Statins – The Good, the Bad and the Ugly

Many of us find ourselves prescribed one or other of the Statins by our GPs nowadays, often as a result of a routine health check.

But are they really necessary, and what are the risks of taking them ?

In this article, we’ll try to explain exactly what the statins, as a group of pharmaceuticals, actually look like chemically, how they work, and why the medical profession are so keen on prescribing them for us ‘en masse’.

I’ll jump ahead a bit and start with the ‘why’, to try to put the need for these key drugs into context….

Our modern diet is rich in carbohydrates and fats, and often takes the form of highly processed 'ready meals', which also contain a lot of salt. The problem is that this type of ‘challenge’ to our digestive systems and physiology on a continuous basis is an issue for us – our guts, brains and metabolism simply weren’t designed for it, and the excess salt that most of us consume in our modern diet is also likely to compromise our circulatory health. Ready meals certainly live up to their name from the point of view of convenience, but are more ready to do us harm than provide us with balanced healthy nutrition.

The explanation for this nutritional mis-match is relatively simple. For the vast majority of our evolutionary history, food was scarce, and whatever came along had to be pounced upon and used to the full…otherwise our ancestors simply starved. Our digestive systems and metabolism evolved to cope with this ‘boom and bust’ cycle, such that those with the biggest appetites and the best hunting skills got the most food, were best able to make good use of it to keep them and their offspring alive, and were therefore the most likely to survive and reproduce successfully.

The profusion of cheap and calorie-rich food that is now available to us is actually a very recent event in evolutionary terms (only really the last 75 years since the end of WW2. Homo sapiens is reputed to have been around for ca 200,000 years, so ca 0.04% of our species' lifespan to date). We were never designed to live with a continuous surplus of this sort, and our sedentary existence, increasingly spent peering at computer screens for long periods nowadays, merely compounds the problem by not allowing us to ‘burn off’ any of the excess calories it delivers (neither has it helped our eyesight, with myopia already at epidemic proportions). To add insult to physiological injury, evolutionary biology has played another trick on us by making it far harder to burn off calories than to consume them in the first place.

One of the most noticeable direct consequences of this is another ‘epidemic’… obesity. This problem is particularly worrying in that it has also spread by example to our kids, thus affecting their health prospects, and probably also their ability to support themselves in adult life. The increasing demand for the new GLP-1 therapies shows that we all want to get thinner, but in many cases our appetites are preventing us from doing so without medical help.

Both government and our healthcare professionals are becoming increasingly worried about the problem, not least because of the huge drain on NHS resources that obesity and type 2 diabetes and their consequences present. The increasing number of affected individuals who are signed-off as permanently unfit for work as a result of obesity- and diet-related health conditions also contribute significantly to the benefits bill, which is adversely affecting our economic prospects…..and their own mental health. The withdrawal of some of these benefits, which has to come eventually to keep the economy afloat, will doubtless cause even more pain.

But there is a less obvious, but more direct and insidious threat to our health from our ‘bad’ dietary habits and lifestyles in the form of excess blood lipids.

To explain how this excess develops, and before we look at its consequences, let’s first take a look at some basic biochemistry. We all carry fats around in our blood circulation in various different forms. Fats are important energy-rich ‘fuels’, and they need to be moved between the our gut, where our food is absorbed, to the sites where they are either processed and stored, or used to provide rapidly available chemical energy to ‘power’ our life processes.

Fats, along with carbohydrates are the principal fuels we all need to stay alive. If we have too much fat in our blood, however, we run the risk of our blood vessels ‘furring up’ with so-called ‘plaques’ of lipid-related material. (This process is similar to what happens to water pipes and the insides of our kettles in hard water areas, where calcium and other insoluble salts in the water precipitate out and coat the inside of our pipes and our heating elements, eventually causing them to fail.)

If this is allowed to continue, eventually one or more of our key arteries or veins may become partially or even completely blocked, cutting off the flow of glucose and oxygen to the tissue it supplies. If this happens to the coronary arteries, part of the heart muscle will die, and our heart may stop altogether. If it happens anywhere in the brain, it can cause a stroke, with loss of function to the area affected. Both of these events are potentially fatal, and may occur without any warning, or prior symptoms.

Modern diets, unfortunately for us, are rich in the very agents that encourage high lipid and glucose levels in the blood, and therefore drive the furring-up process. There is a known strong correlation between high lipid levels and risk of heart attack or stroke; Type 2 diabetes is associated with high glucose levels, and the condition produces blunted responses to a carbohydrate-rich meal, with higher than ideal peak- and average-blood glucose levels as a result. Diabetes has many unpleasant consequences, and can result in poor circulation and even blindness if not properly managed with the correct treatment and dietary restrictions.

Hence the desire on the part of our clinicians to screen for high blood lipid levels, and recommend therapies to reduce them if they are deemed to be too high. Many of us do have raised lipid levels (the UK population mean for Total Cholesterol is around 6.7 mmol/l, whereas the ideal range is below 5.0 mmol/l), so most patients registering with a new GP practice are normally offered a blood test at which time a lipid profile sample is usually taken. This test may also include HbA1C, which is form of haemoglobin known to give an indication of our ‘body exposure’ to glucose over time, and thus assesses our risk of developing Type 2 diabetes.

What do we mean by a lipid ‘profile’, and what is its significance ?

As already mentioned, fats are carried around the bloodstream in various different forms – usually associated with more soluble molecules (notably proteins) to ensure they don’t clump together and block our blood vessels in the way that so-called 'fatbergs' often block our sewers. Cholesterol is an important endogenous precursor of the bile acids involved in digestion, and of steroid hormones such as oestradiol and testosterone, so we can't do without it altogether. The standard blood lipid profile will measure ‘Total’ Cholesterol, as well as Triglycerides and High- and Low-Density Lipoproteins (HDL and LDL). HDL and LDL are large soluble fat-protein complexes. LDL in particular has a tendency to drive plaque formation, and has thus acquired the moniker of ‘Bad’ cholesterol.

If you’ve recently had a lipid profile done, you should be able to access your results through the NHS smartphone app or via SystmOnline on your pc – you can check out the data and what it actually means using the Health.xlsm Excel app, which you can download here. The Excel app also provides interpretation and advice on BMI and blood pressure, and explains what we can all do at home with minimal equipment to monitor our own health. All the figures used are based on NHS recommended values.

If, as is quite likely, you have a total cholesterol value above the idealised threshold of 5.0 mmol/l, and /or a LDL value much above 3.0 mmol/l, you may be recommended to start on one or other of the statins. This is particularly likely to happen if you are deemed to be ‘at high risk’ of cardiac ill-health for other reasons.

What are Statins ?

Statins are a class of drug designed to reduce lipid levels, in particular the ‘bad’ form of blood cholesterol (i.e. LDL). Contrary to what you might expect from their class name, they are not just designed keep them static. They are designed to achieve a positive reduction by altering cholesterol metabolism such that less of it is produced by the liver. To understand this fully, we need to delve into a bit more biochemistry and look at how lipids in our food are absorbed and transported, and how this ties up with how they are used by the body, and ultimately, disposed of.

Human Lipid Metabolism

As discussed, lipids are key to our existence, and serve many functions, not simply acting as fuels to provide us with energy. Lipid metabolism encompasses the digestion, absorption, transport, synthesis, and breakdown of fats to provide energy, and produce structural components for our cells and tissues. They also provide the precursors for important signalling molecules such as steroids.

Lipid metabolism involves a complex set of biochemical processes that allow the body to utilise fats from dietary intake, or from stored fat reserves. Lipids, including triglycerides, cholesterol, fatty acids, and phospholipids (see figure 3 for chemical structures), serve as energy sources, components of cell membranes and precursors for steroid hormones. The body does in fact regulate lipid metabolism quite tightly for us so as to maintain energy balance and prevent disorders such as dyslipidemia, fatty liver disease, and cardiovascular disease.

Digestion and Absorption

The process of absorbing fats begins in the digestive tract, where dietary fats are emulsified by bile salts. These are produced by the liver, and released into the gut via the gall bladder. This process increases the surface area of the food for the digestive enzymes to work on. Pancreatic lipase then hydrolyses triglycerides into monoglycerides and free fatty acids, while cholesterol esters are de-esterified into free cholesterol.

These digestive products form micelles, which transport the lipid products to the intestinal epithelial cells (enterocytes) for absorption into the circulation. Inside the enterocytes, fatty acids and monoglycerides are re-esterified into triglycerides and packaged with cholesterol and proteins into chylomicrons, which enter the lymphatic system before reaching the bloodstream (for those brave enough to look at their blood tubes during sampling, chylomicrons are what cause the milky appearance of some samples taken too soon after a meal.)

Transport and Storage

Because lipids are hydrophobic (i.e. don’t mix with water on their own), they require combination with proteins for effective and safe transport in the blood. Chylomicrons are the ‘first line’ lipoproteins, which facilitate absorption of dietary lipids in the gut, while very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) are effectively circulating transporters, which move endogenous triglycerides and cholesterol from the liver to peripheral tissues via the bloodstream.

High-density lipoproteins (HDL) mediate reverse cholesterol transport back to the liver for reprocessing, and their role in reducing blood levels has earned them the name of 'Good' cholesterol. Triglycerides are a convenient space-saving energy store, and are stored in adipocytes, and in muscle cells as an energy reserve. Cholesterol itself is either incorporated into cell membranes or used for steroid hormone synthesis. As discussed, LDL is the ‘villain of the piece’ when it comes to blood vessel plaque formation, and is therefore the primary target of statin therapy.

Lipid Breakdown

Stored triglycerides are broken down through lipolysis, releasing free fatty acids and glycerol when energy is needed. Fatty acids undergo beta-oxidation in mitochondria and peroxisomes, producing acetyl-CoA, which enters the citric acid cycle to generate Adenosine TriPhosphate (ATP), which is the universal ‘energy currency’ of our cells. During prolonged fasting or carbohydrate restriction, acetyl-CoA can also be converted into ketone bodies in the liver, providing an alternative energy source for the brain, heart and muscles.

Lipid Biosynthesis

Lipogenesis is the synthesis of fatty acids and triglycerides from excess carbohydrates or proteins. This process occurs primarily in the liver and adipose tissue. Cholesterol is synthesised via the mevalonate pathway (Figure 2) and is essential for maintaining cell membrane structure, and producing bile acids and steroid hormones. Phospholipids are also produced to construct and replenish cell membranes and generate signalling molecules.

Regulation and Clinical Significance

Lipid metabolism is regulated by hormones such as insulin, glucagon, and epinephrine, which control lipogenesis, lipolysis, and beta-oxidation. Poor metabolic control of these processes can lead to so-called dyslipidemia, characterized by elevated LDL, low HDL, and high triglycerides, and this contributes to atherosclerosis and cardiovascular disorders. Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome are also linked to impaired lipid handling and insulin resistance.

Where do the statins fit in ?

Now we’ve looked in more detail at general biochemistry surrounding the way we handle the fats in our diet, we can focus on how the statins work. As a drug class, statins are inhibitors of one of the key enzymes in the lipid biosynthesis pathway, HMG CoA reductase. Figure 1 shows a schematic diagram of the various different lipoprotein forms and the way in which their synthesis is achieved in the liver. By inhibiting this key biosynthetic pathway early on, it is possible to reduce the amount of cholesterol produced, and hence the amount circulating in the blood, without causing harmful accumulations of other precursors, or adversely affecting other life processes. Since this is the main pathway to cholesterol production, the overall level of cholesterol in the blood should decrease as a result of statin therapy, hence reducing the risk of plaque formation.

Therapy, Side Effects and Treatment Programs

Statins, once prescribed, are generally taken long-term, or until treatment is discontinued for a specific reason. To maintain lower blood levels of Total cholesterol and LDL, a steady state level of the drug is needed to keep the enzyme inhibition in place; if we stop taking it, there is a risk that inhibition will cease and lipid levels will rise again.

All drugs produce side effects if taken in sufficient quantities. The objective of therapy for any drug is to minimise the side effects while maximising the benefits of the drug. The statins, by interfering with a key step in lipid metabolism, do produce significant side effects, ranging from common mild and transient ones such as headache and effects on the gut to (fortunately) much rarer ones such as severe allergic reactions and acute muscle damage. You’ll find a full list of side effects and reactions in the product leaflet supplied with each pack. With statins, side effects or often transitory, and disappear as the body adapts to the new challenge.

Pharmacokinetics and drug dosing

One important feature of a drug’s behaviour we need to consider when deciding what dose of a drug to take is its pharmacokinetics (PK). This describes to the level of the active drug we find in the circulation after a dose, and will depend on how quickly it’s absorbed, and how rapidly it’s removed.

PK can be a complex subject, so I won’t bore the reader with too much detail here, but it’s useful to take a quick look at how a frequently prescribed ‘first line’ statin, Atorvastatin (Lipitor), is likely to behave after multiple dosing at the lowest dose of 10 mg; we’ll also see how this relates to its functional role in inhibiting HMG CoA Reductase in liver cells.

How often might we need to take Atorvastatin, bearing in mind we're aiming at a steady level in the blood ? Using a simple one-compartment PK model, the blood concentration profile expected for the standard daily dosing regime at 10 mg is shown in Figure 5. Comparing this with the profile with 12 hourly dosing with 5mg, and we get a much less ragged profile with lower peaks and comparable trough values (Figure 6). Why then isn’t a 12 hourly regime recommended ?

The answer is 2-fold: 1) a 24 hourly dose is more convenient for the patient and 2) what’s important here is the therapeutic ‘end point’ i.e the inhibition of the enzyme, rather than the blood level of the drug itself. Before the enzyme can be inhibited, the drug has to get from the bloodstream into the liver and find its way to the cells where cholesterol biosynthesis is going on. This takes time, as does the binding of the inhibitor to the enzyme, and by the same token, the dissociation from it which happens if circulating levels of the drug fall.

In practice these lags involved in drug distribution mean that a 24-hourly dosing regime is adequate to keep the enzyme sufficiently inhibited to reduce blood levels of Cholesterol, triglycerides and LDL effectively without producing side effects at the peak concentrations.

Clinicians will normally start patients on a low dose (typically 10 mg for Atorvastatin) and work upwards, while monitoring for any side effects early on in the treatment program and testing for changes in lipid profiles over time (usually at 1 month and 3 months post first dose) to ensure the medication is actually doing its job (and the patient is remembering to take the tablets!). The side effect profiles for different statins do vary somewhat, so in the event of Atorvastatin presenting with tolerability issues early on, there is also scope for switching to other statins.

When starting a statin for the first time, it’s wise to start with the lowest possible dose and work upwards, to ensure any serious side effects are picked up early. If you do encounter problems when starting treatment, always report them to a pharmacy or your GP, and if necessary stop taking the medication while you're seeking advice if the side effects are severe.

Some other benefits of Statin therapy

Apart from reducing the risk of blood vessel occlusion, the statins also have other beneficial effects, in particular on the heart. There is good evidence that they reduce cardiac excitability - anyone with a raised ventricular ectopic burden (often described as palpitations i.e. more frequent 'missed' or 'extra' beats) may well find this is reduced or even disappears after they start statin therapy. In this respect they can be a valuable adjunct to anti-arrythmic therapy with cardioselective beta-blockers such as bisoprolol. They can also reduce the likelihood of further myocardial infarcts in patients already diagnosed with an MI.

It also appears that certain statins may have a neuroprotective effect on brain function. A recent study confirmed that some commonly prescribed statins (notably Rosuvastatin and Atorvastatin) can reduce the risk of developing Alzheimers by up to 28%. The effect requires long term dosing with maximum protective effect being reached only after 3 years exposure.

The Importance of Dietary Control

One of the problems that emerges when a patient is prescribed statins after a sustained period spent attempting lipid lowering via dietary restrictions alone is the ‘relaxation effect’. Once on statin therapy, there is a temptation to resume our old ‘bad’ dietary habits, (which for most of us were probably at least partly responsible for the high lipid burden) once we are established on statins. The reasoning is typically “..the statins will always keep my cholesterol low whatever I eat, won't they, so I can just eat what I want now..”.

This is, unfortunately, a common misunderstanding of the power of statins to ‘cure all dietary ills’. They can’t, and we shouldn’t expect them to. They will only work properly if we maintain a ‘sensible’ balanced diet with minimal exposure to highly processed foods and plenty of fruit, vegetables and other roughage-containing foods. We should treat them as a valuable tool in reducing cholesterol exposure to 'safe' levels when we can't manage to do so by dietary restriction alone, and not as a cure-all for our dietary 'sins'.

This admittedly rather disappointing reality does generate other benefits, though, if we take it on board. A balanced diet won’t just improve our heart and circulatory health by preventing the effects of atherosclerosis, but will help us prevent obesity and control our blood sugar levels more effectively. Poor control of both contributes to development of type 2 diabetes and all its associated ills. 'You are what you eat', after all....

The harsh reality is that if you want a longer life with minimal ill-health, particularly in your final years, a sensible diet and control over blood glucose and lipid levels is a must.

Non-dietary alternatives to statins

If for some reason you’re unable to tolerate effective doses of one or other of the statins, and find it impossible to reduce your lipid levels by dietary control alone (as unfortunately do many people who try it) all is not lost. Here is a brief list of the alternative options:

* Ezetimibe (Zetia) – Reduces cholesterol absorption in the small intestine, lowering LDL by about 20% and can be combined with other therapies for greater effect

* Bempedoic Acid (Nexletol) – Works in the liver to reduce cholesterol production, lowering LDL by 20–25% with fewer muscle-related side effects than statins.

* Combination Pills – Ezetimibe with bempedoic acid (Nexlizet) or with simvastatin (Vytorin) can reduce LDL by 40–60%.

* PCSK9 Inhibitors – Injectable drugs like alirocumab (Praluent), evolocumab (Repatha), and inclisiran (Leqvio) enhance liver clearance of LDL cholesterol, offering substantial reductions, especially for familial hypercholesterolemia.

* Bile Acid Sequestrants – Medications such as cholestyramine bind bile acids in the gut, prompting the liver to convert more cholesterol into bile acids, lowering LDL levels that way.

* Fibrates – Drugs like gemfibrozil primarily lower triglycerides but can modestly affect LDL and HDL cholesterol.

Please note that most if not all of these are prescription medicines in UK, so will need to be discussed with your GP before you can obtain them.

Final Thoughts

In this (not so!) brief review, I’ve tried to explain how statins can be used as a ‘therapeutic management tool’ to keep our lipid profiles healthy and prevent serious damage to our blood vessels, with all that implies. I’ve also looked at some basic lipid biochemistry, to provide some background for explaining how the statins actually work, and considered briefly how the drug is handled by the body and how this relates to dosing.

We’re all living longer, but sadly we haven't yet made much impression on slowing down the ageing process itself. This 'survival with ill-health' syndrome is placing ever increasing pressure on the NHS as well as blighting our later lives. We really need to be more proactive in managing our own health – the lack of availability of GP appointments isn’t likely to be remedied soon, so the more we can do to prevent chronic illness, and avoid the need to see our GPs, or worse still, end up languishing in a hospital corridor, the better. There’s a lot we can do to monitor our own health – take a look at the Excel app (Health.xlsm), which you can download using the link above, to find out more about what you can do at home, and how to interpret your GP test results.

First published: 22.7.26; Revised 28.8.26

Figure 1: Chemical Structures of Key Lipids