Evidence-Based Nutrition For Chronic Disease Prevention

Prevention and Reversal of Chronic Disease (Why Nutrition Matters, Part C)

By Mario Kratz, PhD

Published April 20, 2022

Can we Prevent or Even Reverse Type 2 Diabetes or Heart Disease?

Can we prevent or even reverse chronic diseases such as type 2 diabetes or heart disease by changing our diet? In this blog post, we will take a look at a few studies that have put that question to the test.

This is the last article in this three-part series on why nutrition matters.

In the first part, we talked about how common micronutrient deficiency diseases still are all around the world, illustrating that it is critical for a long and healthy life that our diet provides us regularly with all of the essential vitamins, minerals, and trace elements.

In the second part, we discussed the currently ongoing global nutrition transition towards more and more industrially-designed ultra-processed foods, and how that transition is strongly linked to increasing rates of obesity and associated diseases such as type 2 diabetes in populations all around the world.

In this third part today, we will look at a few studies that provide evidence that nutrition is not just about meeting micronutrient needs or avoiding overeating, but that changing one’s diet can prevent or even reverse common chronic diseases such as type 2 diabetes or heart disease.

Now, I have picked these studies not because they are the most rigorous or best of the best. In fact, each of these studies is more or less flawed in one way or another, but I still felt that each provides interesting and inspiring insights. And I’ll share my concerns about each in this blog post, so if you have watched the YouTube video and would like to know more about the strengths and limitations of each study, you are in the right place.

Prevention of Type 2 Diabetes with a Low-Fat Diet

The first study I would like to talk about is the grand-daddy of prevention studies: the Diabetes Prevention Program, or DPP, the main paper of which was published about 20 years ago.

The objective of the Diabetes Prevention Program was to find out if the development of type 2 diabetes can be prevented in people who are at very high risk. They enrolled 3,234 participants with prediabetes.

Prediabetes is basically a pre-disease stage where blood sugar levels are no longer regulated perfectly within the normal range. As a result, blood sugar levels in the fasting state and/or after a meal are slightly elevated, but not high enough to be called diabetes.

Men and women with prediabetes were randomized to either receive a placebo drug or a diabetes drug, metformin (850 mg twice daily), or a comprehensive diet and lifestyle modification program.

Created by the author. Based on: Diabetes Prevention Program Research Group. New Engl. J. Med. 2002; 346: 393-403.

That lifestyle program was designed to get people to eat a healthier diet, lose some weight and keep it off, and move more by regularly going on brisk walks. The lifestyle intervention was taught in person on a one-to-one basis where participants met 16 times with a case manager over 24 weeks. The emphasis of these 16 lifestyle change units was to get people to eat less fat and fewer junk foods, and to engage in moderate-intensity physical activity for at least 150 min per week.

And, indeed, the investigators did manage to get participants to lose weight and keep that weight off to some extent over 4 years. The line marked lifestyle in the figure below shows that participants lost an average of about 14 pounds or 6.5 kilos, in the first 6 months of the lifestyle change intervention. And even though they regained about half of the weight they had lost over the next three and a half years, they were still weight-reduced compared to baseline and compared to the other two intervention groups. 

Diabetes Prevention Program Research Group. New Engl. J. Med. 2002; 346: 393-403.

The investigators also got participants to move more. Physical activity was fairly stable in the placebo and metformin groups, but participants in the lifestyle group increased their activity by walking briskly for an extra 90-120 min (in science nerd terms, 6-8 Metabolic Equivalent of Task-hours) per week. So, not all that much, but it was certainly a notable increase, and a notable difference to the other two groups.

In terms of the dietary changes, participants in the lifestyle intervention group ate fewer calories, and less total and saturated fat. They ate a lot fewer sweets. less red meat and dairy, and they also ate fewer servings of grains, which at the time were mostly bread and baked goods made from refined, white wheat flour (see graph below for changes in the first year post randomization). The only foods that participants ate more of were fruit and vegetables.

Interestingly, some of these changes were also seen in the other two intervention groups, even though they were not given instructions to eat differently. Specifically notable was that the consumption of sweets, dairy, and grains also declined quite notably in both the placebo and the metformin groups. These findings suggest that just being in a diabetes prevention study made participants, in general, more aware of their diet, and they made efforts to eat better even if they were not randomized to the lifestyle change program.

In my experience, this is typical for this type of intervention. Participants need to be told during the consenting process which intervention groups they may be randomized to, and my guess is that most people were eager to be randomized to the (free) lifestyle change group. Those who ended up being randomized to the placebo or metformin groups may have been dissapointed and – having just learned of the hypothesis that a low-fat dietary pattern may reduce progression to type 2 diabetes – may have secretly ‘opted-in’ to a dietary change as well. This is a known problem in these types of randomized controlled trials, and would be expected to reduce differences between the intervention groups.

Diabetes Prevention Program Research Group. New Engl. J. Med. 2002; 346: 393-403.

So what was the effect of these lifestyle changes on diabetes incidence? The investigators assessed every 6 months which participants had progressed to diabetes. The cumulative incidence shown on the y-axis in the graph below means new cases of diabetes that was diagnosed among participants over the 4-year follow-up period.

At baseline, no one had diabetes yet, because only people with prediabetes were enrolled. But then, over time, some people developed diabetes, and we are seeing clearly that there is a separation between the groups. After 4 years, we see that about 37% of participants in the placebo group had developed diabetes, but only 28% in the metformin group and only 20% in the lifestyle change group. That is certainly a very notable difference. And, by the way, in case this is unclear, the vast majority of these new cases of diabetes here would be expected to be type 2 diabetes.

Diabetes Prevention Program Research Group. New Engl. J. Med. 2002; 346: 393-403.

Let’s be clear that we cannot attribute this entire effect to the dietary changes, because people also moved a bit more. However, given the relatively small increase in physical activity, it seems very likely that the dietary changes and the weight loss largely explain the substantial reduction in diabetes incidence.

The Diabetes Prevention Program certainly has had a major impact on how we view type 2 diabetes, namely as a disease that can largely be prevented by our diet and lifestyle. I will say though that the low-fat diet that was taught in this lifestyle change program is, let’s say, a bit outdated. The program they developed focused mostly on cutting out fat and junk food, but gave little guidance on what to eat instead. With my research group, we have used the Diabetes Prevention Program materials several times for lifestyle change interventions, and we all have always felt that a bit more information should have been included on which specific foods are particularly recommended vs. discouraged.

Another aspect is that one could argue that low-carbohydrate diets would be at least as suitable, or even better, for the prevention of type 2 diabetes in people with prediabetes. That is because in both prediabetes and manifest diabetes, the body is no longer able to regulate blood sugar levels within the normal range. It would therefore seem plausible that a dietary intervention that reduces carbohydrate intake would be more suitable for this population. 

Either way, the Diabetes Prevention Program showed quite clearly that a change in diet and lifestyle can substantially reduce the development of type 2 diabetes. With that knowledge, we should be able to prevent all or at least most cases of type 2 diabetes. Sadly, these data do not seem to have slowed the worldwide diabetes pandemic, with more than 460 million people suffering from type 2 diabetes worldwide today. And the prevalence is expected to increase dramatically in the years to come.

Prevention of Type 2 Diabetes with a Low-Carbohydrate Diet

Are there any data to support my comment that low-carb diets would also be a good, maybe even better option, for the prevention of type 2 diabetes? 

Yes, there are some, but let me first clarify what we are looking for in an intervention to prevent type 2 diabetes.

When we change our diet to prevent or reverse type 2 diabetes, we have one primary goal, and that is to lose some weight, and to do so in a sustainable fashion (i.e., not to go on repeated jo-jo diets). That is because we understand clearly that the primary defects in sugar metabolism that lead to type 2 diabetes are caused by having excess body fat. Losing some weight and fat mass and keeping it off will almost always improve our body’s ability to regulate our blood sugar levels.

Now, losing some weight in the short term is usually achievable by going on any kind of calorie-restricted diet. The problem is that most people quickly grow tired of constantly being hungry and therefore regain the weight they lost.

It is therefore important to find a way of eating that will help with that weight loss and that we can happily live with in the long term. Now, we’ll discuss this in much more detail on this website, but I do think that most evidence suggests that people tend to overeat calories whenever they are eating a lot of the hyper-palatable, highly seductive, energy-dense foods that are rich in both refined carbs and fat. Say, donuts, muffins, cookies, cakes, pizza, ice cream, hot dogs, burgers, potato chips, or french fries. Or if they drink a lot of their calories, in the form of soda, energy drinks, beer, or other alcoholic beverages.

So one benefit of the dietary intervention in the Diabetes Prevention Program we discussed above is that if people are asked to eat a low-fat diet and cut out junk foods, all of those foods that people tend to overeat on are suddenly off-limits, and instead, the foods they can eat are unprocessed low-fat foods, such as fruits and vegetables, beans and lentils, fish, lean meats, whole grains, potatoes, or sweet potatoes (see figure below). All of these are nutritious foods, but not hyper-appealing when eaten without added fats or oils, and so overeating becomes rather hard on these types of foods and most people spontaneously lose weight. And, as the Diabetes Prevention Program shows, people keep some of that lost weight off for years if they can maintain this low-fat dietary pattern long enough.

But what if you made a shift in your diet in the other direction, going high-fat, but low-carb. Again, these highly seductive foods shown on top of the graph above would be largely off-limits, because while they usually are high in fat, they are also rich in sugar or other refined carbs. Instead, you would be eating a lot of fatty meats, fatty fish, nuts and seeds, full-fat dairy, in addition to non-starchy vegetables.

Well, you would also be expected to lose a bunch of weight, and – as long as you stick to this low-carb diet – keep at least some of it off. There are good quality data showing that people lose weight without even trying when they switch from a diet that heavily features ultra-processed junk foods and sugar-sweetened or alcoholic beverages to a diet that includes mostly unprocessed or minimally processed foods, be they low-fat or low-carb

For this article, let’s stay focussed on the question at hand, and that is whether such a low-carb diet could also be used to prevent progression from prediabetes to type 2 diabetes. I couldn’t find an actual trial, but I found a 2-year single-arm study in which people with prediabetes at baseline were switched to a very-low-carbohydrate diet. Now, in this study, people just received information and online support to follow a very low-carb diet, there were no in-person one-on-one meetings and no suggestion that people exercise more. And there were no other groups that would allow us to compare clinical outcomes to, as in the Diabetes Prevention Program. The authors report that this very low-carbohydrate diet was very successful in preventing progression to type 2 diabetes, because at the 2-year mark, only 3% of patients had developed manifest diabetes. Now, in the Diabetes Prevention Program, about 22% of participants in the placebo group, and about 8% of participants in the lifestyle intervention arm had developed diabetes at the 2-year time point. It therefore would seem that the cumulative incidence of 3% in this very low-carb intervention is encouragingly low.

Unfortunately, that would be an overly optimistic conclusion. The problem is that in this very-low-carb study, 33 of 96 participants, more than a third, dropped out of the study prior to the 2-year follow-up time point, and no data were reported on their clinical outcomes. Why is that a problem?

Created by the author. Based on: McKenzie et al.; Nutrients 2021; 13: 749

Well, just imagine you were enrolled in a study like this where suddenly many of your favorite foods are taboo. Would you be excited to do this for two full years? I guess the answer is maybe if you see some short- to medium-term benefit from this sacrifice. If you lose some weight, or if you feel better, for example. But what if you didn’t lose weight, or you suddenly even had additional health issues? What if you were diagnosed with type 2 diabetes in these two years of follow-up, would that make you more or less likely to continue this diet? You would be more likely to drop out, right? And so, what we need to assume is that the benefits from this very-low-carb diet were less pronounced in those participants who dropped out.

That is the reason why the standard in clinical trials is to conduct all analyses using the intent-to-treat method. In that approach, you conduct your statistical analyses on all participants who were randomized, not just those who completed the study or those that were compliant. That’s the scientifically proper way, and that’s also how the Diabetes Prevention Program handled it. Conducting intent-to-treat analyses is so important because it ensures that your randomization is still valid. After all, you randomize research participants because you hope that this will distribute them evenly across the intervention groups. If you conducted your analyses only on those who complete the study, that may no longer be the case, and then the effects of the interventions may be affected by differences between the intervention groups at baseline. Another point is the one discussed above: participants who are not benefiting from an intervention, or are even experiencing adverse effects, are more likely to drop out. If we completely ignore those individuals, then the interventions will look better than it is in reality.

The fact that no intent-to-treat analysis was conducted in this very-low-carb dietary intervention is also one reason why we should not be tempted to compare the 3% figure in this low-carb study with the cumulative incidence numbers seen in the Diabetes Prevention Program. Of note, this does not mean that the very-low-carb diet tested here should be seen as worse than the low-fat diet used in the Diabetes Prevention Program; it may well be better, it’s effectiveness is just a lot less certain because of the study limitations.

In other words, this study looking at the prevention of type 2 diabetes using a very-low-carb diet is quite promising and suggests that this could be an alternative approach to the low-fat diet used in the Diabetes Prevention Program, but the evidence is weak and we clearly need actual randomized controlled trials that compare low-carb to control diets such as a low-fat diet.

Reversal of Type 2 Diabetes with Low-Fat and Low-Carb Diets

What makes me pretty optimistic that low-carb diets will turn out to be an alternative to, or even better than, low-fat diets for the prevention of diabetes are data from several randomized controlled trials in people with manifest type 2 diabetes.

Let’s just talk about one of these: a randomized controlled dietary intervention trial in 115 adults with type 2 diabetes who were randomized to either a low-carb diet or a high-carb diet. Both diets were designed to impose a small daily energy deficit, and specific recommendations were given to both groups about which foods to consume and which ones to minimize. 

Over 6 months, participants lost ~12 kg or 26 pounds on average in both groups.

Blood glucose control improved in both groups, but the improvements were a bit more pronounced in the low-carb group. For example, let’s look at HbA1c, which is a major measure of importance in people with diabetes, because it gives us information about average blood sugar concentrations over the last ~3 months. An HbA1c of 6.5% or more is used as a diagnostic criterium for diabetes. Some have therefore argued that if we manage to get HbA1c below 6.5%, this would indicate remission or reversal of type 2 diabetes.

Created by the author. Based on: Tay et al.; Diabetes Care 2014; 37: 2909-2918

In this study, 30 out of 47 participants who completed the low-fat high-carb diet achieved HbA1c levels below 6.5% at the 6-month time point. That is a very respectable 64%. Among the 46 participants who completed the low-carb diet, though, 36 achieved HbA1c levels below 6.5%, so that is an even higher 78%.

Now, I would only consider this true remission of diabetes if the HbA1c of less than 6.5% were achieved without taking any diabetes medications. I personally would also want to see normalization of glucose tolerance in an oral glucose tolerance test, but that is a very high bar to clear, and not all experts would agree with me on this point.

So, if we use HbA1c of less than 6.5% while off all diabetes medications as a less-strict criterion on which to assess whether a participant is in remission from diabetes, this was still not the case in all participants in this study. We therefore clearly cannot assume that all of these participants were truly in remission from their type 2 diabetes.

However, what we can say is that their disease was at least very well controlled, which is important to minimize long-term risks such as cardiovascular disease, and that the effectiveness of the low-carb diet was a little bit better than that of the high-carb diet. And, on average, people on the low-carb diet were able to reduce their use of diabetes medications more than those on the high-carb diet. So they achieved a greater reduction in their HbA1c levels while also taking fewer diabetes medications. Quite promising.

There are many more studies that have compared low-carb and high-carb diets for the treatment or management of type 2 diabetes. The data in this field tend to be a bit messy and not very straightforward to interpret, because each study approached the question a little bit differently. Some studies asked participants to reduce their calorie intake in one or both intervention groups, some didn’t. Some studies defined low-carb as very low-carb or ketogenic, others called a fairly high carb intake in the range of 20-40% of total energy intake ‘low-carb’ because it’s lower than typical. Some studies followed participants for 3 months, some for 2 years. However, when we consider the totality of the evidence from randomized controlled trials, what we can still say with good certainty is that low-carb and low-fat diets are either similarly effective at reversing type 2 diabetes, or that low-carb is slightly better.

To conclude this portion on diet and type 2 diabetes, what we can confidently say is that we have very solid evidence that we can prevent and probably reverse type 2 diabetes by changing our diet. To be clear, I am not suggesting that diet is the only important factor: for example, exercising more can clearly also make an important contribution.

Whether a low-carb or low-fat diet is best is less clear, but I would wager that the main factor is the one that low-carb and low-fat diets have in common. Both diets, when implemented properly, are very limited in ultra-processed foods that tend to be hyper-palatable, added sugars and refined grains from soda, sweets or baked goods, and fried foods. There is good evidence for all of these that they trigger overeating and an increase in body weight. And even independent of that, these types of foods pretty likely have negative effects on our body’s ability to keep our blood sugar levels within the normal range.

Secondary Prevention (Arrest or Reversal) of Coronary Heart Disease

Let’s move to cardiovascular disease. Now, cardiovascular diseases are so common around the world that most of us think that it’s normal to have a heart attack or a stroke at some point in our life. Several studies suggest that this doesn’t have to be case, and I would just like to highlight two particularly interesting ones.

I’d like to start with an experiment led by a former surgeon, Dr. Caldwell Esselstyn. In the mid-1980s, Dr. Esselstyn developed the idea that total serum cholesterol levels below 150 mg/dL would halt or even reverse coronary heart disease. He proceeded to recruit a small group of highly motivated people, 24 initially, who had severe coronary artery disease. He convinced them to change their diet, a lot, to prevent further progression of their heart disease, and they agreed to follow a very low-fat diet. This diet had less than 10% of energy from fat, and consisted mostly of whole grains, legumes such as beans and lentils, vegetables, and fruit. With the exception of nonfat milk and yogurt, animal foods including meat, fish, and eggs were not allowed, and neither were nuts or oils of any kind. Dr. Esselstyn calls this a low-fat plant-based diet.

Created by the author. Based on: Esselstyn et al.; J. Fam. Pract. 1995; 41: 560-8.

Now, this is obviously a very extreme diet, and so six of the 24 dropped out of the experiment within the first 2 years.

Created by the author. Based on: Esselstyn. Am. J. Cardiol. 1999; 84: 339-41.

The remaining 18 who committed to the experiment in the long term were in pretty bad shape when they started to work with Dr. Esselstyn. Collectively, they had experienced 49 coronary events in the 8 years prior to the start of the experiment, and given their advanced age and advanced heart disease, one would have expected most of them to have more heart attacks in the near future. What happened instead was that none had any additional heart attacks, only one died from arrhythmia, and 17 of the 18 were still alive 12 years later.

Created by the author. Based on: Esselstyn. Am. J. Cardiol. 1999; 84: 339-41.

I completed my PhD at an institution in Germany that specialized in heart disease, and if you had shown me the clinical data of these 18 people at baseline, I would have guessed that most of them would have at least one additional heart attack over 12 years, and that at least some of them would have died from their advanced heart disease. The fact that none of them had a heart attack, and 17 out of 18 were still alive 12 years later is nothing short of amazing.

Now, when I first read the papers describing this experiment, I initially discarded them as worthless, because this is a clinical investigation that didn’t adhere to most scientific standards in terms of conduct or reporting of clinical studies. 

First, this was not a randomized controlled trial, so participants were not randomly assigned to one of several treatment arms. Instead, everyone was enrolled into the same diet group. This raises several issues, most importantly that we don’t have a comparison group. It’s therefore hard to know what would have happened if these participants had not followed the prescribed low-fat plant-based diet.

Second, this experiment clearly didn’t analyze outcomes using the intent-to-treat approach that I mentioned above as being critical in these types of studies. And actually, in one of the papers, the six who dropped out are used as a control group, which is certainly not appropriate.  From this report, we do know, however, that these 6 participants collectively had 13 more clinical coronary events during the rest of the 12-year follow-up period. The paper makes it seem that these patients had cardiac events because they dropped out and no longer followed the low-fat plant-based diet. The problem is that these patients did follow the low-fat diet for 12-18 months, and it is also possible that at least some of them dropped out because the diet didn’t work well for them and they lost the motivation to adhere to it. Or maybe they had other health issues pop up that caused them to discontinue this diet. All of this would be important to know to really interpret the results of this experiment properly, but unfortunately, that’s not how the data were reported.

The third point is that the low-fat plant-based diet was not the only intervention here. Instead, all patients were also on lipid-lowering medications, such as statins. I don’t think that’s a major problem, and quite frankly, lipid-lowering medications or not, most of these participants would almost certainly not have done as well as they did on medications alone. But, by the same token, it’s also fair to say that the low-fat plant-based diet alone likely would not have been as effective without lipid-lowering medications.

There are a whole bunch of other problems with the papers describing this experiment. For one, it isn’t really clear how many people were studied and how many dropped out over time, because the numbers mentioned in the papers are not consistent. Dr. Esselstyn also claims that his data show regression of coronary heart disease, an assertion that I know many cardiologists would not agree with. And lastly, Dr. Esselstyn makes a lot of claims, in the papers and in his books, that his data demonstrate that fat causes endothelial dysfunction and atherosclerosis, which then leads to heart disease, and that it’s critical to minimize total fat intake. That claim is not at all supported by his data, because the study did not include any assessments of mechansism through which the diets affected clinical outcomes. It could simply be that cutting out certain fats is important and that including, say, nuts, olives, and avocados would not have made any difference. It could also be that a plant-based diet rich in unprocessed whole grains, legumes, fruit, and vegetables that is also rich in certain fats is as good or even better. So, we need to be careful with the interpretation of this study. 

So why did I decide to talk about this experiment here if it’s so poorly executed, and undoubtedly has many limitations? Well, as much as there are a lot of things one can criticize about the design of the experiment itself and the reporting of it in the paper, the results are hard to argue with. Even if we consider that the health benefits of a low-fat plant-based diet on coronary heart disease risk almost certainly look better here in this experiment than they actually are, the data are still pretty amazing. Unless the investigators made up data or stories, which I don’t believe, I feel comfortable concluding that the experiment strongly suggests that a combination of lipid-lowering therapy and the low-fat plant-based diet they prescribed here was associated with an arrest of clinical heart disease. Admittedly, that is likely relevant only in those who are willing and able to adhere to this strict diet in the long term, but that still is very important and noteworthy.

With all of the critiques I have heaped upon this work here, I would also like to make it clear that I commend Dr. Esselstyn on doing this work. He made a major commitment to work with his participants for 12 years, which apparently included communal dinners at his home every 3 months. I certainly love to see a medical doctor showing this much passion for trying to heal his patients by addressing what he considers the root cause, rather than patching up symptoms or relying mostly on medications.

Now, would I wish that an actual high-quality randomized controlled trial was done to put this to a more rigorous test? Yes, absolutely, because first I’d like to gain a higher level of confidence that this particular low-fat plant-based diet actually does arrest coronary artery disease. Second, I would be curious what percentage of patients with advanced heart disease are able and willing to adhere to such a strict diet for an extended period of time. And then third, I would be extremely curious to figure out whether the assertions of the authors are correct that it is critical to eliminate most fat and most animal foods. Personally, I would wager that including, say, fish, nuts, lean meats, or an oil such as olive oil would not make this diet worse for heart disease. Maybe even better, or at least more feasible for most people. I do think all of these would be critical questions to address.

Primary Prevention of Coronary Heart Disease

Now, what made me question Dr. Esselstyns’s assertion that total fat intake is the cause of endothelial dysfunction, thereby leading to cardiovascular disease? Let me show you some data from another, more recent study, the PREDIMED trial

PREDIMED was a much larger and much higher quality dietary intervention study to test the hypothesis that a Mediterranean diet with either extra olive oil or extra nuts can prevent a first major cardiovascular event, such as a heart attack or a stroke. This was actually a randomized controlled trial, conducted in 7,447 Spanish men and women who were at high cardiovascular risk. 

High cardiovascular risk was defined as having type 2 diabetes or at least three of the following major risk factors: smoking, hypertension, elevated LDL-cholesterol levels, low HDL-cholesterol levels, overweight or obesity, or a family history of premature coronary heart disease.

At the beginning of the trial, participants were 55 to 80 years old, with a mean of about 67 years. Most were either overweight or obese, but none had had any prior heart attack or stroke, or other major cardiovascular event.

These 7,447 were randomly assigned to one of three intervention groups. Two groups were asked to follow a Mediterranean diet, and one was asked to follow a low-fat diet.

Created by the author. Based on: Estruch et al.; N. Engl. J. Med. 2018; 378:e34.

Participants in these two Mediterranean diet groups were given mostly the same recommendations: eat plenty of fresh fruits and vegetables, fish, especially fatty fish, legumes such as beans and lentils, and dress vegetables, pasta, or rice with a sauce called sofrito. Spanish sofrito is basically a tomato sauce with onions, garlic, herbs, and plenty of olive oil. They were also asked to replace red and processed meat with white meat that contains less fat, and interestingly, habitual drinkers were explicitly asked to drink wine with meals. Soda, commercially baked bread and pastries, sweets, spreaded fats such as butter or margarine, and red and processed meats were specifically discouraged in both of these groups.

The only difference between the two Mediterranean diet groups was that in one group, participants were specifically asked to consume more than 4 tablespoons of olive oil per day, and that olive oil was provided free of charge to this group. And in the second group, participants were asked to consume at least one serving every day of nuts. These nuts, specifically walnuts, almonds, and hazelnuts, were again provided free of charge to that group. So, basically, we have two groups following a Mediterranean diet pattern, one specifically enriched in olive oil, and the other enriched in nuts.

Created by the author. Based on: Estruch et al.; N. Engl. J. Med. 2018; 378:e34.

These two intervention groups were compared to a control group that was asked to follow a low-fat diet. They were specifically told to consume at least 3 servings per day of low-fat dairy, at least 3 servings per day of bread, potatoes, and pasta, at least 3 servings per week of lean fish and seafood, and plenty of fresh fruit and vegetables. They were specifically told to limit their consumption of vegetable oils, including olive oil, nuts and fried snacks, red and processed meats, fatty fish, spreaded fats, commercially baked breads and pastries, sweets, and sofrito.

Participants were followed up for almost five years. Compliance was pretty good in the two Mediterranean diet groups, but less good in the low-fat control group. Basically, that group continued to eat quite a bit of olive oil, nuts, and sofrito sauce, so the difference in these foods ended up being a lot smaller than planned. I guess this just shows how hard it is to do these studies as a randomized controlled trials. Spaniards simply love their olive oil and their traditional dishes made with it, and randomizing people to stay away from it for 5 years is easier said than done.

Now, still, overall fat intake went up quite a bit in the two Mediterranean diet groups and went down in the low-fat control group, so even though the compliance was not as good as the investigators had hoped, they did achieve a pretty good difference in fat intakes. And the increase in fat intake in the two Mediterranean diet groups was mostly from either extra-virgin olive oil or unprocessed nuts.

What was the impact on cardiovascular disease? Did people in the Mediterranean diet groups have fewer or more heart attacks and strokes? If Dr. Esselstyn was correct that it is critical to keep fat intake as low as possible, then surely a change in diet towards more fatty foods could not be good, right?

Estruch et al.; N. Engl. J. Med. 2018; 378:e34.

Well, no. The two high-fat Mediterranean diet groups actually experienced an about 30% lower risk in the combined endpoint of heart attack, stroke, and cardiovascular death. Now, to some of you, this may seem like a tiny difference, but consider that the dietary changes in the two Mediterranean diet intervention groups were fairly small, and probably pretty pleasant with more olive oil or nuts, regular wine with meals, and more of this delicious oily tomato sauce. And the benefits would likely become more substantial over time.

Again, this study had a few issues that I’d like to go over briefly. One is that some major mistakes were made in the conduct of the trial, particularly with the enrollment and randomization procedures that resulted in a retraction and re-publication of the study data (data above are from the revised paper). That’s unfortunate, but now that the data have been corrected, should not be a major concern. A bigger issue is that the investigators initially conducted the study such that participants in the two Mediterranean diet groups regularly met with study investigators, while those in the low-fat control group were given a pamphlet. That is not adequate, because the frequency and intensity of interactions very likely have an impact on compliance and outcomes all by themselves. The investigators corrected this issue halfway through the study, but the argument could be made that it may have been too late at that point. Another point is that, in my opinion, the differences between the three groups were too small. Specifically, I feel that the control group was not really a suitable control group because control participants also received numerous dietary recommendations that would be expected to reduce cardiovascular risk, and – as mentioned above – they also continued to consume quite a bit of olive oil and other fatty foods. Further, the Spanish diet is generally pretty healthy to start with. For example, ultra-processed foods account for only ~17% of total calories consumed, as compared to 50-60% in the United States. That leaves me to wonder what the impact of average Americans would be if they switched to any of the diets studied in this trial. My guess is that the beneficial impact of this change would be much more substantial than in the PREDIMED trial.

In spite of these issues, this study does again suggest that we can affect our risk of cardiovascular disease quite substantially by changing what we eat. It also suggests that it isn’t all about removing as much fat from our diet as possible. In my read of the literature (which also includes many other studies that we will discuss over time), it is more important to limit the consumption of specific fats (trans-fatty acids from hydrogenated oils and saturated fatty acids) and to generally eat nutritious, unprocessed or minimally processed foods.


Well, then, what do we learn from all of these different studies?

Sure, they all showed that to some degree we can reduce our risk, entirely prevent, maybe even reverse type 2 diabetes or cardiovascular disease, but they all used totally different diets. The Diabetes Prevention Program used a low-fat diet, and the Esselstyn experiment a very low-fat diet, but then PREDIMED used a diet pretty high in fat in the two Mediterranean diet intervention arms, and we’ve also seen that a low-carb high-fat diet may be pretty effective at preventing or even reversing type 2 diabetes. 

I actually picked these studies deliberately to convey three specific points:

First, to show that our diet can have a very substantial, and very concrete impact on our risk of having severe clinical disease. I certainly feel very motivated to eat well to not develop diabetes or heart disease, and I think all of these studies provide – more or less – good evidence that eating well is worth it.

Second, I wanted to show that there is no one ‘healthy diet’. I’d say that taken together, the research we discussed along with numerous other studies suggests that people can be healthy eating a wide variety of diets. 

And third, the research we discussed in this article is informative about what we should NOT be eating too much of. In all studies, either explicitly or implicitly, certain foods were discouraged. These include:

  • Products rich in refined grains and often also added sugars and oils, such as white bread, donuts, cookies, cakes, pastries, or breakfast cereals;
  • Fried foods such as potato chips or french fries;
  • Sugar-sweetened beverages;
  • Sweets and ice cream;
  • Fast foods such as hot dogs, burgers, or pizza.

What you may notice is that there is a lot of overlap of these foods with the ultra-processed foods we discussed in our last article in relation to the global obesity epidemic. As a reminder, these tend to be industrially designed and -produced foods rich in salt, added sugars, and added fats and oils, as well as artificial colorants, artificial flavors, flavor enhancers, emulsifiers, and many other ‘substances not commonly found in culinary preparations’.

Eating less of these foods for an extended period of time would be expected to have a lot of different health benefits. For one, most of these are so-called empty-calorie foods, meaning they have a lot of calories but very little of the essential micronutrients our bodies need. So replacing these with any whole, unprocessed food will clearly increase the amount of vitamins, minerals, and trace elements we get from our diet. The second point is that these are all foods that we tend to overeat on: soda because we know that our total calorie intake goes up if we drink sugar-sweetened beverages (we’ll talk about that in a separate post in detail), and the other foods possibly because they are very energy-dense or hyper-palatable. So eating less of these foods would be expected to spontaneously make people eat fewer calories and potentially lose weight, which is a good thing, particularly for type 2 diabetes.

The topic we addressed here, prevention or reversal of type 2 diabetes and cardiovascular disease, is a huge one, and thousands of studies have been published that are relevant to this topic. Obviously, this post is not meant to summarize all of these. This post was meant to make the point that limiting empty calorie-foods and ultra-processed foods is almost certainly a major factor, I would argue the most important factor, if we want to prevent these chronic diseases, and particularly if we want to improve our health if we already suffer from them. We’ll dig into the many more factors of importance in future posts, so make sure you are subscribed to our newsletter if you’d like to be notified whenever new content is published.

Why Nutrition Matters: Overall Take-Home Message

So, the main overall take-home message of this blog post, and our entire series on Why Nutrition Matters, is that we have plenty of scientific evidence that suggests that we’d do well to eat whole, largely unprocessed or minimally processed foods that are nutrient-dense, and stay away from ultra-processed foods as well as refined grains and added sugars. As we discussed in these past three articles, such a diet would minimize the risk of micronutrient deficiency diseases, minimize weight gain throughout our lives, and reduce our risk of major chronic diseases such as type 2 diabetes or heart disease. That, to me, is the very basic foundation of healthy eating that – I think – most professionals and researchers in this field would agree with. And in that framework, we can find a diet, be it low-fat or low-carb or one with a mixed macronutrient composition, that we can happily live with in the long term.

Take care!


  1. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 2002; 346: 393-403.
  2. Diabetes Prevention Program Research Group. The Diabetes Prevention Program (DPP). Description of lifestyle intervention. Diabetes Care 2002; 25: 2165-71.
  3. Mayer-Davis et al.; Dietary intake in the Diabetes Prevention Program cohort: baseline and 1-year post-randomization. Ann. Epidemiol. 2004; 14: 763-72.
  4. Jaacks et al.; Long-term changes in dietary and food intake behaviour in the Diabetes Prevention Program outcomes study. Diabet. Med. 2014; 31: 1631-42.
  5. Khan et al.; Epidemiology of type 2 diabetes – global burden of disease and forecasted trends. J. Epidemiol. Glob. Health 2020; 10: 107-11.
  6. McKenzie et al.; Type 2 diabetes prevention focused on normalization of glycemia: a two-year pilot study. Nutrients 2021; 13: 749.
  7. Tay et al.; A very low-carbohydrate, low-saturated fat diet for type 2 diabetes management: a randomized trial. Diabetes Care 2014; 37: 2909-18.
  8. Goldenberg et al.; Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data. Br. Med. J. 2021; 372: m4743.
  9. Esselstyn et al.; A strategy to arrest and reverse coronary artery disease: a 5-year longitudinal study of a single physician’s practice. J. Fam. Pract. 1995; 41: 560-8.
  10. Esselstyn. Updating a 12-year experience with arrest and reversal therapy for coronary heart disease (an overdue requiem for palliative cardiology. Am. J. Cardiol. 1999; 84: 339-41.
  11. Esselstyn et al.; A way to reverse CAD? J. Family Pract 2014; 63: 356-364b.
  12. Estruch et al.; Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N. Engl. J. Med. 2018; 378: e34.
  13. Gardner et al.; Effect of low-fat vs. low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion. J. Am. Med. Assoc. 2018; 319: 667-79.

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