MD Notes

creation date: 2026-06-08 11:06
tags: Pharmacology

Lipid-Lowering Medications

Background

Pharmacotherapy for control of dyslipidemia is integral to management of ASCVD risk.

Lipids is often used clinically to refer to LDL or non-HDL but exact definitions are:

  • VLDL (very low density lipid): made in liver and transports to muscle and adipose; TG and cholesterol rich
  • IDL (intermediate density lipid): after TG is removed from VLDL; cholesterol rich
  • LDL (low density lipid): from VLDL/IDL, transports cholesterol in blood
  • HDL (high density lipid): transports from peripheral tissue to liver (good)

Targets

Lipid targets vary based on comorbidities (secondary prevention) but generally, pharmacotherapy is considered for primary prevention if:

  • High risk of ASCVD (FRS ≥20%)
  • Intermediate risk of ASCVD (FRS 10-19%) with any of the following:
    • LDL-C ≥3.5 mmol/L
    • Non-HDL-C ≥4.2 mmol/L
    • Apo B ≥ 1.05 g/L
    • Age ≥50 (men) or ≥60 (women) with one additional CVD risk factor

Targets are:

  • LDL-C <2.0 mmol/L
  • Apo B <0.8 g/L
  • Non-HDL-C <2.6 mmol/L

Targets for patients with recent ACS:

  • LDL-C ≤1.8 mmol/L
  • Apo B ≤0.7 g/L
  • Non-HDL-C ≤2.4 mmol/L

LDL-C Lowering Medications

HMG-CoA Reductase Inhibitor (Statins)

Mechanism of Action
  • Competitive inhibition of HMG-CoA reductase (rate-limiting step of endogenous cholesterol production)
  • Increases LDL receptors on hepatocyte surfaces
  • Note, in east Asian populations, a lower starting dose is recommended due to higher plasma concentrations
Additional Indications
  • First line for ASCVD risk reduction
  • Secondary prevention of ASCVD
Side Effects
  • Hepatic dysfunction (uncommonly raises AST, ALT)
  • Muscle injury (increased risk with hypothyroidism)
  • Kidney dysfunction (atorvastatin preferred over rosuvastatin in cases of poor kidney function)
Examples

High-intensity (expected reduction ≥50%)

  • Atorvastatin 40mg
  • Rosuvastatin 20mg

Moderate-intensity (expected reduction 30-49%)

  • Atorvastatin 10mg (preferred)
  • Rosuvastatin 10mg (preferred)
  • Fluvastatin XL 80mg
  • Fluvastatin 40mg BID
  • Lovastatin 40mg
  • Pitavastin 1, 2, 4mg
  • Pravastatin 40mg
  • Simvastatin 20, 40mg

Low-intensity (expected reduction <30%)

  • Fluvastatin 20, 40mg
  • Lovastatin 20mg
  • Pravastatin 10, 20mg
  • Simvastatin 10mg

Cholesterol Absorption Inhibitor

Mechanism of Action
  • Blocks NPC1L1 (steroid transporter protein) which inhibits intestinal and biliary sterol absorption
  • Increases LDL receptors on hepatocyte surfaces (reduces hepatic sterol levels secondarily)
Additional Indications
  • Sitosterolemia
Side Effects
  • Hepatic dysfunction (uncommonly raises AST, ALT)
  • Arthralgia
Examples
  • Ezetimibe 10mg (expected reduction: 18% monotherapy, 25% with statin)

PCSK9 Inhibitor

Monoclonal Antibodies

Mechanism of Action
  • Human monoclonal antibodies bind to PCSK9 (convertase that destroys hepatic LDL receptors) in circulation and decreases degradation of LDL receptors
  • Subcutaneous administration
  • Expected LDL-C reduction: 45-64%, may be less in some gene variants
Additional Indications
Side Effects
Examples
  • Alirocumab
  • Evolocumab

Small Interfering RNA

Mechanism of Action
  • Small interfering RNA results in cleavage of PCSK9 mRNA
  • Decreases degradation of LDL receptors
  • Subcutaneous administration by health care provider
  • Expected LDL-C reduction: 48-52%
Additional Indications
Side Effects
Examples
  • Inclisiran q3months for first two dose, then q6months

ATP Citrate Lyase Inhibitor

Mechanism of Action
  • Inhibits ATP citrate lyase in liver
  • Decreases cholesterol production upstream of HMG-CoA reductase
  • Increases LDL receptors on hepatocyte surfaces
  • Expected LDL-C reduction: 21-24% monotherapy, 17-18% combined with statin
Additional Indications
  • Monotherapy for patients with statin-attributed side effects
Side Effects
Examples
  • Bempedoic acid

Bile Acid Sequestrants

Mechanism of Action
  • Binds bile acids in the gut, interrupting enterohepatic recirculation of bile acids and impede reabsorption
  • Decreases bile acid pooling in liver
  • Increases conversion of cholesterol to bile acid
  • Expected LDL-C reduction: 10-27%
Additional Indications
  • Nonsystemic option, either as add on to statin or for statin intolerance
Side Effects
  • May increases serum TG; avoid if TG >3.5 mmol/L
Examples
  • Cholestyramine
  • Colesevelam
  • Colestipol

Microsomal TG Transfer Protein Inhibitor

Mechanism of Action
  • Binds and inhibits TG transfer protein (required for assembly of apoB lipoproteins)
  • Inhibits synthesis of chylomirons and VLDL which lowers LDL-C
  • Expected LDL-C reduction: 40-50%
Additional Indications
Side Effects
  • Hepatotoxicity
  • Drug-drug interaction (associated with CYP3A4)
  • Deficiency in vitamin E, linoleic acid, alpha-linolenic acid, EPA, and DHA (requires supplementation)
Examples

Only available through restricted program due to side effects:

  • Lomitapide

ANGPTL3 Inhibitor

Mechanism of Action
  • Human monoclonal antibody binding to ANGPTL3
  • Increases remnant lipoprotein clearance, reducing VLDL and thus their conversion to LDL
  • Intravenously administered
  • Expected LDL-C reduction: 49%
Additional Indications
Side Effects
Examples
  • Evinacumab-dgnb

Triglyceride-Lowering Medications

Fibrates

Mechanism of Action
  • Stimulates PPAR-alpha, activating lipoprotein lipase and reduces apolipoprotein C-III production
  • Increases lipolysis and elimination of TG-rich particles
  • Expected TG reduction: 30-50%
Additional Indications
  • First line for severe hypertriglyceridemia (≥5.7 mmol/L, especially ≥11.4 mmol/L)
Side Effects
  • Gemfibrozil has severe drug interaction with statin
Examples
  • Fenofibrate
  • Fenofibric acid
  • Gemfibrozil

Omega-3 Fatty Acids

Mechanism of Action
  • Reduces hepatic VLDL TG synthesis and/or secretion
  • Enhances TG clearance from circulating VLDL
  • Taken with fat-containing meal to ensure absorption
  • Expected TG reduction: 15-61%
Additional Indications
  • First line for severe hypertriglyceridemia (≥5.7 mmol/L)
Side Effects
  • Omega-3 acid ethyl esters contains DHA and EPA which can modestly raise LDL-C
Examples
  • Icosapent ethyl
  • Omega-3 acid ethyl esters

Niacin

Mechanism of Action
  • Reduces esterification of hepatic TG
  • Decreases release of fatty acids from adipose tissue
  • Increases lipoprotein lipase activity, removing TG-rich lipoprotein fatty acids
  • Expected TG reduction: 10-30% extended release, 20-50% immediate release
Additional Indications
  • Last line agent for severe hypertriglyceridemia due to side effects
Side Effects
  • Increases insulin resistance
  • Skin flushing
  • Significant hepatotoxicity
Examples
  • Extended release niacin (daily)
  • Immediate release niacin (BID/TID)

ApoC-III Inhibitor

Mechanism of Action
  • Binds to apoC-III mRNA and degrades
  • Reduces apoC-III protein, resulting in clearance of plasma TG and VLDL
  • Subcutaneous agent
  • Expected TG reduction: 30-40%
Additional Indications
  • Familial chylomicronemia syndrome (only)
Side Effects
Examples
  • Olezarsen

References

Tools / Guidelines

2021 CCS Dyslipidemia
2026 ACC/AHA Guideline on the Management of Dyslipidemia

Additional Reading