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

Abstract

Objective: To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death.

Design: Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data.

Setting: Ambulatory, coronary care clinic in Sydney, Australia.

Participants: 458 men aged 30-59 years with a recent coronary event.

Interventions: Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups.

Outcome measures: All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group.

Results: The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07).

Conclusions: Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats.

Trial registration: Clinical trials NCT01621087.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support from the Life Insurance Medical Research Fund of Australia and New Zealand and the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1 Trial profile. An intention to treat analysis included all randomized participants. Participant exclusion data from before randomization were not recovered. Numbers lost to follow-up were comparable in the two groups; reasons for dropout were not recovered

Fig 2 Kaplan-Meier estimates of five year cumulative death rates after randomization to the intervention or control group. Results of Cox proportional hazards model include all follow-up data (≤83 months) on an intention to treat basis

Fig 3 Updated meta-analysis of effects of LA selective interventions and mixed n-3/n-6 PUFA interventions on risk of death from coronary heart disease. LA selective interventions selectively increased n-6 LA without a concurrent increase in n-3 PUFAs. Mixed PUFA interventions increased n-3 PUFAs and n-6 LA. PUFA interventions replaced high SFA control diets in each trial. *Significant heterogeneity between groups. Full methods and results in part 8 of the web appendix

Fig 4 Updated meta-analysis of effects of LA selective interventions and mixed n-3/n-6 PUFA interventions on risk of cardiovascular death. LA selective interventions selectively increased n-6 LA without a concurrent increase in n-3 PUFAs. Mixed PUFA interventions increased n-3 PUFAs and n-6 LA. PUFA interventions replaced high SFA control diets in each trial. *Significant heterogeneity between groups. Full methods and results in part 8 of the web appendix

Fig 5 Proposed mechanistic model linking dietary LA to cardiovascular disease pathogenesis. Conversion of LA to OXLAMs can proceed enzymatically, or via free radical mediated oxidative stress. Major sources of oxidative stress such as cigarette smoking and chronic alcohol exposure facilitate LA oxidation and production of oxidized low density lipoprotein (LDL). OXLAMs are the most abundant oxidized fatty acids in oxidized LDL and in atherosclerotic lesions. OXLAMs have been mechanistically linked to cardiovascular pathogenesis via multiple mechanisms. LDL=low density lipoprotein; CD36=cluster of differentiation 36 scavenger receptor; LOX 1=lectin like oxidized LDL receptor 1