Prof. Ye Zhu: The History, Present and Future of Cholesterol-lowering Therapy | CCIF 2024

Cholesterol is an essential lipid in the human body, which is involved in important physiological processes such as cell membrane composition and hormone synthesis. However, when blood cholesterol levels are too high, it becomes an "accomplice" to cardiovascular disease. Hypercholesterolemia is an important risk factor for cardiovascular disease, and therefore, lowering cholesterol levels is a key strategy for the prevention and treatment of cardiovascular disease.

At the 27th Interventional Cardiology Conference of the Chinese Medical Doctor Association and the 13th China Chest Pain Center Conference (CCIF&CCPCC2024) held recently, Professor Zhu Ye from West China Hospital of Sichuan University brought a wonderful report, reviewing the history of cholesterol-lowering therapy, expounding the current situation and future development of cholesterol-lowering therapy, and letting us explore the development of this field together.

Exploring the history of cholesterol-lowering therapy

As early as the 60s of the last century, in the absence of lipid-lowering drugs, the medical community began to pay attention to the effect of diet on cholesterol levels. Studies at the time showed that strict control of dietary cholesterol levels could significantly reduce long-term mortality from myocardial infarction (MI) in very high-risk patients.

In the 70s of the last century, ileal bypass surgery studies also confirmed the effectiveness of surgery to lower low-density lipoprotein cholesterol (LDL-C). Due to various limitations, these methods have not been widely promoted.

In the 80s of the last century, lipid-lowering drug therapy began to emerge. Cholestyramine (also known as cholestyramine) is one of the first cholesterol-lowering drugs that lowers cholesterol levels by inhibiting enterohepatic circulation, thereby reducing the risk of coronary heart disease. Strict full dose of cholestyramine significantly reduces LDL-C levels by 35% and the risk of coronary heart disease by 49%, but many patients have difficulty tolerating full-dose cholestyramine therapy. In addition, various drug-related studies such as chlorphentermine and niacin were conducted in the early days, but the side effects of the drugs limited their widespread use, but these efforts also laid the foundation for later research.

In 1984, the NIH launched the cholesterol education program, and in 1988, the first target value guideline for adult LDL-C was released, ATPI (First Report of the Expert Committee on Adult Cholesterol Therapy), recommending that LDL-C should be < 130mg/dl. Over time, this target has been revised downward, reflecting a deepening understanding of cholesterol control.

Summary of the current status of cholesterol-lowering therapy

1. The rise of statins

In 1994, the advent of statins was like a revolution, completely changing the landscape of cholesterol-lowering treatment. The Scanlinavian simvastatin survival trial (4S) study validated that simvastatin significantly reduced coronary heart disease mortality and all-cause mortality. Since then, numerous studies have confirmed the efficacy of statins in primary and secondary prevention, making them the cornerstone of cholesterol-lowering therapy.

Despite the great success of statins, their side effects and intolerance to some patients have also prompted scientists to continue looking for new treatments. In 2015, the IMPROVE-IT study demonstrated for the first time that the addition of non-statins (ezetimibe) to statins can further reduce cardiovascular events, providing a new direction for subsequent drug development.

2. R&D of new drugs

(1) PCSK9 inhibitors

In 2017, the emergence of PCSK9-based monoclonal antibody drugs brought new hope for cholesterol-lowering treatments. These drugs can further significantly reduce LDL-C levels and reduce the risk of cardiovascular events in addition to statin therapy.

In 2018, another PCSK9 monoclonal antibody, Inclisiran, emerged, providing patients with more options with its semi-annual dosing frequency and significant lipid-lowering effect.

（2）ATP柠檬酸裂解酶（ATP-citrate lyase, ACL）抑制剂

The CLEAR Outcomes study, published in 2023, explored the efficacy of the ACL inhibitor bempedoic acid in statin-intolerant patients. Bempedoic acid treatment has been shown to reduce the overall risk of cardiovascular events by 13% in patients without statins.

Notably, ACL is located upstream of the cholesterol synthesis pathway and is a key enzyme for acetyl-CoA production. It is not involved in cholesterol synthesis in muscle, so unlike HMG-CoA reductase, bempedoic acid does not cause muscle-related adverse effects. Thus, for those patients who are intolerant to statins or have adverse muscle reactions, bepetrolic acid offers a new treatment option.

(3) Angiopoietin-like protein 3

In the treatment of familial hypercholesterolemia (FH), traditional drugs such as statins, ezetimibe, and PCSK9 inhibitors often rely on low-density lipoprotein receptors (LDLRs) on the surface of liver cells to work. However, in cases of extreme lack of LDLR expression, such as in patients homozygous for FH, these drugs tend to be less effective.

Recent studies have pointed out that angiopoietin-like protein 3 (ANGPTL3) is a new therapeutic target, and its mechanism of action is not related to LDLR, but reduces blood lipids by inhibiting the lipoproteinsterase (LPL) pathway. A 2020 study published in the New England Journal of Medicine showed that patients who were homozygous for FH who did not respond to conventional drug treatment had an average 50% reduction in LDL-C levels after treatment with evinacumab, a monoclonal antibody targeting ANGPTL3. Subgroup analyses showed that evinacumab significantly reduced LDL-C levels regardless of LDLR activity (<15% or ≥15%). Studies have shown that ANGPTL3 as a therapeutic target provides a new treatment option for FH patients with LDLR deficiency.

(4) Miscellaneous

In the treatment of FH, non-pharmacological treatment strategies such as liver transplantation and plasmapheresis can be performed in addition to traditional medical therapy. Plasmapheresis, although effective, is performed on a regular basis, is costly, and can be adversely affected when cholesterol or triglyceride levels fluctuate greatly.

Future prospects for cholesterol-lowering therapy

The future of cholesterol management will be more than just medications. Non-pharmacological treatments such as gene therapy are also evolving.

In addition, gene therapy, as an emerging therapeutic modality, encompasses both DNA and RNA therapeutic strategies. Small interfering RNAs (e.g., Inkslane) and antisense oligonucleotides (e.g., Mipomersen) are examples of RNA treatments. DNA therapy, on the other hand, aims to deliver the target gene to the nucleus, which theoretically may lead to lifelong benefits from one treatment.

In the field of gene therapy, viral vectors [such as adeno-associated virus (AAV)] and gene editing technologies (such as CRISPR-Cas9) are being investigated for the treatment of cardiovascular diseases. The choice of AAV serotype depends on the tissue of interest, e.g., AAV9 in the heart and AAV6, AAV8, and AAV9 in the liver. In animal model studies, AAV8-mediated overexpression of the low-density lipoprotein receptor (LDLR) gene, combined with knockout of the PCSK9 gene, significantly slowed the progression of atherosclerosis and significantly reduced blood lipid levels, including total cholesterol and LDL-C. These findings underscore the potential of PCSK9 as a therapeutic target, with significant and stable lipid-lowering effects at the protein, RNA, and DNA levels.

Some recommendations for future cholesterol-lowering management

Professor Chu first said that it is important to raise the awareness of hypercholesterolemia among the public and primary healthcare settings. At present, China is facing the challenge of joint management of the "three highs" (hypertension, hyperglycemia and hyperlipidemia), of which the number of patients with dyslipidemia exceeds 400 million, the number of hypertension patients is about 330 million, and the number of diabetes patients is more than 100 million. In the face of such a large patient population, the efforts of a single medical institution or professional group are far from sufficient, and must be dealt with through the joint efforts of the whole society.

Secondly, the prevention, screening and treatment of FH should also be emphasized. As an autosomal dominant disease, early recognition and intervention of FH is essential to reduce the risk of cardiovascular disease. Therefore, establishing an effective screening and treatment strategy is an important task for us.

Third, the development of more effective and safe medicines is our ongoing goal. Research and development efforts are underway to provide patients with better treatment options.

Finally, for the elderly population in China, we need to find the most suitable cholesterol management and treatment options. Older populations have specific physiological and social characteristics that require customized treatment strategies to meet their health needs.

summary

The historical evolution of cholesterol management is the epitome of medical progress. From early diet control to modern drug treatment, to possible gene therapy in the future, every step has condensed the wisdom and efforts of countless medical workers. There is reason to believe that in the near future, more innovative treatments will emerge, bringing new hope to patients with hypercholesterolemia.

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