2023: The year in cardiovascular disease - the year of new and prospective lipid lowering therapies. Can we render dyslipidemia a rare disease by 2024?

Abstract

In 2023 there are still even 75% of patients over the target of low-density lipoprotein cholesterol (LDL-C), and hypercholesterolemia is the most common and the worst monitored cardiovascular risk factor. How it is possible, considering the knowledge we have on the role of cholesterol in the process of atherosclerosis, atherosclerotic cardiovascular disease (ASCVD) and its complications, on the methods of lipid disorders diagnosis, prevention, and treatment. Nowadays, almost 4 million deaths per year are attributed to LDL-C, and even 2/3 of all CVD deaths to ASCVD, therefore hypothetically we should easily prevent few to several million of deaths with early diagnosis, and early and intensive non-pharmacological and pharmacological therapies. Moreover, lipidology is now, besides oncology, the area with the highest number of new and ongoing trials with new effective and safe medications that have already appeared and will soon be available. Therefore, we have no doubt that year 2023 should be called the year of new and prospective lipid lowering therapies (LLTs). In this State-of-the-Art paper we summarized the most important trials, studies, and recommendations on the new and prospective LLTs, with suitable graphical summaries that might be helpful for the physicians in their practice with a look to the nearest future with prospective therapies being still under investigation. Let's hope all those medications helps to render dyslipidemia a rare disease in next few years.

Keywords: atherosclerotic cardiovascular disease; combination therapy; innovative therapies; lipid lowering therapies; lipids; polypills.

Figure 1

Basics of lipid-lowering treatment – method of management, impact on prognosis, safety, and biological mechanisms. Based on information from [, , , –18] CVD – cardiovascular disease, LLT – lipid-lowering treatment, CV – cardiovascular, ASCVD – atherosclerotic cardiovascular disease, SI – statin intolerance, OR – odds ratio, LDL-C – low density lipoprotein cholesterol.

Figure 2

Mechanism of action of lipid-lowering drugs (available and in clinical trials), major nutraceuticals and other therapeutic strategies Apo(a) – apolipoprotein (a), mRNA – messenger ribonucleic acid, ANGPTL3 – angiopoietin like protein 3, CRISPR-Cas9 – clustered regularly interspaced short palindromic repeats – caspase 9, ASGPR –asialoglycoprotein receptor, ApoC-III – apolipoprotein CIII, ApoB100 – apolipoprotein B100, PCSK9 – proprotein convertase subtilisin/kexin 9, VLDL – very low-density lipoprotein, LDL-R – low-density lipoprotein receptor, Lp(a) – lipoprotein (a), TG – triglycerides, MTP – microsomal triglyceride transfer protein, IDL-R – intermediate-density lipoprotein receptor (VLDL remnants), LDL – low-density lipoprotein, CETP – cholesterol ester transfer protein, HDL – high-density lipoprotein, ApoA-I – apolipoprotein A-I, LRP1 – low density lipoprotein receptor-related protein 1, LPL – lipoprotein lipase, HL – hepatic lipase, IDL – intermediate-density lipoprotein (VLDL remnants), ABCG5/8 – ATP binding cassette subfamily G member 5/8, acetyl-CoA – acetyl coenzyme A, FDC – fixed dose combination, HMG-CoA – β-hydroxy β-methylglutaryl-CoA, FA – fatty acid, NPC1L1 – Niemann-Pick C1-Like 1, ACSVL1 – very long-chain acyl-CoA synthetase, ChMR – chylomicron remnants, ChM – chylomicron, PPARa – peroxisome proliferator-activated receptor α, FFA – free fatty acid, ApoA-II – apolipoprotein A-II, DGAT – diglyceride acyltransferase, PPARg – peroxisome proliferator-activated receptor g, PPARd – peroxisome proliferator-activated receptor d, SC-A – scavenger receptor A, CD36 – cluster of differentiation 36, IsmA – intestinal sterol metabolism A. Modified and updated with permission based on: Surma S, Burchardt P, Banach M, Leki hipolipemizujące. In: Kardiologia - Podręcznik Polskiego Towarzystwa Kardiologicznego. Wydanie II, Via Medica 2023, Rycina 2.1.13.1, page 133.

Figure 3

Lipid-lowering treatment algorithm in patients with high or very high cardiovascular risk now and the possible prospective management, including drugs being under investigations ¹Pitavastatin is preferable in patients with risk factors of diabetes or with diabetes; 2IPE is still not available in most of the countries in Europe. *In patients with severe hypertriglyceridemia and/or familial chylomicronaemia syndrome (FCS). FDC – fixed dose combination, LLT – lipid lowering treatment, TGs – triglycerides, PCSK9m – proprotein convertase subtilisin/kexin 9 modulator.

Figure 4

Lipid-lowering combination therapy in very high cardiovascular risk patients now, and the possible prospective combinations, including drugs being under investigations (*for some of the presented combinations the suggested reduction is assumption based on the available data) ASCVD – atherosclerotic cardiovascular disease, ACS – acute coronary syndrome, PAD – peripheral artery disease, HeFH - heterozygous familial hypercholesterolemia, FDC – fixed dose combination, HIS – high intensity statin, EZE – ezetimibe, BA – bempedoic acid, OBICE – obicetrapib, PCSK9m – proprotein convertase subtilisin/kexin 9 modulator.

Figure 5

The suggested pathway of management with patients with elevated Lp(a) concentration. Based on Banach M. Eur Heart J Open 2023; 3: oead080 [76] with License Permission No. 5658420691033