Pemafibrate is drug that has been designed to selectively and potently activate a receptor in the nucleus of the cell called PPARα (Peroxisome proliferator-activated receptor, subtype alpha). Activation of the PPARα receptor leads to changes in the activity of a number of different genes in the nucleus, which in turn leads to a range of metabolic effects in the body. The main change is a reduction in the concentration of blood triglycerides, even in patients taking statins. Pemafibrate is licenced for use in Japan, as PARMODIA®, for the reduction of triglycerides, but is not yet approved for use in Europe and is currently undergoing clinical trials to assess its ability to reduce serious cardiovascular events in high risk populations.
There is increasing evidence that triglycerides are associated with the risk of cardiovascular events such as heart attacks, stroke, and sudden death. The effect of pemafibrate on triglyceride concentrations, along with other beneficial effects on glucose metabolism and inflammation are expected to reduce the incidence of these events in patients who continue to be at risk of cardiovascular disease, despite statin therapy.
A large clinical trial (the PROMINENT study) has recently recruited 10,000 patients from around the globe to determine the extent to which pemafibrate can reduce heart attacks, stroke, hospitalisations for heart disease, and cardiovascular death in patients taking statins who continue to have high triglyceride concentrations. If the trial is successful, then pemafibrate could be an important treatment for use alongside statins to prevent what is still one of the leading causes of death in Europe.
Kowa already has a lipid lowering drug – pitavastatin – why do we need another one?
Pitavastatin (LIVAZO®, ALIPZA®) is the most recent member of the class of drugs known as the statins. The management of atherosclerosis has been revolutionised by the discovery that statins will reduce the concentration of cholesterol associated with low-density lipoprotein (LDL-C or so-called ‘Bad cholesterol’) in the blood. This class of drug is the most studied in the history of medicine, and all of the members of the class have demonstrated that lowering LDL-C with a statin reduces the risk of cardiovascular events, such as myocardial infarction (a ‘heart attack’). However, in spite of the success of statins, and other treatments which can reduce LDL-C concentrations, myocardial infarction remains a leading cause of death in Europe.
Blood lipids that don’t respond well to statins must be rare?
Elevated concentrations of triglycerides are actually quite common in the general population, and the distribution is skewed so that some patients have very high concentrations indeed. Data from Denmark suggest that 45% of men and 30% of women have high triglyceride concentrations in the blood (hypertriglyceridaemia) greater than 150 mg/dL (1.7 mmol/L), a level which is associated with an increased risk of cardiovascular disease. Many of these patients will receive treatment with statins since there are cardiovascular benefits in reducing LDL-C concentrations in patients at high cardiovascular risk, and some statins may also reduce concentrations of triglycerides. Nevertheless, a survey in the USA indicated that more than 30% of patients taking statins, some 12 million people, will have triglyceride concentrations exceeding 150 mg/dL. These patients will remain at risk of cardiovascular disease in spite of their statin.
Does reducing triglycerides and increasing HDL-C reduce cardiovascular event rates?
This is an area of controversy, with an increasing body of evidence which indicates that there is disease-causing cholesterol associated with triglycerides in the blood, carried by a range of lipoproteins collectively classed as triglyceride-rich lipoproteins (TRL). The cholesterol associated with TRL (TRL-C) seems to be as likely as LDL-C to be associated with cardiovascular events, but is less influenced by statins and other LDL-C reducing therapies. It is hoped that the PROMINENT trial will resolve this controversy.
Where is the PROMINENT Study running?
The PROMINENT trial is running in a total of 24 countries world-wide, including the following countries in Europe:
- Czech Republic
- Russian Federation
- United Kingdom
Also countries in North America
- United States
In South America:
The Middle East:
- South Africa
When will the results of PROMINENT be available?
The current estimated completion date for the PROMINENT Study is May 2022