To mark my 10th anniversary as a consultant cardiologist in Bournemouth, I am writing a blog series on what I regard as the most important developments in heart health over the last decade. It’s rare in our frantic modern lives that we stop to reflect, but it’s only in doing so that we realise quite how far we have come. Last week I wrote about heart imaging tests, and this week, I’m turning to something relevant to each and every one of us: cholesterol, and its management.
I have written and recorded lots of content on cholesterol, which I won’t repeat in detail here, but suffice it to say, it is one of the areas with the most misconceptions in the public domain that I come across. We all need cholesterol, it forms key components of certain hormones, cell membrane transport mechanisms, and in short, we couldn’t live without it. We have known for decades however, that high levels of LDL cholesterol cause heart disease, and lowering those levels reduces the risk of heart attacks and strokes. The original major trials of statins came out in the 1990s when I was at medical school, but it wasn’t until the mid-2000s that we had an alternative (ezetimibe) that actually worked. Let me be clear here (and address one of the misconceptions) – there are a number of treatments that lower cholesterol, but precious few until recently that have actually been proven in good quality randomised controlled trials to actually reduce heart attack and stroke risk, and that, of course, is the name of the game. I’m certainly not saying that nutrition isn’t important, it absolutely is, but I want to differentiate between the results of various drug trials.
We must recognise that all medicines can have side effects however, and in the case of statins, in the real world about 8% of patients can’t take them for that reason. We should also recognise that in some patients who are able to take statins and ezetimibe, they still do not get their cholesterol low enough to reach the targets that have been proven to help.
In the last decade, this has all changed. Doctors now have a veritable menu of options to choose from. The first is a drug called bempedoic acid. This works in the liver, and in the key trial, reduced LDL cholesterol by 21%, and a composite of death, non-fatal heart attack and stroke by 11%. It comes as a standalone medication, or combined with the drug above ezetimibe, and is taken as a daily tablet.
The next options are injectables. The liver is the main producer of cholesterol in the body, and it makes it via a complicated series of pathways. Different medicines work on different parts of this pathway, but one class of drugs works on what we call the ‘final common pathway’. In other words, all cholesterol synthesis has to pass through it. The liver cells express receptors on their surface, and these receptors take in LDL cholesterol so that the cells can recycle it. The enzyme PCSK-9 blocks these receptors, meaning less LDL cholesterol is taken up by the liver, and more is floating around in the bloodstream where it can get deposited in the heart and elsewhere. PCSK-9 inhibitor drugs block this enzyme, and as it is the final common pathway, are incredibly effective at lowering LDL cholesterol, with typical reductions of 50-60%! They are often administered every fortnight, and not unsurprisingly, they are not cheap. Because of this, on the NHS they are reserved for very high risk patients.
The final injectable drug is rather different again. Called Inclisiran, this medicine works on RNA. You will I’m sure be familiar with DNA, and RNA is a similar molecule. It carries messages within cells, telling them which proteins to produce. In this case, it tells liver cells to produce less PCSK-9 protein, therefore more LDL receptors are available, and cholesterol is lower. RNA was first discovered in the 1960s, earning the scientists a Nobel Prize, but the first RNA therapy wasn’t available until the new Millennium. Inclisiran is undoubtedly effective at reducing cholesterol, and the trials testing death, heart attack and stroke risk reduction are due to be published next year.
It’s amazing that we now have these options, but equally important is that we identify the people that can benefit from them. I regard a plain old cholesterol test these days as just that, plain, and frankly, old. Whilst they are still great for monitoring response to treatment or lifestyle changes, we have far better blood tests available for overall risk. Just measuring LDL, HDL and triglyceride levels (which you get on a standard cholesterol test) misses out on a number of other heart disease-casuing particles. Having a test which includes Apolipoprotein B, and measures LDL particle size will give you far more information. Even in people with ‘normal’ LDL levels, the size of the LDL particles can matter. Small particles are considered more harmful than large ones, because they can more easily get into an artery wall and cause inflammation and plaque.
Current guidelines recommend all adults have a Lipoprotein (a) measured once in their life. This is a genetically inherited marker of cardiovascular risk. Drugs are now in development to specifically target Lp (a) and I fully expect to be discussing them in the next few years.
PCSK-9, Apolipoprotein, and Lipoprotein (a) are long, complicated, scientific words that I had barely heard of a decade ago, yet now I regularly discuss and test for in my patients. They enable me to be far more precise with risk stratification, and testing is relatively inexpensive.
It’s been a strong decade in the world of cholesterol management, and I really hope you have found this article interesting. Please don’t worry about the tricky words (I’m sure doctors just come up with these things so people will think they are cleverer than they are!) but take away that the field of cholesterol assessment and treatment is a world away from 10 years ago, and maybe it can serve as a prompt to get yours checked, or embark on some lifestyle measures to help it.