A tale of two (recent) studies: isocaloric high-meat and ketogenic diets worsen important heart disease markers LDL and CRP compared to their low-meat and baseline diet counterparts

Two exciting studies with relevance to the currently popular high-meat, low-carbohydrate diets have been published in the past month.

One, conducted by Kevin Hall and Juen Guo at the NIH and co-authored by researchers at Columbia, Pennington, and Florida, looked at the changes in glucose and lipid markers important for cardiometabolic disease risk after switching to a ketogenic diet.

https://onlinelibrary.wiley.com/doi/10.1002/oby.22468

The other, led by Ronald Krauss’s group in Oakland, looked at the effects of red vs. white vs. non-meat sources of protein on important lipid markers of cardiovascular disease risk.

https://academic.oup.com/ajcn/advance-article/doi/10.1093/ajcn/nqz035/5494812

For short, we will call the first study “the keto study” and the second by the name preferred by the investigators: “Animal and Plant Protein and Cardiovascular Health”, or APPROACH.

What did these studies find? The keto study, predictably, found an increase in LDL cholesterol levels:

The effect of saturated fat on LDL-C levels is well-established, both by controlled feeding trials (see this meta-analysis of 84 trials) and long-term clinical trials. For the latter, there are at least three relevant trials, whose relevant findings will be very briefly summarized below.

Here are the results from the Los Angeles Veterans Trial when saturated fat was replaced by linoleic acid (a polyunsaturated fatty acid):

https://www.ahajournals.org/doi/10.1161/01.CIR.40.1S2.II-1

The results from a large 1968 trial published in the Lancet, this time replacing saturated fat with soybean oil:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(68)90746-0/fulltext

And this one from the Oslo Diet Heart study with a similar design:

https://www.ahajournals.org/doi/abs/10.1161/01.cir.42.5.935

All said, it is important to note that many factors affect the response of each person to saturated fat, as noted in a 2010 review by Krauss and colleagues:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824150/

But what many people may not have expected were the effects of the ketogenic diet on CRP, an important inflammatory mediator that closely correlates with the progression of cardiovascular disease. Here is an illustration of this point from a review on cardiovascular risk factors:

And here are the unexpected results from the keto study (second-to-last row):

https://onlinelibrary.wiley.com/doi/10.1002/oby.22468

If we average weeks 3 and 4, we have 1.27 for the baseline diet (“BD” in the above table) and 1.63 for the ketogenic diet, a nearly 30% increase in just 3-4 weeks.

To make sense of these results, it is worth noting some details about the study design. 17 overweight or obese men were assigned to consume a weight-maintaining baseline diet (15% protein, 50% carbohydrate, 35% fat) on a metabolic ward (which has the subjects living for the entire study duration at the study site, receiving all food from staff and having weight and other biomarkers checked periodically). Once the subjects were shown to be weight-stable (within 2-3 weeks), the subjects then spent 4 weeks consuming this baseline diet, followed by 4 weeks consuming the ketogenic diet.

Since the study was published, it has been suggested that the changes in CRP on the ketogenic diet may have resulted from the baseline diet itself, since the study was not randomized and each participant consumed a ketogenic diet after consuming a baseline diet. However, this study’s findings with respect to CRP are consistent with other studies, including low-carbohydrate diet proponent and Harvard professor David Ludwig’s 2012 low-carbohydrate diet study (“CRP tended to be higher with the very low-carbohydrate diet (median [95% CI], 0.78 [0.38-1.92] mg/L for low-fat diet; 0.76 [0.50-2.20] mg/L for low–glycemic index diet; and 0.87 [0.57-2.69] mg/L for very low-carbohydrate diet; P for trend by glycemic load = .05″) and another study by Rankin and Turpyn from 2007 (“Although LC lost more weight (3.8 +/- 1.2 kg LC vs. 2.6 +/- 1.7 HC, p=0.04), CRP increased 25%; this factor was reduced 43% in HC (p=0.02)”).

It is reasonable therefore to regard the effect of the ketogenic diet on CRP as potentially real. This is important, because although professional cardiovascular disease researchers believe both lipids and inflammation are important for cardiovascular disease (and other factors) inflammation is frequently proposed as the sole cause of cardiovascular disease by many non-scientist advocates of low-carbohydrate diets. Yet, if both harmful lipids and major inflammatory markers like CRP are increased on a low-carbohydrate diet, then this poses a problem for the claim that low-carbohydrate dieting is innocuous for cardiovascular disease risk.

To be clear, for many people, most markers of cardiovascular disease risk (including LDL cholesterol and CRP) will decrease on a low-carbohydrate diet if weight loss is robust enough (see, e.g., here and here). However, what the studies above suggest is that if weight is maintainable at these lower levels after switching to a higher-carbohydrate diet, on average these lipid and inflammatory markers will improve still further. A key unresolved question is whether the ability to maintain such weight loss on a low-carbohydrate diet sufficiently compensates for the increases in these cardiovascular disease markers, if long-term weight maintenance on a low-carbohydrate diet is preferred. I suspect that it is–and thus, for those who can only maintain their weight loss on a low-carbohydrate diet, the tradeoff may on balance be worthwhile. But this remains to be seen. (Also, this may depend on the extent of the weight loss. More long-term weight loss would more likely justify the tradeoff.)

A similar calculation might be at play for the weight-stable management of type 2 diabetes with a low-carbohydrate diet. Might the gains from better glycemic regulation sufficient to offset the losses to lipids and CRP? Study authors, fortunately, put this concern to rest, noting that for subjects with type 2 diabetes, no such increase in CRP has been observed:

https://onlinelibrary.wiley.com/doi/10.1002/oby.22468

That inflammatory biomarker increases are also not seen among diabetics might suggest that the reduction in blood glucose is sufficiently anti-inflammatory so as to obviate any pro-inflammatory downside of the ketogenic diet.

This brings us to APPROACH, the second of the two studies that is the subject of this article. The findings of APPROACH:

  1. Meat versus non-meat protein increased LDL cholesterol;
  2. There was no difference in LDL response between white and red meat;
  3. Saturated fat increased LDL cholesterol;
  4. These effects were all independent of each other: meat increased LDL cholesterol independent of the saturated fat content, and vice versa.

The design of the study:

“Generally healthy men and women, 21–65 y, body mass index 20–35 kg/m2, were randomly assigned to 1 of 2 parallel arms (high or low SFA) and within each, allocated to red meat, white meat, and nonmeat protein diets consumed for 4 wk each in random order. The primary outcomes were LDL cholesterol, apolipoproteinB (apoB), small+medium LDL particles, and total/high-density lipoprotein cholesterol.”

Which authors visualized as follows:

The diets were as follows:

Here is a sample menu:

The study was an outpatient study, and participants picked up the food weekly and were weighed at that time:

And here are the study’s main findings:

And here:

Just eyeballing the LDL findings from Table 3 (the first the two tables immediately above), we see:

High-SFA vs. low-SFA red meat: 2.64mM vs. 2.35mM—a 12% increase
High-SFA vs. low-SFA white meat: 2.61mM vs. 2.38mM—a 10% increase
High-SFA vs. low-SFA red meat: 2.46mM vs. 2.22mM—an 11% increase

Meat (averaged) vs. nonmeat, high-SFA: 2.63mM vs. 2.46mM—a 7% increase
Meat (averaged) vs. nonmeat, low-SFA: 2.37mM vs. 2.22mM—a 7% increase

High-SFA meat (averaged) vs. low-SFA nonmeat: 2.63mM vs. 2.22mM—an 18% increase

In other words, according to these data and assuming that they are generalizable to the population as a whole…

An average high-saturated fat, high-meat dieter would be expected to have an 18% higher LDL than a low-saturated fat, low-meat eater.

To put this in perspective, PCSK9 mutations, which reduce the ability of PCSK9 to degrade the LDL receptor, which causes greater uptake of LDL, are associated with a 28% reduction in lifetime LDL cholesterol and an 88% reduction in the risk of cardiovascular disease.

http://clinchem.aaccjnls.org/content/60/11/1380

Can we estimate the precise reduction in coronary heart disease risk resulting from a lifetime of such LDL reduction? After all, lifetime exposure to LDL, cumulatively and in an area-under-the-curve-fashion is what causes cardiovascular disease. This is beautifully demonstrated in the following figure, which shows how lifetime, genetic reduction in LDL produces a steeper decline in risk than that of a reduction in cohort studies with a median follow-up to 12 years, which produces a steeper reduction in risk than that observed in randomized clinical trials with a median follow-up of 5 years:

We can estimate such lifetime risk, by looking more closely at a study similar to the one that provided the blue line in the figure immediately above.

In short, the reduction in risk from lifelong LDL reduction (from birth) has been estimated by looking at genetic mutations that produce a lower LDL-C level, and then looking at risk of coronary heart disease for people with each mutation. These were then plotted to produce a graph that can estimate the effect of lifelong reduction in risk of death from CHD.

https://www.sciencedirect.com/science/article/pii/S0735109712047730

Since the figures given in the APPROACH paper are in millimoles/liters, we need to convert to mg/dl to use the above graph to make estimates. That is done by using the conversion factor 38.67. We can therefore recalculate the comparisons between diets in mg/dL, with risk reduction estimates as follows:

High-SFA vs. low-SFA red meat: 102.1mg/dL vs. 90.9mg/dL—a 20% decrease in CHD risk
High-SFA vs. low-SFA white meat: 100.9mg/dL vs. 92.0mg/dL—a 15% decrease in CHD risk
High-SFA vs. low-SFA red meat: 95.1mg/dL vs. 85.8mg/dL—an 17% decrease in CHD risk

Meat (averaged) vs. nonmeat, high-SFA: 101.7mg/dL vs. 95.1mg/dL—an 11% decrease in CHD risk
Meat (averaged) vs. nonmeat, low-SFA: 91.6mg/dL vs. 85.8mg/dL—an 11% decrease in CHD risk

High-SFA meat (averaged) vs. low-SFA nonmeat: 101.7mg/dL vs. 85.8mg/dL—a 29% decrease in CHD risk

(Note: I do not have access to the formula used to generate this graph, so I eye-balled the graph to provide the above estimates. This “eye-balling” is within a few % of a formula-calculated estimate, and therefore adequate for illustration purposes.)

This is a huge reduction in risk. Given that 360,000 Americans died of coronary heart disease in 2016, a 29% decrease in risk would save the lives of 104,400 people each year, or more than 1 million Americans per decade. That is 34 September 11s per year. Such a reduction in LDL-C would reduce the rate of physical disability by a similar magnitude. The magnitude of this benefit, if applied universally across the population, would therefore be several-fold greater than universally prescribed statin therapy for all patients with dyslipidemia.

This does not take into account the impact of elevated LDL on other cardiovascular diseases, such as stroke, cerebrovascular disease, and cancer, which are likely to dramatically increase the magnitude of these rough estimates.

One objection to this kind of thinking is that such a dietary intervention may have pleiotropic effects: it may impact health in other ways than coronary heart disease. I am eager for readers to share well-designed studies that demonstrate such effects.

Another objection to this analysis is that the American diet is not likely to be precisely the same as that consumed in the high-SFA, high-meat group, thereby making the benefits less substantial than those I have presented. While this is true, even if the benefits are only half of what I have mentioned, they would be a major achievement of public health.

Another objection is that the benefits of a lifetime dietary approach achieving such LDL reductions overstate what would be achieved clinically, since as mentioned, lifetime exposure to LDL has cumulative effects, and dietary approaches adopted in, say, middle age are likely therefore to produce less benefit. This is true, but my goal was to demonstrate what a lifelong, public health oriented transformation could achieve. If we wanted to calculate what could be achieved clinically, we should look at the first of the two graphs, included here a second time for convenience:

In this case, the magnitude of effect on LDL of the difference between high-SFA, high-meat and low-SFA, low-meat is only about 0.4mmol/L (remember: 2.63mM vs. 2.22mM), which along the red line translates into a modest ~9% reduction. This is perhaps one of the main reasons why clinical trials into LDL lowering via diet have shown such modest and uncertain effects: changing the diet during late age simply will not produce benefits that are as substantial as optimizing the diet at birth.

Authors note that the selective increase in large LDL and not in medium or small LDL implies that the changes may be less atherogenic than might be expected by looking at total LDL cholesterol changes. They write:

This claim is controversial, as the authors themselves acknowledge. Lipid experts indeed seem to be getting increasingly heated on the subject online:

Others leap into the fray:

An earlier review in the American Journal of the College of Cardiology agrees, writing that “Cholesterol, largely transported through the body as LDL-C, has clearly been established as a causal agent in atherosclerosis over many decades of extensive research. Regardless of size, LDL particles are atherogenic.” Kjellmo’s paper, linked in the tweet thread above, concurs.

Hedging probably because of the current lack of clarity in the literature, Krauss and colleagues conclude their paper:

It is important to note, however, that medium LDL certainly increased on the meat diet, and that there was a nonsignificant increase in small LDL. Would a higher number of subjects produced more clarity on this question?

In any case, what is the cause of the higher LDL levels in the meat vs. nonmeat diets? One might suspect that, because the large LDL was the fraction raised the most and because dietary cholesterol predominantly raises the large LDL fraction, that the dietary cholesterol found in the meat was perhaps the culprit. However, Krauss et al are quick to point out that this probably isn’t quite right:

One guess is that the dietary fiber in the matrix of the plant proteins (such as peas) might have contributed to the effects.

It is worth noting that fiber was nearly equated on all diets, suggesting that adding additional fiber to the diet in the form of a higher fruit and vegetable intake may not be sufficient to counteract the lipid-raising effects of animal protein.

According to these studies, because low-carbohydrate diets high in meat and saturated fat are likely to, on average, raise both inflammatory and lipid biomarkers in healthy people–if avoiding atherosclerosis is the goal, then minimizing animal-sourced protein while maximizing other high-nutrient foods is likely to be best practice according to the totality of current evidence. There may be plausible arguments in favor of low-carbohydrate diets if they help to maintain a sufficient degree of weight loss to mitigate the inflammatory or lipid effects of these diets. Likewise, among persons with type 1 or type 2 diabetes, the euglycemic effects of low-carbohydrate diets may outweigh any negatives. However, all else equal, it may be appropriate to exercise caution about committing to low-carbohydrate diets if weight and glucose can be optimally maintained with other dietary strategies.

If you have enjoyed this post or my other work, please consider donating or becoming a patron. Your support enables me to continue spending my time doing this.

Kevin

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2 Comments

  1. This was an extraordinary post. I can’t overstate how refreshing it is to see polarizing, seemingly controversial papers situated in an appropriate context, with findings extrapolated to meaningful clinical endpoints. Thank you for your skillful work on this.

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