Intended for healthcare professionals

CCBYNC Open access

Rapid response to:

Research

Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.e8707 (Published 05 February 2013) Cite this as: BMJ 2013;346:e8707

Rapid Response:

Re: Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

Gerard Hornstra PhD,
Professor of Experimental Nutrition (Rtd), Maastricht University,
Maastricht, The Netherlands
and
Connie Diekman MEd, RD, FADA,
Director of University Nutrition, Washington University in St Louis,
Academy of Nutrition and Dietetics Past President

on behalf of the International Expert Movement on Health Significance of Fat Quality of the Diet, a working group under the auspices of the International Union of Nutritional Sciences

Dear Sir,
We congratulate Christopher Ramsden and colleagues on an elegant piece of ‘scientific archeology’, in which they recalculated and re-evaluated the results of the 40-year-old Sydney Diet Heart Study (SDHS) 1 and concluded that ‘substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease’ 2.

In fact, their findings confirm the original SDHS results, that excess consumption of linoleic acid (LA) to replace saturated fatty acids (SAFA) in the diet of male coronary heart disease patients was associated with reduced survival after 2-7 years of follow-up. Unfortunately, the participants were not blinded to the treatment, because the intervention group received special instructions, oils, and margarines to increase their polyunsaturated fatty acid (PUFA) intake and to reduce SAFA consumption, whereas the control group did not receive a similar treatment with control products. In addition, the trial was confounded by multiple changes within both groups, not only in diet (see below) but also in lifestyle (e.g. sharp decrease in cigarette smoking, considerable reductions in caloric in take, body weight, and alcohol consumption, and substantial increase in physical exercise). These lifestyle changes commenced after the cardiovascular event, continued during the trial, and could not be corrected for.

In the original SDHS paper 1, the authors clearly stated that, based on multivariate analyses, ‘none of the dietary factors were significantly related to survival’. In contrast, Ramsden and colleagues, who applied different statistics, held the high linoleic acid intake fully responsible for the negative outcome observed. Results of Ramsden’s diet recalculations differed only slightly from the original dietary composition data, which is quite an achievement, since post hoc diet calculations are acknowledged to be extremely difficult and can be rather inaccurate 3. Because of these relatively small dietary discrepancies, the different statistical methods applied must have been crucial to the dissimilarity between both outcomes.

Ramsden’s approach inevitably needed to violate the golden rule of Good Clinical Practice, that any study evaluation plan needs to be part of the study design and should, therefore, precede study execution. However, Ramsden and colleagues should have explained why they decided to use different statistics. Moreover, it would have been illustrative and more convincing if the reason(s) for the different outcomes had been described, and if results had been presented of cross-validation studies (evaluation of original data with present statistics, and assessment of recalculated data with original statistics).

Inclusion of the present results in Ramsden’s earlier meta-analysis of linoleic acid-specific saturated fat replacements 4 strengthened the initial trend for a cardiovascular risk increase of an excessively high LA intake. The hazard ratio increased from about 1.1 to 1.3, but possibly because of the limited size of the SDHS (63 all cause mortality cases and just 7 additional deaths in the intervention as compared to the control group), it still did not reach significance.
We doubt whether this inclusion is justified, however, because the SDHS, originally planned as a dietary replacement trial, turned out to be flawed by multifactorial changes, as mentioned above. In addition, certain interpretations of the re-evaluation results deserve some scrutiny. Thus, although the dietary intervention intended to be an LA-specific SAFA replacement, it also significantly reduced the consumption of monounsaturated fatty acids, the impact of which on cardiovascular risk is not clear as yet 5. In addition, the authors neither excluded, nor corrected for, the possibility that the SDHS intervention reduced the omega-3 PUFA intake as a result of replacing the habitual cooking oils. Further, a possible increase in the consumption of industrial trans fatty acids by the intervention group was not accounted for, whereas at that time high PUFA margarines contained significant amounts (as high as 15 - 20%) of these cardiovascular risk increasing fatty acids (P. Clifton, W. Shrapnel, http://www.smc.org.au/2013/02/round-up-dietary-fats-and-heart-disease-bm... , and P. Zock, personal communication). These unintentional further changes may have affected mortality in the intervention group independent from an assumed LA effect.

Considering these issues, we believe that the conclusion of Ramsden and colleagues that their findings ‘could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats’ is not justified. This conclusion is incompatible with Ramsden’s earlier 4 and present 2 meta-analyses and with the meta-analysis of Mozaffarian and colleagues 6, all demonstrating that replacing SAFA (and industrial trans) with PUFA (being a mix of 15-20 en% LA and some omega-3 PUFA) significantly reduces the risk of coronary heart disease.

Nonetheless it would be unwise to ignore the present outcome of Ramsden’s recalculation study, since it adds to the growing concern about the safety of an unlimited increase in LA consumption. Other contributions to the emerging LA skepticism are the well-documented reduction of the omega-3 long-chain PUFA status by dietary LA 7 8, its possible effects on early human development 9, its controversial pro-inflammatory potential 10 11, and its alleged contributing role in the present obesity epidemic 12 13.

Finally, Ramsden and colleagues correctly stated that any potential adverse effect of linoleic acid from 8.5 (not 6, as mentioned in their paper) to 15 %, as possibly observed in the SDHS cohort, does not necessarily apply to lower LA intakes. Since the maximum recommended LA intake for the prevention of cardiovascular disease is about 10 % 14, WHO recommendations maximize LA intake to 9 % 15, and LA intake in most countries is between 3 and 7 % 16, we believe that Ramsden’s recalculation study need not affect current LA intake recommendations. It also does not mitigate the beneficial effect of replacing dietary saturated for polyunsaturated fats to reduce cardiovascular risk.

References

1. Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exp Med Biol 1978;109:317-30.
2. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ 2013;346:e8707.
3. Nettleton JA, Koletzko B, Hornstra G. ISSFAL 2010 Dinner Debate: Healthy Fats for Healthy Hearts - Annotated Report of a Scientific Discussion. Ann Nutr Metab 2011;58(1):59-65.
4. Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM. n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials. Br J Nutr 2010;104(11):1586-600.
5. Jakobsen MU, O'Reilly EJ, Heitmann BL, Pereira MA, Balter K, Fraser GE, et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr 2009;89(5):1425-32.
6. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med 2010;7(3):e1000252.
7. Rump P, Hornstra G. The n-3 and n-6 polyunsaturated fatty acid composition of plasma phospholipids in pregnant women and their infants. relationship with maternal linoleic acid intake. Clin Chem Lab Med 2002;40(1):32-9.
8. Liou YA, King DJ, Zibrik D, Innis SM. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr 2007;137(4):945-52.
9. Hornstra G. Essential fatty acids in mothers and their neonates. Am J Clin Nutr 2000;71(5 Suppl):1262S-9S.
10. Fritsche KL. Too much linoleic acid promotes inflammation-doesn't it? Prostaglandins Leukot Essent Fatty Acids 2008;79(3-5):173-5.
11. Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr 2012;95(5):1003-12.
12. Ailhaud G, Massiera F, Weill P, Legrand P, Alessandri JM, Guesnet P. Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 2006;45(3):203-36.
13. Moon RJ, Harvey NC, Robinson SM, Ntani G, Davies JH, Inskip HM, et al. Maternal Plasma Polyunsaturated Fatty Acid Status in Late Pregnancy Is Associated with Offspring Body Composition in Childhood. J Clin Endocrinol Metab 2013;98(1):299-307.
14. Kris-Etherton PM, Innis S, Ammerican Dietetic A, Dietitians of C. Position of the American Dietetic Association and Dietitians of Canada: dietary fatty acids. J Am Diet Assoc 2007;107(9):1599-611.
15. WHO/FAO. Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser 2003;916:i-viii, 1-149, backcover.
16. Elmadfa I, Kornsteiner M. Dietary fat intake--a global perspective. Ann Nutr Metab 2009;54 Suppl 1:8-14.

Competing interests: “The International Expert Movement (IEM) is a group of experts committed to improving the fat quality of the diet of everyone. IEM’s activities are funded by an unrestricted educational grant from Unilever N.V. under the auspices of the International Union of Nutritional Sciences”. www.theiem.org <http://www.theiem.org>

22 February 2013
Gerard Hornstra
Prof. of Experimental Nutrition
Connie Diekman
Maastricht University (Retired)
Brikkenoven 14, 6247BG Gronsveld, the Netherlands