The need to Go Beyond LDL-C Reduction in Managing Atherosclerosis

The last two decades have seen the rise of statins from obscurity to being one of the most prescribed medications worldwide to combat cardiovascular disease. In fact, the introduction of statins has significantly shared the current guidelines on lipid management that many clinicians follow today. Despite the significant reduction in low-density lipoprotein cholesterol (LDL-C) achieved by sensitive statin therapy, many patients are still at risk of developing cardiovascular disease

Why is LDL-C lowering not enough?
In their paper published in controversies in Cardiovascular Medicine. Drs. H. Robert Superko and Spencer King III said that it is not surprising that there is a myopic focus on lowering LDL-C alone because guidelines have not adequately addressed other evidence. They noted that as early as 1996, clinicians were already aware that despite significant LDL-C reduction, large numbers of subjects in the treatment groups continued to have cardiovascular events . In the subsequent 10 years, important advances have been made in the understanding of lipoproteins that have clinical relevance for patient management and improved clinical outcomes beyond LDL-C reduction alone.

According to them, one of the dangers of following the results clinical trials is the assumption that when a compound shows benefits, almost all patients will benefit from it in a uniform manner, Therefore, other potentially beneficial treatments are ignored. For instance, the results of a recent series of statin-inducted cholesterol-lowering trials have been used to suggest that a new LDL-C goal of less than 70 mg/dL should be embraced.

However, one of the conclusions of the 1996 article “Beyond LDL Cholesterol” is that a large number of patients continued to experience cardiovascular events (myocardial infarction, stroke) despite achieving target LDL-C levels, And this continues to be true even with the substantially greater absolute LDL-C reduction achieved in recent trials. Drs. Superko and King said: “At this point in the history of cholesterol reduction, it is important to pause and discuss the possibility that statistical (mathematical) significance does not necessarily equate to clinical relevance.”

Drs. Superko and King cited three important reasons why clinicians should appreciate the need for additional treatment other than simple LDL-C reduction. First, Treatment that focuses exclusively on LDL-C lowering reduction. First, treatment that focuses exclusively on LDL-C lowering brings patients to a condition that still puts them at risk for cardiovascular events despite achieving adequately controlled LDL-C values. Second, disorders that contribute to cardiovascular risk other than LDL-C are common in the CAD population even with LDL-C level of less than 100 mg/dL. Third, effective therapies currently exist to treat these other disorders, and new therapies under development will greatly expand armamentarium. A key component of the most successful arteriograhic “regression” trials has been the combination of LDL-C reduction with enhanced reverse cholesterol transport.

The crucial role of Reverse Cholesterol Transport
Understanding the reverse cholesterol transport process is a clinically important topic because current and future pharmacological treatments can have a beneficial effect on reverse cholesterol transport and play an important therapeutic role that amplifies the benefit of LDL-C reduction, explained Drs. Superko and King. Reverse cholesterol transport is a pathway by which accumulated cholesterol is transported from the vessel wall to the liver fr excretion and, thus, preventing atherosclerosis. “There are five components of reverse cholesterol transport that are useful for the clinician to understand: enzyme activity, transfer proteins, membrane modulators, apoproteins, and HDL subclasses.”

Decreased CEPT activity associated with increased risk of cardiovascular disease
According to Bruce and Tall, CETP (Cholesteryl estertransfer protein) mediates the exchange of HDL cholesteryl esters with triglycerides of ApoB-Containing lipoproteins, and it plays a central role in the reverse cholesterol transport from the peripheral tissues to the liver.
Vasan and colleagues undertook a prospective analysis of plasma CETP activity and its association with cardiovascular disease risk in the Framingham Heart Study, published in Circulation in 2009. Plasma CETP activity was measured in 1, 978 men and women free of cardiovascular disease when examined between 1987 and 1990. After a mean follow-up of 15years, 320 individuals had a first event, defined as fatal or nonfatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure.

Plasma CETP activity at or above the median (131 nmol/L per hour) was associated with a 25% to 28% lower risk of cardiovascular disease. When modeled as a continuous variable, each standard-deviation increase in plasma CETP levels was associated with a 12% to 14% lower risk of disease. The inverse relationship was maintained in analyses looking only at hard cardiovascular end points, including MI, stroke, or heart failure.

In their paper, the researchers say that although the findings are observational, there is a strong possibility that the relationship between lower CETP activity and increased cardiovascular disease is causal. They said that a recently shelved CETP inhibitor, irrespective of the toxicity issues, resulted in a significant increase in HDL cholesterol but failed to reduce atherosclerosis in the carotid and coronary vessels. The authors proposed that the HDL cholesterol produced through CETP inhibition might be less functional or even dysfunctional.

A CETP-activator drug that goes beyond LDL-C lowering
In the journal Atherosclerosis, Drs. Shizuya Yamashita and Yuji Matsuzawa of Osaka University Graduate School of Medicine said that it could be worthwhile to revisit a drug that was earlier discovered to promote cholesterol efflux and enhance reverse cholesterol transport by activation of CETP and scavenger receptor class B type 1. This CETP activator drug, instead of the inhibitor might provide a partly rational therapeutic approach to prevent atherosclerosis, after a review of the evolving field of pro-atherogenic HDL, a novel role for human CETP in the defense against an exacerbated production of pro-inflammatory mediators, and CETP polymorphism among individuals or ethnic groups. A report by Milda et al. suggested the possibility that is CETP enhancer activates the endothelial lipase by inhibiting angiopoietin-like protein (ANGPTL3) and enhances HDL metabolism and cholesterol efflux by increasing preB1-HDL levels.

In line with its philosophy of creating innovative products for better health worldwide, Otsuka Philippines will soon launch a lipid-lowering agent with a unique mode of action that will go beyond LDL-C reduction and argument the current management of dyslipidemia leading to atherosclerosis. Indeed, the provision of products that make a milestone difference in the health and lives of Filipinos drives Otsuka Philippines to fuel an enduring promiseto care for Filipinos in ways that only it can deliver.

Sources: 1. Superko H et al. Circulation 2008; 117:560-568.; 2. Superko H. Circulation 1996; 94:2351-2354.; 3. Bruce C, et al. Curr Opin Lipidol 1995; 6: 306-311.; 4. Vasan RS, et. al. Circulation 2009; 120: 2414-2420.; 5Yamashita S, et al. Atherosclerosis 2009; 207: 17-23; 6. Milda T, et al. Atherosclerosis 2008;200; 329-335.