Lipids: All you need to know in 2022

By Professor Derek Connolly, Consultant Cardiologist and the Director of Research and Development at Birmingham City Hospital.

It is over a century, since it was demonstrated that cholesterol was a key component in atherosclerotic plaques. Classic experiments showed the animals fed a diet in cholesterol, rich feed resulted in atherosclerosis. One of the key questions therefore, is whether reduction in cholesterol would result in less atherosclerosis and potentially less cardiovascular events such as strokes, heart attacks, and arterial disease? Early experiments by Professor Michael Oliver and his team in Edinburgh, initially suggested this might not be the case. Of course, the big change occurred with the development in Japan of statins. The first large trial of statins in secondary prevention, the 4S trial was undertaken in Scandinavia by  Terje Pedersen and colleagues. They gave patients with heart attacks or known coronary artery disease either simvastatin or placebo in a randomised control trial. I was lucky enough to be in the audience in Anaheim California when this was presented in 1994. The massive reduction in events and the need for revascularisation and a reduction in total mortality was unprecedented. This of course changed everything and over the next 30 years we did trials in patients with higher doses of statins versus lower doses and more potent statins versus less potent statins. With statins, whenever we lowered the cholesterol further, we saw a reduction in cardiovascular events. There was speculation that the effect was not about lowering LDL cholesterol, but about a “pleotropic effect” of the treatments. However, when Chris Cannon stood up to present the results of the Improve it study in 2014, using ezetimibe to lower the LDL cholesterol further, he announced that this was evidence that it was about lowering the LDL as the study was also positive. Subsequently, I was delighted to be involved in the Fourier trial of PCS K9 inhibitors as the UK chief investigator. PCSK9 is a protein that binds to the LDL receptor in the liver. In 1985, Goldstein and Brown had won the Nobel prize for the discovery of LDL receptors function.They work by binding LDL in the circulation on the surface of the liver. The LDL receptor is then internalised in the hepatocyte and the LDL is thrown out into the biliary system and the gut. The LDL receptor, then goes back to the surface of the liver and grabs another LDL and repeats the cycle up to 100 times per LDL receptor. We know the 90% of cases of familiar hyperlipidaemia are because of abnormalities of the LDL receptor. A much smaller percentage of patients have abnormalities of PCSK9. This protein binds to the LDL receptor so that when the liver internalises the LDL receptor and LDL complex, instead of just getting rid of the LDL, the liver also gets rid of the LDL receptor. If you have very high levels of PCSK9, then you have very low levels of LDL receptors and thus hypercholesterolaemia. It therefore seemed like an ideal target for therapeutics. Two human monoclonal antibodies, evolcumab and alirocumab passed their phase 3 studies and are now used worldwide. The Fourier Study looked at patients with stable coronary disease. In these patients with high cholesterols in spite of statin therapy, we were able to lower the LDL cholesterol to less than 1 mmol per litre in more than half the patients. This reduction produced a large reduction in cardiovascular events. The study also showed no major side-effects. In particular a sub study called Ebbinghaus showed no effect on brain function. In our “total events paper”, we showed that blocking PCS K9 reduces the first events, but the second, third and fourth events were increasingly less likely. Overall, there was about a 25% reduction in total events. The recent open-label extension study of Fourier, ongoing safety continued to be demonstrated but now also showed a reduction in cardiovascular death in patients on active treatment. Simultaneously, the Odyssey study, using alirocumab showed similar data in patients within a year of an acute coronary syndrome. This led to the European Society of cardiology, and the North American society is suggesting the combinations of lipid lowering therapy with statins, ezetimibe, PCSK9 monoclonal antibodies could and should be used to hit the new, much lower targets of LDL reduction particularly in secondary prevention.

More recently, we have had the development of bempedoic acid. This blocks cholesterol synthesis in the liver, a couple of enzymes above where statins work to block HMG CoA reductase. Several studies led by Kausik Ray and his team at Imperial in London have shown that this drug is very effective in lowering LDL cholesterol. In combination with ezetimibe you get a 38% reduction in LDL cholesterol. This is particularly useful in people who are statin intolerant. This has been approved by NICE in the UK. It appears to have a few side-effects but can raise the uric acid. We are anticipating the Clear Outcomes cardiovascular outcome trial to be presented in the early spring of 2023. However, this gives an excellent treatment for patients who will not take statin therapy.

The PCSK9 studies with the monoclonal antibodies have shown that this modality is effective in lowering LDL cholesterol, but involves injections every 2 to 4 weeks to maintain the level of antibody. In 2006, Andy Fire and Craig Mello Nobel prize for the discovery and development of small interfering RNA technology. This uses the body’s own system to block any protein of choice being produced. This seemed like a perfect methodology for inhibiting PCSK9. Inclisiran was develop to do this. This reduces LDL cholesterol by around 50% for over 6 months. This has also now been recommended by NICE in the UK, where as of November 2022, over 5000 patients have received the therapy. Other than occasional mild erythema at the injection sites, we are seeing no significant side-effects.

This means that there are now five ways of lowering LDL cholesterol. In the Da Vinci study, Kosh Ray and colleagues have shown that the only way of attaining the current European Society of cardiology guidance is to use combinations of therapies. These were not being used much in Europe, but in a recent Santorini study, we have shown an improvement in usage with more patients getting combinations of therapies and reaching target.Of course, this is very much like hypertension where combinations of therapies are needed in many patients to reach more stringent guidelines targeted levels then we had previously.

There is increasing evidence that cardiovascular risk, like smoking risk is dependent on both the level of cholesterol, but also the time of exposure. Lowering cholesterol over long periods has a much bigger effect than over shorter periods. Clearly, having a very high cholesterol over a shorter period, may result in events early in life and this explains why people with familial hyperlipidaemia, who often have very, very raised LDL can have heart attacks in their 20s. Wonderful work by Brian Ference and colleagues has shown that Gene polymorphisms in the human Biobank project project predicts your cholesterol and your blood pressure and most patients with these high polygenic scores for cholesterol are very prone to early heart attacks.

There are several other therapies coming. There is a beautiful hilltop village halfway between Rome and Naples in Italy called Campodimele. Here people lived into very old age, and this was attributed to the wine, good air and the lifestyle. However, it was discovered that the populous had a large incidence of a gene with reduced function of a protein called ANGPTL3. This blocks lipoprotein lipase and if you don’t have ANGPTL3 then you have lower cholesterol levels. An inhibitor to ANGPTL3 lowers cholesterol by 38%. This may have use in the future as it’s particularly beneficial to people with homozygous familial hyperlipidaemia. 

About one and five over heart attacks and strokes worldwide are due to another lipid protein called lipoprotein [a] and this risk seems independent of LDL cholesterol. There are many current studies underway to assess whether blocking this may improve survival and reduce cardiovascular events impatience with raised lipoprotein [a]. We are hopeful that the first of these trials called Horizon will present in 2024. The prediction by Naveed Sattar from Glasgow and his colleagues, using information from the human biobank project, is that this will have a substantial benefit in reducing events.

One of the most exciting developments in the future will be the ease of gene therapy using a technique called CRISPR. A spin out company from Harvard University called Verve therapeutics have developed a single injection technique that will change someone’s genetics permanently and switch off a protein such as PCSK9. They are currently undertaking early human phase trials. This would seem a long way off, but it does seem to work and may give a permanent solution to stop heart disease. 

Lastly, the Reduce it study by Deepak Bhatt using highly purified, EPA called icosapent ethyl has brought back the idea of fish oils. In the study, there was a big reduction in cardiovascular events. This mirrored registry studies in Japan. In a CT scan study called , Matthew Budoff and colleagues, show the highly purified EPA stablised paths. Again, NICE in the UK has recommended this for patients with higher triglycerides as this was an entry criteria for the trial.

To summarise, we have come a long way in the last 30 years, since that presentation of the forest trial in Anaheim. We can now control the cholesterol level of the vast majority of the population using combinations of therapies. These seem safe and effective. Atorvastatin is the most prescribed drug in the United Kingdom with over 50 million prescriptions each year. The cost per patient is less than £20, so these are among the most effective therapies in medicine. Going forward all of the new therapies that are both available and those in development have the potential to completely revolutionise the way we treat patients. It has been an amazing journey.