Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs investigated for their potential to alter cholesterol levels in the body. The main purpose of these medications is to interact with and block the function of a specific protein involved in how cholesterol is transported through the bloodstream. By doing so, they were developed with the goal of creating a more favorable lipid profile, which was thought to translate into a lower risk for cardiovascular diseases like atherosclerosis.
The Role of CETP in Cholesterol Transport
To understand how these inhibitors are meant to work, it is necessary to understand the role of cholesterol and its transport system. Cholesterol is carried through the blood in particles called lipoproteins, the two most well-known being high-density lipoprotein (HDL) and low-density lipoprotein (LDL). HDL is often referred to as “good” cholesterol because it helps remove cholesterol from arteries, while LDL is known as “bad” cholesterol due to its role in cholesterol buildup and plaque formation.
The CETP protein acts as a shuttle, facilitating the transfer of cholesteryl esters and another type of fat called triglycerides between these lipoproteins. Specifically, CETP collects cholesteryl esters from HDL particles and delivers them to LDL and very-low-density lipoprotein (VLDL) particles. In exchange, it moves triglycerides from VLDL and LDL back to HDL, which leads to lower overall levels of HDL cholesterol.
This transfer process is a normal part of lipid metabolism, but the activity of CETP can be seen as counterproductive from a cardiovascular risk perspective. It depletes the “good” HDL particles of their cholesterol content while enriching the “bad” LDL particles.
The Promise and Premise of Inhibition
The rationale for developing CETP inhibitors was the “HDL hypothesis.” This concept originated from studies showing that individuals with naturally higher HDL cholesterol levels had fewer heart attacks and strokes, leading to the belief that raising HDL would be protective.
Based on this premise, the goal of CETP inhibitors was to block the protein to prevent it from moving cholesterol away from HDL particles. By inhibiting this transfer, researchers theorized that HDL levels would increase as the cholesterol remained trapped within the HDL particles. This was expected to enhance reverse cholesterol transport, where excess cholesterol is carried from the body’s tissues back to the liver for removal.
The promise was that these drugs could raise HDL cholesterol by 70% or more, a feat not achievable with other therapies. This anticipated benefit was the driving force behind the investment in developing these medications, with the hope of creating a new tool against heart disease.
A History of Clinical Trial Outcomes
Despite the theoretical foundation, the journey of CETP inhibitors through clinical trials has been marked by setbacks, forcing a re-evaluation of the HDL hypothesis. Four major drugs in this class illustrate these challenges.
- Torcetrapib: Although it substantially raised HDL cholesterol, its trial was terminated in 2006 due to an unexpected increase in deaths and cardiovascular events, later attributed to off-target effects like increased blood pressure.
- Dalcetrapib: While it did not show the harmful effects of its predecessor, it also failed to provide any benefit and showed no reduction in heart attacks or strokes, leading to the termination of its development in 2012.
- Evacetrapib: A more potent inhibitor that raised HDL and lowered LDL, its large-scale trial was stopped in 2015 due to a lack of efficacy.
- Anacetrapib: This drug showed a small reduction in cardiovascular events, but the company decided not to pursue regulatory approval for commercial reasons.
These repeated failures demonstrated that raising the quantity of HDL cholesterol did not automatically translate into the expected clinical benefits.
Current Research and Future Outlook
The failures of early CETP inhibitors have led to a shift in scientific thinking. The focus has moved from simply raising HDL toward a more nuanced understanding of lipoprotein dynamics. Researchers now believe the benefit of newer CETP inhibitors may be their ability to reduce LDL cholesterol and other harmful particles that contain a protein called apolipoprotein B (ApoB).
This revised approach is guiding the development of the next generation of these drugs. A prominent example is obicetrapib, a CETP inhibitor in late-stage clinical trials. This compound is being evaluated for its ability to lower LDL cholesterol, especially in combination with other lipid-lowering therapies. The focus of these new trials is on reducing plaque-causing lipoproteins as the primary driver of benefit.
The future of this drug class depends on whether this refined strategy can succeed where previous attempts failed. Scientists are also exploring whether these inhibitors have other effects, such as reducing levels of lipoprotein(a), another particle linked to cardiovascular risk. The ongoing research with molecules like obicetrapib will determine if this mechanism can provide a therapeutic option for patients at risk of cardiovascular disease.