Cholesterol and Lipids - What's new? PCSK9 inhibitors

I enjoy my time managing thyroid disease as a consultant endocrinologist but the scope of the endocrinologist is broad. We are all trained as general and metabolic physicians, including diabetes mellitus; right across our practice it is important to consider and reduce the risk of cardiovascular disease (CVD).

When considering the heart and the blood vessels why are cholesterol and the lipid profile so important? Because abnormalities in cholesterol and the lipid profile are often found in people with avoidable illnesses and in those who die earlier than we believe they should. Further more if we change the cholesterol and lipid profile we can change what happens to people, we can prevent cardiovascular illness and for some people that will include changing the risk of death, and it is worth being absolutely clear this will, for some people, avoiding a fatal cardiovascular event.

How can we prevent a cardiovascular event? If we prevent the blockage in the blood supply to the heart in a critical artery at a critical moment, or prevent the clot being flung out of the heart to block a large vessel in the brainstem then that person may not have a fatal heart attack or stroke.

We have conditions where these events happen all too early - familial hypercholesterolaemia is an excellent example and I will discuss it briefly.

Familial hypercholesterolemia (FH) is an inherited disorder where the defective gene can be inherited from one parent (heterozygote) or more rarely both parents (homozygote) causing elevations in serum cholesterol within the low density lipoprotein particle (LDL). There is cholesterol deposited in the tendons (xanthoma), skin (xanthelasma) and most importantly perhaps the coronary arteries (atherosclerosis).

The coronary atherosclerosis dramatically increases the risk of heart attack. In heterozygote FH this becomes evident in the 30s or 40s, but in homozygote FH it can be in the first or second decade of life!

Not every patient with cholesterol or lipid problems, or CVD has a familial or inherited condition where one single gene is responsible for their increased risk (like FH). For some patients we believe there are multiple genes relevant to their individual risk, and there are lifestyle factors that raise the risk eg smoking, diabetes or thyroid disease. That is to say that not everyone who has hypercholesterolaemia has FH.

Studies in these conditions - where the risk of heart attack is so high - showed that reducing cholesterol also reduced the risk of heart attack and death.

This has been seen in other patients at high risk; if a patient has had a heart attack and we can lower the cholesterol we can reduce the risk of a second heart attack. In patients at high risk of heart attack, without having already having one eg smokers, patients with diabetes mellitus, hypertension, bad lipid profiles that are not FH, if we reduce the LDL cholesterol (LDL-C) we reduce the risk of heart attack and death.

The drugs that have really provided the benefit for patients are statins. Statins are associated with very small increases in muscle inflammation, new onset diabetes mellitus and possibly haemorrhagic stroke but it is very important to state that there is still net benefit for patients taking them - the fact that these things happen is already factored into their net benefit. Statins reduce the risk of heart attacks and strokes, the higher the risk the more the absolute reduction for a patient is as the cholesterol falls - you can only prevent something that might have happened anyway. This consideration of the absolute risk for the patient is critical to providing safe care and a topic I discuss with my patients at LondonSwissMedical at King's College Hospital. If the risk of what you are trying to prevent is low you might indeed reduce it further, but it was unlikely to happen in the first place, so the patient may just be left with the side effects of treatment - ie the net benefit may not be there. This cannot be stressed enough. My old patients at Whipps Cross and Southend Hospitals will know this just as well as my new patients at King's in London..

Many patients are at high risk of cardiovascular disease and even with the most effective therapy available they still have heart attacks and strokes, that is to say there is still residual risk to reduce. This residual risk is a problem that has faced diabetologists, endocrinologists, hypertension and lipid specialists for years. We have had various other techniques to reduce the risk, some effective (ezetimibe) some less so (fibrates), some palatable (omega 3 fatty acids), some quite burdensome (cholestyramine), some requiring intermittent hospital treatment (LDL apheresis, for homozygote FH, in a specialist hospital centre!). Good sense and the training of the endocrinologist has always made sure the common causes of secondary dyslipidaemia are not present including uncontrolled diabetes mellitus, obesity, excess alcohol consumption, untreated hypothyroidism and some medications, eg, thiazide diuretics (eg bendroflumethiazide and indapamide) and the immunosuppressant ciclosporin.

So what is new? What do we have to offer for hypercholesterolaemia to deal with residual risk once we have optimized statin therapy? Usually this means the patient is on the maximum tolerated dose of one of atorvastatin, rosuvastatin, simvastatin, pravastatin or fluvastatin. Ezetimibe will reduce the risk a little further and lipid specialists will consider the pros and cons of adding in a fibrate to statin therapy, but it is a mixture with increased risk of myopathy.

Now however we have two new monoclonal antibody treatments inhibiting the enzyme PCSK9 in liver cells. The development of this drug came about from studying people who genetically had too much PCSK9, who have higher cholesterol and suffered with more cardiovascular disease, and from those with too little PCSK9 who had life-long low cholesterol and lower risks of cardiovascular disease. PCSK9 is responsible for breaking down the receptors for LDL-cholesterol (LDL-r) on the liver cells, if there is too much PCSK9 then the receptors are not there to transport the LDLc into the cell, so the LDL-C stays in the blood and can be deposited in the arterial wall around the body - with important effects narrowing the arteries in the heart and brain.

PCSK9 inhibitors target the enzyme, reducing its effect, allowing the LDL-r to stay on the cell surface and do its job, lowering the serum total and LDL cholesterol and hopefully lowering the risk of cardiovascular disease. This lowering of cardiovascular risk has been borne out in clinical trials and this is why these drugs have a licence for use in the UK for:

Primary hypercholesterolaemia or mixed dyslipidaemia in patients who have not responded adequately to other appropriate measures (in combination with a statin, or with a statin and other lipid-lowering therapies, or with other lipid-lowering therapies or alone if a statin contra-indicated or not tolerated).

Two drugs are currently available in the UK (as of 11 Dec 2017) and have been considered by the National Institute for Clinical Excellence (NICE) in technology appraisals are alirocumab (Praluent made by Sanofi) [NICE TA 393] and evolocumab (Repatha made by Amgen) [NICE TA 394] both published on 22 June 2016.

They are recommended for patients without cardiovascular disease only if they have FH.

In patients with CVD who are at high risk of further CVD - high risk being defined as:

a history of any of the following: acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation); coronary or other arterial revascularisation procedures; coronary heart disease; ischaemic stroke; peripheral arterial disease

- or are very high risk of further CVD - defined as:

recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed (that is, polyvascular disease)

these drugs can be considered depending on the magnitude of persistent LDL-C and whether they do or do not have FH.

These drugs are monoclonal antibodies and cannot be given by mouth but have to be injected subcutaneously one fortnightly to monthly depending on the drug and dose.

They are generally well tolerated and we will gather longer and longer term safety and efficacy information about them over the coming years and decades.

It is important to have new therapies considered by specialists in lipid management and if you would like to have the diagnosis and/or treatment of your lipid disorder considered or have a review of your cardiovascular risk then please make an appointment.

If this blog post is useful please leave comments and do share it (but please make sure it is attributed appropriately).

Dr Philip Kelly is a consultant endocrinologist, general and metabolic physician at King's College Hospital who practices within the NHS and on the Guthrie Wing. He sees a wide variety of patients with and/ or at high risk of cardiovascular disease. He managed the King's Hypertension Clinic until April 2017 and now runs a monthly specialist hypertension clinic seeing patients from across South East London, Kent and beyond. He manages patients cardiovascular risk within both his inpatient and outpatient work at King's and in those with hypertension and works closely with colleagues in biochemistry and diagnostic imaging at King's, and clinical genetics at Guy's if appropriate, to ensure patients have an accurate diagnosis and receive tailored therapy for them. If you would like a referral please go to www.LondonSwissMedical.com/contact or call 020 3299 3848 or book directly from the website.

The information in this blog post is not personal medical advice and must never replace an individual consultation with an appropriately trained doctor. Dr Philip Kelly will not be responsible for the use of this post to consider therapy for individual patients.