High blood cholesterol – problem (almost) solved?

“Your cholesterol is a little high”. How many of us have been given this slightly worrying news after a routine blood test? This post aims to help readers put this news into context and decide how to respond to this news. It will also show how mass use of statins has transformed the blood cholesterol profile of older people in Britain.

What blood level of cholesterol is considered high?

A high blood cholesterol has been known to cause an increased risk of heart attacks and other cardiovascular diseases since the 1950s. One of the core aims of UK and US dietary guidelines has been to lower average cholesterol levels and so minimise the number of people having heart attacks and dying prematurely from them. Table 1 shows a widely used classification of people according to their blood cholesterol level.

Table 1  A classification of people on the basis of their plasma cholesterol concentration

Plasma cholesterol concentration (mmol/L)                Classification

Under 5.2                                                            optimal range

5.2-6.5                                                                 mildly elevated

6.5-7.8                                                                 moderately elevated

7.8+                                                                     severely elevated

So your cholesterol level may be deemed “a little high” if it is above 5.2 and maybe even slightly less than that if you have other cardiovascular risks like smoking, high blood pressure, obesity or diabetes.

Efforts to reduce blood cholesterol before statins?

Table 2 shows the percentages of people in these blood cholesterol categories according to data collected as part of the National Diet and Nutrition Survey in around 1986 (1994 for the over 65s). These data were collected before the mass use of statins began but after many years of dietary advice and substantial changes in British diets aimed at lowering blood cholesterol levels.

Table 2   Percentage of British adults of different ages in different cholesterol categories before the advent of mass statin use.

Men (%)                                  Women (%)

Age                             18-24   50-64   18-64   65+      18-24   50-64   18-64   65+

Concentration

<5.2                             75        13        32        34        66        10        36        28

5.2-6.5                         21        45        40        45        28        31        38        37

6.5-7.8                         4          32        22        18        4          38        18        26

>7.8                             0          10        6          3          2          21        8          9

 

Average (mmol/L)       4.7       6.4       5.8       5.6       4.9       6.8       5.8       6.0

Table 2 shows that in the 1980s, two-thirds of middle-aged and elderly people had blood cholesterol levels that were above the ideal range and the majority of men and women aged 50-65 had levels that were moderately or severely elevated. There was a very pronounced trend in both sexes for plasma cholesterol to increase with age with only a quarter of young adults having even slightly elevated cholesterol levels (i.e. above 5.2mmol/L) and only a few percent with values in the moderately or severely elevated ranges. The numbers having values above the optimum and those with more seriously elevated levels both rose steeply with age. There was a marked tendency for women’s values to rise more steeply than men’s values after the menopause. In the over 65s, there were three times more women than men with severely elevated cholesterol levels (above 7.8mmol/L).

Any individual’s personal risk directly attributable to their cholesterol level rises as they get further above 5.2 and it is relatively small unless they are substantially above the optimal range. However, for the population as a whole, there were so many people in the mildly and moderately elevated categories that only reductions in these categories would have a serious impact upon population rates of heart attacks and cardiovascular deaths. The long-term aim of dietary guidelines has therefore been to persuade the whole population to embrace dietary changes that would shift the population distribution of cholesterol levels downwards.

Plasma cholesterol is made up of two major fractions which have traditionally been separated on the basis of their density:

Low density lipoprotein (LDL) or the “bad cholesterol”

High density lipoprotein (HDL) or the “good cholesterol”

The total cholesterol is usually taken as an indicator of the LDL cholesterol but more sophisticated testing does now routinely measure these separately. Raised levels of LDL cholesterol in blood cause fatty deposits in arteries and this can lead to furring up of arteries or atherosclerosis. This in turn restricts blood flow and increases the risk of thrombosis which is what causes most heart attacks and strokes. HDL on the other hand seems to help clear away surplus cholesterol and take it back to the liver, so it is protective against cardiovascular disease. The LDL cholesterol level can readily be altered by dietary changes and this can be demonstrated in short-term experiments with volunteers. The HDL is less affected by dietary modification although it is increased by regular exercise. A recent American Heart Association (AHA) report confirmed the principles of how dietary fats affect LDL cholesterol that had first been laid down in the early 1960s:

  • Saturated fats from meat, dairy produce, palm oil and coconut oil raise LDL cholesterol levels
  • Polyunsaturated fats like sunflower oil, corn oil, peanut oil and soya oil lower LDL cholesterol levels
  • Monounsaturated fats like olive oil and rapeseed oil have smaller beneficial effects upon LDL
  • Dietary cholesterol normally has only a small raising effect upon LDL cholesterol.

The most effective dietary means to reduce blood cholesterol levels and thus the risk of cardiovascular disease is to replace saturated fat in the diet with polyunsaturated fat from vegetable sources. This explains why dietary guidelines since the 1970s and 1980s have emphasised the need to reduce saturated fat intakes. Such advice has transformed elements of the British diet. Back in the early 1970s butter or cheap hard margarine were the predominant spreading fats and animal fats (lard and beef tallow) were the principal cooking fats. Almost all of the milk sold was full fat milk. Now, most milk is semi-skimmed or skimmed and most people cook with a vegetable oil and use a spreading fat that has less saturated fat than butter; low-fat spreads now have a very large share of the market. Old fashioned hard margarine and vegetable shortening made by hydrogenation of vegetable or fish oil is no longer sold in the UK because it is high in artificial trans-fatty acids which are now known to greatly increase cardiovascular disease risk.

What are statins and do they work?

Statins are a class of drug that lower LDL and total cholesterol. They have become one of the most widely prescribed groups of drugs in industrialised countries. The first statin (lovastatin) was approved for use in the USA in late 1987 and simvastatin first approved for prescription in the UK in August 1989. In 2004 the UK became the first country to permit the sale of low dose statins in pharmacies without the need for a prescription. Statins work by inhibiting a key enzyme in our synthetic pathway for cholesterol (HMG CoA reductase). Most of the cholesterol in our blood and bodies is synthesised by us and only 10-20% derived from food; a vegan diet is essentially cholesterol-free. Statins cause large reductions in total and LDL cholesterol levels. In the longer term they also reduce heart attacks, strokes, cardiovascular and total deaths.  A 2003 paper in the BMJ by Professor Malcolm Law and colleagues quantified the effects of statins and table 3 shows the reductions in LDL-cholesterol levels that statins produce.

Table 3            Percentage reductions in LDL-cholesterol levels caused by 3 selected statins. Based on an amalgamation of 164 controlled trials by Law et al (2003)

Drug/dose        10mg/day                    20                    40                    80mg/day

Atorvastatin    37%                             43%                 49%                 55%

Rosuvastatin   43                                48                    53                    58

Simvastatin     27                                32                    37                    42

This table leaves no doubt that statins are very effective at reducing total and LDL cholesterol. To put these numbers into perspective, early intensive long-term trials of cholesterol-lowering diets generally achieved a 10% reduction at best in free-living subjects. Professor Law and his colleagues went on to assess the impact of a 1mmol/L reduction in LDL cholesterol on heart attack rates:

 1st year             11% reduction

 2nd year            25% reduction

 3-5th year         33% reduction

 6th or more        36% reduction

Note that all of the values in table 3 represent a fall of at least 1.5mmol/L and one reaches 3mmol/L.

In the so-called Jupiter trial the effect of a statin (rosuvastatin) was measured in a trial involving subjects in 26 countries who did not have high cholesterol levels but had high levels of an inflammatory marker. This trial was terminated early by the independent monitors because the effects were so marked. After around 2 years of treatment there was a 54% reduction in heart attacks, a 48% reduction in strokes, and a 20% reduction in deaths from all causes. So statins produced big reductions in deaths and cardiovascular events, even in people with normal blood cholesterol levels.

Increases in statin use

Current NICE guidelines suggest that anyone over 40 who has a 10% risk of developing cardiovascular disease within 10 years should be considered for a 20mg/day prescription of atorvastatin; most diabetics and anyone over 85 should also be considered. Almost all people with existing heart disease (e.g. angina or a previous heart attack) should be prescribed 80mg/day of atorvastatin. Physicians assess the risk of cardiovascular within 10 years using a simple online calculator (QRISK2). QRISK2 predicts 10 year risk when physicians insert the patient’s age, sex, ethnicity, postcode (to indicate socio-economic status), smoking habits, family heart disease history, a cholesterol measure, blood pressure, BMI and 4 other existing conditions or treatments. In 2014, these NICE recommendations replaced an earlier version which used a 20% risk of cardiovascular disease within 10 years as the key threshold; a 7.5% 10 year risk threshold is now recommended in the USA.

Statin use in the UK has soared in the last decade or so. At least 8 million people in Britain currently (2017) take prescribed statins and the latest guidelines would make a further 2 million people with chronic kidney disease eligible for a prescription. Substantial numbers are also taking low dose statins bought without prescription. The trend in statin use seems to be continuing rapidly upwards. In 2017, the authors of a study published in the influential journal Circulation called for people in their 20s and 30s who have cholesterol levels above the optimal range to be made eligible for a statin prescription and this might add a further 1.6 million to the eligible number. We may be approaching the point where any adult with a cholesterol level above 5.2 mmol/L, plus substantial numbers below this threshold who have other risk factors for cardiovascular disease, may be offered a statin prescription. This might amount to three-quarters of the adult population.

Aidan O’Keefe and colleagues from University College London analysed trends in statin prescribing over the period 1995-2013 based upon a sample of 7 million UK adults. These data were collected before NICE cut the threshold for a low dose statin from a 20% to a 10% risk of developing cardiovascular disease within 10 years. Initiation rates for statin therapy (i.e. new recipients) rose sharply up until 2006 and then declined steadily, presumably as the reservoir of eligible but untreated people in the population was diminished. Since 2004, the initiation rate has been lower in women and men because the assessment tools (e.g. QRISK) were less likely to classify women as having a 10 year 20% risk of developing cardiovascular disease. The prevalence of statin prescriptions (i.e. total proportion of people being prescribed) rose quite slowly between 1995 and 2001 and then exponentially between 2001 and 2007. Total prevalence growth slowed in the last years of this survey. By 2013 there was quite a pronounced gap between prescription prevalence in men (higher) and women.

What are cholesterol levels like now?

Table 4 shows current cholesterol levels in British adults as measured in blood samples collected between 2014-16 as part of the National Diet and Nutrition Survey.

Table 4            Distribution of plasma cholesterol (mmol/L) levels in British Adults in around 2015

Men (%)                      Women (%)

Age group                   19-64               65+                  19-64               65+

Concentration

<5.2                             73                    69                    65                    48

5.2-6.5                         24                    21                    28                    38

6.5-7.8                         3                      0                      6                      11

>7.8                             0                      0                      1                      3

 

Mean                           4.7                   4.2                   4.8                   5.3

 

The strong upward trend for statin prescriptions and the inclusion of large new groups of eligible people means that these values are likely to be even lower now. Serious elevation of blood cholesterol has largely been eliminated in the middle-aged and elderly men. High blood cholesterol levels are now much more common in women than in men and significant numbers of older women (14%) still have cholesterol levels that are moderately or severely elevated. High blood cholesterol and coronary heart disease have traditionally been seen as predominantly male problems; the lower prevalence of statin use in women was noted earlier.

What about side-effects?

In Law’s 2003 BMJ paper they discuss the side effects by participants reported in 48 trials. In those receiving the statin 1063 out of 14197 (7.5%) patients reported at least one adverse symptom that might be due to the drug.  This compared to 923 out of 10568 (8.7%) of those in the placebo group i.e. the crude rates were slightly higher in the placebo group. The prevalence of 12 specific symptoms, including muscle pain and gut problems were similar in the placebo and control groups. They calculated that on a worse-case scenario, that statins did not cause adverse effects in more than 2% of recipients.

The rare but serious side effects of statin use are rhabdomyolysis and liver failure due to hepatitis. Rhabdomyolysis is a rapid breakdown of muscle tissue and release of muscle contents into the blood; it is frequently seen in victims of crush injuries. It can lead to cardiac arrest and kidney failure if not promptly treated. Blood levels of a muscle enzyme, creatine kinase, and potassium rise and patients produce “tea coloured” urine due to the presence of myoglobin (a haemoglobin-like compound normally found in muscle cells). In the 35000 patients for whom side effects were reported, 8 cases of rhabdomyolysis were diagnosed in the statin group and five in the placebo group, none of which resulted in death or serious illness. The US FDA estimated that deaths from rhabdomyolysis associated with current statins was about 1 per million patient years. No cases of liver failure were seen in the sample of the BMJ paper but 449 patients (1.3%) showed elevated levels of an enzyme in blood used to test for hepatitis; 338 placebo patients (1.1%) showed a similar rise in this enzyme. What these data suggest is that not only are statins effective but they also appear to be remarkably safe. No treatment or intervention is guaranteed to be 100% safe and it is worth noting that initial dietary advice that warned against saturated fat led to large increases in the use of margarine and shortening made from hydrogenated oil. All of these hydrogenated fats contained artificial trans-fatty acids and some had very high concentrations of them. These are now known to be much worse than saturated fats at increasing cardiovascular disease risk and they have been banned or voluntarily reduced to minimal amounts in the UK, USA and may other western countries. No traditional margarine made from hydrogenated oil is now sold in the UK.

A medical success story?                                 

The mass use of statins has certainly helped to get average cholesterol levels sharply down and seriously elevated blood cholesterol has been all but eliminated in men. High cholesterol levels are still often found in older women. Should we regard this as a success story in which doctors have made effective use of a powerful new tool to finally and rapidly make huge progress in eliminating the problem of high cholesterol and its consequences? Or is it an admission that health promotion based upon cholesterol-lowering dietary guidelines have largely failed and we have had to resort to putting a high proportion of the disease-free adult population on a drug for the rest of their lives? This failure is despite huge changes in the British diet since the 1970s. I will leave readers to come to their own conclusion but as a man of mature years I would not hesitate to try a statin if my cholesterol was significantly above 5.2 (last measured at exactly 5.2).

 

 

 

 

   

 

 

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