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Does lower cholesterol mean less chance of dying?

By Terry Maguire - 05th Oct 2024

lower cholesterol

Readers may remember a cardiac event suffered by your columnist while trying to enjoy a short break in France. Where the French health service did patch me up, coronary artery disease is progressive, therefore when I finally got plugged back into the flagging NHS, I had been assessed for ongoing anginal symptoms. I was referred to a clinical pathology consultant to see if he could do anything for my appalling cholesterol, a trait inherited from my mother.

A rare genetic anomaly has been identified and on that basis, I was prescribed twice-weekly injections of a new class of drug, the monoclonal antibody, evolocumab. Any medicine with a name ending in ‘mab’ scares the life out of me, mainly because I don’t have any understanding of what they are and what they do.

So, this offer of treatment seemed a good opportunity to earn some CPD points.

Over the last 20 years, biologicals have seeped into clinical practice without me even noticing. They
are a drug class most community pharmacists in N Ireland have little knowledge or experience of, as they are normally not confined to the poorly-lit corners of hospital pharmacies, where hospital colleagues pride themselves in their ability to pronounce these convoluted names.

I learned that these medicines are grown from large-scale cell cultures of bacteria or yeast, or plant or animal cells. They are a diverse group and very different to the ‘small molecules’ that I have spent my career understanding, supplying and advising on.

Biological therapeutics, due to their method of production, are regulated, tested, and controlled differently than other medicines. To help ensure their quality, safety, and efficacy, each batch of a biological therapeutic product must be tested extensively at each stage of production in order to ensure consistency with prior batches.

In my case, the monoclonal antibody drug evolocumab is precisely targeted at the proprotein convertase subtilisin/ kexin type 9 enzyme (PCSK9). We know that higher than normal levels of PCSK9 is associated with increased low-density lipoprotein (LDL) and poorer cardiovascular outcomes. So, anything that reduces levels of PCSK9 is likely to reduce LDL cholesterol, and that surely is a good thing. Is it not?

Antibodies to PCSK9 work well, and have been approved by regulatory agencies for the treatment of individuals, like me, with inadequately treated levels of LDL-cholesterol (LDL-C) and indeed, they are capable of lowering LDL-C by as much as 60 per cent in patients already on statin therapy. In addition, they produce clinical benefits, such as reductions in the rates of stroke or myocardial infarction, according to the literature. Well, we’ll come back to that.

Mechanisms of action

The enzyme PCSK9, encoded by the PCSK9 gene, is predominantly produced in the liver and binds to the LDL receptor (LDL-R) on the surface of liver cells, leading to the degradation of the LDL-receptor and subsequently to higher plasma LDL-C levels.

Antibodies to PCSK9 interfere with binding of the LDL-R, leading to higher liver cell LDL-receptors and, as more LDL cholesterol is taken up by the liver, lower plasma LDL-C levels.

Evolocumab is a human monoclonal antibody that binds to PCSK9, destroying this enzyme. Evolocumab (Repatha) was licenced in 2015 as first-in-class and has been widely prescribed, claiming minimal side- effects and has, as advertised, a stunning impact of cholesterol levels, especially LDL cholesterol.

I was satisfied with what I had read and conscious of a nod from my clinical pathology consultant suggesting I was a lucky boy getting this drug, as the NHS has very strict guidelines on who gets it.

Over three months the effect of evolocumab, 140mgs every two weeks, was simply stunning.

When I first had a heart attack in 2016, my untreated total cholesterol (TC) was a whopping 9.2mmol/L
and my LDL cholesterol (LDL-C) was 6.3mmol/L. I was put on atorvastatin 80mg daily and in three months, I was down to TC 6.00mmol/L and LDL-C 3.5mmol/L, and it stayed there until my second heart attack in 2022. You might think this cholesterol drop was not bad, but my consultant was unimpressed and thus my referral to clinical pathology.

Three months after starting evolocumab, my TC was 2.8mmol/L and my LDL C was 0.8mmol/L. The fall in LDL C to 0.8mmol/L over three months is certainly impressive. I
very much appreciate that I have been fortunate getting access to evolocumab on the Health Service at a cost of £500 per month, but as the L’Oriel advert confirms, “I’m worth it”.

Evolocumab is not without side- effects and I experienced some in the day or two after injection. Flu-like symptoms created physical and mental exhaustion, making all forms of work impossible. Over a number of days, this resolves and the longer I take the drug, the less significant this is.

But I suppose my wider concern is being convinced of the evidence for positive outcomes. It is important to understand that this new class of drug was given a license on the basis of its impact on cholesterol levels alone. This is pretty unusual. Only when the drug got a license and was being used widely in real live patients were the cardiovascular outcome studies started. When statins first got licensed, that was on the basis of the two pivotal studies; the 4S study and the WOSCOP study, that identified a 35 per cent relative risk reduction of heart attack in patients who took statins compared to placebo. The studies on evolocumab outcomes, sponsored by the manufacturer, only appeared in the literature after licensing.


I have been trying to assess in the real world the benefits of continuing to take this relatively new drug therapy

1. The GalGov study looked at the impact of evolocumab on arterial atheroma plaque. The results from 968 patients over 76 weeks showed a small but significant difference in plaque density between drug and placebo groups. Placebo had a 0.05% increase, with a 0.95% decrease in drug group. A commentator identified this absolute reduction as “quite modest”.

2. The main outcome study, the FOURIER trial 2017, claims a 15 per cent relative risk reduction for cardiovascular disease in the drug group compared to the placebo group. This is certainly a big study, with 27,000 patients. One research group has challenged the scoring/ categorisation of cardiovascular deaths in the study and is suggesting

Opinion | COMMENT more cardiac deaths occurred in the drug group compared to placebo group, asking if there could be a direct drug impact on the heart. The NNT is identified as 66, which seems high. The absolute risk reduction between the groups is 2 per cent on a good day.

I have been trying to assess in the real world the benefits of continuing to take this relatively new drug therapy, given what we currently know. My main question is, would I be better focusing on: Normalising my BP, stopping the booze and losing 10 per cent of body weight, as the evidence supports a much great risk reduction from these interventions.

Given the study data, I believe the following scenario to be valid. If we take 2,000 men aged 65 with CHD and currently on statins, aspirin and BP management, and to 1,000 we give evolocumab (140mg every two weeks) while we keep the other 1,000 on the same medicines; a control group.

We can assume a 10 per cent death rate in the cohort over the follow-up 2.2 years. At that point, the deaths in the placebo group will be 100, whereas the deaths in the evolocumab group will be 80. So, 2 per cent of 1,000, or 20 lives saved? On a good day. This hardly seems worth it, unless you turn out to be one of the 20, but you have no way of knowing if it will be you.

I must be wrong in these calculations, as my clinical pathology consultant and my cardiovascular consultant seem to see my new cholesterol level as a great and wonderful thing and are convinced that I will still be doing this column in 2.2 years.


Terry Maguire owns two pharmacies in Belfast. He is an honorary senior lecturer at the School of Pharmacy, Queen’s University Belfast. His research interests include the contribution of community pharmacy to improving public health.

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