A network meta-analysis on the comparative efficacy of different dietary approaches on glycaemic control in patients with type 2 diabetes mellitus
European Journal of Epidemiology
A network meta-analysis on the comparative efficacy of different dietary approaches on glycaemic control in patients with type 2 diabetes mellitus
Lukas Schwingshackl 0 1 2 3 4 5 6 7
Anna Chaimani 0 1 2 3 4 5 6 7
Georg Hoffmann 0 1 2 3 4 5 6 7
Carolina Schwedhelm 0 1 2 3 4 5 6 7
Heiner Boeing 0 1 2 3 4 5 6 7
0 Georg Hoffmann
1 Anna Chaimani
2 & Lukas Schwingshackl
3 Department of Nutritional Sciences, University of Vienna , Althanstraße 14, 1090 Vienna , Austria
4 Cochrane France , Paris , France
5 INSERM, UMR1153 Epidemiology and Statistics, Sorbonne Paris Cite ́ Research Center (CRESS), METHODS Team , Paris , France
6 Paris Descartes University , Paris , France
7 Carolina Schwedhelm
The aim of the present study is to assess the comparative efficacy of different dietary approaches on glycaemic control in patients with type 2 diabetes mellitus using a systematic review of the literature. Electronic and hand searches were performed until July 2017. The inclusion criteria were defined as follows: (1) randomized trial with a dietary approach; (2) adults with type 2 diabetes mellitus; (3) outcome either HbA1c (%) and/or fasting glucose (mmol/l); (4) minimum intervention period of 12 weeks. For each outcome measure, random effects network meta-analysis was performed in order to determine the pooled effect of each intervention relative to each of the other interventions. A total of 56 trials comparing nine dietary approaches (low-fat, Vegetarian, Mediterranean, high-protein, moderatecarbohydrate, low-carbohydrate, control, low GI/GL, Palaeolithic) enrolling 4937 participants were included. For reducing HbA1c, the low-carbohydrate diet was ranked as the best dietary approach (SUCRA: 84%), followed by the Mediterranean diet (80%) and Palaeolithic diet (76%) compared to a control diet. For reducing fasting glucose, the Mediterranean diet (88%) was ranked as the best approach, followed by Palaeolithic diet (71%) and Vegetarian diet (63%). The network analysis also revealed that all dietary approaches significantly reduce HbA1c (- 0.82 to - 0.47% reduction) and fasting glucose (- 1.61 to - 1.00 mmol/l reduction) compared to a control diet. According to the network meta-analysis the Mediterranean diet is the most effective and efficacious dietary approach to improve glycaemic control in type 2 diabetes patients.
Systematic review; Evidence synthesis
Department of Epidemiology, German Institute of Human
Nutrition Potsdam-Rehbruecke (DIfE),
Arthur-ScheunertAllee 114-116, 14558 Nuthetal, Germany
According to the most recent data by the International
Diabetes Federation and the World Health Organization,
type 2 diabetes (T2D) represents one of the most important
health problems, causing enormous costs, with an
estimated prevalence of 350–400 million cases worldwide
To prevent onset of T2D, high-quality diets have been
recognized to play a critical role [
]. Nutrition therapy
plays an integral role in the management of T2D,
particularly after initial clinical diagnosis, in order to reduce or
delay diabetes associated complications. One major
approach is the loss of weight by a hypocaloric diet [
However, there is limited evidence on the optimal dietary
approaches to control hyperglycaemia in T2D patients [
and uncertainty regarding the optimal proportion of energy
coming from carbohydrates, protein, and fat for patients
with T2D [
Meta-analyses showed that some dietary approaches
such as a low-carbohydrate, low-glycaemic index/load,
high protein-, Vegetarian-, and Mediterranean dietary
approaches were effective in reducing HbA1c [
Nevertheless, other meta-analyses reported conflicting
7, 11, 12
One of the most important questions that remain to be
answered is which dietary approach offers the greatest
benefits. For answering this question, a promising method
is network meta-analysis (NMA), which is an extension of
pairwise meta-analysis that enables a simultaneous
comparison of multiple interventions. NMA combines direct
(i.e., from trials comparing directly two interventions) and
indirect (i.e., from a connected root via one more
intermediate comparators) evidence in a network of trials
(Fig. 1). In this way, it enables inference about every
possible comparison between a pair of intervention in the
network even when some comparisons have never been
evaluated in a trial. A fundamental assumption of NMA,
often called the transitivity assumption, is that trials
comparing different sets of interventions (e.g., AB and AC
Fig. 1 Example of direct,
indirect and mixed relative
effects in a hypothetical triangle
comparing three interventions
trials) should be similar enough in all characteristics that
may affect the outcome. For more details on the
methodology of NMA we directed the readers to relevant tutorials
To our knowledge, no study has been conducted that
compared simultaneously different dietary approaches in
the management of T2D. Therefore, our aim is to compare
the efficacy of different dietary approaches in clinical trials
on glycaemic control in patients with T2D using the novel
method of NMA.
The review was registered in PROSPERO International
Prospective Register of Systematic Reviews https://www.
464 and our strategy for the systematic review and NMA
was pre-defined in a published protocol [
]. The present
systematic review was planned, conducted, and reported in
adherence to standards of quality for reporting systematic
reviews and NMA [
The literature search was performed using the electronic
databases PubMed, Cochrane Central Register of
Controlled Trials (CENTRAL), and Google Scholar until July
2017 with no restriction to language and calendar date
using a pre-defined search strategy (Supplementary
Furthermore, systematic reviews, and the reference lists
from the retrieved articles were screened to search for
additional relevant studies. Searches were conducted by
two authors with disagreements being resolved by
involvement of another reviewer.
of direct AB
and direct AC
> indirect BC
B and C -> direct BC
Combina on of
direct BC and
indirect BC ->
Studies were included in the review if they met all of the
Randomized comparison study design (parallel or
cross-over) between different dietary approaches
(energy restricted diets, iso-caloric, or ad libitum
Low carbohydrate (LC) diet (\ 25%
carbohydrates of total energy intake; high intake
of animal and/or plant protein; often high
intake of fat) [
Moderate-carbohydrate diet (25–45%
carbohydrates of total energy intake; 10–20%
protein intake) [
High protein (HP) diet ([ 20% protein
intake of total energy intake; high intake
of animal and/or plant protein; \ 35% fat)
Low fat (LF) diet (\ 30% fat of total energy
intake; high intake of cereals & grains;
10–15% protein intake) [
Low glycaemic index/load (LGI/GL) diet
Vegetarian/Vegan diet (no meat and fish/no
animal products) [
Mediterranean dietary pattern: fruit,
vegetables, olive oil, legumes, cereals, fish, and
moderate intake of red wine during meals
Palaeolithic diet ;
Control diet: no intervention or minimal
The following studies were excluded:
Minimum intervention period of 12 weeks;
Patients with a mean age C 18 years, following
the diagnosis criteria of the American Diabetes
Association or according to the internationally
recognized standards for patients with T2D [
The primary outcome is glycosylated
haemoglobin HbA1c (%) and the secondary outcome was
defined fasting glucose (mmol/l).
Randomized trials including pregnant women,
children, and adolescents, patients with abnormal
Intervention studies solely based on dietary
supplements or single foods;
Intervention studies using dietary supplements as
Studies with an exercise/medication [
cointervention that was not applied in all the
Interventions based on very low energy diets (i.e.,
\ 600 kcal/day).
After determination of the study selection, two reviewers
extracted the following characteristics: name of first author,
year of publication, study origin (country), study design
(RCT: parallel or cross-over), sample size, mean baseline
age, mean baseline BMI, mean baseline HbA1c, study
duration, sex, description of the different dietary
intervention arms, specification of the control group, type of
diet (energy restricted, ad libitum, iso-caloric), drop outs,
presence of comorbidities, hypoglycaemic drugs,
antihypertensive medication, lipid lowering medication. Outcome
data include: post-intervention values with corresponding
standard deviations for glycosylated haemoglobin and
fasting plasma glucose.
Risk of bias assessment
Full copies of the studies were assessed by two authors for
methodological quality using the risk of bias assessment
tool from the Cochrane Collaboration [
]. The following
sources of bias were assessed: selection bias (random
sequence generation and allocation concealment),
performance bias (blinding of participants and personnel),
attrition bias (incomplete outcome data), and reporting bias
Studies were classified as being at low risk of bias (if at
least three out of a maximum of five items were rated as
low risk; and maximum one item rated with a high risk of
bias), high risk of bias (if at least two out of a maximum of
five items were rated as high risk), and moderate/unclear
risk (all other studies) using the risk of bias assessment tool
from the Cochrane Collaboration.
Dealing with missing data
We contacted authors to receive missing outcome data (3
authors sent additional data, see acknowledgements). If the
post-intervention values with the corresponding standard
deviations were not available, the change scores with the
corresponding standard deviations were used, according to
the guidelines of the Cochrane Handbook [
Evaluation of synthesis assumptions
Description of the available data
We present for all included trials study and population
characteristics describing the available data and important
variables (e.g., age, length of follow-up, outcome relevant
baseline risk factors, etc.). We illustrate the available direct
comparisons between different dietary interventions and
control group using a network diagram for each outcome
]. The size of the nodes is proportional to the sample
size of each dietary intervention and the thickness of the
lines proportional to the number of studies available.
Assessment of transitivity
Transitivity is the fundamental assumption of indirect
comparisons and NMA, and its violation threatens the
validity of the findings obtained from a network of studies.
To evaluate the assumption of transitivity we compared the
distribution of the potential effect modifiers across the
available direct comparisons. We considered the following
effect modifiers: body weight, duration of diabetes, mean
baseline age, and study duration.
For each outcome measure of interest, we performed
random effects NMA in order to determine the pooled relative
effect of each dietary intervention against every other
intervention in terms of the post-intervention values. NMA
was used to synthesize the direct and indirect effects. The
method of NMA is an extension of the standard pairwise
meta-analysis that enables a simultaneous comparison of
multiple interventions, forming a connected network while
preserving the internal randomization of individual trials.
We ran random effects NMA for each outcome to estimate
all possible pairwise relative effects and to obtain a
clinically meaningful relative ranking of the different dietary
interventions. We present the summary mean differences
with their 95% CI in a league table. We estimated the
relative ranking of the different diets for each outcome
using the distribution of the ranking probabilities and the
surface under the cumulative ranking curves (SUCRA)
]. For each outcome we assumed a common
networkspecific heterogeneity parameter and estimated the
predictive intervals to assess how much this heterogeneity
affects the relative effects with respect to the additional
uncertainty anticipated in future studies [
]. We fitted all
analyses described in a frequentist framework using Stata
] (network package [
]) and produced presentation
tools with the network graphs package [
Assessment of inconsistency
To evaluate the presence of statistical inconsistency (i.e.,
disagreement between the different sources of evidence) in
the data, we employed both local and global approaches
]. Specifically, we used the loop-specific approach [
to detect loops of evidence that might present important
inconsistency as well as the side-splitting approach [
detect comparisons for which direct estimates disagree
with indirect evidence from the entire network. Global
methods investigate the presence of inconsistency jointly
from all possible sources in the entire network
simultaneously. For this purpose, we used the design-by-treatment
interaction model [
Subgroup and sensitivity analyses
For comparability reasons, we performed subgroup
analyses in accordance to previous pairwise meta-analyses
investigating the effects of dietary interventions, by taking
into account study duration (C 12 vs. \ 12 months)
], sample size (C 100 vs. \ 100) , and age
(C 60 vs. \ 60 years) [
]. We also conducted sensitivity
analyses by analysing only studies considered being at low
risk of bias, and by excluding risk of bias trials. We ran
also a meta-regression analysis to investigate the
association between the primary outcome (HbA1c) and mean
differences in weight change.
Small study effects and publication bias
We drew inference on the risk for publication bias based
primarily on non-statistical considerations; hence by
considering how likely it is that studies may have been
conducted but not published based on the expertise of the
investigators in the field. We also produced the
comparison-adjusted funnel plot [
] and fit a network
meta-regression model to assess the magnitude of funnel plot
asymmetry for the primary outcome.
Credibility of the evidence
To make inferences about the credibility of evidence from
the NMA we used the GRADE system extended for NMA
following the approach suggested by Salanti et al. (see the
Supplementary Appendix S2 for details) [
Out of 3852 records identified by the literature search, 115
full text articles were assessed in detail as they reported on
one or more of dietary approaches and T2D in the title/
abstract (Supplementary Figure S1). Of these, 59 were
excluded, with the reasons for exclusion summarized in
Supplementary Table S1.
Overall, 56 trials [
] met the eligibility criteria
and provided sufficient data to be included in the
metaanalysis. The included studies were published between
1978 and 2016 and had enrolled a total of 4937 T2D
patients. Eighteen trials were conducted in North America,
14 trials in Europe, 8 trials in Asia, and 16 trials in
Australia and New Zealand. The study duration ranged
between 3 and 48 months; the patients’ mean age was
between 44 and 67 years, and their BMI between 25 (Asian
population) and 43 kg/m2. The general and specific study
characteristics are summarized in Supplementary Table S2
Twenty-one trials were judged to be low risk–, seven
trials to be high risk of bias, and 28 trials were classified as
moderate/unclear risk of bias studies. With regard to the
specific items of the risk of bias assessment tool by the
Cochrane Collaboration, 56% of the included studies
indicate a low risk of bias for random-sequence generation,
23% for allocation concealment, 0% for blinding, 63% for
incomplete data outcome, and 79% for selective reporting
(Supplementary Figure S2).
The studies applied heterogeneous definitions for the
different intervention diets. The fat intake varied across the
different LF trials by * 10–15% of total energy intake,
and also the intervention protocols varied among the trials
(i.e., group meeting, dietary counselling, and intensity).
Moreover, hypocaloric, iso-caloric, and ad libitum diets
were included in the NMA. Moreover the definition of a
control diet showed some difference across the included
trials. Four out of the ten trials were based on ‘‘no
intervention’’, whereas the other six trials were based on
minimal intervention (standard dietary advice). We thus had to
harmonize the single studies and formed classes of dietary
Figure 2 shows the network diagrams of direct
comparison for HbA1c with the number of studies reflected by
the size of the edges, and the number of patients reflected
by the size of the nodes. The highest number of trials
include moderate-carbohydrate diet compared to LF diets
] (n = 13), LF diet compared to control diets
72, 73, 88–95
] (n = 10), HP diet compared to LF diets
] (n = 8), and LC diet compared to LF diets
] (n = 8).
NMA simultaneously analyse both direct comparisons
of interventions within trials and indirect comparisons
across trials based on a common comparator. Since none of
the studies have compared B (Vegetarian) and C
(Mediterranean), but each has been compared with a
common comparator A (LF), then we assume an indirect
comparison of B and C on the direct comparison of B and
A and the direct comparison of C and A [
]. Table 1
shows the percentage of statistical contribution coming
from direct and indirect comparisons for each dietary
approach compared to each other. It was shown that most
of the contribution to the study effects came from indirect
comparisons. Direct comparisons dominated the
Vegetarian/Mediterranean/HP/moderate-carbohydrate/LC/LGI/GL/Palaeolithic/control diet with a LF diet
for both outcomes. In general, there are no important
differences in the examined effect modifiers across
comparisons apart from the duration of diabetes which does not
seem to be distributed similarly across the different
comparisons. For some comparisons such as LC versus LGI/
GL, LC versus moderate carbohydrate, LGI/GL versus
moderate carbohydrate, and Palaeolithic versus LF, we do
not have enough studies and we could not test transitivity
appropriately (Supplementary Figure S3–6).
The effect size estimates for the comparison of every
dietary approach compared with each other dietary
approach on HbA1c and fasting glucose outcomes are
given in Table 2. All dietary approaches were more
effective in reducing HbA1c (- 0.82 to - 0.47%
reduction) and fasting glucose (- 1.61 to - 1.00 mmol/l
reduction) compared to a control diet. The Mediterranean
(MD: - 0.32, 95% - 0.53, - 0.11) and the LC diet (MD:
- 0.35, 95% - 0.56, - 0.14) were more effective in
reducing HbA1c compared to a LF diet. Moreover, the LC
diet was also more effective in HbA1c reduction compared
to a HP diet (MD: - 0.33, 95% - 0.61, - 0.05). The
Mediterranean diet was more effective in reducing fasting
glucose compared to a LF- (MD: - 0.61 mmol/l, 95%
- 1.03, - 0.20) and LGI/GL diet (MD: - 0.59 mmol/l,
95% - 1.13, - 0.04) (Supplementary Figure S7 and S8,
Table 2). In addition, the LGI/GL diet was associated with
a trend for a reduction in HbA1c compared to the LF diet
(MD: - 0.16, 95% - 0.31, - 0.00). The LC diet had the
highest SUCRA value (84%), followed by the
Mediterranean diet (80%), and Palaeolithic diet (76%) for HbA1c,
whereas the Mediterranean diet (88%) had the highest
SUCRA value for fasting glucose, followed by Palaeolithic
diet (71%) and Vegetarian diet (63%) (Table 2). The
rankograms did not imply the presence of important
uncertainty in ranking for HbA1c; more uncertain appeared
to be the relative ranking for fasting glucose though
(Supplementary Figure S9 and S10).
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The side-splitting approach suggested important
inconsistency for HbA1c in the comparisons of LF versus LC,
LF versus control diet, and moderate-carbohydrate versus
LC diet (Supplementary Table S4 and S5). For fasting
glucose, significant inconsistency was observed for LF
versus LC diet and moderate-carbohydrate versus LC diet.
The loop-specific approach showed important
inconsistency in the loop formed by the aforementioned diets for
both outcomes (Supplementary Figure S11 and S12). The
design-by-treatment model showed also significant
inconsistency for HbA1c (p = 0.03), but not for FG (p = 0.32).
This apparent inconsistency might reflect the low
contribution of direct comparisons to the total estimate. The
important inconsistency in the loop for LF versus
moderate-carbohydrate and LC might be explained by several
differences across LF dietary approaches (hypocaloric if
compared to a control diet; often iso-caloric if compared to
other dietary approaches), differences in ratio of fat to
carbohydrate intake, and differences in fatty acid
composition among moderate carbohydrate approaches and LC
dietary approaches (larger weight loss compared to other
In the subgroup analyses for study duration, sample size,
and age we could show that LC diets were more effective
in reducing HbA1c in the shorter-term (\ 12 months), in
smaller size studies, and including patients C 60 years.
Mediterranean, moderate-carbohydrate and LGI/GL, HP,
and LF diets were more effective in reducing HbA1c in the
longer-term, in larger size studies, and in studies including
patients \ 60 years (Supplementary Table S6–11).
Although the power was very small for several
comparisons, these characteristics may partly explain the presence
of inconsistency. Furthermore, in the low-risk of bias
sensitivity analysis the results of the primary analysis were
generally confirmed. Hence, both the Mediterranean diet
and the LC diet were more effective to decrease HbA1c
compared to a LF diet, whereas the results for FG were not
significant (Supplementary Table S12). All the results of
the main analysis were confirmed in the sensitivity analysis
excluding high risk of bias trials (Supplementary
Table S13). In univariate meta-regression analysis we
could show that mean reduction in HbA1c was significantly
(p = 0.04) related to mean difference in weight change
between dietary approaches (Supplementary Figure S11).
The comparison-adjusted funnel plots for both outcomes
appear slightly asymmetric when LF dietary approaches
were compared to all other dietary approaches. However,
the network meta-regression model that accounted for
differences in study variance did not yield a statistically
significant coefficient (Supplementary Figure S14 and
The credibility of evidence was rated very low for the
comparisons Mediterranean versus LF; LC versus LF; LGI
versus LF, moderate-carbohydrate versus LC,
Mediterranean versus HP, and LC versus HP. The very low
credibility was driven by significant inconsistency. For the
other comparisons the credibility of evidence was rated
low, and for three comparisons the quality of evidence was
rated moderate (LF vs. Palaeolithic, Mediterranean vs.
Palaeolithic, LGI/GL vs. Palaeolithic) (Supplementary
Figure S16, Supplementary Appendix S2).
By applying NMA, we ranked 9 different dietary
approaches (Vegetarian, Mediterranean, HP,
moderate-carbohydrate, LC, LGI/GL, Palaeolithic, LF and control diet)
regarding their comparative efficacy for glycaemic control
in patients with T2D. The ranking according to SUCRA
showed the highest value for the LC diet, followed by the
Mediterranean diet, and Palaeolithic diet for HbA1c,
whereas the Mediterranean diet had the highest SUCRA
value for fasting glucose, followed by Palaeolithic diet and
Vegetarian diet. However, the credibility of evidence was
rated very low for the LC, as well as for some comparison
with the Mediterranean diet. The NMA also revealed that
all dietary approaches significantly reduce HbA1c (- 0.47
to - 0.82% reduction) and fasting glucose (- 1.00 to
- 1.61 mmol/l reduction) compared to a control diet.
In line with our observations, pairwise meta-analyses
have shown that LC diets were more effective in HbA1c
and body weight reduction in the short-term compared to
other diets, whereas no superiority was observed in the
]. Weight loss as an important effect
modifier for HbA1c and fasting glucose reduction may
potentially explain the observed inconsistency between LC
and the other dietary approaches. Despite the moderate
quality of evidence grading in the NMA, the findings for
Palaeolithic diet should be interpreted with caution since
only one trial was available. Finally, it is important to note
that LC diets were more effective in reducing HbA1c in
patients C 60 years, whereas the Mediterranean,
moderatecarbohydrate, LGI/GL, HP, and LF diets were more
effective in HbA1c reduction in patients \ 60 years,
compared to patients C 60 years. Irrespective of the age of
the study participants, HbA1c reductions have been
reported to be of similar degree following either LC or LF
dietary regimens . In contrast, other studies
demonstrated stronger decreases in HbA1c in individuals
subjected to a LC approach [
]. It remains speculative
whether these differences might be due to an
age-dependency of LC effectiveness as shown in the present
subgroup analysis. Given the fact that various authorities have
proposed specific guidelines for glycemic control in older
] to minimize the risk of hypoglycemia,
these observations need to be confirmed by larger RCTs
mainly in patients C 60 years.
In the past, with traditional pairwise meta-analysis,
Ajala and co-workers compared various diets modifying
macronutrient intake on glycaemic control and weight loss
in patients with T2D [
]. In 2003, Brand-Miller et al.
] could show a beneficial effect specifically of LGI
foods as compared to regular or high GI diets on HbA1c
and fructosamine in subjects with type 1 or type 2 diabetes,
however, this study included mostly randomized trials with
a duration time of less than 12 weeks, whereas we included
only trials with a minimum intervention period of
12 weeks. The duration of time is an important factor in
dietary- and overall lifestyle intervention trials, since
participants adherence declines over time, and improvements
in risk factors are often larger in the short term, compared
to the longer term [
Comparable effects were shown for
carbohydrate-restricted diets by Kirk et al. [
]. In a meta-analysis of
RCTs by Huo et al. [
], a Mediterranean diet did result in
significantly more pronounced decreases in parameters of
glycaemic control and weight loss as compared to control
diets. In addition, Dong et al. [
] observed improvements
in HbA1c but not in fasting plasma glucose following a
meta-analytical synthesis of data from randomized trials
comparing HP with low-protein diets. In another
metaanalysis, Yokoyama et al. [
] demonstrated favourable
effects of Vegetarian diets on glycaemic control in patients
with T2D. The results of our NMA extend the current
knowledge from previous pairwise meta-analyses, since we
were the first to rank 9 different dietary approaches
regarding their comparative efficacy by analysing
simultaneously both direct and indirect effects. We could show
that a plant-based diet such as the Mediterranean diet is the
most effective dietary approach to improve glycaemic
control in T2D patients. This will affect evidence-based
decision-making with respect to dietary regimens by
providing a reliable basis for dietary recommendations in the
management of T2D.
With respect to mechanisms of action, the effects of LC
diets, Mediterranean diets or Palaeolithic diets on HbA1c
might be mediated by their higher amounts of food groups
such as fruits, vegetables, or whole grains providing
antioxidants or fibre, known to improve insulin sensitivity
or to directly inhibit production of advanced glycosylated
end products [
]. The additional benefit of a
Mediterranean diet on fasting plasma glucose might be
exerted via dietary polyphenols (e.g., flavonoids, phenolic
acids, resveratrol, lignans) provided by key components of
the Mediterranean diet such as olive oil, nuts, red wine,
legumes, fruits, and vegetables [
the meta-regression analysis showed that HbA1c reduction
was significantly related to mean differences in weight
change, indicating that weight loss is another important
mechanism to improve glycaemic control.
Both HbA1c and fasting plasma glucose are considered
to be clinical tools for the assessment of glycaemic control.
However, these parameters might not accurately determine
short-term fluctuations in glycaemia within a day or
longterm variations within several months. Glycaemic
variability is supposed to be an independent predictor of
diabetic complications [
Optimal control of glycaemic parameters in T2D
subjects is an essential step to reduce the risk of long-term
health damages associated with the disease. According to
the Asian Pacific Study, attenuations in fasting glucose
levels of 1 mmol/l are associated with a 23% lower risk of
]. Moreover, the authors of the United Kingdom
Prevention Study considered hyperglycaemia to be a more
relevant predictor of coronary events in the course of T2D
when compared with increased insulin levels [
]. In a
retrospective study by Currie et al. [
47,970 patients with T2D, HbA1c values higher than 6.5%
were associated with an increased mortality rate. In the
EPIC-Norfolk study, an increase in HbA1c of 1 percentage
point was associated with a 20–30% increase in mortality
or in risk of cardiovascular events [
]. Likewise, an
HbA1c increase of 1 percentage point was associated with
a relative risk for death from any cause of 1.24 in men and
1.28 in women [
]. This underlines the validity of
HbA1c and fasting plasma glucose in monitoring the
management of T2D.
Strength and limitations
This systematic review includes the application of novel
NMA methods, which simultaneously combine direct and
indirect evidence. Additional strengths are the high number
of included trials, the comprehensive literature search, the a
priori published systematic review protocol, identification
of inconsistency, and the credibility of evidence
A limitation of this review lies within the number and
qualities of the studies available. Overall, 7 of 56 trials
were at high risk of bias mostly due to lack of allocation
concealment, and blinding. However, the sensitivity
analysis excluding the high risk of bias trials confirmed all the
results of main NMA. Another important limitation is that
analyses were based on the original intended randomized
design, not by adherence to the actual dietary approach
and/or macronutrient composition and caloric intake
consumed. This means that although patients were randomized
to various diets or controls, details on their actual
adherence to the dietary program were not accounted for in the
analyses. The heterogeneous definition for the different
dietary approaches and the overlap between some dietary
approaches is another limitation. In some cases a LGI/GL
or a HP diet would also fulfil the criteria of a LF diet,
whereas on the contrary a LF would never fulfil the criteria
of other dietary approaches. The observed statistical
inconsistency, which was also reflected in the GRADE
assessments, is another important limitation of the ranking
and lowers the confidence in the effect estimates being
used in the analysis. As shown in the subgroup analyses we
observed significant differences between LC compared to
other dietary approaches for study duration, sample size,
and patients’ age.
According to the NMA, the Mediterranean diet seems to be
the most effective and efficacious dietary approach to
improve glycaemic control in T2D patients. These findings
need to be seen under the light of very low to moderate
credibility of evidence. However, the findings could
nevertheless influence dietary recommendations in the
management of T2D.
Acknowledgements We thank Iris Shai, Ph.D.; Thomas Wolever,
Ph.D.; and Miguel Martinez-Gonzalez, Ph.D. for sending us
additional data for the corresponding meta-analysis.
Authors’ contributions LS, AC, HB, GH contributed to the
conception and design of the systematic review and meta-analysis. LS,
AC, CS, HB, were involved in the acquisition and analysis of the data.
LS, AC, CS, HB, interpreted the results. LS, AC, GH, CS, HB, drafted
this manuscript. All authors provided critical revisions of the protocol
and approved submission of the final manuscript.
Compliance with ethical standards
Competing interests The authors declare that they have no competing
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://creative
commons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
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