Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc
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Review

Volume 18, Number 3, March 2026, pages 121-141

Novel Approaches to Lipid Management: Beyond Statins and PCSK9 Inhibitors

Figure

↓  Figure 1. Mechanism-based overview of lipid metabolism and therapeutic targets. ATP: adenosine triphosphate; ANGPTL3: angiopoietin-like protein 3; ApoC-III: apolipoprotein C-III; CETP: cholesteryl ester transfer protein; CRISPR: clustered regularly interspaced short palindromic repeats; EPA: eicosapentaenoic acid; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; LDL: low-density lipoprotein; LDLR: low-density lipoprotein receptor; PCSK9: proprotein convertase subtilisin/kexin type 9; siRNA: small interfering ribonucleic acid; TGs: triglycerides.
Figure 1.

Tables

↓  Table 1. Summary of Possible Adverse Events Associated With Pharmacotherapy
 
PharmacotherapyAdverse effects
Bempedoic acidGout, cholelithiasis, small increases in serum creatinine, uric acid, and hepatic enzymes
InclisiranMost frequent events are injection-site reaction
EvinacumabDiarrhea, dyspepsia, toothache, dizziness, nasopharyngitis, influenza-like illness, urinary tract infection, increased aspartate aminotransferase (AST), myalgia, suicide attempt (rare)
ZodasiranTransient elevation in glycated hemoglobin (HbA1c) with pre-existing diabetes
VolanesorsenInjection-site reactions, thrombocytopenia
OlezarsenHeadache, injection-site reactions, upper respiratory infections, liver enzyme elevation, Thrombocytopenia, decrease in estimated glomerular filtration rate
PlozasiranUpper respiratory tract infection, headache, abdominal pain, diarrhea, urinary tract infection
AnacetrapibMild increase in blood pressure, diarrhea, constipation, dyspepsia, myalgias
Icosapent ethylDiarrhea, increased atrial fibrillation/flutter, bleeding risk, peripheral edema

 

↓  Table 2. A Consolidated Summary of Studies on Lipid Pharmacotherapies
 
AuthorYearStudy typeSample sizeInterventionDurationKey clinical outcome
HeFH: heterozygous familial hypercholesterolemia; HoFH: homozygous familial hypercholesterolemia; hs-CRP: high-sensitivity C-reactive protein; LDL: low-density lipoprotein; MACEs: major adverse cardiovascular events.
Lincoff et al [26]2024Double blind, placebo-controlled trial13,970Bempedoic acid vs. placebo40.6 monthsBempedoic acid reduced major adverse cardiovascular events by 15% compared to placebo.
Nicholls et al [27]2024Randomized, double-blind, placebo-controlled, clinical trial13,970Bempedoic acid vs. placebo3.4 yearsBempedoic acid was associated with a 20% reduction in the total number of major cardiovascular events compared to placebo in high-risk, statin-intolerant patients.
Bays et al [28]2025Subset analysis of randomized, double-blind, placebo-controlled, clinical trial13,970Bempedoic acid vs. placebo40.7 monthsBempedoic acid resulted in a placebo-corrected reduction in LDL-C of 22.5% and hs-CRP of 23.2%, and a 23% reduction in the composite MACE-4 endpoint compared with placebo in people with obesity.
Duell et al [29]2024Pooled patient-level data analysis of two phase 3 randomized clinical trials217Bempedoic acid vs. placebo52 weeksIn patients with HeFH, adding bempedoic acid to maximally tolerated statin therapy resulted in a significant LDL-C reduction of −21.2% at week 12 versus placebo.
Taub et al [30]2025Randomized, double-blind, phase 3 trial350Inclisiran vs. ezetimibe vs. placebo6 monthsInclisiran monotherapy reduced LDL-C by 46.5% at day 150 vs. placebo (1.4% increase) and vs. ezetimibe (−11.2%).
Basit et al [31]2025Meta-analysis of randomized controlled trials5,016Inclisiran vs. placeboTrials included up to July 2024Inclisiran significantly reduced LDL-C by a mean difference of −50.42% compared with control, without increasing serious adverse event risk.
Saad Cleto et al [32]2025Systematic review and meta-analysis30,718Inclisiran vs. alirocumab24 weeksAlirocumab demonstrated greater efficacy than inclisiran in enhancing lipid parameters.
Rai et al [33]2024Systematic review and meta-analysisInclisiranThe meta-analysis found significantly greater reductions in lipid-parameters in HeFH compared to HoFH.
Rangwala et al [34]2024Systematic review and meta-analysis270Evinacumab vs. placeboHigh dose evinacumab significantly reduce lipid parameters with no excess adverse events.
Rosenson et al [35]2020Randomized, double-blind, placebo-controlled Phase 2 clinical trial272Evinacumab vs. placebo16 weeksEvinacumab reduced LDL-cholesterol by more than 50% at the highest dose compared to placebo.
Rosenson et al [36]2024Phase 2b, randomized, double-blind, placebo-controlled trial204Zodasiran vs. placebo36 weeksZodasiran resulted in dose-dependent triglyceride reductions.
Kim et al [37]2024Systematic review and meta-analysis53,231Fibrate vs. placeboFibrate therapy was linked to a lower incidence of major cardiovascular events, with its beneficial impact primarily attributed to reductions in LDL-cholesterol rather than triglyceride levels.
Jakob et al [38]2016Systematic review and meta-analysis16,135Fibrate vs. placebo4.8 yearsFibrate therapy lowered the combined risk of cardiovascular-disease death, non-fatal myocardial infarction, or non-fatal stroke in primary prevention.
Sahebkar et al [40]2017Systematic review and meta-analysis1,388Fibrate vs. statinFibrate therapy led to a markedly greater decrease in plasma lipoprotein(a) levels than statin treatment.
Gouni-Berthold et al [41]2021Randomized, double-blind, placebo-controlled phase 3 clinical trial114Volanesorsen vs. placebo26 weeksVolanesorsen resulted in a 71.2% decrease in triglyceride levels, compared to only a 0.9% change observed in the placebo group.
Bergmark et al [42]2024Randomized, double-blind, placebo-controlled, phase 2b trial154Olezarsen vs. placebo6 months with follow-up up to 12 monthsOlezarsen at doses of 50 and 80 mg produced triglyceride reductions of approximately 49.3% and 53.1%, respectively, when compared with the placebo group.
Gaudet et al [43]2024Randomized clinical trial226Plozasiran vs. placebo48 weeksPlozasiran produced robust triglyceride lowering, with a least-squares mean reduction of 57% at the highest dose; ApoC-III decreased by 77%, and more than 90% of treated participants achieved triglyceride levels below 500 mg/dL.
Zhou et al [45]2018Systematic review and meta-analysis of randomized controlled trials34,781Anacetrapib vs. placeboAnacetrapib significantly improved lipid parameters, increasing HDL-C and reducing LDL-C, non-HDL-C, triglycerides, ApoB, and Lp(a), without a significant increase in adverse events compared with placebo.
Kastelein et al [46]2024Narrative review of phase 2 and phase 3 randomized trials_Obicetrapib vs. placebo/statin_Obicetrapib produced substantial LDL-C reductions of approximately 45–51% in phase 2 studies and 36.3% at day 84 in the phase 3 BROOKLYN trial, with sustained benefit and favorable tolerability.
Sayah et al [47]2024Randomized clinical trial_Icosapent ethyl vs. placebo5 yearsIcosapent ethyl reduced the primary composite cardiovascular endpoint by 25% and cardiovascular death by 20% in statin-treated patients with elevated triglycerides and high cardiovascular risk.
Hafiane et al [48]2025Phase 3 trial17Lomitapide vs. baselineLomitapide significantly reduced LDL-C and ApoB in patients with HoFH, with larger reductions at higher doses and associated changes in HDL function.
Karwatowska-Prokopczuk et al [49]2023Randomized, double-blind, placebo-controlled phase 1 study29Pelacarsen vs. placebo204 daysPelacarsen produced marked dose-dependent reductions in lipoprotein(a), reaching up to approximately 84% with repeated dosing, with acceptable short-term safety.

 

↓  Table 3. Medications Summary
 
DrugTargetPrimary mechanismLDL-CTGHDL-C
↓↓↓: strong reduction; ↓↓: moderate reduction; ↓: mild reduction; ↑: increase; -: no significant effect. ACL: ATP-citrate lyase; ANGPTL3: angiopoietin-like protein 3; Apo(a): apolipoprotein(a); ApoC-III: apolipoprotein C-III; ASO: antisense oligonucleotide; CE: cholesterol ester; CETP: cholesteryl ester transfer protein; EL: endothelial lipase; HDL: high-density lipoprotein; HMG-CoA-3: hydroxy-3-methylglutaryl-CoA; LDL: low-density lipoprotein; LDLR: LDL receptor; Lp(a): lipoprotein(a); LPL: lipoprotein lipase; MTP: microsomal TG transfer protein; PCSK9: proprotein convertase subtilisin/kexin 9; PPARα: peroxisome proliferator-activated receptor α; siRNA: small interfering RNA; TG: triglyceride; VLDL: very low-density lipoprotein.
StatinHMG-CoA reductaseBlocks cholesterol synthesis↓↓↓↓↑
PCSK9 inhibitorPCSK9 proteinIncreases LDL receptor recycling↓↓↓_↑
Bempedoic acidACL enzymeBlocks acetyl-CoA production↓↓__
EvinacumabANGPTL3 proteinActivates LPL and EL↓↓↓↓↓
ZodasiranANGPTL3 mRNAsiRNA silences ANGPTL3↓↓↓↓↓
ApoC-III inhibitorApoC-III proteinEnhances LPL and TG clearance_↓↓↓↑
CETP inhibitorCETP enzymeBlocks CE transfer HDL→LDL↓↓↓↑↑↑
FibratesPPARα receptorActivates LPL, reduces TG synthesis↓↓↓↓↑↑
Icosapent ethylMultiple (TG pathway)Reduces TG, anti-inflammatory_↓↓_
LomitapideMTP proteinBlocks VLDL assembly↓↓↓↓↓↓
PelacarsenApo(a) mRNAASO reduces Lp(a) production___