Drug Name Intervention	Intervention	Type of Study	Most Relevant Effects of Drug	Safety/Potential Serious Side Effects	Ref.
2-hydroxypropyl-β-cyclodextrin		Animal study (mice)	-Reduction in atherosclerotic plaque size and CC load -Plaque regression even in mice on a cholesterol-rich diet -Increased oxysterol production in macrophages and human atherosclerotic plaques -No change in the relative plaque composition -Stimulation of LXR–mediated transcriptional reprogramming to improve cholesterol efflux -Decreased the production of aortic ROS and plasma concentrations of proinflammatory cytokines—anti-inflammatory effects	Generally well tolerated, but the latest research indicated the increased risk of ototoxicity in the form of iatrogenic hearing loss [148]	[6]
		Animal study (rabbits fed a high-fat diet)	-Reduced plasma levels of TG and inflammatory cytokines -Increased plasma HDL-C -Reduction in atherosclerotic lesion area -Diminished macrophage and collagen content in the lesions -Significant decrease in expression levels of inflammatory genes in aortic plaques -Increased expression of ABCA1 and ABCG1 in aortic plaques and liver		[35]
2-hydroxybenzylamine (2-HOBA)		Animal study (hypercholesterolemic Ldlr−/− mice) – model of FH	-Decreased atherosclerosis by 60% in en face aortas of mice compared to mice treated with vehicle or a nonreactive analogue (4-HOBA) -Reduced MDA-LDL and MDA-HDL levels -Increased capacity of HDL to reduce macrophage cholesterol -Reduction in MDA- and IsoLG-lysyl content in atherosclerotic aortas -Diminished inflammation and plaque apoptotic cells -Stimulation of efferocytosis and features of stable plaques	2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers [45]. Adverse events reported in this trial were mild and considered unlikely to be related to 2-HOBA	[37]
Inclisiran	One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo	Randomized, double-blind, placebo-controlled multicentre phase 2 clinical trial (ORION-1)	-Treatment with inclisiran resulted in durable reductions in LDL-C -Time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year	Well tolerated Mild rash in some participants	[54]
	One intravenous dose (doses ranging from 0.015 to 0.400 mg/kg) or placebo	Randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3.00 mmol/L or higher	-A mean 70% reduction in circulating PCSK9 plasma protein (p < 0·0001) -A mean 40% reduction in LDL cholesterol from baseline relative to placebo (p < 0·0001)	No drug-related serious adverse events. Mild to moderate treatment-emergent adverse events A transient mild, macular, erythematous rash	[52]
	Subcutaneous injection. Single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran	Phase 2, multicentre, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels	-Mean reductions in LDL cholesterol levels: 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (p < 0.001 for all comparisons vs. placebo) -At day 240, PCSK9 levels were 56.1% lower and LDL cholesterol levels 47.2% lower than at baseline, with a mean absolute reduction in LDL cholesterol level of 58.9 mg/dL (1.52 mmol/L)	Rarely symptoms of immune activation. Rare transient elevations in hepatic enzyme levels	[53]
		ORION-10 trial: patients with atherosclerotic cardiovascular disease with elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose	-At day 510, a reduction in LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) (p < 0.001 for all comparisons vs. placebo) -Decreased levels of triglycerides and lipoprotein(a) and increased HDL cholesterol levels at day 510	injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9%) Adverse reactions were generally mild, and none were severe or persistent	[49]
		ORION-11 trial: patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent with elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose	-At day 510, reduction in LDL cholesterol levels by 49.9% (95% CI, 46.6 to 53.1) with corresponding time-adjusted reductions of 49.2% (95% CI, 46.8 to 51.6) (p < 0.001 for all comparisons vs. placebo) -Decreased levels of triglycerides and lipoprotein(a) and increased HDL cholesterol levels at day 510	injection-site adverse events were more frequent with inclisiran than with placebo (4.7% vs. 0.5%) Adverse reactions were generally mild, and none were severe or persistent	[49]
Antisense oligonucleotides targeting Angptl3 mRNA	Subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg/week for 6 weeks)	Clinical trial including 44 human participants (with TG levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group)	-Dose-dependent reduction in levels of hepatic Angptl3 mRNA, Angptl3 protein, TG, and LDL cholesterol -Reduced liver TG content -Hampered atherosclerosis progression -Increased insulin sensitivity -Multiple-dose groups: reduced levels of ANGPTL3 protein (46.6 to 84.5% from baseline, p < 0.01 for all doses vs. placebo), TG (33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), VLDL (27.9 to 60.0%), non–HDL cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%) after 6 weeks of treatment	No serious adverse events. Rarely dizziness or headache	[63]
Evinacumab (fully human anti-ANGPTL3 monoclonal antibody)	Placebo subcutaneously (75, 150, or 250 mg) Intravenously (5, 10, or 20 mg/kg)	A phase 1, first-in-human, randomized, placebo-controlled, double-blind, ascending single-dose clinical trial Healthy persons with a fasting TG level of 150 to 450 mg/dL (1.7 to 5.1 mmol/L) or an LDL cholesterol level of 100 mg/dL (2.6 mmol/L) or greater	-Dose-proportional magnitude and duration of lipid reductions (placebo-corrected) -The maximal changes in lipid levels found among patients who received a dose of 20 mg/kg intravenously were as follows: triglycerides, −76.0% (day 4); directly measured LDL cholesterol, −23.2% (day 15); and HDL cholesterol, −18.4% (day 15).	The most frequent adverse event—headache (11%). Transient, single elevations of the alanine aminotransferase level to more than 3 times the upper limit of the normal range	[59]
Atorvastatin Alirocumab; Evinacumab	Diet alone (control) or atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks	APOE*3-Leiden.CETP mice (model for hyperlipidemia)	-All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all p < 0.001). -Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; p < 0.001). -Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both p < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity.	-	[68]
Colchicine	1 mg daily for 30 days	A pilot randomized controlled trial 80 patients with ACS or acute ischemic stroke	-No significant reduction in absolute hs-CRP at 30 days [median 1.0 mg/L (range 0.2, 162.0) versus 1.5 mg/L (0.2, 19.8), p = 0.22] -No difference in platelet function	Occurrence of diarrhoea (X(2) 4.14, p = 0.04)	[70]
	Low-dose colchicine (0.5 mg/day) or a placebo for 7 days	Double-blind, randomized, placebo-controlled, crossover-within-subject clinical trial 28 patients with CAD	-Significantly decreased serum concentration of hs-CRP compared with placebo [median (interquartile range): 0.04 (0.02–0.08) mg/dL vs. 0.07 (0.04–0.11) mg/dL, p = 0.003] -No significant difference in FMD between the treatments [median (interquartile range): 3.1% (1.5–5.3%) vs. 3.3% (1.9–5.2%), p = 0.384]	-	[71]
	0.5 mg/day or no colchicine; Follow-up: a median of 3 years.	Clinical trial with a prospective, randomized, observer-blinded endpoint design 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%)	-Occurrence of primary outcome (composite incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke) in 5.3% patients on colchicine and 16.0% patients assigned no colchicine (hazard ratio: 0.33; 95% confidence interval [CI] 0.18 to 0.59; p < 0.001) -Colchicine in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease	Intestinal intolerance	[72]
	1 mg followed by 0.5 mg 1 hour later or no colchicine, 6 to 24 h prior to cardiac catheterization	Randomized controlled trial 40 ACS patients, 33 with stable CAD, and 10 controls	-Significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (p = 0.028, 0.032, and 0.032, for IL-1β, IL-18, and IL-6, respectively		[73]
	Oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment	Randomized controlled trial 21 ACS patients compared with 9 untreated healthy controls	-Markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (p < 0.05 for both) -Significantly diminished pro-caspase-1 mRNA levels (by 57.7%) and secreted caspase-1 protein levels (by 30.2%) compared with untreated patients (p < 0.05 for both)	-	[74]
	Orally 1.5 mg or no treatment	Randomized controlled trial 12 patients with ACS on colchicine vs. 13 assigned to no treatment	-Markedly reduced transcoronary levels of CCL2, CCL5, and CX3CL1 in patients with ACS (p < 0.05) -In vitro colchicine suppressed CCL2 gene expression in stimulated monocytes (p < 0.05) -- Reduced the intracellular concentration of all 3 chemokines (p < 0.01) and impaired monocyte chemotaxis (p < 0.05)	-	[75]
	Either 0.5 mg/day colchicine plus OMT or OMT alone; follow-up for 1 year.	Prospective nonrandomized observational study of 80 patients with recent ACS (<1 month)	-Significantly reduced LAPV (mean 15.9 mm3 [−40.9%] vs. 6.6 mm3 [−17.0%]; p = 0.008) and hsCRP (mean 1.10 mg/l [−37.3%] vs. 0.38 mg/L [−14.6%]; p < 0.001) versus controls -Comparable decrease in total atheroma volume (mean 42.3 mm3 vs. 26.4 mm3; p = 0.28) and LDL levels (mean 0.44 mmol/L vs. 0.49 mmol/L; p = 0.21) in both groups	-	[76]
	Either low-dose colchicine (0.5 mg once daily) or placebo	Randomized, double-blind trial involving 4745 patients with fresh myocardial infarction (within 30 days form event)	-The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization -Significantly lower risk of ischemic cardiovascular events compared to placebo	Pneumonia as a serious adverse event in 0.9% of the patients in the colchicine group vs. 0.4% of those in the placebo group (p = 0.03)	[77]
	Colchicine or placebo within 30 days post-MI	The COLchicine Cardiovascular Outcomes Trial (COLCOT)	-Significant reduction in the incidence of the primary endpoint for patients in whom colchicine was initiated < day 3 compared with placebo [HR = 0.52, 95% CI 0.32-0.84], in contrast to patients in whom colchicine was initiated between days 4 and 7 (HR = 0.96, 95% CI 0.53-1.75) or > day 8 (HR = 0.82, 95% CI 0.61–1.11). -Beneficial effects of early initiation of colchicine were seen for urgent hospitalization for angina requiring revascularization (HR = 0.35); all coronary revascularization (HR = 0.63); and the composite of cardiovascular death, resuscitated cardiac arrest, MI, or stroke (HR = 0.55, all p < 0.05).	-	[80].
Canakinumab	Subcutaneous placebo or canakinumab at doses of 5, 15, 50, or 150 mg monthly (follow-up: 4 months)	Double-blind, multinational phase IIb trial of 556 patients with well-controlled diabetes mellitus and high cardiovascular risk	-Modest but nonsignificant effects on the change in hemoglobin A1c, glucose, and insulin levels -Median reductions in C-reactive protein at 4 months were 36.4%, 53.0%, 64.6%, and 58.7% for the 5-, 15-, 50-, and 150-mg canakinumab doses, respectively, compared with 4.7% for placebo (all p ≤ 0.02) -Median reductions in interleukin-6 at 4 months across the canakinumab dose range tested were 23.9%, 32.5%, 47.9%, and 44.5%, respectively, compared with 2.9% for placebo (all p ≤ 0.008) -Median reductions in fibrinogen at 4 months were 4.9%, 11.7%, 18.5%, and 14.8%, respectively, compared with 0.4% for placebo (all p ≤ 0.0001)	Clinical adverse events were similar in the canakinumab and placebo groups	[101]
	50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months vs. placebo	A randomized, double-blind trial involving 10,061 patients with previous myocardial infarction and a hs CRP level of 2 mg/L or more	-Reduction in hsCRP (at 48 months): median 26% in the group receiving 50-mg dose, 37% in 150-mg group, and 41% in the 300-mg group compared to the placebo -Dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events (HR, 0.85 (95% CI, 0.74 to 0.98; p = 0.021) -The 150-mg dose met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point (HR vs. placebo, 0.83; 95% CI, 0.73 to 0.95; p = 0.005)	Higher incidence of fatal infection compared to placebo.	[7]
	3 subcutaneous doses of canakinumab (50 mg, 150 mg, or 300 mg) once every 3 months	Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) 4833 stable atherosclerosis patients	In patients with on-treatment IL-6 levels <1.65 ng/L: -32% reduction in MACE (HRadj) 0.68, 95% CI 0.56–0.82; p < 0.0001) -30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE +, HRadj 0.70, 95% CI 0.59–0.84; p < 0.0001) -52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34–0.68; p < 0.0001) -48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40–0.68; p < 0.0001) with prolonged treatment. -Patients with on-treatment IL-6 levels ≥ 1.65 ng/L—no significant benefit for any of these endpoints	No related hepatic or renal toxicities Reduced rates of lung cancer increase in fatal infection	[101]
	Canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months	Multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial involving outpatients with PAD and IC	-Reduced markers of systemic inflammation (Il-6 and hsCRP) as early as 1 month after treatment -Lack of plaque progression alteration in the SFA, (however, early signal of improvement of maximum and pain-free walking distance in patients with symptomatic PAD)	Safe and well tolerated	[102]
Ziltivekimab	Subcutaneous administration of placebo or ziltivekimab 7.5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks	RESCUE, a randomised, double-blind, phase 2 trial carried out at 40 clinical sites in the USA. Participants with moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L	-median reduction in hsCRP levels: 77% for the 7.5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group (all p < 0.0001) -Stable effects over the 24-week treatment period -Dose-dependent reductions in fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a)	Well tolerated, No serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia.	[104]
Losmapimod	Losmapimod 7.5 mg once daily (lower dose), twice daily (higher dose) or placebo for 84 days	99 patients with atherosclerosis on stable statin therapy	-Statistically significant reduction in average TBR in active segments (TBR ≥ 1.6) (HD vs. placebo: ΔTBR: −0.10 [95% CI: −0.19 to −0.02], p = 0.0125; LD vs. placebo: ΔTBR: −0.10 [95% CI: −0.18 to −0.02], p = 0.0194) -High dose group: decreased placebo-corrected inflammatory biomarkers including hsCRP (% reduction: −28% [95% CI: −46 to −5], p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: −0.05 [95% CI: −0.09 to −0.01], p = 0.018), but not subcutaneous fa	-	[109]
	Oral losmapimod (7.5 mg or 15.0 mg loading dose followed by 7.5 mg twice daily) or matching placebo	A double-blind, randomised, placebo-controlled trial of patients with NSTEMI	-Decreased hsCRP concentrations at 72 h in the losmapimod group compared to the placebo group (geometric mean 64.1 nmol/L, 95% CI 53.0–77.6 vs 110.8 nmol/L, 83.1–147.7; p = 0.0009) -Significantly lower geometric mean BNP concentrations at 12 weeks (37.2 ng/L, 95% CI 32.3–42.9 vs 49.4 ng/L, 38.7–63·0; p = 0.04)	Safety outcomes did not differ between groups	[110]
	Either twice-daily losmapimod (7.5 mg) or matching placebo on a background of guideline-recommended therapy.	LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries 3503 participants (part A)	Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events (primary end point occurrence by 12 weeks: placebo (7.0%) and patients treated with losmapimod: 8.1%; hazard ratio, 1.16; 95% CI, 0.91–1.47; p = 0.24	Similar on-treatment rates of serious adverse events: 16.0% with losmapimod and 14.2% with placebo	[111]
MK2206	Injection of MK2206 at a dose of 4 mg/kg/d, or equal volume of saline (containing 0.1% DMSO)	In vitro, animal study	-Significant reduction in vascular inflammation, atherosclerotic lesions, and inhibition of proliferation of VSCM in ApoE−/− mice in vivo -Diminished lipid accumulation (associated with the enhanced cholesterol efflux) -Decreased inflammatory response by modulating inflammation-related mRNA stability in macrophages -Suppression of migration, proliferation, and inflammation in VSCMs -Inhibition of proliferation and inflammation of endothelial cells	-	[112]
		Cultured human hepatoma cells	-Stimulated proteolytic processing of SREBP-2 -Upregulation of LDLR expression -Stimulation of LDL uptake	-	[115]
Inclacumab	1 infusion of placebo or inclacumab (5 or 20 mg/kg, administered between 1 and 24 h before PCI)	The Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non-ST-Segment Elevation Myocardial Infarction (SELECT-ACS) 544 patients	Patients receiving inclacumab 20 mg/kg with a short time interval between infusion and PCI: -placebo-adjusted geometric mean percent changes in troponin I, creatine kinase-myocardial band, and peak troponin I at 24 h were −45.6% (p = 0.005), −30.7% (p = 0.01), and −37.3% (p = 0.02), respectively Patients with a long time interval between infusion and PCI: no significant changes were observed in -Dose of 20 mg/kg significantly reduces myocardial damage after PCI in NSTEMI patients and benefits are greater when the infusion is administered <3 h before PCI	-	[145]
	Each dose level (0.03–20 mg/kg) investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo)	Randomized, double-blind placebo-controlled study 56 healthy subjects	-	Inclacumab was well tolerated Most common AEs: headache, cough, sore throat, and upper respiratory tract infection, one serious AE (rhabdomyolysis)	[142]