Sunday, July 5, 2015

Houtsmuller et al (Linoleic Acid for Diabetic Angiopathy)

Hooper et al included this trial by Houtsmuller et al in their 2012 meta-analysis as a fat modification trial and in their 2015 meta-analysis as a reduced SFA trial

Studies Associated with the Trial

Unsaturated fats and progression of diabetic retinopathy (1979) [1] (preliminary results)
Influence of different diets on the progression of diabetic retinopathy (1980) [2] (no access)
Favorable influences of linoleic acid on the progression of diabetic micro- and macroangiopathy in adult onset diabetes mellitus (1980) [3] (this post came entirely from this paper)


102 people who were recently (< 1 year) diagnosed with type 2 diabetes, but otherwise were healthy and didn’t have CHD, were stratified to one of two diet groups for 6 years (don’t know the age of participants).  Diet 1 was a control diet, high in SFA.  Diet 2 (the experimental diet) had a similar macronutrient composition but contained approximately 4 times more linoleic acid.  There is very limited dietary information, the totality of which is quoted below

“Diet I contained carbohydrate 50cal%, saturated fats 35 cal%, proteins 15 cal% (diet I), and diet II contained carbohydrate 45 cal%, fats 40 cal% (1/3 linoleic acid) and proteins 15 cal%. The linoleic acid content of diet II was 4 times that of diet I, being 20.4 gr/1000 kcal for group II and 5.3 gr/1000 Kcal for group I. The fiber content was similar in both groups as was the cholesterol content, being 88 mg/1000 Kcal in both groups except for 4 patients of group I who preferred butter over saturated margarines. The cholesterol content of the diet for these 4 patients was 148 mg/1000 Kcal.”

In the results section the authors mention that “differences in body weight between several groups were never found”, suggesting that changes in calorie intake were most likely very similar

Linoleic Acid*

The major source of fat for most of the participants in the control group is “saturated margarines”, which is almost certainly not of animal origin as the cholesterol intake was identical to the control group and 41% less than the participants who ate butter instead, therefore it’s very likely that the control group in this study had a much greater intake of TFA (unless they used unhydrogenated palm or coconut oil, or cocoa butter), which is also the most likely explanation for the trial’s pretty incredible results

The description of the diets not only lacks detail, but is also poor and inconsistent.  Earlier they said linoleic acid was 1/3 of total fat intake in the experimental group, which makes it 13.3% of total calories.  However, 20.4g/1000kcal is equal to 18.36% of total calories (compared to 4.77% in the control group).  The control diet is described as containing “saturated fats 35 cal%”, but this obviously can’t mean 35% of calories from SFA as 35% of calories came from fat and approximately 5% of calories came from linoleic acid.


The experimental group had significantly fewer people develop mild diabetic retinopathy and ‘signs of cardiac ischaemia’ (which seems like it would be angina)

Experimental (M/F)
N = 26/22
Control (M/F)
N = 26/22
Mild Diabetic Retinopathy at Baseline
6/6 (23%/27%)
6/6 (23%/27%)
Mild Diabetic Retinopathy at 6 Years
9/7 (35%/32%)
17/12 (66%/55%)

Experimental (M/F)
N = 51
Control (M/F)
N = 51
“Developed signs of cardiac ischaemia”
Myocardial Infarction
CHD Mortality

Hooper, et al reported 8/51 vs. 30/51 for ‘combined CVD events’, which includes cardiac ischemia and myocardial infarction and reported 0/51 vs. 6/51 for myocardial infarction.  This is exactly the same as the figures I’ve got

Experimental (N = 51)
Control (N = 51)
Myocardial Infarction
Combined CVD Events

The glucose and insulin response to a glucose tolerance test improved due to some unspecified ‘treatment’/‘therapy’* in both groups.  There wasn’t any difference between the two diet groups in men, whereas in women the ‘treatment’ only slightly improved glucose levels and didn’t improve insulin levels in the control group.  It’s interesting that among men, fewer people developed mild diabetic retinopathy and angina in the experimental group, despite glucose tolerance and insulin resistance being equal

After the ‘initial therapeutic improvement’, serum lipids and/or cholesterol increased in both groups, but to a greater extent in the control group and mainly among women

In addition, there was no correlation between “platelet agrregation and linoleic acid, progression of retinopathy, sex or age, serum glucose, insulin or lipids”

In their ‘characteristics of included studies’, Hooper et al drew attention to the many unknowns in this trial, particularly regarding the dietary advice and their execution, as well as the fact that neither the participants nor the researchers were blinded, leading to a ‘high risk of bias’.

Due to the likelihood that the “saturated margarines” were rich in trans fat and may have been a major source of fat in the control diet, the control group likely had a very high intake of trans fats.  If I had to include this trial in a meta-analysis it would probably fall in the ‘adequately controlled’ category because there’s no solid evidence of this, but it would definitely be excluded alongside the Sydney Diet Heart Study as a trial that could be heavily confounded by differences in TFA intake.  After all, the results seem too good to be true: ‘eat 13.3% or 18.36% linoleic acid and reduce your risk of CHD events by 73.3%’ (very believable).  The diet heart advocates can’t have it both ways

* I’m not sure what the treatment is.  It could be the two diets, which may be calorie restricted, or perhaps it could be insulin or an insulin-sensitising drug

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