FormalPara Key Points

Statins remain the cornerstone for the primary and secondary prevention and cardiovascular events in patients with hypercholesterinaemia and hypertriglyceridemia.

Ezetimibe, alirocumab, evolocumab, icosapent ethyl and fenofibrate are second-line treatment alternatives as add-on treatment to statin or as monotherapy for statin-intolerant patients with dyslipidaemia.

Notable emerging lipid-lowering treatments include bempedoic acid, the siRNA PCSK9 inhibitor inclisiran, the ANGPTL3 inhibitor evinacumab, the MTP inhibitor lomitapide, the ApoB-100 inhibitor mipomersen and the ApoC-III degradation molecules volanesorsen and olezarsen, as well as the Lp(a) inhibitors pelcarsen and olpasiran.

1 Introduction

Cardiovascular diseases (CVD) are the leading cause of death worldwide [1]. In 2019, out of a total of 56.5 million deaths, 32.8% (18.6 million) were attributable to CVD—compared with 17.8% (10.1 million) deaths from neoplasms [2]. Among CVD, most deaths are attributable to ischemic heart diseases (16.2%, 9.1 million), strokes (11.6%, 6.6 million) and hypertensive heart diseases (2.0%, 1.2 million) [2].

Metabolic, behavioural, environmental and occupational risk factors adversely affect the incidence and progression of CVD [1, 3,4,5,6]. High systolic blood pressure, dietary risks and elevated low-density lipoprotein cholesterol (LDL-C) levels count among the top three cardiovascular risk factors; each attributable for 25.0%, 17.2%, and 11.0% of CVD deaths, respectively [2]. Despite the widespread availability of low-cost statins, the majority of patients with dyslipidaemia do not attain adequate LDL-C levels by existing lifestyle modifications and pharmacological treatment strategies [7,8,9,10,11]. The DA VINCI study found that out of 5888 patients with dyslipidaemia who were enrolled in 18 European countries, only 33% achieved their risk-based LDL-C goal recommended in the European Society of Cardiology (ESC) 2019 guidelines [12]. These results were consistent across European countries [13,14,15]. Accordingly, an Australian study of 61,407 patients reported that only 36% achieved their recommended LDL-C levels [16]. Similarly, Klimchak et al. use claims data from 44 million US inhabitants to estimate that only 36% of high-risk patients with atherosclerotic CVD attain the recommended LDL-C level of < 70 mg/dL [17]. There are several reasons why the majority of patients do not sufficiently reach LDL-C levels. First, ESC and AHA/ACC/multi-society guidelines have recently pursued more string LDL-C reductions according to the principle ‘the lower, the better’ [18,19,20] For example, the recommended LDL-C level for very high-risk patients has been lowered from < 70 to < 55 mg/mL. Second, patients may be reluctant to pursue lower LDL-C levels with lifestyle modifications and regular pharmaceutical therapy in absence of short-term consequences. Third, high prices for new treatments, such as PCSK9 inhibitors, have been identified as a barrier to swift coverage and reimbursement by insurers [21,22,23,24]. Finally, there may simply not be a sufficient number of add-on and alternative therapies to statins given that approximately 9.1% of patients are intolerant to statins [25].

As a consequence, multiple authors have concluded that there is a significant unmet medical need for patients with dyslipidaemia to reduce blood lipid levels to prevent the incidence of adverse cardiovascular events [26,27,28,29,30]. Therefore, in this article, we describe and review established and emerging lipid-lowering drugs regarding their molecular mechanism of action, effects on blood lipids, reduction of cardiovascular morbidity and mortality in primary and secondary prevention, and side effects.

2 Established Pharmaceutical Therapies

Available guidelines (ESC 2019 and AHA/ACC/multi-society 2018) entail a list of pharmaceutical interventions that may be used in patients with dyslipidaemia to lower blood lipids and ultimately the risk of adverse cardiovascular events [19, 20]. An overview of these drugs is provided in Fig. 1.

Fig. 1
figure 1

Established lipid-lowering therapies for cardiovascular prevention. LDL-C, TG and MACE reductions for ezetimibe, evolocumab, alirocumab, fibrates and icosapent ethyl are presented for combination therapy with statins. Data sources as referenced in the accompanying text passages. aThe presented MACE reduction for high-intensity statins refers to the incremental benefit relative to low-/medium-intensity statins. HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A, IV intravenous, LDL-C low-density lipoprotein cholesterol, MACE major adverse cardiovascular events, MoA mechanism of action, NPC1L1 Niemann-Pick C1-like 1 protein, PCSK9 proprotein convertase subtilisin-kexin type 9, PO perioral, PPAR-α peroxisome proliferator receptor alpha, RoA route of administration, SC subcutaneous, TG triglyceride

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For hypercholesterinaemia (Fig. 2), the ESC and AHA/ACC/multi-society guidelines recommend a risk-stratified treatment with statins, ezetimibe and PCSK9 inhibitors. Both guidelines recommend statins as the first-line therapy in primary and secondary prevention for patients with hypercholesterinaemia. Ezetimibe is recommended as the second-line treatment in patients who do not attain their LDL-C goal on maximum tolerated statin therapy by both guidelines for primary and secondary prevention. PCSK9 inhibitors are recommended by both guidelines for secondary cardiovascular prevention in very high-risk patients who do not reach their LDL-C goal with maximum tolerated statin therapy and ezetimibe. ESC guidelines further state that PCSK9 inhibitors may be considered for primary cardiovascular prevention in very high-risk patients who do not achieve their LDL-C goal with maximum tolerated statin therapy and ezetimibe. AHA/ACC/multi-society guidelines specify that treatment with PSCK9 inhibitors should include a physician–patient discussion about the net benefit and cost, given that PCSK9 inhibitors were found to be of low value. ESC guidelines further specify that ezetimibe and/or PSCK9 inhibitors should be considered in patients with hypercholesterinaemia who are intolerant to statins.

Fig. 2
figure 2

ESC and AHA/ACC guidelines for cholesterol-lowering treatments. We extracted recommendations for statins, ezetimibe and PCSK9 inhibitors in the treatment of patients with elevated plasma cholesterol from ESC 2019 and AHA/ACC/multi-society 2018 guidelines. For AHA/ACC/multi-society guidelines, the COR is categorized as class I (strong), class IIa (moderate), class IIb (weak), class III: no benefit (moderate) and class III: harm (strong). For ESC guidelines, the COR is categorized as class I (recommended) class IIa (should be considered), class IIb (may be considered) and class III (not recommended). For US guidelines, the LOE is categorized as level A (high-quality randomized evidence), level B-R (moderate-quality randomized evidence), level B-NR (moderate-quality non-randomized evidence), level C-LD (limited data) and level C-EO (expert opinion). For EU guidelines, the LOE is categorized as level A (data from multiple RCT or meta-analyses), level B (data from one RCT or large non-randomized trial) and level C (consensus expert opinion and/or small studies, retrospective studies, registries). ACC American College of Cardiology, AHA American Heart Association, ASCVD atherosclerotic cardiovascular disease, COR class (strength) of recommendation, CVD cardiovascular disease, ESC European Society of Cardiology, FH familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, LOE level (quality) of evidence, PCSK9 proprotein convertase subtilisin-kexin type 9, RCT randomized controlled trial

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For hypertriglyceridemia (Fig. 3), both guidelines recommend a risk-stratified treatment with statins, icosapent ethyl and/or fibrates. Statins are the first-line treatment for hypertriglyceridemia in both guidelines. Icosapent ethyl and fibrate are second-line treatments that should/may be considered in combination with a statin. ESC guidelines refer to triglyceride levels > 2.3 mmol/L (> 200 mg/dL) for icosapent ethyl and/or fibrates, whilst AHA/ACC/multi-society guidelines refer to triglyceride levels beyond > 5.6 mmol/L (> 500 mg/dL).

Fig. 3
figure 3

ESC and AHA/ACC guidelines for hypertriglyceridemia treatments. We extracted recommendations for statins, icosapent ethyl and fibrates in the treatment of hypertriglyceridemia from ESC 2019 and AHA/ACC/multi-society 2018 guidelines. For AHA/ACC/multi-society guidelines, the COR is categorized as class I (strong), class IIa (moderate), class IIb (weak), class III: no benefit (moderate) and class III: harm (strong). For ESC guidelines, the COR is categorized as class I (recommended) class IIa (should be considered), class IIb (may be considered) and class III (not recommended). For US guidelines, the LOE is categorized as level A (high-quality randomized evidence), level B-R (moderate-quality randomized evidence), level B-NR (moderate-quality non-randomized evidence), level C-LD (limited data) and level C-EO (expert opinion). For EU guidelines, the LOE is categorized as level A (data from multiple RCT or meta-analyses), level B (data from one RCT or large non-randomized trial) and level C (consensus expert opinion and/or small studies, retrospective studies, registries). ACC American College of Cardiology, AHA American Heart Association, ASCVD atherosclerotic cardiovascular disease, COR class (strength) of recommendation, CVD cardiovascular disease, ESC European Society of Cardiology, LDL-C low-density lipoprotein cholesterol, LOE level (quality) of evidence, RCT randomized-controlled trial, TG triglyceride

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In this section, we review the clinical trial evidence that supports these recommendations. Furthermore, we briefly summarize these lipid-lowering drugs’ mechanism of action, side effects and effects on blood lipids.

2.1 Statins

Statins reduce the internal synthesis of cholesterol by a competitive inhibition of the rate-limiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [19]. The reduced internal synthesis of cholesterol results in an increased surface expression of LDL-C receptors, which then increases the uptake of LDL-C. Ultimately, this results in lower serum LDL-C, ApoB-100 and triglyceride levels. Given the competitive inhibition of HMG-CoA, statins’ dose-dependent efficacy is used in clinical practice to escalate treatment from low-/medium-intensity to high-intensity statin treatment for at-risk patients. Low-/medium-intensity statins reduce LDL-C by − 30% to − 50% and triglycerides by − 20%, whilst high-intensity statins reduce LDL-C by more than − 50% and triglycerides by up to − 40% [19, 31]. Statins also elevate high-density lipoprotein cholesterol (HDL-C) in a dose-dependent manner by up to + 10% [32]. Studies reported no or only a minor increase in lipoprotein (a) (Lp(a)) levels among patients treated with statins [33, 34]. Beyond the modification of blood lipid levels, in vitro and in vivo studies showed that statins exert beneficial cardioprotective pleiotropic effects [35, 36]. These ‘include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques’ [35]. However, the significance of these pleiotropic effects in clinical practice remains debated [37].

Statins’ relevance in cardiovascular prevention is supported by multiple meta-analyses across several patient subgroups [38,39,40,41,42,43,44,45,46,47,48,49,50]. According to an analysis of 170,000 patients, a 38.67 mg/dl (1 mmol/l) reduction in LDL-C was associated with a − 22% (95% CI − 20 to − 24, p < 0.0001) decreased risk in major adverse cardiovascular events (MACE) [38], thereby confirming LDL-C as a valid surrogate parameter for the clinical endpoints MACE and cardiovascular death. Overall, low-/moderate-intensive statin therapy reduces the risk of MACE by − 22% (95% CI − 19 to − 24, p < 0.0001) [38]. Further intensifying statin therapy provides an additional MACE risk reduction of − 15% (95% CI − 11 to − 18, p < 0.0001) [38]. Results were consistent across primary and secondary prevention cohorts [40, 41, 48, 49, 51]. In patients with low risk of CVD (< 10% risk), statin therapy reduced the risk of major vascular events (RR 0.79, 95% CI 0.77–0.81 per 1.0 mmol/L reduction in LDL-C) irrespective of previous vascular diseases [40]. Statin therapy reduced the risk of all-cause mortality by 9% per 1.0 mmol/L LDL-C reduction.

The most clinically significant adverse effects of statin therapy are muscle-associated symptoms including myopathy (11 per 100,000 patient years) up to rhabdomyolysis (3 per 100,000 patient years) [52], an elevation of liver enzymes, hyperglycaemia [53], new onset of diabetes mellitus type 2 [54] and proteinuria. Evidence for an increased risk of haemorrhagic stroke remains inconclusive [38, 54, 55]. As statins are metabolized through the hepatic pathway, inhibitors and inducers of the cytochromes P450 (CYP) system, for example, anti-infectives, calcium antagonists, cyclosporine and grapefruit juice, may cause drug–drug interactions which impact their bioavailability; ultimately leading to the aggravation of side effects or a limited therapeutic efficacy. A recent meta-analysis of 176 studies with a total of 4.1 million patients found that 9.1% of patients are intolerant to statins [25]. Age, female gender, Asian and Black race, obesity, diabetes mellitus, hypothyroidism, chronic liver disease, renal failure, antiarrhythmic drugs, calcium channel blockers, alcohol consumption and higher statin dose were associated with a greater risk of statin intolerance [25].

Albeit statins are the first-line therapeutic option to lower blood lipids in patients with dyslipidaemia, for example, those with hypercholesterinaemia or hypertriglyceridemia, many patients’ blood lipids remain above the risk-stratified target levels defined by ESC guidelines. To reduce the risk of adverse cardiovascular events among these at-risk patients, new pharmacological treatment options have been developed over the past two decades. New treatments may be prescribed adjuvant to moderate-/high-intensity statins or as monotherapy for patients who are intolerant to statins.

2.2 Ezetimibe

Ezetimibe selectively inhibits the absorption of cholesterol in the small intestine [by interfering with the Niemann-Pick C1-like 1 protein (NPC1L1)] without modifying uptake of other nutrients and vitamins [56, 57]. A genetic sequencing study involving more than 90,000 patients found significantly lower LDL-C levels and a lower risk of coronary heart diseases among patients with NPC1L1 mutations [58] Compared with statin monotherapy, a combination of ezetimibe and statins reduces LDL-C by − 24%, ApoB-100 by − 14%, triglycerides by − 12% and high-sensitivity C-reactive protein (hsCRP) by − 13%, whilst maintaining HDL-C levels [59,60,61]. The randomized controlled double-blind Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) entailing 18,144 patients after acute coronary syndrome with a follow-up of 6 years found that ezetimibe added to simvastatin compared with simvastatin monotherapy significantly reduced the risk of MACE by − 6% (95% CI − 1 to − 11, p = 0.016). Although the earlier ENHANCE trial could not confirm that an addition of ezetimibe to statins significantly reduces intima-media thickness in patients with familial hypercholesterolemia, the SHARP and SEAS trials highlight ezetimibe’s role in the prevention of ischaemic cardiovascular events [62,63,64,65]. Ezetimibe’s safety and efficacy has been confirmed in multiple meta-analyses [61, 66,67,68,69,70].

The Japanese EWTOPIA 75 trial investigated ezetimibe as monotherapy for primary cardiovascular prevention in patients aged 75 years or older. A total of 3796 patients were randomly assigned to ezetimibe (10 mg daily) versus usual care. After a median follow-up of 4.1 years, ezetimibe reduced the incidence of MACE by − 34% (HR 0.66, 95% CI 0.50–0.86, p = 0.002) [71].

Compared with statin monotherapy, adjuvant ezetimibe was not found to increase the occurrence of side effects or treatment discontinuation.

2.3 PCSK9 Inhibitors

Evolocumab and alirocumab are monoclonal antibodies which inhibit the proprotein convertase subtilisin-kexin type 9 (PCSK9). These antibodies reduce the concentration of PCSK9 plasma levels, which results in an increased expression of LDL-C receptors and in turn reduced LDL-C levels. Consequently, genetic studies found significantly lower LDL-C levels and fewer cardiovascular events in patients with PCSK9 loss-of-function mutations compared with control [72,73,74]. Treatment with PCSK9 inhibitors reduces LDL-C by approximately − 60% [75,76,77,78,79]. PCSK9 inhibitors also lower triglycerides and Lp(a), whilst increasing ApoA-I. Coherent with the LDL-C reduction, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY) trials found that PCSK9 inhibitors significantly reduce the risk of MACE by − 15% in patients with prior acute cardiovascular syndrome. These double-blinded trials randomized 27,564 and 18,924 patients, respectively, to receive evolcoumab/alirocumab or placebo in addition to statins with a follow-up period of 2.2 and 2.8 years, respectively. The cardioprotective effects of PCSK9 inhibitors were subsequently confirmed in other clinical trials and meta-analyses [80,81,82,83,84,85].

Schmidt et al.’s meta-analysis of PCSK9 inhibitors includes trials with primary and secondary prevention cohorts [80]. Trials either include patients with established CVD or at high CVD risk. However, outcome data are infrequently reported for the primary and secondary prevention cohorts, separately. Data from the GLAGOV, ODYSSEY COMBO I and ODYSSEY LONG TERM trials show greater efficacy of PCSK9 inhibitors in patients with prior CVD (or myocardial infarction) in terms of LDL-C and percent atheroma volume [86,87,88].

Subcutaneous application of the monoclonal antibodies results in local injection site reactions. PCSK9 inhibitors were also discussed to induce the expression of auto-antibodies and increase the risk of diabetes mellitus [89, 90].

2.4 Fibrates

Fibrates, such as fenofibrate, bezafibrat and gemfibrozil, activate the peroxisome proliferator receptor alpha (PPAR-α) and thereby reduce blood lipid levels. Fibrates reduce concentrations of triglycerides by approximately − 50% and LDL-C by − 20% whilst increasing HDL-C by up to + 20% depending on the fibrate class [19]. Treatment with fibrates is associated with an increased risk of gastrointestinal pain, skin rashes, myopathy and liver enzyme elevation [19]. Evidence supporting the prescription of fibrates for cardiovascular prevention remains debated. The ACCORD, LEADER and VA-COOP trials could not confirm that fibrates reduce the incidence of MACE at a 5% significance level, whilst a significant MACE reduction was observed in the FIELD and VA-HIT trials [91,92,93,94]. A meta-analysis pooling outcomes from these trials found that fibrates significantly reduce the risk of MACE by −10% (95% CI − 0 to − 18, p = 0.048) [94, 95]. The same analysis also finds that fibrates reduce the incidence of coronary events, but not death. Consequently, fibrates’ role in cardiovascular prevention remains debated. ESC and AHA/ACC/multi-society guidelines recommend fibrates for patients with dyslipidaemia with elevated triglycerides despite statin treatment. However, their role in cardiovascular prevention and triglyceride reduction is projected to diminish following icosapent ethyl’s approval.

2.5 Omega-3 Fatty Acids

Since observational studies suggested high omega-3 fatty acid levels are associated with a lower risk of cardiovascular events and death, researchers evaluated these acids in randomized controlled trials (RCTs). Particular interest surrounded the ‘fish oils’ docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and most recently docosapentaenoic acid (DPA). Although several large-scale RCTs evaluated these omega-3 fatty acids, the public and scientific community remains puzzled about their differential outcomes. The STRENGTH, VITAL, ASCEND, ORIGIN, OMEGA, ALPHA-OMEGA, GISSI-HF and GISSI-P trials randomized patients to receive either a combination of EPA and DHA or placebo; yet only the GISSI trials noted a statistically significant effect on cardiovascular events and mortality [96,97,98,99,100,101,102,103]. In contrast, patients receiving only high-dose EPA in the REDUCE-IT and JELIS trials were at − 25% (95% CI − 17 to − 32, p < 0.001) and −19% (95% CI − 5 to − 31, p = 0.011) lower risk for MACE, respectively [104, 105].

These differential treatment effects could be subject to the administered omega-3 fatty acid, dosing regimen, comparator and studied patient population. In vitro and in vivo experimental studies highlight EPA’s and DHA’s distinct effects on inflammation, cellular membranes, platelets and triglycerides, which could result in the observed differential MACE outcomes [106, 107]. Albeit the exact MoA is unknown, scientists hypothesize that EPA exerts pleiotropic cardiovascular effects beyond lowering triglycerides: anti-inflammatory, anti-thrombotic, membrane stabilizing, plaque stabilizing, anti-arrhythmic and anti-hypertensive [105, 106, 108, 109]. Systematic reviews of the aforementioned studies with meta-analyses and meta-regressions show a dose-dependent association between omega-3 fatty acids’ titration and cardiovascular events [104, 106, 109,110,111]. The REDUCE-IT and JELIS trials randomized patients to receive 4 g and 1.8 g of highly purified EPA, whilst the EPA dosage was significantly lower in the other trials. Although there has been significant public debate surrounding the comparator used in the REDUCE-IT trial (mineral oil) [112, 113], experts in both regulatory agencies in the USA and the European Union (EU)—from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)—approved highly purified EPA, icosapent ethyl, for cardiovascular prevention in patients with dyslipidaemia. It is estimated that the inappropriate use of mineral oil as a comparator may have overestimated the MACE outcome by up to 3% [114]. The resulting net MACE reduction of − 22% then closely resembles the − 19% MACE reduction observed in the JELIS trial.

Notably, the REDUCE-IT trial enrolled 29% of patients without CVD (primary prevention) and 71% of patients with established CVD (secondary prevention) [105]. Subgroup analyses showed a non-significantly greater MACE reduction in the secondary prevention (HR 0.73, 95% CI 0.65–0.81) than the primary prevention cohort (HR 0.88, 95% CI 0.70–1.10, p = 0.14). A post hoc analysis of the REDUCE-IT trial confirmed icosapent ethyl’s efficacy among patients with prior myocardial infarction (MACE HR 0.74, 95% CI 0.65–0.85, p < 0.001) [115]. Similarly, the JELIS trial, which predominantly included patients without established CVD, demonstrated a consistent efficacy of EPA in the primary (HR 0.82, 95% CI 0.63–1.06, p = 0.132) and secondary prevention cohorts (HR 0.81, 95% CI 0.657–0.998, p = 0.048) [104]. Consequently, recent economic analyses found icosapent ethyl could be a cost-effective treatment, particularly for secondary cardiovascular prevention, in the USA, Germany, UK, Canada, Australia, and Japan [22, 23, 116,117,118,119,120,121].

Treatment with EPA was observed to be associated with a higher incidence of arterial fibrillation, serious bleeding events (e.g. haemorrhagic strokes) and peripheral oedema, but with a lower incidence of diarrhoea, gastrointestinal pain and anaemia than monotherapy with statins [105, 106]

2.6 Other Drugs

Several other pharmacological treatments are/were used to treat patients with dyslipidaemia, such as bile acid sequestrants and niacin. Bile acid sequestrants, such as cholestyramine, colesevelam and colestipol, bind to intestinal cholesterol and thereby inhibit its absorption in the small intestine, effectively removing it from the enterohepatic cholesterol circulation [19]. Although bile acid sequestrants are associated with a significant reduction in LDL-C and MACE, clinical trials supporting their efficacy were conducted before the introduction of statins, ezetimibe, PCSK9 inhibitors and icosapent ethyl [122]. In the EU, treatment with niacin was stopped after the AIM-HIGH and HPS2-THRIVE trials showed no improvement in MACE and an increased occurrence of undesirable side effects [123, 124].

3 Emerging Pharmaceutical Therapies

Recently, several novel pharmaceutical therapies with innovative MoA have been approved by the FDA and/or EMA to treat patients with dyslipidaemia [125], many of which are currently being investigated in cardiovascular outcome trials (CVOT). An even greater number of therapeutics are currently under clinical development. If successful, these novel pharmaceutical therapies could soon be approved and could transform the management of patients with dyslipidaemia. This section reviews these emerging pharmaceutical therapies regarding their MoA, first safety and efficacy results, and ongoing clinical trials (Fig. 4).

Fig. 4
figure 4

Emerging pharmaceutical therapies for the treatment of dyslipidemia. Drug types were categorized and illustrated as small molecules (capsule), antibodies (syringe) and gene therapeutics (double-stranded DNA helix). Data sources as referenced in the accompanying text passages. aThe drug class could not be identified for the compound NNC0385-0434 A. ANGPTL3 angiopoietin-like 3, ApoB-100 apolipoprotein B-100, ApoC-III apolipoprotein C-III, ATP adenosine triphosphate, CVOT cardiovascular outcome trial, FCS familial chylomicronemia syndrome, FDA US Food and Drug Administration approval, HeFH heterozygous familial hypercholesterolemia, HoFH homozygous familial hypercholesterolemia, HTG hypertriglyceridemia, IV intravenous, Lp(a) lipoprotein(a), MoA mechanism of action, MTG microsomal triglyceride transfer protein, P0 pre-clinic, P1 phase 1, P2 phase 2, P3 phase 3, PCSK9 proprotein convertase subtilisin-kexin type 9, PPAR-α peroxisome proliferator receptor alpha, PO perioral, RoA route of administration, SC subcutaneous, sHTG severe hypertriglyceridemia, siRNA small interfering ribonucleic acid

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3.1 Bempedoic Acid

Bempedoic acid inhibits adenosine triphosphate (ATP)-citrate lyase and thereby cholesterol biosynthesis [126]. The ATP-citrate lyase enzyme specifically catalyses the synthesis of Acetyl-CoA, which is an underlying substrate to synthesize HMG-CoA. Although both statins and bempedoic acid inhibit the cholesterol biosynthesis, bempedoic acid inhibits an enzyme that is located upstream of the HMG-CoA-reductase. Furthermore, bempedoic acid is a prodrug that is activated by the SLC27A2 enzyme which is not present in muscle cells. In contrast to statins, a lower incidence of myopathy, rhabdomyolysis or other muscle-related side effects were observed in patients receiving bempedoic acid [127]. The most common side effects are increased uric acid levels and gout [128]. Therefore, bempedoic acid has been an eagerly awaited pharmacological alternative to reduce LDL-C levels among statin-intolerant patients.

Bempedoic acid’s safety and efficacy in statin-intolerant patients has been evaluated across the family of phase 3 CLEAR trials: [127, 129,130,131]

  • The CLEAR Tranquillity trial evaluated bempedoic acid compared with placebo in 269 patients receiving ezetimibe as background therapy [132]. Relative to placebo, bempedoic acid reduced LDL-C by − 29%, non-HDL-C by − 24%, total cholesterol by − 18%, ApoB-100 by −19% and hsCRP by − 31%.

  • The CLEAR Serenity trial randomized 345 statin-intolerant patients with hypercholesterolemia to receive bempedoic acid or placebo [127]. Bempedoic acid lowered LDL-C by − 21%, non-HDL-C by − 18%, total cholesterol by − 15%, ApoB-100 by − 15% and hsCRP by − 24%.

  • The CLEAR Wisdom trial randomized 779 patients with atherosclerosis or heterozygous familial hypercholesterolemia (HeFH) to receive bempedoic acid or placebo [129]. Bempedoic acid reduced LDL-C by − 17%, non-HDL by − 13%, total cholesterol by − 11%, ApoB-100 by −13% and hsCRP by − 9% compared with placebo.

  • The CLEAR Harmony trial assessed bempedoic acid’s safety and efficacy in 2230 statin-treated patients with atherosclerosis or HeFH compared with placebo [130]. Relative to placebo, bempedoic acid reduced LDL-C by − 16%, non-HDL-C by − 13%, total cholesterol by − 11%, ApoB-100 by − 12% and hsCRP by − 22%. The incidence of adverse events was similar across both interventional groups, yet a higher percentage discounted treatment with bempedoic acid than placebo (10.9% versus 7.1%). Gout was more frequently observed among patients treated with bempedoic acid (1.2% versus 0.3%).

  • The CLEAR Outcomes trial randomized 13,970 patients with established or high risk for CVD, intolerance to statins, and LDL-C level ≥ 100 mg/dL to receive bempedoic acid (180 mg daily) or placebo [131]. Bempedoic acid reduced the risk of MACE by − 13% (HR 0.87, 95% CI 0.79–0.96, p = 0.004) and resulted in a − 21.1% greater reduction in LDL-C levels compared with placebo [133]. A higher frequency of gout (3.1% versus 2.1%) and cholelithiasis (2.2% versus 1.2%) was observed with bempedoic acid than with placebo [133].

On the basis of these clinical trials, bempedoic acid has been approved to lower LDL-C in patients with HeFH or established atherosclerotic cardiovascular disease by the FDA and for primary hypercholesterolemia or mixed dyslipidaemia by the EMA. Even though data for primary CVD prevention is missing, the International Lipid Expert Panel concludes that bempedoic acid’s ‘favourable effects on plasma glucose and inflammatory markers make this drug a rational choice in the patient-centred care of specific groups of primary prevention’ [134].

3.2 Inclisiran

Inclisiran is a small interfering ribonucleic acid (siRNA) inhibitor of the PCSK9 biosynthesis. Although the underlying MoA is similar to evolocumab and alirocumab, the novel siRNA technology permits an infrequent subcutaneous administration (initially 284 mg for two doses 3 months apart and 284 mg every 6 months thereafter) with potentially fewer injection site reactions and improved patient adherence. Inclisiran’s efficacy was and is evaluated across the family of ORION trials in patients receiving maximum tolerable statins and other lipid-lowering agents: [135,136,137,138,139]

  • The phase 3 ORION-10 and ORION-11 trials evaluated inclisiran compared with placebo across a total of 1561 and 1617 patients with atherosclerosis or an atherosclerotic CVD risk-equivalent, respectively [137]. Compared with placebo, inclisiran reduced LDL-C levels by − 52% and − 50%, respectively.

  • These results were confirmed in the phase 3 ORION-9 trial which showed a − 48% LDL-C reduction of inclisiran relative to placebo among 482 patients with HeFH [138].

  • The ORION-2 pilot trial showed inclisiran could also be effective for patients with homozygous familial hypercholesterinaemia (HoFH) [139]. On the basis of these results a phase 3 study involving 56 patients with HoFH has been initiated (ORION-5) [135].

  • Results of the ORION-9, ORION-10, and ORION-11 trials were consistent in pooled patient- and trial-level meta-analyses [140, 141]. Across all three trials, LDL-C reductions amounted to −51%. Except for injection site rejections, patients were not at an increased risk for any adverse events. In contrast to the other PCSK9 inhibitors, inclisiran does not induce the expression of auto-antibodies according to results from the ORION-1 trial [142].

Inclisiran has been approved to lower LDL-C in patients with HeFH or clinical atherosclerotic cardiovascular disease by the FDA and in patients with primary hypercholesterolemia or mixed dyslipidaemia by the EMA. The CVOT, enrolling a total of 15,000 participants (ORION-4), is expected to be completed by July 2026 [136].

3.3 Evinacumab

Evinacumab is a monoclonal antibody inhibiting angiopoietin-like 3 (ANGPTL3). ANGPTL3 inhibits the lipoprotein lipase, which results in increased blood lipid levels [143,144,145]. Consequently, ANGPTL3 loss-of-function mutations result in lower triglycerides, LDL-C and a − 41% decreased risk of coronary heart diseases, despite reduced HDL-C levels [146, 147]. In contrast to other pharmacological treatments, evinacumab’s MoA is therefore independent of the LDL-C receptor [143, 148], providing new options for more synergistic combination treatments.

After evinacumab’s proof of concept was established in a single-group phase 2 trial [149], the phase 3 ELIPSE trial was conducted [150]. In total, 65 patients with HoFH were randomized to evinacumab (15 mg per kilogram body weight intravenous) or placebo every 4 weeks. Evinacumab lowered LDL-C by − 49% compared with placebo without a significant increase in adverse events. Evinacumab also significantly reduced ApoB-100 by − 37%, non-HDL by − 52%, total cholesterol by − 48%, triglycerides by − 50%, and ApoC-III by − 90%. Another phase 2 trial studied evinacumab in 272 patients with refractory hypercholesterinaemia (either HeFH or established atherosclerosis). At a dose of 450 mg per week, evinacumab reduced LDL-C levels by − 56% compared with baseline [151].

Evinacumab has been approved by the FDA and EMA to lower LDL-C in patients aged 12 years and older with HoFH. Ongoing trials are evaluating evinacumab for paediatric patients with HoFH [152] and for patients with severe hypertriglyceridemia at high risk of pancreatitis [153], as well as its long-term safety and efficacy profile [154].

3.4 Lomitapide

Lomitapide lowers cholesterol by inhibiting the microsomal triglyceride transfer protein (MTG) [155, 156]. MTP facilitates the transfer and loading of triglycerides and phospholipids onto ApoB-100 in hepatic cells’ endoplasmic reticulum. Thereby, the assembly of very-low-density lipoprotein (VLDL) particles, which turn into LDL-C after release into the blood serum, is inhibited. After conducting a successful dose-escalation study [157], a single-arm, open-label, phase 3 study of 29 patients with HoFH showed that lomitapide lowers LDL-C by − 50% and reduces the frequency of lipid apheresis [158]. Due to the accumulation of lipids in hepatocytes, increased aminotransferase levels alongside gastrointestinal symptoms, which can be well managed by dose reductions or treatment suspensions, were noted in the clinical trial.

Lomitapide is approved for the treatment of HoFH adjunct to a low-fat diet and therapy with other lipid-lowering therapies by the FDA and the EMA. Lomitapide’s effect on CV outcomes has not been established. Lomitapide is currently evaluated in paediatric patients with HoFH, in pregnant patients, and a real-world evidence study [159,160,161].

3.5 Mipomersen

Mipomersen is an antisense oligonucleotide that is administered via a weekly subcutaneous injection, inhibiting the messenger ribonucleic acid (mRNA) of ApoB-100 [19, 162]. By inhibiting the synthesis of ApoB-100, mipomersen also inhibits the assembly and synthesis of VLDL, which in turn results in lower LDL-C serum concentrations. A systematic review and meta-analysis of 13 trials with a total of 1053 patients found mipomersen significantly reduces LDL-C, total cholesterol, non-HDL-C, ApoB-100, Lp(a), triglycerides, VLDL and ApoA-I without effecting HDL-C [163]. Treatment with mipomersen was frequently associated with injection site reactions, hepatic steatosis, elevated liver enzymes and flu-like symptoms [163].

Mipomersen is approved for HoFH adjunct to lipid-lowering therapies and diet by the FDA. However, the EMA refused to grant marketing authorization due to the frequent gastrointestinal and cardiovascular side effects observed in clinical trials that could outweigh mipomersen’s potential beneficial cardiovascular benefits. Mipomersen’s long-term safety and efficacy is currently under investigation [19].

3.6 Volanesorsen

Volanesorsen is a second-generation hepatocyte-directed antisense oligonucleotide that reduces mRNA levels of ApoC-III. ApoC-III serves as an independent risk marker for CVD due to its central role in lipid metabolism [164, 165]. High ApoC-III levels were shown to increase total triglyceride levels by an accumulation of VLDL and chylomicrons [166,167,168,169] In contrary, loss-of-function mutations of the ApoC-III are associated with a lower risk of CVD [170,171,172].

After a first proof-of-concept study [173], volanesorsen’s dose-dependent efficacy has been established in a phase 1 trial of three patients with familial chylomicronemia syndrome (FCS) and elevated triglycerides [174]. In a randomized, placebo-controlled, double-blind phase 2 trial of 57 patients with elevated triglycerides, volanesorsen reduced ApoC-III by up to − 80% and triglycerides by − 71% [175]. A similar trial design enrolling 114 patients with established CVD and elevated triglycerides demonstrated an up to − 60% reduction in triglyceride levels [176]. Consistently, volanesorsen reduced triglycerides by − 71% in a trial of 114 patients with severe hypertriglyceridemia or FCS [177]. However, between 24% and 61% of patients treated with volanesorsen suffered from injection site reactions. Further side effects include serious bleeding and thrombocytopenia. Volanesorsen was approved by the EMA but not the FDA due to safety concerns for the treatment of patients with FCS.

3.7 Pemafibrate

Pemafibrate is a fibrate that modulates PPAR-α [178]. In contrast to fenofibrate, pemafibrate is selective for PPAR-α and exerts a higher potency. On the basis of promising results from multiple phase 1, 2 and 3 trials [178], the double-blind, randomized, placebo-controlled trial PROMINENT investigated pemafibrate’s effect on MACE in 10,497 patients with diabetes mellitus type 2 and hypertriglyceridemia [179, 180]. At a median follow-up of 3.4 years, pemafibrate lowered triglycerides by − 26%, VLDL by − 26%, remnant cholesterol by − 26% and ApoC-III by − 28% compared with placebo. However, pemafibrate did not significantly reduce the risk of MACE (HR 1.03, 95% CI 0.91–1.15).

3.8 Pelacarsen

Pelacarsen is a second-generation hepatocyte-directed antisense oligonucleotide that lowers Lp(a) levels [181]. Lp(a) has been identified as an independent risk marker for CVD as it exerts pro-atherogenic, pro-inflammatory, and pro-thrombotic effects which may play a critical role in the pathogenesis of atherosclerosis [182]. Patients’ serum Lp(a) levels are primarily (> 90%) genetically determined by the apo(a) gene [183]. Consequently, genetic studies found a causal link between elevated Lp(a) levels and a higher risk for CVD diseases,[184,185,186,187,188,189] and vice versa [190]. However, the risk increase was of lower magnitude than the one observed with LDL-C [186, 191, 192]. In the FOURIER trial, greater MACE reductions were seen among patients whose highly elevated Lp(a) levels were reduced by evolocumab [193]. Two studies reported a significantly lower cardiovascular event rate in patients treated with lipid apheresis for Lp(a) [194, 195]. However, substantial reductions in Lp(a) levels are necessary to provide a clinically meaningful effect on cardiovascular outcomes [186, 196].

Pre-clinical studies confirmed the concept (proof of concept) that antisense oligonucleotides specifically lower Lp(a) levels [197, 198]. Subsequently, phase 1 and 2 trials enrolling a total of 103 patients with elevated Lp(a) and CVD showed that treatment with antisense oligonucleotides reduced Lp(a) levels by up to − 80% [199, 200]. Consistently, in a randomized, double-blind, placebo-controlled phase 2 trial of 286 patients with elevated Lp(a) levels and established CVD, pelacarsen reduced Lp(a) in a dose-dependent manner by up to − 80% from baseline [182]. At the same time, pelacarsen was well tolerated. Only injection site reactions were more frequently observed in the treatment group. HORIZON, the multi-centre CVOT investigating pelacarsen’s effect on MACE in 7680 patients, is currently ongoing and expected to be completed by 29 May 2025 [201].

3.9 DPA and EPA

A combination therapy of the omega-3 fatty acids EPA, DHA and DPA is currently in clinical development. According to the manufacturer Matinas Biopharma, their product MAT9001 contains a significant amount of EPA and DPA mixed with a small dose of DHA. After promising experimental studies and a clinical pharmacokinetic trial [202, 203], MAT9001 (4 g per day) was compared with icosapent ethyl (4 g per day) in a phase 2 head-to-head crossover trial enrolling 42 patients with hypertriglyceridemia [204] MAT9001 achieved significantly greater reductions in triglycerides (− 33% versus −11%, p < 0.001), VLDL-C (− 33% versus − 8%, p < 0.001), non-HDL-C (− 9% versus − 5%, p = 0.027), total cholesterol (− 9% versus − 6%, p = 0.0013), ApoC-III (− 26% versus − 5%, p = 0.006), ApoA-I (− 15% versus − 10%, p = 0.003) and PCSK9 (−12% versus +9%, p < 0.001), yet not ApoB-100 (− 4% versus − 1%, p = 0.058), HDL-C (− 11% versus − 11%, p = 0.337) and LDL-C (− 2% versus − 4%, p = 0.116). However, the ENHANCE-IT trial could not reproduce MAT9001’s superior efficacy to icosapent ethyl in patients undergoing a therapeutic lifestyle change diet [205]. No difference in triglyceride, LDL-C and other lipoprotein levels could be observed between the two interventional groups except for hsCRP (− 6% versus − 9%, p = 0.034). Although Matinas Biopharma planned to investigate MAT9001’s efficacy in a CVOT, active clinical development has been suspended in light of the ENHANCE-IT trial.

3.10 Olezarsen

Olezarsen is a next-generation ApoC-III hepatocyte-directed antisense oligonucleotide, which is conjugated with n-acetylgalactosamine. This novel molecular design resulted in an improved efficacy and safety profile compared with volanesorsen. In a phase 1/2a trial enrolling 40 healthy volunteers, olezarsen reduced ApoC-III by up to − 92% and triglycerides by − 77%, whilst only 1 participant (2.5%) suffered from an injection site reaction [206] Olezarsen is currently being investigated in five phase 2 and 3 trials for patients with (severe) hypertriglyceridemia and FCS [207,208,209,210,211].

3.11 NNC0385-0434 A

NNC0385-0434 A is the first oral PCSK9 inhibitor that is currently under phase 2 development in a trial of 255 patients with established CVD [212]. This novel route of administration is expected to improve adherence compared with PCSK9 inhibitors that are currently injected subcutaneously every 2–4 weeks.

3.12 Olpasiran

Olpasiran is a siRNA that reduces Lp(a) levels. In pre-clinical studies olpasiran successfully reduced Lp(a) levels in transgenic mice and cynomolgus monkeys [213]. In a phase 1 trial of 64 patients, olpasiran reduced Lp(a) by − 71% to − 97% [213]. A phase 2 dose-finding study of 281 patients with established CVD, OCEAN(a)-DOSE, is currently ongoing [214]. Topline results ‘demonstrated a significant reduction from baseline in Lp(a) of up to or greater than 90 percent at week 36 (primary endpoint) and week 48 (end of treatment period) for the majority of doses’ [215].

3.13 Other therapeutics

Beyond the presented clinical development programs, there are a variety of innovative small molecules, monoclonal antibodies, vaccines and gene therapies currently in pre-clinical development [216]

4 Conclusion

In this article, we reviewed the mechanism of action, targets, efficacy and safety of established and emerging lipid-lowering drugs. Emerging drugs could offer patients’ benefit in multiple regards. Bempedoic acid presents a viable alternative for statin-intolerant patients. Inclisiran could improve patient adherence to PCSK9 inhibitor therapy due to its semi-annual administration. Pelacarsen and olpasiran could be the first treatments that reduce the independent cardiovascular risk factor Lp(a). Evinacumab, lomitapide, mipomersen volanesorsen and olezarsen are new treatments that primarily affect aspects of the lipid metabolism other than LDL-C synthesis or triglycerides, and thereby present a first step towards patient-tailored treatment approaches in cardiovascular prevention.

Furthermore, this extensive review highlights that many new treatments are first developed by pharmaceutical companies to treat patients with rare genetic diseases, for example, FeFH, FoFH and FCS. Thereafter, these treatments are typically tested for patients with established cardiovascular diseases (secondary prevention), and then for patients with high-risk for cardiovascular diseases (primary prevention). Ultimately, new drugs must not only demonstrate efficacy in large, randomized, cardiovascular outcomes trials to improve patients’ morbidity and mortality, but also demonstrate cost-effectiveness to be swiftly adopted into clinical routines. The journey for emerging to established pharmaceutical treatments entails a lengthy and costly process of small and large clinical trials that is plagued by attrition. To overcome the unmet needs for patients with dyslipidaemia, we must not only find more targets and developed better treatments, but also improve clinical trial design and execution.

The authors are hopeful that the presented ‘new wave’ of lipid-modifying drugs with innovative treatment modalities will further reduce patients’ risk of adverse cardiovascular events. With this arsenal of new drugs, we will eventually be able to personalize lipid-lowering treatment according to patient-specific needs.