Reducing atherosclerotic cardiovascular disease risk: A focus on lipid lowering drugs
In the ensuing piece, l will be using lots of materials from Wilkinson et al. Evolving Management of Low-Density Lipoprotein Cholesterol: A Personalised Approach to Preventing Atherosclerotic Cardiovascular Disease Across the Risk Continuum. J. Am. Heart Assoc 2023.
Cardiovascular disease (CVD) is a leading cause of death globally. In 2020, CVD resulted in about 19 million deaths, an increase of 18.7 per cent over 10 years. More than 80 per cent of these deaths were attributable to atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) is a major causal factor in the pathophysiology of atherosclerotic cardiovascular disease (ASCVD). Elevated LDL-C is a key modifiable risk factor contributing to CVD burden. There is a linear relationship between LDL-C levels and the risk of ASCVD. Management of LDL-C levels is central to ASCVD prevention strategies.
Several studies have shown that it is not only the magnitude of LDL-C elevation but also the duration of exposure to elevated LDL-C that is associated with ASCVD risk. This makes the timing of implementing strategies to decrease lipid levels key to slowing the progression of atherosclerotic plaques and reduction of risk of ASCVD events. Persons who maintain lifetime exposure to low plasma levels of LDL-C have low lifetime risk of ASCVD. It means that making lifetime choices of low exposure to LDL-C translates into significant reduction in the risk CV events. Furthermore where pharmacotherapy is clearly indicated the use is less.
Even for persons who are given lipid-lowering therapies the management is suboptimal with many not receiving appropriate treatment intensity or available combination therapies needed to achieve LDL-C goals. Another study of about 1.5 million patients with a history of >1 major ASCVD event reported that >50% of patients meeting the 2018 American Heart Association (AHA) American College of Cardiology (ACC) guideline very high-, risk criteria had LDL-C levels >1.8mmol/L despite receiving statins and/or ezetimibe. In the GOULD (Getting to an improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidaemia Management) registry over a 2-year period, two-thirds of patients with ASCVD remained with LDL-C levels above 1.8mmol/L and only 17% received treatment intensification.
![IT must be one of the most difficult – and exasperating – tasks in the world to be the President of a nation like Ghana. For you may travel all over4 the world, talking to the leaders of “the developed nations”, to try persuade them that the pandemic that is afflicting the world, Covid-19 (with its variants) is a truly global destroyer and thatnowhere is safe from it, until everywhere is safe. You may deploy your most eloquent language to point out that although, the scientists of the “developed countries” have managed to manufacture a vaccine that has been seen to work against the pandemic, the politicians of the “developed countries” are, contrary to undertakings they have made to the World Health Organisation (WHO) hoarding the vaccine in their countries. Reports suggest that whereas the governments of the “developed countries” are targeting 100 percent of their populace for vaccination, and getting closer to their objective every day, less than 10% of the populace of the developing countries have so far been vaccinated, as a result of a lack of vaccines. Is this fair? you ask. Air travel (you continue) has made international contacts extremely easy. And since the Covid-19 virus and its latest variant (Omicron) in particOman Ghana versus Covid-19 08 www.ghanaiantimes.com.gh GHANAIAN Times Features TUESDAY, DECEMBER 21, 2021ular, are very transmissible. So it is in everyone's educated self-interest to see that all people on the planet are fully vaccinated. As a result of your Government's efforts, you hear that plenty of vaccines have arrived in your country and you are emboldened to announce that your Government will soon be able to vaccinate its entire adult population. Then, you get the shock of your life: an intelligence report tells you that some mischievous people are spreading the fake news that if a person allows himself or herself to be vaccinated, the “vaccine will make that person vote for your governing NPP whether he/she wants to do so or not!” WHAAAAT! How does one counter such fake news? If the Government say it is not true, the conspiracy theorists shoot back, “And are you so naïve as to expect them to admit that the vaccine will make you vote for the NPP?” Wow! Are people so wicked that despite the gains that the world has already made through vaccination (such as the elimination of small pox from the world and the near-extinction of polio and yellow fever) they try to dissuade others from taking advantage of anti-Covid vaccination? Especially since people who are clever enough to invent such fake news must know of the horrible pain that Covid-19 subjects people to, before it finally kills them? What makes the anti-Covid vaccination story doubly awful is that its seeds are sown on pre-fertilised ground. In the past, some wicked scientists in the developed countries have allowed themselves to be used by their [usually racist] governments to administer harmful vaccines and other medications to people, using the lie that such interventions can save them from certain disease. One of the most devastating such deceptions occurred in the United States in 1932. Below is the horrible story as told on the OFFICIAL website of the US CENTRES FOR DISEASE CONTROL [CDC]: https://www.cdc.gov/tuskegee/timeline.htm QUOTE: THE U.S. PUBLIC HEALTH SERVICE SYPHILIS STUDY AT TUSKEGEE In 1932, the USPHS, [US Public Health Service] working with the Tuskegee Institute, began a study to record the natural history of syphillis. It was originally called the “Tuskegee Study of Untreated Syphillis in the Negro Male” (sic) [now referred to as the “USPHS Syphilis Study at Tuskegee”]. The study initially involved 600 Black men — 399 with syphillis, 201 who did not have the disease. Participants’ informed consent was not collected. Researchers told the men they were being treated for “bad blood,” a local term used to describe several ailments, including syphillis, anaemia, and fatigue. In exchange for taking part in the study, the men received free medical exams, free meals, and burial insurance (sic)! By 1943, penicillin was the treatment of choice for syphilis and becoming widely available, but the participants in the study were not offered treatment. In 1972, an Associated Press story about the study was published. As a result, the Assistant Secretary for Health and Scientific Affairs appointed an Ad Hoc Advisory Panel to review the study. The advisory panel concluded that the study was “ethically unjustified”; that is, the “results [were] disproportionately meagre, compared with known risks to [the] human subjects involved.” In March 1973, the panel advised the Secretary of the Department of Health, Education, and Welfare to instruct the USPHS to provide all necessary medical care for the survivors of the study. The Tuskegee Health Benefit Programme was established to provide these services and in 1975, participants’ wives, widows and children were added to the program. In 1995, the program was expanded to include health, as well as medical, benefits. The last study participant died in January 2004. The last widow receiving THBP benefits died in January 2009. ... I973, a class-action lawsuit was filed on behalf of the study participants and their families, resulting in a $10 million, out-of-court settlement in 1974. On May 16, 1997, President Bill Clinton issued a formal Presidential Apology [over the study.] UNQUOTE In Ghana, the fake news that the anti-Covid vaccine would make people “vote for the NPP” has already begun to cause disagreements in some households. A family known to me has had to dismiss its house-help because she obstinately refused to take the jab. To illustrate the way the way the political message contained in the fake news has been camouflaged, I offer a version of the last conversation between the head of the household and the house-help: BOSS: Hey, “A”, you are very lucky! Instead of you going around to look for the vaccinators, they are coming to our estate! HOUSE-HELP: They are coming here? B: Yes! H: But Boss, I told you that my brother took the jab and had to be admitted into hospital. B: It doesn't mean that you too will become ill if you get the jab. It affects different people in different ways. Look, as you know, I have had all my own jabs and I have never been ill – as you know! H: But Boss, if you have taken all your jabs, then you are PROTECTED, are you not? B: Yes, I am. H: In that case, even if I become infected because I have not taken the jab, I cannot transmit the disease to you and YOU will be all right? B: I can't say that! Because, as I have explained to you, the pandemic can affect different people in different ways. H: Then the jab is useless? B: Listen, I can't take any risks with such a dangerous disease. Either you take it or you leave, I am sorry. I cannot allow you to expose me and my family to the risk of catching Covid. As I reported earlier, the House-help chose to leave. Both her Boss and I are convinced that it wasn't mere logicthat made her decide not to take the jab. She was probably under the influence of a church/cult. Or political propaganda! • Omicron cases at Kotoka International Airport are amongst the unvaccinated](https://ghanaiantimes.com.gh/wp-content/uploads/2021/12/GT-8.pdf-Adobe-Acrobat-Pro-DC-4-220x150.jpg)
Pooled analyses of lipid-lowering therapies have shown a linear association between achieved LDL-C levels and absolute coronary heart disease event rates. Every 1.0-mmol/L reduction in LDL-C confers about 22% reduction in the risk of major vascular events.
There are several barriers to the use of lipid-lowering therapy. These include poor patient adherence, lack of health professional familiarity, uncertainty about treatment recommendations, time constraints, clinical inertia, and cost issues, others are inadequate patient education, and adverse effects.
Lipid lowering with statin therapy (e. g. Atorvastatin, Rosuvastatin) has been the cornerstone of the prevention and treatment of ASCVD for several years. High-intensity statins can reduce LDL-C levels by >50% with a consequent significant risk reduction of major ASCVD events. The magnitude of LDL-C lowering is directly linked to efficacy of the selected lipid-lowering therapy. At the same time data from JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) confirm wide variation in the degree of LDL-C reduction achieved among individuals treated with statins.
The goal of lipid-lowering therapy is to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein (LDL) is a well-known causal factor of ASCVD. Statins are administered as first-line agents to lower plasma LDL cholesterol (LDL-C) levels. A number of outcome trials have demonstrated that statins have a consistent benefit in reducing the risk of ASCVD in primary and secondary prevention. Therefore, current guidelines on the management
of blood cholesterol recommend statin administration in all patients treated for secondary prevention, patients with familial hypercholesterolemia, patients aged 40 to 75 years with diabetes and plasma LDL-C ≥1.81mmol/L, and patients treated for primary prevention without diabetes and with estimated 10-year ASCVD risk ≥7.5%. However, despite optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there is a clinical need for additional agents which will help in lowering plasma LDL-C and other atherogenic particles effectively.
Ezetimibe reduces cholesterol absorption from the intestine. Ezetimibe in combination with statins is well tolerated and significantly reduces LDL-C levels by up to an additional 24% compared to statins alone.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme predominantly produced in the liver, binds to the LDL receptor (LDLR) present on the surface of the hepatocytes, leading to its degradation and a subsequent increase in plasma LDL-C levels. Thus, inhibition of PCSK9 causes an increase in LDLR number and a subsequent decrease in plasma LDL-C levels. Monoclonal antibodies that target PCSK9 (proprotein convertase subtilisin/kexin type 9) e.g. Alirocumab, Evolocumab, reduce LDL-C levels by about 60% when added to statin therapy in very high risk patients.
ATP-citrate lyase (ACLY) catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA. Acetyl-CoA, the precursor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), is crucial for the biosynthesis of cholesterol. Thus, inhibition of ACLY leads to a reduction of acetyl-CoA and cholesterol synthesis, resulting in an increased number of LDLRs, causing a subsequent reduction of plasma cholesterol. Bempedoic acid is an oral, once-daily, hypolipidaemic prodrug that targets cholesterol synthesis in the liver by inhibiting ATP-citrate lyase. It is used as an adjunct treatment to maximally tolerated statins. In the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL (ATP-Citrate Lyase-Inhibiting Regimen) Harmony trial of patients with ASCVD, HeFH, or both, bempedoic acid added to statin therapy reduced LDL-C levels by 18.1 per cent.
Inclisiran is a first-in-class small interfering RNA that uses RNA interference to degrade PCSK9 mRNA, reducing the hepatic synthesis of PCSK9 protein and thereby increasing hepatic LDL receptor expression. The magnitude of LDL-C lowering with inclisiran is about 50 per cent, slightly less than the levels achieved with anti-PCSK9 monoclonal antibodies and greater than for bempedoic acid as monotherapy and in combination with ezetimibe.
Elevated plasma triglycerides (TG) level is associated with increased risk of ASCVD. However, TG can be degraded by most cells in the body and, therefore, does not accumulate in the atherosclerotic plaque. Therefore, TG itself is unlikely the cause of atherosclerosis. Instead, TG-rich lipoproteins enter into the arterial intima and contribute to plaque formation, eventually leading to a high ASCVD risk. American guidelines recommend the administration of fibrates or omega-3 fatty acids in patients with persistently elevated severe hypertriglyceridemia (TG ≥565mmol/L) to prevent pancreatitis. European guidelines recommend the administration of n-3 polyunsaturated fatty acids (icosapent ethyl 2×2 g/day) in combination with a statin in high-risk (or above) patients with TG levels between 1.52mmol/L and 5.63mmol/L despite statin treatment (Kim et al. New Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins. Diabetes Metab J. 2022;46:517-53).
Overall, although statins form the backbone of therapy, achieving a >50% reduction in LDL-C levels with high-intensity statins is often insufficient for patients at the highest risk of ASCVD events. It is therefore critical to identify high-risk and provide the most effective lipid lowering combination to reduce the ASCVD risk aggressively. Polyphenol-rich cocoa protect LDL from oxidation and enhance high-density lipoprotein cholesterol (HDL-C) concentration. Regular consumption of polyphenol-rich cocoa is beneficial in the prevention of ASCVD (Baba et al. Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am J Clin Nutr 2007;85:709 –17)
BY DR EDWARD O. AMPORFUL
CHIEF PHARMACIST
COCOA CLINIC
