Preventive Cardiology – Lipid Metabolism
Total cholesterol, HDL, and LDL
Cholesterol is a lipid molecule essential for human life: it is a key component of cell membranes, a precursor to steroid hormones (cortisol, aldosterone, estrogen, testosterone), bile acids, and vitamin D, and is largely synthesized by the liver, with additional amounts obtained from the diet. Insoluble in water, it circulates in the blood in the form of soluble complexes called lipoproteins, which are spherical particles composed of a lipid core surrounded by a shell of specific proteins (apolipoproteins) that enable their transport within the circulation. The two main lipoproteins measured in clinical practice are LDL (low-density lipoproteins, Low-Density Lipoproteinsoften called «bad cholesterol»—which carry cholesterol from the liver to peripheral tissues, and whose excess accumulation in the artery walls is the main mechanism for the formation of atheroma plaques, and HDL (high-density lipoproteins, High-Density Lipoproteins) - the «good cholesterol» - which transports cholesterol in the opposite direction from peripheral tissues to the liver for elimination, thus exerting a cardioprotective effect. The standard lipid profile - or fasting lipid profile - measures total cholesterol, HDL cholesterol and triglycerides, and calculates LDL cholesterol according to the Friedewald formula, making it the reference tool for assessing cardiovascular risk and deciding on therapeutic intervention. Hypercholesterolemia, defined as an excess of circulating LDL cholesterol, is the main modifiable cardiovascular risk factor apart from hypertension and smoking, and its correction by hygienic dietary measures and lipid-lowering drugs - first and foremost the statins - demonstrably reduces cardiovascular mortality. In Quebec, the recommendations of Hypertension Canada and the Canadian Cardiovascular Society guide cardiovascular risk stratification and lipid therapy targets according to each patient's individual profile.
Lipoproteins: Roles and Mechanisms
Understanding the different lipoproteins and their physiological roles allows for correct interpretation of lipid panel results:
| Lipoprotein | Physiological role | Relation with cardiovascular risk |
|---|---|---|
| LDL (Low-Density Lipoprotein) — «bad cholesterol» | Transport of cholesterol from the liver to peripheral cells for their structural and metabolic needs; cells capture LDL via specific receptors (LDL receptors, LDLR) which regulate their plasma levels | A direct, dose-dependent causal relationship with the risk of atherosclerotic cardiovascular disease (ACVD); LDL accumulates in the arterial wall, oxidizes, and triggers the formation of atherosclerotic plaques; each 1 mmol/L reduction in LDL-C reduces the risk of a major cardiovascular event by approximately 22% |
| HDL (High-Density Lipoprotein) — «good cholesterol» | Reverse cholesterol transport: collects excess cholesterol in arterial walls and peripheral tissues and returns it to the liver for elimination in bile (reverse cholesterol transport pathway); additional anti-inflammatory and antioxidant properties | Inverse relationship with cardiovascular risk: high HDL is cardioprotective; low HDL (< 1.0 mmol/L in men, < 1.2 mmol/L in women) is an independent cardiovascular risk factor; however, therapeutic trials aiming to raise HDL have not demonstrated a reduction in cardiovascular risk proportional to their biological elevation |
| VLDL (Very Low-Density Lipoprotein) | Transport of endogenously synthesized triglycerides from the liver to tissues; precursor to LDL after hydrolysis of their triglyceride content by lipoprotein lipase | Not measured directly in the standard lipid panel; estimated from triglycerides (VLDL ≈ triglycerides / 2.2); contributes to residual cardiovascular risk in severe hypertriglyceridemia |
| Lp(a) - Lipoprotein (a) | LDL-like particle covalently linked to apolipoprotein (a); genetically determined cardiovascular risk factor, little influenced by statins | Important, underestimated independent cardiovascular risk factor; high levels associated with increased risk of myocardial infarction, ischemic stroke, and calcified aortic stenosis; to be measured at least once in a lifetime in patients at intermediate or high risk or with a family history of cardiovascular disease |
Reference values and therapeutic targets
Normal lipid panel values vary depending on the clinical context and the patient's overall cardiovascular risk level. Therapeutic targets are stricter in high-risk patients:
| Parameter | Optimal / normal value | Matter of concern | Target in patients at high CV risk |
|---|---|---|---|
| Total cholesterol | < 5.2 mmol/L (200 mg/dL) | 6.2 mmol/L (240 mg/dL) | Less used alone as a target; the primary goal is LDL-C |
| LDL cholesterol (LDL-C) | < 3.4 mmol/L in primary prevention for low-risk individuals | 4.1 mmol/L | < 1.8 mmol/L for high CV risk (established ASCVD, diabetes with organ damage); < 1.4 mmol/L for very high risk (recent CV event < 2 years, ASCVD + diabetes) |
| HDL cholesterol (HDL-C) | > 1.0 mmol/L in men; > 1.2 mmol/L in women | < 1.0 mmol/L (men and women) | No numerical target defined; low HDL is a residual risk factor; raising HDL with fibrates or niacin has not demonstrated a reduction in cardiovascular events in clinical trials |
| Total cholesterol / HDL-C ratio | < 4.0 (optimal < 3.5) | 5.0 | Used by Hypertension Canada and the CCS for overall cardiovascular risk stratification; better reflects risk than LDL-C alone in certain situations (hypertriglyceridemia, metabolic syndrome) |
| Triglycerides | < 1.7 mmol/L (150 mg/dL) | 5.6 mmol/L (500 mg/dL): Risk of acute pancreatitis | No primary target defined; very high triglycerides increase residual cardiovascular risk and the risk of acute pancreatitis |
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The Friedewald formula—LDL-C = total cholesterol − HDL-C − (triglycerides / 2.2) in mmol/L—is the most commonly used method for calculating LDL in Canadian laboratories. It is only valid if triglycerides are below 4.5 mmol/L and the sample is taken after a 12-hour fast. Above this triglyceride threshold, calculated LDL is underestimated and must be measured directly (direct LDL-C) or estimated using the Martin-Hopkins formula, which is more accurate for elevated triglycerides.
Cardiovascular risk stratification
Lipid therapeutic targets are defined based on the patient's overall cardiovascular risk, assessed according to Canadian Cardiovascular Society (CCS) guidelines:
| Risk level | Clinical profile | Recommended LDL-C target |
|---|---|---|
| Very high risk | Established atherosclerotic cardiovascular disease (ASCVD) AND diabetes or metabolic syndrome; major cardiovascular event in the last 2 years (ACS, ischemic stroke); familial hypercholesterolemia with established ASCVD | < 1.4 mmol/L or a reduction of at least 50% in baseline LDL-C; consider adding a PCSK9 inhibitor if the target is not met with statin + ezetimibe |
| High risk | Established MCAS without diabetes; type 1 or 2 diabetes with organ damage (nephropathy, retinopathy, neuropathy) or duration > 15 years; chronic kidney disease (eGFR < 60 mL/min/1.73 m²); familial hypercholesterolemia without established MCAS; 10-year Framingham risk > 20 % | < 1.8 mmol/L or a reduction of at least 50% in baseline LDL-C; drug therapy (statin) is recommended regardless of baseline LDL-C |
| Medium risk | 10-year Framingham risk of 10 to 19 %; type 2 diabetes without organ damage and duration < 15 years in patients under 40 years of age; certain additional risk factors (elevated Lp(a), metabolic syndrome, chronic inflammation) | < 2.0 mmol/L; drug treatment to be discussed according to baseline LDL-C, additional risk factors, and patient preferences |
| Low risk | 10-year Framingham risk < 10 (%); no major cardiovascular risk factors | < 3.5 mmol/L; drug treatment rarely indicated; priority to dietary and lifestyle measures |
Causes of hypercholesterolemia
Elevated LDL cholesterol can result from genetic, dietary, metabolic, or medication-related factors:
| Category | Cause | Mechanism and clinical particularities |
|---|---|---|
| Primary (genetics) | Familial hypercholesterolemia (FH) | Mutation of the LDL receptor (LDLR), apolipoprotein B (ApoB), or PCSK9; reduced or absent uptake of LDL by liver cells; very high LDL-C (> 5 mmol/L in heterozygotes, > 13 mmol/L in homozygotes) from childhood; major early cardiovascular risk; cholesterol deposits in tendons (tendinous xanthomas) and cornea (corneal arcus before age 45); frequency: 1/250 for the heterozygous form |
| Primary (genetics) | Polygenic hypercholesterolemia | The most common form of primary hypercholesterolemia; results from the interaction of multiple genetic variants of low individual effect with the environment; moderately elevated LDL-C (3.5 to 5.0 mmol/L); responding well to dietary measures and statins |
| Secondary (medical) | Hypothyroidism | Reduction in hepatic LDL receptor expression and lipoprotein lipase activity; reversible hypercholesterolemia after normalization of TSH; to be systematically excluded before attributing hypercholesterolemia to a primary cause |
| Secondary (medical) | Nephrotic syndrome | Compensatory hepatic hyper-synthesis of lipoproteins in response to urinary albumin loss and decreased oncotic pressure; severe dyslipidemia with elevated LDL-C and triglycerides |
| Secondary (medical) | Chronic cholestasis | Biliary cholesterol retention with reflux into circulation; often marked hypercholesterolemia in PBC, PSC, and drug-induced cholestasis |
| Secondary (medical) | Type 2 diabetes and metabolic syndrome | Atherogenic dyslipidemia characterized by: elevated triglycerides, low HDL, LDL often within normal range but with smaller, denser, more atherogenic LDL particles; increased cardiovascular risk even for LDL within usual values |
| Secondary (drug-induced) | Corticosteroids, cyclosporine, retinoids, antiretrovirals | Direct dyslipidemic effect on lipoprotein hepatic metabolism; to be taken into account when evaluating lipid profiles in patients undergoing chronic treatment with these drugs. |
| Food | Diet high in saturated and trans fats | Increased hepatic cholesterol synthesis and reduced LDL receptor expression by saturated fatty acids (fatty meats, processed meats, cheeses, palm oil, ultra-processed products); trans fatty acids from partially hydrogenated oils raise LDL and lower HDL simultaneously. |
Causes of low HDL
An HDL-C level below 1.0 mmol/L is an independent cardiovascular risk factor with multiple causes:
- Sedentary lifestyle: Regular moderate- to high-intensity physical activity is the most effective way to naturally raise HDL-C; even a brisk 30-minute walk each day increases HDL by 5 to 10 %
- Active smoking: Tobacco significantly lowers HDL-C (by 5 to 10 mg/dL) through oxidative mechanisms; quitting smoking leads to a gradual increase in HDL levels over a period of weeks to months
- Abdominal obesity and metabolic syndrome: visceral fat accumulation increases lipolysis and VLDL production, accelerating HDL catabolism; weight loss increases HDL by 0.01 mmol/L for each kilogram lost
- Hypertriglyceridemia: Lipid exchanges between VLDL and HDL deplete HDL of cholesterol ester and promote its rapid catabolism; triglyceride reduction secondarily improves HDL.
- Type 2 diabetes with insufficient control: Insulin resistance disrupts HDL metabolism; improving glycemic control partially improves lipid profile
- Certain medications: non-selective beta-blockers, androgenic progestins, anabolic steroids, isotretinoin
- Rare genetic causes: Apolipoprotein A-I deficiency, Tangier disease (total absence of functional HDL)
Support and treatments
The management of dyslipidemia systematically combines lifestyle and dietary measures with drug treatment, depending on the cardiovascular risk level:
| Intervention | Mechanism and modalities | Expected LDL-C reduction |
|---|---|---|
| Cardioprotective diet | Reduction of saturated fat (<7% of total calories) and trans fats (target of 0%); Increase in soluble fiber (oats, legumes, psyllium) that binds intestinal cholesterol; addition of phytosterols (2 g/day in fortified margarines) that block intestinal cholesterol absorption; Mediterranean diet or DASH | An 8–10 mg/dL reduction in LDL-C; phytosterols reduce LDL by an additional 8–10 mg/dL when added to a balanced diet |
| Regular physical activity | At least 150 minutes of moderate-intensity aerobic activity per week; primarily improves HDL-C and triglycerides; modest effect on LDL-C but significant overall cardiovascular benefit regardless of lipids | Limited direct effect on LDL (3 to 5 %); increase in HDL of 5 to 10 % |
| Statins (HMG-CoA reductase inhibitors) | Inhibition of the key enzyme in hepatic cholesterol synthesis, leading to overexpression of hepatic LDL receptors and increased uptake of circulating LDL; first-line drugs for all patients requiring pharmacologic therapy; rosuvastatin and atorvastatin are the most potent statins available in Canada | 30 to 55 mg/dL depending on the drug and dose; doubling the statin dose reduces LDL by approximately an additional 6 mg/dL (the doubling rule) |
| Ezetimibe | Inhibits the intestinal transporter NPC1L1 responsible for the absorption of dietary and biliary cholesterol; used in addition to a statin when the LDL target is not reached with statin alone or as monotherapy in case of statin intolerance | 15–20% additional reduction in LDL-C when added to a statin; reduction in cardiovascular risk demonstrated in the IMPROVE-IT trial |
| PCSK9 inhibitors (evolocumab, alirocumab) | Monoclonal antibodies that inhibit PCSK9, a protein that degrades hepatic LDL receptors; their inhibition massively increases the number of LDL receptors available on hepatocyte surfaces; subcutaneous injections every 2 to 4 weeks | An additional 50–65 mg/dL reduction in LDL-C when added to a maximum statine dose; covered in Quebec for patients at very high cardiovascular risk who do not reach their target levels with statin plus ezetimibe, and for patients with familial hypercholesterolemia |
| Inclisiran (anti-PCSK9 siRNA) | Small interfering RNA inhibiting hepatic PCSK9 synthesis; administered by subcutaneous injection twice a year after the initial dose, unlike PCSK9 antibodies requiring monthly or bi-monthly injections | 45% to 55% additional reduction in LDL-C; reimbursement in Quebec currently under review for certain indications |
| Fibrates (fenofibrate, bezafibrate) | Nuclear receptor PPARα agonists activating lipolysis of triglyceride-rich VLDL and increasing HDL apolipoprotein production; main effect on triglycerides and HDL, less marked on LDL | Reduction in triglycerides by 30–50 mg/dL; increase in HDL by 10–20 mg/dL; variable effect on LDL-C; primarily indicated for severe hypertriglyceridemia and mixed dyslipidemia |
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Muscle pain is the most commonly reported adverse effect of statins, affecting 5 to 10% of patients in clinical practice, although placebo-controlled trials report similar rates in both groups (significant nocebo effect). Severe myopathies (rhabdomyolysis) are very rare (< 0.01%). If muscle pain occurs while taking a statin, it is important to consult your doctor to have your CPK (creatine phosphokinase) levels checked rather than stopping treatment without medical advice, as a non-drug-related cause is frequently found. Switching to a different statin, reducing the dose, or switching to a water-soluble statin (pravastatin, rosuvastatin) can often resolve the issue.
Screening and biological monitoring
Canadian recommendations define the indications for lipid screening and monitoring frequency in treated patients:
- Universal screening is recommended for all men 40 years and older, all women 50 years and older (or menopausal), and earlier for individuals with cardiovascular risk factors (diabetes, high blood pressure, smoking, family history of early cardiovascular disease, abdominal obesity) or suspected familial hypercholesterolemia.
- The lipid panel is ideally performed after a 12-hour fast to allow calculation of LDL-C using the Friedewald formula and accurate measurement of triglycerides; a non-fasting lipid panel is acceptable for initial screening (LDL-C can be measured directly) but a fasting panel will be required for monitoring and therapeutic decision-making.
- After initiating lipid-lowering treatment, a lipid profile check is recommended at 4 to 8 weeks to assess response, then every 6 to 12 months once the target is reached.
- A baseline creatine phosphokinase (CPK) level is recommended before starting statins in patients at risk of myopathy (elderly, renal insufficiency, hypothyroidism, history of myopathy, concomitant treatment with fibrates or cyclosporine).
- A baseline and 3-month follow-up liver function test (AST, ALT) after initiating a statin is recommended; transaminase elevations greater than 3 times the norm require discontinuation or dose reduction of the statin.
- Lp(a) testing is recommended once in a lifetime for any patient with unexplained premature cardiovascular disease, a significant family history of cardiovascular disease, familial hypercholesterolemia, or an intermediate risk to refine stratification.
Situations requiring prompt medical evaluation
Very high LDL-C (> 5.0 mmol/L) discovered incidentally or during screening, particularly in a young adult or in the presence of a family history of early cardiovascular disease (heart attack or stroke before age 55 in men or before age 65 in women in a first-degree relative), should prompt an immediate medical consultation to evaluate familial hypercholesterolemia, perform a complete cardiovascular assessment, and initiate early treatment. Patients on statins who develop severe muscle pain, muscle weakness, or dark urine (tea-colored) should seek urgent medical attention to measure CPK levels and rule out rhabdomyolysis.
Clinique Omicron offers consultations for lipid profile prescription and interpretation, cardiovascular risk stratification, and the initiation or adjustment of lipid-lowering treatment at its service points in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron supports patients in the prevention and management of cardiovascular diseases, notably through lipid profiling, global cardiovascular risk stratification, and dyslipidemia management, at its service points in Quebec and via telemedicine. A physician or a nurse practitioner (NP) can prescribe a complete lipid profile, interpret your results based on your individual risk factors, advise you on dietary and lifestyle modifications, and initiate or adjust lipid-lowering medication according to Canadian recommendations. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for the advice of a qualified healthcare professional. Consult a physician for any abnormal lipid results, before starting or changing lipid-lowering treatment, or for any decisions regarding your cardiovascular health.
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