The distinction between “good” and “bad” cholesterol is a thing of the past. The approach to lipid disorders is changing

Cardiovascular diseases that develop from atherosclerosis are the main cause of deaths across the world. Lipid metabolism disorders play a decisive role in the process of atherogenesis, i.e. the formation of atheroma in blood vessels.

Non-HDL cholesterol – cardiovascular risk predictor

The level of low-density lipoprotein (LDL) cholesterol is a key parameter in diagnosing hypercholesterolemia and monitoring the efficacy of its treatment. However, the development of atherosclerosis is also facilitated by lipoprotein(a) [Lp(a)], as well as by a group of triglyceride-rich lipoproteins. The composition of all atherogenic lipoproteins is reflected by the level of non-HDL cholesterol, which has proved to be a better predictor than LDL. That is why non-HDL cholesterol serves as a secondary treatment goal, and has been used for cardiovascular risk assessments since 2021, in the SCORE2 and SCORE2-OP scales.

Towards personalized medicine: apolipoprotein B 

An component shared by atherogenic lipoproteins is apolipoprotein B (apoB). Latest research shows that it is the evaluation of the amount of apoB molecules in the blood, rather than the composition, size, or type of lipoproteins, that may be the most precise way to evaluate cardiovascular risk. When looking at the levels of LDL cholesterol, non-HDL cholesterol, triglycerides, and apoB simultaneously, a significant relationship with the risk of cardiovascular events has only been demonstrated for the last molecule. The ranges of possible apoB levels that go with specific levels of LDL and non-HDL cholesterol as well as triglycerides are very broad, which supports the need for laboratory and clinical practice to include direct tests of the levels of apoB. 

A new item in the lipid panel: lipoprotein(a) 

Lp(a) has a similar structure to LDL, but apart from apoB, it also contains apolipoprotein(a) [apo(a)], whose size – which varies from person to person – determines how quickly it is synthesized. Elevated Lp(a) levels are an independent cardiovascular risk factor, which implies a predisposition for the development of atherosclerosis and the narrowing of the aortic valve. The current recommendation is for the level of Lp(a) to be checked at least once in a person’s lifetime. 

More research is needed to confirm the cause-and-effect relationship between Lp(a) and the risk of cardiovascular disease, to analyze the dependence between low Lp(a) level and diabetes, as well as to identify the potential non-genetic factors that determine the level and pathogenic character of Lp(a) – and the team at MUW’s 1st Chair and Department of Cardiology has been seeking answers to these and other questions.

Triglycerides – an important residual risk factor

Elevated triglyceride levels are a signal of the accumulation of very-low-density lipoproteins (VLDL), chylomicrons and their remnants. Hypertriglyceridemia, or the elevated levels of triglycerides in the blood, increases cardiovascular risk even for people with LDL cholesterol at target levels. VLDL particles have been shown to be more atherogenic than LDL, but they account for less than 10% of apoB present in the blood. The atherogenicity of remnants results from their higher cholesterol content and small size, which make it possible for them to cross the endothelium. The cholesterol in the remnants is related to the risk of ischemic heart disease and cardiovascular death, so it may soon be included in the lipid panel.

The myth of “good” HDL cholesterol

For years, the common belief has been that high levels of high-density lipoprotein (HDL) cholesterol prevent cardiovascular diseases. In fact, however, inflammatory processes that come with atherosclerotic disease reduce the ability for HDL to remove cholesterol from macrophages, which eliminates their protective qualities and makes them atherogenic. HDL cholesterol levels do not reflect the functionality or amount of HDL molecules, so at present it is neither a predictor of cardiovascular events nor a goal for therapy. A relationship with mortality has been observed for both low and high levels of HDL cholesterol. It has also been demonstrated that treatments that increase the level of HDL cholesterol and A1 apolipoprotein, i.e. the major protein component of HDL, do not reduce the incidence of cardiovascular events.

Treating hyperlipidemia – intensity matters

Hypercholesterolemia affects nearly 60% of Poles, yet only one in four people reach target levels for LDL cholesterol. The treatment is usually too gentle and introduced too late. Cardiovascular risk increases with the time when vessels are exposed to LDL. Yet it only drops by about 1% with each 1% drop in the level of LDL cholesterol. Lowering the level by 1 mmol/L (≈38.67 mg/dL) reduces the risk of cardiovascular events by 12% in the first year and up to 29% in the seventh year of treatment. Therefore, there are three rules of thumb in treating hypercholesterolemia: “the earlier the better”, “the lower the better”, and “the longer the better”. 

Early combination therapy – the key to success

High doses of atorvastatin and rosuvastatin lower LDL cholesterol levels by nearly 50%. Pitavastatin has been gaining significance, as it does not increase the risk of diabetes or higher Lp(a) levels. Contrary to bad fame, statin intolerance only affects 6–9% of patients, with up to 70–90% of the side effects explained by the nocebo and drucebo effects. Statins remain the golden standard in treatment. However, when compared to monotherapy, combining high doses of statins with ezetimibe ensures a greater reduction in LDL cholesterol levels, the risk of death, and cardiovascular events. Combination therapy in the form of a complex tablet, introduced immediately, should be the first choice for patients with high and very high cardiovascular risk. 

Further escalation, especially if the patient does not tolerate statins, is possible with bempedoic acid. Including a third agent, PCSK9 inhibitor, decreases LDL cholesterol levels by up to 85%. Alirocumab, evolocumab, and inclisiran are available in Poland as part of the B101 drug program, open to patients of the MUW University Clinical Center with familial hypercholesterolemia or very high cardiovascular risk. The armamentarium may soon be expanded to include oral PCSK9 inhibitors, as well as lerodalcibep – a protein that binds PCSK9, and obicetrapib – an inhibitor of the protein that transports cholesterol esters between HDL, LDL, and triglyceride-rich lipoproteins.

Hope in the fight against lipoprotein(a)

Lifestyle changes and available drug interventions do not significantly affect the levels of Lp(a). That is why the current treatment mainly focuses on optimizing other cardiovascular risk factors. Dedicated therapies that inhibit the synthesis of apo(a) by interfering with mRNA may lower Lp(a) levels by up to 90%. Phase III studies currently underway have been testing pelacarsen, an antisense oligonucleotide, as well as olpasiran and lepodisiran, small interfering RNA. The safety and efficacy has also been demonstrated in phase II clinical trials for zerlasiran, and for muvalaplin – an orally administered small molecule that blocks the interaction between apoB and apo(a).

Current goals in treating hypertriglyceridemia

Statins are only moderately efficient in reducing triglyceride levels, and the impact of fibrates and omega-3 acids on cardiovascular risk remains unclear. A new goal in treating hypertriglyceridemia has been to inhibit the synthesis of apolipoprotein C-III (apoC-III) and angiopoietin-like protein 3 (ANTPTL3), i.e. natural inhibitors of lipoprotein lipase, which is responsible for the katabolism of triglyceride-rich lipoproteins. The latest apoC-III inhibitors, i.e. olezarsen and plozasiran, are used in severe hypertriglyceridemia, including genetically-conditioned familial chylomicronemia. Next, zodasiran, an ANGPTL3 inhibitor, has been demonstrated in a Phase II trial to reduce the levels of atherogenic lipoproteins in patients with mixed hyperlipidemia. 

Lipidology – from theory to everyday practice

Modern lipidology involves precise diagnostic tools, efficient treatment regimes, and novel therapies. Systemic solutions – such as including the lipid panel in check-ups for 6-year-olds – are intended to facilitate the early diagnosis of dyslipidemia, including familial hypercholesterolemia. Translating scientific evidence into clinical practice is facilitated by interdisciplinary guidelines developed under the direction of the Polish Society for Lipidology, which includes representatives of the MUW. Personalized combination therapy allows for controlling lipid metabolism disorders, prevent cardiovascular events, and prolong patients’ lives. Education is of key importance, so that intensive treatment of hypercholesterolemia is seen not as a threat but as an opportunity.

Jakub Zimodro is a fifth-year student of medicine and a doctoral student at the 1st Chair and Department of Cardiology at the Medical University of Warsaw. Member of the Young Lipidologists Section of the Polish Society for Lipidology. In his doctoral dissertation, he mainly focuses on the role of lipoprotein(a) in acute coronary syndromes. His academic research has earned him a scholarship of the Minister of Health, and an award from the MUW Rector. He has gained clinical and research experience abroad, including at the University Hospital in Cologne, and at the Berlin-based Charité.