms → stop → severe hepatotoxicity: very rare → no routine transaminase monitoring required (AAC/ACC 2013) → T2DM: slightly increased risk of developing T2DM on statin (10-12 % increase in relative risk - Sattar 2010 - Lancet) → but cardiovascular benefit far outweighs this risk + drug interactions: CYP3A4 inhibitors (amiodarone + diltiazem + macrolides + azoles + grapefruit juice) → increase levels of some statins → risk of myopathy (atorvastatin + simvastatin ++ ) → rosuvastatin and pravastatin: less CYP3A4 metabolism → fewer interactions → CONTRAINDICATION in pregnancy (teratogenic - category X) | CTT Collaboration 2010 — Lancet (meta-analysis 26 RCTs n=170,000): each -1 mmol/L LDL-C → -22 % MACE → linear relationship → absolute reference + 4S 1994 Lancet: simvastatin secondary prevention → -30 % mortality + HPS 2002 Lancet: simvastatin + CVD → -25 % MACE + JUPITER 2008 NEJM n=17,802: rosuvastatin 20 mg primary prevention → -44 % MACE + TNT 2005 NEJM: atorvastatin 80 mg vs 10 mg → «the lower the better» + Cohen 2020 EHJ: statin nocebo effect + Sattar 2010 Lancet: statins + T2DM risk +10-12 % + Pearson 2021 — Canadian Journal of Cardiology (CCS 2021): Canadian lipid guidelines → statins + LDL-C targets + ApoB + INESSS Quebec + RAMQ: reimbursed high-intensity statins |
| Ezetimibe, PCSK9 Inhibitors, and Novel Agents Ezetimibe — IMPROVE-IT — Evolocumab — Alirocumab — FOURIER — ODYSSEY — Inclisiran RNA interference — Bempedoic acid — Bempedoate — Combinations — Very low LDL — Lp(a) — PCSK9 inhibitors indication — RAMQ reimbursement |
Ezetimibe - 2nd-line treatment in combination with statins: mechanism: selective inhibition of NPC1L1 (Niemann-Pick C1-Like 1) protein in enterocytes → reduced intestinal cholesterol absorption (dietary + biliary) → LDL-C reduction of an additional 15-25 % in addition to a statin → IMPROVE-IT (Cannon 2015 - NEJM n=18 144): ezetimibe + simvastatin vs simvastatin alone after ACS → LDL-C reduction of an additional 0.4 mmol/L (1.8 → 1.4 mmol/L) → MACE reduction of an additional 6.4 % → validation of the «the lower the better» principle → use as 2nd line if statin alone insufficient to reach target → well tolerated + low risk of adverse effects → dose: ezetimibe 10 mg/d → PCSK9 inhibitors (anti-PCSK9) - 3rd line: mechanism: monoclonal antibodies inhibiting PCSK9 → PCSK9 normally binds to LDL receptors and directs them to degradation → inhibition of PCSK9 → more LDL receptors available → massive uptake of LDL → reduction of LDL-C by a further 50-60 % beyond statin + ezetimibe → evolocumab (Repatha) 140 mg SC every 2 weeks → or 420 mg SC/month : FOURIER (Sabatine 2017 - NEJM n=27,564): evolocumab + high-dose statin + established DCV → LDL-C 0.78 mmol/L → reduction in MACE by 15 % + alirocumab (Praluent) 75-150 mg SC every 2 weeks: ODYSSEY OUTCOMES (Schwartz 2018 - NEJM n=18,924): alirocumab + post-SCA → reduction in MACE + all-cause mortality → indications recognized for reimbursement by RAMQ (INESSS): DCV established + LDL-C ≥2.6 mmol/L despite high-intensity statin + ezetimibe → or HF (familial hypercholesterolemia) + LDL-C insufficiently controlled → additional benefit at very low LDL: CTT 2022 - Lancet: LDL-C <1.0 mmol/L → no increase in adverse effects + proportional benefit maintained → LDL-C / MACE dose-response curve is linear without plateau; inclisiran (Leqvio) - RNA interference (RNAi): siRNA against PCSK9 → SC administration × 1 injection/6 months (after initial dose and at 3 months) → LDL-C reduction of 50 % → ORION-10 (Ray 2020 - NEJM) + ORION-11 (Raal 2020 - NEJM) → Health Canada 2022: approved → major advantage: twice-yearly administration → superior compliance + bempedoic acid (Nexletol) 180 mg/d: inhibitor of ACL (ATP citrate lyase) → precursor upstream of HMG-CoA → same mechanism as statins but activated only in the liver (not in muscle → less myalgias) → CLEAR (Lincoff 2023 - NEJM n=13,970): bempedoate + primary or secondary prevention in statin intolerant patients → reduction in MACE by 13 % → alternative if statin intolerance proven | Cannon 2015 — NEJM (IMPROVE-IT n=18 144) : ézétimibe + simvastatine → −6,4 % MACE supplémentaires + « lower is better » validé + Sabatine 2017 — NEJM (FOURIER n=27 564) : évolocumab → LDL-C 0,78 mmol/L → −15 % MACE → PCSK9i = standard DCV réfractaire + Schwartz 2018 — NEJM (ODYSSEY n=18 924) : alirocumab → −MACE + mortalité toutes causes + Ray 2020 — NEJM (ORION-10) + Raal 2020 — NEJM (ORION-11) : inclisiran → −50 % LDL-C × biannuel + Lincoff 2023 — NEJM (CLEAR n=13 970) : bempédoate + intolérants statines → −13 % MACE + CTT 2022 — Lancet : LDL très bas + pas d'augmentation EI + bénéfice linéaire maintenu + Pearson 2021 — CJC : lignes directrices canadiennes lipides + ézétimibe + PCSK9i → INESSS Québec : PCSK9i remboursés si DCV + LDL ≥2,6 mmol/L malgré statine + ézétimibe + HF + Santé Canada : évolocumab + alirocumab + inclisiran approuvés |
| Lifestyle, HF, and special situations Nutrition — saturated trans fats — Mediterranean diet — exercise — weight — familial hypercholesterolemia FH — LDL >5 mmol/L — xanthomas — corneal arcus — family screening — child — pregnancy statin CI — statin intolerance — myalgia — statin switch — CK testing |
Lifestyle modifications - non-pharmacological measures: diet: reduction of saturated fats (5 mmol/L + family history of MI before age 55 (men) or age 65 (women) + tendinous xanthomas + corneal arc <40 → LDLR mutation + ApoB + PCSK9 gain-of-function → treatment: high-intensity statin from diagnosis (from childhood if homozygous HF) + ezetimibe + PCSK9i if target not reached → LDL-apheresis (purification of LDL by apheresis - severe homozygous HF) → cascade screening of family (parents + siblings + children) + HF in children: screening recommended from age 2 if parent affected → statin from age 8-10 (unlike healthy adults without VCD) + statin intolerance: defined as inability to use ≥2 statins at lowest dose → disabling myalgias + elevated or normal CK → alternative: bempedoate + ezetimibe + PCSK9i → avoid concluding intolerance without trying ≥2 different statins at different doses + nocebo effect (Cohen 2020 - EHJ): double-blind → 90 % of muscle symptoms on statin are not pharmacological → attempt reintroduction at low dose with CK monitoring | Estruch 2013 — NEJM (PREDIMED): Mediterranean diet → −30 % MACE → reference diet + CTT 2010 + 2022 — Lancet: statins + LDL-C + MACE + Cohen 2020 — European Heart Journal: nocebo effect + statins + myalgias → 90 % non-pharmacological double-blind + Lincoff 2023 NEJM CLEAR bempedoic acid statin intolerant + Pearson 2021 — Canadian Journal of Cardiology (CCS guidelines): HF + screening + treatment + Familial Hypercholesterolemia Canada (FH Canada): screening + national registry + DLCN score + Grundy 2019 — Journal of the American College of Cardiology (ACC/AHA 2019 guidelines): lipids + LDL-C targets + statins + PCSK9i + INESSS Quebec + RAMQ: statins + ezetimibe + PCSK9i + bempedoic acid → reimbursement according to INESSS criteria + FH Canada + Health Canada + drug approvals |
ℹ️
The relationship between LDL-C and cardiovascular risk is linear and causal — each 1 mmol/L reduction in LDL-C reduces major cardiovascular events by 22% % (CTT 2010): There is no lower threshold of LDL-C below which the benefit stops or adverse effects increase. The majority of muscle symptoms reported with statins are related to the nocebo effect and not to the statin itself—before concluding intolerance, at least 2 statins at different doses should be tried. In secondary prevention, the goal is an LDL-C <1.8 mmol/L with a reduction ≥50%% — if not achieved with statin alone, add ezetimibe then a PCSK9 inhibitor.
Situations requiring urgent or specialized care
Patient with LDL-C >5 mmol/L in a young adult (<40 years old) + family history of MI before 55 years old + tendinous xanthomas in Achilles tendons or finger extensors + or corneal arcus <40 years old → Probable familial hypercholesterolemia → DLCN score → Lipidology or cardiology consultation → High-intensity statin + immediate ezetimibe → LDLR genetic testing → Cascade screening of the family → PCSK9i if LDL not controlled → DO NOT wait for the patient to develop MI.
Patient on high-intensity statin + ezetimibe for secondary prevention (MI + stroke + angina + PAD) with LDL-C >2.6 mmol/L at 3 months of optimal treatment → Target not met → Eligibility for PCSK9 inhibitors according to INESSS criteria → Evolocumab (Repatha) or Alirocumab (Praluent) → Further reduction of 50–60 % of LDL-C → RAMQ authorization request if criteria are met.
Patient reporting intense myalgias on atorvastatin 40 mg with normal CK → statin discontinued → myalgias persist → probable nocebo effect → no true pharmacological intolerance → reintroduce a different statin at a low dose (rosuvastatin 5–10 mg) → explain the nocebo effect → if myalgias reappear reproducibly with ≥2 statins → true intolerance → switch to bempedoate + ezetimibe + PCSK9i according to risk level.
Consult at Clinique Omicron
Clinique Omicron physicians prescribe and interpret a complete lipid profile (LDL-C + non-HDL-C + ApoB + Lp(a)), stratify cardiovascular risk (FRS + modifying factors), initiate and adjust high-intensity statins, add ezetimibe if the target is not met, request authorization for PCSK9 inhibitors if INESSS criteria are met, and screen for FH in patients with LDL-C >5 mmol/L. Consultations are available at several service points in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is provided for informational purposes only and does not substitute for the advice of a physician or cardiologist. LDL-C therapeutic goals should be determined individually according to the patient's global cardiovascular risk level.
Omicron Clinic
Need to consult a doctor?
Treatment within 24-48 hours. In-clinic or telemedicine, anywhere in Quebec.
Insurance receipts. 7j/7. No family doctor required.