Effects of Replacing Saturated Fat with Vegetable Oils Rich in Linoleic Acid on Coronary Heart Disease Mortality: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
In the systematic review and meta-analysis included in Ramsden et al, randomized controlled trials that specifically tested replacement of saturated fat with vegetable oil rich in linoleic acid provide no indication of benefit, even though the interventions effectively lowered serum cholesterol.
We invite readers seeking the broader context that is needed to evaluate this conclusion to read the detailed appendix (p. 15-37) at
Some key points are summarized below.
The traditional diet-heart hypothesis predicts that replacing dietary saturated fat with vegetable oils rich in linoleic acid (LA) will reduce coronary heart disease and deaths by lowering serum cholesterol. Advice to replace saturated fat with LA-rich vegetable oils (e.g., corn oil, sunflower oil, safflower oil, cottonseed oil, or soybean oil) has been a cornerstone of dietary guidelines for the past half-century (see main paper, Figure 10).
However, the lack of supporting evidence from randomized controlled trials for such advice has been a source of controversy [13, 19]. Several diet-heart meta-analyses have been published, but they have not specifically examined the effects of replacing saturated fat with LA-rich vegetable oils. For example, a meta-analysis by Hooper et al  included randomized controlled trials that lowered saturated fat but did not distinguish between trials that replaced saturated fat with LA-rich oils, from those that replaced total and saturated fat with carbohydrates, and also included randomized controlled trials that markedly increased dietary n-3 EPA+DHA alongside LA. Similarly, Mozaffarian et al  included randomized controlled trials that markedly increased dietary EPA+DHA from seafood and cod liver oil, among other diet changes (e.g. sugar restriction, increase in fiber). EPA and DHA are not present in vegetable oils and are reported to influence coronary heart disease by mechanisms independent of cholesterol lowering. Therefore, it is not clear whether the results of previous meta-analyses are driven by 1) reductions in saturated fat, 2) replacement of saturated fat with LA-rich vegetable oil, 3) or to increases in EPA+DHA. The objective of this systematic review and meta-analysis is to determine whether randomized controlled trials that specifically replaced saturated fat with LA-rich vegetable oils provide evidence to support the traditional diet-heart hypothesis.
RANDOMIZED CONTROLLED TRIALS INCLUDED IN MAIN ANALYSIS
Only five randomized controlled trials met the inclusion criteria: the Minnesota Coronary Experiment (MCE), the Sydney Diet Heart Study (SDHS), the Rose Corn Oil Trial (RCOT), the Los Angeles Veterans study (LA Vet), and the Medical Research Council Soy study (MRC Soy) (table K). These are the five known trials that randomly assigned individual participants to a diet intervention that provided vegetable oil rich in linoleic acid in place of saturated fat compared to a usual care control diet, reported deaths from coronary heart disease or all-causes, and had no between-group differences in major concomitant interventions. Compared to control groups, all five intervention groups lowered serum cholesterol (mean range from 8 to 14% lower). They represent a total of 10,808 individuals.
EXPLANATION OF STUDIES NOT INCLUDED IN MAIN ANALYSIS
Exclusion of the Finnish Mental Hospital Study (FMHS)
The FMHS has been included in some previous meta-analyses of randomized controlled trials . However, the FMHS is not a randomized controlled trial and has other critical limitations [Reviewed in 109, 137]. For example, there was disproportionate exposure to the cardiotoxic drug thioridazine in the control arm. The FMHS was a 12-year crossover study that assigned two hospitals (Hospital N and Hospital K) of mostly schizophrenic patients (77% in K and 69% in N) in 1959 to either a soybean oil based serum cholesterol-lowering diet (N) or the usual hospital diet (K) for 6 years. After this initial 6-year phase, diets were switched so that Hospital N patients received the Hospital N usual diet and Hospital K patients received a soybean oil diet. Issues related to within-hospital diet exposures at crossover in 1965 also confounded this unusual design. For example, study populations were ‘rejuvenated by discarding the six oldest annual cohorts and admitting six new annual cohorts on the younger end of the age range’ in 1965 .
Randomized controlled trials included in sensitivity analyses
Three additional randomized controlled trials were included in a sensitivity analysis: the Oslo Diet Heart Study, the St. Thomas Atherosclerosis Regression Study, and the Diet and Re-infarction Trial (tableK). These diet-heart trials, which randomly assigned individual participants and reported deaths from coronary heart disease and all-causes, have been included in previous meta-analyses on this topic. However, two of these trials were confounded by unequal application of other dietary factors, and another achieved only a very modest change in dietary LA without provision of study oils.
Oslo Diet Heart Study (ODHS)
The ODHS has often been represented as a test of the replacement of saturated fat with an LA-rich vegetable oil (soybean oil). However, in addition to soybean oil, the intervention group received a very large dose (~5 grams per day) of n-3 EPA+DHA from provision of sardines canned in cod liver oil, and was advised to restrict sugar intake and to replace refined carbohydrates with less processed selections [125-127]. Since EPA+DHA (and sugar) are reported to influence coronary heart disease risk by mechanisms independent of serum cholesterol lowering, it is not possible to determine which intervention components were responsible for study results.
St. Thomas Atherosclerosis Regression Study (STARS)
STARS [128-130] has often been represented as a test of the replacement of saturated fat with an LA-rich vegetable oil. However, unequal administration of multiple dietary factors do not allow for determination of the effects of LA. For example, the STARS intervention group received advice (and some study foods) to: (1) reduce total fat and saturated fat; (2) increase n-6 and n-3 polyunsaturated fatty acids, (3) avoid processed foods, and (4) increase dietary fiber (especially the soluble fiber polygalacturonate). While this intervention had only a very modest (non-statistically significant) increase in n-6 LA (+1.6%E), it doubled EPA+DHA from (100 to 210 mg per day), lowered total fat by 27%, and increased fiber by 53%. Given these multifaceted changes, the very modest increase in LA likely accounted for only a small fraction of the observed 12.2% serum cholesterol lowering achieved. Taken together, this study design provides little insight into whether replacement of saturated fat with LA rich vegetable oils can reduce coronary heart disease and death. Nevertheless, since other meta-analyses on this topic included STARS, we include it here in sensitivity analysis.
Diet and Re-infarction Trial (DART)
The DART ‘fat advice’ intervention group achieved only a very modest reduction in serum cholesterol (-4%), and only modestly increased total polyunsaturated fatty acids, without providing study oils or reporting the specific n-6 and n-3 content of such increases. Given these limitations, it is not clear how much the DART results can be expected to help determine whether replacement of saturated fat with LA-rich oil  reduces risk of coronary heart disease and death (the traditional diet heart hypothesis) 131-136. Nevertheless, since other meta-analyses on this topic included DART, we include it here a sensitivity analysis.
SUMMARY OF EVIDENCE
In our main meta-analyses, based on the five randomized controlled trials that provided LA-rich vegetable oil in place of saturated fat, we found no evidence for reductions in either coronary heart disease mortality or all-cause mortality. This conclusion was unchanged after sensitivity analyses that either 1) included randomized controlled trials that offered advice only or that, in addition to LA sources, also provided n-3 EPA and DHA, or 2) included composite or nonfatal endpoints. However, evidence of moderate heterogeneity weakens the conclusions we can make about the coronary heart disease mortality findings and their ability to translate into recommendations for the population. Exploratory analyses suggest that neither the between-group differences in serum cholesterol lowering nor the doses of LA provided help to explain this heterogeneity.
The small number of randomized controlled trials that have tested the traditional diet-heart hypothesis replacing saturated fat with LA-rich vegetable oil is an important limitation of our meta-analysis. Remarkably, only five diet-heart randomized controlled trials have specifically tested whether provision of an LA-rich vegetable oil in place of saturated fat reduced risk of coronary heart disease mortality or all-cause mortality. The fact that the Minnesota Coronary Experiment (MCE) accounted for about 80% of all randomized participants in these trials highlights the paucity of causal evidence supporting the traditional diet heart hypothesis and the importance of the MCE in assessing the evidence base for LA-rich interventions. Even with inclusion of advice-only trials (with only modest diet changes and other limitations) and trials confounded by provision of large quantities of n-3 EPA+DHA in sensitivity analyses, MCE still accounted for 68% of all randomized participants. The small number of randomized controlled trials, coupled with differences in methodological quality and design, and population characteristics of the individual trials (tables K and L) [reviewed in 13, 109] indicate that more research is needed in this area before evidence-based recommendations can be supported.
Competing interests: No competing interests