Mipomersen is a second-generation drug designed to reduce the levels of LDL-C by inhibiting the synthesis of apolipoprotein B-100 (apoB). The U.S. Food and Drug Administration has approved mipomersen as third-line therapy for patients with homozygous familial hypercholesterolemia (HoFH) ^[1][2][33,34]. It functions as an antisense oligonucleotide, binding complementarily to human apo-B 100 messenger RNA (mRNA) ^[3][35]. This binding triggers the recruitment of a specific catalytic enzyme (Rnase H1), leading to the degradation of the apo-B RNA complex ^[4][36]. By reducing the cytoplasmic apo-B 100 mRNA concentration, mipomersen plays a role in lowering the final production of LDL-C.

Administered subcutaneously once a week in a preformulated syringe with 200 mg/mL, mipomersen exhibits good absorption and distribution throughout the human body. It undergoes metabolism not by cytochrome P450 in the liver but by endonucleases in the tissues, with its metabolites ultimately eliminated in the urine. Common adverse events include injection-site reactions (erythema, pruritus, pain), and a flu-like syndrome is reported in about 30% of cases. Clinical trials have indicated the potential for hepatotoxicity; thus, constant monitoring of serum alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin, and alkaline phosphatase is crucial during treatment ^[5][6][37,38]. Mipomersen should be discontinued if hepatic cytolysis index levels exceed three times the normal range in the serum or if liver toxicity becomes clinically significant ^[7][39]. Contraindications for mipomersen include hypersensitivity/allergic reactions and moderate or severe hepatic impairment (Child–Pugh B or C). In patients with HF and affected by documented atherosclerotic cardiovascular disease (ASCVD), mipomersen significantly reduced apolipoprotein B by 26.3%, total cholesterol by 19.4%, and lipoprotein(a) by 21.1% compared to the placebo (all p < 0.001). These reductions contribute to the improvement of atherosclerotic disease ^[8][40].

Lomitapide is a novel drug designed to lower the cholesterol concentration in the blood. It is indicated for the treatment of patients with HoFH who have an inadequate response to PCSK9 inhibitors. Additionally, it is prescribed for patients with ASCVD whose LDL-C levels exceed 190 mg/dL and do not respond to statin treatment. It has proven effective in reducing cholesterol levels in patients with HoHF, showing reductions in LDL-C and apoB of up to 51% and 56%, respectively. However, there is still a lack of evidence regarding the overall improvement in survival in patients with ASCVD ^{[9][10][11][12][13][14]}[41,42,43,44,45,46]. In contrast to the three main classes of cholesterol-lowering drugs (statins, ezetimibe, and bile acid sequestrants), lomitapide acts independently of the expression of LDLR. It achieves this by inhibiting the microsomal triglyceride transfer protein (MTP) in the endoplasmic reticulum lumen, effectively binding to and deactivating MTP. MTP is crucial in cholesterol synthesis as it transports lipid molecules (triglycerides, phospholipids, and cholesterol esters) to apoB-lipoproteins in the endoplasmic reticulum, facilitating the formation of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and chylomicrons ^[15][47].

Lomitapide is taken orally on an empty stomach, preferably at least 2 h after meals to mitigate the risk of gastrointestinal side effects. The initial dose is 5 mg per day, gradually increasing over 2–4 weeks to a maximum dose of 60 mg per day if well tolerated. The primary side effects include nausea, vomiting, diarrhea, abdominal pain, and potential liver toxicity. While lomitapide may elevate transaminases, clinically significant elevations in alkaline phosphatase, total bilirubin, or the international normalized ratio (INR) are rare ^[16][17][48,49]. Monitoring liver and renal function tests before initiating treatment and at least monthly during the first year is recommended. Contraindications include pregnancy, liver impairment (Child–Pugh B or C) or unknown increased levels of transaminases ^[18][50], and hypersensitivity to the active principle.

Inclisiran, a novel drug approved for hypercholesterolemia treatment, acts by inhibiting PCSK9 protein translation in hepatocytes ^[19][51]. PCSK9, produced in the liver, is involved in the degradation process of LDL-R on the cell membrane. Inclisiran, a small interfering ribonucleic acid molecule (siRNA), interacts with the RNA-induced silencing complex (RISC), cleaving PCSK9 mRNA, preventing translation of the target protein ^[20][52]. The reduction in PCSK9 increases LDL-R availability on the membrane, leading to a greater uptake of circulating LDL and a reduction in serum LDL-C.

The regimen, based on the ORION-1 study’s results, involves administering a dose of 284 mg with one subcutaneous injection on day 1, another on day 90, and then one administration every 6 months ^[21][53]. The results from the ORION-1 study with a 300 mg dose showed an average reduction of 52.6% (48% to 71%) in LDL-C levels at day 180, with a mean reduction of 47.2% at day 240 after receiving the two doses. In these studies, a reduction in PCSK9 levels by an average of 69.1 ± 12.1% at day 180 and at day 240 of 40% was observed. A one-year follow-up of the ORION-1 participants showed an LDL-C reduction of 31.4% at 360 days, signifying a sustained but waning effect over time ^[22][54].

The inclisiran phase 3 trials, particularly ORION-9, evaluated the efficacy of inclisiran in patients with HoFH already treated with the maximum dose of statin and ezetimibe with a baseline level of LDL-C more than 100 mg/dL; it showed an average reduction of 47.9% (95% CI −53% to −42.73 p ˂ 0.001) compared to a placebo ^[23][55]. ORION-10 and -11 evaluated the efficacy of inclisiran in patients with ASCVD or ASCVD equivalent risk and LDL levels of more than 70 mg/dL; in t his study, it was seen how inclisiran is able to lead to an average reduction of 52.3% (−52.3% (95% CI −55.7 to −48.8%; p < 0.001), thus proving effective in improving ASCVD ^[24][56].

Regarding the impact of inclisiran in cardiovascular outcomes trials, the results are still ongoing; however, a recently published pooled patient-level analysis of ORION-9, -10, and -11 showed that the occurrence episodes of major adverse cardiovascular events (MACE) (131 vs. 172 events; hazard ratio (HR) 0.75, 95% CI 0.60–0.94), fatal/non-fatal MI (33 vs. 41 events; HR 0.81, 95% CI 0.51–1.29), and fatal/non-fatal stroke (13 vs. 15 events; HR 0.80, 95% CI 0.39–1.67) were all lower in the group of patients treated with inclisiran ^[25][57]. This is indicated in the treatment of hypercholesterolemia in patients with HeFH or ASCVD already treated with the maximum dose of statins and ezetimibe that require further lowering of LDL-C ^[26][58]. Off-label, it could be useful also in patients with contraindication or intolerance to statin treatment.

Safety and side-effects were evaluated in all of these three clinical trials; the most common side effects are injection site reactions (5% in the inclisiran vs. 0.7% in the placebo group; risk ratio 7.54), bronchitis (4.3% for inclisiran vs. 2.7% placebo; risk ratio 1.55), hypertension (5.7% for inclisiran vs. 5.7% for placebo), arthralgia (5.0% for inclisiran vs. 4.0% for placebo), back pain (4.5% for inclisiran vs. 4.2% for placebo), urinary tract infection (4.4% for inclisiran vs. 3.6% for placebo), and an increase in serum creatine phosphokinase (2.3% in inclisiran vs. 3.2% in placebo) ^[27][59]. Longer-term information about safety and tolerability is not currently available; however, recently published data from the ORION-4 study showed good results ^[28][60]. The safety data of inclisiran in patients with CKD, severe hepatic dysfunctions, and pregnancy are not yet available; however, data suggest that it could be considered safe in patients with CKD ^[29][61].

The need for increasingly stringent targets in controlling LDL-C values for preventing cardiovascular risk, coupled with the not-very-strict adherence to statin treatment ^[30][62], has spurred growing interest in developing new oral drugs for cholesterol therapy. Bempedoic acid (formerly ETC1002), a long-chain tetramethyl-substituted keto diacid, is a molecule first studied in 2003 that belongs to the family of so-called “fraudulent fatty acids”, along with fibrates, ω-3 fatty acids, and pantethine ^[31][63]. This acid inhibits ATP citrate lyase (ACLY), a cytosolic enzyme involved in lipid and glycide metabolism and synthesis. Specifically, ACLY plays a role in the complex reaction transforming citrate into acetyl-coA, a fundamental precursor for HMG-coA synthesis, an essential substrate for cholesterol production ^[32][64]. Blocking this enzyme increases LDL-R on the membrane, resulting in reduced circulating LDL, lipid reduction, decreased hepatic steatosis, and increased weight loss ^[33][34][65,66].

Bempedoic acid exhibits good absorption after oral administration, with excellent gastrointestinal tolerability and bioavailability. It is strongly bound to plasma proteins, possesses a half-life of about 21 h, and is primarily metabolized by the liver through hepatic glucuronidation ^[35][67]. Metabolism by cytochrome P-450 is minimal, avoiding significant drug interactions and allowing administration in patients with mild–moderate renal impairment ^[36][68]. Currently available commercially in 180 mg tablets ^[37][69], it is also available in a fixed combination with 10 mg of ezetimibe ^[38][70]. Indications include treating adult patients with hypercholesterolemia (familial and non-familial) and mixed dyslipidemia in addition to statins if the target is unattainable with the maximum tolerated dose of statins and ezetimibe or when statins are not tolerated or contraindicated.

The tolerability and safety profile were addressed naïvely the CLEAR program, comprising four phase 3 trials: (1) CLEAR Tranquility (in statin-intolerant patients) ^[39][71]; (2) CLEAR Harmony (patients with LDL-C ≥ 70 mg/dL despite maximally tolerated statin therapy) ^[40][72]; (3) CLEAR Wisdom (patients with ASCVD, HeFH, or both, on optimal statin treatment) ^[41][73]; and (4) CLEAR Serenity (statin-intolerant patients with ASCVD and inadequately controlled LDL-C) ^[42][74]. Despite the excellent results of bempedoic acid in the CLEAR studies in terms of LDL-C reduction (18% in combination with statin and 24% when administered in patients intolerant to statins or contraindicated) ^[43][75], a challenge arises from the reported meta-analyses, as the trials lasted a maximum of 52 weeks ^[44][76]. An open-label extension emerged to extend the drug evaluation period.

Regarding adverse reactions, bempedoic acid proves to be a safe drug. Notably, significant hepatic or muscular cytolysis occurs in only 2.8% compared with a placebo. Compared to statins, muscle damage is minimal because the enzyme it acts upon is predominantly concentrated in hepatocytes rather than muscle cells ^[43][75]. Severe complications, such as Achilles tendon rupture, have only been observed in patients with other associated risk factors ^[45][77]. The sole drug-related adverse effect is increased uric acid (mean rise is 0.7 mg/dL, 95% CI, 0.5–0.9 mg/dL) with a higher rate of gout flare (OR = 3.2; 95% CI, 0.12–8.2), primarily due to renal organic anion transporter 2 inhibition ^[46][78]. Therefore, evaluating uric acid before treatment and monitoring during treatment is recommended ^[47][79].

Pelacarsen is a new type of antisense oligonucleotide drug involved in reducing the level of Lp(a) by inhibiting the translation of mRNA of the Lp(a) gene in hepatocytes ^[48][80]. Lp(a), a lipoprotein similar to LDL in which ApoB is linked to Apo(a) ^[49][50][81,82], appears to be involved in the development of ASCVD. Although there is not yet a precise analysis of the role of Lp(a) in ASCVD due to a lack of FDA-approved pharmacological therapies, it should be considered an independent risk factor with values in the blood above 30 mg/dL to 50 mg/dL ^{[51][52][53][54][55]}[83,84,85,86,87]. Lp(a) seems to exert this negative action in the development of atherosclerotic disease through three different ways: firstly, it carries out proinflammatory activity due to its high content of oxidized phospholipids; then, it has a prothrombotic effect due to the plasminogen-like protease domain on Apo(a), with a possible role also as an antifibrinolytic agent; finally, it has proatherogenic activity for the LDL-like moiety ^[56][57][88,89].

The first randomized trial to evaluate the use of a specific drug that acts on reducing Lp(a) levels was the IONIS-APO(a)Rx phase 2 trial. This has shown that this new drug is able to reduce Lp(a) levels by between 67% and 72%; moreover, a simultaneous reduction was also noted in the overall levels of LDL-C, Apo(a), and ApoB, which finally leads to a reduction in the inflammatory activity of monocytes associated with oxidized phospholipids. The IONIS-APO[a]-LRX phase ½a trial showed how the conjugation of IONIS-APO(a)Rx with the GalNAc3 complex, mediating hepatocyte delivery via asialoglycoprotein ^[41][73], improves the potency of the drug by about 30 times, with an average reduction in Lp(a) blood levels of about 92.4%, also reducing the dose and without particular side effects. The AKCEA-APO(a)-LRx phase 2 trial, in which 286 patients with cardiovascular maladaptive disease and Lp(a) levels greater than 60 mg/dL were recruited, showed a dose-dependent reduction in patients treated with APO(a)-LRx compared to a placebo ^[56][88]. In particular, it has been seen how a dose of 20 mg per week is able to lead to an average reduction in Lp(a) blood levels of about 92% in the absence of serious adverse reactions such as flu-like syndrome, liver impairment, kidney damage, or thrombocytopenia. Finally, Lp(a) HORIZON, a phase 3 randomized controlled trial that started in 2019 and will probably end in 2024, aims to study the occurrence of major cardiovascular events as the primary outcome in a cohort of 8323 patients with blood levels of LPA greater than 70 mg/dl and randomly treated with pelacarsen or a placebo.