Prescribing lipid-lowering drugs

Lipid modification is a prime example of the increasing trend for healthcare professionals to treat risk rather than disease, yet the benefits in primary prevention are small. Practice Nurse weighs the evidence and discusses the options for lipid lowering

You might be forgiven for concluding that the problem of cardiovascular disease (CVD) had been solved. The statistics are really quite encouraging: in the last 50 years the chance of dying from CVD has fallen in England by three quarters,¹ and is now well below the chance of dying from cancer.² So surely the fight against CVD is being won?

Earlier this year, NICE produced yet more guidance on the management of CVD risk.³ The reality is that problems caused by CVD have been falling due to a combination of:

• Managing lifestyle risk (in particular, the rate of tobacco smoking in England is at a 50 year low.⁴ Improvements in other things like obesity and exercise are much less impressive)
• Better treatments when a CVD event has occurred
• More aggressive management of cholesterol levels.

The dramatic fall in the CVD death rate is largely due to the work of the NHS, and in particular primary care. As general practice nurses (GPNs) are pivotally involved in the community management of CVD risk, they should take most of the credit.

Yet the battle is not over. Even though the rate of CVD death has fallen markedly, there are still 125,000 CVD deaths in England each year, which is over a quarter of all deaths.¹ Also a quarter of these deaths are in the under-75 age group, which these days is considered ‘premature’.¹ There is plenty of work to do to sustain and continue the progress.

Cholesterol was discovered in 1784, and the first hints that cholesterol might be responsible for CVD date back to 1910, but these early findings were largely ignored.⁵ The connection between familial hypercholesterolaemia and CVD was established in 1939, and by the early 1950s Gofman at the University of California at Berkley had confirmed that not only was cholesterol implicated in CVD but also, because he had access to a spanking new state-of-the-art centrifuge, he was able to differentiate the nasty low density lipoprotein from the (relatively) nice high density lipoprotein (HDL).

Once the role of raised cholesterol in CVD was confirmed, there was potential benefit to be gained (and money to be made) from the development of drugs to bring cholesterol levels down. Heart UK6 contends that 60% of people have raised or abnormal serum cholesterol – that’s a lot of potential pill-takers. So as you might have guessed, there are now lots of cholesterol-lowering drugs on the market.

THE EVIDENCE

The role of cholesterol-lowering drugs and CVD management is not without controversy. The evidence is rather clearer for secondary prevention (the reduction of cholesterol by drugs after a CVD event, such as a heart attack or stroke). It is recommended that everyone who has had a heart attack should take cholesterol-lowering medication (specifically a statin) for the rest of their days,7 though the evidence for starting a statin at age over 80 is less compelling.⁸

On the other hand the evidence for the benefit of drugs to lower cholesterol in primary prevention (the prevention of a CVD event before it has happened, with intervention just based on the level of risk) still causes debate. The Cochrane Collaborative,⁹ which is usually regarded as the gold standard when it comes to the evaluation of medical evidence, concluded in 2013 that drug use is beneficial and that: ‘Statins are likely to be cost-effective in primary prevention’ (of CVD) – hardly an enthusiastic endorsement, but an endorsement nonetheless. The debate, which is ongoing,10 hinges on:

• The benefits achieved from drug use are small (in primary prevention)
• Some studies show a reduction of CVD events, but not all-cause death
• Many studies have used surrogate end-points – the fact that a drug reduces cholesterol levels does not necessarily mean that it reduces CVD events
• Publication bias suggests that research that does not give ‘interesting’ results is more likely never to be written up for publication, and so is not available for analysis11
• The pharmaceutical industry has been responsible for much of the research, and cannot be regarded as a disinterested party
• There is little agreement on the possible harms of statins (not including the cost and the creation of ‘patients’): e.g. diabetes, and muscle pains falling short of rhabdomyolysis.

Yet in the Land of the Guidelines, where they wouldn’t recognise a nuance if it came and sat on them, the recommendations are clear as crystal: prescribe statins.

THE DRUGS

In humans, cholesterol is made in 30 distinct biochemical stages from acetyl-coenzyme A (CoA).⁵ During the 1950s and 1960s, many efforts were made to find drugs that would block one or more of these stages, and so reduce the amount converted to blood cholesterol. In the early days there were several near misses.

• Nicotinic acid (discovered 1955) has too many side effects for widespread use, but it is still available as a third-line treatment if statins and fibrates have not had the desired effect. Common side effects include abdominal pain, diarrhoea, dyspepsia, flushing and vomiting.¹² When used it is usually initiated in secondary care (i.e. by a specialist following a referral).
• Clofibrate (1958) and its subsequent derivatives are collectively called fibrates and they don’t work very well. Fibrates are not bad at reducing triglyceride levels, but the effect on non-HDL cholesterol is variable. (Non-HDL cholesterol is considered a better way of assessing risk than the old Low Density Lipoprotein.13)They can be prescribed in the UK for mixed hyperlipidaemia when lifestyle changes are insufficient and a statin is either contraindicated or not tolerated. Four are available in the UK: bezafibrate and fenofibrate are relatively cheap; ciprofibrate and gemfibrozil are not.¹² Fibrates are sometimes initiated from primary care.
• Cholestyramine (1959) is an anion exchange resin that binds with bile acid in the gut, so instead of being absorbed the bile acid is excreted. Cholestyramine works well, but is said to be poorly tolerated5 despite the rather short list of side effects in the British National Formulary.¹² It remains available to prescribe in a limited range of circumstances where other strategies have not worked.
• Ezetimibe (1995) also inhibits the intestinal absorption of cholesterol. Used alone it has a modest effect on non-HDL cholesterol, and little effect on other cholesterol subfractions. It is usually used in combination with a statin for a limited range of indications, even though this combination may increase the risk of rhabdomyolysis.¹² Ezetimibe can cause gastro-intestinal disturbance (as its mode of action would imply), and also fatigue, headache and myalgia. It is occasionally prescribed in primary care.
• Evolocumab and alirocumab are the new kids on the block, and NICE has now approved their use to lower cholesterol as drugs of last resort, when all else has failed.³ Accordingly, they are in the province of specialist practice and so are unlikely to be initiated from primary care. However GPNs may start to come across patients using these drugs, so knowledge of their existence may help. Both are monoclonal antibodies and work by blocking PCSK9, a protein that prevents the liver absorbing non-HDL cholesterol from the blood: blocking PCSK9 means that more non-HDL cholesterol is absorbed and less is left in the blood. Side effects include joint pain; back pain; runny nose; flu-like symptoms; nausea and a rash. They should not be used in patients who are pregnant (toxic in animal studies), breastfeeding or who have liver or kidney impairment, mainly because they are so new that their safety has not been confirmed. They both can only be given by injection and are expensive (about £4000 per patient per year). NICE recommends that patients should be taught to self-inject: I do not know of any instances where GPNs have been asked to take on this task, but the time will surely come. The BNF does not suggest that there are any special monitoring or safety requirements.¹²

STATINS

And so we come to the statins, the mainstay of cholesterol-lowering-with-medication treatment. They are used in all varieties of CVD prevention and raised cholesterol, often alone, and sometimes in combinations with other drugs previously mentioned.

Statins are neither the oldest nor the newest lipid-lowering drugs, but at present they are the most widely prescribed in the UK. According to NHS Digital, in 2015 66.5 million prescriptions were dispensed in the community in England for the five statins available in the UK, at a total cost of £153.7m.¹⁴ These were all prescriptions issued from general practice.

A type of natural statin is found in fungus of the Penicillium and Aspergillus varieties, and it is from this source that statins were discovered and eventually prepared for human consumption. They all work by inhibiting an enzyme that is involved in cholesterol synthesis, especially in the liver. The enzyme has the racy name 3-hydroxy-3-methylglutaryl coenzyme A reductase, or HMG CoA reductase.

GPNs will be involved with patients on statins in a number of situations.

Routine monitoring

Your patient is established on a statin, and agrees that continuing is a good idea. Any side effects are either non-existent or are being tolerated, and there are no other health issues that might interfere with carrying on with the medication. This sounds like an easy consultation, but there are still things to be done.

• Liver function tests need to be done after 3 and 12 months of starting a statin, but not thereafter unless there is a problem. If any of the readings are more than 3 times the upper limit of normal, tell a GP as the statin may be responsible
• Check on compliance with the statin
• Check on progress with lifestyle issues. CVD prevention is not just about serum cholesterol levels: smoking, alcohol use, hypertension, obesity and exercise are also important.

Unsure about statins

Doctors can be bullies when it comes to telling patients what they should and shouldn’t do. You may well come across a patient who has been so bludgeoned but is now getting cold feet. Taking a statin is not without risk. There is evidence that statins may increase the chance of developing diabetes.¹⁵ Rhabdomyolysis is a rare but rather nasty complication of taking statins: muscle tissue breaks down (leading to a rise in serum creatinine kinase to more than five times the upper limit of normal), with a mortality of around 20%.¹⁶ Aching muscles is very much more common, falling short of actual muscle toxicity, but annoying nevertheless: for an age group often plagued with muscle aches anyway, the prospect of more is unwelcome. Also, some people just do not like the idea of having to take tablets.

However, side effects from taking a statin are not inevitable, and are largely reversible if problems are encountered. Regular monitoring and the prompt reporting of symptoms will minimise any mischief. And there is clear evidence that statins do prevent problems for the future – an argument harder to believe for primary than for secondary prevention. (Declaration of interest: I have no plans to have my own serum cholesterol measured unless or until I have a CVD event, in case some fool wants me to take a statin).

Statin side effects

But some people do develop side effects, and will quite rightly come and complain to you about them. There are several options.

• Put up with the side effects (as long as creatinine kinase levels are acceptable) – they may subside.
• Stop the statin temporarily to make sure it is the culprit. A short withdrawal of the drug will not cause any great harm, and if symptoms restart on resumption you can be sure that the statin is to blame.
• Reduce the statin dose. Even a smaller dose is better than nothing. In any event the effect of statins on cholesterol levels is one of diminishing returns. For example 40mg atorvastatin (the statin-de-jour) reduces non-HD cholesterol by 49%, but doubling the dose to 80mg reduces non-HD cholesterol by 55%, i.e. only an extra 6%.³
• Change the statin. Five are available and (depending on dose) are characterised as ‘high’, ‘medium’ and ‘low intensity’. High intensity is atorvastatin 20g and above, rosuvastatin 10mg and above, simvastatin 80mg. Try one from the low intensity group. You can always try with a high intensity one later when things have settled.
• Abandon the statin if three different ones have been tried and they all cause side effects.

Cholesterol still too high

Patients taking a high-intensity statin should have their total cholesterol, HDL cholesterol and non-HD cholesterol measured annually.³ If the non-HD cholesterol has fallen by less than 40% from the initial reading, then (having discussed adherence and lifestyle issues) the statin dose might need increasing. For those on a low intensity statin regime, only the non-HD cholesterol needs review, but no targets are suggested.³ A discussion of the pros and cons of moving to high intensity statins is recommended.

POSTSCRIPT

The story of lipid manipulation, especially by medication, continues to highlight what is becoming an accelerating trend for medical professionals to be involved with the treatment of risk rather than illness. A new set of rules of engagement and ethical considerations must be established to deal with this change – it is not at all clear that the traditional methodologies lend themselves to this emerging reality, and indeed whether the way that medical professionals (doctors and nurses) are trained remains applicable.

REFERENCES

1. British Heart Foundation. CVD Statistics – BHF England Factsheet. https://www.bhf.org.uk/research/heart-statistics

2. Macmillan. Statistics fact sheet. https://www.macmillan.org.uk/_images/cancer-statistics-factsheet_tcm9-260514.pdf

3. NICE. Lipid modification therapy for preventing cardiovascular disease.

4. Office for National Statistics. Adult smoking habits in the UK: 2016.

5. Endo A. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci 2010 May 11;86(5):484-493. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108295/

6. Heart UK. Cholesterol and health – frequently asked questions. https://heartuk.org.uk/health-and-high-cholesterol/cholesterol-and-health-faqs

7. NICE Clinical Knowledge Summaries. MI – secondary prevention. https://cks.nice.org.uk/mi-secondary-prevention#!scenario

8. Desai DA, Zakaria S, Ouyang P. Initiation of statin therapy: are there age limits? Curr Atheroscler Rep. 2012 Feb;14(1):17-25. https://www.ncbi.nlm.nih.gov/pubmed/22086344

9. Cochrane. Statins for the primary prevention of cardiovascular disease. http://www.cochrane.org/CD004816/"‹"‹"‹"‹"‹"‹"‹VASC_statins-primary-prevention-cardiovascular-disease

10. Cochrane review group responds to Abramson and colleagues’ article on statins in low risk people. BMJ 8 March 2014;348:27-28. https://www.bmj.com/bmj/section-pdf/751786?path=/bmj/348/7948/Observations.full.pdf

11. Song F, et al. Publication bias: what is it? How do we measure it? How do we avoid it? Dove Press 2013;5:71-81

12. NICE. BNF. https://bnf.nice.org.uk/

13. NICE CG181. Cardiovascular disease: risk assessment and reduction, including lipid modification, 2014 (updated 2016) https://www.nice.org.uk/guidance/cg181/chapter/Key-priorities-for-implementation

14. NHS Digital. National Statistics. Prescriptions dispensed in the community.

15. Sattar N et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42. doi: 10.1016/S0140-6736(09)61965-6. Epub 2010 Feb 16.

16. McMahon GM, Zeng X, Waikar SS. Risk Prediction Score for Kidney Failure or Mortality in Rhabdomyolysis. JAMA Intern Med. 2013;173(19):1821-1827. doi:10.1001/jamainternmed.2013.9774

17. McGrath L T. How much faith can you place in a plasma lipid result? Update 1992;45:745-56.

18.QRISK^®2. https://qrisk.org/

19. Editorial. Whatever happened to the polypill? BMJ 2017; 356 doi: https://doi.org/10.1136/bmj.j1474