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.

Resolution of Extensive Xanthomas Associated With Severe Hypertriglyceridemia via Modified Therapeutic Plasma Exchange

“…If lifestyle modifications are insufficient, pharmacological interventions are contemplated, and fibrates are commonly chosen as the initial treatment due to their effectiveness in reducing TG levels by up to 50%; fenofibrate is the preferred choice in this case as gemfibrozil should not be combined with statin medications due to the risk of myopathy. Other effective medications include statin medications, niacin, bile acid sequestrants, and omega-3 fatty acids ( 1 , 2 , 8 , 9 ). By implementing lifestyle modifications and utilizing pharmacological interventions, eruptive xanthomas can exhibit a positive response within a few weeks.…”

Bioactive Compounds Formulated in Phytosomes Administered as Complementary Therapy for Metabolic Disorders

“…They target endogen cholesterol synthesis, by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway. Another class of drugs used for this purpose are Niemann-Pick C1-Like 1 (NPC1L1) inhibitors, such as ezetimibe, which inhibits the absorption of cholesterol in the intestine [143]. A novel class of lipid-lowering drugs that has emerged are monoclonal antibodies, such as evolocumab, an inhibitor for proprotein convertase subtilisin/kexin type 9 (PSCK9), a known ligand of LDL receptor (LDLR) [144].…”

The 10 essential questions regarding lipoprotein(a)

“…Significant alcohol intake has been associated with reductions in Lp(a) in some but not all studies. Nutraceuticals such as omega-3 fatty acids, plant sterols, soy and fibre do lower LDL cholesterol but generally have little influence on Lp(a) levels (all reviewed in [31]).…”