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@ -31,14 +31,26 @@ It is also suggested that saturated fatty acids (SFA) are resistant to this sort
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As it turns out, we've thoroughly investigated the effects of altering the fatty acid composition of the diet on LDL oxidation rates in humans. For example, Mata et al. (1996) explored this question with one of the most rigorous studies of its kind. No statistically significant differences between the effects of high-SFA diets and high-PUFA diets on the lag time to LDL oxidation were observed [[2](https://pubmed.ncbi.nlm.nih.gov/8911273/)].
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![][image1]
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[image1]: /blog/image1.png
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However, diets high in monounsaturated fat (MUFA) diets might actually increase the lag time to LDL oxidation more than either SFA-rich or PUFA-rich diets. It would appear as though this effect could be explained due to the fact that MUFA might be better than SFA at replacing LA in LDL particles. So, it seems as though the implication that SFA could offer unique protection against LDL oxidation is less straightforward than originally suggested.
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![][image2]
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[image2]: /blog/image2.png
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When comparing LDL that were enriched with PUFA to LDL that were enriched with MUFA, Kratz et al. (2002) observed a stepwise decrease in LDL lag time to oxidation with increasing PUFA, specifically linoleic acid (LA) [[3](https://pubmed.ncbi.nlm.nih.gov/11840183/)]. These results cohere with the results of Mata el al., suggesting that MUFA increases the lag time to LDL oxidation more than SFA or PUFA.
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![][image3]
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[image3]: /blog/image3.png
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In short, it would at least seem to be true that vegetable oil consumption, when investigated in isolation, increases the susceptibility of LDL to oxidize. But, don't get too excited. As we will discuss, these are paltry changes compared to what can be accomplished with antioxidants.
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Despite Kratz et al. claiming that vitamin E doesn't mask the effects of dietary fatty acids on LDL susceptibility to oxidation, their reference for this claim does not clearly support this conclusion. The work of Reaven et al. (1994) was their supporting reference for this claim and it actually paints a slightly different picture [[4](https://pubmed.ncbi.nlm.nih.gov/8148354/)]. The Lag time to LDL oxidation with vitamin E supplementation was more than double that which was observed in the previous study (or nearly any other random population sample from any other study that I've seen for that matter).
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![][image4]
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[image4]: /blog/image4.png
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Reaven et al. discovered that the lag time to LDL oxidation was enormously high in all groups after a run-in diet that included 1200mg/day of vitamin E for three months before randomization. Compared to the previous study by Kratz et al. (2002), the LDL lag time to oxidation was 150% higher (~60 minutes to ~150 minutes). This is consistent with other research showing that the vitamin E content of LDL particles linearly increases the lag-time to LDL oxidation [[5](https://pubmed.ncbi.nlm.nih.gov/1985404/)].
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The effect of dosing vitamin E on increasing the lag time to LDL oxidation observed by Reaven et al. is approximately 7.5x stronger than the effects observed by either Kratz et al. or Mata et al., which involved altering the fatty acid composition of the diet. This strongly suggests that antioxidants are a much stronger lever to pull if one wants to decrease the susceptibility of LDL to oxidize.
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@ -47,16 +59,25 @@ All three studies used the same copper sulfate solution methodology to measure t
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Which brings me back to the trial by Kratz et al. (2002), which compared olive oil (OO) versus sunflower oil (SU). Despite the fact that all diet groups were receiving roughly the same amount of vitamin E, the OO group ended up with significantly higher vitamin E status compared to the SU group. This is consistent with the observations that MUFA increases the lag time to LDL oxidation to a greater degree than SFA or PUFA. Which leads to higher vitamin E representation in the end.
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![][image5]
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[image5]: /blog/image5.png
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It is well understood that higher PUFA intakes increase vitamin E requirements in humans [[7](https://pubmed.ncbi.nlm.nih.gov/26291567/)]. However, the OO group also started with much higher status to begin with, which likely contributed to the effect. Lastly, the run-in diet was high in SFA. Such a diet is almost assuredly to be lower in vitamin E, which could exaggerate the effects of high-PUFA diets.
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As discussed earlier, SFA is not vulnerable to lipid peroxidation in any way similar to that of PUFA. However, SFA being less vulnerable to lipid peroxidation typically means that sources of SFA contain very low amounts of antioxidants [[8](https://pubmed.ncbi.nlm.nih.gov/14100992/)]. For example, both coconut oil and butter contain negligible vitamin E and have minimal polyphenols. The potential importance of polyphenol antioxidants in protecting LDL from oxidation has been demonstrated in research investigating OO [[9](https://pubmed.ncbi.nlm.nih.gov/15168036/)].
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![][image6]
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[image6]: /blog/image6.png
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Figure 2 from Marrugat et al. (2004) shows that virgin OO increases the lag time to oxidation to a greater degree than that of refined OO, with the primary differences between these different OOs being their polyphenol content. Many polyphenols act as antioxidants once they're inside our bodies, so these results are not particularly surprising.
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It is likely that the overall dietary pattern matters more than PUFA, or even LA, in altering the susceptibility of LDL to oxidation. This principle has been demonstrated multiple times [[1](https://pubmed.ncbi.nlm.nih.gov/28371298/)0-[1](https://pubmed.ncbi.nlm.nih.gov/30282925/)3].
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For example, in a trial by Aronis et al. (2007), diabetic subjects were placed on either a fast food diet that was formulated to be "Mediterranean diet-like" or assigned to follow their usual diet. There was also a third arm of non-diabetics placed on the Mediterranean-style fast food diet. Lag time to LDL oxidation was measured according to the same methodology as described above, with a copper sulfate solution.
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![][image7]
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[image7]: /blog/image7.png
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It should be noted that the foods were specifically formulated to increase the lag time to LDL oxidation. However, what makes these results more impressive is that the fast food groups (groups A and B) were consuming twice as much PUFA than they were at baseline. Despite this we see some of the longest lag times to LDL oxidation observed in the literature in a population that has not been primed with megadoses of vitamin E for three months.
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Altogether this would seem to divulge that diet quality matters more than PUFA, or even LA, for LDL oxidation in the aggregate. We've seen multiple times that low-PUFA or low-LA diets can be outperformed by high-PUFA or high-LA diets of better overall quality. Little things add up, and the effect of diet is greater than that of MUFA alone, SFA alone, or even polyphenols alone. Perhaps not vitamin E alone, though.
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@ -69,12 +90,18 @@ For example, it may be the case that when you expose LDL particles to copper sul
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One particularly long crossover-style RCT by Palomäki et al. (2010) compared the effects of butter to that of canola oil (CAO) on oxLDL [[1](https://pubmed.ncbi.nlm.nih.gov/21122147/)4]. Overall the butter diet resulted in higher LDL and higher oxLDL. I wasn't able to find many PUFA-SFA substitution trials that measured oxLDL beyond this one study, unfortunately.
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![][image8]
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[image8]: /blog/image8.png
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Again, I speculate that this is likely the result of SFA being a poor source of antioxidants. Or perhaps it's because baseline diets could have been higher in PUFA, and reducing vegetable oil intakes might just be cutting off robust sources of antioxidants and increasing LDL oxidation. There are not many studies investigating this, so it's not clear at the moment.
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But, just for the sake of argument let's assume that high-PUFA diets do increase LDL oxidation relative to high-SFA diets. Would that actually be a bad thing? Perhaps not. One study by Oörni et al. (1997) has identified that oxidized LDL are less likely to be retained within the arterial intima when compared to native LDL [[1](https://pubmed.ncbi.nlm.nih.gov/9261142/)5]. If the LDL are oxidizing in the serum, perhaps this just opens up more disposal pathways for LDL and lowers its chances of getting retained in the subendothelial space to begin with.
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Lastly, while we have established that vegetable oil consumption does appear to have an independent impact on LDL oxidation (though the effect is dwarfed by the effect of antioxidants), it is also true that oxLDL isn't actually a robust risk factor for CHD. Wu et al. (2006) discovered that the association between oxLDL and CHD does not survive adjustment for traditional risk factors like apolipoprotein (ApoB) or TC/high density lipoprotein cholesterol (HDL-C) [[1](https://pubmed.ncbi.nlm.nih.gov/16949489/)6].
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![][image9]
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[image9]: /blog/image9.png
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Essentially this means that after accounting for ApoB or TC/HDL, risk is more closely tracking ApoB or TC/HDL-C, and is not particularly likely to be tracking oxLDL at all. So even if it were the case that diets high in vegetable oils simply increased oxLDL, it wouldn't appear that it moves the needle for risk in the real world. It would also suggest that the hypothetical detriments of increasing LDL oxidation aren't significant enough to offset the LDL-lowering benefits of a high-PUFA diet. As we will discuss later in this section.
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In the above study by Wu et al. (2006), the Mercodia 4E6 antibody assay was used to measure oxLDL. Some have argued that this assay is invalid due to supposedly making poor distinctions between native LDL and oxLDL [[1](https://www.ahajournals.org/doi/full/10.1161/01.CIR.0000164264.00913.6D?related-urls=yes&legid=circulationaha%3B111%2F18%2Fe284)7]. However, if the 4E6 assay was truly making poor distinctions between oxLDL and native LDL, the two biomarkers would essentially be proxying for one another to the point of being either interchangeable or even being the same thing. In this scenario, the results of the model would suggest extreme multicollinearity as indicated by similarly (extremely) wide confidence intervals for both results.
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@ -95,6 +122,9 @@ Because lipid peroxidation of the LDL particle's phospholipid membrane is not re
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This is relevant because the immune cells that mediate the formation of atherosclerotic plaques only tend to take up maximally oxidized LDL particles, not minimally oxidized LDL particles [[2](https://pubmed.ncbi.nlm.nih.gov/6838433/)0][[2](https://pubmed.ncbi.nlm.nih.gov/24891335/)1]. Maximally oxidized LDL have to be disposed of through scavenger receptor-mediated pathways, rather than LDL receptor-mediated pathways.
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![][image10]
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[image10]: /blog/image10.png
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If minimally oxidized LDL likely contribute as little to foam cell formation as native LDL, why favour measures of minimally oxidized LDL such as the E06 antibody assay over measures of maximally oxidized LDL such as the 4E6 antibody assay?
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Unfortunately, so far no studies have attempted to explore the relationship between oxLDL, as measured by the E06 antibody assay, and CHD outcomes after adjustment for total ApoB. The closest we have is a single study by Tsimikas et al. (2006) that found no correlation between oxPL/ApoB and ApoB [[2](https://pubmed.ncbi.nlm.nih.gov/16750687/)2].
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@ -105,6 +135,9 @@ Nevertheless, if merely having more LA in your body meant that you would increas
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It’s important to note that there was not a single statistically significant increase in risk observed in any of the included cohorts when comparing the lowest tissue LA to the highest tissue LA. One of the more interesting findings was from a regression analysis of the Scottish Heart Health Extended Cohort by Wood et al. (1984), which found a strong inverse correlation between adipose LA and CHD incidence [[2](https://pubmed.ncbi.nlm.nih.gov/6146032/)4].
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![][image11]
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[image11]: /blog/image11.png
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This certainly isn't what we would expect if the chain of causality is LA -> OxLDL -> CHD. However, as we'll discuss in the next section, this is what we'd expect if the chain of causality is SFA -> LDL -> CHD. So, let's go ahead and dive into that data next.
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###### **HEART DISEASE**
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@ -115,16 +148,28 @@ Let's start with the epidemiological evidence, being sure to keep the original q
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The relationship between SFA and CVD is nonlinear, and significantly influenced by the degree of replacement with PUFA. As such, the linear summation of prospective cohort studies can hide the nonlinear effect. For example, let's have a look at one of the most heavily-cited meta-analyses by Siri-Tarino et al. (2010), which investigated the relationship between SFA and CVD in prospective cohort studies [[2](https://pubmed.ncbi.nlm.nih.gov/20071648/)5].
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![][image12]
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[image12]: /blog/image12.png
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As we can see, the aggregated results are null (P = 0.22). However, the I² (a measure of heterogeneity) is 41%, and no attempt was made to investigate the source of that heterogeneity. If we take the time to calculate the intake ranges of each cohort study (when possible), we can test for nonlinearity.
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![][image13]
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[image13]: /blog/image13.png
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After stratifying the included studies by intake range, we see a statistically significant 30% increase in risk in subgroup one (~25±15g/day) and null results for subgroups two and three (35±15g/day and 45±15g/day, respectively). This is precisely what we'd expect to see if the risk threshold presupposed by the Dietary Guidelines was correct. McGee et al. (1984) needed to be removed for this analysis because SFA intake ranges could not be determined from the provided data.
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But perhaps this is an isolated finding. There are many other meta-analyses on this subject [[2](https://pubmed.ncbi.nlm.nih.gov/27697938/)6-[2](https://pubmed.ncbi.nlm.nih.gov/19752542/)9]. Maybe the other meta-analyses on this subject would find something different? Let's find out.
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![][image14]
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[image14]: /blog/image14.png
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Applying the same methodology to all of the available meta-analyses yields the same result. This time subgroup two is representing the intake threshold presupposed by the Dietary Guidelines (~25±15g/day). We see similar increases in risk in the same subgroup across all published meta-analyses investigating the relationship between SFA and CVD (RR 1.14 [1.07-1.22], P<0.0001).
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You may be asking why subgroups one, three, and four are null, whereas subgroup two is not. The answer is quite simple. It's because those ranges are not crossing the threshold of effect. The range of intake represented in subgroup one exists below the threshold of effect, whereas subgroups three and four exist above the threshold of effect. As such, comparing lower intakes to higher intakes within those ranges does not show an additional increase in risk. The relationship between SFA and CVD is sigmoidal.
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![][image15]
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[image15]: /blog/image15.png
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Comparing intakes that exist on either the floor or ceiling of the risk curve will typically produce null results. Only when the middle intake range is investigated is the increase in risk observable.
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But how does PUFA play into this? To answer this question, let's make our own meta-analyses. Let's take all of the cohort studies that fall within that middle range and plot them out for both SFA and PUFA.
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@ -166,22 +211,37 @@ Drag-netting the literature yielded a total of 74 studies. 20 studies were exclu
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Altogether there were 21 studies that met all of the inclusion criteria [[3](https://pubmed.ncbi.nlm.nih.gov/15668366/)0-[5](https://pubmed.ncbi.nlm.nih.gov/15668366/)0]. Cohorts were stratified across four subgroups, based on absolute grams-per-day intakes of SFA. Total pooled results across all subgroups showed a non-significant increase in risk (RR 1.07 [0.97-1.18], P=0.16). Subgroup two was the only subgroup to reach statistical significance (RR 1.24 [1.10-1.40], P=0.0005).
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![][image16]
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[image16]: /blog/image16.png
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Again, we see the exact same thing. The increase in risk occurs in the same subgroup, in the same intake range— the same intake range presupposed by the Dietary Guidelines to increase risk.
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**Results for Polyunsaturated Fat:**
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Altogether there were 10 studies that met all of the inclusion criteria. In order to preserve the PUFA to SFA ratio, cohorts were stratified across four subgroups, based on absolute grams-per-day intakes of SFA. Total pooled results across all subgroups showed a statistically significant reduction in CVD risk (RR 0.91 [0.83-1.00], P=0.04). Subgroup two was the only subgroup to reach statistical significance (RR 0.87 [0.80-0.93], P=0.0002).
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![][image17]
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[image17]: /blog/image17.png
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This second forest plot was not stratified by PUFA intake. As mentioned above, it was instead stratified by SFA intake. This way the ratio of SFA to PUFA would be better preserved. This is important for understanding the relationship between these two dietary fats.
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![][image18]
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[image18]: /blog/image18.png
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Both SFA and PUFA have inverse sigmoidal relationships with CVD. The more PUFA you replace with SFA, the higher your risk. The more SFA you replace with PUFA, the lower your risk.
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This is exactly the same relationship we see in the RCTs as well [[5](https://pubmed.ncbi.nlm.nih.gov/32827219/)1]. Recently, Hooper et al. (2020) published an enormous meta-analysis and meta-regression analysis for the Cochrane Collaboration, which investigated CVD-related outcomes of many PUFA-SFA substitution RCTs.
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![][image19]
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[image19]: /blog/image19.png
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Their analysis shows that substituting SFA for PUFA, and crossing the 10% of energy threshold as SFA, increases CVD risk in the aggregate. Especially for CVD events, CVD mortality, CHD mortality, and non-fatal acute myocardial infarction (AMI).
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Cochrane also performed multiple meta-regression analyses on the included data. Meta-regression is a tool used to investigate the relationship between two variables when they are controlled by a moderator variable. In this case, the two variables in question are SFA intakes (or PUFA-SFA substitution) and CVD. Multiple moderator variables were modeled.
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![][image20]
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[image20]: /blog/image20.png
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The only statistically significant moderator variable was total cholesterol (TC) (P=0.04). This suggests that the chain of causality is SFA -> TC -> CVD. This therefore suggests that to the extent that a dietary modification reduces TC, reductions in CVD should follow. This is confirmed in their exploratory analysis later on in the paper.
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Additional exploratory meta-analyses by Hooper et al. (2020) also further divulge that SFA reduction lowers total CVD events (analysis 1.35), the best replacement for SFA is PUFA from vegetable oils (analysis 1.44), and the effect is likely via lowering TC (analysis 1.51). This evidence dovetails perfectly with the epidemiological evidence discussed above.
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Neither trial saw a statistically significant difference in either CVD mortality or total mortality.
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![][image21]
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[image21]: /blog/image21.png
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However, in the aggregate, there is a significant increase in CVD mortality between the two trials. This is concerning, seeing as though these two trials are often touted as the best designed trials that have been conducted in the investigation of this research question, aside from the LA Veterans Administration Hospital Study (LAVAT) by Dayton et al. (1969) [[5](https://www.ahajournals.org/doi/10.1161/01.CIR.40.1S2.II-1)4]. However, the MCE's design ended up allowing participants to enter in and exit out of the trial at their leisure, and this ended up resulting in a mean follow-up time of around 1.5 years. Which is abysmal.
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It should be noted that the SDHS was a secondary prevention trial, which means that the subjects had already had a single CVD event at the time of enrollment. Given the questionable clinical relevance of the final differences in TC, it is even more ambiguous how meaningful the findings were. It has been observed that differences in SFA intake don't always change CVD outcomes in high-risk populations [[5](https://www.nature.com/articles/s41598-021-86324-w)5].
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@ -204,16 +267,28 @@ First, we can harden oils through hydrogenation or through emulsification. Howev
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TFAs are associated with an increased risk of many diseases, including CVD. However, TFAs are the only known fatty acid subtypes that have been associated with increased CVD mortality when replacing SFA on a population-level [[5](https://pubmed.ncbi.nlm.nih.gov/30636521/)7].
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![][image22]
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[image22]: /blog/image22.png
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Basically, TFAs are fucking dangerous— more dangerous than SFA. The CO-based margarine used in the SDHS was "Miracle" brand margarine [[5](https://pubmed.ncbi.nlm.nih.gov/23386268/)8]. According to Dr. Robert Grenfell of the National Cardiovascular Health Director at the Australian Heart Foundation and the Deputy Chairman of the Sydney University Nutrition Research Foundation, Bill Shrapnel, Miracle brand margarine was up to 15% TFA at the time the study was conducted [[5](https://www.ausfoodnews.com.au/2013/02/11/heart-foundation-takes-swipe-at-butter-and-new-study-on-margarine.html)9].
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>_When this study began, Miracle margarine contained approximately 15 per cent trans fatty acids, which have the worst effect on heart disease risk of any fat. The adverse effect of the intervention in this study was almost certainly due to the increase in trans fatty acids in the diet_
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If Woodhill et al. (1978) truly fed the subjects in the vegetable oil group (group F) as much of that margarine as they seem to be claiming to in their publication, that could be around 5.7g/day of TFA.
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![][image23]
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[image23]: /blog/image23.png
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The margarine used in the MCE was likely to be Fleischmann's Original, due to the availability and popularity at the time of the intervention. As well as the fact that the product was developed in direct response to pro-PUFA research that was being conducted at the time.
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![][image24]
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[image24]: /blog/image24.png
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The only other two margarines that were potentially available in the region at the time the MCE was conducted were Imperial margarine and Mazola margarine. Some Imperial products remained high in TFA until very recently [[6](https://abcnews.go.com/Business/story?id=8182555&page=1)0]. Mazola was pretty much the only non-hydrogenated margarine on the market at the time.
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![][image25]
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[image25]: /blog/image25.png
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The answer to the question of which margarine was used in the MCE is anybody's guess at this point. But if I were generous, I'd say that based on the margarines that were available (and most likely to be used) at the time the MCE was conducted, there is roughly a 67% chance that the trial was potentially confounded by TFA in the vegetable oil diet. Though Ramsden et al. (2016) remain skeptical that confounding such as this was likely [[6](https://pubmed.ncbi.nlm.nih.gov/27071971/)1].
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However, even if the MCE was not confounded by TFA, we would still have a good reason to exclude it from consideration. Like I mentioned earlier, the trial was designed in such a way that the participants had the liberty to enter and exit the trial at their leisure. In the aggregate, there was only a 12-18 month follow-up time. As such, the trial has significantly less power than all other trials that investigated this particular sort of dietary substitution.
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@ -222,6 +297,9 @@ Ramsden et al. have argued at length that the control group was likely confounde
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Fully hydrogenated oils contain very little TFA [[6](https://pubmed.ncbi.nlm.nih.gov/26048727/)2]. However, partially hydrogenated oils such as most soft margarines of the period contain high levels of TFA. Here is a selection of SOs taken from the USDA's SR28 Nutrient Database [[6](https://www.ars.usda.gov/northeast-area/beltsville-md-bhnrc/beltsville-human-nutrition-research-center/methods-and-application-of-food-composition-laboratory/mafcl-site-pages/sr11-sr28/)3].
|
||||
|
||||
![][image26]
|
||||
[image26]: /blog/image26.png
|
||||
|
||||
As you can see, a tablespoon of partially hydrogenated SO margarine contains 2200% more TFA than a tablespoon of fully hydrogenated SO shortening.
|
||||
|
||||
Ramsden et al. (2016) also acknowledge that the vegetable oil group's diet used soft margarines that were likely to contain some TFA. However, they also under-appreciate the fact that fully hydrogenated vegetable shortening contains pretty much the same amount of TFA as its unadulterated, non-hydrogenated counterpart. In fact, this is precisely why fully hydrogenated shortenings are still on the market despite the TFA ban in most developed countries. It's because those fats never had much TFA to begin with.
|
||||
|
|
@ -236,6 +314,9 @@ The trial did achieve statistically significant differences in LA intake between
|
|||
|
||||
So, why did the trial see such a massive reduction in risk? Likely because, as far as multifactorial interventions go, this trial did its best to knock the ball out of the park. Just take a look at the diets.
|
||||
|
||||
![][image27]
|
||||
[image27]: /blog/image27.png
|
||||
|
||||
Firstly, the groups achieved a difference of 10g/day in SFA and the between-group differences in SFA cross the 25g/day threshold that we discussed earlier. Secondly, the intervention group was consuming significantly fewer foods that are positively associated with CVD, such as whole meat, processed meat, and butter. Lastly, the intervention group was consuming significantly higher amounts of fruit and vegetables (considered together), as well as unsaturated fats, which are strongly inversely associated with CVD.
|
||||
|
||||
Bottom line is that there is a lot going on in these diets that could be strongly modifying CVD risk. To attribute the massive 73% reduction in CVD risk to 4.5g/day of LA is frankly dubious, and not replicated anywhere else in the literature, despite it being directly tested. Virtually all other trials that were well controlled found the opposite effect of increasing LA. Honestly, based on what is currently known about LA, I would sooner suspect that the lower LA in the intervention group was likely working against them, not for them.
|
||||
|
|
@ -246,6 +327,9 @@ The study methods of MR also assume that genes are randomly distributed in the p
|
|||
|
||||
Even though MR data doesn't really need to be mentioned, because we have actual RCT data on this subject. However, it's worthwhile to add it in here just to hammer home how utterly consistent this evidence actually is. This time the data is being sourced from the UK Biobank, which is a massive prospective cohort study that also leverages a repository of biological samples from over 500,000 subjects [[6](https://pubmed.ncbi.nlm.nih.gov/33924952/)6].
|
||||
|
||||
![][image28]
|
||||
[image28]: /blog/image28.png
|
||||
|
||||
Here we see that Park et al. (2021) observed the same relationship yet again. Genetically elevated serum LA was inversely associated with AMI, whereas genetically elevated serum AA was positively associated with AMI. The gene variants that were investigated were related to the function of fatty acid desaturase (FADS) enzymes.
|
||||
|
||||
It would seem that those who are less able to convert LA to AA have a decreased risk of AMD, whereas those who are more able to convert LA to AA have an increased risk. Considering the fact that AA conversion is highly regulated, as well as the fact that dietary LA is virtually unavoidable, it seems unlikely that modulating dietary LA would be a reliable way to modulate the conversion of LA into AA [[6](https://pubmed.ncbi.nlm.nih.gov/21663641/)7]. On balance, these findings support increasing dietary LA for CVD prevention.
|
||||
|
|
@ -264,6 +348,9 @@ It's important to preface this discussion with an acknowledgment that the trial
|
|||
|
||||
Essentially, the concern that increasing vegetable oils in the diet increases cancer risk originates from the following figure. Figure 1 from the original analysis by Pearce at al (1971) clearly shows that the cumulative deaths due to carcinoma rise faster in the vegetable oil group than in the control group after around two years into the study.
|
||||
|
||||
![][image29]
|
||||
[image29]: /blog/image29.png
|
||||
|
||||
I must admit that the graph looks pretty scary, and narratives surrounding the findings of this study had me convinced for a while too. However, this graph is incredibly misleading when taken out of context.
|
||||
|
||||
Firstly, cancer deaths were not a pre-specified primary endpoint of the trial itself, which means it is questionable whether or not the study was even appropriately powered or equipped to investigate this endpoint in any rigorous way. Secondly, the results are not statistically significant, despite the above figure showing what appears to be a massive divergence in cancer outcomes.
|
||||
|
|
@ -278,52 +365,94 @@ This basically means that the excess cancer deaths seen in the vegetable oil gro
|
|||
|
||||
Pearce et al. also included a table that stratifies cancer outcomes by the degree of adherence per group.
|
||||
|
||||
![][image30]
|
||||
[image30]: /blog/image30.png
|
||||
|
||||
As mentioned above, the vegetable oil group had significantly more low adherers. As we can see, about 33% of the excess cancer was occurring among low adherers in the vegetable oil group. Let's see what happens when we not only remove the low adherer subgroup, but also compare the between-group difference in carcinoma risk among the highest adherers.
|
||||
|
||||
![][image31]
|
||||
[image31]: /blog/image31.png
|
||||
|
||||
Removing the low adherers nullifies the effect of the vegetable oil diet on cancer outcomes. There are also other plausible explanations for the effect as well. For example, the vegetable oil group contained many more moderate smokers than the animal fat group.
|
||||
|
||||
Moderate smokers were defined as those smoking 0.5-1 packs of cigarettes per day. As you can see, observed cancer among moderate smokers was 3x higher in the vegetable oil group, and this is where all the excess cancer risk is accumulating.
|
||||
|
||||
![][image32]
|
||||
[image32]: /blog/image32.png
|
||||
|
||||
This means that low adherers in the vegetable oil group were likely to be smokers, and the smokers were likely to get more cancer. As we would expect [[7](https://pubmed.ncbi.nlm.nih.gov/22943444/)0].
|
||||
|
||||
To suggest that the results of the LAVAT demonstrate a higher cancer risk for those consuming vegetable oils is just to misunderstand or misrepresent the data that Pearce et al. reported. The study did not actually divulge an independent effect of vegetable oil intake on cancer mortality. In fact, if we only look at high adherers, there are no statistically significant differences in cancer.
|
||||
|
||||
![][image33]
|
||||
[image33]: /blog/image33.png
|
||||
|
||||
As the authors reported, if the increase in cancer risk was actually a consequence of the vegetable oil diet, we would see more cancer risk among higher adherers. But we don't. We see no statistically significant differences.
|
||||
|
||||
Overall, there is insufficient evidence to declare higher vegetable oil intakes to be an independent risk factor for cancer. The available data suggests that, at worst, higher vegetable oil intakes likely have a neutral effect compared to high animal fat intakes. But, the LAVAT was not the only trial to report cancer as a secondary endpoint. Three other trials that substituted vegetable oils for SFA also reported cancer outcomes.
|
||||
|
||||
![][image34]
|
||||
[image34]: /blog/image34.png
|
||||
|
||||
When considering all of the studies in the aggregate (subgroup 2.1.1), we see that the effect of substituting vegetable oils for SFA on cancer is null. But, the LAVAT is still boasting its (dubiously) large effect size. When we remove the moderate smokers, the increased risk is nullified (subgroup 2.1.2). However, further excluding all regular smokers pushes the aggregated results to a non-significant decrease in cancer risk with substituting vegetable oils for SFA (subgroup 2.1.3).
|
||||
|
||||
The direction of effect that we see is actually consistent with the wider epidemiology investigating the relationship between LA biomarkers and cancer mortality. Here we see a strong inverse association between tissue LA representation and cancer risk overall [[7](https://pubmed.ncbi.nlm.nih.gov/32020162/)1].
|
||||
|
||||
![][image35]
|
||||
[image35]: /blog/image35.png
|
||||
|
||||
However, this is total cancer. There is still some controversy surrounding whether or not vegetable oils may increase the risk of other cancers. So, let's dive into that literature next.
|
||||
|
||||
###### **SKIN CANCER**
|
||||
|
||||
There is a meta-analysis by Ruan et al. (2020) investigating the limited epidemiological research on the subject. The results suggest that higher intakes of PUFA could also increase the risk of skin cancer in prospective cohort studies [[7](https://pubmed.ncbi.nlm.nih.gov/31298947/)2]. However, if we take a look at the author's data, we have some troubling findings.
|
||||
|
||||
![][image36]
|
||||
[image36]: /blog/image36.png
|
||||
|
||||
Increasing PUFA intake seems to increase the risk of squamous cell carcinoma (SCC). However, a single study by Park et al. (2018) is contributing 92.6% of the weight [[7](https://pubmed.ncbi.nlm.nih.gov/29636341/)3].
|
||||
|
||||
![][image37]
|
||||
[image37]: /blog/image37.png
|
||||
|
||||
This could be due to the fact that the study's adjustment model lacked several important covariates that may have plausibly changed the association. For example, the multivariate adjustment model adjusted for hair colour rather than skin tone. This is problematic because hair colour does not sufficiently capture the differential effects of skin tone on skin cancer [[7](https://pubmed.ncbi.nlm.nih.gov/23107311/)4].
|
||||
|
||||
![][image38]
|
||||
[image38]: /blog/image38.png
|
||||
|
||||
In at least one of the included prospective cohort studies by Ibiebele et al. (2009) that investigated the relationship between LA and skin cancer included adjustments for skin colour, and their results were null [[7](https://pubmed.ncbi.nlm.nih.gov/19462452/)5]. This further casts doubt on the veracity of the findings reported by Park et al. (2018).
|
||||
|
||||
In fact, when tissue representation of LA was investigated by Wallingford et al. (2013) in a separate cohort study, non-significant reduction in the risk of basal cell carcinoma (BCC) can be observed [[7](https://pubmed.ncbi.nlm.nih.gov/23885039/)6]. Additionally, among those with previous skin cancers, higher tissue representation of LA was associated with a statistically significant decrease in risk of re-occurrence (RR 0.54 [0.35-0.82]) A very odd finding if having more LA inside your body is supposed to predispose you to developing skin cancer.
|
||||
|
||||
There is also one study by Harris et al. (2005) that investigates the relationship between red blood cell cis-LA content and squamous cell carcinoma [[7](https://pubmed.ncbi.nlm.nih.gov/15824162/)7]. While it is a case-control study and lacks the temporal component that is necessary to establish causality, it is some of the only human outcome data we have on the subject, and the results are null.
|
||||
|
||||
![][image39]
|
||||
[image39]: /blog/image39.png
|
||||
|
||||
If one still believes that higher intakes of LA increases the risk of skin cancer, I have a treat for them. Do you remember the LAVAT we mentioned in the cancer section? It turns out that skin cancer was actually one of their secondary endpoints.
|
||||
|
||||
![][image40]
|
||||
[image40]: /blog/image40.png
|
||||
|
||||
In table II from the post-hoc analysis by Pearce et al. (1971), we see that in the vegetable oil group, there were ten cases of skin cancer, whereas in the animal fat group there were 21. This produces a statistically significant increase in skin cancer risk for the animal fat group, whether or not we exclude or include the post-diet period (RR: 2.11 [1.01-4.43] and 2.09 [1.07-4.11], respectively).
|
||||
|
||||
![][image41]
|
||||
[image41]: /blog/image41.png
|
||||
|
||||
As we discussed earlier, there were no statistically significant differences in cancer risk among heavy smokers, of which there were only two cases in the animal fat group. However, there was a non-significant increase in cancer risk among moderate smokers, of which there were 19 cases in the vegetable oil group.
|
||||
|
||||
This suggests that the increase in skin cancer seen in the animal fat group is not due to heavy smoking, as there were only two cases of cancer among heavy smokers in the animal fat group, and we have 21 cases of skin cancer. The vegetable oil group had lower rates of skin cancer despite the fact that there were more moderate smokers, and more cancer risk among moderate smokers, in the vegetable oil group. This increase in risk seen in the animal fat group can't be explained by differences in smoking habits.
|
||||
|
||||
Additionally, the methods of MR have also been used by Seviiri et al. (2021) to investigate the relationship between elevated plasma LA and skin cancer [[7](https://pubmed.ncbi.nlm.nih.gov/34088753/)8]. Data was collected for two different keratinocyte cancers, which were BCC and SCC, and the results are consistent with those found in the LAVAT.
|
||||
|
||||
![][image42]
|
||||
[image42]: /blog/image42.png
|
||||
|
||||
There was a statistically significant 6% reduction in BCC risk with genetically elevated plasma LA, whereas AA showed a statistically significant 4% increase in risk. Oddly, the effect size of eicosapentaenoic acid (EPA) was actually larger than that of AA, which would seem to be at odds with the RCT data on the subject [[7](https://pubmed.ncbi.nlm.nih.gov/24265065/)9].
|
||||
|
||||
![][image43]
|
||||
[image43]: /blog/image43.png
|
||||
|
||||
For SCC, the only statistically significant relationship between genetically elevated plasma PUFA was a 4% increased risk with plasma AA. The results for all other PUFA were null.
|
||||
|
||||
In conclusion, it is true that there are some cohort studies suggesting that higher intakes of PUFA may increase the risk of skin cancer. However, the results from the LAVAT and MR are actually stronger evidence and concordant in the opposite direction. As such, it would not appear likely that increasing vegetable oil consumption is an independent risk factor for developing skin cancer. In fact, increasing vegetable oil intake could actually reduce the risk of skin cancer.
|
||||
|
|
@ -336,10 +465,16 @@ The notion that vegetable oils are responsible for the obesity epidemic is extre
|
|||
|
||||
Indeed, this mechanism does appear to work— in mice [[8](https://pubmed.ncbi.nlm.nih.gov/22334255/)1]. In this study by Alvheim et al. (2012), mice were fed two different diets with varying fatty acid compositions. Essentially, mice were randomized to two diets that contained either moderate fat (35% of energy) or high fat (60% of energy). Within each diet group there were three distinct diet conditions. One of the diet conditions was low in LA (1% of energy), and the two remaining diet conditions were "high" in LA (8% of energy), with one of which also being supplemented with long-chain omega-3s.
|
||||
|
||||
![][image44]
|
||||
[image44]: /blog/image44.png
|
||||
|
||||
By the end of the study, the mice receiving 8% of their energy from LA had consistently higher body weight, with a slightly mitigating effect of supplemented omega-3s in the mice fed a high-fat diet (chart e). The increases in body weight in the mice that were fed high-LA diets was commensurate with increases in 2-AG. Ergo, consuming a high-LA diet will increase 2-AG and facilitate obesity— in mice. But what about humans?
|
||||
|
||||
A study by Blüher et al. (2006) involving 60 subjects explored the correlation between body fatness and a number of markers related to the endocannabinoid system. There ended up being significant correlations between circulating 2-AG and obesity [[8](https://pubmed.ncbi.nlm.nih.gov/17065342/)2].
|
||||
|
||||
![][image45]
|
||||
[image45]: /blog/image45.png
|
||||
|
||||
However, there is an issue. Unlike mice, circulating levels of the 2-AG precursor, ARA, did not differ between lean and obese subjects. For this reason, the authors go on to express skepticism toward the hypothesis that 2-AG synthesis is driven passively by the supply of precursors in humans. Instead, they point out that there is more evidence that obesity itself acts to inhibit the degradation of 2-AG.
|
||||
|
||||
>_Which mechanisms lead to increased endocannabinoid levels in abdominal obesity? One possibility is the increased supply of precursors for endocannabinoid biosynthesis and/or increased activity of enzymes involved in endocannabinoid synthesis. When studying circulating levels of the precursor arachidonic acid and of oleoylethanolamide, a molecule with endocannabinoid structure and synthesized by the same enzymes that do not activate [cannabinoid] receptors, we did not find any significant correlation with measures of adiposity._
|
||||
|
|
@ -350,6 +485,9 @@ This would not be surprising, considering that the impaired clearance and/or deg
|
|||
|
||||
While somewhat tangential to the point, it is interesting to note that we have tested the effects of selective CB1-antagonism in humans with a pharmaceutical called Rimonabant [[8](https://pubmed.ncbi.nlm.nih.gov/17054276/)4]. Overall, this drug does appear to reduce energy intake and result in weight loss that is equal to just over a quarter-pound per week.
|
||||
|
||||
![][image46]
|
||||
[image46]: /blog/image46.png
|
||||
|
||||
The reason this is tangential is because CB-antagonists such as Rimonabant are not specifically targeting LA metabolism. All this research tells us is that the endocannabinoid system is involved with the regulation of body weight in humans, but it does not tell us what independent contributions are being made by 2-AG, or even dietary LA for that matter.
|
||||
|
||||
###### **ENERGY INTAKE**
|
||||
|
|
@ -358,10 +496,16 @@ If we wish to explore the effects of dietary LA on appetite, there have been a n
|
|||
|
||||
Of the trials that actually reported ad libitum energy intake in response to diets of varying fatty acid composition, no consistent effects are observed [[8](https://www.ncbi.nlm.nih.gov/pubmed/14694208)6-[9](https://pubmed.ncbi.nlm.nih.gov/28760423/)1]. All together, the short-term evidence is largely a wash. In fact, this was remarked upon by Strik et al. (2010) in table 4 of one such publication, and they included the aggregated findings across a number of different trials investigating the relationship between fatty acid saturation, satiety, and energy intake [[9](https://pubmed.ncbi.nlm.nih.gov/20492735/)2]. Overall, when there was an effect of LA, it tended to decrease energy intake.
|
||||
|
||||
![][image47]
|
||||
[image47]: /blog/image47.png
|
||||
|
||||
In one particularly well-done trial by Strik et al., participants in the three groups were given unlimited access to muffins made using either SFA, MUFA, or PUFA. They would consume these muffins ad libitum one variety at a time, with a washout period between different muffin types.
|
||||
|
||||
By the end, all three groups experienced all three muffin types. Each time researchers collected subjective data on satiety and the general satisfaction of the food experience. No differences in any parameters reached statistical significance.
|
||||
|
||||
![][image48]
|
||||
[image48]: /blog/image48.png
|
||||
|
||||
There were no statistically significant differences in hunger, fullness, satisfaction, or prospective consumption (how much more subjects suspected they could eat at that moment). It appeared as though SFA trended toward a decrease in fullness, perhaps. There were also no observed differences in ad libitum energy intake.
|
||||
|
||||
>_Mean total [energy intake] and energy contributed by CHO, fat and protein respectively at the ad lib lunch is presented for each treatment in Figure \u{200B}3. There was no significant difference in total [energy intake] between lipid treatments (treatment, P > 0.05). Mean (SEM) [energy intake] at lunch was 5275.9 (286.5) kJ, 5227.7 (403.9) kJ, and 5215.6 (329.5) kJ following the SFA-, PUFA-, and MUFA-rich breakfasts respectively._
|
||||
|
|
@ -372,32 +516,53 @@ I have also heard it proposed that in order to study this effect, researchers ma
|
|||
|
||||
This difference in LA intake produced an enormous increase in adipose LA in the vegetable oil group. It's probably safe to say that these people reached a maximal saturation point, as evidenced by the hyperbolic curve in adipose LA representation over time.
|
||||
|
||||
![][image49]
|
||||
[image49]: /blog/image49.png
|
||||
|
||||
The median LA representation in adipose tissue increased from around 8-11% of total fatty acids to over 30% of total fatty acids across the eight year study. The baseline levels are consistent with levels found in traditional populations like the Tsimane, Inuit, and the Navajo aboriginals [[9](https://pubmed.ncbi.nlm.nih.gov/22624983/)3-[9](https://onlinelibrary.wiley.com/doi/10.1002/cphy.cp050117)5]. While the data published by Martin et al. (2012) is representing the fatty acid composition of breast milk in the Tsimane, it is also true that the LA contents of both breast milk and adipose tissue correlate extremely tightly [[9](https://pubmed.ncbi.nlm.nih.gov/16829413/)6-[9](https://pubmed.ncbi.nlm.nih.gov/9684741/)8].
|
||||
|
||||
![][image50]
|
||||
[image50]: /blog/image50.png
|
||||
|
||||
There were no statistically significant differences between the baseline tissue LA presentation in the LAVAT and measurements taken from either the Navajo or Tsimane (SD estimated for Navajo). However, tissue LA was statistically significantly higher among Inuit when compared to the baseline measurements observed in the LAVAT.
|
||||
|
||||
From this, we can likely infer that the subjects in the LAVAT were largely starting from ancestral levels of tissue LA, and increasing tissue LA to approximately threefold higher levels over the eight year trial period. So how did this threefold increase in tissue LA affect their body weight over time? Long story short, it didn't.
|
||||
|
||||
![][image51]
|
||||
[image51]: /blog/image51.png
|
||||
|
||||
Some may speculate that perhaps the 10.8g of LA being consumed in the control group was simply too high, and that the hyperphagic effects of the LA could have been masked by both groups exceeding a particular threshold. This is difficult to reconcile with the fact that the LA intake of the animal fat group was perfectly within bounds when compared to all known estimates of preagricultural LA intakes, as mentioned above [[9](https://pubmed.ncbi.nlm.nih.gov/20860883/)9]. Also, this was an ad libitum trial in normal weight subjects and body weight remained within 2% of baseline.
|
||||
|
||||
The LA intakes in the vegetable oil group universally overshoot the upper bounds of all of those same estimates of preagricultural LA intakes. This means that the animal fat group was consuming levels of LA that were consistent with those consumed before the obesity epidemic occurred. However, the vegetable oil group was consuming a level of LA that far surpassed all known preagricultural estimates of LA consumption.
|
||||
|
||||
This wasn't the only RCT that substituted vegetable oils for animal fat to measure body weight over time. According to the secondary endpoint analysis done by Hooper et al. 2020 with the Cochrane Collaboration, Olso Diet-Heart saw a 2.5kg reduction in body weight during their study period, whereas the Medical Research Council saw no change in body weight as well [[1](https://pubmed.ncbi.nlm.nih.gov/2607071/)00-[1](https://pubmed.ncbi.nlm.nih.gov/4175085/)01].
|
||||
|
||||
![][image52]
|
||||
[image52]: /blog/image52.png
|
||||
|
||||
Altogether, it does not appear as though vegetable oils uniquely increase body weight in humans. So, while vegetable oils may increase 2-AG and induce obesity in mice, this does not appear to pan out in humans. Large scale RCTs in humans do not support the hypothesis that vegetable oils lead to weight gain over time in humans.
|
||||
|
||||
###### **THERMOGENESIS**
|
||||
|
||||
The effect of varying PUFA and SFA in the diet on measures of energy expenditure (EE) have been tested numerous times and show unambiguously consistent results [[1](https://pubmed.ncbi.nlm.nih.gov/24363161/)02]. Overall, diets higher in PUFA and lower in SFA tend to increase EE in humans [[1](https://pubmed.ncbi.nlm.nih.gov/1556946/)03-[1](https://pubmed.ncbi.nlm.nih.gov/9467221/)04].
|
||||
|
||||
![][image53]
|
||||
[image53]: /blog/image53.png
|
||||
|
||||
Here is an example from that body of literature. In this study by Lichtenbelt et al. (1997), we can clearly see a consistent effect across all six subjects with higher PUFA intakes increasing postprandial EE. The same trend was also observed for resting metabolic rate (RMR). Ultimately, high-SFA, low-PUFA diets tend to lower EE and RMR compared to high-PUFA, low-SFA diets. This finding is incredibly consistent, though PUFA and MUFA seem to trade blows in some studies, the overall trend of SFA being least thermogenic is clear.
|
||||
|
||||
The effects of high-PUFA feeding on fat oxidation have also been studied by Casas-Agustench et al. (2009) as well [[1](https://pubmed.ncbi.nlm.nih.gov/19010571/)05]. When using the respiratory quotient to compare the effects of diets that are high in PUFA, MUFA, and SFA on EE and fat oxidation, we see a similar trend emerge once again.
|
||||
|
||||
![][image54]
|
||||
[image54]: /blog/image54.png
|
||||
|
||||
High-PUFA feeding resulted in higher postprandial EE as well as a higher thermic effect of feeding (TEF). Though the differences in the rate of fat oxidation did not reach significance between groups, there was an obvious trend that reflected the degree of fatty acid saturation. PUFA was the most thermogenic, SFA was the least thermogenic, and MUFA was somewhere in between.
|
||||
|
||||
The same results were observed by DeLany et al. (2000), only this time different dietary fats containing labeled carbon isotopes are used [[1](https://pubmed.ncbi.nlm.nih.gov/11010930/)06]. You can measure these isotopes in the breath in order to measure how much of the dietary fat a subject has consumed was burned in the time after a meal.
|
||||
|
||||
![][image55]
|
||||
[image55]: /blog/image55.png
|
||||
|
||||
Using this methodology, we see that there is one type of SFA that is preferentially oxidized over all other FAs that were tested, and that is lauric acid. However, lauric acid might have ketogenic properties, so interpret with caution. Looking over the rest of the tested FAs, we see that PUFA once again has the highest oxidation rate, followed by MUFA, and SFA once again comes in last place.
|
||||
|
||||
Vegetable oils don't appear to make you fat. But even if they did, it does not appear that their effects on thermogenesis and EE are likely to be mediating factors. In fact, vegetable oils appear as though they could potentially have the opposite effect.
|
||||
|
|
@ -406,16 +571,25 @@ Vegetable oils don't appear to make you fat. But even if they did, it does not a
|
|||
|
||||
The idea that vegetable oils are the primary driver of obesity and/or type 2 diabetes mellitus (T2DM) has deep roots in many diet communities. However, the evidence cited to support this assertion is typically animal research investigating the effects of LA on hypothalamic function and energy intake. Not to mention that, as we discussed earlier, altering the fatty acid saturation of the diet has no discernable effect on ad libitum energy intake. So, let's investigate the effects on insulin sensitivity.
|
||||
|
||||
![][image56]
|
||||
[image56]: /blog/image56.png
|
||||
|
||||
When the relationship between tissue LA and insulin sensitivity was investigated by Iggman et al. (2010), the results are null for leaner individuals. However for overweight individuals, adipose LA is associated with a statistically significant increase in insulin sensitivity [[1](https://pubmed.ncbi.nlm.nih.gov/20127308/)07].
|
||||
|
||||
This study into T2DM incidence is the closest thing I've been able to find investigating the association between adipose tissue fatty acids and insulin sensitivity that also adjusts for the fewest mediators of T2DM, such as energy intake.
|
||||
|
||||
Again, we can turn our attention to well-conducted crossover RCTs for clearer answers to these sorts of questions. Fortunately, we have one such trial by Heine et al. (1989), investigating the effects of altering fatty acid saturation on measures of insulin sensitivity and glucose homeostasis [[1](https://pubmed.ncbi.nlm.nih.gov/2923077/)08]. Subjects were placed on either a high-LA diet (10.9% of energy) or a low-LA diet (4.2% of energy) for 30 weeks, after which measures of plasma insulin and glucose clearance were taken.
|
||||
|
||||
![][image57]
|
||||
[image57]: /blog/image57.png
|
||||
|
||||
While there were no statistically significant differences between groups in most ways, the high-LA group has a significantly higher glucose clearance rate during the first infusion test. Overall, there was an obvious trend toward a benefit with the high-LA diet.
|
||||
|
||||
Another trial by Zibaeenezhad et al. (2016) compared 15g of walnut oil (containing approximately 8g of LA) to no intervention, and measured a number of endpoints relevant to T2DM [[1](https://pubmed.ncbi.nlm.nih.gov/28115966/)09]. Presumably, randomization balanced baseline LA between groups, so we can assume that the trial is effectively testing the effects of adding a tablespoon of walnut oil to the diet.
|
||||
|
||||
![][image58]
|
||||
[image58]: /blog/image58.png
|
||||
|
||||
By the end of the trial, the walnut oil diet improved both HbA1C and fasting blood glucose. There were also no statistically significant changes in body weight or BMI. Which suggests that these effects were independent of weight loss. This is not what we'd expect if the vegetable oils were increasing the risk of developing T2DM.
|
||||
|
||||
We also have at least one study by Pertiwi et al. (2020) investigating the relationship between LA and both glycemic control and liver function [[1](https://pubmed.ncbi.nlm.nih.gov/32546275/)10]. LA seems to have no association with glycemic control, and is associated with better liver function in the minimally adjusted model. The association is then null in model 2, which adjusts for a few T2D mediators. Lastly, after a better adjustment for diet quality, many of the associations gain significance again.
|
||||
|
|
@ -424,18 +598,30 @@ There are a few more studies that do not adjust for many T2D mediators. In this
|
|||
|
||||
Ultimately, it appears that neither LA biomarkers nor intake associate with negative outcomes with regards to insulin sensitivity, obesity, T2D, or liver function. These results are pretty consistent with existing meta-analyses on this question (which I combed through to find minimally adjusted data) [[112](https://pubmed.ncbi.nlm.nih.gov/29032079/)].
|
||||
|
||||
![][image59]
|
||||
[image59]: /blog/image59.png
|
||||
|
||||
These are not at all the results that we would expect to see if merely having more LA in either your body or your diet increased the risk of T2DM. Although, there are some who would claim that associations between LA biomarkers and diseases are unreliable.
|
||||
|
||||
Essentially, the idea is that LA can oxidize for various reasons and potentially skew the biomarker in different directions. For example, if higher tissue representation of LA is inversely associated with a disease, but the disease itself predisposes LA to oxidation (and thus creates the potential for the LA biomarker to appear artificially lower), the data could be confounded. However, there is fascinating data that would seem to contradict this [[113](https://pubmed.ncbi.nlm.nih.gov/30987358/)].
|
||||
|
||||
![][image60]
|
||||
[image60]: /blog/image60.png
|
||||
|
||||
In analysis of a prospective cohort study by Yepes-Calderón et al. (2019), levels of the LA peroxidation products, malondialdehyde (MDA), was strongly and inversely associated with new onset T2DM after kidney transplant. Even after applying seven different multivariate adjustment models, no adjustment succeeded in nullifying the effect.
|
||||
|
||||
Perhaps the reason LA is inversely associated with T2DM is _because_ it undergoes peroxidation. Perhaps MDA is a signaling molecule that has some protective benefit for T2DM in the long run, despite lipid peroxidation sounding very bad and spooky. Who knows. I don't feel particularly bad for speculating. Many of my opponents in this debate often base entire positions almost entirely on speculation, and refer to much weaker evidence to boot.
|
||||
|
||||
Lastly, in a multinational MR study of almost a million participants by Chen et al. (2017), there was an inverse association between elevated plasma LA levels and incidence of T2DM [[114](https://pubmed.ncbi.nlm.nih.gov/28032469/)].
|
||||
|
||||
![][image61]
|
||||
[image61]: /blog/image61.png
|
||||
|
||||
Once again, we see the same thing that we saw in the MR studies investigating CVD. Genetically higher plasma LA is inversely associated with lower fasting blood glucose and T2DM incidence, whereas genetically higher plasma AA is positively associated with both higher fasting blood glucose and T2DM incidence. We also see in their subgroup analysis that the conversion of LA to AA through FADS is once again mediating.
|
||||
|
||||
![][image62]
|
||||
[image62]: /blog/image62.png
|
||||
|
||||
When excluding gene variants affecting the function of FADS, the association between genetically elevated plasma LA and T2DM is null. However, when FADS gene variants are considered, the association is statistically significant. This once again suggests a causal relationship between the conversion of LA to AA and disease incidence. Strangely, long chain omega-3s are positively associated as well, which is in contrast to the RCT data on the subject [[115](https://pubmed.ncbi.nlm.nih.gov/31434641/)].
|
||||
|
||||
Overall it would appear that higher intakes of LA are inversely associated with T2DM. In conclusion, LA does not appear to negatively affect body weight, ad libitum intake, EE, insulin sensitivity, or T2DM rates in humans. The current evidence does not support lowering vegetable oil intake for the purposes of preventing T2DM, and the evidence may even suggest that vegetable oils may play a role in T2DM prevention.
|
||||
|
|
@ -450,6 +636,9 @@ However, within this body of literature, the primary hypothesis that has been pu
|
|||
|
||||
Because it would be unethical to truly test the effects of IVLE overfeeding in humans, we have to rely on animal models to provide us with insights. In one well-designed mouse study by Ksami et al. (2013), both SO- and FO-IVLEs were fed to mice with intestinal injuries [[121](https://pubmed.ncbi.nlm.nih.gov/24107776/)]. Except there were additional groups that were fed FO-IVLEs that also contained SO-derived phytosterols. Markers of liver pathology were comparable between phytosterol-containing FO-IVLEs and controls fed SO-IVLEs.
|
||||
|
||||
![][image63]
|
||||
[image63]: /blog/image63.png
|
||||
|
||||
When tested in humans at matched, eucaloric dosages, there are no clinically meaningful differences between SO-IVLEs and FO-IVLEs [[122](https://pubmed.ncbi.nlm.nih.gov/23770843/)-[123](https://pubmed.ncbi.nlm.nih.gov/22796064/)]. Across all of the markers investigated by Nehra et al. (2014), the only significant changes were increases in alkaline phosphatase, but they occurred in both groups.
|
||||
|
||||
Since FO-IVLEs are extremely low in LA, it is unlikely that LA is the mediator of this change. Despite the fact that dosages were titrated down to tolerable levels, such to be compliant with current standards of care for IVLEs, tissue LA increased significantly in subjects receiving SO-IVLEs.
|
||||
|
|
@ -464,14 +653,23 @@ There is just a tiny little problem, though. They actually weren't testing the e
|
|||
|
||||
Ultimately, they likely did not significantly alter the LA content of the diet itself, as evidenced by the fact that tissue LA went largely unchanged throughout the duration of the trial.
|
||||
|
||||
![][image64]
|
||||
[image64]: /blog/image64.png
|
||||
|
||||
Fortunately, we do have better, more direct experiments investigating the effects of dietary fatty acid composition and fatty acid saturation on measures of liver fat in humans [[126](https://pubmed.ncbi.nlm.nih.gov/22492369/)]. First is an isocaloric feeding study by Bjermo et al. (2012) that largely found non-inferiority between LA and SFA on measures of visceral adipose tissue (VAT). However, the high-LA diet resulted in a greater overall improvement in the subjects' metabolic profile.
|
||||
|
||||
The high-LA diet did result in lower waist circumference, PCSK9, cholesterol, serum insulin, and ALT, though it did not necessarily result in a difference in VAT compared to the high-SFA diet. The results are slightly different when looking at human overfeeding [[127](https://pubmed.ncbi.nlm.nih.gov/24550191/)]. In this trial by Rosqvist et al. (2014), which compared hypercaloric diets that were either high-LA or high-SFA, the high-LA diet did appear to be protective against VAT accumulation.
|
||||
|
||||
![][image65]
|
||||
[image65]: /blog/image65.png
|
||||
|
||||
The high-LA diet seemed to be uniquely protective against liver fat accumulation in particular. Additionally, the high-LA diet seemed to be associated with a greater increase in lean body mass (LBM) when compared to the high-SFA diet. But not only that, the high-LA diet seemed more resistant to fat gain overall compared to the high-SFA diet. These are not the results we'd expect if LA was uniquely causal in NAFLD.
|
||||
|
||||
These human experimental finding are perfectly consistent with the observational evidence on the subject as well, which typically shows that either high-PUFA or high-LA diets protect against NAFLD at the population level as well [[128](https://pubmed.ncbi.nlm.nih.gov/22209679/)-[129](https://pubmed.ncbi.nlm.nih.gov/27618908/)].
|
||||
|
||||
![][image66]
|
||||
[image66]: /blog/image66.png
|
||||
|
||||
Overall there is an inverse association between high-PUFA intake and measures of hepatic lipid concentrations. There is, however, an association between high-SFA diets, just like the experimental literature. There is also evidence from Wehmeyer et al. (2016) that suggests that the effect of total energy intake on NAFLD is greater than either high-PUFA or high-SFA diets [[130](https://pubmed.ncbi.nlm.nih.gov/27281105/)]. Regardless, there does not appear to be any clear or persuasive evidence that LA is uniquely causal of NAFLD.
|
||||
|
||||
# **AUTOIMMUNE DISEASE**
|
||||
|
|
@ -482,10 +680,16 @@ If you've spent any amount of time in any low carb or vegan diet community or bl
|
|||
|
||||
There is an analysis of the Epidemiological Investigation of Rheumatoid Arthritis cohort by Lourdudoss et al. (2018) that investigated the relationship between dietary fatty acids and RA pain [[131](https://pubmed.ncbi.nlm.nih.gov/28371257/)]. As per the recurring theme throughout much of the dietary fat literature, a high O6:O3 ratio is associated with an increased risk of both unacceptable pain and refractory pain (RR 1.70 [1.03-2.82] and 2.33 [1.28-4.24], respectively.
|
||||
|
||||
![][image67]
|
||||
[image67]: /blog/image67.png
|
||||
|
||||
However, if we look at omega-3 we see that there is a statistically significant decrease in both unacceptable pain and refractory pain (RR 0.57 [0.35-0.95] and 0.47 [0.26-0.84], respectively). Whereas for omega-6, results for all three endpoints are null. If we do a little math (1/0.54 and 1/0.47), we see that the risk increase when going from the highest to lowest intakes of omega-3 for both unacceptable pain and refractory pain are pretty much the same as the risk ratios for the lowest to highest O6:O3 ratio. Which are 1.75 and 2.12, respectively.
|
||||
|
||||
When considered together, this likely means that the effect of a high O6:O3 ratio has more to do with insufficient omega-3 than it has to do with excessive omega-6, which is consistent with the experimental literature on the subject [[132](https://pubmed.ncbi.nlm.nih.gov/29017507/)-[133](https://pubmed.ncbi.nlm.nih.gov/28067815/)]. However, these results are not consistent across all measures of RA, such as bone marrow lesions in those without RA at baseline [[134](https://pubmed.ncbi.nlm.nih.gov/19426478/)].
|
||||
|
||||
![][image68]
|
||||
[image68]: /blog/image68.png
|
||||
|
||||
In an analysis of this Australian cohort by Wang et al. (2009), neither omega-3, omega-6, nor the O6:O3 ratio had a statistically significant effect on the incidence of bone marrow lesions. However, intakes of saturated fat were associated with a statistically significant increase in risk in both multivariate models (RR 2.62 [1.11-6.17] and 2.56 [1.03-6.37], respectively).
|
||||
|
||||
As far as experimental evidence goes, the effects of all sorts of high-LA oils on RA-related endpoints have been investigated over the years. First we have 3-10.5g/day of blackcurrant seed oil (BCSO) [[135](https://pubmed.ncbi.nlm.nih.gov/8081671/)-[136](https://pubmed.ncbi.nlm.nih.gov/1397534/)]. BCSO has an LA content in excess of 40% by weight [[137](https://pubmed.ncbi.nlm.nih.gov/23341215/)]. Though most of these findings were null, there is one trial by Watson et al. (1993) that did have interesting results [[138](https://pubmed.ncbi.nlm.nih.gov/8252313/)].
|
||||
|
|
@ -498,6 +702,9 @@ Next up is evening primrose oil (EPO), which contains approximately 72% LA by we
|
|||
|
||||
However, EPO trials using this design have been criticized by Horrobin (1989) for having a number of potential methodological errors [[141](https://pubmed.ncbi.nlm.nih.gov/2688567/)]. In another trial by Belch et al. (1988) using more robust methodology and more complex comparisons, EPO seems to do quite well in moderate doses [[142](https://pubmed.ncbi.nlm.nih.gov/2833184/)]. In this trial, 49 subjects with RA, managed with nonsteroidal anti-inflammatory drugs (NSAID), were randomized to three groups. One group had 12g/day of EPO, another group received 12g/day of EPO+FO, and the final group was placed on a placebo.
|
||||
|
||||
![][image69]
|
||||
[image69]: /blog/image69.png
|
||||
|
||||
While EPO alone resulted in significant reduction in the use of NSAIDs, the largest reductions in NSAID usage was seen when EPO was paired with FO. Not only does this detract from the notion that LA increases RA, this also lends further credibility to the beneficial effects of increasing dietary omega-3.
|
||||
|
||||
However, the double blind RCT conducted by Volker et al. (2000) would seem to contradict this finding [[143](https://pubmed.ncbi.nlm.nih.gov/11036827/)]. In this trial, it is claimed that FO may improve symptoms as long as the background diet is low in omega-6. However, it is unclear if these results are actually compared to a high omega-6 diet, or if all of the study subjects were on low omega-6 diets. These results seem odd, as there are plenty of studies using high omega-6 oils that show positive results [[144](https://pubmed.ncbi.nlm.nih.gov/28699499/)-[146](https://pubmed.ncbi.nlm.nih.gov/29705470/)].
|
||||
|
|
@ -522,6 +729,9 @@ Not only that, but there was no multivariable adjustment to ascertain whether or
|
|||
|
||||
Puzzlingly, in stark contrast to these findings, other cross-sectional data seems to suggest that LA has either a neutral or beneficial effect on SLE, at least once people are diagnosed [[148](https://pubmed.ncbi.nlm.nih.gov/31074595/)-[149](https://pubmed.ncbi.nlm.nih.gov/26848399/)]. In the first paper by Charoenwoodhipong et al. (2020), it was observed that LA had no association with worsening SLE-related symptoms.
|
||||
|
||||
![][image70]
|
||||
[image70]: /blog/image70.png
|
||||
|
||||
As you can see in Figure 3, there is no consistent relationship between LA and SLE-related symptoms in either direction. However, a consistent trend toward favourable outcomes was observed with higher omega-3, and the inverse of which was observed with a high O6:O3. This suggests that while a high O6:O3 is a correlate for worse outcomes, it does not appear to be a function of LA, but rather a function of insufficient omega-3. This is a consistent trend in the literature so far.
|
||||
|
||||
There is also evidence from Vordenbäumen et al. (2020) suggesting that among SLE patients, LA is associated with higher C-reactive protein (CRP), which is a marker of systemic inflammation [[150](https://pubmed.ncbi.nlm.nih.gov/32188303/)].
|
||||
|
|
@ -530,10 +740,16 @@ However, this correlation may be spurious considering that people diagnosed with
|
|||
|
||||
Again, at the risk of sounding like a broken record, the inverse of this has been suggested in additional research by Lourdudoss et al. (2016) investigating the relationship between LA and the risk of increasing glucocorticoids [[152](https://pubmed.ncbi.nlm.nih.gov/26848399/)].
|
||||
|
||||
![][image71]
|
||||
[image71]: /blog/image71.png
|
||||
|
||||
This is particularly odd since LA was associated with systemic inflammation in the previous study. Like I said in the beginning, the data is a mess. Nothing seems congruent, because most of it is either cross-sectional or completely uncontrolled or unadjusted. However, there are a few prospective studies investigating SLE and vegetable oil intake.
|
||||
|
||||
First up is a study by Shin et al. (2017) involving 82 subjects which aimed to explore the differences in plasma fatty acids between those with SLE and those without [[153](https://pubmed.ncbi.nlm.nih.gov/30830319/)]. Ultimately, they discovered that plasma SFAs are more likely to be elevated in those with SLE, whereas plasma PUFA— particularly LA— was more likely to be reduced.
|
||||
|
||||
![][image72]
|
||||
[image72]: /blog/image72.png
|
||||
|
||||
At first glance, this may seem like a win for PUFA, or LA more specifically, but there are some interpretive challenges here. For example, PUFA concentrations in tissue could plausibly reduce in the presence of lipid peroxidation cascades, and there is evidence from Shah et al. (2014) that lipid peroxidation metabolites are higher in subjects with SLE [[154](https://pubmed.ncbi.nlm.nih.gov/24636579/)].
|
||||
|
||||
However, the authors remarked that antioxidant status plays an important role in the severity of lipid peroxidation when it does occur. It has been shown that antioxidant supplementation significantly reduces markers of lipid peroxidation in subjects with SLE [[155](https://pubmed.ncbi.nlm.nih.gov/17143589/)-[156](https://pubmed.ncbi.nlm.nih.gov/17143589/)]. It has also been shown by Bae et al. (2002) that antioxidant status can be impaired in subjects with SLE [[157](https://pubmed.ncbi.nlm.nih.gov/12426662/)].
|
||||
|
|
@ -544,6 +760,9 @@ However, echoing the sentiments toward antioxidants that have been discussed in
|
|||
|
||||
Much to my surprise, the relationship between both SLE and RA have been investigated using MR. In this MR study by Zhao and Schooling (2019), three different statistical tests across two gene variant subgroups were performed [[161](https://pubmed.ncbi.nlm.nih.gov/30409829/)].
|
||||
|
||||
![][image73]
|
||||
[image73]: /blog/image73.png
|
||||
|
||||
Generally speaking, statistically significant inverse associations between genetically elevated plasma LA and both RA and SLE were consistently found. The only inconsistency was when the Egger MR or the MR PRESSO methods were applied. The application of the Egger MR method seemed to nullify the effect in all cases, and the application of the MR PRESSO method only seemed to nullify the effect for RA in the second subgroup analysis.
|
||||
|
||||
Overall, the epidemiological data seems suggestive that antioxidant status likely matters more for SLE than PUFA or LA intakes, or even Western diets for that matter. However, the most robust evidence we have on the subject is the MR data, which suggests that genetically elevated plasma LA may even lower the risk of both SLE and RA.
|
||||
|
|
@ -567,6 +786,9 @@ So, as I do, I decided to gather all the data I could and compile a meta-analysi
|
|||
|
||||
Altogether, 10 prospective cohort studies were included in the analysis. With respect to the exposures specified in the inclusion criteria, Delcourt et al. (2007) reported only on PUFA [[164](https://pubmed.ncbi.nlm.nih.gov/17299457/)]. Whereas Seddon et al. (2003) investigated both PUFA and vegetable fat [[165](https://pubmed.ncbi.nlm.nih.gov/14662593/)]. Chong et al. (2009), Chua et al. (2006), Cho et al. (2000), and Tan et al. (2009) all explored LA, PUFA, and TFA in their analyses [[166](https://pubmed.ncbi.nlm.nih.gov/19433719/)-[169](https://pubmed.ncbi.nlm.nih.gov/19433717/)]. Parekh et al. (2009) additionally included vegetable fat in their analysis, but did not investigate TFA [[170](https://pubmed.ncbi.nlm.nih.gov/19901214/)]. Similarly, Sasaki et al. (2020) reported on LA and PUFA, but did not report on TFA or vegetable fat [[171](https://pubmed.ncbi.nlm.nih.gov/32181798/)]. Both Christen et al. (2011) and Mares-Perlman et al. (1995) studied associations pertaining to both LA and PUFA [[172](https://pubmed.ncbi.nlm.nih.gov/21402976/)-[173](https://pubmed.ncbi.nlm.nih.gov/7786215/)]. There was significant heterogeneity across all investigated exposures, and no single exposure reached statistical significance.
|
||||
|
||||
![][image74]
|
||||
[image74]: /blog/image74.png
|
||||
|
||||
Among the studies with the longest follow-up time, largest cohort size, best adjustment models, and the widest exposure contrasts, the results tended to be null. For example, Chong et al. (2009) adjusted for lutein, zeaxanthin, and sources of omega-3, which are inversely associated with late AMD [[174](https://pubmed.ncbi.nlm.nih.gov/21899805/)-[175](https://pubmed.ncbi.nlm.nih.gov/18541848/)]. Their results were null for every exposure.
|
||||
|
||||
The strongest study of all was Christen et al. (2011). Their analysis included three different adjustment models that help us better ascertain the relationship between AMD and vegetable oils. For example, their analysis showed that LA was associated with AMD only before adjustment for AMD risk factors, and that the association was likely a function of insufficient omega-3.
|
||||
|
|
@ -607,6 +829,9 @@ Altogether 43 studies were obtained from a PubMed and Google Scholar literature
|
|||
|
||||
**Alzheimer's Disease:**
|
||||
|
||||
![][image75]
|
||||
[image75]: /blog/image75.png
|
||||
|
||||
For Alzheimer's disease, results across all exposures were null. However, there were not many studies per subgroup. When the subgrouping is removed the results still don't reach statistical significance (RR 0.74 [0.43-1.26], P=0.26). There is also decently high heterogeneity between the included studies. For example, Rönnemaa et al. (2012), saw a non-significant increase in Alzheimer's risk with increasing LA intake, but Morris saw a statistically significant decrease in Alzheimer's risk with increasing vegetable oil intake.
|
||||
|
||||
The adjustment model used by Rönnemaa et al. (2012) includes no adjustments for dietary covariates. As a consequence, it would be dubious to infer that we're observing an independent effect of LA, as LA might simply be a correlate for a different, undisclosed dietary exposure that is actually increasing risk. It is unknown. However, Morris et al. (2003) found an opposite, statistically significant effect of vegetable fats and did include some adjustments for diet quality.
|
||||
|
|
@ -617,6 +842,9 @@ Given that the two datasets that were investigated in these two studies were pri
|
|||
|
||||
**Dementia:**
|
||||
|
||||
![][image76]
|
||||
[image76]: /blog/image76.png
|
||||
|
||||
Again, we see null findings across all of the investigated exposures. The only statistically significant study, Beydoun et al. (2007), found a 23% reduction in the risk of cognitive decline (RR 0.77 [0.65-0.91], P=0.002). What sets this study apart from most of the others was its robust multivariate adjustment model. In fact, the adjustment model was so comprehensive, it was given its own section in the paper.
|
||||
|
||||
In fairness, Okereke et al. (2012), found a non-significant increase in cognitive decline with increasing PUFA intake, and also had a reasonably good multivariate adjustment model. The multivariate adjustment model included TFA as a covariate, and even considered a number of micronutrients and comorbidities.
|
||||
|
|
@ -625,6 +853,9 @@ However, the cohort study had half as much follow-up time and used different met
|
|||
|
||||
**Total Dementia:**
|
||||
|
||||
![][image77]
|
||||
[image77]: /blog/image77.png
|
||||
|
||||
Results are slightly different when Alzheimer's disease, cognitive decline, and general dementia are all considered together, however. It is noteworthy to point out that when all of the studies are aggregated, vegetable fat associates with a statistically significant 58% reduction in total dementia (RR 0.42 [0.21-0.84], P=0.01). Though, to be clear, more than two thirds of the weight are derived from a single study, so interpret with caution.
|
||||
|
||||
In conclusion, it does not appear as though LA, PUFA, or vegetable fat are associated with an increased risk of Alzheimer's disease, cognitive decline, or dementia in humans. These results are consistent with previous meta-analyses by Cao et al. (2019) and Ruan et al. (2018) investigating these particular relationships [[193](https://pubmed.ncbi.nlm.nih.gov/31062836/)-[194](https://pubmed.ncbi.nlm.nih.gov/29701155/)]. However, when all endpoints are considered together, vegetable fat seems to be associated with a reduced risk of total dementia.
|
||||
|
|
@ -655,14 +886,29 @@ I scoured the literature for as many LA substitution trials as I could find. Alt
|
|||
|
||||
Four studies met the inclusion criteria and were included in the analysis [[195](https://pubmed.ncbi.nlm.nih.gov/11246548/)-[198](https://pubmed.ncbi.nlm.nih.gov/25319187/)]. The LA intakes in the high-LA diets ranged from 22.2g/day with Vafeiadou et al. (2015) to 50.8g/day with Junker et al. (2001), with an average of 33.5g/day, across all included studies. The LA intakes in the low-LA diets ranged from 4.8g/day with Iggman et al. (2014) to 7.8g/day with Junker et al. (2001), with an average of 6.4g/day, across all included studies. The average contrast in LA intake was 27g/day across all included studies.
|
||||
|
||||
![][image78]
|
||||
[image78]: /blog/image78.png
|
||||
|
||||
There were 12 studies that were captured by the exclusion criteria and had to be excluded from the analysis.
|
||||
|
||||
![][image79]
|
||||
[image79]: /blog/image79.png
|
||||
|
||||
**Results:**
|
||||
|
||||
![][image80]
|
||||
[image80]: /blog/image80.png
|
||||
|
||||
Altogether, high-LA diets yielded a non-significant increase in CRP when compared to control (P=0.15). The results are ultimately null. However, it may still be possible that the true effect of LA on CRP is hidden. It's plausible that high-LA diets do increase CRP, but they don't tend to increase CRP much more than control.
|
||||
|
||||
![][image81]
|
||||
[image81]: /blog/image81.png
|
||||
|
||||
When the effects of high-LA diets are compared to baseline, the results are almost squarely null (P=0.62). Even Junker, 2001, which saw the widest contrast in LA intake ultimately had a null result. But, we're not out of the woods yet. There are still other possibilities to consider. What if the subjects' usual diets are already high in LA that dosing more in an intervention trial doesn't actually do anything to CRP? Perhaps the comparator diets could still prove to be anti-inflammatory in some way.
|
||||
|
||||
![][image82]
|
||||
[image82]: /blog/image82.png
|
||||
|
||||
Comparing the effects of low-LA diets to baseline yielded a non-significant decrease in CRP (P=0.21). Again, the results are ultimately null. So, at present it does not appear as though low-LA diets are terribly protective compared to high-LA diets on measures of CRP.
|
||||
|
||||
But there is one last thing to discuss. Junker et al. (2001), saw the widest contrast in LA intake and was also the only study to show a statistically significant increase in CRP when comparing a high-LA diet to a low-LA diet. However, this effect likely isn't accurate. Let me explain.
|
||||
|
|
@ -671,6 +917,9 @@ But there is one last thing to discuss. Junker et al. (2001), saw the widest con
|
|||
|
||||
As described in the Statistical Analyses section, the Mann-Whitney-Wilcoxon test was used to test for statistical significance when distributions were non-normal. This test is specifically designed for non-normal distributions, and applying this test is also best practice in this case.
|
||||
|
||||
![][image83]
|
||||
[image83]: /blog/image83.png
|
||||
|
||||
Here we see that CRP is actually reported as median and range, because the distributions of CRP were non-normal. We can also see that all three groups saw non-significant decreases in median CRP from baseline, falling from 0.9 (0.17-5.9) to 0.75 (0.17-7.7). However, the upper bounds for CRP during the starting week of the trial are unusually high in the OO group. This means that estimating the mean and standard deviation will actually yank the variance and the mean much higher than it rightfully should be.
|
||||
|
||||
This gives the illusion that the drop in CRP in the OO group was much larger than it actually was, which in turn bloats the treatment effect seen when using estimated means and standard deviations [[199](https://pubmed.ncbi.nlm.nih.gov/15840177/)]. This also happened in the SU group. The range is much narrower at baseline than it was post-intervention, which pulled the variance and the mean toward showing an increase in CRP that didn't actually happen. In reality, the OO and SU groups saw a non-significant decrease in CRP.
|
||||
|
|
@ -700,38 +949,83 @@ To test this, I scoured the literature for any randomized controlled trials (RCT
|
|||
|
||||
Altogether, five studies were included in the analysis. The vast majority of data was collected from Freese et al. (2008), which included data for 8-oxodG, GR, GPx, and CAT [[200](https://pubmed.ncbi.nlm.nih.gov/17671440/)]. Whereas Jenkinson et al. (1999) additionally investigated SOD and LO2 in their investigation [[201](https://pubmed.ncbi.nlm.nih.gov/10452406/)]. Exploration of MDA was contributed by both de Kok et al. (2003) and Södergren et al. (2001) [[202](https://pubmed.ncbi.nlm.nih.gov/12504167/)-[203](https://pubmed.ncbi.nlm.nih.gov/11641740/)]. Lastly, Parfitt et al. (1994) contributed data for CD [[204](https://pubmed.ncbi.nlm.nih.gov/8181259/)].
|
||||
|
||||
![][image84]
|
||||
[image84]: /blog/image84.png
|
||||
|
||||
**Results:**
|
||||
|
||||
Normally when I see a bunch of null results I feel like I may have wasted my time. However, these results make me giggle. The only significant finding was an effect of PUFA lowering 8-oxodG compared to baseline (P=0.02), however the results were null when compared to control (P=0.83). This means that both the high-PUFA and low-PUFA diets lowered this marker of lipid peroxidation.
|
||||
|
||||
**8-oxo-7,8-dihydro-20-deoxyguanosine (8-oxodG) vs Control**
|
||||
|
||||
![][image85]
|
||||
[image85]: /blog/image85.png
|
||||
|
||||
**8-oxo-7,8-dihydro-20-deoxyguanosine (8-oxodG) vs Baseline**
|
||||
|
||||
![][image86]
|
||||
[image86]: /blog/image86.png
|
||||
|
||||
**Glutathione Reductase (GR) vs Control**
|
||||
|
||||
![][image87]
|
||||
[image87]: /blog/image87.png
|
||||
|
||||
**Glutathione Reductase (GR) vs Baseline**
|
||||
|
||||
![][image88]
|
||||
[image88]: /blog/image88.png
|
||||
|
||||
**Glutathione Peroxidase (GPx) vs Control**
|
||||
|
||||
![][image89]
|
||||
[id]: /blog/image89.png
|
||||
|
||||
**Glutathione Peroxidase (GPx) vs Baseline**
|
||||
|
||||
![][image90]
|
||||
[image90]: /blog/image90.png
|
||||
|
||||
**Superoxide Dismutase (SOD) vs Control**
|
||||
|
||||
![][image91]
|
||||
[image91]: /blog/image91.png
|
||||
|
||||
**Superoxide Dismutase (SOD) vs Baseline**
|
||||
|
||||
![][image92]
|
||||
[image92]: /blog/image92.png
|
||||
|
||||
**Malondialdehyde (MDA) vs Control**
|
||||
|
||||
![][image93]
|
||||
[image93]: /blog/image93.png
|
||||
|
||||
**Malondialdehyde (MDA) vs Baseline**
|
||||
|
||||
![][image94]
|
||||
[image94]: /blog/image94.png
|
||||
|
||||
**Catalase (CAT) vs Control**
|
||||
|
||||
![][image95]
|
||||
[image95]: /blog/image95.png
|
||||
|
||||
**Catalase (CAT) vs Baseline**
|
||||
|
||||
![][image96]
|
||||
[image96]: /blog/image96.png
|
||||
|
||||
**Conjugated Dienes (CD) vs Control**
|
||||
|
||||
![][image97]
|
||||
[image97]: /blog/image97.png
|
||||
|
||||
**Conjugated Dienes (CD) vs Baseline**
|
||||
|
||||
![][image98]
|
||||
[image98]: /blog/image98.png
|
||||
|
||||
The only statistically significant finding was a reduction in 8-oxodG with high-PUFA diets (P=0.02). Which is interesting, because 8-oxodG is a marker of DNA damage, and as such its implications extend far beyond oxidative stress. I thought PUFA was supposed to destroy your DNA with all of those highly reactive, toxic byproducts they create when they oxidize? Well, apparently, like most mechanistic reasoning, that shit just doesn't pan out in the real world.
|
||||
|
||||
In fact, even if we ignored the P-values and just looked at trends or directionality, the results would overwhelmingly favour high-PUFA diets over low-PUFA diets. Especially for MDA, which saw non-significant decreases for high-PUFA diets compared to baseline (P=0.11).
|
||||
|
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Add table
Add a link
Reference in a new issue