Association of specific dietary fatty acids with total and cause specific mortality.

1. Journal club

2. JAMA Internal Medicine Published online July 5, 2016

3. Fatty acids structure
• Fatty acids are carboxylic acids with
hydrocarbon side chain
• Hydrocarbon chain RCOOHCarboxylic
group.

4. Classification
D/U Total no of
carbon atoms
Even chain FA
Odd chain FA
D/U Length of
hydrocarbon
chain
Short chain FA
Medium chain FA
Long chain FA
Very long chain FA
D/U Nature of
hydrocarbon
chain
Saturated FA
Unsaturated FA
Branched chain FA
Hydroxy FA

5. Saturated fatty acids
• In which hydrocarbon side chain is saturated
(no double bonds).

7. Unsaturated fatty acids
In which hydrocarbon side chain is unsaturated.
(One or more double bonds are present)
Classified into :
1. Monounsaturated fatty acids – one double
bond
2. Polyunsaturated fatty acids – two or more
double bonds.

10. Cis and trans isomers in unsaturated
fatty acids
• Depends upon the
orientation of radicals
around the axis of the
double bond.
• Cis – if the radicals on
the same side of the
bond .
• Trans – if radicals on the
opposite side of the
bond.

11. Sources of SFA

12. Sources of UFA

13. Introduction
• Health effects of different types of dietary fats
have been a long-standing research topic of
interest for decades.
• Literature indicates that specific types of
dietary fat have distinct effects on the risk for
cardiovascular disease (CVD), and replacing
saturated fats with unsaturated fats and
avoidance of trans-fat is widely
recommended.

14. • However data from small clinical trials
regarding the effects of ω-3 PUFAs on total
and cause-specific mortality remains
inconsistent.
• The health benefits of ω-6 PUFA intake are
still contentious; concern has been raised over
the hypothesized proinflammatory and
prothrombotic effects of ω-6 PUFA.

15. • Effects of dietary fatty acids on blood lipid are
documented levels but other mechanistic
pathways such as insulin resistance,
endothelial function, electrophysiologic
phenomena, carcinogenesis, and systemic
inflammation are also influenced.
• In addition to CVD, association with
incidence of other major chronic diseases,
including type 2 diabetes, cancer, multiple
sclerosis, and respiratory diseases, in
prospective cohort studies have been seen.

16. • Investigators prospectively examined the
associations of specific dietary fats with total
and cause-specific mortality in 2 large ongoing
prospective cohort studies, the Nurses’ Health
Study (NHS) and the Health Professionals
Follow-up Study (HPFS).
• Repeated dietary assessments in the cohorts
provided a unique assessment of diet during
multiple decades.

17. Methods

18. Study population
• The NHS is a prospective cohort study of
1,21,700 registered female nurses aged 30 to 55
years in 1976; 92,468 participants responded to
the semiquantitative food frequency
questionnaire (SFFQ) in 1980.
• The HPFS is a prospective cohort study of 51,529
male health care professionals aged 40 to 75
years in 1986. The baseline of this analysis was
defined as 1980 for the NHS and 1986 for the
HPFS.

19. • Both cohorts were followed up via biennial
mailed questionnaires that inquired about
lifestyle risk factors and as well as newly
diagnosed diseases.
• Information on race, marital status, and family
history of major chronic diseases was also
collected.

20. • Investigators excluded participants with
a) history of diabetes, CVD, or cancer;
b) who did not provide information on dietary fat
intake;
c) who reported implausible SFFQ data (total
energy intake <800 or >4200 kcal/d for men and
<600 or >3500kcal/d forwomen) at baseline .
• After exclusions, the analytical population
consisted of 83,349 women and 42,884 men.

21. Dietary assessment
• Dietary information was collected with SFFQs.
• In each SFFQ, it was asked, on average, the
participant had consumed a specified portion
size of each food during the preceding year.
• The number of listed foods was 61 in 1980 and
was expanded to 116 to 150 in 1984 and
thereafter; additional frequently used foods were
reported in an open-ended section.
• Detailed information on the type of fat or oil used
in food preparation and the brand or type of
margarines on the SFFQ.

22. • Mean daily nutrient and total energy intakes
by multiplying the frequency of consumption
of each item by its nutrient content and
summing the products across all foods was
calculated, taking into account the specific
brand and type of margarines and the types of
fat used in food preparation.

23. • The correlations between energy-adjusted
intakes assessed by the 1986 questionnaire and
the mean of diet records collected in 1980 and
1986, corrected for variation in the records, were
0.67 for total fat, 0.70 for SFAs, 0.69 for
monounsaturated fatty acids (MUFAs), and 0.64
for PUFAs.
• Correlations increased when the mean of 3
SFFQs (1980, 1984, and 1986) was used; for
example, for SFAs the correlation was 0.95.

24. The correlations between dietary fatty acid intake
assessed by the SFFQ and the composition fatty acids in
adipose tissue were
• 0.51 for TFAs,
• 0.35 for linoleic acid,
• 0.48 for marine ω-3
PUFAs in women.
• 0.29 for TFAs,
• 0.48 for linoleic acid,
• 0.47 for
eicosapentaenoic acid
in men.

25. • In the NHS, dietary questionnaires used in this
analysis were completed in 1980, 1984, 1986,
and then every 4 years , for a total of 9
assessments.
• In the HPFS, dietary questionnaires were
completed in 1986 and then every 4 years for
a total of 7 assessments.

26. Ascertainment of death
• Systematic searches of the vital records of
states and of the National Death Index,
supplemented by reports from family
members or postal authorities were
performed by investigators.
• More than 98% of the deaths in each cohort
were identified.

27. Statistical analysis
• Data were analyzed from September 18, 2014, to
March 27,2016.
• The percentages of energy intake from total fat and
specific dietary fats were calculated as cumulative
means to the start of each 2- or 4-year follow-up
interval to best represent long-term dietary intake.
• Participants were cateogorized into quintiles of intake
levels.
• Person-years of follow-up were calculated from
baseline to the earliest of time of death, loss to or
unavailability for follow-up, or the end of follow-up.

28. • Cox proportional hazards regression models were
applied to estimate hazard ratios (HRs) and their
95%CIs of mortality by comparing participants in
each quintile with those in the lowest quintile.
• For multivariable analyses, isocaloric substitution
models were made that simultaneously included
energy intake, the percentages of energy derived
from protein, and specific types of fat and other
potentially confounding variables.

29. • For repeatedly measured covariates,
investigators included their updated values as
time-varying variables in the model.
• To evaluate the effect of substituting specific
types of fat for saturated fat , intake was
treated as a continuous variable and
calculated the difference in coefficients.

30. Results

31. Population Characteristics
• During 32 years of follow-up in the NHS (2,464
852 person years), 20,314 deaths were
documented.
• During 26 years of follow-up in the HPFS (975
102 person-years), 12,990 deaths were
documented (total, 33,304 deaths in 3,439
954 person-years of follow-up).

34. Total mortality
• Total fat intake was positively associated with total
mortality in age-adjusted models, an inverse
association became apparent after adjusting for
other potential confounding variables.
• For TFA intake, a significant positive association with
total mortality was observed.

38. Intakes of PUFA and MUFA were inversely associated with total mortality.

39. • The inverse association between total PUFA
and mortality was mainly driven by linoleic
acid.
• Intake of total ω-3 PUFA was associated with
modestly lower total mortality, which was
mainly driven by the inverse association of
marine ω-3 PUFAs (docosahexaenoic acid and
eicosapentaenoic acid) with total mortality.

42. Cause specific mortality
• Intake of SFA, when substituted for total
carbohydrates, was not significantly associated
with CVD mortality.
• Whereas TFA intake was associated with a 20%
higher CVD mortality across quintiles.
• Intake of PUFA was inversely associated with
CVD mortality.
• Among specific PUFAs, linoleic acid intake was
most strongly related to a lower risk for CVD
mortality.

43. • Dietary intake of SFA, when substituted for
total carbohydrates, was associated with
slightly higher cancer mortality, whereas
PUFA intake, especially linoleic acid intake,
was associated with modestly lower cancer
mortality.

44. • Investigators observed inverse associations of PUFA
and MUFA intakes and strong positive associations of
TFA intake with neurodegenerative and respiratory
disease mortality.
• Higher SFA intake was associated with a substantial
increase of mortality due to respiratory disease.
• Among major PUFAs, ω-3PUFA intake, primarily α-
linolenic acid, was inversely associated with
neurodegenerative disease mortality.
• Marine ω-3 PUFA intake was inversely associated with
respiratory disease mortality.

45. Fat substitution analysis
• Replacing 5%of energy from SFAs with the same
energy from PUFAs and MUFAs was associated
with an estimated reduction in total mortality of
27% and 13%.
• Replacing SFAs with the same energy from PUFAs
was associated with a lower risk for mortality due
to CVD, cancer, and neurodegenerative disease.
• Replacement of 5% of energy from SFAs with 5%
of energy from MUFAs was associated with a 29%
estimated reduction in neurodegenerative
disease mortality.

47. Discussion
• Higher intakes of PUFA and MUFA  lower
mortality, whereas higher intakes of SFA and
TFA  increased mortality.
• Replacing SFAs with MUFAs and/or PUFAs 
lower risk for total and cause-specific
mortality due to several major chronic
diseases.

48. • Dietary intake of total fat, compared with total
carbohydrates, was inversely associated with total
mortality.
• Association between total fat intake and mortality
largely depends on specific types of fat.
• Intake of linoleic acid, the most abundant ω-6 PUFA,
showed strong inverse associations with total and
most cause specific mortality, without any evidence of
detrimental effects.
• A higher ω-6:ω-3 PUFA ratio was not associated with
increased mortality, but with a slightly lower CVD and
cancer mortality.

49. • A modest inverse association between marine
ω-3 PUFA intake and total mortality was noted.
• Previously, prospective cohorts yielded mixed
results, whereas most randomized clinical trials
found non significant effects of fish oil
supplementation on total mortality.
• The significant inverse association between
intake of ω-3 PUFAs and death due to
neurodegenerative diseases has not been
previously reported.

50. • There was a inverse association between MUFA
intake and total mortality.
• In contrast, previous studies demonstrated
nonsignificant or even positive associations with
MUFA.
• This discordance might be owing to the strong
correlations between MUFA and SFA, because
animal fats are major sources of both types of
fats in most Western diets, and between MUFA
and TFA, because partial hydrogenation produces
both.

51. • In these 2 cohorts, the correlation between
MUFA and SFA decreased during the follow-
up, as major food sources of MUFA shifted
from animal sourced to plant-sourced foods
over time.
• Consistent with investigators analysis, the
major source of MUFA in Mediterranean
populations, olive oil, has been associated
with a substantially lower total mortality.

52. • Compared with overall carbohydrates, higher SFA
intake was associated with a slight increase in
total mortality, but not significantly associated
with CVD mortality.
• The lack of the association with CVD is expected
because the major sources of carbohydrates in a
typical Western diet are highly processed foods
with large amounts of refined starch and sugar,
providing a high glycemic load that can increase
CVD risk independent of SFA.

53. • This study provides strong evidence that using
PUFAs and/or MUFAs as the replacement
nutrients for SFAs can confer substantial
health benefits, whereas replacing SFAs with
total carbohydrates has little effect on CVD
mortality.

54. • No major effects of most types of dietary fat on cancer
mortality, although a modest inverse association with
linoleic acid was observed.
• α-linolenic acid was associated with lower mortality
due to neurodegenerative diseases such as, including
Alzheimer disease, amyotrophic lateral sclerosis and
Parkinson Disease.
• Positive association between saturated and trans-fat
intakes and respiratory disease mortality, and an
inverse association with PUFAs was observed.
• Novel findings require confirmation.

55. Limitations
1) Reverse causation is a possible explanation for
findings, because people with chronic disease
and poor health might change their habitual diet
although participants with known major chronic
diseases were excluded at baseline.
2) As it was observational study, causality cannot
be established.
• However, results were largely consistent with
results from existing observational studies and
randomized clinical trials on diet and CVD-related
outcomes.

56. 3) Although many potential confounders were
adjusted ,residual confounding could not be
ruled out.
4) Measurement errors are inevitable in estimates
of food and nutrient intakes.
• However, adjustment for energy intake and use of
prospectively collected, cumulative mean intake
using many repeated dietary assessments
reduced the impact of measurement errors.

57. Strentghs
1) Large sample size,
2) High rates of follow-up,
3) Repeated assessments of dietary and lifestyle
variables during a long period.

58. Conclusions
• Different types of dietary fats have divergent
associations with total and cause-specific
mortality.
• Replacement of saturated fats with
unsaturated fats confer substantial health
benefits.
• These findings also support the elimination of
partially hydrogenated vegetable oils, the
primary source of trans-fatty acids.