REVIEWS

Prevention of CVD

Dietary fats and cardiometabolic

disease: mechanisms and effects
on risk factors and outcomes
Jason H. Y. Wu 1
*, Renata Micha2 and Dariush Mozaffarian 2

Abstract | The effect of dietary fats on cardiometabolic diseases, including cardiovascular

diseases and type 2 diabetes mellitus, has generated tremendous interest. Many earlier
investigations focused on total fat and conventional fat classes (such as saturated and
unsaturated fats) and their influence on a limited number of risk factors. However, dietary fats
comprise heterogeneous molecules with diverse structures, and growing research in the past two
decades supports correspondingly complex health effects of individual dietary fats. Moreover,
health effects of dietary fats might be modified by additional factors, such as accompanying
nutrients and food-​processing methods, emphasizing the importance of the food sources.
Accordingly, the rapidly increasing scientific findings on dietary fats and cardiometabolic
diseases have generated debate among scientists, caused confusion for the general public and
present challenges for translation into dietary advice and policies. This Review summarizes the
evidence on the effects of different dietary fats and their food sources on cell function and on risk
factors and clinical events of cardiometabolic diseases. The aim is not to provide an exhaustive
review but rather to focus on the most important evidence from randomized controlled trials and
prospective cohort studies and to highlight current areas of controversy and the most relevant
future research directions for understanding how to improve the prevention and management
of cardiometabolic diseases through optimization of dietary fat intake.

1
The George Institute for
Global Health, Faculty of
Medicine, University of New
South Wales, Sydney,
Australia.
2
Friedman School of Nutrition
Science & Policy, Tufts
University, Boston, MA, USA.
*e-​mail: jwu1@
georgeinstitute.org.au
https://doi.org/10.1038/
s41569-019-0206-1
Dietary fats have been studied extensively as risk factors
for cardiometabolic diseases, including cardiovascular
diseases (CVDs) and type 2 diabetes mellitus. In the
latter half of the 20th century, early research was based
primarily on cross-​national (ecological) comparisons
and experiments of single surrogate end points (for
example, serum total cholesterol levels), leading to rec-
ommendations to lower the consumption of total fat,
total saturated fat and cholesterol1. Subsequent advances
in nutrition science have highlighted the complex aeti-
ology of cardiometabolic diseases, the diversity of the
underlying pathophysiological pathways and the cor-
respondingly complex health effects of dietary fats and
their food sources. Compared with earlier investigations,
the field of nutritional science also now benefits from
a richer repertoire of methodologies available to assess
diet–disease relationships, including controlled trials
with multiple end points, prospective cohort studies,
use of dietary biomarkers and randomized controlled
trials (RCTs) to evaluate clinical outcomes2. Overall,
accumulating evidence suggests that the health effects
of dietary fats vary depending on both the specific
fatty acid and the food source, potentially related to
interactions with accompanying nutrients, food matrices
and food-​processing methods. The resulting growth of
the evidence base has substantially expanded our under-
standing of the effects of specific fats on a diverse array
of cardiometabolic disease risk factors and outcomes
while helping to elucidate current controversies and
uncertainties.
In this Review, we summarize the evidence on the
effects of dietary fats on the mechanisms, risk factors
and clinical events of cardiometabolic diseases. Given
the multiple previous reviews on dietary fats3–9, the aim
of this article is not to provide an exhaustive account of
each individual research study on these topics but to
highlight the particularly salient lines of evidence, the
current areas of controversy and the most relevant future
research directions for understanding how to improve
the prevention and management of cardiometabolic
diseases through optimization of dietary fat intake.
Effect of dietary fats on cell processes
Dietary fats are conventionally grouped by one chemical
characteristic: the presence or absence of carbon–carbon
double bonds. Fats with no double bonds are saturated

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Key points
• In addition to their role as metabolic fuel, fatty acids modulate diverse cell processes
including transcription regulation, cellular and organelle membrane structure and
function, ion channel activity and electrophysiology.
• Dietary fats comprise a wide range of fatty acids, and growing evidence demonstrates
heterogeneity in the health effects of specific fatty acids as well as their food sources.
• Robust evidence from multiple research studies demonstrates no health benefits
of lowering total dietary fat in foods or overall diets.
• For both saturated fatty acids and monounsaturated fatty acids, which have highly
diverse dietary sources, considering the food sources and types separately might be
most meaningful for understanding their health effects.
• The overall evidence strongly supports cardiometabolic benefits of total
polyunsaturated fatty acid (PUFA), n-6 PUFA and seafood-​derived n-3 PUFA
consumption.
• People consume complex foods, not individual fatty acids; therefore, guidance and
policies to improve general population diets should place greater emphasis on
specific food sources of dietary fats.
(that is, every carbon in the fatty acid chain is saturated
with hydrogen atoms), those with one double bond are
monounsaturated, and those with two or more double
bonds are polyunsaturated (which can be further sub­
divided by the position of the first double bond at the
third (n-3) or sixth (n-6) carbon from the amino terminus
of the carbon chain) (Box 1). This conventional classifi-
cation disregards numerous additional structural and,
importantly, biological differences between fatty acids
within each of these groups. For example, fatty acids can
also be categorized by their carbon chain length, vary-
ing from 2 to 6 carbons (short-​chain), 8 to 12 carbons
(medium-​chain), 14 to 18 carbons (or 20 in some classi-
fication schemes; long-​chain) or 20 (or 22) to 24 carbons
(very-​long-chain)10. In addition to differences in double
bonds and chain length, fats can have structural varia-
tion through branching of methyl groups attached to the
main hydrocarbon backbone, giving rise to branched-​
chain saturated fatty acids (SFAs). Unsaturated double
bonds can also be in cis (synthesized by mammals) or
trans (synthesized by certain bacteria in cows, goats and
sheep and through industrial partial hydrogenation of
plant oils) configurations6. On the basis of these mul-
tiple characteristics, each of the conventional classes of
dietary fats (saturated, monounsaturated and polyun-
saturated) actually represents heterogeneous fatty acids
with diverse structures and biological effects. To add
complexity, the health effects of each individual fatty
acid might also be further modified by the food source
in question.
Although fats are often thought of only for their role
as metabolic fuel and energy storage, fats are diverse and
complex molecules with remarkable bioactivity. Cellular
and animal experimental studies have demonstrated
diverse molecular effects of fatty acids that jointly medi-
ate effects on biological pathways influencing the risk of
cardiometabolic diseases (Fig. 1).
Membrane structure and function
Incorporation of specific fatty acids into cellular and
organelle membrane phospholipids leads to alterations
in the characteristics of lipid microdomains around
transmembrane receptors (Fig. 1) . These lipid rafts
modulate diverse cellular processes, including tran-
scriptional activation, signal transduction and protein
production11,12. For example, phospholipids containing
trans-​fatty acids have greater affinity for cholesterol
than phospholipids with the corresponding cis-​fatty
acids and cause reduced activation of rhodopsin, a
G protein-​coupled membrane receptor (GPR) critical for
visual signalling13. SFAs can modulate the recruitment of
Toll-​like receptors (TLRs) and their downstream adaptor
molecules to lipid rafts, as well as the consequent inflam-
matory responses14,15. In experimental studies, n-3 poly­
unsaturated fatty acid (PUFA)-mediated modulation of
lipid rafts is linked to changes in cytokine production
and immune cell function, reduced levels of TLR4 and
enhanced GPR signalling efficiency16–21.
Ion channels and electrophysiology
In vitro cell assays and animal studies have shown that
certain fatty acids can alter the function of membrane
ion channels (Fig. 1). These effects can be mediated by
altered cell membrane properties, for example, as sug-
gested by the in vitro effects of n-3 PUFAs on transmem-
brane sodium channels, the sodium–calcium exchanger
and L-​type calcium channels5. Similarly, the n-6 PUFA
arachidonic acid modulates the activity of several ion
channels both through its incorporation into the cell
membrane and indirectly via its downstream bioactive
eicosanoid metabolites22–24 (see below). Emerging but
not yet conclusive evidence suggests that some fatty
acids might also directly interact with membrane ion
channels. For example, point mutation and molecular
dynamic simulation studies have identified important
amino acid residues of voltage-​gated potassium channels
and large-​conductance, calcium-​activated potassium
channels that are potential sites of action for PUFAs25–28.
Transcriptional regulation
An important effect of dietary fats is the direct regu-
lation of gene expression. Specific non-​esterified fatty
acids and their acyl-​CoA thioesters are natural ligands
for numerous nuclear receptors and transcription fac-
tors that are crucial for metabolic pathways, such as
peroxisome proliferator-​activated receptors (PPARs),
retinoid X receptors (RXRs) and liver X receptors
(LXRs)29. These activities are often facilitated by cyto-
plasmic lipid-​binding proteins, which channel free fatty
acids or fatty acyl-​CoA into the nucleus to interact with
the receptors30–32. In addition to the effects on nuclear
receptors, fatty acids also influence gene expression
by acting as ligands for certain cell surface GPRs (the
free fatty acid receptors) and influencing downstream
signalling cascades33. In summary, these effects control
a number of critical metabolic pathways that are rele-
vant to cardiometabolic diseases. For example, palmitic
acid (16:0)-mediated activation of PPARγ might con-
tribute to reduce endothelial progenitor cell availabil-
ity and impair vessel repair34. In cellular and animal
experiments, α-​linolenic acid (18:3n-3) and oleic acid
(18:1n-9) each reduce tissue inflammation and insu-
lin resistance, at least partly mediated by activation
of GPR40 (also known as FFAR1) and GPR120 (also
known as FFAR4)35–37. The triglyceride-​lowering class
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Box 1 | Classification and nomenclature of major classes of dietary fatty acid

Classification
Fatty acids are conventionally grouped according to the number of double bonds in their structure. Specifically, saturated
fatty acids (SFAs) have no double bonds, monounsaturated fatty acids (MUFAs) have one, and polyunsaturated fatty acids
(PUFAs) contain two or more. Each of these classes comprises heterogeneous fatty acids with diverse chemical structures
and biological effects. Examples of an SFA, a MUFA and two PUFAs are shown in the figure.
Nomenclature
A system of shorthand nomenclature is typically used to describe the structure of fatty acids and is applied throughout
this paper. The shorthand description is illustrated as XX:Yn-​Z, in which XX is the number of carbon atoms in the fatty acid,
Y indicates the number of double bonds in the carbon chain, and n-​Z indicates the position of the first double bond
counting from the methyl (also called omega) end of the fatty acid. Therefore, for example, for α-​linolenic acid, 18:3n-3
indicates a fatty acid with 18 carbons and 3 double bonds, with the first double bond occurring 3 carbons from the methyl
end. The common name of each fatty acid is shown in the figure within the brackets.
SFA MUFA
O O

HO HO
16:0 (palmitic acid) 18:1n-9 (oleic acid)

PUFA

n-6 PUFA n-3 PUFA

O O

HO HO
18:2n-6 (linoleic acid) 18:3n-3 (α-linolenic acid)

effect of n-3 PUFAs is also influenced by genetically
mediated effects on hepatic production of VLDL and
secondarily from increased VLDL clearance38.
Bioactive metabolites
Dietary fats are metabolized into diverse sets of highly
bioactive metabolites. For instance, both n-6 PUFAs
and n-3 PUFAs are converted into eicosanoids through
enzymatic and non-​enzymatic processes39. Important
examples of these eicosanoids that are gaining recogni-
tion for their potential role in cardiometabolic diseases
include the cytochrome P450-generated mono-​epoxides
(MEFAs), such as epoxyeicosatrienoic acids, and special-
ized pro-​resolving mediators (SPMs), such as resolvins
and protectins40–42. Animal and in vitro models demon-
strate robust metabolic effects of MEFAs, including
reduced inflammation, attenuated tissue fibrosis and
improved vasodilatation43–45. SPMs seem to be critical
regulators that induce active resolution of inflamma-
tion, for example, inducing improved cardiac healing
and ventricular function in animal models of myocar-
dial infarction46–48. In clinical studies, consumption of
n-3 PUFAs raises tissue and circulating levels of MEFAs
and SPMs within days to weeks49–51. Arachidonic acid
is also metabolized into leukotrienes (such as LTB4),
prostaglandins (such as PGE2) and thromboxanes52.
Total dietary fat
Main lines of evidence
On the basis of ecological studies (such as the Seven
Countries Study53) and the effects of dietary fat on serum
levels of total and LDL cholesterol (LDL-​C) (for exam-
ple, the Keys and Hegsted equations54,55), US and inter-
national guidelines have historically limited total dietary
fat. However, these guidelines have evolved over time as
a result of multiple lines of evidence showing no health
benefits of decreasing total dietary fat. Between 1980
and 2000, US guidelines restricted dietary fat to ≤30%
of energy (%E) but were revised in 2005 to 20–35%E
following recognition of potential harms of low-​fat
diets, and most recently in 2015, the Dietary Guidelines
Advisory Committee (DGAC) recommended removal
of any limit on total fat consumption56. In controlled-​
feeding trials, changes in total fat consumption pro-
duced contrasting effects on different surrogate end
points. For example, in overweight or obese individuals,
a low-​fat diet reduces serum levels of total cholesterol
and LDL-​C compared with a high-​fat diet but increases
triglyceride-​rich lipoprotein levels and decreases HDL
cholesterol (HDL-​C) levels57,58 (Fig. 2). In randomized tri-
als in patients with diabetes, increasing dietary fat and
lowering carbohydrate intake reduced haemoglobin A1c
(HbA1c) levels and diabetes medication requirements59.
Evidence for the effects of altering dietary fat levels on
weight loss is discussed below.
Consistent with the mixed effects on surrogate end
points, differences in total fat consumption are not
related to the incidence of either cardiovascular events
or type 2 diabetes60–62. For instance, total fat intake was
not associated with risk of type 2 diabetes after pool-
ing results across four study cohorts, with median total
fat intake in individual cohorts ranging from ~25%E to
40%E across quintiles60. In the Women’s Health Initiative
(WHI), the largest dietary RCT ever performed, nearly
50,000 postmenopausal women were randomly assigned
to a low-​fat dietary intervention or usual care63. Despite
a substantial achieved reduction in total fat intake (from
37.8%E to 28.8%E, a 24% relative reduction), no dif-
ferences were seen in the incidence of coronary heart
disease, stroke or diabetes63,64. Indeed, in the subset of
women with pre-​existing CVD, the low-​fat diet signi­
ficantly increased the risk of coronary heart disease

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Direct interaction with

membrane proteins and Direct regulation Metabolism into
ion channels of gene expression bioactive molecules
SFA Long-chain
MUFA and PUFA n-3 PUFA
MUFA
n-3 PUFA n-6 PUFA Na+ L-type Ca2+ TLR Fatty acid
channel channel GPR40 transporter

cPLA2 cPLA2
Na+ Ca2+
Regulation of signalling Fatty acid-binding
cascades such as protein
• Alteration of protein localization and function β-arrestin 2 and NF-κB
• Changes in ion channel function
• Modulation of TLR and adaptor molecule recruitment
Endoplasmic
reticulum
Free radical
catalysed
CYP peroxidation
NF-κB PPARα RXR COX
LOX • Prostaglandins
FASN • Leukotrienes
COX2 • Mono-epoxides
• SPMs
Nucleus • Isoprostanes

Fig. 1 | Effects of dietary fats on cell processes. Fatty acids have diverse effects that influence pathways linked to
cardiometabolic risk. First, fatty acids in cellular and organelle membranes alter membrane fluidity and lipid raft
properties, which regulate signalling pathways and protein function. For instance, saturated fatty acids (SFAs) can alter
inflammatory responses by modulating the recruitment of Toll-​like receptors (TLRs) and their downstream adaptor
molecules to lipid rafts. Incorporation of fatty acids into lipid membranes can also alter the function of ion channels, such
as Na+ channels and L-​type Ca2+ channels, which might underlie the capacity of n-3 polyunsaturated fatty acids (PUFAs) to
reduce cardiomyocyte excitability and, therefore, the antiarrhythmic potential of n-3 PUFAs. Second, fatty acids can
directly interact with membrane proteins and ion channels. For instance, activation of G protein-​coupled membrane
receptor 40 (GPR40) and GPR120 by long-​chain unsaturated fatty acids can reduce inflammation and improve glucose
homeostasis. Third, an important effect of dietary fatty acids is through direct regulation of the expression of genes
related to critical metabolic pathways. Fatty acids are transported to the nucleus by cytoplasmic lipid-​binding proteins,
such as fatty acid-​binding proteins. For example, unsaturated fatty acids are natural ligands for nuclear receptors, such as
peroxisome proliferator-​activated receptor-​α (PPARα) and retinoid X receptors (RXRs). Fatty acids can also regulate other
transcription factors, such as nuclear factor-​κB (NF-​κB), which might not require their direct binding. Finally, dietary fatty
acids are metabolized into diverse sets of highly bioactive metabolites. For instance, after their release from phospholipids
(mediated by cytosolic phospholipase A2 (cPLA2)), both n-3 PUFAs and n-6 PUFAs are converted through enzymatic and
non-​enzymatic processes into eicosanoids, such as leukotrienes, isoprostanes and specialized pro-​resolving mediators
(SPMs) such as resolvins. These highly bioactive metabolites regulate a myriad of pathways involved in cardiometabolic
diseases. For example, cytochrome P450 (CYP) converts arachidonic acid into epoxyeicosatrienoic acid, which has
shown robust metabolic effects in animal models, including anti-​inflammatory, antifibrotic and pro-​vasodilatory effects.
COX, cyclooxygenase; LOX, lipoxygenase; MUFA, monounsaturated fatty acid.

(CHD) events (P = 0.006 for interaction). This finding
is consistent with the increased susceptibility of women
to atherogenic dyslipidaemia (low HDL-​C and high tri-
glyceride levels) and the adverse effects of high intake
of glycaemic carbohydrates65–67, all risk factors that are
exacerbated by low-​fat diets. In contrast to the WHI,
the PREDIMED trial68 assigned participants to high-​fat
Mediterranean diets supplemented with extra-​virgin
olive oil or mixed nuts, compared with a control diet
recommending reduced dietary fat. The intervention
groups achieved higher intake of total fat than the con-
trol groups (41%E versus 37%E) and had a significantly
lower risk of CVD and diabetes68,69.
Together, the findings from RCTs on clinical risk fac-
tors and long-​term observational studies and RCTs on
clinical events provide strong corroboratory evidence that
lowering total fat intake produces no significant cardio­
metabolic benefits, whereas increasing total fat intake
from healthy foods can lower the risk of cardiometabolic
disease. Therefore, a focus on total fat intake misses a
larger point that health effects of macronutrients are
modified by their underlying subtypes and food sources.
Areas of controversy
Conflicting national and international guidelines on
total fat intake. Not unexpectedly, the advances in sci-
ence on total dietary fat are inconsistently reflected and
not fully accepted across different dietary guidelines. For
instance, whereas the 2015 US DGAC recommended
no upper limit on total fat intake70, the US Institute of
Medicine dietary reference values for total fat intake
(20–35%E) have not been updated since 2002 (ref.71).
The WHO retains an even older restriction for total
fat intake (≤30%E)72 on the basis of their concerns over
the role of dietary fat consumption in obesity, despite
growing evidence to the contrary, as discussed below.

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Parameter Weighted mean difference (95% CI)
Total cholesterol (mmol/l) –0.18 (–0.29 to –0.07)
LDL cholesterol (mmol/l) –0.11 (–0.20 to –0.03)
HDL cholesterol (mmol/l) –0.07 (–0.10 to –0.03)
Triglycerides (mmol/l) 0.13 (0.07 to 0.20)
–0.3 –0.2 –0.1 0 0.1 0.2
Fig. 2 | Effects of high-​fat versus low-​fat diets on cardiometabolic risk factors.
Findings from randomized controlled trials indicate that in overweight or obese
individuals, total cholesterol, LDL cholesterol and HDL cholesterol levels were lower
while triglyceride levels were higher after a low-​fat diet than after a high-​fat diet.
Data in the graph are pooled weighted mean differences and 95% CIs from a random-​
effect meta-​analysis by Lu and colleagues57. Studies were included in the meta-​analysis
if they were randomized controlled trials, if the participants’ BMI was ≥25 kg/m2 and if
the interventions compared a low-​fat diet (<30% of total energy) with a high-​fat diet
(≥30% of total energy). The number of studies available for each outcome was 16 for
total cholesterol, 18 for LDL cholesterol and HDL cholesterol and 19 for triglycerides.
These inconsistencies in incorporation of new evi-
dence into guidelines influence government policies,
industry product formulations and public perceptions56.
For example, many new front-​of-pack warning labels
and icons continue to warn against the total fat content
of foods, while government procurement standards (for
example, for US public schools) also retain a preference
for low-​fat products56. In the USA, nearly two-​thirds of
consumers still report avoiding dietary fat as a way to
achieve better health73. The food industry also contin-
ues to promote low-​fat products as being more healthful,
even though many such products are highly processed
and laden with refined starch, added sugar and salt.
Low-​fat versus low-​carbohydrate diets for weight loss
and diabetes. Low-​fat foods have long been recom-
mended for weight loss and weight control, largely on the
basis of the higher calorie density of fat (9 kcal/g) than
proteins and carbohydrates (4 kcal/g). However, system-
atic reviews of RCTs with equal intensity dietary inter-
ventions demonstrate that high-​fat, low-​carbohydrate
diets produce weight loss among overweight and obese
individuals that is similar to or greater than that of
low-​fat, high-​carbohydrate diets, with corresponding
similar or greater improvements in metabolic risk fac-
tors, such as blood pressure, blood lipids and glycaemic
control74,75. Meta-​analyses of clinical trials also suggest
that a high-​fat, low-​carbohydrate diet is more effective
for glycaemic control in patients with diabetes76,77. Of
note, these benefits are seen even though most high-​fat,
low-​carbohydrate diets (such as the Atkins diet) are ad
libitum (lacking any calorie guidance or restriction),
whereas low-​fat diets for weight loss generally also have
a second intervention component that emphasizes calo-
rie restriction and portion control. In one RCT compar-
ing an ad libitum high-​fat, low-​carbohydrate diet with a
low-​fat, high-​carbohydrate diet, the high-​fat diet led to
significant weight loss and improved body composition,
whereas the low-​fat diet led to loss of lean muscle mass
and little overall weight loss78. Proponents of low-​fat
diets have focused on weight loss results in studies of die-
tary interventions not intended for weight loss79 or raised
concerns that the duration of most clinical trials has
been <2 years. However, at the end of the PREDIMED
trial80, a 5-year clinical trial on cardiovascular outcomes
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that was not focused on weight loss, participants on
the higher-​fat diets supplemented with nuts or extra-​
virgin olive oil had similar BMI to and lower waist cir-
cumference than those on the low-​fat diet. Additional
long-​term observational and interventional studies are
needed that carefully define the proportions of carbo-
hydrate and total fat intake as well as, more importantly,
their different foods sources to clarify the cardiometa-
bolic effects of low-​fat versus low-​carbohydrate diets81,82.
Because carbohydrate-​rich foods in most modern diets
and packaged and restaurant food products predomi-
nantly contain refined starch and sugar, implementation
of a low-​carbohydrate diet will generally provide weight
loss by reducing refined starch and sugar intake, espe-
cially when replaced with foods that are rich in healthful
fats. However, when food choices prioritize minimally
processed, low-​glycaemic and phenolic-​rich healthful
foods, the proportion of fat versus carbohydrate might
have little additional influence on weight loss83.
Potential harms of very low total fat diets. The multina-
tional PURE study61 found that very low dietary fat con-
sumption (<10%E) was associated with greater all-​cause
mortality among ~130,000 adults in 18 low-​income,
middle-​income and high-​income countries (compar-
ing the highest and lowest quintiles; HR 0.77, 95% CI
0.67–0.87). Semi-​parametric analyses suggested a non-
linear, decreasing trend for mortality with higher total
fat intake. When cause-​specific mortality was evaluated,
the increased risk at low levels of fat intakes was related
to stroke and non-​CVD, rather than CHD, deaths.
Owing to the mix of low-​income, middle-​income and
high-​income countries in the PURE study, the observed
higher risk of death with very low fat intakes should be
interpreted cautiously: these intakes might be a marker
of severe poverty and poor economic development, with
corresponding dependence on starchy staples and lack of
access to more costly dairy and meat products. In other
words, even with covariate adjustment, very low fat
diets in the PURE study could remain influenced by low
socio-​economic status. However, in the US-​based ARIC
study84, higher total carbohydrate intake (and accord-
ingly, very low total fat and low protein intake) was also
associated with higher all-​cause mortality. Potential
harms of very low total fat diets need to be examined
in additional prospective cohorts and clinical studies
of events and surrogate end points. In summary, find-
ings to date suggest no meaningful health benefits, and
potential for harms, of low-​fat diets in both Western
and international regions.
Future directions
Robust evidence from multiple research paradigms,
including RCTs of multiple risk pathways and clinical
end points and prospective cohort studies of clinical end
points, demonstrates no health benefits of lowering total
dietary fat in foods or overall diets. Dietary guidelines
have not kept up with this new evidence base, partly
owing to the ever-​increasing volume, type, complex-
ity and variable accuracy of nutritional information
available in the media and online. Efficient systems to
assess and deliver high-​quality evidence at the point
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a Lipids by their underlying types and food sources, as discussed

Parameter Mean change per 5% isocaloric substitution (95% CI) further below.
SFA replacement with carbohydrates A major area for future research, not only for total
LDL cholesterol (mmol/l) –0.17 (–0.19 to –0.14) fat but for all dietary fats, is personalized nutrition: the
HDL cholesterol (mmol/l) –0.05 (–0.06 to –0.04) assessment of genetic, demographic, microbiome, med-
Triglycerides (mmol/l) 0.05 (0.04 to 0.07) ical and other relevant individual factors to inform more
Total:HDL cholesterol ratio 0.00 (–0.03 to 0.04) individualized dietary advice and food formulations85–87.
SFA replacement with MUFAs For instance, variants in genes such as APOC3 and APOE
LDL cholesterol (mmol/l) –0.21 (–0.23 to –0.19) might modify blood lipid or glycaemic responses to die-
HDL cholesterol (mmol/l) –0.01 (–0.02 to 0.00) tary fats88–93. However, many studies to date testing gene–
Triglycerides (mmol/l) –0.02 (–0.04 to 0.00) dietary fat interactions have had insufficient statistical
–0.14 (–0.17 to –0.11)
power and inadequate control of diet intake, with small
Total:HDL cholesterol ratio
SFA replacement with PUFAs
effect sizes and low reproducibility of findings90 that limit
the translation into clinical practice. One promising ave-
LDL cholesterol (mmol/l) –0.28 (–0.31 to –0.25)
nue is the potential for personalized dietary advice to
HDL cholesterol (mmol/l) –0.02 (–0.03 to –0.01)
enable greater and more sustained dietary changes than
Triglycerides (mmol/l) –0.05 (–0.07 to –0.04)
conventional, population-​b ased recommendations,
Total:HDL cholesterol ratio –0.17 (–0.20 to –0.14)
although to date, only limited clinical evidence sup-
–0.3 –0.2 –0.1 0 0.1 ports this concept94. Personalized interventions could
also increase health disparities, for example, if requiring
b Apolipoproteins costly or difficult-​to-access genomics, metabolomics and
Parameter Mean change per 5% isocaloric substitution (95% CI) other high-​dimensional data85. In summary, whether
SFA replacement with carbohydrates personalized nutrition for dietary fats, or indeed other
ApoB (mg/dl) –3.60 (–5.40 to –1.70) aspects of diet, can result in greater cardiometabolic
ApoA-I (mg/dl) –7.00 (–9.00 to –5.10) bene­fits than conventional, population-based approaches
SFA replacement with MUFAs remains unclear.
ApoB (mg/dl) –7.80 (–9.50 to –6.00)
ApoA-I (mg/dl) –1.80 (–3.70 to 0.10) Major classes of dietary fat
SFA replacement with PUFAs The main lines of evidence, uncertainties and controver-
ApoB (mg/dl) –10.20 (–12.40 to –8.10) sies and the future directions for the conventional classes
ApoA-I (mg/dl) –4.90 (–7.30 to –2.50) of dietary fat are described in this section. The physio-
–15 –10 –5 0 0.1 logical and health effects of individual types of fatty acid
within these classes are reviewed in subsequent sections.
Fig. 3 | Effects of replacing dietary saturated fatty acids on cardiometabolic lipid Health effects of trans-​fatty acids have been reviewed in
risk factors. The graphs show the mean change in serum levels of lipids (panel a) and
detail previously and are not covered here6,95.
apolipoproteins (Apo; panel b) when 5% of dietary energy from saturated fatty acids
(SFAs) is isocalorically replaced by carbohydrates, monounsaturated fatty acids (MUFAs)
or polyunsaturated fatty acids (PUFAs). Data are from the systematic review and meta-​ Main lines of evidence
analysis by Mensink96. Studies were included in the meta-​analysis if they were Meta-​analyses of controlled-​feeding RCTs and blood
randomized trials in which food intake was controlled and had a parallel or crossover lipid changes. In controlled-​feeding studies, total SFA
design, if the dietary periods were ≥13 days (to allow lipids to reach a steady-​state consumption — the average intake of different SFAs, pre-
condition), if protein and alcohol intake were constant, if fatty acids were exchanged for dominantly palmitic acid, across typical Western food
other fatty acids or for carbohydrates, if no other concomitant interventions (such as sources — raises serum LDL-​C concentrations, a causal
weight loss) were implemented and if daily cholesterol intake between the diets within a risk factor for CHD. However, other effects of different
study was similar (<100 mg difference). Diets focused on long-​chain n-3 PUFAs (such as types of dietary fat on serum lipids are complex96 (Fig. 3).
fish oils) were excluded; therefore, total PUFA in the studies can be considered to be
Reducing SFA intake by isocaloric exchange for total
linoleic and α-​linolenic acid. Mensink used multiple regression analyses to predict the
carbohydrate lowers the levels of LDL-​C and apolipopro-
mean serum lipid or Apo concentration of a group of individuals from the changes in
percentage of total energy intake of fatty acids or carbohydrates in the diets. The tein B (ApoB) but also lowers HDL-​C and ApoA-​I levels,
numbers of diets/studies for each outcome are as follows: LDL cholesterol: 165/69; increases triglyceride-​rich lipoprotein levels and has no
HDL cholesterol: 163/68; total:HDL cholesterol ratio: 159/66; triglycerides: 172/72; significant effect on the total cholesterol:HDL-​C ratio.
ApoB: 104/42; and ApoA-​I: 102/41. Consistent with these changes towards a profile of ath-
erogenic dyslipidaemia, substitution of SFA intake with
total carbohydrate also shifts the distribution of LDL
of individual, clinical and policy decision making are particles towards (potentially more pro-​atherogenic)
needed to facilitate consistent and timely incorporation small dense LDL97,98. By comparison, replacement of total
of new science into practice. High-​fat, low-​carbohydrate SFAs with either monounsaturated fatty acids (MUFAs;
diets seem to be beneficial for weight loss and glycae- in the diet, nearly entirely oleic acid) or PUFAs, predomi-
mic control, which is probably as much related to the nantly linoleic acid (18:2n-6), lowers the levels of LDL-​C,
harms of refined starch and sugar as to the health bene- triglycerides, ApoB and ApoA-​I as well as the total
fits of total fat per se. However, rather than focusing on cholesterol:HDL-​C ratio, although HDL-​C levels are
either total fat or total carbohydrate levels, we believe also lowered. Of note, given similar effects of total SFA
this debate misses a larger point that health effects of intake compared with total carbohydrate intake on the
both dietary fats and carbohydrates are further modified total cholesterol:HDL-​C ratio, consuming unsaturated

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 Reviews

fats in place of either SFAs or carbohydrates will produce factors. Finally, the effect of an intervention on any sin-
similar improvements in this important risk predictor. gle surrogate outcome, even one as important as LDL-​C,
When considering the effects of dietary fats on blood is useful to predict clinical effects only if no other off-​
lipids, several critical points must be considered. First, target or pleotropic effects of the intervention occur. In
LDL-​C concentrations (or, more accurately, ApoB con- the present case, dietary fats and their food sources have
centrations, especially when ApoB is linked to ApoC-​III) pleotropic effects on multiple lipid, lipoprotein and other
are causally related to the risk of CVD. Second, while the pathways. Ignoring these pleotropic effects and focusing
evidence is not yet as widely recognized as for LDL-​C, only on LDL-​C provides misleading inference about clini­
levels of triglycerides (representing VLDL cholesterol, cal effects. Consistent with this point, the US Institute of
chylomicrons and chylomicron remnants) are also caus- Medicine has concluded that LDL-​C concentration is not
ally linked to CVD as well as to all-​cause mortality on the a reasonable sole surrogate outcome for understanding
basis of findings from some clinical trials on triglyceride-​ the health effects of dietary factors104. Accordingly, if the
lowering agents99 as well as Mendelian randomization effects of only dietary SFAs on LDL-​C levels were rele­
studies100–103. Third, although HDL-​C concentrations vant for atherosclerotic CVD, then one would expect
are not clearly causally related to CVD, they are highly that the substitution of total SFA intake with total
and independently predictive of CVD, that is, HDL-​C carbo­hydrate (refined or otherwise) would consistently
level is at least a surrogate marker of other causal risk lower the risk of CVD. However, this outcome is clearly
not the case, as concluded by the US DGAC in 2015
Parameter Mean change per 5% isocaloric substitution (95% CI) (ref.70). For dietary interventions with pleotropic effects,
SFA replacement with carbohydrates reliance on a sole surrogate outcome, even one that is
Glucose (mmol/l) –0.02 (–0.04 to 0.01) causally established, such as LDL-​C, is not appropriate.
HbA1C (%) –0.03 (–0.09 to 0.02)
Insulin (pmol/l) 1.10 (0.50 to 1.70) Meta-​analyses of controlled-​feeding RCTs and glycaemic
HOMA-IR (% change)a –0.14 (–0.62 to 0.32) control. Similar to the findings for blood lipids, replace-
SFA replacement with MUFAs ment of total SFA intake with total carbohydrates has
Glucose (mmol/l) –0.02 (–0.04 to 0.00) little overall effect on glycaemic responses105 (Fig. 4). By
HbA1C (%) –0.12 (–0.19 to –0.05) comparison, dietary MUFAs and PUFAs seem to have
Insulin (pmol/l) 1.20 (0.60 to 1.80) beneficial effects on HbA1c and insulin resistance, as
HOMA-IR (% change)a –0.62 (–1.16 to –0.08) evaluated by insulin resistance as defined by homeo-
SFA replacement with PUFAs static model assessment (HOMA), whether MUFAs
Glucose (mmol/l) –0.04 (–0.07 to –0.01) and PUFAs are replacing SFAs or carbohydrates, whereas
HbA1C (%) –0.15 (–0.23 to –0.06) increasing PUFAs additionally improves insulin secre-
Insulin (pmol/l) –0.50 (–2.00 to 1.10)
tion capacity (a measure of pancreatic β-​cell function)
compared with carbohydrates, SFAs or even MUFAs105.
HOMA-IR (% change)a –0.82 (–1.28 to –0.32)
Carbohydrate replacement with MUFAs
These findings support increased dietary PUFAs as
a means to improve long-​term glycaemic control and
Glucose (mmol/l) 0.00 (–0.02 to 0.02)
HbA1C (%)
reduce insulin resistance. Increased dietary MUFAs
–0.09 (–0.12 to –0.05)
might also be beneficial, although this association
Insulin (pmol/l) 0.10 (–0.30 to 0.40)
remains controversial and might be influenced by the
HOMA-IR (% change)a –0.48 (–0.92 to –0.06)
food source (see discussion below).
Carbohydrate replacement with PUFAs
Glucose (mmol/l) –0.02 (–0.05 to 0.01)
Prospective observational studies on clinical end points.
HbA1C (%) –0.11 (–0.17 to –0.05)
Consistent with RCT findings on blood lipids and
Insulin (pmol/l) –1.60 (–2.80 to –0.40) glycaemic control, total SFA consumption is not asso-
HOMA-IR (% change)a –0.68 (–1.18 to –0.16) ciated with incidence of CHD, stroke or diabetes com-
–2 –1 0 1 2 pared with total carbohydrate or the average background
Fig. 4 | Effects of replacing dietary saturated fatty acids and carbohydrates on diet (that is, a mix of carbohydrate, protein and unsatu-
glycaemic markers. Mean changes in metrics of glucose and insulin homeostasis when rated fats from diverse food sources)60,106–108. However,
5% of dietary energy from saturated fatty acids (SFAs) is replaced isocalorically by this neutral average effect obscures the evidence for
carbohydrates, monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids considerable heterogeneity depending on the specific
(PUFAs), and when 5% of dietary energy from carbohydrates is replaced isocalorically by types and food sources of total SFAs as well as the spe-
MUFA and PUFA. Data are from the systematic review and meta-​analysis by Imamura cific types and food sources of total carbohydrates. This
and colleagues105. Studies were included in the meta-​analysis if they were randomized evidence is further described in sections below.
trials in adults with food intake controlled with provision of meals, if they compared In long-​term observational studies, total dietary
isocaloric interventions varying in composition of specific fats and/or carbohydrate MUFAs (predominantly oleic acid) seem to have a fairly
and if they assessed relevant glucose and insulin metrics. The number of trials and
neutral effect on the risk of cardiometabolic diseases60,108.
participants in the pooled analyses varied widely; for example, 23 trials (with 54 groups
and 618 participants) included haemoglobin measurements, as compared with 99 trials These observational findings contrast with the benefits
(with 237 groups and 4,144 participants) that included blood glucose measurements. of MUFAs on cardiometabolic risk factors observed in
The unit for haemoglobin A1c (HbA1c) is absolute change in measured levels (percentage RCTs, including blood lipids, HbA1c and insulin resist-
glycosylation). aMean changes are per 5% of dietary energy replacement, except for ance as defined by HOMA. The findings from observa-
insulin resistance as defined by homeostatic model assessment (HOMA-​IR), which is tional studies might be influenced by differential food
per 1% of dietary energy replacement. sources. For example, plant MUFA sources, such as

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Reviews

extra-​virgin olive oil and nuts, are linked to lower risk
of CVD and diabetes, dairy sources are also generally
linked to lower risk of CVD and diabetes, and unpro-
cessed red meats are linked to modestly higher risk of
diabetes and no significant effect on CVD, whereas pro-
cessed meats are linked to significantly higher risk of
diabetes and CVD (see the section on MUFAs).
Among conventional classes of dietary fat, total
PUFAs (predominantly linoleic acid) have shown the
most consistently protective effects against CVD and
type 2 diabetes in prospective cohorts108–112. As with total
SFAs (and, to a lesser extent, MUFAs), these observed
associations are consistent with significant benefits of
total PUFA intake on blood lipids and glycaemic control
observed in RCTs. Also consistent with this RCT evi-
dence, total dietary PUFAs are associated with lower risk
of clinical events in cohort studies, whether replacing
total SFA or total carbohydrate intake109.
In the international PURE study61, neither total die-
tary SFAs nor MUFAs were associated with the risk of
CVD, whereas very low SFA intake was linked to higher
risk of stroke, consistent with earlier reports in Asian
cohorts113–115. Higher PUFA consumption replacing car-
bohydrates was associated with lower risk of all-​cause
death, although largely related to non-​CVD rather than
CVD deaths. Overall, the PURE results are generally
concordant with findings in higher income (Western
or Asian) populations, except for the observed benefits
of PUFAs in reducing non-​CVD deaths. Relationships
between dietary fats and the incidence of total CVD
events, which could differ from all-​cause mortality, were
not reported in the PURE study.
RCTs on disease outcomes. Several clinical trials have
evaluated interventions to replace SFA-​rich animal fats
with PUFA-​rich plant oils to reduce CVD. Most had
considerable limitations, including small numbers of
events and limited statistical power, lack of participant
blinding, mixed and heterogeneous clinical end points,
absence of randomization in some instances116,117 and
intervention (high-​PUFA) diets confounded by indus-
trial trans-​fats owing to unrecognized harms of par-
tially hydrogenated margarines 118,119. Most of these
trials were also performed many decades ago, when
prevalent medical treatments (for example, use of
aspirin, statins and coronary revascularization) and
population trends (such as in ageing, obesity, diabetes
and atherogenic dyslipidaemia) were quite different
from present circumstances. Keeping these limitations
in mind, a meta-​analysis of these trials nevertheless
identified clinical benefits of consuming PUFAs from
plant oils in place of SFAs from animal sources120. Of
note, both the direction and magnitude of this pooled
benefit (10% lower risk of CHD per 5%E exchange;
relative risk (RR) 0.90, 95% CI 0.83–0.97) were consist-
ent with both predicted effects on the basis of RCTs of
blood lipid measurements and observed associations
with CHD in long-​term cohort studies120 (Fig. 5).
Areas of controversy
SFAs versus carbohydrates. Evidence remains conflicting
on whether total SFA intake should be considered similar
to, better than or worse than total carbohydrate or refined
carbohydrate for cardiometabolic diseases. In a pooled,
participant-​level analysis of 11 prospective cohorts,
replacing 5%E from total SFA intake with total carbohy-
drate was associated with a slightly higher risk of coro-
nary events (HR 1.07, 95% CI 1.01–1.14), suggesting the
superiority of total dietary SFAs for cardiovascular health
compared with total carbohydrates108. However, in this
study as well as in important meta-​analyses on the effects
of dietary fats versus carbohydrates on cardiometabolic

Parameter Relative risk of CHD per 5% of energy intake (95% CI)

SFA replacement with carbohydrates
Predicted effect from change in total:HDL-C ratio 1.01 (0.98–1.04)
Results from WHI RCT 0.98 (0.88–1.09)
Pooled analysis of 11 observational cohort studies 1.07 (1.01–1.14)
SFA replacement with MUFAs
Predicted effect from change in total:HDL-C ratio 0.93 (0.89–0.96)
No RCTs available –
Pooled analysis of 11 observational cohort studies 1.19 (1.00–1.42)
SFA replacement with PUFAs
Predicted effect from change in total:HDL-C ratio 0.91 (0.87–0.95)
Meta-analysis of 8 RCTs 0.90 (0.83–0.97)
Pooled analysis of 11 observational cohort studies 0.87 ( 0.77–0.97)
0.7 1.0 1.5

Fig. 5 | Effect of replacing dietary saturated fatty acids on the risk of coronary heart disease. The figure shows the
predicted relative risks of coronary heart disease (CHD) according to changes in the total cholesterol:HDL cholesterol
ratio (total:HDL-​C ratio) on the basis of data from randomized controlled trials (RCTs) — for example, replacement of 5% of
energy intake from saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFAs) lowers the total:HDL-​C ratio by
0.16 (ref.306) — together with observational data in middle-​aged adults relating the total:HDL-​C ratio with the risk of CHD
(each 1 unit lower total:HDL-​C is associated with 44% lower risk of CHD)307. Evidence for the effect of SFA replacement
with carbohydrates or PUFAs on CHD events is based on the Women’s Health Initiative (WHI) study63 and a meta-​analysis
of eight RCTs120, respectively. The association between usual dietary habits and CHD events is based on observational
evidence from a meta-​analysis of 11 prospective cohort studies108. Reproduced from ref.120, CC-​BY-4.0 (https://
creativecommons.org/licenses/by/4.0/).

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 Reviews

risk factors96,105, insufficient information was provided by processed meats123,124. For both SFAs and carbohydrates,
individual studies on quality or source of carbohydrates, considering food sources and types separately might be
which prevented subgroup analyses by the type or food most meaningful for understanding their health effects.
source of carbohydrate. Because carbohydrates in mod-
ern diets are predominantly refined starch and sugar, less Optimal public communication on SFA evidence. Most
can be inferred from these studies on the health effects scientists agree on the overall evidence — that is, that the
of carbohydrates from other sources, such as minimally effects of total dietary SFAs on cardiometabolic diseases
processed whole grains, fruits or legumes. For example, are broadly similar to those of total dietary carbohydrate,
in some individual observational studies, consumption that consumption of PUFAs from plant oils is protective
of refined starches and added sugars had associations whether it replaces total SFA or total carbohydrate and
with CHD similar to those of total SFA intake, whereas that heterogeneity exists in the health effects of different
whole grains seemed to be more healthful121,122. In a SFAs (such as lauric acid, myristic acid, palmitic acid and
similar fashion, the optimal fat composition of high-​fat, stearic acid) and potentially their food sources. However,
low-​carbohydrate diets for weight loss and treatment of the optimal way to communicate this evidence remains
diabetes is debated, with many nutrition scientists and controversial. Some scientists favour continuity of focus
clinicians recommending the replacement of carbo- on total dietary SFA restriction, with clarification that
hydrates with unsaturated fats from plant sources but SFAs should be replaced with PUFAs125–127. However,
other clinicians recommending replacement of carbohy- in most diets, carbohydrates represent approximately
drates with diverse fat sources including red meats and fourfold greater calories than SFAs: if average health
effects are similar, why should there be restrictions on
Parameter Mean change per 5% isocaloric substitution (95% CI) calories from total SFAs but not total carbohydrates?
Carbohydrate replacement Furthermore, similar to the heterogeneity in the health
with lauric acid (12:0) effects of different carbohydrate-​rich foods, the hetero-
LDL cholesterol (mmol/l) 0.09 (0.01 to 0.18) geneity in health effects of different SFAs and their food
HDL cholesterol (mmol/l) 0.10 (0.09 to 0.13) sources (for example, unprocessed red meat, processed
Triglycerides (mmol/l) –0.08 (–0.13 to –0.03) meat, poultry, cheese, yogurt, milk, nuts, avocados and
Total:HDL cholesterol ratio –0.17 (–0.24 to –0.09) tropical oils), together with evidence for health benefits of
Carbohydrate replacement PUFAs regardless of the macronutrient comparison, sug-
with myristic acid (14:0) gest a need to move away from guidance on total dietary
LDL cholesterol (mmol/l) 0.21 (0.13 to 0.29) SFAs towards recommendations on specific foods4,81,128,129.
HDL cholesterol (mmol/l) 0.10 (0.08 to 0.13)
Triglycerides (mmol/l) –0.05 (–0.10 to –0.01) Future directions
Total:HDL cholesterol ratio –0.05 (–0.12 to 0.03) Uncertainties about the cardiometabolic effects of
Carbohydrate replacement SFAs versus carbohydrates, as well as about the optimal
with palmitic acid (16:0)
communication to the public, must be resolved. Future
LDL cholesterol (mmol/l) 0.18 (0.13 to 0.24) research must also clarify the varying effects of specific
HDL cholesterol (mmol/l) 0.05 (0.04 to 0.06) SFAs and their diverse food sources, whether these
Triglycerides (mmol/l) –0.06 (–0.09 to –0.03) effects differ according to individual risk predisposition
Total:HDL cholesterol ratio 0.03 (–0.01 to 0.08) (for example, on the basis of age, sex and presence or
Carbohydrate replacement absence of hyperlipidaemia, mixed dyslipidaemia, ath-
with stearic acid (18:0)
erogenic dyslipidaemia, prediabetes or diabetes) and
LDL cholesterol (mmol/l) 0.00 (–0.06 to 0.06) whether recommendations should vary depending on
HDL cholesterol (mmol/l) 0.00 (–0.02 to 0.01) clinical goals (for example, rapid weight loss, prevention
Triglycerides (mmol/l) –0.03 (–0.06 to 0.01) of weight gain, treatment targeting specific blood lipids
Total:HDL cholesterol ratio 0.01 (–0.05 to 0.06) or glycaemic control). The potential adverse effect of
–0.3 –0.2 –0.1 0 0.1 0.2 0.3 very low SFA intake on stroke should also be examined
in additional experimental and prospective studies.
Fig. 6 | Effects of specific types of saturated fatty acid on cardiometabolic lipid risk
factors. The graph shows the mean change in serum lipid levels when 5% of dietary Effects of dietary fats on novel lipid risk factors also
energy from carbohydrates is isocalorically replaced by different types of saturated fatty remain uncertain. For example, in a limited number
acid. Data are from the systematic review and meta-​analysis by Mensink96. Studies were of trials, SFA consumption lowered the serum levels of
included in the meta-​analysis if they were randomized trials in which food intake was lipoprotein(a), a causal risk factor for CHD and aortic
controlled and had a parallel or crossover design, if the dietary periods were ≥13 days valve disease130, whereas low-​fat diets raised lipopro-
(to allow lipids to reach steady-​state conditions), if protein and alcohol intake were tein(a) levels131–133. The magnitudes, mechanisms and
constant, if fatty acids were exchanged for other fatty acids or for carbohydrates, if no clinical relevance of these effects are not established.
other concomitant interventions (such as weight loss) were implemented and if daily Similarly, whereas n-3 PUFA intake lowers the serum
cholesterol intake between the diets within a study was similar (<100 mg difference). levels of ApoC-​III134–136, an apparent modifier of athero-
Diets focused on long-​chain n-3 polyunsaturated fatty acids (such as fish oils) were
genicity of LDL-​C and HDL-​C137,138, the effects of other
excluded; therefore, total polyunsaturated fatty acids in the studies can be considered
to be linoleic acid and α-​linolenic acid. Mensink used multiple regression analyses to dietary fats on ApoC-​III are not well established. Because
predict the mean serum lipid concentration of a group of individuals from the changes ApoC-III levels generally correlate with serum triglyc-
in percentage of total energy intake of fatty acids or carbohydrates in the diets. The eride concentrations, the triglyceride-​lowering effects of
numbers of diets/studies for each outcome are as follows: LDL cholesterol: 118/46; PUFA, MUFA and SFA consumption, compared with
HDL cholesterol: 120/47; total:HDL cholesterol ratio: 116/45; and triglycerides: 123/49. carbohydrate intake, suggest that each type of fat might

Nature Reviews | Cardiology

Reviews

lower ApoC-​III levels as well, as has been observed in a higher risk of diabetes162,164,167,172,173. The higher risk of
small number of controlled-​feeding trials133,139,140. CVD with consumption of processed meats is con-
sistent with their high sodium content (~400% higher
SFAs and their food sources than unprocessed red meats), as well as possible (but
Main lines of evidence not well-​established) harms of other preservatives, such
RCTs on risk factors. Different medium-​chain and long-​ as nitrites174 (often hidden as ‘celery juice’ in ostensibly
chain SFAs have very different effects on blood lipids96 ‘nitrite-​free’ processed meats). The common finding of
(Fig. 6). Effects of short-​chain SFAs or very-​long-chain elevated risk of diabetes with both processed and unpro-
SFAs on blood lipid levels, or of any different SFAs on cessed red meat consumption suggests a role for haem
glycaemic markers, are not well established; although iron, a risk factor for diabetes in animal experiments, in
on the basis of in vitro and animal experiments, pregnancy and in individuals with inborn errors of iron
medium-​chain SFA intake might confer metabolic ben- metabolism, such as haemochromatosis175,176.
efits including induction of energy metabolism path- Different dairy foods, such as milk, cheese, yogurt
ways, increase in lean body mass and protection against and butter, also show variable relationships with the
diabetes141–144. Few trials have investigated the metabolic incidence of CHD, stroke, diabetes and weight gain in
effects of branched-​chain or odd-​chain SFAs128. long-​term observational studies163,165,166,168,169,177–186 (Fig. 7).
As with red meats, these differences seem to be unrelated
Prospective cohort studies on clinical end points. Few to varying total fat or total SFA content but are possibly
studies have evaluated the effect of individual die- related to other characteristics such as probiotics, fer-
tary SFAs on cardiometabolic disease outcomes145–152. mentation, dairy amino acids, specific fatty acids or vita-
Observational studies are limited by challenges in min K2 (ref.128). For example, in a meta-​analysis of RCTs,
accurately distinguishing consumption of different cheese consumption reduced serum levels of LDL-​C by
SFAs from self-​reported questionnaires. Individual SFA 6.5% and HDL-​C by 3.9% compared with butter, despite
biomarkers can also be measured in blood or adipose similar SFA and PUFA content in the cheeses and but-
tissue, but for many SFAs, these levels reflect endog- ters used in the studies187. The effects of these foods on
enous synthesis and metabolism in addition to direct glucose–insulin homeostasis seem also to vary by food
dietary intake153. For example, fatty acid products of source, although fewer studies have investigated these
hepatic de novo lipogenesis (for example, endogenous associations188.
fat synthesis in response to high doses of dietary starch Tropical fruit oils (such as palm and coconut oil) are
and sugar) include myristic acid (14:0), palmitic acid major food sources of SFAs in East Asian countries and
(16:0), stearic acid (18:0), palmitoleic acid (16:1n-7) increasingly in global processed and packaged foods
and oleic acid (18:1n-9). Therefore, for these individ- as a replacement for partially hydrogenated fats. In
ual SFAs and MUFAs, circulating and tissue levels are controlled-​feeding trials, evidence for effects of tropi-
influenced by other aspects of diet (especially dietary cal oils on surrogate outcomes is mixed and inconclu-
starch and sugar), the individual’s sensitivity to carbohy- sive189–194. For instance, consuming palm oil in place of
drate handling and the endogenous metabolism of these other plant oils containing mixed amounts of MUFAs
fats154,155. By contrast, odd-​chain SFAs (15:0 and 17:0) are and PUFAs increases LDL-​C and HDL-​C levels and
not synthesized by humans and seem to be reasonable has no significant effect on the total cholesterol:HDL-​C
biomarkers of dairy fat consumption156. Cohort studies ratio or on blood triglyceride levels189. Few studies have
measuring 15:0 and 17:0 biomarkers show associations evaluated tropical oils and clinical end points. A retro-
with protection against incident diabetes156. Meta-​ spective, case–control study in Costa Rica found that,
analyses of prospective studies also suggest that 17:0, compared with soybean oil, use of palm oil for cooking
but not 15:0, intake is inversely associated with the risk was associated with higher risk of myocardial infarction,
of CVD157. suggesting that PUFA-​rich plant oils are better for cardio­
vascular health than palm oil195. However, evidence on
Food sources of SFAs. Major food sources of SFAs include long-​term effects is otherwise quite limited, and no pro-
milk, cheese, butter, margarine, plant oils, red and pro- spective studies have reported on consumption of trop-
cessed meats, poultry, chocolate, baked desserts and, in ical oils and incident cardiometabolic disease outcomes
tropical nations, fruit oils such as palm and coconut158–161. or on comparisons between tropical oils and different
Estimated SFAs from these foods as well as the overall carbohydrate food sources.
consumption of these foods demonstrate contrasting
associations with cardiometabolic disease events162–170 Areas of controversy
(Fig. 7). For example, SFAs from meats have been linked Health effects of red meats. The causality of observed
to higher risk of CVD, whereas SFAs from dairy have differences in health effects of unprocessed red meat ver-
been linked to lower risk171. Furthermore, despite having sus processed meats, the underlying molecular mech-
similar contents of total fat, total SFAs and cholesterol, anisms and the relevance for dietary guidance remain
consumption of processed meats is associated with an controversial196–199. Little evidence exists for differential
elevated risk of all-​cause death, CVD death, stroke, CHD health effects of conventionally grown versus grass-​fed
and diabetes, whereas consumption of unprocessed red beef or for major health benefits of red meats or pro-
meats is not significantly associated with the risk of all-​ cessed meats commonly proposed by popular advocates
cause death, CVD death or CHD, is weakly associated for low-​carbohydrate and/or paleo diets (although low-
with the risk of stroke and is associated with modestly ering of refined starch and sugar in these diets should

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 Reviews

Prospective
cohort Participants/
Outcome Unit RR (95% CI) studies events (n) Ref.
Total dairy
CHD High versus low intake 0.94 (0.82–1.07) 10 253,260/8,792 175

Stroke High versus low intake 0.88 (0.82–0.94) 16 764,635/28,138 173

Diabetes Each serving per day 0.98 (0.96–1.01) 14 459,790/35,863 171

Milk
CHD Each serving per day (200 ml) 1.00 (0.96–1.04) 6 259,162/4,391 176

Stroke High versus low intake 0.91 (0.82–1.01) 9 525,609/22,382 173

Diabetes Each serving per day (200 ml) 0.87 (0.72–1.04) 7 167,982/15,149 170

Cheese
CHD High versus low intake 0.84 (0.71–1.00) 7 NA/NA 175

Stroke High versus low intake 0.94 (0.89–1.00) 5 282,439/9,919 173

Diabetes Each serving per day (50 g) 0.92 (0.86–0.99) 8 242,960/17,620 170

Butter
CHD High versus low intake 1.02 (0.88–1.20) 5 NA/NA 175

Stroke High versus low intake 0.95 (0.85–1.07) 3 173,853/5,299 173

Yoghurt
CHD High versus low intake 1.06 (0.90–1.34) 5 NA/NA 175

Diabetes Each serving per day (½ cup) 0.82 (0.70–0.96) 9 408,096/32,995 171

Chocolate
CHD High versus low intake 0.90 (0.82–0.97) 6 144,822/7,267 303

Stroke High versus low intake 0.84 (0.78–0.90) 7 231,038/8,197 303

Diabetes High versus low intake 0.82 (0.70–0.96) 5 132,845/13,271 303

Unprocessed meats
CVD death High versus low intake 1.12 (0.95–1.33) 13 1,070,215/24,241 162

Stroke Each serving per day (100 g) 1.13 (1.03–1.23) 5 239,251/9,593 163

Diabetes Each serving per day (100 g) 1.19 (1.04–1.37) 9 447,333/28,206 164

Processed meats
CVD death Each serving per day (50 g) 1.24 (1.09–1.40) 6 1,186,761/35,537 162

Stroke One serving per day (50 g) 1.11 (1.02–1.20) 5 239,251/9,593 163

Diabetes Each serving per day (50 g) 1.51 (1.25–1.83) 8 372,391/26,234 164

0.5 1 2
RR (95% CI)

Fig. 7 | Food source of saturated fat and risk of cardiometabolic disease. Consumption of different major sources
of saturated fatty acids (SFAs) has been shown to have contrasting associations with cardiometabolic disease events.
For instance, despite having a similar content of total fat, total SFAs and cholesterol, consumption of processed meats
is associated with an elevated risk of coronary heart disease (CHD), stroke and diabetes mellitus, whereas consumption
of unprocessed red meats is not significantly associated with the risk of CHD, is weakly associated with the risk of stroke
and is associated only modestly with a higher risk of diabetes. Data in the figure are from the referenced systematic
reviews and meta-​analyses of prospective cohorts studies162–170 and are summarized from ref.4. CVD, cardiovascular
disease; NA, not available; RR, relative risk.

certainly produce metabolic benefits)200,201. The incor-
poration of adverse environmental effects of red meat
production — including extensive greenhouse-​gas emis-
sions, water pollution and deforestation — into dietary
guidance also remains controversial70,197. While the
current evidence suggests clear cardiometabolic harms
of processed meats and a fairly neutral effect of modest
intake of unprocessed red meat (such as up to 1–2 times
per week), this distinction has not been incorporated
into most dietary guidance.
Health effects of dairy foods. Dairy foods are important
sources of calories and nutrients for many populations
globally, especially in low-​income and middle-​income
countries202. Low-​fat dairy foods are also core compo-
nents of several healthy dietary patterns, such as the
Dietary Approaches to Stop Hypertension (DASH) and
US Dietary Guidelines125. By contrast, some scientists
and popular anti-​inflammatory diets advocate com-
plete avoidance of dairy foods203–205. Current dietary
guidelines also make little distinction between types of
dairy (such as yogurt, milk and cheese), which can have
differing health effects. The effects of dairy fat are also
controversial, with evidence of protective associations
with diabetes and perhaps CVD in observational studies
but a long history of emphasis on low-​fat dairy in die-
tary guidelines. Health effects of dairy fat could also be
modified by the background dietary pattern206.
Health effects of tropical fruit oils. Although conven-
tional dietary guidance recommends against consump-
tion of tropical oils owing to their high SFA content, the
composition of tropical oils is complex, and their long-​
term health effects remain uncertain. Except for palm

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Reviews
stearin, most palm oil products (palm oil, red palm oil
and palm olein) contain approximately half SFAs (pre-
dominantly palmitic acid) and half unsaturated fats
(mainly oleic acid but also linoleic acid). Coconut oil is
approximately 80% SFA, but half of this is medium-​chain
lauric acid (12:0), which significantly increases serum
HDL-​C levels, lowers serum triglyceride-​rich lipopro-
tein levels and lowers the total cholesterol:HDL-​C ratio
(Fig. 6). In addition, in contrast to animal fats, palmitic
acid in palm oil triacylglycerol is mostly attached to the
sn-1 and sn-3, rather than sn-2, positions of the glycerol
backbone207,208. This structure has been proposed as an
explanation for the unique effects of palm oil on blood
lipids compared with other fats, but studies have been
few and inconsistent194,208–210. In addition, virgin tropi-
cal oils can contain other nutrients, such as carotenoids,
vitamin E, potassium and phenolics, which could all
have health benefits128,211,212. As with red meats, produc-
tion of palm oil is also associated with major environ-
mental concerns related to deforestation and reduced
biodiversity213. This complexity, in combination with
very little empirical study of the health effects of tropical
oils, has led to controversy over their role in the diet.
Future directions
Health effects of different SFA-​containing foods. Given
the uncertainties and controversies described above,
substantial new research is needed on the cardiometa-
bolic effects of differing food sources of SFAs. The mech-
anistic reasons for the observed differing relationships
of unprocessed red meats versus processed meats with
cardiometabolic diseases require elucidation. Additional
experimental, observational and clinical studies should
also assess the health effects of different combinations
of individual SFAs (for example, in meats versus dairy
versus coconut oil), the modifying effects of other
nutrients (for example, calcium and amino acids) or
structural differences (such as the sn position of SFAs
in palm oil) and, perhaps most importantly, the effects
of food processing, such as preservation of meats with
sodium and nitrates, homogenization and loss of milk
fat globule membrane214, fermentation (which is relevant
for propionate and vitamin K2 in cheese)215 and the use of
different probiotics in yogurt and cheese128.
Health effects of trace SFAs. Little is known about
potential cardiometabolic effects of trace SFAs, such
as branched-​chain SFAs128 or very-​long-chain SFAs
(20–24 carbons), the circulating levels of which are
robustly associated with lower risk of CHD and diabe-
tes216–220. Very-​long-chain SFAs can be endogenously
synthesized through elongation of long-​chain SFAs
or obtained from a limited number of dietary sources
such as canola oil, peanuts and macadamia nuts217.
Very-​long-chain SFAs are major components of cer-
amides and sphingomyelin, which have roles in insulin
resistance, inflammation and liver homeostasis10,221,222.
In experimental studies, ceramides with different SFAs
(for example, palmitic acid versus very-​long-chain SFA)
have different biological activities223, although how these
changes might relate to the risk of cardiometabolic
disease remains to be elucidated.
MUFAs and their food sources
Oleic acid accounts for >90% of dietary MUFAs8, and
little is known about the health effects of other trace die-
tary MUFAs. Oleic acid is often considered for its role in
the traditional Mediterranean diet in the form of olives
and extra-​virgin olive oil (~70% oleic acid). However,
in non-​Mediterranean countries, dietary oleic acid is
derived in much higher amounts from other plant foods
(such as high-​oleic soybean oil, rapeseed oil, avocados,
and nuts and seeds and their spreads) and, importantly,
from animal fats including in meats (in which approx-
imately half of the total fat content is MUFAs) and in
dairy (approximately one-​fifth MUFAs). As mentioned
earlier, although total MUFA consumption improves
lipid profiles, HbA1c and insulin resistance in RCTs,
long-​term associations with clinical cardiometabolic dis-
ease events are generally neutral in observational studies.
This observation could partly relate to the varying health
effects of the diverse food sources of total MUFAs: for
example, plant foods with higher MUFA content often
demonstrate protective effects for cardiometabolic
diseases, as discussed below.
Main lines of evidence
RCTs on risk factors. Most RCTs on surrogate outcomes
have utilized plant rather than animal sources of MUFAs,
particularly olive oil and high-​oleic soybean oil. These
oils improve serum levels of total cholesterol and LDL-​C
when replacing animal fats or tropical oils and further
reduce serum ApoB and triglyceride levels and the total
cholesterol:HDL-​C ratio when replacing trans-​fatty
acid-​containing fats224. A 2017 meta-​analysis of RCTs
suggests that consumption of olive oil, compared with
an assortment of control fats or low-​fat diets, improves
glycaemia (fasting glucose and HbA1c) in patients with
diabetes225. In the PREDIMED trial80, extra-​virgin olive
oil and nuts rich in oleic acid reduced abdominal obesity
compared with a low-​fat control diet. These effects could
relate to increased fat oxidation and energy expenditure,
although the effects of high-​oleic oils on these physiolog-
ical parameters seem to be mixed226–229. Tree nuts, includ-
ing almonds, cashews, hazelnuts, macadamias, pecans
and pistachios, are rich sources of MUFAs, as are pea-
nuts230,231. In RCTs, tree-​nut consumption reduced serum
levels of total cholesterol, LDL-​C, ApoB and triglycerides
but had no effects on HDL-​C levels232. On the basis of
a limited number of RCTs, avocado consumption does
not alter total cholesterol, LDL-​C or triglyceride levels
but moderately increases HDL-​C levels, although there
was substantial heterogeneity in the observed effects
between the RCTs233. Few trials have aimed specifically
to evaluate or isolate the effects of MUFAs in meats or
dairy products.
Prospective cohort studies on clinical end points. In a
meta-​analysis of prospective cohorts, total MUFAs from
mixed animal and vegetable sources were not signifi-
cantly associated with the risk of CVD events, all-​cause
death or CVD death234. Conversely, higher olive oil con-
sumption was significantly related to lower risk of cardio­
vascular events (RR 0.72, 95% CI 0.47–0.77) and stroke
(RR 0.60, 95% CI 0.47–0.77)234. In a US cohort of male
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 Reviews

health professionals, dietary MUFAs from plant sources, have relevance to dietary guidance as well as to food and
but not from animal sources, were associated with lower oil processing methods, which can destroy these other
risk of CHD235. We are not aware of prospective stud- beneficial compounds243–246.
ies examining MUFAs from different food sources in
relation to stroke or diabetes. n-6 PUFAs and their food sources
Linoleic acid, the major dietary PUFA, is present in
RCTs on disease outcomes. As described above, the soybean, sunflower, corn and other plant oils as well
PREDIMED trial68 showed that advice to consume a as in peanuts, pecans and other nuts and seeds7. Along
traditional Mediterranean diet supplemented with tree with α-​linolenic acid (see below), linoleic acid is one of
nuts or extra-​virgin olive oil, compared with a low-​fat two essential fatty acids that cannot be synthesized by
control diet, reduced the primary end point of myocar- humans and must be obtained from the diet. Linoleic
dial infarction, stroke or CVD death by 30%. Secondary acid is converted endogenously into several other n-6
analyses in a subsample of the PREDIMED study also PUFAs including γ-​linolenic acid (18:3n-6), di-​homo-
showed that both interventions reduced the risk of inci- γ-linolenic acid (20:3n-6) and arachidonic acid (20:4n-6);
dent diabetes by ~50% over a median of 4 years follow-​ these other n-6 PUFAs are also present in small amounts
up compared with the control diet236 and reduced the in foods such as eggs, poultry and other meats247,248.
average waist circumference by ~0.6 cm and 0.9 cm in
the olive oil and nut groups, respectively80. Of note, ~60% Main lines of evidence
of the supplemented extra-​virgin olive oil in this trial Randomized controlled trials on risk factors. As dis-
replaced regular (non-​virgin) olive oil. Because these oils cussed above, RCTs have documented that consuming
have equivalent contents of total MUFAs and oleic acid, PUFAs (predominantly linoleic acid but also arachidonic
this finding suggests potential additional relevance of acid) improves major risk factors for cardiometabolic
phenolics in virgin oil (such as oleocanthal)237–240, rather diseases including blood lipids and markers of glycae-
than of only oleic acid per se. mia96,105 (Figs 3,4). Some RCTs have demonstrated pos-
sible additional benefits of linoleic acid-​rich plant oils,
Areas of controversy such as reduced liver fat accumulation and postprandial
Health effects of total MUFAs from diverse food sources. lipaemia249,250. Although linoleic acid and/or arachidonic
For decades, dietary guidelines have recommended con- acid have been hypothesized to be pro-​inflammatory,
sumption of unsaturated fats (MUFAs or PUFAs) in place RCTs have found no appreciable effects of dietary lino­
of SFAs. However, with the growing mixed data on the leic acid or arachidonic acid on inflammatory biomark-
health effects of total dietary MUFAs, the 2015 US DGAC ers and other related indices, including platelet function
revised these recommendations to conclude “evidence is and immune activation251–254.
limited regarding whether replacing SFA with MUFA
confers overall CVD benefits” and instead highlighted the Prospective cohort studies on clinical end points. In a
evidence for the cardiovascular benefits of olive oil and meta-analysis of prospective cohort studies, self-
nuts70. The causality and mechanisms for divergent asso- reported linoleic acid consumption, compared with
ciations of plant versus animal sources of MUFA remain either total SFA or total carbohydrate consumption,
unclear. Because the MUFA itself (oleic acid) is similar, was associated with an ~10% lower risk of CHD and a
differences in associations might relate to residual con- 13% lower risk of CHD death109. Because linoleic acid
founding from other dietary or lifestyle patterns, to other cannot be synthesized endogenously, blood and adipose
healthful compounds in plant sources of MUFA (such tissue levels can also be used as objective biomarkers of
as vitamins and phenolics) or to harmful compounds in dietary intake255–257. In a pooling project involving new
animal sources (for example, sodium and haem). individual-​level analyses from 20 prospective cohorts
across 10 countries, higher biomarker levels of lin-
Dietary oleic acid and atherosclerosis. In certain rodent oleic acid were associated with a 35% lower incidence
and primate models, dietary oleic acid from plant oils of diabetes (per interquintile range: RR 0.65, 95% CI
produced expected benefits in serum LDL-​C levels 0.60–0.72), with consistent findings in subgroups by age,
and the total cholesterol:HDL-​C ratio but did not pre- sex, ethnicity, BMI and n-3 PUFA biomarker levels258.
vent atherosclerosis241. Experimental studies suggested A meta-​analysis on the basis of new individual-​level
this lack of protective effect was due to enrichment of analyses of 30 prospective cohorts also found that linoleic
LDL-​C with cholesteryl oleate, which increased LDL-​C acid biomarkers were inversely associated with incident
binding to proteoglycans and retention in the arterial CVD, CVD death and ischaemic stroke259,260. Inconsistent
wall intima241. In a follow-​up trial in humans, however, with the hypothesized pro-​inflammatory effects, pro-
canola oil (which is rich in oleic acid) similarly enriched spective cohort studies have shown that higher blood
cholesteryl oleate in LDL-​C but did not increase binding biomarker concentrations of arachidonic acid are not
to proteoglycans242. significantly associated with incident diabetes258 and are
associated with moderately lower risk of CHD106.
Future directions
Additional research is needed to understand whether RCTs on disease outcomes. As described above, sys­te­ma­
the health benefits of plant sources of MUFAs relate tic reviews and meta-​analyses of (older and methodo­
to the MUFA itself, to other compounds in these foods lo­g ically limited) RCTs demonstrated significant
or to an interaction between these factors. These findings reductions in CHD events with consumption of PUFA-rich

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Reviews
(predominantly linoleic acid) oils in place of animal
fats120,261.
Areas of controversy
Potential harms of n-6 PUFAs. Two re-​analyses of old
RCTs have fuelled the debate regarding linoleic acid-​rich
plant oils118,119, although these findings must be inter-
preted cautiously given the use of partially hydrogen-
ated margarines rich in industrial trans-​fatty acids as
the source of linoleic acid, among other methodologi-
cal limitations127,262. As described above, a meta-​analysis
of all available clinical trials on PUFAs demonstrated a
significant reduction in the risk of CHD with increased
PUFA intake as a replacement for SFAs. The pooled risk
estimate (~10% lower risk per 5%E increase in PUFA
intake) (Fig. 5) is consistent with the estimated benefits
from controlled-​feeding RCTs assessing changes in
lipid levels (9% lower risk per 5%E increase in PUFA
intake) and prospective observational studies on die-
tary n-6 PUFAs and clinical CHD events (13% lower
risk per 5%E higher PUFA intake). The consistency
of the findings across these different lines of evidence
provides substantial confidence in both the qualita-
tive benefits of n-6 PUFAs and a fairly narrow range
of quantitative uncertainty. Several studies in the past
few years further support cardiometabolic benefits of
PUFA consumption, as summarized in the previous
section. In summary, the overall evidence strongly sup-
ports cardiometabolic benefits of total PUFA and n-6
PUFA consumption, including on the basis of evidence
from controlled-​feeding studies on blood lipid changes,
controlled-​feeding studies on glucose–insulin homeo-
stasis, prospective cohort studies on estimated dietary
PUFA and clinical outcomes, prospective cohort studies
on objective PUFA biomarkers and clinical outcomes
and controlled clinical trials on PUFA consumption and
clinical outcomes.
Competition between n-6 PUFAs and n-3 PUFAs; the
n-6:n-3 ratio. On the basis of potential mechanistic com-
petition between n-6 PUFAs and n-3 PUFAs for certain
enzymes (such as the fatty acid desaturases FADS1 and
FADS2) and the hypothetical pro-​inflammatory effects
of n-6 PUFAs, some scientists believe that dietary n-6
PUFAs are harmful and should be avoided263,264. This
rationale has popularized the notion of an optimal die-
tary n-6:n-3 ratio, hypothesized to be ~1:1, with higher
ratios (higher relative n-6 PUFA consumption) being
harmful and with corresponding recommendations
to lower dietary n-6 PUFAs263,264. However, as summa-
rized above, independent and complementary lines of
evidence all support cardiometabolic benefits of higher
n-6 PUFA consumption. In addition, use of a ratio has
many conceptual challenges and limitations, particu-
larly when the main effects of each component (that is,
the health effects of the absolute intakes of n-3 PUFA
and n-6 PUFA) are not simultaneously considered265,266.
Accordingly, major organizations including the US
Dietary Guidelines, AHA and United Nations Food and
Agricultural Organization have each concluded that die-
tary linoleic acid is beneficial and consumption should
be increased7,125,267.
Potential harms of industrialized plant oils. Extensive
posts from online and social media sources state that
industrial or refined plant oils, especially those rich in
n-6 PUFAs, are harmful to health268–271. The origin of
concerns regarding industrialized plant oils is unclear.
However, nearly all the interventional and observational
studies of total and n-6 PUFA summarized above evalu-
ated linoleic acid as usually consumed in modern pop-
ulations, that is, largely from industrialized plant oils.
Therefore, the cumulative evidence supports clear bene-
fits, not harms, of these plant oils. Whether or not virgin
versions of these oils would have even greater benefits,
for example, owing to greater concentrations of phenolics
and phytosterols272–274, remains to be investigated.
Future directions
Cumulative evidence suggests that plant oils rich in
linoleic acid protect against cardiometabolic diseases,
whereas other individual n-6 PUFAs, such as arachi-
donic acid, do not seem to confer major benefits or
harm. Given that RCTs on clinical outcomes used plant
oils containing both n-6 PUFAs and low amounts of n-3
PUFA, selection of these oils (such as soybean or canola
oil) might be most relevant for lowering the risk of CHD.
The large RCTs that tested the effect of linoleic acid-​rich
plant oil on the risk of CHD were conducted decades
ago with important design limitations. Additional, well-​
designed RCTs that investigate how intake of specific
linoleic acid-​rich plant oils affects CHD and type 2 dia-
betes will be highly informative. Future studies should
also test the feasibility and effectiveness of substitut-
ing refined carbohydrate foods with foods high in n-6
PUFAs (such as plant oils, seeds and nuts) to reduce the
incidence of cardiometabolic diseases because RCTs on
physiological risk factors and prospective cohort stud-
ies found substantial benefit of replacing carbohydrates
with n-6 PUFAs.
n-3 PUFAs and their food sources
n-3 PUFAs include α-​linolenic acid, the major plant-​
derived n-3 PUFA, which is found in a limited number
of foods and their oils (for example, walnuts, flaxseed,
soybean oil and rapeseed oil), eicosapentaenoic acid
(EPA; 20:5n-3) and docosahexaenoic acid (DHA;
22:6n-3), which is found mostly in fish and shellfish,
with smaller amounts in eggs, red meats and poultry5.
Like its 18-carbon n-6 cousin linoleic acid, and in con-
trast to major SFAs and MUFAs, α-​linolenic acid is an
essential fatty acid that cannot be synthesized by humans.
α-​Linolenic acid can to some extent be enzymatically
converted into EPA and then DHA, but these conver-
sions occur in low quantities, such that tissue and cir-
culating levels of EPA and DHA are mostly determined
by their direct dietary intake5.
Main lines of evidence
RCTs on risk factors. In meta-​analyses of RCTs, long-​
chain n-3 PUFA intake improves multiple cardiovascu-
lar risk factors, including leading to reduced triglyceride
levels, heart rate and blood pressure and improved
endothelial function5. Additional benefits might include
improved cardiac function and filling, reduced levels
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 Reviews

of inflammatory mediators and improvements in adi- RCTs on disease outcomes. A substantial number of
pocyte function275–279. In RCTs, long-​chain n-3 PUFA RCTs have investigated long-​chain n-3 PUFA (EPA
consumption did not significantly affect glycaemia or and DHA) and the risk of CVD. Whereas the majority
insulin sensitivity280,281. RCTs suggest that foods rich in of earlier RCTs indicated benefits of these n-3 PUFAs,
α-​linolenic acid, such as walnuts and flaxseeds, decrease particularly for fatal CHD, later trials generally did not
total cholesterol and LDL-​C levels in serum232,282, and find a significant effect of n-3 PUFA supplementation
walnuts also improved endothelial function283. Effects on the risk of CVD292. Of note, the dose–response of
of α-​linolenic acid-​rich foods on other cardiometabolic the effect of long-​chain n-3 PUFAs on CVD risk fac-
risk factors, such as glucose–insulin homeostasis, are not tors varies, which might correspondingly influence the
well established. effects of differing doses of n-3 PUFAs on clinical risk5.
Two large clinical trials published in 2018 provide fur-
Prospective cohort studies on clinical end points. In ther evidence in this regard. In the VITAL study293, a
prospective cohort studies, higher intake of fish or long-​ trial on primary prevention of CVD including
chain n-3 PUFAs was related to significantly lower risk 25,871 adults, low-​dose fish oil supplementation (840 mg
of fatal CHD, including fatal myocardial infarction and per day of EPA plus DHA) had no significant effect on
sudden cardiac death. Dose–response analyses suggest a the composite primary end point of CHD, stroke or
nonlinear effect, with lower risk observed for moderate death from CVD but reduced the risk of total CHD
consumption of EPA and DHA (~250 mg per day) and (HR 0.83, 95% CI 0.71–0.97), percutaneous coronary
fish (~2 servings per week) than with little or no con- intervention (HR 0.78, 95% CI 0.63–0.95), total myo-
sumption and no appreciable further reduction in risk cardial infarction (HR 0.72, 95% CI 0.59–0.90) and fatal
with higher intakes284,285. Compared with their effects on myocardial infarction (HR 0.50, 95% CI 0.26–0.97).
the risk of fatal CHD, fish and n-3 PUFA consumption Consistent with previous evidence for a nonlinear
demonstrate weaker or null associations with the risk dose–response of certain physiological benefits of n-3
of non-​fatal CHD and stroke106,286,287. Specific associa- PUFAs5,284, in a prespecified subgroup analysis, the com-
tion with lower risk of CHD-​related death suggests that posite primary end point was also significantly reduced
the relationship is unlikely to be entirely due to residual in the subset of participants with lower baseline fish
confounding, and experimental studies demonstrating consumption293. By contrast, in the REDUCE-​IT trial99,
antiarrhythmic properties of EPA and DHA provide high-​dose n-3 PUFA (4 g per day of EPA) significantly
additional biological plausibility to the association5. reduced serum triglyceride levels and the composite
Consistent with RCTs on markers of glycaemia and primary end point of CVD among 8,179 patients with
insulin sensitivity, pooled analyses of prospective cohort moderately elevated triglyceride levels who were taking
studies found little to no association between fish-​ stable statin therapy.
derived and seafood-​derived n-3 PUFA intake and risk Only a few RCTs have assessed whether α-linolenic
of type 2 diabetes, although protective associations were acid-rich foods prevent cardiometabolic diseases.
observed only in Asian populations288. In meta-​analyses In a trial conducted in the Netherlands, supplemen-
of longitudinal studies, plant-​derived α-​linolenic acid tation with a margarine enriched with α-linolenic
was not significantly related to total CHD, stroke or acid (increasing participant intake of α-linolenic acid
type 2 diabetes288,289 but was inversely associated with by 2 g per day) did not significantly reduce major
incident fatal CHD289. cardio­vascular events (RR 0.91, 95% CI 0.78–1.05)294.
Circulating or adipose tissue levels of α-​linolenic acid, Conversely, in the PREDIMED trial68, the intervention
EPA and DHA are biomarkers of their intake255. In a large group receiving mixed nuts containing 50% walnuts had
global consortium that included 19 prospective cohort reduced risk of CVD compared with those receiving the
studies, α-​linolenic acid and DHA, but not EPA biomark- control diet.
ers, were associated with lower risk of fatal CHD290. The
relative risks per one standard deviation (s.d.) increase Areas of controversy
were 0.91 (95% CI 0.84–0.98) for α-​linolenic acid and Long-​chain n-3 PUFA supplements derived from sea-
0.90 (95% CI 0.84–0.96) for DHA. α-​Linolenic acid, food. Several systematic reviews and meta-​analyses
EPA and DHA biomarkers were not significantly asso- of RCTs have concluded that n-3 PUFA supplements
ciated with total CHD or non-​fatal myocardial infarc- do not reduce the risk of total death, cardiovascular
tion290. Therefore, biomarker-​based studies also suggest events, total CHD, fatal CHD or stroke295,296. Such find-
a specific protective association between n-3 PUFAs ings have led to increasing uncertainty regarding the
and CHD death and highlight the need to investigate cardiovascular benefits of n-3 PUFA supplementation.
individual n-3 PUFAs. In the EPIC-​Interact project with However, one meta-​analysis including all major trials
participants from eight countries (including 12,132 indi- conducted until 2012 identified a reduction in cardiac
viduals with incident type 2 diabetes), higher levels of death (RR 0.91, 95% CI 0.85–0.98) with n-3 PUFA
α-​linolenic acid biomarkers were related to lower risk supplementation (although this was reported as non-
of type 2 diabetes, with an HR of 0.93 (95% CI 0.88–0.98) significant owing to an unusual adjustment for mul-
per one s.d. increase in α-​linolenic acid biomarker lev- tiple comparisons testing in the meta-​analysis) and a
els291. These findings were consistent with pooled analy­ similar nonsignificant trend towards lower risk of total
ses of other prospective cohort studies291. Conversely, myocardial infarction (RR 0.89, 95% CI 0.76–1.04)297.
EPA and DHA biomarkers were not associated with the A 2017 AHA Advisory reviewed the available evidence
risk of type 2 diabetes. and concluded that n-3 PUFA supplements might

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Reviews

reduce CHD-​related death among patients with pre- Conclusions

vious CHD298. Generally, on the basis of the cumula-
tive evidence from controlled studies on risk factors,
prospective observational studies and clinical trials, in
combination with the low risk profile of n-3 PUFAs, n-3
PUFA supplements are safe and a reasonable option to
lower the risk of CVD in individuals who do not fre-
quently consume fish or are at high risk of CVD298,299.
The VITAL and REDUCE-​IT trials, described above,
together provide further general support for this
conclusion.
Future directions
Uncertainties related to the types and doses of seafood-​
derived n-3 PUFA intake or supplementation that will
reduce the risk of CVD need to be resolved. Future
research should focus on whether these benefits might
be more relevant for populations with low background
seafood consumption and on whether the effects
are more specific to CHD-​related death at low doses
and more broadly applicable to composite CVD events at
higher doses292. Some prospective cohort studies sug-
gest that fish and long-​chain n-3 PUFA might also be
associated with lower risk of stroke, atrial fibrillation
and heart failure, although the evidence remains lim-
ited and mixed286,300–304. Additional longitudinal cohort
studies and clinical trials to assess fish and n-3 PUFA
intake with these outcomes are warranted. Given that
recent data suggest varying cardiometabolic effects
of different n-3 PUFAs 305, the use of circulating or
tissue biomarkers might be particularly informative
to improve the assessment of specific n-3 PUFAs.
Finally, compared with seafood sources of n-3 PUFA,
α-​linolenic acid is relatively inexpensive and widely
available. Additional RCTs should investigate the cardio­
metabolic effects of α-​linolenic acid-​rich foods, such as
walnuts and flaxseed oil.
Advances in nutrition science have rapidly expanded our
understanding of the cardiometabolic effects of dietary
fats. In addition to their role as metabolic fuel and energy
stores, fatty acids modulate diverse molecu­lar pathways
including genetic regulation, cellular and organelle
membrane structure and function, ion channel activity
and electrophysiology and further influence these and
other pathways via their downstream bioactive metabo-
lites. Dietary fats are also heterogeneous, representing a
wide range of different fatty acids with distinct structures
and functions, with heterogeneity in their health effects
depending on the specific fatty acid as well as their food
sources. Further research into the mechanistic and
health effects of individual fatty acids and their differ-
ent food sources will be important. In addition, because
people consume foods, not individual fatty acids, guid-
ance and policies to improve general population diets
should place greater emphasis on specific food sources
of dietary fats. As a useful analogy, public health and
scientific communities do not make recommendations
for levels of total carbohydrate in the diet for the general
population, recognizing that different food sources —
for example, fruits, beans, starchy vegetables, nonstarchy
vegetables, whole grains, refined flours, added sugars
and sugary beverages — have very different effects on
health. Similarly, current recommendations for dietary
total fat, SFAs and MUFAs, which have highly diverse
dietary sources, and possibly even PUFAs, which have
fewer major dietary sources, should be replaced with
food-​specific guidance and targets. Future research must
also address major areas of uncertainty and controver-
sies related to dietary fats, which will be critical given
the evidence for important effects of fatty acids and their
food sources on cardiometabolic health.
Published online xx xx xxxx

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Acknowledgements
J.H.Y.W. received support from a Scientia Fellowship from the
University of New South Wales, Australia. R.M. and D.M.
received funding from the US National Institutes of Health
Reviews
(NIH) and the US National Heart, Lung and Blood Institute
(NHLBI) (R01HL130735 and R01HL115189).
Author contributions
J.H.Y.W. and D.M. researched data for the article, and J.H.Y.W.
wrote the manuscript. All authors provided substantial contri-
bution to the discussion of content and reviewed and/or edited
the manuscript before submission.
Competing interests
J.H.Y.W. and R.M. received research support from Unilever
for projects on fatty acid biomarkers not related to the pres-
ent article. D.M. received research funding from the US
National Institutes of Health (NIH) and the Gates Foundation;
received personal fees from Acasti Pharma, Amarin,
America’s Test Kitchen, Bunge, DSM, GOED, Indigo
Agriculture, Nutrition Impact and Pollock Communications; is
on the scientific advisory board of DayTwo, Elysium Health
and Omada Health; and received chapter royalties from
UpToDate; none of these is related to the present article.
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Reviewer information
Nature Reviews Cardiology thanks G. Riccardi and the other
anonymous reviewer(s) for their contribution to the peer
review of this work.