Dyslipidemia Management

Last updated: 14 May 2025

Content on this page:

Evaluation

Content on this page:

Evaluation

Evaluation

The relative reduction of risk is proportional to the absolute LDL-C reduction and the absolute LDL-C reduction resulting from a particular drug regimen depends only on baseline LDL-C; at any given level of baseline risk, the higher the initial LDL-C level the greater the absolute reduction in risk.

Cardiovascular Disease Risk Category Untreated LDL-C Levels That Warrant Drug Therapy
Very High Risk >1.4 mmol/L (>55 mg/dL)
High Risk >1.8 mmol/L (>70 mg/dL)
Moderate Risk >2.6 mmol/L (>100 mg/dL)
Low Risk >3 mmol/L (>116 mg/dL)
Reference: Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020.


The 2021 Canadian Cardiovascular Society (CCS) guideline recommends initiation of statin therapy for primary prevention based on the Framingham Risk Score (FRS) and are as follows:

 

  • High risk 
  • Intermediate risk: FRS (10-19.9%) and any of the following: LDL-C of ≥3.5 mmol/L (≥135 mg/dL), non-HDL-C of ≥4.2 mmol/L (≥162 mg/dL), ApoB of ≥105 mg/dL, men aged ≥50 years and women aged ≥60 years with additional risk factors or with the presence of other risk modifiers
  • Low risk: Not recommended for statin therapy except for individuals with any of the following: LDL-C of ≥5.0 mmol/L (≥193 mg/dL), non-HDL-C of ≥5.8 mmol/L (≥225 mg/dL), ApoB of ≥145 mg/dL or FRS is 5-9.9% with an LDL-C of ≥3.5 mmol/L (≥135 mg/dL), non-HDL-C of ≥4.2 mmol/L (≥162 mg/dL), ApoB of ≥105 mg/dL with other cardiovascular risk modifiers
    •   Consider estimating cardiovascular risk again in 5-10 years



Risk Stratification  

The evaluation of lipid profile must be performed in parallel with the risk assessment for CVD. LDL-C is used as the primary lipid analysis for screening and risk estimation. Cardiovascular risk determines the patient’s target lipid levels and intensity of risk factor reduction.  

Risk assessment tools (eg Framingham risk score [FRS], Reynold’s risk score, Systemic Coronary Risk Estimation [SCORE], Risk Factor Counting, Multi-Ethnic Study of Atherosclerosis [MESA] 10-year ASCVD risk with coronary artery calcification calculator, United Kingdom Prospective Diabetes Study [UKPDS] risk engine in individuals with type 2 diabetes mellitus, etc) are commonly used to assess a patient’s risk for cardiovascular disease. The point system for cardiovascular disease risk differs by gender.  

For the Framingham risk score, the predictors include age, sex, smoker or non-smoker, TC and HDL cholesterol levels, systolic blood pressure, and if the patient is being treated with antihypertensive drugs. High systolic blood pressure, age, TC, and smoking are more significant in women. Systolic blood pressure of 130-139 mmHg has more points in women (untreated - 2; treated - 4) than in men (untreated - 1; treated - 2) but overall points have a lower threshold for men than in women (10 total points = 6% 10-year risk in men vs 1% in women).  

ASCVD risk assessment is not necessary for secondary prevention, in individuals with LDL-C of ≥190 mg/dL, or in those 40-75 years old with diabetes mellitus.  SCORE can be used in different populations when recalibrated by adjusting for secular changes in CVD mortality and risk factor prevalence.  

In the Philippines, Risk Factor Counting is used as the method of identifying the risk of the Filipino individual for CVD. Statin therapy can be considered for primary prevention in individuals without diabetes aged ≥45 years old with an LDL-C of ≥130 mg/dL and at least ≥2 risk factors.  

Identify patients with established CVD or with CVD risk equivalents such as diabetes mellitus, peripheral artery disease, or abdominal aortic aneurysm.  

The major independent risk factors for CVD are cigarette smoking, age (men ≥45 years; women ≥55 years), low HDL cholesterol (<40 mg/dL), increased total serum cholesterol levels, increased non-HDL-cholesterol levels, increased LDL-cholesterol levels (≥190 mg/dL), chronic kidney stages 3 or 4, hypertension (elevated blood pressure or on antihypertensive medication) including a history of preeclampsia or pregnancy-induced hypertension in women, family history of premature ASCVD (male first-degree relative <55 years, female first-degree relative <65 years), and diabetes mellitus including those with a history of gestational diabetes in women. For individuals with high HDL cholesterol of 1.5 mmol/L (>60 mg/dL), subtract one risk factor from the total.  

Additional risk factors include dyslipidemic triad (hypertriglyceridemia, low HDL-C, and excess of small, dense LDL), chronic inflammatory conditions (eg HIV or AIDS, psoriasis, rheumatoid arthritis), obesity, abdominal obesity, elevated apo B, elevated LDL particle number, fasting or postprandial hypertriglyceridemia, history of premature menopause, family history of hyperlipidemia, polycystic ovarian syndrome (PCOS) in women, elevated small, dense LDL-C, microalbuminuria or proteinuria, and South Asian ancestry.  

Non-traditional risk factors include elevated lipoprotein (a), elevated clotting factors, elevated inflammation markers, elevated triglyceride-rich remnants, elevated homocysteine levels, apo E4 isoform, and elevated uric acid. 

ATHEROSCLEROTIC CARDIOVASCULAR DISEASE RISK CATEGORIES
Risk Category  ACC/AHA 2019 CCS 2021  ESC 2021
 10-Year ASCVD Risk1 FRS2  Apparently Healthy Individuals3   Patients with Risk Factors  
Very High Risk Not applicable Not applicable
 • <50 years: ≥7.5%
• 50-69 years: ≥10%
• ≥70 years: ≥15%		 • Documented clinical ASCVD4 or unequivocally documented ASCVD finding (eg significant plaque) on imaging that does not include some increase in continuous imaging parameters (eg intima-media thickness of the carotid artery) 
• Type 2 diabetes mellitus with established ASCVD and/or severe target organ damage (TOD)5
• Without diabetes or ASCVD but with severe CKD (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) or eGFR 30-44 mL/min/1.73 m2 and albumin-to-creatinine ratio (ACR) >30
High Risk ≥20%  ≥20%  • <50 years: 2.5-<7.5%
• 50-69 years: 5-<10%
• ≥70 years: 7.5-<15%		 • Type 2 diabetes mellitus without ASCVD and/or severe TOD with moderate risk criteria not met5
• Without diabetes or ASCVD but with moderate CKD (eGFR 30-44 mL/min/1.73 m2) and ACR <30 or eGFR 45-59 mL/min/1.73 m2 and ACR 30-300 or eGFR ≥60 mL/min/1.73 m2 and ACR >300
• Familial hypercholesterolemia associated with markedly increased levels of cholesterol (≥190 mg/dL) 
Moderate Risk Not applicable Not applicable • <50 years: <2.5%
• 50-69 years: <5%
• ≥70 years: <7.5%
 • Patients with <10 years of well-controlled type 2 diabetes mellitus without TOD or other ASCVD risk factors5 
Intermediate Risk 7.5-<20%  10-19.9% Not applicable
Borderline Risk 5-<7.5% Not applicable
 Not applicable
Low Risk <5% <10% • <50 years: <2.5%
• 50-69 years: <5%
• ≥70 years: <7.5%		  
1ASCVD risk estimator (http://tools.acc.org/ldl/ascvd_risk_estimator/index.html#!/calculate/estimator/) estimates the 10-year ASCVD risk for asymptomatic individuals 40-75 years old.  
2Based on the Framingham risk score (FRS) screening every 5 years for ages 40-75 years.
3Based on SCORE2 and SCORE2-Older Persons (SCORE2-OP); can be accessed in the ESC CVD Risk Calculation app. 
SCORE2 estimates the 10-year risk of fatal and non-fatal CVD events (eg stroke, MI) in apparently healthy individuals 40-69 years old with risk factors that are not treated or have been stable for several years. SCORE2-OP estimates the 5- and 10-year fatal and non-fatal CVD events (eg stroke, MI) adjusted for competing risks in apparently healthy individuals ≥70 years old.  
4Eg previous acute myocardial infarction (AMI), acute coronary syndrome (ACS), coronary revascularization and other arterial revascularization procedures, transient ischemic attack (TIA) and stroke, aortic aneurysm and peripheral arterial disease (PAD)
5Patients >40 years old with type 1 DM may also be classified according to these criteria. 
References:
Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019.
Pearson GJ, Thanassoulis G, Anderson TJ, et al. 2021 Canadian Cardiovascular Society (CCS) Guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol. 2021.
Visseren FLJ, Mach F, Smulders YM, et al; ESC National Cardiac Societies, ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021.



Metabolic Syndrome  

Non-HDL-C is the secondary target of therapy in metabolic syndrome (LDL-C lowering is primary). Upfront combination therapy of Pitavastatin with Ezetimibe may be considered in very high-risk patients with ASCVD and metabolic disorders. 

Clinical Identification  

Any 3 or more of the following (including those on treatment) are considered to have metabolic syndrome: 

 

  • Increased waist circumference (Asian cut off: ≥80 cm for females; ≥90 cm for males)
  • Raised TG level of ≥1.7 mmol/L (≥150 mg/dL) or specific treatment for this lipid abnormality
  • Reduced HDL cholesterol of <1 mmol/L (<40 mg/dL) in males and <1.3 mmol/L (<50 mg/dL) in females or specific treatment for this lipid abnormality
  • Raised blood pressure (systolic blood pressure of ≥130 mmHg or diastolic blood pressure of ≥85 mmHg) or treatment of hypertension

  • Disorders of glycemia:

    • Type 2 diabetes mellitus, or
    • Impaired glucose tolerance (IGT): Fasting plasma sugar of <7 mmol/L (<125 mg/dL) and 2 hours post 75-g glucose load of 7.8-11.1 mmol/L (140-200 mg/dL), or
    • Impaired fasting glucose (IFG): Fasting plasma sugar of 6.1-7.0 mmol/L (110-125 mg/dL)

Principles of Therapy

Lipid Treatment Goals  

The targeted approach to lipid management is primarily aimed at reducing atherosclerotic risk by substantially lowering LDL-C levels. Target LDL-C levels may also include ≥50% reduction from the baseline for patients at high risk, and for primary and secondary prevention of patients at very high risk. Consider an LDL-C goal of <1 mmol/L (<40mg/dL) in patients with ASCVD who had a second vascular event within 2 years while on maximally tolerated statin therapy, and those who are not on LDL-C target despite maximally tolerated statin therapy and Ezetimibe and considered to be at extremely high risk. 

Those at extremely high risk include:

  • Myocardial infarction plus previous vascular event within 2 years
  • Acute coronary syndrome plus multivessel coronary disease
  • Acute coronary syndrome plus peripheral vascular disease
  • Acute coronary syndrome plus familial hypercholesterolemia
  • Acute coronary syndrome plus diabetes mellitus plus at least one additional risk factor (high-sensitivity C-reactive protein >2 mg/L and/or CKD and/or Lp(a) >50 mg/dL)


Currently, no specific treatment goals for HDL-C or TG levels have been established in clinical trials. 


Lipid Treatment Goals Based on Cardiovascular Disease Risk
 Risk Categories LDL-C Non-HDL-C Apolipoprotein B
Very High Risk  <1.4 mmol/L
(55 mg/dL)
 <2.2 mmol/L
 (<85 mg/dL)		 <0.0013 mmol/L
(<65 mg/dL)
High Risk <1.8 mmol/L
(<70 mg/dL)
 <2.6 mmol/L
(<100 mg/dL)
<0.0016 mmol/L
(<80 mg/dL)
Moderate Risk <2.6 mmol/L
(<100 mg/dL)
 <3.4 mmol/L
(<130 mg/dL)		  <0.002 mmol/L
(<100 mg/dL)
Low Risk  <3 mmol/L
(<116 mg/dL)
  -- --
Reference: Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020.


Metabolic Syndrome

For metabolic syndrome, the principle of management is to manage the underlying causes.  With regards to obesity and physical activity, weight loss and increased physical activity will reduce all of the above risk factors.  

See Metabolic Syndrome under Evaluation.  

COVID-19 and Lipid Lowering Therapy  

Current evidence shows that lipid-lowering therapy is safe in patients with COVID-19 infection. Lipid-lowering therapy should be continued in patients with confirmed COVID-19 diagnosis and abnormal liver function tests (LFTs) unless alanine transaminase (ALT) or aspartate transaminase (AST) progressively increases, a significant drug-drug interaction between the lipid-lowering agents and COVID-19 drugs has been identified, or patient is critically ill and/or cannot take oral medications.  

 

Pharmacological therapy

LDL-C-Lowering Pharmacological Therapy  

LDL-C is the primary target of lipid management in both primary and secondary prevention  


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Lipid lowering therapy should be given to all patients with CVD. The greater the LDL-C level is reduced, the more significant the amount of cardiovascular risk reduction. Assess the patient’s response to LDL-C-lowering therapy and lifestyle modifications with a repeat lipid profile 4-12 weeks after starting statin therapy or dose adjustment then every 3-12 months as needed. Patients with extreme cardiovascular risk would benefit from earlier lipid monitoring (4 to 6 weeks) and early follow-ups (3 months). In these patients, dual therapy should be initiated using maximally tolerated statin and Ezetimibe. Triple therapy may be considered to lower LDL-C as early as possible.  

Statins (Beta-hydroxy-beta-methylglutaryl-Coenzyme A [HMG-CoA] Reductase Inhibitors)  

Statins reduce the risk for acute coronary syndrome (ACS), coronary procedures, and other coronary outcomes in both primary and secondary coronary heart disease prevention.  

It is recommended for the following patients: 

  • Adults ≥21 years old with clinical ASCVD
  • Adults ≥21 years old with an LDL-C of ≥190 mg/dL
  • Adults 40-75 years of age without ASCVD but with diabetes mellitus (especially type 2 diabetes mellitus) and LDL-C levels of 70-189 mg/dL
  • Adults 40-75 years of age without ASCVD and diabetes mellitus but with LDL-C levels of 70-189 mg/dL and an estimated 10-year risk of ≥7.5% for ASCVD
    • If the decision to start statin therapy is uncertain, measure coronary artery calcium (CAC); statin therapy is favored with a CAC score of 1-99 and is indicated with a CAC score of ≥100 Agatston units or ≥75th percentile
  • Adults 40-75 years of age without diabetes mellitus but with risk-enhancing factors and an estimated 10-year ASCVD risk of 7.5-19.9%

It is reasonable to initiate statin therapy in patients 20-39 years old with longstanding diabetes or to continue moderate- or high-intensity statin therapy in patients >75 years old with diabetes. Statins should also be started in all patients with prior non-cardioembolic ischemic stroke or TIA.  

Statins are also effective in patients with nephrotic syndrome. Statins should be initiated in non-dialysis stage 3-5 chronic kidney disease patients for primary and secondary CVD prevention. Statins work by inhibiting HMG-CoA reductase which is the rate-limiting step in cholesterol biosynthesis. Their effects on lipid and lipoprotein levels include decrease in LDL-C, non-HDL-C and apo B while effect on TG is variable (TG levels will decrease if levels are elevated), small increase in HDL-C, and no change or small increase in Lp(a).

Statins are the most effective class of drugs at lowering LDL-C levels, with moderate effects on lowering TG and elevating HDL-C. They decrease LDL-C in a dose-dependent manner by 20-55%, decrease TG by up to 6-30%, and increase HDL-C by 2-10%.  

Statins are considered the drugs of choice for LDL lowering and in reducing CVD risk in high-risk patients (eg diabetes mellitus) with hypertriglyceridemia. Statin dose may be increased, or a non-statin drug (eg Ezetimibe, fibrates, or Nicotinic acid) may be added if TG levels remain at >2 mmol/L (>200 mg/dL) after achieving the LDL-C target level.  

High-intensity statins include Atorvastatin (80 mg) and Rosuvastatin (20-40 mg). It is the statin regimen that helps lower LDL-C by ≥50%. High-intensity statins are recommended to be given at the highest tolerated dose to achieve the LDL-C goals set for a specific risk group. High-intensity statins are recommended as first-line treatment for patients ≤75 years old with clinical ASCVD.  They should be initiated before percutaneous coronary intervention and coronary artery bypass graft and continued indefinitely.  

High-intensity statins may be used for patients ≥21 years old with LDL-C of ≥190 mg/dL or TG of ≥500 mg/dL especially those trying to achieve at least 50% LDL-C level reduction. A non-statin drug may be added if the LDL-C goal has not been achieved with a high-intensity regimen. They may be used for ≥75-year-old patients with ASCVD, without contraindications. They may also be used for 40-75-year-old patients with diabetes mellitus with a ≥7.5% 10-year ASCVD risk1, and for 40-75-year-old patients with diabetes mellitus or LDL-C of ≥190 mg/dL.  

Moderate-intensity statins include Atorvastatin (10-20 mg), Rosuvastatin (5-10mg), Simvastatin (20-40 mg), Pravastatin (40-80 mg), Lovastatin (40 mg), Fluvastatin (40 mg 12 hourly), and Pitavastatin (2-4 mg). Daily dose helps lower LDL-C by 30-49%. It is considered an alternative treatment for patients with clinical ASCVD with contraindications against high-intensity statins or with side effects from statin therapy. They may be used for ≥75-year-old patients with ASCVD, with contraindications or intolerance to high-intensity statins; for 40-75-year-old patients with diabetes mellitus with or without 5-≤7.5% 10-year ASCVD; for 40-75-year-old patients with diabetes mellitus and LDL-C of 70-189 mg/dL; for 40-75-year-old patients with diabetes mellitus or LDL-C of ≥190 mg/dL with contraindications or intolerance to high-intensity statins; and for 40-75-year-old patients without diabetes mellitus but LDL-C of ≥70 mg/dL and ≥7.5% 10-year ASCVD risk.    

Low-intensity statins include Atorvastatin (5mg), Rosuvastatin (2.5mg), Simvastatin (5-10 mg), Pravastatin (10-20 mg), Lovastatin (20 mg), and Fluvastatin (20-40 mg). Daily dose of low-intensity statins helps lower LDL-C by <30%.  

Treatment with statins is associated with the risk of developing statin-associated muscle symptoms (SAMS) or new-onset diabetes mellitus but the benefits of statin therapy for cardiovascular risk reduction outweigh the risk. Notably, studies have shown that Pitavastatin reduces the risk of SAMS and new-onset diabetes mellitus. A statin rechallenge is considered in a patient with non-severe statin intolerance: Continue the same statin at the same dose, lower the dose or intensity, use a different statin, or consider alternate-day dosing. A non-statin drug may be added to a maximally tolerated statin therapy if the LDL-C goal based on cardiovascular disease risk has not been achieved.  

1Risk of developing a first ASCVD event, defined as nonfatal myocardial infarction or coronary heart disease death or fatal or nonfatal stroke, over a 10-year period among people free from ASCVD at the beginning of the period.  

Selective Cholesterol-Absorption Inhibitor  

Example drug: Ezetimibe  

Ezetimibe is used as an adjunct to diet and exercise for the reduction of elevated TC, LDL-C, apo B, and non-HDL-C in patients with primary hyperlipidemia alone or in combination with statin therapy, or in combination with Fenofibrate in patients with mixed hyperlipidemia. It is the first optional non-statin to consider for patients with poor tolerance to statins. It may be used as monotherapy with primary prevention in patients intolerant of statins.  

It is also the first option to add onto maximally tolerated statin therapy in patients who are less responsive to statins and failed to reach LDL-C goals. It may be added to a maximally tolerated statin therapy in patients with high to very high-risk clinical ASCVD when the LDL-C level remains ≥70 mg/dL. Combination therapy is a strategy to prevent side effects associated with statin monotherapy and encourages better therapy adherence. Combination products of selective cholesterol-absorption inhibitor plus statin (eg Ezetimibe/Simvastatin, Ezetimibe/Atorvastatin, Ezetimibe/Rosuvastatin), are available and may be used to reduce TC, LDL-C, apo B, TG, and non-HDL-C, and to increase HDL-C in patients with homozygous familial hypercholesterolemia. If the addition of Ezetimibe to a statin achieved therapy goals, the combination therapy may be continued with continuous monitoring of the treatment response.  

Ezetimibe/statin combination is recommended in patients with chronic kidney disease stage 3-5 not dependent on dialysis. It is a selective potent inhibitor of cholesterol absorption in the intestinal lumen and reduces the overall delivery of cholesterol to the liver. Its effects on lipid and lipoprotein levels include a decrease in LDL-C, non-HDL-C, and apo B, a small decrease in TG, small increase in HDL-C and no change in Lp(a). 

Ezetimibe causes a moderate reduction in LDL-C levels. When used alone, Ezetimibe decreases LDL by 10-20% with favorable effects on HDL and TG. When used in combination with statins, there is an additional reduction in LDL-C by 18-25% with favorable effects on HDL and TG, with Fenofibrate there is 20-22% reduction in LDL-C.

 
Proprotein Convertase Subtilisin or Kexin Type 9 Monoclonal Antibodies (PCSK9 mAbs)  

Example drugs: Alirocumab, Evolocumab  

PCSK9 mAbs may be given alone or in combination with other lipid-lowering therapies as an adjunct to diet to reduce LDL-C in patients with primary hyperlipidemia including heterozygous familial hypercholesterolemia.  

PCSK9 mAbs are recommended as an adjunct to diet and maximally tolerated statin therapy plus Ezetimibe for the treatment of homozygous familial hypercholesterolemia with very high-risk clinical ASCVD and patients with high-risk clinical ASCVD or severe primary hypercholesterolemia with multiple risk factors for ASCVD events that need a further reduction of LDL-C.  

PCSK9 mAbs are given also to patients with high and very high cardiovascular risk with intolerance to statin therapy. It may be preferred as the initial non-statin agent in addition to maximally tolerated statin therapy in patients with clinical ASCVD at very high risk that still requires ≥25% LDL-C reduction. As a human monoclonal PCSK9 antibody, it binds to PCSK9 which then increases LDL receptor density to aid in clearing circulating LDL-C. Its effects on lipid and lipoprotein levels include decrease in LDL-C, non-HDL-C, and apo B, no change or small decrease in TG, small increase in HDL-C, and a decrease in Lp(a). It lowers LDL-C levels by 48-71%, TC by 36-42%, apo B by 42-55% and non-HDL-C by 49-58%.  

Bempedoic Acid  

Bempedoic acid is indicated for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional lowering of LDL-C. The addition of Bempedoic acid may be considered if additional LDL-C lowering is needed in patients with clinical ASCVD at high or very high risk despite treatment with a maximally tolerated statin therapy with Ezetimibe and/ or a PCSK9 mAb.  

Bempedoic acid lowers LDL-C by inhibiting the action of adenosine triphosphate-citrate lyase, which is an enzyme that works upstream of HMG-CoA reductase. It has also been shown to modestly improve blood glucose levels. It may be used in statin intolerant patients with ASCVD or increased risk for ASCVD. It may be used alone or in fixed combination with Ezetimibe in statin intolerant patients. It has been shown to decrease LDL-C by 15-30% and in combination with Ezetimibe by 40% in clinical trials. Its effects on lipid and lipoprotein levels include a decrease in LDL-C, non-HDL-C, and apo B; no change in TG, a small decrease in HDL-C, and no change in Lp(a).

Bile Acid Sequestrants  

Example drugs: Cholestyramine, Colesevelam, Colestipol  

Bile acid sequestrants are adjuncts to diet for LDL-C reduction in patients with primary hyperlipidemia. They have been shown to reduce the risk of CVD and are considered in patients who have contraindications or intolerance to statin therapy. It is also effective in LDL lowering in patients with diabetes mellitus.  

Bile acid sequestrants bind bile acids in the intestine through anion exchange and impede their reabsorption. Their effects on lipid and lipoprotein levels include a decrease in LDL-C, non-HDL-C, and apo B; variable effect on TG (will decrease if TG levels is elevated), a small increase in HDL-C, and no change in Lp(a). They cause moderate reduction in LDL-C levels. LDL-lowering potential increases when combined with other agents (eg statins). They decrease LDL-C by 15-30% and increase HDL-C by 3-11%; however, they may raise TG levels in some patients.  

Evinacumab  

Evinacumab is an add-on treatment for patients ≥12 years old with homozygous familial hypercholesterolemia. It may also be considered in patients without clinical ASCVD or with clinical ASCVD at very high risk and baseline LDL-C ≥190 mg/dL, not from secondary causes who had an inadequate response to maximal doses of statin with Ezetimibe and/or a PCSK9 mAb, Bempedoic acid, or Inclisiran.  

Evinacumab is a fully human monoclonal antibody that binds to angiopoietin-like protein 3 (ANGPTL3) which in turn inhibits lipoprotein and endothelial lipase. The mean LDL-C reduction in combination with other lipid-lowering therapies has been shown to be 47%. It also lowers non-HDL-C by 50%, apo B by 41%, and HDL-C by 30% with no change in Lp(a).

Inclisiran  

Inclisiran is indicated for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, or clinical ASCVD requiring additional lowering of LDL-C. It is given as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with a max tolerated statin dose; or alone or in combination with other lipid-lowering therapies in patients who are statin intolerant or for whom a statin is contraindicated. It may be used in place of a PCSK9 mAb in patients with poor adherence to PCSK9 mAbs, adverse effects from both PCSK9 mAbs, or those who may not be able to self-inject.  

Inclisiran is a small-interfering RNA (siRNA) LDL-C-lowering treatment that targets hepatic PCSK9 synthesis which prolongs LDL receptor activity. The dosing regimen is infrequent (the initial dose is given subcutaneously which is repeated at 3 months and then every 6 months) and side effects are acceptable. The mean LDL-C reduction has been shown to be 48-52%. The ORION-10 trial showed a decrease in the levels of non-HDL-C, apo B, TG, and Lp(a), while HDL-C levels were slightly elevated. It must be noted that more long-term studies are needed to evaluate its effects on CV effects and mortality.  

Microsomal Triglyceride Transfer Protein (MTP) Inhibitor  

Example drug: Lomitapide  

This class is used for patients with homozygous familial hypercholesterolemia as an adjunct to a low-fat diet and other lipid-lowering treatments including LDL apheresis. It may also be considered in patients without clinical ASCVD or with clinical ASCVD at very high risk and baseline LDL-C of ≥190 mg/dL not from secondary causes who had an inadequate response to maximally tolerated statin therapy with Ezetimibe and/or PCSK9 mAb, Bempedoic acid, or Inclisiran.  

It inhibits chylomicron and VLDL synthesis by direct binding and inhibition of MTP. It lowers LDL-C levels by 40%, non-HDL-C by 50%, apo B by 39%, TG by 45%, Lp(a) by 15%, and TC by 36%. 

Nicotinic Acid  

Nicotinic acid favorably affects all lipids and lipoproteins when given in the proper dosage. Lower doses increase HDL-C. Two to three grams per day are needed to lower LDL-C. It produces a moderate reduction in CVD risk.  

Nicotinic acid alters lipid levels by inhibiting lipoprotein synthesis and decreasing the production of VLDL particles by the liver. It is most effective at raising HDL levels among lipid-modifying drugs. It decreases LDL-C by 10-25%, increases HDL-C by 10-35%, and decreases TG by 20-30% in a dose-dependent manner.  

Nicotinic acid may be combined with statins in managing diabetes mellitus patients with hypertriglyceridemia and may increase blood glucose levels.  

Intensified LDL-C-Lowering Pharmacotherapy  

Intensified LDL-C lowering pharmacotherapy means an increase in statin dose and an escalation of the intensity of statin therapy. The combination therapy includes a statin with Ezetimibe with or without a PCSK9 mAb, statin with PCSK9 mAb, Ezetimibe with PCSK9 mAb, and statin with bile acid sequestrant. LDL apheresis may be considered in patients with familial hypercholesterolemia unresponsive to dietary management and pharmacological therapy.  

TG-Lowering and HDL-C Raising Pharmacological Therapy  

Fibrates  

The primary use of fibrates is for lowering TG as they decrease TG by 20-35%. They may be combined with statins in managing diabetes mellitus patients with hypertriglyceridemia and low HDL-C. If TG is not elevated, fibrates may lower LDL-C by 20-35%.  

Fibrates are also useful in combined or mixed dyslipidemia and in increasing HDL-C by 6-18%. They are recommended for patients with very high TG (>4.5 mmol/L) who are at risk for pancreatitis. They moderately reduce the risk of coronary heart disease and favorably lower LDL in patients with diabetes mellitus.  

Fibrates down-regulate the apolipoprotein C-III (apoC-III) gene and up-regulate genes for apolipoprotein A-1, fatty acid transport protein, fatty acid oxidation, and possibly lipoprotein lipase. They primarily target atherogenic dyslipidemia including diabetic dyslipidemia. Fenofibrate with or without statin therapy reduces the progression of diabetic retinopathy.  

When used in combination with LDL-lowering drugs, it improved the overall lipoprotein compared to either agent alone. In combination with statins, Fenofibrate is the preferred fibrate to use due to the lower risk of myopathy and rhabdomyolysis.  

Fibrates provide an alternative treatment in statin-intolerant patients with mild to moderate hypercholesterolemia. In patients in whom a fibrate is recommended, Nicotinic acid can also be considered.  

Pemafibrate is a novel selective peroxisome proliferator-activated receptor alpha (PPARα) modulator with a favorable benefit-risk balance compared to conventional fibrates. It may be used to treat patients with hypertriglyceridemia and to prevent cardiovascular events in those with hypertriglyceridemia.  

Nicotinic Acid  

Please see Nicotinic Acid under LDL-C-Lowering Pharmacological Therapy.  

Omega-3 Fatty Acids  

Total eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) acid at dosages between 2-4 grams per day can lower serum TG levels. Studies showed that EPA reduced serum TG levels by up to 45% in a dose-dependent manner.  

Icosapent ethyl (IPE) is a highly purified, non-oxidized form of EPA and is indicated for patients with TG levels ≥150 mg/dL with established ASCVD or diabetes with ≥2 ASCVD risk factors and on maximally tolerated statins to prevent ASCVD morbidity and mortality. IPE is considered once other therapeutic options have been explored (eg Ezetimibe or PCSK9 inhibitor) given its potential adverse effects (eg atrial fibrillation, bleeding).  

Volanesorsen  

Clinical trials have shown Volanesorsen’s efficacy in the treatment of patients with elevated TG and familial chylomicronemia syndrome (FCS). It is given to adult patients with familial chylomicronemia syndrome and at high risk for pancreatitis with inadequate response to a low-fat diet and TG-lowering therapy.  

Volanesorsen is an antisense oligonucleotide that binds to apoC-III mRNA and prevents translation of apoC-III allowing for the metabolism and breakdown of TG and chylomicrons.  


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Treatment of Specific Dyslipidemias  

Very High LDL Cholesterol (≥4.9 mmol/L [≥190 mg/dL])  

Very high LDL cholesterol is usually caused by genetic forms of hypercholesterolemia. For patients at very high risk and with persistent high risk, use a maximally tolerated statin and, if necessary, Ezetimibe to lower LDL-C levels; if still not at the treatment goal, a PCSK9 mAb may be added.  

The addition of a bile acid sequestrant may be considered in patients 20-75 years old with an LDL-C level of ≥4.9 mmol/L (≥190 mg/dL) with a <50% reduction in LDL-C and TG of ≤3.4 mmol/L (≤300 mg/dL) while on maximally tolerated statin and Ezetimibe therapy.  

Elevated TG  

There is a strong association between high TG levels and coronary heart disease risk. TG levels ≥2.3 mmol/L (≥200 mg/dL) indicate the need to identify non-HDL-C levels, which is the secondary target of lipid-lowering therapy in these patients (LDL-C is still the primary goal of therapy). Non-HDL-C is more representative of all atherogenic lipoproteins than LDL-C. Non-HDL-C (mmol/L) = TC-HDL-C; non-HDL-C levels can be calculated from non-fasting serum.  

The acquired causes of elevated TG include obesity, physical inactivity, excess alcohol intake, and high carbohydrate diet. It may be due to secondary causes (eg diabetes mellitus, chronic renal failure, chronic liver disease, hypothyroidism, Cushing’s disease, various medications, etc) or genetic causes.  

Elevated TG can often be effectively treated through lifestyle changes; however, fibrates and combination therapy with statins may be appropriate options for many patients.  

For very high TG (>5.6 mmol/L [≥500 mg/dL]), treatment should be likened to an emergency to avoid acute pancreatitis. Fibrate (preferably Fenofibrate), prescription omega-3 fatty acids, or Nicotinic acid should be started. Fish oils can replace some long-chain TG in the diet. Lifestyle modifications should be advised.  

If LDL-C is still elevated despite a fibrate, consider adding a statin. The decision must be individualized, and the patient must be started only when it is strongly indicated. The recommended fibrate to be combined with a statin is Fenofibrate.  

For high TG (2.3-5.6 mmol/L [200-499 mg/dL]), lifestyle modifications should be advised. If LDL-C or non-HDL-C levels are high or ASCVD risk is ≥5%, statin therapy is started. Consider combination therapy with Fenofibrate if LDL-C is at goal but TG level remains >200 mg/dL in primary prevention or high-risk patients. Consider combination therapy with IPE if the TG level is between 135-499 mg/dL despite statin therapy in patients at high risk (or above).  

For borderline high TG (1.7-2.2 mmol/L [150-199 mg/dL]), lifestyle modifications should be advised. Medications are rarely required unless LDL-C is elevated above the target level.  

Low HDL-C (<1 mmol/L [<40 mg/dL])  

Low HDL-C is a strong, independent predictor of coronary heart disease. Excluding secondary causes of low HDL-C and in the presence of other risk factors (eg borderline LDL-C, personal history of coronary artery disease, or a family history of premature coronary artery disease), HDL-C levels should be raised by as much as possible to levels of at least >40 mg/dL in both men and women. Raising HDL-C levels alone in patients without accompanying risk factors is not recommended.  

Low HDL-C without Hypertriglyceridemia  

Causes of low HDL-C without hypertriglyceridemia include obesity, physical inactivity, cigarette smoking, type 2 diabetes mellitus, certain drugs, etc. Treatment in patients with coronary heart disease or coronary heart disease-risk equivalents when lifestyle modifications fail to increase HDL include fibrates or Nicotinic acid.  

Low HDL-C with Hypertriglyceridemia  

If HDL-C is low and TG is high and LDL-C is not significantly elevated, start fibrates or Nicotinic acid. The primary target goal is to lower LDL-C to target level.  

Elevated Lipoprotein(a)  

Aggressive reduction of LDL-C will help lower Lp(a). Agents that have been shown to reduce Lp(a) by approximately 20-30% include high-dose Niacin, PCSK9 mAbs, Estrogen, and Aspirin. Both PCSK9 mAbs (Alirocumab and Evolocumab) decrease Lp(a) by 15-30% and may be given to patients with elevated Lp(a) and hypercholesterolemia with elevated LDL-C despite maximum tolerated statin therapy and Ezetimibe. Due to the several side effects associated with Niacin, its use as a Lp(a)-lowering therapy is currently not recommended.  

Atherogenic Dyslipidemia (TG of ≥1.7 mmol/L [≥150 mg/dL] and HDL-C of <1 mmol/L [<40 mg/dL])  

The patient likely has metabolic syndrome, type 2 diabetes mellitus, and obesity. Adequate trial of lifestyle modification should be attempted to meet LDL-C goals. LDL-lowering drug therapy should be added if lifestyle modification fails to reach LDL-C goals.  

For patients with TG of <2.3 mmol/L (<200 mg/dL), drug therapy to lower TG is not necessary. If the patient has coronary heart disease or coronary heart disease risk equivalents, consider using drug therapy to raise HDL-C (eg fibrates or Nicotinic acid).  

For patients with TG of 2.3-5.7 mmol/L (200-499 mg/dL), if non-HDL-C remains elevated after adequate LDL-C-lowering therapy, a higher dose of statin or statin plus TG-lowering drug (fibrate or Nicotinic acid) may be considered.  

Apolipoproteins  

Target apo B level at <90 mg/dL for patients at risk of coronary artery disease, including those with diabetes mellitus. Target apo B level at <80 mg/dL for patients with established coronary artery disease or diabetes mellitus plus ≥1 additional risk factor.  

Familial Hypercholesterolemia  

Familial hypercholesterolemia is a common autosomal dominant genetic disease that causes LDL-C level elevation and causes early-onset coronary heart disease.  

The Dutch Lipid Clinic Network criteria are used for the diagnosis of heterozygous familial hypercholesterolemia in adults and include the following:

  • Family history:
    • First-degree relative with known premature* coronary or vascular disease, or a first-degree relative with known LDL-C of >95th percentile: 1 point
    • First-degree relative with tendinous xanthomata and/or arcus cornealis, or children <18 years old with an LDL-C of >95th percentile: 2 points
  • Clinical history:
    • Premature* coronary artery disease: 2 points 
    • Premature* cerebral or peripheral vascular disease: 1 point 
  • Physical examination
    • Presence of tendinous xanthomata: 6 points
    • Presence of arcus cornealis before 45 years old: 4 points
  • LDL-C levels (without treatment)
    • LDL-C of ≥8.5 mmol/L (≥325 mg/dL): 8 points
    • LDL-C of 6.5-8.4 mmol/L (251-325 mg/dL): 5 points 
    • LDL-C of 5.0-6.4 mmol/L (191-250 mg/dL): 3 points 
    • LDL-C of 4.0-4.9 mmol/L (155-190 mg/dL): 1 point 
  • DNA analysis
    • Functional mutation in the LDLR, apoB, or PCSK9 genes: 8 points
  • Definite diagnosis of familial hypercholesterolemia can be made if the score is >8 points, probable if 6-8 points, and possible if 3-5 points

The treatment of familial hypercholesterolemia includes lifestyle modification that includes intervention on smoking, diet, and physical activity; and initiation of cholesterol-lowering drugs that include statins (maximal potent dose), Ezetimibe, PCSK9 mAbs (Alirocumab, Evolocumab), bile acid-binding resins, Inclisiran, Bempedoic acid, or Evinacumab.  

*Premature: <55 years old in men, <60 years old in women  

Pediatric Dyslipidemia  

The benefits of developing healthy lifestyle habits in children have been recognized. The recommended first-line approach is intensive lifestyle modifications (with emphasis on improved dietary intake and normalization of body weight). It is recommended that lifestyle changes in children should be implemented for at least 6-12 months prior to considering pharmacologic therapy.  

Studies have shown that high-fiber, low-fat diets are also beneficial in children by helping reduce cholesterol levels. However, monitoring of fat-soluble vitamin status in children on low-fat diets is recommended since this may reduce the absorption of these vitamins.  

Avoid a high carbohydrate diet in children with hypertriglyceridemia. Smoking cessation should also be implemented. Fish oil supplements are considered to have significant effects on TG levels in children, especially in those with end-stage renal insufficiency.  

Dietary supplementation with plant stanols and sterols (eg orange juice, yogurt drinks, cereal bars, margarine or spreads, dietary supplements) may be considered for children with severe hypercholesterolemia or those who are at high risk. These supplements may also reduce the absorption of fat-soluble vitamins; monitoring of fat-soluble vitamin status is also recommended. Pharmacotherapy is generally reserved for those with severe dyslipidemia or those with genetic lipid disorders.  

Other candidates for pharmacotherapy include children and adolescents >8 years of age who satisfy the following criteria:  

  • LDL-C level of ≥190 mg/dL
  • LDL-C level of ≥160 mg/dL plus the presence of ≥2 coronary artery disease risk factors; or a family history of premature coronary artery disease (<55 years of age); or being overweight or obese, or having other elements of insulin resistance syndrome
  • Pediatric diabetic patients with an LDL level of ≥130 mg/dL

Pharmacotherapeutic options for pediatric dyslipidemia include statins, bile acid sequestrants, fibrates, Ezetimibe, and Evolocumab.  

Based on available evidence, statins are considered safe and effective. It can be initiated at 6-10 years of age for the treatment of children with familial hypercholesterolemia in addition to healthy lifestyle measures.  

Pediatric studies have demonstrated 15-20% reductions in LDL-C levels with bile acid sequestrants. Cholestyramine is currently approved for hypercholesterolemia in children and should be initiated at <8 grams daily. The safety and efficacy of Colestipol and Colesevelam have not yet been established in pediatric patients although Colestipol may be started at <10 grams daily while Colesevelam is approved for children ≥8 years of age. Bile acid sequestrants may lead to folic acid and cholecalciferol depletion, therefore, multivitamins should be used. Bile acid sequestrants should not be used in children with hypertriglyceridemia.  

Fibrates may be useful in children with severe hypertriglyceridemia and at increased risk of pancreatitis. The use of fibrates in children or adolescents with type I or V hyperlipoproteinemia warrants close monitoring.  

Ezetimibe may be used in children ≥10 years of age and adolescents with homozygous familial hypercholesterolemia or sitosterolemia. Evolocumab is used as an adjunct to diet and other LDL-C-lowering therapies in children ≥10 years of age and adolescents with heterozygous familial hypercholesterolemia. Experience with Niacin therapy in children is limited. 

Nonpharmacological

Lifestyle Modification

Patients with dyslipidemia are advised to have lifestyle modifications regardless of their risk profile. ASCVD risk is reduced by a healthy lifestyle in all age groups. Consider starting statin therapy if the LDL-C target is not met after 3 months of non-pharmacological therapy.  

Dietary Recommendations  

The recommended LDL-C-lowering diet is comprised of an increased intake of vegetables, fruits, whole grain products, low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oil, and nuts along with the limitation in the consumption of red meat, sweetened beverages, chocolates, and sweets. The Mediterranean diet is recommended for cardiovascular risk reduction.  

The total calories should be enough to balance energy intake and expenditure to maintain body mass index (BMI) for Asian adults of 18.5-23 kg/m2 or BMI for European adults of 20-25 kg/m2. Protein should be 15-20% of the total calories. Dietary fat should range from 20-30% of the total calories. Saturated fat should be <10% of the total calories. Cholesterol should be <300 mg/day. Polyunsaturated fat can be up to 6-10% of the total calories. Monounsaturated fats are computed by the formula: Total Fats - (Saturated plus Polyunsaturated fats) and they may comprise up to 20% of the caloric intake. Reducing trans fat (<1% of total calories) may decrease LDL-C.  

Carbohydrates should range between 45-55% of the total energy intake. Advise to lower carbohydrate intake if with high TG and low HDL-C. The source of carbohydrates should be mainly from complex carbohydrates which include grains (especially whole grains), fruits, and vegetables.  

Advice to reduce sodium consumption to ≤2,000 mg/day as decreasing sodium intake to 1,150 mg/day may reduce blood pressure in 30- to 80-year-old patients with or without hypertension by up to 4/2 mmHg. When reduced to 1,000 mg/day, studies showed a decrease in cardiovascular events by 30%. Fiber intake should ideally be between 25-40 g/day of total dietary fiber.    

Moderate intake of fatty fish that is boiled, broiled, or baked but not fried. Up to 2 servings of fatty fish per week for the general population are recommended while patients with coronary artery disease should consume 1 g of EPA and DHA through fatty fish or high-quality dietary supplements. Omega-3 fish oil supplements may be considered to treat severe hypertriglyceridemia (TG >500 mg/dL) and may also be given as secondary prevention for cardiovascular disease. EPA (not EPA plus DHA) may be given with statin therapy to patients with hypertriglyceridemia (150-499 mg/dL) with ASCVD or increased ASCVD risk.     

A clinical study showed that Vitamin D supplementation has benefits in reducing TC, LDL-C, and TG levels. Lastly, a meta-analysis also demonstrated that green tea or its extracts can moderately reduce TC and LDL-C levels.  

Increase Physical Activity  

Physical activity can reduce the risk of CVD. Along with increased physical activity, patients should also be advised to reduce sedentary time. Moderate intensity exercise at 150-300 minutes per week or vigorous intensity exercise at 75-100 minutes per week is recommended. Aerobics may reduce LDL-C levels in adults by 3-6 mg/dL and non-HDL-C by 6 mg/dL. Studies show that resistance training helps lower LDL-C, TG, and non-HDL-C levels by 6-9 mg/dL. This is especially helpful in patients with metabolic syndrome. Muscle-strengthening exercise is recommended ≥2 days per week in addition to aerobic exercises. Studies have shown that weight and resistance training may benefit patients with insulin resistance syndrome regardless of body fat or aerobic fitness.  

Weight Loss

Weight loss is mainly achieved by dietary changes and exercise. It should be done gradually with the goal of losing 5-10% of body weight in 6 months. Waist circumference should also be maintained at <90 cm for men and <80 cm for women.  

Alcohol Intake  

Alcohol intake should be limited to ≤2 drinks per day (up to 20 grams per day) for men and ≤1 drink per day (up to 10 grams per day) for women.  

Smoking Cessation  

Advise patients to quit immediately. Smoking cessation has beneficial effects on overall cardiovascular risk, specifically on HDL-C levels.  

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Intensifying Lifestyle Modifications  

Increasing Viscous Fiber  

Increasing viscous fiber is a therapeutic option to help lower LDL-C. Viscous (soluble) fiber is found in oats, pectin-rich fruit, barley, psyllium, beans, etc. Five to ten grams per day can reduce LDL-C levels by ~5%.  

Plant Stanols or Sterols  

Sterols are isolated from soybean and tall pine tree oils. Lipids are needed to solubilize stanol or sterol esters, found in commercial kinds of margarine, where available. Two grams per day lower TC and LDL-C by 7-10%. They help reduce cholesterol absorption.  

Referral to Dietitian  

Consultation with a qualified professional for medical nutrition therapy may be offered. Foods rich in omega-3 fatty acids EPA and DHA should be listed.