Classification of Lipid-Lowering Drugs
Lipid-lowering drugs are classified into two primary categories: LDL-cholesterol lowering agents (statins, ezetimibe, bile acid sequestrants, PCSK9 inhibitors, bempedoic acid) and triglyceride-lowering agents (fibrates, omega-3 fatty acids, niacin), with statins serving as the cornerstone of therapy. 1
Primary LDL-Cholesterol Lowering Agents
Statins (HMG-CoA Reductase Inhibitors)
Statins remain the first-line therapy for both primary and secondary cardiovascular prevention. 1 They are categorized by intensity based on their LDL-C lowering capacity:
- High-intensity statins (≥50% LDL-C reduction): Atorvastatin 40-80 mg, Rosuvastatin 20-40 mg 1
- Moderate-intensity statins (30-49% LDL-C reduction): Atorvastatin 10-20 mg, Rosuvastatin 5-10 mg, Simvastatin 20-40 mg, Pravastatin 40-80 mg, Lovastatin 40-80 mg, Fluvastatin XL 80 mg, Pitavastatin 1-4 mg 1
- Low-intensity statins (<30% LDL-C reduction): Simvastatin 10 mg, Pravastatin 10-20 mg, Lovastatin 20 mg, Fluvastatin 20-40 mg 1
Non-Statin LDL-Lowering Agents
Ezetimibe (Niemann-Pick C1-Like 1 protein inhibitor): Blocks intestinal cholesterol absorption and serves as second-line therapy for secondary prevention, either as statin add-on or for statin-intolerant patients 1, 2
PCSK9 Inhibitors (Alirocumab, Evolocumab): Monoclonal antibodies that enhance LDL receptor recycling; recommended for very high-risk ASCVD patients on maximally tolerated statin therapy with LDL-C ≥70 mg/dL 1, 2
Bile Acid Sequestrants (Colesevelam): Reduce LDL-C by binding bile acids in the intestine, effective alone or combined with statins 1, 3
Bempedoic Acid: ATP-citrate lyase inhibitor that works through a similar pathway to statins but without associated myopathy risk 2, 4, 5
Triglyceride-Lowering Agents
Primary Triglyceride-Targeting Drugs
Fibrates (Fenofibrate, Pemafibrate): PPAR-α activators that primarily lower triglycerides with mild LDL-lowering effects; however, RCTs do not support their use as add-on drugs to statin therapy for most patients 1, 3
Omega-3 Fatty Acids (Icosapent ethyl): EPA-only formulation recommended for secondary prevention in hypertriglyceridemia as statin add-on therapy; note that EPA/DHA mixtures are not supported by the same evidence 2, 6
Niacin (Nicotinic acid): Raises HDL-C and lowers triglycerides with mild LDL-lowering action, though RCTs do not support add-on use with statins 1, 3
Emerging and Novel Agents
Advanced Biotechnology-Based Therapies
Small interfering RNA: Inclisiran (targets PCSK9), Olpasiran (targets Lp(a)) 2, 4, 5
Antisense Oligonucleotides: Mipomersen (ApoB-100), Volanesorsen and Olezarsen (ApoC-III), Pelcarsen (Lp(a)) 2, 4, 5
Monoclonal Antibodies: Evinacumab (ANGPTL3 inhibitor) targeting both LDL-C and triglycerides 2, 4, 5, 6
Other Novel Agents: Lomitapide (MTP inhibitor), gene therapies including AAV vectors and CRISPR/Cas9-based therapeutics 2, 4, 5
Clinical Application Framework
The 2018 AHA/ACC guidelines establish a hierarchical approach: statins form the foundation, with ezetimibe as the preferred second-line agent for inadequate LDL-C control, followed by PCSK9 inhibitors for very high-risk patients who remain above goal despite maximally tolerated therapy. 1 For hypertriglyceridemia in secondary prevention, icosapent ethyl and fenofibrate serve as statin add-on options, though robust primary prevention data for these combinations remains limited. 2
Important caveat: Simvastatin 80 mg should not be initiated or titrated to due to increased myopathy and rhabdomyolysis risk, despite evaluation in RCTs. 1