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Low-carbohydrate diets impair flow-mediated dilatation: Evidence from a systematic review and meta-analysis

Authors:
Letter to the Editor
Low-carbohydrate diets impair flow-mediated dilatation: evidence
from a systematic review and meta-analysis
With great interest, we read the meta-analysis of Bueno
et al.
(1)
‘Very-low-carbohydrate ketogenic diet v. low-fat diet
for long-term weight loss: a meta-analysis of randomised con-
trolled trials’, published ahead of print in the British Journal
of Nutrition
(1)
. In their article, the authors compared the
effects of very-low-carbohydrate (VLC) diets v. low-fat (LF)
diets on the biomarkers of obesity and their associated dis-
orders. With respect to different outcomes between both
the regimens, VLC diets turned out to be more effective in
lowering body weight, TAG levels and diastolic blood press-
ure and in increasing HDL-cholesterol levels. However, one
established risk factor of CVD, i.e. LDL-cholesterol, still
turned out to be harmfully affected by the VLC regimen,
most probably attributable to the larger amounts of saturated
fat in the diet
(1)
. In their discussion, the authors stated that
future meta-analyses should investigate the impact of low
carbohydrates (LC) v. LF on other important pathological
markers, e.g. endothelial function, in order to further assess
the safety of LC dietary therapies. This is reasonable, since
evidence from prospective cohort studies has shown that
endothelial dysfunction represents an independent risk
factor for the development of many CVD including athero-
sclerosis
(2)
. We, therefore, carried out a meta-analysis to com-
pare the effects of LC and LF regimens on flow-mediated
dilatation (FMD). FMD of the brachial artery is a non-invasive
measure of endothelial function, furthermore reflecting the
local bioavailability of endothelium-derived vasodilators,
especially NO. Inflammation of the endothelium is regarded
to play a major role in the destabilisation of atherosclerotic
lesions, therefore paving the way for future CVD events
(2)
.
A literature search was performed using the electronic data-
bases MEDLINE (until April 2013), EMBASE (until April
2013) and the Cochrane Trial Register (until April 2013),
with restrictions to randomised controlled trials, but no
restriction to language using the following search terms:
low fat diet AND endothelial function and low carbohydrate
diet AND endothelial function (Supplementary material, avail-
able online). Studies were included in the meta-analysis if they
met all of the following criteria: (1) randomised controlled
design with a minimum intervention period of 3 weeks;
(2) comparing a LC diet (# 45 % carbohydrates of total
energy content, TEC) with a LF diet (# 30 % fat of TEC)
(3)
;
(3) report of post-intervention values with standard devi-
ations; when the results of a study were published more
than once, only the most recent or most complete article
was included in the analysis; (4) participants age . 18 years;
(5) exclusion of subjects with CHD.
A meta-analysis was carried out in order to determine
the pooled effect of the intervention in terms of weighted
mean differences (WMD) between the post-intervention
values of the LC group and those of the LF group. All data
were analysed using the Review Manager 5.1 software, pro-
vided by the Cochrane Collaboration (http://ims.cochrane.
org/revman). Overall, six trials with a sample size of 210
subjects were included
(4 9)
. Study duration ranged between
3·5 weeks and 12 months. Decreases in FMD (WMD: 2 1·01
(95 % CI 2 1·83, 2 0·19) %, P¼ 0·02) were significantly more
pronounced following consumption of LC diets than following
that of LF diets (Fig. 1). The I
2
test showed very low hetero-
geneity (I
2
¼ 10 %).
Study or subgroup
Mean
SD Total Mean SD Total
Weight
(%)
Mean difference
(95 % CI)
Mean difference
IV, random, 95 % CI
Buscemi et al.
(4)
de Roos et al.
(5)
Phillips et al.
(6)
Varady et al.
(7)
Volek et al.
(8)
Wycherley et al.
(9)
Total (95 % CI)
Heterogeneity: t
2
= 0·11; c
2
= 5·56, df = 5 (P = 0·35); I
2
= 10 %
Test for overall effect: Z = 2·41 (P = 0·02)
LC LF
3·79
2·72
1·89
2·1
2·5
3·63
0·40 (–4·00, 4·80)
–0·67 (–2·06, 0·72)
–1·90 (–4·01, 0·21)
–2·90 (–4·98, –0·82)
–0·60 (–2·31, 1·11)
–0·20 (–1·90, 1·50)
3·4
28·6
13·7
14·1
20·0
20·2
10
32
10
8
20
23
6
2·94
2·84
2·26
3
2·39
10·6
4·8
8·7
9·8
6·1
5·9
10
32
10
9
20
26
107 103 100·0 –1·01 (–1·83, –0·19)
11
4·13
6·8
6·9
5·5
5·7
–4 –2 0
LC LF
24
Fig. 1. Forest plot showing pooled weighted mean differences (WMD) with 95 % CI for flow-mediated dilatation (%) of six randomised controlled low-carbohydrate
diet studies. For each low-carbohydrate trial,
represents the point estimate of the intervention effects. The horizontal line joins the lower and upper limits of the
95 % CI of these effects. The area of
reflects the relative weight of the study in the respective meta-analysis. At the bottom of the graph, represents the
pooled WMD with 95 % CI.
British Journal of Nutrition, page 1 of 2
q The Authors 2013
British Journal of Nutrition
In our meta-analysis, LC dietary protocols were associated
with a significant decrease in FMD when compared with
their LF counterparts. A recent meta-analysis of observational
studies including a sample size of 5·547 subjects has observed
that a 1 % decrease in FMD is associated with a 13 % increase
in the risk of future cardiovascular events
(2)
. In another recent
meta-analysis of cohort studies carried out by Noto et al.
(10)
,
an association between LC diets and increased risk of all-cause
mortality could be observed, although not for cardiovascular
(CVD) mortality as well as CVD incidence
(10)
. It should be
noted that in direct comparison with the meta-analysis carried
out by Bueno et al.
(1)
, we had to modify the inclusion criteria,
since only a few dietary intervention trials had reported FMD
as an outcome parameter. However, in consideration of the
fact that LC was associated with a higher all-cause mortality
risk, further trials are required to confirm the mechanisms of
FMD impairment following LC regimens.
Supplementary material
To view the supplementary material for this article, please visit
http://dx.doi.org/10.1017/S000711451300216X
Lukas Schwingshackl
Georg Hoffmann
Department of Nutritional Sciences,
Faculty of Life Sciences, University of Vienna,
Althanstreet 14 UZA II, A-1090 Vienna,
Austria
email lukas.schwingshackl@univie.ac.at
10.1017/S000711451300216X
References
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L. Schwingshackl and G. Hoffmann2
British Journal of Nutrition
... Endothelial dysfunction and reduced vasodilatation have been identified as an early feature of atherosclerosis. Both are linked to high levels of LDL (Schwingshackl and Hoffmann, 2013) and hyperglycemia (Kawano et al., 1999). Low-carbohydrate diets have been associated with a significant decrease in FMD when compared to a low-fat diet (Varady et al., 2011). ...
... No changes in FMD were seen after the intervention in our young healthy participants. Previous studies among dyslipidemic, overweight and obese individuals have shown a decrease in FMD after a LCHF diet (Schwingshackl and Hoffmann, 2013). Overweight and obese participants often have underlying conditions that have taken years to develop. ...
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... Previous studies demonstrated an amelioration of glucose metabolism and endothelial function, measured as flow-mediated dilation (FMD), in obese patients after VLCKD; however, the results are still conflicting about the effects on FMD [4][5][6][7][8][9][10]. ...
... We did not observe a significant variation in FMD mean values. Although most previous studies in obese subjects reported a significant improvement in FMD after VLCKD [8,9], a meta-analysis conducted by Schwingshackl et al. [10] reported a significant impairment. The lack of statistical significance in our results prevents us from supporting one of these two hypotheses; this might be attributable to the short duration of the observation (four to five weeks). ...
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Low-fat diets, in which carbohydrates replace some of the fat, decrease serum cholesterol. This decrease is due to decreases in LDL-cholesterol but in part to possibly harmful decreases in HDL-cholesterol. High-oil diets, in which oils rich in monounsaturated fat replace some of the saturated fat, decrease serum cholesterol mainly through LDL-cholesterol. We used these two diets to investigate whether a change in HDL-cholesterol would change flow-mediated vasodilation, a marker of endothelial function. We fed thirty-two healthy volunteers two controlled diets in a weeks' randomised cross-over design to eliminate variation in changes due to differences between subjects. The low-fat diet contained 59.7 % energy (en%) as carbohydrates and 25.7 en% as fat (7.8 en% as monounsaturates); the oil-rich diet contained 37.8 en% as carbohydrates and 44.4 en% as fat (19.3 en% as monounsaturates). Average (sd) serum HDL-cholesterol after the low-fat diet was 0.21 (sd 0.12) mmol/l (8.1 mg/dl) lower than after the oil-rich diet. Serum triacylglycerols were 0.22 (sd 0.28) mmol/l (19.5 mg/dl) higher after the low-fat diet than after the oil-rich diet. Serum LDL and homocysteine concentrations remained stable. Flow-mediated vasodilation was 4.8 (SD 2.9) after the low-fat diet and 4.1 (SD 2.7) after the oil-rich diet (difference 0.7 %; 95 % CI -0.6, 1.9). Thus, although the low-fat diet produced a lower HDL-cholesterol than the high-oil diet, flow-mediated vasodilation, an early marker of cardiovascular disease, was not impaired.
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To compare the effects of an energy reduced very low carbohydrate, high saturated fat diet (LC) and an isocaloric high carbohydrate, low fat diet (LF) on endothelial function after 12 months. Forty-nine overweight or obese patients (age 50.0 +/- 1.1 years, BMI 33.7 +/- 0.6 kg m(-2)) were randomized to either an energy restricted ( approximately 6-7 MJ), planned isocaloric LC or LF for 52 weeks. Body weight, endothelium-derived factors, flow-mediated dilatation (FMD), adiponectin, augmentation index (AIx) and pulse wave velocity (PWV) were assessed. All data are mean +/- SEM. Weight loss was similar in both groups (LC -14.9 +/- 2.1 kg, LF -11.5 +/- 1.5 kg; P = 0.20). There was a significant time x diet effect for FMD (P = 0.045); FMD decreased in LC (5.7 +/- 0.7% to 3.7 +/- 0.5%) but remained unchanged in LF (5.9 +/- 0.5% to 5.5 +/- 0.7%). PWV improved in both groups (LC -1.4 +/- 0.6 m s(-1), LF -1.5 +/- 0.6 m s(-1); P = 0.001 for time) with no diet effect (P = 0.80). AIx and VCAM-1 did not change in either group. Adiponectin, eSelectin, tPA and PAI-1 improved similarly in both groups (P < 0.01 for time). Both LC and LF hypoenergetic diets achieved similar reductions in body weight and were associated with improvements in PWV and a number of endothelium-derived factors. However, the LC diet impaired FMD suggesting chronic consumption of a LC diet may have detrimental effects on endothelial function.
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We previously reported that a carbohydrate-restricted diet (CRD) ameliorated many of the traditional markers associated with metabolic syndrome and cardiovascular risk compared with a low-fat diet (LFD). There remains concern how CRD affects vascular function because acute meals high in fat have been shown to impair endothelial function. Here, we extend our work and address these concerns by measuring fasting and postprandial vascular function in 40 overweight men and women with moderate hypertriacylglycerolemia who were randomly assigned to consume hypocaloric diets (approximately 1500 kcal) restricted in carbohydrate (percentage of carbohydrate-fat-protein = 12:59:28) or LFD (56:24:20). Flow-mediated dilation of the brachial artery was assessed before and after ingestion of a high-fat meal (908 kcal, 84% fat) at baseline and after 12 weeks. Compared with the LFD, the CRD resulted in a greater decrease in postprandial triacylglycerol (-47% vs -15%, P = .007), insulin (-51% vs -6%, P = .009), and lymphocyte (-12% vs -1%, P = .050) responses. Postprandial fatty acids were significantly increased by the CRD compared with the LFD (P = .033). Serum interleukin-6 increased significantly over the postprandial period; and the response was augmented in the CRD (46%) compared with the LFD (-13%) group (P = .038). After 12 weeks, peak flow-mediated dilation at 3 hours increased from 5.1% to 6.5% in the CRD group and decreased from 7.9% to 5.2% in the LFD group (P = .004). These findings show that a 12-week low-carbohydrate diet improves postprandial vascular function more than a LFD in individuals with atherogenic dyslipidemia.
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Background Obesity is a cardiovascular risk factor associated with endothelial dysfunction, but the effect of different weight loss strategies on endothelial function is not known. The effect of diet on endothelial function in two hypocaloric diets, a very-low-carbohydrate diet (A) and a Mediterranean diet (M), was measured by brachial artery flow-mediated dilation (FMD). Design Using a longitudinal, randomized, open study design, subjects were engaged in a 2-month weight loss diet. FMD, inflammatory cytokines [interleukin-6 (IL-6) and tumour necrosis factor-α] and a marker of oxidative stress [8-iso-prostaglandin F2α (8-iso-PGF2α)] were measured in subjects on three occasions: before initiating the diet (T0), after 5–7 days of dieting (T5) and after 2 months of dieting (T60). The very short- and medium-term time points were established to discriminate respectively the effect of the diet itself (T5) from that of weight loss (T60). Twenty overweight/obese but otherwise healthy women (BMI: 27–34·9 kg m−2; age 30–50 years) completed the study. Results Group A lost more weight (mean ± SEM; −7·6 ± 0·8 kg) than group M (−4·9 ± 0·6 kg, P = 0·014) at T60. The FMD was not significantly different between the two groups at T0 (group A: 12·2 ± 2·9% vs. group B: 10·3 ± 2·3%, P = ns). In group A, FMD was significantly reduced at T5 and returned to baseline at T60; in group M, FMD increased at T5 and returned to baseline at T60 (P = 0·007 for diet × time interaction). Serum concentrations of IL-6 and 8-iso-PGF2α were not significantly different between the two groups at T0 and increased significantly at T5 only in group A (P < 0·001 and P < 0·005 respectively). Conclusion As endothelial dysfunction is known to be associated with acute cardiovascular events, this study suggests that the cardiovascular risk might be increased in the first days of a very-low-carbohydrate diet.
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Obesity is associated with impaired endothelial-dependent flow-mediated dilation, a precursor to hypertension and atherosclerosis. Although dieting generally improves cardiovascular risk factors, the direct effect of different dietary strategies on vascular endothelial function is not known. The purpose of this study was to test the hypothesis that a low-fat (LF) diet improves endothelial function compared with an isocaloric low-carbohydrate (LC) diet. Obese (n=20; body mass index: 29 to 39; mean systolic blood pressure: 107 to 125 mm Hg) and otherwise healthy volunteers were randomly assigned to either the American Heart Association modeled LF (30% fat calories) diet or an isocaloric LC Atkins' style diet (20 g of carbohydrates) for 6 weeks (4-week weight loss and 2-week maintenance phase). Brachial flow-mediated dilation and dilation to nitroglycerin were measured with ultrasound using automated edge detection technology (baseline, week 2, and week 6). Blood pressure, weight loss, and cholesterol profiles were measured throughout the study. Weight loss was similar in LF (100+/-4 to 96.1+/-4 kg; P<0.001) and LC (95.4+/-4 to 89.7+/-4 kg; P<0.001) diets. Blood pressure decreased similarly in both groups (LF: 8/5 mm Hg; LC: 12/6 mm Hg) at 6 weeks. After 6 weeks, the percentage of flow-mediated dilation improved (1.9+/-0.8; P<0.05) in the LF diet but was reduced in the LC diet (-1.4+/-0.6; P<0.05) versus baseline. Dilation to nitroglycerin and lipid panels was similar at 0, 2, and 6 weeks. Despite similar degrees of weight loss and changes blood pressure, LF diets improved brachial artery flow-mediated dilation over LC diets. LF diets may confer greater cardiovascular protection than LC diets.