Dietary Fat. A Doctor's Review. (Extended version)

Dietary Fat. A Doctor’s Review

Dr Magda Robinson

(Extended Review)

21.11.17

As a medical doctor specialising in the treatment of obesity, I often get asked which the best fats are. Butter? Coconut oil? Olive oil? Lard? This article will look at saturated fat (SFA), which is found in coconut oil and animal fats such as butter, meat and cheese, and the evidence for the link to cardiovascular disease (CVD). Is there an increase in the risk of heart attacks and strokes with an increased intake of SFA? Is there any protection from CVD through the intake of polyunsaturated fats (PUFA) such as rapeseed oil or flaxseed oil, or monounsaturated fats (MUFA) such as olive oil?

There have been many confusing articles recently about the relationship between saturated fatty acids (SFA) and cardiovascular disease (CVD). Some claim that there is no evidence for a link, despite the National Institute for Clinical Excellence (NICE) guidelines stating: “Lifestyle modifications for the primary and secondary prevention of CVD. Cardioprotective diet: to eat a diet in which total fat intake is 30% or less of total energy intake, saturated fats are 7% or less of total energy intake, intake of dietary cholesterol is less than 300 mg/day and where possible saturated fats are replaced by mono-unsaturated and polyunsaturated fats.” (NICE 2014).

I researched the literature from the 1960’s to the present day, and now present a brief summary of the evidence. Cardiovascular disease (CVD) is the leading cause of death worldwide: 31.5% of the population dies of coronary heart disease or stroke or other CVDs. It is caused by thrombosis (the blocking of an artery due to a blood clot), arising from atherosclerosis (the build-up of cholesterol and triglycerides (fats) in the artery wall). One of the major well-established major risk factors is dyslipidaemia (raised serum cholesterol and low-density lipoprotein cholesterol). The latter is ‘bad’ cholesterol: plasma proteins which transport cholesterol and triglycerides to the tissues.

The link between low-density lipoprotein cholesterol (LDLC) and the risk of CVD is well known, as there is a direct correlation between levels of LDLC and the risk of CVD: GPs and cardiologists use the QRISK®2 Calculator, which includes serum cholesterol levels, to work out the risk of having a heart attack or stroke over the next ten years. Furthermore, in the genetic condition familial hypercholesterolaemia, the body is unable to remove LDLC from the blood, leading to extremely high serum cholesterol and LDLC levels. The consequences are that before the age of 50, men with the condition have a 50% chance of suffering from angina or a heart attack. The treatment is to take cholesterol-lowering drugs, which reduce the risk of CVD by up to 40%, and eat a diet reduced in saturated fat and cholesterol. The subsequent reduction in LDLC is directly correlated with a reduction in CVD. The link between saturated fat and CVD was originally documented in large scale epidemiological studies such as the Framingham Heart Study (US based) and the Seven Countries Study, in which it was observed that serum cholesterol levels were directly correlated with coronary heart disease (CHD), and this was related to the amount of animal

fat in the diet (Castelli 2001). The Framingham Heart Study found that the risk of CHD was raised by 90% with a serum cholesterol of 7.76mmol/L; 40% at 5.8mmol/L, and a low risk at 3.8mmol/L or less. Note that over half the UK population has a high serum cholesterol of over 5mmol/L. The Seven Countries’ Study reported that in some rural parts of Asia, Africa and Latin America where cholesterol levels were less than 3.6mmol/L, CHD was not seen. Likewise, the China Study observed that in rural China, where serum cholesterol levels were low and animal protein was less than 7% of total protein intake, among 427,000 people under the age of 64, not one person died of CHD in a 3 year observation period (Campbell 2006). This compares with the autopsy results on 300 young fit US soldiers killed in Korea (average age 22): 77.3% had some evidence of heart disease (Enos 1953).

Further epidemiological evidence linking diet to CHD stems from data looking at vegetarians and vegans, who have lower serum cholesterol and LDLC than meat eaters, and a 34%-37% lower risk of CHD than meat eaters (Key & Fraser et al 1999).

The recent controversial studies claiming no link were only based on epidemiological data, which was in itself flawed because it compared diets high in SFA with diets high in unhealthy refined carbohydrates, sugars and trans fats, but lower SFA; thus no advantage was detected with the lower SFA diet. Furthermore, the evidence for saturated fat inducing atherosclerosis isn’t based on epidemiology alone. It also stems from decades of research in pathology, biochemistry, genetics, metabolism, pharmacology, and animal and human clinical studies.

Saturated fat-mediated inflammation and insulin resistance Saturated fat not only raises LDLC, it also has been proven via numerous mechanisms to cause chronic inflammation and insulin resistance, which also increase the risk of CVD. The latter’s mechanisms include an increase in inflammatory signally, gene expression and oxidative stress in fat cells and skeletal muscle cells, which in turn alters insulin receptors, resulting in insulin resistance and a consequent increase in the risk of CVD (Kennedy et al 2009).

A human study induced decreased insulin sensitivity after only 24 hours of a high SFA diet (45%) (Xiao et al 2006). Another human study demonstrated that consuming a high (17%) SFA diet for 3 months impaired insulin sensitivity compared with a low SFA diet (8%), which actually improved insulin sensitivity by 8.5% (Vessby et al 2001). (Both diets contained 37% total fat, with the same amount of protein and carbohydrate). The authors discussed how dietary fat is incorporated into phospholipid membranes. A high proportion of SFA and a low proportion of unsaturated fatty acids causes the cell membranes to become more rigid, which is detrimental to insulin receptor binding activity, ion permeability and cell signalling i.e. insulin resistance. The opposite proportions of plasma fatty acid composition lead to fluid cell membranes and improved insulin receptor binding activity i.e. greater insulin sensitivity.

Long term a high SFA diet has serious consequences: in a 10-year investigation, it was found that the risk of developing type 2 diabetes was directly related to higher proportions of SFA and lower proportions of omega 6 (n-6) PUFA in serum cholesterol esters compared to the opposite proportions, even after controlling for BMI (Vessby et al 1994).

Saturated fat Long-chain SFAs increase serum LDLC, the commonest being myristic acid (e.g. butter, meat, coconut and palm oil) and palmitic acid (e.g. butter, red meat, chicken, eggs, palm oil and chocolate). Human feeding studies illustrate that when diets rich in butter, coconut oil and PUFA are compared, the cholesterol and LDLC are consistently raised to atherogenic levels in the butter and coconut oil diets (butter more than coconut), compared to the PUFA diets, in as little as 9 days (Eyres et al 2016). For example, one randomised controlled trial (RCT) assessed diets high in SFAs (12.6%): butter or cheese; polyunsaturated fats (PUFA); monosaturated fats (MUFA), and high carbohydrate. After 4 weeks the butter caused the greatest rise in LDLC (16.2%), followed by cheese (12.3%), compared to the other diets.

(Brassard et al 2017). Another RCT compared the consumption of 4.5% of energy from butter with olive oil. After 5 weeks, the total cholesterol and LDLC were significantly higher in the butter group (Engel et al 2015).

A feeding experiment compared eating SFA-rich muffins made with palm oil to PUFA-rich muffins made with sunflower oil. After 7 weeks, the SFA group had significantly greater total fat, liver fat and visceral fat, all of which are known to be precursors to dyslipidaemia, insulin resistance and CVD. One of the mechanisms is that n-6 PUFA is known to inhibit lipogenesis (fat production) in the liver, but SFA does not have this effect (Rosquvist et al 2014).

The World Health Organisation published a meta-analysis of 84 randomised controlled feeding studies examining the effects of increasing or decreasing SFA in the diet (Mensink 2016). Protein levels were kept constant, and the diets had an average duration of 3 to 5 weeks. The results were that replacing 1% of PUFA, MUFA or carbohydrate with SFA increased total cholesterol, LDLC, the LDLC: HDLC ratio and the Apolipoprotein B (ApoB) levels. Conversely replacing 1% of SFA with PUFA, MUFA or carbohydrate decreased the same parameters. ApoB is a type of protein made in the liver and is found in the most atherogenic lipoproteins such as LDL, VLDL and chylomicrons. It is a good predictor of CVD as it represents the total burden of the main lipoproteins involved in the atherosclerotic process. It is alarming that even small changes in SFA content of the diet over a short period of time have such dramatic effects on the atherogenicity of blood lipids. The World Health Organisation recommends that SFA are kept to below 10%.

Reliable evidence There is no doubt that SFA increases LDLC, but what about the evidence for CVD? The results of the largest ever observational study (115,782 people) with the longest duration (28 years) led to The Times printing the headline “Butter is still bad for the heart” (24.11.16): “Recent studies have questioned whether saturated fat in meat and dairy is bad for the heart but the new study, in the BMJ, found the danger had been masked by people switching to equally unhealthy sugar and refined carbohydrates... it concluded that people who eat less saturated fat do have less heart disease.”

This Harvard study was the pooled data from the Nurses’ Health Study and the Health Professionals’ Follow-Up Study, which was of excellent quality due to its size, duration and the controlling of multiple variables, and was the first study to examine specific SFA. The initial findings were that the highest intake of red meat and high fat dairy increased the risk of coronary heart disease (CHD) by 15% and 8% respectively, and consuming one glass a day

of whole milk raised risk by 48% (Hu et al 1999). When long chain SFA such as myristic acid and palmitic acid were increased by 5% of energy intake, CHD risk increased by 29%.

In 2016 the results were that myristic acid led to a 13% higher risk, and palmitic acid to an 18% higher risk of CHD. The highest quintile of SFA led to an 8% increase in total mortality.

Conversely, if particular SFAs were replaced by certain macronutrients, CHD risk was reduced. For example, replacing 1% of palmitic acid with PUFA was associated with 12% less risk; plant protein 11% less risk; wholegrains 10% less risk and MUFA 8% less risk (Zong et al 2016). A further analysis of Harvard data found that replacement of 5% of energy from SFA with PUFA also reduced total, CVD, cancer, neurodegenerative, and respiratory disease mortality (Wang et al 2016).

These results concur with other studies: it has been calculated that replacing 5% of energy from SFA with PUFA is associated with a 25% lower CHD risk (Mozaffarian et al 2010; Li et al 2015). In fact, as a response to the misleading reports, the American Heart Association (AHA) published Dietary Fats and Cardiovascular Disease: A Presidential Advisory, in Circulation (Sacks et al 2017) with a comprehensive review of the evidence. In its assessment of high quality prospective observational studies, which isolated the effects of different macronutrients (unlike the misleading reports), the results revealed that replacing 5% of energy intake from SFA with equivalent energy from other nutrients significantly lowered the risk of CHD: PUFA by 25%, MUFA by 15%, and carbohydrates from whole grains by 9%. Replacement with refined starches and sugars increased risk by 1% (not significant) and replacement of 2% of SFA with trans fats increased risk by 5% (Li et al 2015).

The AHA Advisory included a meta-analysis of four core high quality RCTs, selected because the dietary intakes were controlled, of long duration, proved adherence through measurement of blood or tissue fatty acids, and did not include confounding trans fats: the LA Veteran’s study (Dayton et al 1969); the Oslo Diet-Heart Study (Leren 1970); the British Medical Research Council Study (1968), and the Finnish Mental Hospital Study (Turpeinen et al 1979, Miettinen et al 1972, 1983). Meta-analysis showed that lowering SFA and replacing it with PUFA-rich vegetable oil lowered CHD by 29%, consistent with the effect of the experimental diets on serum cholesterol. The effects were particularly strong for patients under the age of 65, and for those with high serum cholesterol levels.

Of note is the LA Veterans study which was a double-blind high-quality study on 846 men, and had the advantage of being a long duration of 8 years (Dayton et al 1969). The meals were well controlled in an institutional setting and adherence proved with regular blood and tissue analysis. Two thirds of the animal fats were substituted with vegetable oils such as corn, soya, safflower, and rapeseed oil for use in cooking and baking. Skimmed milk was used, and 7 egg yolks were allowed per week. The diets resulted in a 12.7% difference in serum cholesterol levels in the two groups.

The outcome was that heart attacks, sudden death and ischaemic stroke were reduced by 34%, total CVD events decreased by 31%, and there were 41% fewer strokes in the diet groups. The beneficial effects of a low SFA diet were stronger in men under the age of 65 and in those with higher serum cholesterol levels at the start: twice as many men suffered from fatal CVD events in the higher cholesterol groups and in the younger men compared to

the experimental diet. Thus there was evidence of a low SFA high PUFA diet having a secondary prevention effect.

The American Heart Association states: “The scientific rationale for decreasing saturated fat in the diet has been and remains based on well-established effects of saturated fat to raise low-density lipoprotein (LDL) cholesterol, a leading cause of atherosclerosis; to cause atherosclerosis in several animal species, especially nonhuman primates; to clear the atherosclerosis when is it reduced in the diet; and likewise to reverse atherosclerosis in humans. In addition, reducing saturated fat and replacing it with polyunsaturated fat in randomised controlled trials has reduced the incidence of CVD... “In summary, RCTs that lowered intake of dietary saturated fat and replaced it with polyunsaturated vegetable oil reduced CVD by 30%, similar to the reduction achieved by statin treatment. Prospective observational studies in many populations showed that lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD and of other major causes of death and all-cause mortality. In contrast, replacement of saturated fat with mostly refined carbohydrates and sugars is not associated with lower rates of CVD and did not reduce CVD in clinical trials.

Replacement of saturated with unsaturated fats lowers low-density lipoprotein cholesterol (LDL), a cause of atherosclerosis... we conclude strongly that lowering intake of saturated fat and replacing is with unsaturated fats, especially with polyunsaturated fats, will lower the incidence of CVD.� (Sacks et al 2017).

Likewise, the European Atherosclerosis Society has issued a consensus statement summarising the evidence, entitled Low-density Lipoproteins Cause Atherosclerotic Cardiovascular Disease, based on genetic, epidemiologic and clinical studies on more than 2 million participants (Ference et al 2017).

Unreliable evidence What is wrong with the studies claiming no association between SFA and CVD? The main problem is that they only looked at changing the saturated fat intake, without considering the replacement. If a diet high in saturated fat is compared to a diet high in refined grains and sugars or trans fats (which most of the studies did), then the result is no worsening of the CVD risk with SFA (Sacks et al 2017; Briggs et al 2017). However, there is overwhelming evidence detailed in these reviews that replacing saturated fat with polyunsaturated fatty acids (PUFA) significantly reduces CVD risk.

Another criticism of the controversial reports is that they pooled together a number of studies with a huge variation in results and design. Frequently there was inconsistent adjustment for co-variants such as demographic and lifestyle factors or macronutrients. Some of the studies only looked at all-cause mortality, not CVD mortality. Many of the studies were of very low quality, small or of a short duration (less than 2 years). Frequently meals were not controlled, and adherence was poor (as documented by variable serum cholesterol levels). Additionally, most of the studies examined secondary prevention, using patients who already had severe ischaemic heart disease and in whom a change of diet would be too late to be of any benefit.

Other faults were that the meta-analyses were incomplete, either using incorrect figures or omitting studies which found that replacing SFA with PUFA did reduce CVD. The studies were also guilty of selective reporting of the original results: for example they ignored data

which showed a strikingly increased incidence of heart attacks in the younger age groups on the SFA diets, and in those following the diets for 2 years or more. Furthermore, some of these studies did document (in the small print) a strong association between circulating SFA and CVD risk (records of dietary intake can be unreliable): for example a 15% higher risk of CHD with higher serum palmitic acid, but these results were ignored by the media.

There are several issues with the most publicised meta-analysis of observational studies (Chowdhury et al 2014). The analysis was not complete, and two large meta-analyses were omitted, which found that replacing 5% of SFA with PUFA reduced CVD events by 13%, and CVD deaths by between 26% and 31% (Jakobsen et al 2009; Farvid et al 2014). The Department of Nutrition at Harvard School of Public Health (HSPH) criticised the article as it spotted that incorrect figures had been used, generating inaccurate results. Unfortunately, the media had already published glib generalisations from the article, before it was corrected: revised results showed a greater association between SFA and CHD. These corrected results were not reported in the media.

Close inspection of the analysis revealed stronger associations when circulating fatty acids were used and the type of SFA was examined (records of dietary intake can be unreliable): a 6% higher risk of CHD with all SFAs; a 15% higher risk with palmitic acid; and a 16% lower risk with omega 3 fatty acids (n-3 PUFA). None of these statistics were publicised in the press. Additionally, the paper compared the highest third of intake with the lowest third of intake. If the highest and lowest quintiles had been compared, a stronger association would have emerged.

Most importantly many of the analyses did not take into consideration the dietary replacement of SFA. For example, it included the Sydney Heart Study (Ramsden et al 2013), which showed no benefit of a low (less than 10%) SFA diet, but the source of the alternative fat was block margarine, which contains trans fats and is known to cause CVD. Commonly the alternative calories in the studies came from refined grains and sugars, which are not associated with the prevention of CVD. Also, the use of statins can negate the effects of diet.

Harvard School of Public Health stated on their website that the study’s conclusions regarding types of fat were ‘seriously misleading and should be disregarded’.

Likewise a negative editorial (DiNicolantonio 2014), was criticised by Prof Tom Sanders, Head of Diabetes and Nutritional Sciences Division in the School of Medicine at King’s College London. He said: “This article rubbishes the relationship with saturated fat and CVD, misrepresents the scientific evidence and then goes on to put the blame on sugar. It is beyond reasonable doubt that elevated LDL (low density lipoprotein) cholesterol is a major determinant of risk factor for cardiovascular disease. The saturated fatty acids palmitic, myristic and lauric acids raise LDL cholesterol in increasing order in meta-analysis human experimental studies (Sanders 2013). Sugar intake does not affect LDL-cholesterol or blood pressure.

Diabetes increases risk of CVD but diabetes is not caused by eating sugar. The relative risks of sugar intake with risk of obesity are very modest compared with obesity and physical inactivity.” While sugar sweetened beverages contribute to obesity, where intakes are high it’s probably because it is providing extra calories. However, the high consumers of sugar fizzy drinks are young people – not older people who are those most at risk of CVD. It is

likely that high intake of sugar-sweetened beverages is contributing to obesity rather than having direct effects on CVD risk. Refocusing dietary advice on sugar and away from fat modification and reduction is not helpful Large reductions in saturated fatty acid intakes have occurred in the UK and other Western countries over the past 25 years so intakes are now close to guideline amounts (less than 11% energy). This has been achieved by changes in dietary habits (reducing the use of butter/spreads high in saturated fats) and changes in the food supply with unhydrogenated vegetable oils replacing animal fats. The changes have been in parallel with falls in average serum cholesterol levels in the UK, Western Europe, Australasia and the USA as well as in CVD incidence (Sanders 2014).

In the UK total fat intake has fallen in absolute terms and as a proportion of energy, while sugar intake has remained as a proportion of the energy relatively unchanged (around 21% energy) according to the nationwide surveys (with non-milk extrinsic sugars providing 1112% energy). The UK has experienced a 55% fall in cardiovascular disease since 1997 (Bajakal 2012). Some of this is due to lower blood cholesterol and blood pressure and decreased smoking prevalence despite the increase in obesity and diabetes.

People eat foods, not nutrients. Dietary advice to avoid fatty meat products, choose reduced fat dairy produce, and to restrict intakes of cakes, biscuits and puddings, which are often both high in saturated fat and sugar, and to select foods containing unsaturated oils such as nuts, fish and vegetable oils remain good sense. Those who fail to learn the lessons of history are likely to repeat its errors.�(Sanders 2014) Another well-publicised negative study was a meta-analysis of six randomised clinical trials (RCTs) conducted prior to 1983 (Harcombe et al 2015). Its conclusions can be questioned for many reasons: it included small studies, of short duration, and relied on self-reporting of dietary intake; it focussed only on CHD deaths and all cause deaths (not CVD events such as non-fatal heart attacks or strokes, which in some of the studies in question were found to be reduced with PUFA diets); it pooled together studies using PUFA, MUFA and carbohydrates, which confuses the results; and most of the studies were on patients who already had advanced CVD, so any change in diet would have been too late.

Of note is that it omitted a key trial: the Finnish Mental Hospital Study (Turpeinen et al 1979, Miettinen et al 1972, 1983). This latter trial on 1222 patients conducted over 6 years compared a high SFA diet (mostly butter) in one hospital to a high PUFA diet (mostly soya bean oil) in a second hospital, thus ensuring good adherence in the institutional setting. The high PUFA diet led to a serum cholesterol 14% lower and a 41% reduction in CHD death compared to a diet high in SFA. The Harcombe meta-analysis included the results of the corn oil study (Rose et al 1965), in which heart disease patients were allocated to a normal diet or a diet supplemented with corn oil. The problems with this study are numerous. It was very small (only 31 patients were left in the second year of the trial); actual meals weren’t administered; the replacement foods were not accounted for and thus could have been refined carbohydrates or trans fatscontaining margarine (patients were instructed to avoid fried foods, fatty meat, sausages, pastry, ice-cream, cheese and cakes and to cut down on milk, eggs and butter, but not told what to replace them with); adherence was questionable due to the serum cholesterol change

being non-significant by the end of the 2 years, and 2 years is an inadequate duration.

Furthermore, most of the patients had already had a heart attack, so a change in diet would have been unlikely to change outcome. In addition, corn oil is not a healthy replacement for SFA due to the very high level of n-6 compared to n-3 PUFA: the ratio of n-6 to n-3 is 46:1, compared to rapeseed oil (1:2) or flaxseed oil (1:3). The higher the ratio, the less n-3 can be converted into the active forms of EPA and DHA, which are essential fatty acids for health.

Finally, it is of great concern that the key author did not declare any competing interests when she first submitted the article, when in fact she is an author and publisher of diet books, all advocating low carbohydrate diets with no restriction on saturated fats. The article’s claims would have potentially served her well financially, and thus was open to considerable bias. Open Heart had to publish her competing interests in the next edition, following objections by key scientists.

Other meta-analyses reporting no association between SFA and CVD did not look at the replacement of saturated fat, and included studies which used refined carbohydrates or trans fats (e.g. the Sydney Heart Study) as the comparison diets (De Souza et al 2015; Siri-Tarino et al 2010).

There was a well-publicised study which re-examined the Minnesota Coronary Survey (Frantz et al 1989; Ramsden et al 2016). This particular study had been conducted in 6 mental hospitals and 1 nursing home, from 1968 to 1973, with 9570 participants. The differences in the SFA contents of the diets were 18% and 9%, and n-6 PUFA 3% and 13%. Note that only 16% (1568) patients were followed for 2 years or more. The more recent paper chose to highlight the difference in all-cause mortality between the SFA diets and the PUFA diets and also to look at autopsy files of 149 patients. It did not recover data on CHD. Its findings were that there was no mortality benefit for the intervention group, and there was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts at autopsy.

There are several flaws with these conclusions: the experimental diet replaced butter with corn oil margarine, which is known to contain trans fats and is strongly associated with CHD. It only compared deaths from all causes and not cardiac deaths. Deaths from all causes are widely varied, including dementia, cancer, falls and suicides which are not necessarily related to SFA and cholesterol. Additionally, the duration period analysed was only ‘one year or more’. For results to be meaningful, a RCT should be conducted for 2 years or more. Any results from less than 2 years on the diet can be disregarded. The mean duration on the diet was only 384 days, and only 1568 patients were followed for 2 years or more.

The study is also guilty of selective reporting of the original results: if the data is examined for heart attack and sudden death for 2 years or more, more men died on the control (SFA) diet than the experimental diet. (26 vs 20; no significant difference for the women). In the younger age groups of 55 years or less, and following the diets for 2 years or more, there was a strikingly increased incidence of heart attack and sudden death in the control compared to the experimental group: 13 vs 4 in men and 8 vs 3 in women. These results were ignored in the recent paper and therefore not highlighted in the media.

Furthermore, there are issues with the autopsy findings: the study only looked at half of the autopsy results; the mean age was 69.5 years; and the diets had been followed on average for

only 10 months or less. For a diet to have any benefit, it won’t have much effect in only several months on an older person, over 65 years, who already has advanced lesions.

Finally, the paper conducted a meta-analysis of RCTs that specifically tested replacement of saturated fat with vegetable oil rich in linoleic acid, and concluded that they ‘showed no indication of benefit’. However, this meta-analysis included the corn oil study, which was too small and low quality to produce meaningful results (as discussed previously), and the Sydney Heart Study, which used a margarine high in trans unsaturated fat as a major component of the PUFA diet.

Professor Walter Willett of the Harvard School of Public Health voiced many of these criticisms in the BMJ (Willett 2016). He also stated that the level of n-6 PUFA was well above the range recommended by the American Heart Association, and the study had no relevance to current dietary recommendations of replacing SFA with PUFA, including sources of both n-3 and n-6 PUFA. The PUFA diet in the Minnesota study was very low in n3 as vast amounts of corn oil were used, and the unhealthy effects of excessive corn oil have already been discussed.

Animal studies More than 100 years of clinical experiments in animals clearly prove that saturated fat is atherogenic. Atherosclerosis can be induced in as little as 2 months in pigeons, pigs, dogs and monkeys on diets consisting of a low fat control diet combined with added lard, hydrogenated coconut oil, butter, or egg yolks, with added cholesterol (Pick et al 1979; Maruffo & Portman 1968; Bond et al 1980; Gresham et al 1965; Moghadasian et al 2001). The extent of the CVD increases with the severity of the induced hyperlipidaemia. One experiment induced serum cholesterol levels 8 times higher than normal using hydrogenated coconut oil, which caused particularly severe atherosclerotic lesions. However, replacement of 25% of the coconut oil with safflower oil high in PUFA markedly reduced the extent of the hyperlipidaemia and atherogenesis.

Non-human primates rapidly develop high cholesterol and arterial atherosclerosis when fed dietary SFA compared to monkeys fed a ‘standard monkey diet’ (less than 2% SFA) or PUFA (Sacks et al 2017). A control food is used to maintain weight and induce no metabolic or serum changes: a mixture of mostly corn, wheat and soya beans, comprising 69% carbohydrate, 18% protein, and 13% fat (only 1.4% SFA). This can then be easily manipulated to increase the SFA content and induce atherosclerosis. For example, feeding baboons a high-cholesterol, high-fat diet for two years reliably induces atherosclerosis, with risk factor profiles, arterial lesions, and changes in vascular function also seen in humans (Mahaney et al 2017).

Baboons have a cholesterol metabolism and fatty acid composition similar to humans, and are also omnivorous, which makes them useful species to compare to humans. Laboratory baboons fed on a ‘stock diet’ show no atherosclerosis. However, baboons fed an ‘atherogenic’ diet, where the stock diet is enriched with 15% butter and 15% egg yolk, or 20% butter and 2% cholesterol develop arterial lesions within 18 months (Gresham et al 1965). After 3 months, the serum cholesterol and LDLC increased to levels seen in humans, on both the butter and cholesterol diets and the butter and egg yolk diets. All these animals developed aortic atherosclerosis, compared to none on the stock diet.

A moderately atherogenic diet (containing cholesterol) was fed to monkeys, with added fats: SFA from lard or palm oil (17.5% SFA content), MUFA or PUFA (safflower oil).

Remarkably the PUFA diet protected against CHD: after 5 years the extent of atheroma was over twice as large in the MUFA diet, and over 5 times higher in the SFA diet. These changes correlated with the levels of LDLC, which were 61% higher in the SFA diet. (Rudel et al 1995).

It is possible for arterial lesions to regress through diet alone, by manipulation of serum cholesterol. Rhesus monkeys fed an atherogenic diet for 17 months developed 60% luminal narrowing in the coronary and other arteries. Half the monkeys were then given a low fat diet and half an n-6 PUFA-rich diet for 20 months. There was rapid reduction in luminal narrowing to around 20% on both the diets (Armstrong et al 1976). Another study used an atherogenic diet of 1mg/kcal cholesterol to cause hypercholesterolaemia, which in turn induced coronary atherosclerosis. The dietary cholesterol was then reduced, which resulted in regression of the atherosclerosis (Clarkson & Klumpp 1990).

Note that serum cholesterol has to reduce substantially and be maintained for at least 2 years to induce regression of arteriosclerosis: a study reported that monkeys fed an atherogenic diet for 19 months only regressed once the serum cholesterol reduced to less than 5.2 mmol/L, but more severe atherosclerosis (induced over 3 years) required 4 years of dietary-induced cholesterol of less than 5.2mmol/L to trigger regression. (Clarkson et al 1981,1984). These findings underline the importance of maintaining lower serum cholesterol levels long term.

Regression of CVD in humans Two world-renowned American cardiologists have had success in regressing arterial atherosclerosis in human patients through diet alone. Dr Dean Ornish conducted a trial of a 10% fat plant-based diet on patients who needed cardiac surgery, compared to patients with equally severe heart disease who were put on a 25% fat diet. The cholesterol intake was 19mg and 139g respectively. The plant-based diet included fruit, vegetables, pulses, grains, with occasional egg white and skimmed milk. After one year on the plant-based diet, 82% had regression of their heart disease, despite being on no medication. Arteriography showed shrinkage of the blockages, LDLC levels were lower by 40%, and the frequency of chest pain was reduced by 91%. The control group actually had worsened atherosclerosis and cardiometabolic risk factors, despite being on medication, with a rise in chest pain frequency of 165%, and no weight loss. The LDLC reduced by only 5%. At 5 years arteriography showed continued shrinking of the blockages in the plant-based group, and there were less than half as many cardiac events than the usual care group. The usual care group had progressively worsening stenosis throughout the 5 years (Ornish et al 1990;1998).

Dr Caldwell Esselstyn, has had similar success in reversing heart disease using plant-based nutrition (Esselstyn 2001). He offered seriously ill patients, who had had failed interventions such as angioplasty and bypass surgery, an exclusively plant-based diet, in conjunction with their usual lipid lowering medication. The diet consisted of wholegrains, vegetables, fruit and legumes, with no animal products at all. Of those who maintained the diet, they experienced a profound drop in cholesterol: it reduced from an average of 6.4 mmol/L to an average of 3.5 mmol/L. In addition, symptoms were relieved, and there was no recurrence of coronary events in 12 years. Patients lost weight, blood pressure normalized, and type 2 diabetes, erectile dysfunction, angina, peripheral vascular disease, and carotid disease all improved or

resolved. Angiography at 5 years proved that none had progression of the disease, and 70% had significant regression of the coronary blockages.

The evidence above makes it clear that replacing saturated fats with PUFA, plant proteins, wholegrains or MUFA reduces the risk of developing CVD. I will now elaborate on different macronutrients’ effects on CVD. Refined carbohydrates and added sugars In most of the studies claiming no association between SFA and CVD, SFA were replaced by carbohydrates, but the type of carbohydrate makes a large difference: one cohort replacing 5% of energy from SFA with isocaloric amounts of refined starches and added sugars did not affect CHD risk (Li et al 2015). Another showed that replacing 5% of SFA with high glycaemic index (median GI 93) carbohydrates increased risk by 33% (Jakobsen et al 2010).

How could added sugars affect CHD risk? Firstly, the fructose component of sucrose can increase triglyceride (TG) levels if taken in large amounts (more than 100g a day). Raised TGs are a risk factor for CVD (to a lesser degree than raised LDLC). Human isotope studies have shown that up to 5% of fructose is converted to TG in the overfed state (less than 1% at moderate intake) (Sun & Empie 2012). 100g of fructose is the equivalent of consuming 11 apples, 20 bananas, 540g of Frosties or 5.7 cans of coke.

Secondly, sugar-containing highly palatable foods can lead to overconsumption of calories and weight gain, with subsequent cardiometabolic disease, increasing the risk for CVD. This occurs particularly with liquid form sugars, as these are less compensated for than solid calories. (Liquids are less filling than solids.) Importantly, the foods most associated with weight gain are (greatest effect first) chips, crisps, sugary beverages, red meat and processed meat (Mozaffarian et al 2011). (Incidentally the foods most associated with weight loss are yogurt, nuts, fruit, wholegrains and vegetables.) Note that diabetes risk is only increased with sugary beverages and fruit juice; high intake of sugar (sucrose) is not associated with diabetes risk; high fruit intake is associated with a 7% lower risk of diabetes and high wholegrain intake with an 18% lower risk of diabetes (Khan & Sievenpiper 2016).

A comprehensive review of the evidence on sugars and diabetes and cardiometabolic disease stated: Using the totality of the highest quality evidence from controlled feeding trials, we demonstrate that fructose-containing sugars can lead to weight gain, increase in cardiometabolic risk factors and disease only if it provides the excess calories... Prospective cohort studies, which provide the strongest observational evidence, have shown an association between fructose-containing sugars and cardiometabolic risk including weight gain, cardiovascular disease outcomes and diabetes only when restricted to sugar sweetened beverages and not for sugars from other sources. (Khan & Sievenpiper 2016). Thus, it is important to avoid sugar sweetened beverages to reduce CVD risk.

Carbohydrates: wholegrains Higher wholegrain intake has been associated with a reduction of CHD risk by 21% (Tang et al 2015) and CVD mortality by 16% (Benisi-Kohansal et al 2016). Replacing 1% of long chain SFA with wholegrains is associated with a 6% reduced CHD risk (Zong et al 2016), and replacing 5% of SFA with wholegrains reduces risk by 9% (Sacks et al 2017). Replacing

dairy fat with wholegrains also reduces risk of CVD (Chen et al 2016). Research consensus is that wholegrains are protective against CVD. One of the mechanisms for wholegrains reducing CVD risk is that soluble fibre (e.g. oats, barley, pulses, fruit and vegetables) reduces serum cholesterol and triglycerides. Additionally, fibre-rich foods reduce the risk of insulin resistance and diabetes, which are risk factors for CVD. Increasing wholegrain intake over 6 weeks reduced blood glucose, fasting insulin and insulin resistance in obese, insulin-resistant subjects (Pereira et al 2002). Cereal fibre consumption reduces the markers of systemic inflammation (Qi et al 2006). Furthermore, cereal fibre is known to increase adiponectin levels, which is associated with improved glycaemic control, insulin sensitivity, a favourable lipid profile and reduced inflammation (Mantzoros et al 2006).

Polyunsaturated fat A meta-analysis of randomised controlled trials that increased intake of n-3 PUFA together with n-6 PUFA showed a reduced risk of CHD and CHD death by 22% (Ramsden et al 2010). Other studies reveal that the highest quintile of PUFA intake is associated with between a 20% and 32% reduction in CHD risk compared to the lowest quintile (Li et al 2015; Hu et al 1997). Similarly, those with the highest circulating levels of n-6 PUFA have a 49% lower CVD mortality, compared to the lowest levels, and those with the highest circulating levels of both n-3 and n-6 PUFA have a 54% lower mortality risk compared to those with the lowest (Wu et al 2014). Replacing 5% of energy from dairy fat with PUFA decreases risk of CVD death by 26% (Chen et al 2016).

There is strong evidence that replacing SFA with PUFA (with sufficient n-3 PUFA) reduces CVD risk. One meta-analysis reported that for every 5% of energy from SFA exchanged for PUFA in feeding trials, LDLC decreased by 0.26 mmol/L and the total cholesterol:HDL cholesterol ratio decreased by 0.16 (Mozaffarian et al 2010). Other trials have shown that replacing SFA with PUFA reduces the risk of CHD by 17-27% (Hooper et al 2015; Skeaff & Miller 2009). It has been calculated that replacing 5% of energy from SFA with PUFA is associated with a 25% lower CHD risk (Mozaffarian et al 2010; Li et al 2015). Prospective cohort studies show that replacing SFA with PUFA reduces CHD, CVD, total and CVD mortality.

N-3 PUFA is associated with improved cardiovascular health. The mechanisms include: n-3 PUFA reduces platelet aggregation and hence the risk of thrombosis; it relaxes the endothelium of arteries; it suppresses the development of atherosclerotic lesions; and it has anti-arrhythmic effects (Kromhout et al 2012). Guidelines advise 2-3g/day, which can be obtained from e.g. 28g of walnuts or a tablespoon of flaxseeds. A meta-analysis demonstrated that for each 1g/day increase in dietary n-3 PUFA, there is a 10% lower risk of CHD death (Pan et al 2012). Other researchers have calculated that for every 0.1% increase in energy from n-3 PUFA, there is a 12% decrease in sudden cardiac death (Wang et al 2016). Note that if the subject is already taking a statin, the beneficial effect is lost.

A review of 21 clinical trials found that consumption of EPA and DHA by high risk patients was associated with an 18% lower risk of coronary events (Delgado-Lista et al 2012). A study looking at heart attack patients who started consuming a Mediterranean diet (including

n-3 and olive oil in place of SFA), reported a reduced rate of cardiovascular death in the 2year follow-up (De Lorgeril et al 1999).

Protein If protein is substituted for SFA, only plant protein is beneficial: replacing 5% of SFA with animal protein increases risk of CHD by 29% (Praagman et al 2016). Replacing 1% of energy from long-chain SFA from plant protein reduces CHD risk by 7% (Zong et al 2016). The mechanisms for this are numerous (Briggs et al 2017), including the differential effects of amino acids (animal proteins tend to be higher in the sulphur-containing amino acids): high levels of lysine and methionine have been known to induce hypercholesterolaemia.

Methionine also raises homocysteine levels which is another risk factor for CVD. Leucine, inhibits nitric oxide synthesis in vascular endothelium and may also promote insulin resistance. (Nitric oxide dilates blood vessels and reduces blood pressure, so inhibition has the opposite effect.) Haem iron is a pro-oxidant and hence is associated with greater CVD risk. Processed meat is extremely high in sodium and nitrites and nitrates, which are wellestablished risk factors for CVD. Advanced glycation end products (formed by the cooking of red and processed meat) increase inflammation and the CVD process.

Red meat is a rich source of L-carnitine and phosphatidylcholine, which are metabolised by gut bacteria to TMA, and then to trimethylamine N-oxide (TMAO) in the liver, which causes atherosclerosis and increases the risk of CVD (Briggs et al 2017). TMAO alters cholesterol metabolism in the liver, intestines and arterial endothelium, resulting in an increase in atherogenic foam cell formation in artery walls (Liu et al 2015). It has also been indicated in thrombosis (Tilg 2016). A meta-analysis found higher circulating TMAO was associated with a 23% higher risk of CVD events and a 55% higher risk of mortality (Qi et al 2017). Another source of TMAO is gut bacteria metabolising phosphatidylcholine, found in high concentrations in egg yolks and some meats. Interestingly vegans and vegetarians have significantly less carnitine-metabolizing gut bacteria and hence lower circulating levels of TMAO (Koeth et al 2013). Note that a compound in balsamic vinegar and extra virgin olive oil inhibits microbial TMA formation, and resveratrol also has an inhibitory effect on TMAO production (Wang et al 2016).

Plant proteins do not contain these deleterious components, and in fact contain micronutrients beneficial to blood vessels such as potassium, B and C vitamins, polyphenols, phytosterols, and magnesium. Furthermore, studies have shown a 30% reduction in CHD when plant proteins are substituted for carbohydrates or animal proteins (Kelemen et al 2005). Note that eating meat is more detrimental than eating dairy: when 5% of dairy fat is replaced with 5% animal fat from non-dairy sources, risk of CHD increases by 6% (Chen et al 2016).

Cholesterol Dietary cholesterol, which is found in meat, poultry, eggs and high fat dairy products, has three important issues: firstly it increases the susceptibility of LDL to oxidation, which stimulates the formation of atherosclerotic plaques, and inhibits the production of beneficial nitric oxide. Secondly it markedly increases postprandial lipaemia (levels of cholesterol after eating). Thirdly it potentiates the adverse effects of dietary saturated fat, by increasing SFA’s effects on LDLC (the ‘bacon and egg effect’): a study reported a high SFA diet on a low cholesterol intake (200mg) only raised LDLC slightly (0.16mmol/L), but on a high

cholesterol intake (600mg) a high SFA diet led to a substantial increase in LDLC (0.82mmol/L). Conversely, when 600mg cholesterol was combined with a high PUFA diet, the LDLC increased by 0.42mmol/L, half the rise seen with the SFA diet (Spence et al 2010).

This study highlights the diets which raise serum LDLC, (with increasing effect): SFA plus normal cholesterol; PUFA plus high cholesterol; SFA plus high cholesterol. Thus SFA and cholesterol raise serum cholesterol independently, but combined the effects are substantial.

Epidemiological studies show that daily egg consumption increases diabetes risk by 58% for men and 77% for women (Djousse et al 2009), and in diabetics the consumption of one egg a day doubles CVD risk (Qureshi et al 2007). Nutritional guidelines advise less than 300mg/day cholesterol in healthy individuals, and less than 200mg/day in people at risk of CVD. One egg yolk contains around 200mg. Harvard School of Public Health advises a maximum of one egg a day, but 3 or less per week in diabetics, due to the increased risk of heart failure and CHD in larger numbers.

Four foods to lower serum cholesterol Apart from replacing SFA with PUFA, plant proteins and wholegrains, there are four foods proven to lower serum cholesterol levels. These can be eaten every day: oats (soluble fibre); soya protein (e.g. soya mince, soya burgers, soya milk, tofu); nuts (up to 70g a day to avoid weight gain); and plant sterols (e.g. Flora Pro-Active spread). Aim to eat 10-25g of soluble fibre a day (also found in beans, peas, brown rice, barley, citrus fruits, strawberries, and apples).

Three healthy diets One dietary pattern recommended by doctors and nutritionists is the Mediterranean diet, popular in Crete and southern Italy in the 1960’s. It was originally described by researchers who noticed that levels of CHD and certain cancers were very low among people eating a low SFA diet with an abundance of plant foods: fruit, vegetables, bread and other forms of grains, potatoes, beans, nuts, seeds and olive oil. The Mediterranean diet has a high monosaturated/saturated fat ratio, moderate consumption of dairy products, 4 or fewer eggs per week, moderate alcohol, and a low consumption of meat. The diet is low in saturated fat (less than 8% of energy) (Trichopoulou & Lagiou1997).

Another diet associated with low rates of CHD is the Japanese Okinawan: nutrient dense and antioxidant rich. It is notable for having 7 portions of fruit and vegetables, and is also low in meat, refined grains, saturated fat, sugar, salt, and full-fat dairy products (meat and fish are eaten only on holidays). It is high in carbohydrates, due to the very high intake of orangeyellow root vegetables, and contains 80g of soya a day. A typical day consists of sweet potato and miso (soya) soup with plenty of vegetables for breakfast, lunch and dinner, with a little rice and bread added. It contains only 7% saturated fat. Life expectancy in Okinawa is 81.2 years. USA death rates from CHD are 11.8 times higher in women and 5.8 times higher in men than in Okinawa (Willcox et al 2009).

Perhaps the healthiest diet of all belongs to the longest-living people in the world: vegetarian Californian Seventh Day Adventists. Men and women have expected ages at death of 83.3 and 85.7 years respectively. These figures are greater than the Californian population by 9.5 and 6.1 years respectively. The risk of CHD death is 27% lower than the meat eating population (Fraser & Shavlik 2001; Le & Sabate 2014).

Conclusion The American Heart Association an American College of Cardiology have conducted extensive research on all the available evidence, including the critical studies mentioned above, and concur with NICE guidelines, stating that saturated fat should be less than 7% of total energy intake (Sacks et al 2017). Only about 5% of US adults consume less than 7% (Rehm et al 2016). Thus most adults need to reduce saturated fat to reduce their risk of CVD. The SFA should be replaced (in order of greatest benefit first) with PUFA, plant proteins, wholegrains and MUFA. This means minimising meat; replacing butter, palm oil and coconut oil with PUFAs such as rapeseed oil, walnut oil, and flaxseed oil (the latter two both high in essential n-3 PUFA); and using olive oil (MUFA) for cooking. Note that when heating olive oil the temperature should be kept below 180oC. Soft PUFA-rich margarine containing no trans fats or hydrogenated vegetable oils can also be used. The ideal is to consume less than 20g SFA a day in order to reduce the risk of CVD.

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