Reducing the risk of cardiovascular disease by lowering lipids

The recent Irish Cardiac Society (ICS) Annual Scientific Meeting and AGM heard from Prof Chris Packard, Professor of Vascular Biochemistry and Senior Research Fellow at the University of Glasgow, UK, who addressed the attendees on the topic ‘Horizons in Lipid-Lowering Therapy’.

Prof Packard traced the history of lipid therapy, where “we have seen fashions come and go. He stated: “Just last week, we got some results from the REDUCE-IT study in triglyceride-lowering [therapy]… after several somewhat depressing years of HDL-raising trials, the horizon actually looks quite nice at the moment; the vista is very good.”

He asked the conference: “LDL cholesterol and its association with atherosclerosis — are we in the end-game; have we reached the end of that story? And if that’s the case, what are the new targets and therapeutic approaches that we can look forward to in the next five-to-10 years to give cardiologists new tools in preventing coronary disease?”

He told the attendees that there is a coalescence of evidence to show that LDL cholesterol is the “smoking gun” in the development of atherosclerosis. He pointed out: “Where it

[cholesterol]

goes is important; it can end up in the wrong places, such as in the artery wall, where it can build up for decades.

“Lipid-lowering is like blood pressure-lowering — there’s a host of evidence to support our use of drugs and there are some exciting genomic findings that give us extra therapeutic potential,” he said, displaying slides to illustrate progression lines to the conference. “The trials tell us that if you reduce LDL by 1mmol/l, you reduce cardiovascular disease risk by 22 per cent. That’s a good rule of thumb — if you are sitting with a patient and you see the lab result come back 1mmol/l lower, that patient is better off; a 2mmol/l reduction will reduce the risk by approximately 40 per cent, and so it goes on.”

Prof Packard explained that there are between 30 and 40 genes that affect LDL — such as PCSK9, apolipoprotein B and sortilin — and these are the “strongest markers”, he said. “When you look at these genes and know that they lower LDL cholesterol, and if you have one variant that lowers LDL compared to another variant that raises it, you then look at the cholesterol-lowering variant and the risk in people who have that variant — you know their risk [of cardiovascular disease] is lower,” said Prof Packard. “This is part of the genetic underpinning for the causation of LDL cholesterol and atherosclerosis. If a person has a disease like familial hypercholesterolaemia (FH), the risk goes up manifold.”

Prof Packard presented a range of data and slides to illustrate that regardless of the genetic risk factors for raised LDL cholesterol, if a reduction is achieved, genetically or pharmacologically, a similar risk reduction is also observed. “However, if you have the right genetics, a 1mmol/l drop in LDL from birth gives you a 54 per cent risk reduction. The earlier we can lower the LDL, the bigger the impact on risk.”

With regard to treatment strategies in clinical practice, Prof Packard told the conference: “PCSK9 inhibitors are now being widely used for secondary prevention… for a PCSK9 inhibitor, you need to have a high risk to qualify for their use and it is now being used more and more. In some countries, it is only used for FH, but in other countries, it can be used in high-risk individuals and these people get a benefit, as shown by the analysis in the FOURIER trial in those who have had multiple events, those who have had a recent myocardial infarction, patients with peripheral artery disease, with multi-vessel disease and patients with diabetes… you get big risk reductions, small numbers needed to treat, and therefore you are moving into a cost-effective scenario with regard to the use of PCSK9 inhibitors.”

He concluded by telling the attendees that “profound risk reduction” is possible with little or no risk to the patient and it is important to consider LDL exposure in terms of how long LDL has been at a certain level. Knowing this will enable a strategy for primary prevention, he said. “Better genetics and biomarkers will be the clue to more intelligent primary and secondary prevention and more effective lipid-lowering,” he summarised.