New drugs to lower cholesterol: PCSK9 inhibitors

Results from new studies on cardiovascular prevention are due to be presented in mid-March at the 2017 American College of Cardiology Congress in Washington DC – findings from very large studies to test the effects of powerful new drugs to lower cholesterol.

Patients with high blood levels of LDL cholesterol are at higher risk of heart attack, stroke and other serious vascular disorders. 

Healthy lifestyle lowers LDL cholesterol. The benefit for cholesterol lowering and the associated reduction in serious cardiovascular diseases is greater the more approaches to a healthy are followed, including Mediterranean-type diet, avoiding tobacco products, regular exercise and moderation in alcohol. 

Statins are the most effective current treatment available for patients for lowering LDL cholesterol. However not all patients respond to statins and some patients are unable tolerate statins because of troubling or serious adverse effects.

PCSK9 inhibitors (PSK9i) are a new class of powerful drugs that can cause a major fall in high LDL cholesterol levels: by up to 60% when combined with a statin.  

The key questions to be addressed in these studies are whether this "surrogate" end-point of reduced LDL cholesterol translates into clinical benefits for patients – and if so whether the benefits outway risks both to health and in terms of cost-effectiveness,  compared to existing treatments.
 
These biological drugs are given to patients as a treatment by injection because they are designed as monoclonal antibodies (MAbs), proteins which would be inactivated in the gut is swallowed. MAbs use the principle of the body's own immune recognition proteins, which are able to recognise and limit damage from foreign proteins such as are found in viruses or cancers.

There are usually receptors on liver cells that transport LDL into the liver for it to be broken down, thus keeping the circulating level of LDL cholesterol on check. PCSK9 (proprotein convertase subtilisin kexin 9) is a protein in the liver that inactivates these LDL-scavenging liver cell receptors.  
 
The fewer of these receptors that are present in the liver, the more LDL ("bad") cholesterol persists in the blood to contribute to the development of disease of the arteries.  
Thus PCSK9 inhibitors, by inactivating the PCSK9 protein, allow more receptors to be available to capture LDL for removal from the blood.

Research finds new target in search for why statin drugs may cause problems for some patients

10th February, 2016
Research by the University of Warwick, the University Hospital Coventry and Warwickshire NHS Trust (UHCW), and Tangent Reprofiling Limited, has discovered that statin drugs interact with a gap junction protein called GJC3 that releases ATP, a major signaling molecule for inflammation in the body.  This discovery provides a significant new target in the search for why statin drugs can sometimes cause harmful effects such as muscle toxicity in some patients.

GJC3 gap junction proteins

Speaking on behalf of the team in the Department of Chemistry at the University of Warwick, Dr Andrew Marsh said:

“Statins are powerful cholesterol-lowering medicines that are widely prescribed to reduce the burden of cardiovascular disease. Gap junction proteins are important in forming communication channels between cells and organs in the body. In this new research, two clinically used statin therapeutics have been found to interact with an important part of GJC3, a gap junction protein which acts to release ATP, a signaling molecule that is key to the body’s response to injury and inflammation.

“Many people know ATP as the cell’s main energy transfer molecule, but when released outside cells, ATP coordinates how tissues including our liver and muscles deal with recovery from injury. These results may give us better understanding of how some of the harmful effects of statins in some patients, such as muscle toxicity, might come about”.

The new research paper entitled “Simvastatin sodium salt and fluvastatin interact with human gap junction gamma-3 protein” http://dx.plos.org/10.1371/journal.pone.pone.0148266 is published on Wednesday 10th February 2016 in the open access journal PLOS ONE. The study was a collaboration between scientists and clinicians at the University of Warwick, the University Hospital Coventry and Warwickshire NHS Trust (UHCW) and Tangent Reprofiling Limited.

The researchers found that the statins simvastatin sodium salt and fluvastatin were found to interact with a peptide from the gap junction protein GJC3. In work which confirmed the observed interaction, the researchers also found that certain pharmacological probes of other gap junction proteins are also bound to the peptide sequence they had identified. The orange colour in the Figure highlights the important portions of GJC3 gap junction proteins.

University of Warwick research chemist Dr Andrew Marsh also said that

“GJC3 is present in many tissues in the body, but its role in cell signaling is poorly understood. Our work opens doors to its investigation”.

Professor Donald Singer, President of the Fellowship of Postgraduate Medicine and who was the lead investigator of the teams working on this study in Warwick Medical School and UHCW commented

“Finding additional ways in which statins act at the cellular and molecular level is important for giving clues to potential new medical applications for these drugs. 

"These results may also give us better understanding of how some of the harmful effects of statins in some patients might come about”.

Notes for editors:

The research refers to the open access journal PLOS ONE paper http://dx.plos.org/10.1371/journal.pone.pone.0148266, 10 Feb 2016 and the paper was entitled Simvastatin sodium salt and fluvastatin interact with human gap junction gamma-3 protein”. PLOS ONE publishes work from science and medicine and “facilitates the discovery of connections between research whether within or between disciplines”.

The work was funded by the Engineering and Physical Sciences Research Council (EPSRC, UK), the University of Warwick and Tangent Reprofiling Limited. EPSRC’s vision is “for the UK to be the most dynamic and stimulating environment in which to engage in research and innovation.”

https://www.epsrc.ac.uk/about/facts/mission/

Equipment used in this research was obtained through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World with support from Advantage West Midlands (AWM) and part funded by the European Regional Development Fund (ERDF).

For further information please contact:

Dr Andrew Marsh,

Department of Chemistry, University of Warwick, Coventry CV4 7AL. Tel. +44 24 7652 4565

a.marsh@warwick.ac.uk

 or

 Peter Dunn, Director of Press and Policy,

 University of Warwick, Tel UK: 024 76523708 office 07767 655860 mobile

 Tel Overseas: +44 (0)24 76523708 office +44 (0)7767 655860 mobile/cell

 Email: p.j.dunn@warwick.ac.uk

PR31 PJD 9^th February 2016

NICE and wider use of statins?

In the UK it is currently recommended that a statin should be prescribed to lower cholesterol for a
patient in whom the risk of developing cardiovascular disease in the next 10 years is 20% ie 1 in 5.

NICE - the National Institute for Health and Care Excellence - is now consulting on its proposal to reduce the threshold for prescribing a statin to a 10% ie 1 in 10 risk of cardiovascular disease in the next 10 years.

Here are my comments within the 12th February 2014 Science  Media Centre briefing on this new draft guidance from NICE:

"Heart disease, strokes and other serious disorders of the circulation are a major cause of premature ill health and death. 

Statins can help to prevent and reduce the severity of these serious medical problems. 

This initiative from NICE is important in extending to many more people protection from serious cardiovascular risk. 

Clear information will need to be made available on two key points: the need to combine statin use with a healthy lifestyle and addressing the other risk factors commonly present in people with high cholesterol, and information on the balance of risk versus benefit for these powerful medicines."

More comments from the SMC briefing.

The NICE draft proposal on statins.