#439: Prof. David Jenkins – Lipid-Lowering Diets

1. Detailed Study Notes
2. Transcript

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Key Idea: Replacement in Nutrition Science

When talking about addition of a food/nutrient, we need to consider the impact of the overall shift in the diet. There are two elements:

1. Don’t just think of “food X” as “nutrient Y”, e.g. dairy is not just calcium
2. When we add a food/nutrient, we typically end up replacing something else. Therefore the net result is the consequence of both the addition of the nutrient(s) and the nutrients that are reduced (i.e. have been replaced).

As an example, in this episode we considered the impact of introducing soy foods into the diet for cardiovascular disease risk. So in above to the above couple of points, we need to realise that:

1. Introducing soy foods not only increases soy protein intake, but also isoflavones, micronutrients, etc.
2. Typically soy foods take the place of animal-based foods that can be high in saturated fat. For example, using tofu instead of red meat or using soy milk instead of cow’s milk. So the impact on lipids will be influenced not only by what soy contains, but what it is replacing. Therefore, the benefit of adding tofu to the diet will be much larger for someone who replaces fatty cuts of meat, than it will be for someone who already consumes a low saturated fat diet, and includes the tofu instead of chickpeas for example.

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Glossary/Definitions

• Glycaemic Index (GI): A number from 0 to 100 assigned to a food, representing the average blood glucose changes in the two hours after consuming that food. However, individual response can vary significantly. Glucose is the reference food, with an assigned value of 100. “Low GI” is typically 55 or less; high GI is 70 or more; and mid-range GI is 56 to 69.
• LDL-C: Low density lipoprotein cholesterol
• MUFA: Monounsaturated fatty acids
• PUFA: Polyunsaturated fatty acids
• NCEP: National Cholesterol Education Program
• Viscosity: “Viscosity is a physicochemical property associated with dietary fibers, particularly soluble dietary fibers. Viscous dietary fibers thicken when mixed with fluids and include polysaccharides such as gums, pectins, psyllium, and beta-glucans.” – Dikeman & Fahey, 2006

Dr. Jenkins’ Early Work

Jenkins originally developed the concept of the glycaemic index (GI) in the early 80’s (Jenkins et al., 1981), which was a method of quantifying the impact of foods on blood glucose following their ingestion.

In and around 1980, he did pioneering nutrition research, with some examples including:

• Looking at how high-fiber foods impact blood glucose responses
  • Lentils: Jenkins et al., 1982
• The impact of specific fibers like pectin (Jenkins et al., 1977)
• The role of viscosity (Jenkins et al., 1978)

Prof. Jenkins praised the early groundbreaking work on dietary fibre of Denis Burkitt and Hugh Trowell. For more on this work see Cummins & Engineer, 2017: ‘Denis Burkitt and the origins of the dietary fibre hypothesis’.

The Portfolio Diet

The Portfolio Diet was originally created by Dr. Jenkins and his team at the University of Toronto, with the idea of combining a number of nutrients/foods that had some evidence for lipid-lowering, with the goal of the additive effect leading to clinically meaningful reductions in LDL-cholesterol.

The dietary pattern specifically includes four fundamental components that have known lipid-lowering effects:

1. Soy protein
2. Viscous fiber
3. Nuts
4. Plant sterols

Note: Dr. Jenkins mentioned that his colleague Dr. John Sievenpiper will often include monounsaturated fatty acids as the fifth pillar or “leg of the stool”, due to their associations with high HDL-cholesterol levels.

The initial studies (more info below) typically tested the effect of a diet that included:

• ~30g nuts
• 20g viscous fibre
• 80g vegetable protein (with 50% of that being soy protein)
• 2g plant sterols

Portfolio Diet: The Portfolio Diet is a dietary pattern with the inclusion of specific nutrients/foods (namely soy protein, viscous fibre, nuts, and plant sterols/stanols) aimed at reducing LDL-cholesterol beyond that of a healthy background diet.

The early trials (e.g. Jenkins et al., 2003) examined the impact of the addition of the following on top of a baseline diet that was low in saturated fat:

In an initial 2003 trial, they compared the effect of:

• Plant sterols (1.2 g/1,000 kcal)
• Soy protein (16.2 g/1,000 kcal)
• Viscous fibers (8.3 g/1,000 kcal)
• Almonds (16.6 g/1,000 kcal)

1. Portfolio diet
2. Control diet
3. Statin therapy

The nutritional composition of each diet (after 4 weeks) looked like this:

The below graph shows the % change in LDL-C for:

1. Portfolio diet (triangles)
2. Control diet (circles)
3. Statin therapy (squares)

This shows a change in LDL-C of:

• Portfolio = 28.6%
• Control = 8.0%
• Statin = 30.9%

Thus suggesting that a Portfolio diet (in addition to typical recommendations* such as restricting saturated fat) could lead to similar reductions to statin therapy.

• Note: the statin in this study was lovastatin, which is one of the “1st generation statins”. The first generation statins included lovastatin, pravastatin, and fluvastatin. Second generation include simvastatin and atorvastatin. While rosuvastatin and pitavastatin are among third generation statins.
• *the Portfolio dietary pattern was given on a background of a National Cholesterol Education Program (NCEP) Step II diet.

More clinical trials followed, consistently showing beneficial effects:

• Use of a Portfolio diet could decrease LDL-C to a greater extent than a low saturated fat diet alone (Jenkins et al., 2011).
• A systematic review and meta-analysis of controlled trials showed the Portfolio diet (plus NCEP Step II) lead to LDL-C reductions of ~17% and reduced 10-year heart disease risk, compared with an NCEP Step II diet alone (Chiavaroli et al., 2018).

Key Point: While we will look at each pillar of the diet below, and such nutrients can be investigated in isolation, the Portfolio Diet as an intervention is meant as an entire dietary pattern. That is, the benefits are a result of the combined effects of several of these nutrients/foods. And therefore, looking at the impact of one factor in isolation, may not demonstrate the true potential for such a dietary pattern.

Indeed, to look at what would happen if one of the four pillars of the portfolio were removed, Jenkins et al. (2008) conducted a nice study in which:

• For 80 weeks in total, 42 people with high cholesterol were prescribed diets containing:
  • soy protein (22.5 g/1000 kcal)
  • viscous fibers (10 g/1000 kcal)
  • almonds (23 g/1000 kcal)
• They also consumed 1g/1000kcal of plant sterols each day, except for a 10 week period (between weeks 52 and 62)
• While taking the full dietary portfolio, including plant sterols, the average reduction in LDL-C from baseline was 15.4%.
• After sterol elimination, average LDL-C reduction was 9%.
• So if one of the elements of the portfolio isn’t present, then significant changes are still possible. However, they are below that of the full portfolio.
• It’s worth noting that plant sterols are a particularly potent aspect of lipid-lowering via diet, with some studies reporting reductions of LDL-C of 9-14% via plant sterol use alone. Therefore, the degree of LDL-C reduction without them in this trial is encouraging. And inclusion of plant sterols while leaving out another element (e.g. nuts) may allow of a LDL-C reduction even closer to the full portfolio.

Soy Protein

Dr. Jenkins highlighted the work of Prof. Cesare Sirtori – Professor of Clinical Pharmacology at the University of Milan (Italy). His work pointed to the ability of soy protein subunits (particularly the 7S globulin) to directly activate LDL receptors in the human liver.

• Human trials on soy protein (e.g. Ruscica et al., 2018) have continued to support the suggestion that ~30g/d can lead to modest (~5%) reductions in LDL-C

FDA Review of Soy Health Claim

In 2019 Jenkins and colleagues published this cumulative meta-analysis on the effect of soy. The studies selected (43 in total) were those that the FDA (Food and Drug Administration) in the US had selected to form the basis for a review of its own prior approval (in 1999) of the following health claim: “Diets low in saturated fat and cholesterol that include 25g of soy protein a day may reduce risk of heart disease”.

From that Jenkins cumulative meta-analysis paper:

• “… we assessed, using a cumulative meta‐analysis, whether at any time point since 1999 had soy foods failed to lower serum cholesterol and found that LDL cholesterol reductions for soy protein have consistently been between −4.2 and −6.7 mg/dL (P<0.006), with no loss of significance at any time point, so justifying the continued use of soy for health and therapeutic purposes as part of cholesterol‐lowering diets.”

Note: This highlights the goal of a cumulative meta-analysis; i.e. to see whether the publication of new studies after a certain date influence the overall results. In this case, it shows that newer studies do not show a different picture to earlier trials.

A meta-analysis by Anderson & Bush (2011) showed that soy protein consumption (~ 30g/d) had a LDL-C lowering effect.

There have been some (e.g. Sacks et al., 2006) who have claimed that the impact of soy protein in isolation does not lead to a lipid-lowering effect that is great enough to consider it having a clinically meaningful effect, or at least a great enough effect to warrant the allowed health claims.

For more on soy protein and CVD risk, check out episode 430 (specifically from 57:25) of the podcast.

The isoflavones found in soy foods may also be beneficial due to their ability to lower blood pressure (Richardson et al., 2016).

It’s also worth noting, that while there is evidence for both the benefits of soy protein and isoflavones, that the entire food matrix of soy foods could have a composite benefit, rather than just one aspect of the food. However, one of the issues is that much of the evidence on soy protein is based on trials that have use soy protein isolate, as opposed to soy foods.

Viscous Fibers

Viscous fibers include:

• Oat beta glucan
• Barley beta glucan
• Psyllium
• Guar gum
• Pectin

“Viscosity is a physicochemical property associated with dietary fibers, particularly soluble dietary fibers. Viscous dietary fibers thicken when mixed with fluids and include polysaccharides such as gums, pectins, psyllium, and beta-glucans.” – Dikeman & Fahey, 2006

Viscous fibres reduce the rate of absorption of nutrients from the small intestine, and it is this property that is thought to impart the beneficial impacts on blood glucose and lipids. And therefore why they are associated with greater LDL-C reductions than other fibre sources (e.g. oat outperforms wheat bran).

From Jenkins et al., 2004:

• “One of the ways in which viscous fibres appear to achieve their beneficial metabolic effects is through reducing the rate of absorption or spreading the nutrient load over time and thus by converting the small intestine into a reservoir from which nutrients are absorbed and enter the circulation slowly.”
• “Ultimately, the viscosity in the terminal ileum will determine the degree of bile acid loss. This effect, together with blunted post-prandial insulin response, effects on lipids and lipoprotein synthesis, possibly enhanced colonic propionate synthesis and physical binding of bile acids to the fibre are the principle mechanisms by which fibre may reduce serum cholesterol.”

Inulin-type fructans, though non-viscous, can lower fasting glucose and insulin and fasting LDL-cholesterol (Liu et al., 2017).

Nuts

Nut consumption has consistently been shown in epidemiology to be associated with reduced cardiovascular disease risk (Ros, 2015).

Dr. Jenkins noted that the mechanism for improving lipid profiles is dependent on the nut, for example:

• Walnuts are a good source of polyunsaturated fat, and therefore their inclusion may help improve the P:S ratio, which strongly affect LDL-C.
• Almonds on the other hand are mostly monounsaturated fat. Monounsaturated fats have a smaller impact on LDL-cholesterol than do polyunsaturated fat. However, they have a much bigger effect on HDL-cholesterol.
• So you may get more of an LDL-C reduction with walnuts and more of an HDL-C increase with almonds.

Prof. Jenkins’ group examined the effect of almonds as part of a low-saturated fat, high-fiber diet in 26 adults (Spiller et al., 1992):

• Baseline diet:
  • Foundation of the diet: Grains, beans, vegetables, fruit, and low-fat milk products
  • Foods limited: meat, fatty fish, high-fat milk products, eggs, and other saturated fat sources.
• 100g per day of almonds provided:
  • 34 g of monounsaturated fatty acids
  • 12 g of polyunsaturated fatty acids
  • 6 g of saturated fatty acids
• Within 3 weeks of the almond-containing diet, average LDL-C dropped from 154 mg/dL at baseline to 133 mg/dL.
• This reduction was sustained for another 6 weeks fo the diet.
• The main nutritional shift was in MUFA intake. There was also a slight improvement in P:S ratio.

One of the other mechanisms that may explain this effect is the phytosterol content of nuts, as phytosterols have been shown to have a LDL-lowering effect.

RCTs have shown that the energy in nuts is not completely bioaccessible (i.e. the net calorie “intake” is less than that of the calculated calorie in a serving of nuts), with Nishi et al. (2021) recently showing this in almonds.

High MUFA nuts such as macadamia have some evidence for reducing LDL-C, when saturated fat intake is reduced/replaced (Garg et al., 2003).

Plant Sterols & Stanols

Plant Sterol (Phytosterol) Basics:

• Phytosterols are part of plant foods, mainly in unrefined vegetable oils, grains, nuts, and olive oil.
• Different food products have now been fortified with with phytosterols (i.e. functional foods). These include phytosterol-enriched milk, soy, yogurt, fruit drinks and cereal.
• “Unlike cholesterol, phytosterols are not synthesized in humans, phytosterols have no function in human organism and diet is their only source.” – Makhmudova et al., 2021
• Mid-1990s: first phytosterol-containing functional food (a margarine) showed significant (around 14%!) LDL-C reduction (Miettinen et al., 1995).
• Since then a number of meta-analyses show a dose-response relationship with intakes of 1.5 to 3 g/day lowering LDL-C by 7.5% to 12% (Trautwein et al., 2018).

Trautwein et al., 2018 RCT:

• 138 people at-risk of, or with, type 2 diabetes
• 2 g/d of plant sterols (in a spread) for 6 weeks vs. placebo
• Sterol group saw changes in:
  • LDL-C: Dropped by 4.6% (95% CI = -1.2; -8.0)
  • Triglycerides: Dropped by 8.3% (95% CI = -1.1, -15.0)

For most benefit, some have suggested they should be consumed with main meals, however there is still a lot of uncertainty over the best timing and frequency, or its importance.

European Atherosclerosis Society Consensus Panel on Phytosterols (2014): “… functional foods with plant sterols/stanols may be considered”:

1. in individuals with high cholesterol levels at intermediate or low global cardiovascular risk who do not qualify for pharmacotherapy
2. as an adjunct to pharmacologic therapy in high and very high risk patients who fail to achieve LDL-C targets on statins or are statin- intolerant
3. in adults and children (>6 years) with familial hypercholesterolemia, in line with current guidance.

However, the EAS position statement also re-iterates something that Dr. Jenkins highlighted in the episode; that while the evidence for plant sterols reducing LDL-C is consistent and positive, there remains a need for research on their impact on actual hard endpoints (e.g. CV events or mortality).

It should also be noted that some authors have point to recent genetic evidence suggesting that plant sterols could even have atherogenic effects, and thus the need for hard cardiovascular outcomes before a universal recommendation for plant sterol supplementation can be given.

Current evidence: There is consistent evidence that intakes of 1.5 to 3 g/day of plant sterols/stanols can reduce LDL-C by 7-12%. However, there is a lack of evidence looking at hard endpoints such as CV events or mortality.

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