The n e w e ng l a n d j o u r na l of m e dic i n e
clinical implications of basic research
A Look at the Low-Carbohydrate Diet
Steven R. Smith, M.D.
Most fad diets are just that — a bright flash that
quickly fades, only to be followed by another best-
seller and a new face on the talk-show circuit.
The high-fat, high-protein, low-carbohydrate
(HPLC) diet has outlived the rest of the pack.
This diet clearly has its supporters. In many
ways, it is attractive to believe that manipulation
of macronutrient composition might control body
weight and improve health. However, a recent
study by Foo and colleagues1 shows that HPLC
diets may accelerate atherosclerosis through
mechanisms that are unrelated to the classic
cardiovascular risk factors.
Given the associations between a high intake
of saturated fat and cardiovascular diseases,
many scientists have sounded the alarm that
HPLC diets might increase the risk of heart-­
related disorders. However, the HPLC diet has
been associated with short-term improvement in
many of the classic intermediate cardiovascular
risk factors, such as levels of low-density lipo-
protein and high-density lipoprotein cholesterol
and blood pressure.2,3
Foo et al. tested the effect of different diets
on mice that were deficient in apolipoprotein E.
These mice are especially susceptible to athero-
sclerosis when fed a so-called Western high-fat,
moderate-protein, and moderate-carbohydrate
diet. They put one group of mice on a diet of
standard laboratory chow, another group on a
Western diet, and a third group on an HPLC
diet. Instead of measuring plasma risk factors,
the investigators directly measured the formation
of arterial plaque — and found two times more
plaque in the arteries of animals that were fed
the HPLC diet than in those that were fed the
“atherosclerotic” Western diet (Fig. 1).
A common misconception is that HPLC diets
lead to greater weight loss than traditional diets.
In general, they do not,3 but nonetheless, mice
that were fed the HPLC diet gained less weight
than the mice on a Western diet. Cholesterol
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levels were elevated in the mice that were fed
the HPLC diet and those fed the Western diet,
as compared with mice that were fed standard
chow, but there was no significant difference in
the cholesterol levels of mice on the Western diet
and those on the HPLC diet.
So why did the mice on the HPLC diet have
more atherosclerosis? Here is where it gets really
interesting. Experiments that were subsequently
carried out by Foo et al. suggest a couple of
reasons.
First, levels of nonesterified fatty acids (NEFAs)
in the mice on the HPLC diet were nearly twice
those in mice that were fed the other two diets.
There is strong epidemiologic evidence showing
an association between NEFAs and atheroscle-
rotic events and a growing consensus that a high
level of NEFAs is a risk factor for cardiovascular
disease.4 Free fatty acids (including NEFAs) are
released from insulin-resistant adipocytes in obe-
sity, and several studies have shown that NEFAs
cause activation of inflammatory pathways in
multiple tissues.
Second, mice on the HPLC diet, but not the
Western diet, showed markedly low numbers of
circulating endothelial progenitor cells (EPCs).
These cells, which were first identified almost a
decade ago, are formed in the bone marrow and
released into the bloodstream. As circulating
mononuclear cells, they participate in the repair
of damaged vessel walls and improve endothe-
lial function through undefined mechanisms.
Several investigators have observed a reduction
in the number of EPCs in patients with athero­
sclerosis,5 a finding that was strikingly similar
to that of Foo et al. The number of EPCs is also
decreased in patients with type 2 diabetes, a dis-
ease that is associated with an increased risk of
atherosclerosis. Since the publication of these early
clinical reports, the link between a reduced num-
ber of circulating marrow-derived EPCs, vascular
dysfunction, and atherosclerosis has been well
 clinical implications of basic research

A
Low-fat, moderate-protein,
high-carbohydrate diet

Endothelial
progenitor cells

B
Western high-fat,
moderate-protein,
moderate-carbohydrate diet
Arterial plaque
Increased insulin
Increased total cholesterol
Increased triglycerides
Increased oxidized LDL

Endothelial
progenitor cells Arterial plaque

C
High-fat, high-protein,
Arterial plaque
low-carbohydrate diet No change in insulin
Increased total cholesterol
Increased triglycerides
Increased oxidized LDL
Increased free fatty acids
Decreased endothelial
progenitor cells

Comparatively
few endothelial
progenitor cells Arterial plaque

Figure 1. High-Protein, Low-Carbohydrate (HPLC) Diet and Atherosclerosis.

A recent study by Foo et al.1 suggests that an HPLC diet promotes atherosclerosis through mechanisms that do not
COLOR FIGURE
modify the classic cardiovascular risk factors. They studied mice that were fed standard laboratory chow (Panel A),
a so-called Western diet (Panel B), or an HPLC diet (Panel C). They found that mice that were fed the HPLC11/18/09
Rev5 diet had
almost twice the level of arterial plaque as mice that were fed a Western diet. The classic
Author risk factors did not differ-
Dr. Smith
entiate these two groups of mice, even though both were fed atherogenic diets. Normally,
Fig # endothelial
1 progenitor
cells are released from the bone marrow and home in on damaged endothelium toTitle promote repair and maintain
normal vascular reactivity. The mice that were fed the HPLC diet had markedly fewer circulating endothelial progenitor
ME
cells and higher levels of nonesterified fatty acids than mice that were fed the Western diet. LDL denotes low-density
lipoprotein. DE Phimister
Artist Muller
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
supported through additional research, although Traditionally, the atherosclerotic risk profile Please check carefully

the mechanisms that link EPCs to a healthy vas- that is associated Issue
withdatespecific diets is deter-
12-03-2009
culature and a blunting of the atherosclerotic mined by measuring intermediate risk factors,
process are not yet understood. such as levels of low-density lipoprotein choles-

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 clinical implications of basic research

terol, blood pressure, and C-reactive protein. The
work of Foo et al.1 suggests that the HPLC diet
might increase the risk of cardiovascular disease
through mechanisms that have nothing to do
with these “usual suspects” and so provides a
note of caution against reliance on the traditional
cardiovascular risk factors as a gauge of safety.
Fortunately, both EPCs and NEFAs are easily
measured in the research clinic. A focused study
should be conducted to examine whether the
HPLC diet produces the same effects on EPCs
and NEFAs in humans as it does in mice. In the
meantime, the ageless advice applies to the con-
sumer of the HPLC diet and other fad diets:
caveat emptor.
Dr. Smith reports receiving consulting fees from Unilever. No
other potential conflict of interest relevant to this article was re-
ported.
From the Translational Research Institute, Florida Hospital–
Burnham Institute, Orlando, FL.
1. Foo SY, Heller ER, Wykrzykowska J, et al. Vascular effects of
a low-carbohydrate high-protein diet. Proc Natl Acad Sci U S A
2009 August 24 (Epub ahead of print).
2. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a
low-carbohydrate diet for obesity. N Engl J Med 2003;348:2082-
90.
3. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-
loss diets with different compositions of fat, protein, and carbo-
hydrates. N Engl J Med 2009;360:859-73.
4. Smith SR, Wilson PW. Free fatty acids and atherosclerosis
— guilty or innocent? J Clin Endocrinol Metab 2006;91:2506-8.
5. Vasa M, Fichtlscherer S, Aicher A, et al. Number and migra-
tory activity of circulating endothelial progenitor cells inversely
correlate with risk factors for coronary artery disease. Circ Res
2001;89(1):E1-E7.
Copyright © 2009 Massachusetts Medical Society.

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The New England Journal of Medicine

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