Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention

Abstract

Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.

Fig. 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

Fig. 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

Fig. 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

Fig. 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