#19 Does high cholesterol CAUSE cardiovascular disease?

This episode takes a deep dive into the evidence for and against the lipid hypothesis. The lipid hypothesis states that abnormal blood cholesterol levels cause cardiovascular disease. But is this true? Does high LDL (“bad cholesterol”) and/or low HDL (“good cholesterol”) actually CAUSE cardiovascular disease or is it just an association? This episode was recorded live from a General Practitioner conference. To view the presentation with the slideshow visit: www.youtube.com/DrDanMD

#14 Evidence for low fat diet and decreasing saturated fat – PURE Study

Almost all guidelines are recommending that we should reduce dietary fats and restrict saturated fats. The PURE study has called to question these recommendations and in this episode, we explore the evidence.

It’s very hard to find a guideline that does not recommend reducing total fat and saturated fat intake:

  • The Australian Heart foundation guidelines
  • The heart association guidelines
  • The Australian dietary guidelines
  • The RACGP and Diabetes Australia diabetes guidelines
  • The American Heart Association Guidelines
  • The NICE cardiovascular disease guidelines
  • The World Health Organisation healthy diet guidelines
  • The World Heart Federation guidelines

…and the list goes on and on. It seems that every single evidence based guideline has made a statement on limiting fat intake and on avoiding saturated fats, but are these statements evidence based? A study from the Lancet from the PURE trial has resurfaced this controversy and in this episode, we will explore the evidence.

Ecological Evidence

Saturated fats are in eggs, animal meats and milk products like milk, cream, cheese and butter. The recommendation to avoid saturated fats is so well known and so widely adopted that you’d think there was pretty solid evidence to back it.  Well you might be surprised – because the recommendation to decrease fat and avoid saturated fats actually came from pretty weak evidence from ecological studies. This is where you look at different populations, see what they eat and count their heart attacks. If a population is having more heart attacks, see if you can blame something in their diet. The most famous of these studies was the seven countries study by Ancel Keys. Here, Keys showed that the Countries which ate the most saturated fat had the most heart attacks. Fascinatingly, he actually collected data from 21 countries but only reported on the 7. When a guy called Jacob Yerushalmy analysed the data from all 21 countries, the association was no longer there. But it was too late, so to speak, the cat was out of the bag. Fats were deemed bad. And saturated fats…worse.

For a more in depth discussion of the history of fats and diet and guidelines, there’s a book called “Good calories, bad calories” by Gary Taubes that goes into a lot more detail. If you can handle his passive aggressive and sort of salesman type tone, then give it a read.

Surrogate Marker Studies

The second piece of evidence used a few decades ago to launch the saturated fat recommendations, is that eating foods high in saturated fats increases cholesterol. (Actually, while it increases LDL it also increases HDL and some studies suggest it conveys a more favourable HDL:LDL ratio). Does it matter though? The reason we care about cholesterol is because of its link to cardiovascular disease.  It is a surrogate marker for cardiovascular disease. But there are plenty of drugs that lower cholesterol but have no impact on cardiovascular disease. So the fact that something lowers cholesterol doesn’t always mean it is good for us. Not only that, but treatments like the Mediterranean diet reduces cardiovascular disease without having any impact on cholesterol levels. So it’s best we use evidence that assesses the impact of low fat diets and low saturated fat diets directly on cardiovascular diseases, rather than on things like cholesterol.

Cohort Studies

Since this seven countries trial, studies that have tried to back up the claim that saturated fats are bad, have failed to come through with the goods.

The next level of evidence, up from ecological studies, are cohort studies – this is where you take a population, ask them how much fat they eat (among other things), and then follow them up to see how many got cardiovascular disease and whether it was associated with their diet.

A recent review of all of the studies that used this approach was published in the BMJ in 2015 (reference below). They found that there was NO association between saturated fats and death, heart attacks, strokes or diabetes.

Randomised Controlled Trials

The highest level of evidence are randomised controlled trials, where you actually randomise a group of people to either reduce their saturated fat intake or keep it the same. By far the biggest of these studies was the Women’s Health Initiative. If you look at systematic reviews like the Cochrane Review, this trial contributed to about 60% of the power of the review. This is a complicated trial that needs its own episode, but in one of the arms of the trial, 50,000 women were randomised to two groups: The first group simply continued their usual diet, and the second group got a very intensive program of dieticians and eduction to reduce their total fat and saturated fat intake. They followed them up for 8 years and found absolutely no difference in cardiovascular disease whether they continued their usual diet or reduced their fat and saturated fat.

The PURE Study

The PURE study is the latest to stab this saturated fat theory in the back. It’s a huge prospective cohort study – and probably the highest quality one we have to date.

They recruited 156,424 people and got them to complete surveys at the start of the study and then every 3 years after that.  They were interested in things like smoking, physical activity, medications, socioeconomic things like education and income and a full medical history.

They recruited people from 18 countries getting a good mix of  third world and first world countries. This is what sets it apart from other studies.

They recruited from three high income countries – like Canada and Sweden, 11 middle income countries – like Brazil, China, Poland and South Africa, and four low-income countries like India and Pakistan. And they based this on the World Bank classification.

They also tried to get the most accurate representation of what each of these people were eating. They did this by making participants fill out food questionarres on their diet. Every country had its own questionarre that was specific to that country but the questionnaires were standardized across the countries. The problem with this method is that there is good evidence that food questionaries are often not an entirely accurate depiction of what someone is actually eating. Imagine if I asked you what sorts of foods you eat –  How different would your answer be if you were in a good mood compared to being in a bad mood – your diet might not be different, but you might feel guilty and self loathing and inflate all the bad things you eat. If you just got out of gym, on the other hand, and are feeling amazing, you might inflate all the fruits and vegetables you eat. And then there’s the problem of recall – who can remember how many times they added salt to their food? And how are you to know how much butter or oil was in that eggs Benedict you ordered from the restaurant. This is one of the big limitations of any diet study, be it a cohort or even a randomised controlled trial. In order to verify the accuracy of the answers to these questions, they got a sample of about 50-250 participants from each country to keep a 24 hour food diary every now and then. That way they could compare how well matched their actual food intake was to what they had written on their food questionnaire – and they could try and adjust for this.

This PURE study is still ongoing. They are following this population continuously and publishing studies about them left right and centre. The specific study from the PURE data that we’re looking at today was titled: “Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. It was published in the Lancet in August 2017.

Out of the 156,424 people in the PURE cohort, only 135,335 could be included in this study because they didn’t have all the data they needed. They also excluded people who had a history of cardiovascular disease. The average follow up was for 7 and a half years.

The aim of the study was to see if they could make any associations between diet and cardiovascular disease. They followed each patient up every single year to see if they had a heart attack or a stroke or any other cardiovascular outcomes.

They calculated the proportion of carbohydrates, fats and protein in everyone’s diet. They did this by converting the foods they ate into nutrients. They then split up the population into quintiles for each of these macronutrients. So for example, with saturated fat intake, they split the population into 5 groups based on the proportion of saturated fat they were eating. The top 20% – who ate the most saturated fats –  were put in the highest quintile and the 20% who ate the least amount of saturated fat were put in the lowest quintile and so on and so forth. They did this for all the macronutrients. And then for each quintile, they checked to see how many died, how many got strokes, heart attacks and so on.


Saturated Fats

Put that skinny flat white down and and take a seat for this one because you could be in for a bit of a shock. The recommendation is that we eat less than 6-10% of our total energy intake from saturated fat, it differs slightly depending on the guideline. The lowest quintile of saturated fat consumers in this study were eating 2.8% of their total energy intake from saturated fat – so they were well and truly within all the guidelines. And they were the most likely group to die! They were also the most likely group to develop stroke! And while it wasn’t statistically significant, they seemed to be at the greatest risk of all the other cardiovascular outcomes.

There was no difference between any of the other quintiles, only this lowest quintile of saturated fat consumers where at a higher risk. So it didn’t matter if you were getting 13.2% of your total energy from saturated fat or 9.5% or 7.1% or 4.9% – there was no difference in death or cardiovascular disease. But if you were eating a really low amount – 2.8%, then your risk significantly increased. All cause mortality was 7.2% in the lowest saturated fat eaters and this went down to around 4.5% as you increased the amount of saturated fat in your diet.

Total Fats

Again, the lower your total fat intake the more likely you are to die or develop a stroke. The highest quintile of fat eaters were getting 35.3% of their energy from fat and they were the least likely to die. Total death and stroke was more common when total fat made up 10% of your diet compared to if it was 35.3%.


This is where things get interesting. When I was in primary school there was a national program to teach kids about the food pyramid. On the bottom of this food pyramid – the foods we should be eating the most – were all carbohydrate foods – breads, cereals and pasta. Well, what does the PURE study have to say about that? It showed that as your intake of carbohydrates increased, your risk of death and cardiovascular disease also increased. And if you look at the graph it really looks like it’s in a linear fashion. So in the lowest quintile of carbohydrates eaters (those who obtained 46.4% of their total calories from carbs) – 4.1% died during the follow-up period. But among those who ate the most carbohydrates (77.2% of their total calories) – 7.2% of them died.

Other Macronutrients

Interestingly, animal protein intake was associated with lower rates of mortality.


  • Why do we insist on making recommendations when we don’t have sound evidence to support these recommendations. Especially when they involve a radical change in lifestyle.  Using a different example,  most dietary guidelines, up until recently, used to strongly recommend that parents should avoid giving their babies foods that are allergenic. The American Academy of Pediatrics told all mothers not to eat peanuts during pregnancy, while breastfeeding and not to give them to their child until they reach 3 years of age. Then the LEAP trial came along in 2015 and showed that actually, the earlier you give peanut products to babies, the less likely they are to develop allergies. It is clear that these recommendations had actually caused a lot of food allergies.  The difference is that the paediatric nutritional guidelines have been quick to adjust their recommendations after the LEAP trial came out, but the total fat and saturated fat recommendation don’t seem to show any signs of slowing down despite an increasing body of evidence that we were probably wrong.
  • This isn’t perfect evidence. Nothing beats a randomised controlled trial in terms of telling us whether something is causative, but it’s almost impossible to do a good quality randomised controlled trial on diet. Firstly blinding is impossible. Secondly, if I told you to stop eating saturated fats, or you start eating much more saturated fats, would you be able to do that? For 5 years? It’s very tricky. This is one area of medicine that you argue that cohort studies are probably better at giving us answers than randomised controlled trials – just because it’s so hard to control the bias in RCT’s. But even still, we do have randomised controlled trials – which do not find any benefits from a diet low in saturated fats. It would be very unusual not to pick up an association from cohort studies if there was something very bad about saturated fats as the guidelines suggest.  When you look at cohort studies of smoking – there was like 8-10 times higher rates of lung cancer in those who smoked. It was a very robust association. But here, cohort studies just don’t seem to find an association.
  • One might argue that people who are health conscious might exercise more, smoke less and choose their diet carefully – therefore skewing the results. But if anything, this would skew the results towards low-fat diets looking better. Because healthy people are eating less fat and less saturated fat – because that’s what society has been telling them to do – so if the people in the low-fat group are exercising more – this would make the results look even more impressive.
  • Perhaps people who can’t afford meats which are high in fat are more likely to die not because they are eating less fat, but because they don’t have money to pay for healthcare, etc. Interesting potential bias. So the researchers did additional analyses where they adjusted for socioeconomic status and found the same results.

Bottom Line

This is a direct quote from the conclusion of the study:

Global dietary guidelines should be reconsidered in light of the consistency of findings from the present study, with the conclusions from meta-analyses of other observational studies and the results of recent randomised controlled trials.

References and Links

#3 Does CPAP Reduce CVD in Sleep Apnoea? – SAVE trial

In this episode we delve into the SAVE study which was THE landmark trial that investigated whether using CPAP (Continuous Positive Airway Pressure)  to treat Obstructive Sleep Apnoea (OSA) also improved cardiovascular disease. The trial also assessed the impact of CPAP on quality of life.

The study randomised 2,687 patients to either receive CPAP or not. These patients were at very high risk of cardiovascular disease, having a previous history of stroke or myocardial infarction. They all underwent an overnight sleep study in a core sleep laboratory and all had to have moderate to severe sleep apnoea. Those who were dangerously sleepy, with an Epworth Sleepiness Scale of greater than 15, were excluded.

After and average of 3.7 years they found no difference in cardiovascular disease between those getting CPAP versus those who did not. 15.4% of those not getting CPAP developed cardiovascular disease versus 17% of those who did get CPAP. This was not statistically significant but it was favouring those who did not get CPAP.

There was an improvement in sleepiness in the CPAP group, with an average reduction of 2.5 points on the 24 point Epworth Sleepiness Scale. There was also a slight reduction in anxiety and depression scores, but the average change was not clinically significant.

So what’s the bottom line?  In patients who have obstructive sleep apnoea, and are not severely sleepy, as defined by an Epworth sleepiness scale score of 15 or less, CPAP will marginally improve sleepiness but have no impact on their cardiovascular disease.

In this episode we also discuss associations versus causations, appropriate participant numbers for cardiovascular trials and Star Wars?…yep….Star Wars!

The trial was published in NEJM in September 2016 and can be found here: http://www.nejm.org/doi/full/10.1056/NEJMoa1606599#t=article

Music by Polyrhythmics, song title El Fuego

#2 SPRINT trial – which blood pressure target is best?

In episode 2 of the Evidence Based Medicine Podcast we delve into the SPRINT trial.
This trial assessed whether targeting systolic blood pressure to less than 120mmHg is better than targeting to less than 140mmHg it terms of harms and reduction in cardiovascular disease.

The trial was conducted in 9,361 patients with very a very high risk of cardiovascular disease but who didn’t have diabetes or a past history of stroke. They were randomised to 2 groups: A standard blood pressure group who were targeted to a systolic BP of less than 140mmHg or an intensive blood pressure group who were targeted to less than 120mmHg systolic. They were followed for an average of 3.3 years

In this episode we go through the results of the trial, it’s impact on hypertension guidelines across the world and how it sits in the face of other similar trials, most notably the ACCORD BP trial. We also discuss some of the controversy about the trial as reported in many commentaries in the literature.

I was a very well done and important trial published in NEJM in November 2015 and stands for “Systolic Blood Pressure Intervention Trial”…I guess SBPRINT trial wouldn’t have sounded as good!

The bottom line is that for patients with hypertension, at high risk of cardiovascular disease, but without diabetes or previous stroke, treating them to a systolic blood pressure target of less than 120, compared to less than 140 will decrease their chance of cardiovascular disease by 1.6% over 3.3 years and will decrease their chance of dying by about 1%. But it comes at a cost, most important of which is an increase in acute renal failure by 1.8%, an increase in worsening renal function by 2.7% and an increase in being seriously harmed by episodes of hypotension, syncope or electrolyte abnormalities by about 3%

Here is a more in depth look at the results:

The benefits of treating blood pressure to 120 versus 140 systolic are as follows:
1. A reduction in cardiovascular disease from 6.8% to 5.2% with an absolute reduction of 1.6% or a Number Needed to Treat (NNT) of 63 over 3.3 years.
2. Death from any cause decreased by 1.2% – It went from 4.5% to 3.3% with a NNT of 83 over 3.3 years
3. Cardiovascular death decreased by 0.6% – It went from 1.4% to 0.8% with a NNT of 167
4. Heart failure decreased by 0.8% – It went from 2.1% vs 2.3% with a NNT 125
5. There was no difference in AMI or stroke

The harms of treating blood pressure to 120 versus 140 systolic are as follows:
1. Worsening renal function increased by 2.7% – it went from 1.1% to 3.8% with a Number Needed to Harm (NNH) of 37
2. – Acute renal failure increased by 1.8% – it went from 2.6% in the 140 systolic group to 4.4% in the 120 systolic group. NNH 56
3. Serious adverse events increased (events that were either fatal or life threatening, or required prolonged hospitalisation, or resulting in significant disability). Episodes of hypotension increased from 2% to 3.4% with a NNH 71
– Syncope increased from 2.4% to 3.5%, with a NNH 91
– Electrolyte abnormality also increased from from 2.8% to 3.8% with a NNH 100
– There was no difference in injurious falls, it was about 2.2% in both groups.

Reference: http://www.nejm.org/doi/full/10.1056/NEJMoa1511939
Music by Polyrhythmics, track titled “El Fuego”