papamichou2019
papamichou2019
papamichou2019
Received 26 July 2018; received in revised form 11 February 2019; accepted 11 February 2019
Handling Editor: A. Siani
Available online 25 February 2019
KEYWORDS Abstract Background and aim: The aim of the present review is to examine evidence from pub-
Diabetes mellitus; lished studies on the effectiveness of six or more months of low carbohydrate, macrobiotic,
Management; vegan, vegetarian, Mediterranean and intermittent fasting (IF) diets compared to low fat diets
Low carbohydrate; on diabetes control and management.
Intermittent fasting; Methods and results: In accordance with PRISMA guidelines, Cochrane CENTRAL, PubMed and
Mediterranean; Scopus databases were systematically searched for relevant studies. Twenty randomised
Macrobiotic; controlled trials (RCTs) > 6 months that investigated the effectiveness of various dietary patterns
Vegan; on type 2 diabetes mellitus (T2DM) were included. Risk of bias was assessed using the Cochrane
Vegetarian tool.
There were no significant differences in glycemic control, weight and lipids for the majority of
low carbohydrate diets (LCDs) compared to low fat diets (LFDs). Four out of fifteen LCD interven-
tions showed better glycemic control while weight loss was greater in one study. The Mediter-
ranean dietary pattern demonstrated greater reduction in body weight and HbA1c levels and
delayed requirement for diabetes medications. The vegan and macrobiotic diet demonstrated
improved glycemic control, while the vegetarian diet showed greater body weight reduction
and insulin sensitivity.
Conclusions: Although more long-term intervention trials are required, mounting evidence sup-
ports the view that vegan, vegetarian and Mediterranean dietary patterns should be implemen-
ted in public health strategies, in order to better control glycemic markers in individuals with
T2DM.
ª 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the
Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Feder-
ico II University. Published by Elsevier B.V. All rights reserved.
* Corresponding author. 46 Paleon Polemiston St. Glyfada, Attica, 166 74, Greece. Fax: þ30210 9600719
E-mail address: d.b.panagiotakos@usa.net (D.B. Panagiotakos).
https://doi.org/10.1016/j.numecd.2019.02.004
0939-4753/ª 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical
Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
532 D. Papamichou et al.
Figure 1 PRISMA flow diagram for the systematic review of clinical trials regarding dietary patterns and their role in the management of type 2
diabetes mellitus.
reduction in HbA1c concentration following the imple- glycemic control compared to those following a control
mentation of a LCD [10e13]. With the exception of West- diet [18]. There were no long-term (>6 months) in-
man et al. [10], there was no significant difference in terventions on IF and T2DM management. Studies are
weight loss between LCDs and LFDs. In regards to lipid described in more detail in Table 2 (summary of trials).
profile there were no significant differences between the
LCD and LFD, although there were isolated cases in which
lipid markers improved in favor of a specific diet (for de- Discussion
tails, refer to Table 2). LDL cholesterol did not differ be-
tween any of the LCD and high carbohydrate diet (HCD) Low carbohydrate diets
studies. Similar to the observations on the lipid profiles,
the majority of studies reported no significant difference in The use of LCD has attracted a great deal of attention in
blood pressure between the LCD and HCD. Two studies recent years, with review articles suggesting that a LCD
with a duration >6 months were identified using Medi- should be the initial management approach for diabetes
terranean dietary patterns as the comparator intervention [19]. However, the definition of a LCD is inconsistent. A
[14,15]. Both trials showed a greater reduction in body 2014 meta-analysis defined a LCD as one that has <45% of
weight and HbA1c levels compared with LFDs, with one total energy intake (TEI) from carbohydrates [20].
study showing higher rates of diabetes remission, and Although we included studies with a carbohydrate intake
delayed need for diabetes medication [14]. In regards to <45% of TEI there is a great variation in LCDs within our
vegetarian and vegan interventions 2 studies were iden- review with researchers using different LCD interventions
tified. The vegan diet showed improved glycemia and ranking from a very low-carbohydrate intake (20e50 g/d)
plasma lipids [16] while the vegetarian diet showed to a significantly higher intake of 45% of TEI.
greater body weight reduction and increased insulin Fifteen intervention trials with a duration greater than
sensitivity compared with a conventional diabetes diet six months, were identified. In regards to glycemic control,
[17]. Only one study was identified using macrobiotic di- 4 studies reported a reduction in HbA1c concentration
etary regimes and participants on this diet achieved better following the implementation of a LCD [10e13]. The 12-
534
Table 2 A summary of trials included in the systematic review of dietary patterns and management of type 2 diabetes mellitus.
Study n Dietary intervention Macronutrient intake at the end of Duration Relevant variables Significant outcome measures
the intervention
Davis, 2009 105 Dietary data at 3 months Dietary data at 12 months 12 months Weight, blood pressure, No evidence of superior benefit in either
[43] LCD: 24% carbohydrates, LCD: 33.4% carbohydrates, lipids, HbA1c diet
49%fat, 27% protein 43.9%fat (28.7% saturated), 22.7% Higher HDL for the LCD group
LFD: 53% carbohydrates, protein, 15.1 g fiber/day (þ0.16 0.27) compared to the low-fat
25% fat, 22% protein LFD: 50.1% carbohydrates, group (þ0.06 0.21)*
30.8% fat (30.2% saturated), 18.9% Differences in the short-term effects of
protein, each diet were not sustained
17.2 g fiber/day
Tay, 2015 115 (78 LCD:14% carbohydrates 37 weekse12 months 12 months Body composition, HbA1c, No significant difference in weight loss,
[21] completed the (carbohydrate, 50 g/d), LCD:16.6% carbohydrates, Fasting glucose HbA1c and several CVD risk markers
study) 58%fat, (<10% saturated fat), 28% 52.5%fat, (11% saturated, The LCD (high in unsaturated fat and low
protein 28.8% monounsaturated fat), in saturated fat) achieved greater
LFD: 53% carbohydrates, 25.6% protein, 25.7 g improvements in lipid profile [TG (LCD
30% fat (<10% saturated fat), 17% fiber/day diet: 0.4 mmol/L; LFD: - 0.01 mmol/
protein LFD:49% carbohydrates, 26.1% fat, L),** HDL (LCD: 0.1 mmol/L; LFD:
(8.5% saturated, 12% 0.06 mmol/L),* blood glucose stability,
monounsaturated fat), reductions in diabetes medication
18.4% protein, 31.4 g fiber/day requirements and greater attenuation of
diurnal blood glucose fluctuation
Iqbal, 2010 144 (77 assessed From baseline at 6 months Dietary data at 24 months 24 months Weight, HbA1c, lipids No significant difference in weight loss,
[44] at 1 y) (aim<30 g carbohydrates/day) LCD: 47.9% carbohydrates (188gr), glycemic control and lipids
LCD: 35.4% (154 g) carbohydrates, 34.2%fat, 16.9% protein, 23 g fiber/
42.7%fat, day
19.5% protein LFD: 46.7% carbohydrates,
LFD:41.9% carbohydrates, 33.6% fat, 17.6% protein,
36.6% fat, 21.1% protein 23 g fiber/day
Guldbrand, 61 3e6 months (Aim: 20% 24 months 24 months Weight, waist, blood No significant difference in weight loss,
2012 [46] carbohydrates, 50% fat, 30% LCD:31% carbohydrates, 44% fat, pressure, lipids, HbA1c, glycemic control and lipids
protein) 19% saturated fat, Medication use
LCD:25% carbohydrates, 49%fat, 24% protein, 24gfiber/day
20% saturated fat, 24% protein LFD:47% carbohydrates, 31% fat,
LFD:49% carbohydrates, 29% fat, 13% saturated fat, 20%
11% saturated fat, 21% protein
protein
Brinkworth, 66 (38 High-protein diet: 30% protein, (No dietary data at 12 months) 12 months Weight, lipids, HbA1c, No significant difference in weight loss,
2004 [69] completed the 40% carbohydrates, 30% fat, with fasting plasma glucose, glycemic control and lipids.
study) extra 21 g protein after 2 months blood pressure Improvement in blood pressure for the
Low-protein diet: 15% protein, high-protein diet
D. Papamichou et al.
55% carbohydrates, 30% fat, with
extra 7 g protein after 2 months
A systematic review of selected dietary RCTs in T2DM
Krebs, 2012 419 (294 (Aim: 40% carbohydrates, 30%fat, 24 months 24 months Weight, waist No significant differences between
[48] completed the 30% protein) at 6 months High-protein diet: 45.5% circumference, body groups
study) High-protein diet:45% carbohydrates, 45.4%fat, 12.5% fatness, HbA1c, lipids,
carbohydrates, 31.9% fat, 11.9% saturated fat, 32.8% protein, 23.2 g blood pressure and renal
saturated fat, 21.9% protein, 25 g fiber function
fiber High-carbohydrate diet: 48.1%
High-carbohydrate diet:48.5% carbohydrates, 30.4% fat, 11.5%
carbohydrates, 30.1% fat, 10.9% saturated fat, 20.3% protein, 23.7 g
saturated fat, 20.2% protein, 23.9 g fiber
fiber
Westman, 97 (49 Low-carbohydrate, Ketogenic Diet Low-carbohydrate diet: 13% (49 g) 6 months Weight, HbA1c, fasting Higher weight loss (11.1 kg vs.
2008 [10] completed the (LCKD) Group Intervention carbohydrates, 59% fat, 28% plasma glucose, lipids, 6.9 kg),* lower HbA1c (1.5% vs.
study) Aim for <20 g carbohydrates/day protein medication changes 0.5%),* and higher HDL (þ5.6 mg/dL vs.
for the LCKD intervention Control diet (LGID): 44% 0 mg/dL),** for the LCD
Control diet: Low glycemic index carbohydrates, 36% fat, 20% Diabetes medications were reduced or
diet (LGID), 55% carbohydrates protein eliminated in 95.2% of LCKD vs. 62% of
LGID participants*
Larsen, 2011 108 (99 At 3 months At 12 months 12 months Weight, lipids, No evidence of superior benefit in either
[70] completed the High-protein diet: 40.4% High-protein diet: 26.5% protein, HbA1c diet
study) carbohydrates, 30.1% fat 42% carbohydrates, 31% fat
(saturated 40.2%),28.2% protein, (saturated 39%), 22 g fiber
22.5 g fiber Control diet: 48% carbohydrates,
Control diet: 49% carbohydrates, 32% fat (saturated 40%),19%
29.3% fat (saturated fat 40.5%), protein, 24 g fiber
20.8% protein, 23.4 g fiber
Elhayany, 259 (179 LCMD: 35% low-GI carbohydrates, At 6 months 12 months Weight, Hb A1c, lipids HDL cholesterol increased (0.1 mmol/
2010 [11] completed the 45% fat LCMD: 41.9% carbohydrates l 0.02) only in the LCMD*
study) rich in MUFAs, 15e20% TMD: 45.2%, carbohydrates HbA1c greater in the LCMD than in the
protein, 30 g fiber ADA diet: 45.4% carbohydrates ADA diet (2.0 and 1.6%, respectively)*
TMD: 50e55% low-GI No dietary data at the end of the Greater reduction in TGs for the LCMD
carbohydrates, 30% fat intervention (1.3 mmol/l) and TMD (1.5 mmol/l)
rich in MUFAs, 15e20% compared to the ADA diet group
protein, 30 g fiber (0.7 mmol/l)**
ADA diet: 50e55%carbohydrates, No other significant differences
30% fats, 20% protein
Wolever, 162 (156 LCD: 39% carbohydrates, 40% fat, No dietary data at the end of the 12 months Weight, lipids, HbA1c No significant difference in glycemic
2008 [71] completed the 19% protein, 59GI intervention control, weight and lipids
study) High GI: 47% carbohydrates, Differences in total: HDL cholesterol
31% fat, 20% protein, among diets disappeared by six months
63GI Reduction in postprandial glucose and
Low GI:52%, carbohydrates, CRP, with LGID
27% fat, 21% protein,
55GI
535
536
Table 2 (continued )
Study n Dietary intervention Macronutrient intake at the end of Duration Relevant variables Significant outcome measures
the intervention
Jonasson, 61 LCD: 20% carbohydrates LCD:25% carbohydrates, 6 months Weight, lipids, HbA1c, No significant difference in glycemic
2017 [72] LFD:55e60% carbohydrates, <30% 49%fat, 20% saturated fat, inflammatory markers control, weight and lipids
fat 24% protein Improved inflammatory markers for the
LFD:49% carbohydrates, 29% fat, LCD
11% saturated fat,
21% protein
Goldstein, 52 (30 Modified Atkins diet: Modified Atkins diet: 12 months Weight, fasting blood No significant difference in HbA1c weight
2011 [73] completed the 25 g of carbohydrates/day for the 85 g (20%) carbohydrates/day, 23% glucose, lipid profile, blood loss and lipids
study) first 6 weeks increasing to 40 g/ protein, 57% fat pressure
day ADA calorie-restricted diet: 41%
ADA calorie-restricted diet: 10 carbohydrates, 19% protein, 40%
e20% protein, <30% fat, 35 g fiber fat
1500 kcal/day for men and
1200 kcal/day for women
Sato, 2017 66 (62 LCD: 130gr/day carbohydrates LCD: 54% carbohydrates, 17% 18 months HbA1c and BMI No significant difference in HbA1c and
[45] completed the Calorie restricted diet: 50e60% protein, 29% fat BMI
study) carbohydrates, 1.0e1.2 g/kg Calorie restricted diet: 55%
protein carbohydrates, 16% protein, 29%
fat
Yamada, 24 LCD: 70e130 g/day carbohydrates LCD: 30% carbohydrates, 35% fat, 6 months Weight, HbA1c, lipids, Better glycemic control for the LCD
2013 [12] Calorie restricted diet: 25% protein blood pressure compared to calorie restricted diet
50e60% carbohydrates, <25% fat, Calorie restricted diet: 51% (HbA1c 7% and 7.5% respectively)*
<20% protein carbohydrates, 32% fat 17% No significant differences in weight,
protein lipids and blood pressure
Rock, 2014 227 (198 Low fat weight loss program: 60% No dietary data 12 months Weight, HbA1c, lipids, Greater weight loss, improved glycemic
[13] completed the carbohydrates, 20% fat, 20% blood pressure control and lower triglyceride levels for
study) protein low carbohydrate and low fat
Low carbohydrate weight loss intervention groups compared with
program: 45% carbohydrates, 30% usual care group
fat, 25% protein Lower HbA1c for the lower versus higher
Usual care: 55% carbohydrates, carbohydrate group (6.6% vs. 7.2%
30% fat, 15% protein respectively)*
Esposito, 215 LCMD: <50% of energy from LCMD 48 months Time to introduction of Greater reduction in body weight, HbA1c
2009 [14] carbohydrates, >30% fat (30e50 g Year 4: 44.2% carbohydrates antidiabetic medication levels, higher rate of diabetes remission,
olive oil) 18% protein, 10% saturated fat, Weight, HbA1, lipids, and delayed need for diabetes
Control diet (low-fat): 17.6% monounsaturated fat, 11.5% insulin, adiponectin medication for the LCMD compared with
<30% of energy from fat, <10% polyunsaturated fat the low-fat diet
saturated fat Low fat diet At the end of the intervention 44% of
D. Papamichou et al.
Year 4: 51.6% carbohydrates, patients in the LCMD group and 70% in
17.9% protein, 9.4% saturated fat, the LFD group required treatment**
12.4% monounsaturated fat, 7.6% Greater improvements in glucose,
polyunsaturated fat HOMA-IR and HbA1c levels for the LCMD
A systematic review of selected dietary RCTs in T2DM
Toobert, 279 (245 Mediterranean lifestyle program No dietary data at the end of the 6 months HbA1c, lipids, BMI HbA1c decreased from 7.43 to 7.07 mg/
2003 [15] Completed the (MLP) (diet, physical activity, intervention dl** in the MLP, whereas that of the
study) stress management) control subjects remained at 7.4 mg/dl.
Usual care BMI decreased 0.37 in the MLP and
increased 0.20 for the usual care group*
Barnard, 83 Vegan diet: 75% carbohydrate Vegan diet: 22.3 fat (5% saturated 12 months and Weight, HbA1, fasting Improved glycemia (HbA1c (%) 0,4
2009 [16] 10% fat, 15% protein fat), 66.3% carbohydrates, 14.8% 22 weeks plasma glucose, lipids, compare to þ0.01,** and plasma lipids
Conventional diet: 60e70% protein, 21.7 g/1000cal fiber blood pressure (LDL mg/dL, 13.5 compare to 3.4),* for
carbohydrates, <7% saturated fat, Conventional diet: 33.7% fat (10%, the vegan diet (After controlling for
15e20% protein saturated fat), 46.5% medication changes)
carbohydrates, 21% protein,
13.4 g/1000cal fiber
Kahleova. 74 (62 Vegetarian diet: 60% High adherence 6 months Weight, body composition, Decreased body weight (6.2 kg vs.
2011 [17] completed the carbohydrates, 25% fat, 15% 55% in the vegetarian diet and 32% blood pressure, HbA1c, 3.2 kg),** and increased insulin
study) protein in the control group fasting plasma glucose, sensitivity (30% increased metabolic
Conventional diabetic diet: 50% Medium adherence lipids, oxidative stress, clearance rate of glucose (using
carbohydrates, 30% fat, 20% 22.5% in the vegetarian diet and euglycemic clamp technique) vs. 20%)*
protein 39% in the control group for the experimental group
Low adherence Greater reduction in visceral fat (4% vs.
22.5% in the vegetarian diet and 0%)* and subcutaneous fat* for the
29% in the control group vegetarian diet
43% of participants in the experimental
group and 5% of participants in the
control group reduced diabetes
medication** Improvement in oxidative
stress markers for the vegetarian diet
Soare, 2016 40 Ma-Pi 4 diet: 67% carbohydrate, (No assessment of dietary intake 6 months Weight, HbA1c, lipids Better glycemic control with Ma-Pi 4 diet.
[18] 21% fat, 12% protein, fiber was performed during the 6- HbA1c (%) 11.27 compare to 5.88 for
27 g/1000 kcal month follow-up) the control diet**
Control diet: 50% carbohydrate, No other significant differences
30% fat, 20% protein, fiber
20 g/1000 kcal
537
538 D. Papamichou et al.
month three arm intervention [Low carbohydrate Medi- improve coronary risk factors. As chronic inflammation is
terranean diet (LCMD), traditional Mediterranean diet predictive of the future occurrence of both T2DM and
(TMD) and ADA diet] [11] showed greater improvements cardiovascular events [27], it is likely that the proposed
in HbA1c following a LCMD compared to the ADA diet anti-inflammatory effects of a Mediterranean diet may
(Table 2). However, it is unlikely that this improvement in play an important role in mediating their benefits on both
HbA1c was due to the carbohydrate intake because the glycemic status and cardiovascular risk [28,29].
mean intake differed by only 16 g and the use of low GI Two RCTs were identified to evaluate the long-term
foods was encouraged in the LCMD but not addressed in effect of the Mediterranean diet on T2DM patients [14,15].
the ADA diet. Additionally, the lack of improvement in The findings of these studies demonstrated the beneficial
HbA1c between high- and low-carbohydrate Mediterra- effect of a Mediterranean dietary pattern on glycemic
nean diets further suggests that the results were due to a control and insulin sensitivity in patients with T2DM, as
focus on the low-GI Mediterranean eating pattern rather well as their superiority over control diets such as low-fat
than total carbohydrate intake [11]. Yamada et al. reported diet or usual dietary habits. As seen in the paper by
lower HbA1c levels for the LCD group in comparison with Esposito et al. [14,30], the longest to date study to assess
the calorie-restricted diet (7.0 0.7 and 7.5 1.0 respec- the effects of a Mediterranean diet in patients with newly
tively) [12]. Nevertheless, the number of subjects enrolled diagnosed T2DM (total follow-up: 8.1 years), a LCMD
was small (24 participants) therefore studies with a larger postponed the introduction of diabetes medications by
sample size are needed to confirm these findings. Another two years independent of weight loss compared with a
12-month intervention trial showed greater mean [95% CI] traditional low-fat diet. Moreover, a substantial long-term
reductions in diabetes medication for the LCD group reduction of HbA1c levels was observed. At year 4 the
compared with the HCD group [LCD: 0.5 arbitrary units LCMD group achieved a 0.4% (95% CI: 0.9 to 0.1%)
(0.7, 0.4 arbitrary units); HCD:0.2 arbitrary units greater reduction in HbA1c compared to the LFD. Partial or
(0.4, 0.06 arbitrary units)] [21]. complete remission of diabetes occurred in 14.7% (95%
With the exception of Westman et al., there was no CI:13.0e16.5%) of LCMD participants within the first year
significant difference in weight between LCDs and LFDs at of intervention and 5% (95% CI: 4.4e5.6%) after six years;
the time of completion of the studies. However, fat intake these rates were two to four times greater than those of
for participants on the LFD was 36% of TEI at the end of the participants assigned to the low-fat diet group. In another
intervention which is not consistent with a LFD [10]. These RCT with 6-month duration 279 postmenopausal women
findings are consistent with a meta-analysis that examined with T2DM were assigned to either a Mediterranean life-
participants with diabetes following a LCD or a balanced style program-(MLP) or usual care. Subjects allocated to
weight loss diet. The study revealed little or no difference the MLP group exhibited lower HbA1c levels, compared
in weight loss and changes in cardiovascular risk factors up with the control group. However, the relative role of the
to two years of follow-up in overweight or obese adults Mediterranean diet in the context of the program that also
with or without T2DM [20]. included exercise, group support, smoking cessation and
There were no significant differences in lipid profiles stress management training was unclear [15]. As previ-
between the LCDs and LFDs, although there were isolated ously mentioned, while examining the effects of low car-
cases in which lipid markers improved in favor of a specific bohydrate interventions on the management of T2DM a
diet (refer to Table 2 for details). Similar to the observa- significantly greater reduction in HbA1c was observed for
tions on the lipid profiles, the majority of studies reported the LCMD in a 12 month/three-arm intervention trial
no significant difference in blood pressure between the compared to a low-fat (based on the 2003 ADA guidelines)
LCDs and HCDs. diet (2.0 and 1.6%, respectively). A reduction in serum
triglycerides was also observed for patients allocated to
Mediterranean diet the LCMD (1.3 mmol/l) and TMD group (1.5 mmol/l),
compared with patients in the ADA diet (0.7 mmol/l)
The Mediterranean diet, a dietary pattern inscribed on the whereas changes in glucose, insulin, and HOMA-IR levels
Representative List of the Intangible Cultural Heritage of were similar among groups [11].
Humanity, by the UNESCO [22], is a mostly but not
exclusively plant-based diet [23]. Vegan and vegetarian diets
Research on the role of the Mediterranean diet on
T2DM though limited, has provided some preliminary Well planned vegetarian diets [31] may offer an advantage
encouraging results. A Meta-analysis of 10 prospective over non-vegetarian diets with respect to prevention and
studies showed a significant 23% reduction in the risk of management of diabetes. The 7th Day Adventist Health
developing T2DM for the highest versus the lowest centile Studies found that vegetarians have approximately half the
of the Mediterranean diet adherence score [24]. Epidemi- risk of developing diabetes compared with non-
ologic and interventional studies have revealed a protec- vegetarians [32]. Vang et al. [33] reported that non-
tive effect of a Mediterranean diet against chronic vegetarians were 74% more likely to develop diabetes
inflammation [25], insulin resistance, and the metabolic over a 17-year period than vegetarians. A low-fat, plant-
syndrome [26]. Moreover, one of the most desirable fea- based diet with no or little meat may help prevent and
tures of a Mediterranean diet has been the ability to treat diabetes, possibly by improving insulin sensitivity
A systematic review of selected dietary RCTs in T2DM 539
and decreasing insulin resistance [34]. Fruits, vegetables, IF/alternate day fasting (ADF) regimens, yet comparable
whole grains and legumes may contribute to a decreased reductions in visceral fat mass, fasting insulin, and insulin
incidence of T2DM through their low energy density, low resistance have been observed [41]. However as there are
glycemic load, and high fiber and antioxidant content. no long-term interventions on IF regimes and T2DM more
These foods have been shown to improve glycemic control, research is required before robust conclusions can be
slow the rate of carbohydrate absorption and the risk of reached.
diabetes [35,36]. Vegetarian and vegan diets have also The macrobiotic Ma-Pi 2 diet (12% protein, 18% fat and
shown to improve plasma lipid concentrations and reverse 70% carbohydrate), a predominantly vegetarian, whole-
atherosclerosis progression [37]. A recent meta-analysis of food diet has shown benefits in adults with T2DM by
9 RCTs has shown that vegetarian dietary patterns in improving fasting blood glucose, plasma lipids and plasma
comparison with non-vegetarian dietary patterns have insulin. The Ma-Pi 2 and Ma-Pi 4 diets are plant-based
benefits for glycemic control and other established car- diets rich in fibre and fermented foods with a prebiotic
diometabolic risk factors over a median follow-up of 12 potential [42]. The Ma-Pi 4 diet (a recent version of the
weeks [38]. Ma-Pi 2 diet that includes additional fish-derived protein)
A 6-month randomised, open, parallel study comparing has been reported to be more efficient in glycemic control
a vegetarian diet with a conventional diabetic diet (50% than a control diet [18].
carbohydrates, 20% protein and <30% fat) showed a The median percentage reduction in HbA1c levels was
vegetarian diet alone or in combination with exercise is significantly greater for patients in the Ma-Pi 4 group
more effective in increasing insulin sensitivity, reducing [11.27% (95% CI: 10.17; 12.36)] compared with the
body weight [e6.2 kg (95% CI e6.6 to 5.3) for the inter- control group [5.88% (95% CI: 3.79; 7.98)]. These re-
vention group vs. 3.2 kg (95% CI e3.7 to 2.5) for the sults suggest that a macrobiotic diet could be a valid
control group] and diabetes medication [43% for the alternative treatment for patients with T2DM. However, as
experimental group and 5% for the control group; 38% there is only one study with a 6 month follow up exam-
difference between groups (95% CI 17e58%)]. However, the ining the effects of a macrobiotic diet on patients with
number of subjects (37 in the experimental group and 37 T2DM further research is needed to validate these results.
in the control group) did not provide sufficient power to
confirm the superior effect of the vegetarian diet on Adherence and safety of dietary approaches
HbA1c. Furthermore, lower adherence to the prescribed
diet in the control group points to a potential weakness of This review shows that there are no consistent differences
the conventional diabetic diet [17]. in weight and HbA1c changes over the long-term treat-
In individuals with T2DM participating in a 74-week ment with LCD compared to LFD. Thus, a possible expla-
RCT, both a low-fat vegan diet and a diet based on ADA nation for the lack of improvements in HbA1c might be
guidelines, facilitated long-term weight reduction. In an- that people are unable to achieve a strictly prescribed
alyses controlling for medication changes, a vegan diet carbohydrate intake. As seen in Davis et al. [43], at 6 and
appeared to be more effective for control of glycemia and 12 months, there was an increase in energy and macro-
plasma lipid concentrations [16]. Vegetarian diets may nutrients (carbohydrates for the LCD group and fat for the
provide a beneficial alternative for nutritional therapy in LFD group), suggesting decreased adherence. Carbohy-
T2DM however, as there are only two RCTs with a duration drate intake at 3 months was 24% of TEI but this increased
>6 months, further studies should explore the long-term to 33.5% and 33.4% at 6 and 12 months, respectively. Iqbal
effects of vegetarian diets in patients with T2DM. et al. [44] aimed for a carbohydrate intake of <30 g while
examining the effects of a LCD vs. a LFD in obese, diabetic
Intermittent fasting and macrobiotic diets participants. However, the lowest mean carbohydrate
intake was 154 g and the final carbohydrate intake 188 g,
“Intermittent” fasting (IF) is a relatively new dietary far less compared to the aim of <30 g. In addition, West-
approach to weight management that involves inter- man et al. [10] aimed for a carbohydrate intake of <20 g,
spersing usual daily energy intake with a short period of significantly lower from the 49 g consumed by the low
severe calorie restriction or fasting. carbohydrate ketogenic diet (LCKD) group over the 24-
IF has shown to enhance autophagy, reduce levels of week duration of the intervention. As observed in Iqbal
Advance Glycation End-Products [AGEs], increase adipo- et al. and Sato et al. dietary intake with respect to carbo-
nectin levels and improve metabolic parameters in non- hydrate intake was similar for both groups at the end of
diabetic individuals. There are many physical and poten- the intervention with both groups failing to achieve their
tially psychological benefits of fasting or intermittent cal- dietary targets throughout the study [44,45]. Reduced
orie restriction [39]. However, as fasting for weight control compliance with the LCD was also observed after six
purposes has shown to be a more potent and consistent months in a two-year intervention. More specifically par-
predictor of risk for future onset of binge eating and ticipants found it hard to restrain from carbohydrates as
bulimic pathology, some behavioural modifications related well as change from low-fat to high fat products [46,47].
to abstinence of over eating are crucial in maintaining Krebs et al. highlighted how difficult it is to achieve and
weight loss [40]. Short-term interventions revealed supe- maintain any prescribed change in dietary composition,
rior decreases in body weight by caloric restriction (CR) vs. and how individuals turn back to habitual intakes over
540 D. Papamichou et al.
time. The prescribed intervention diet in this study rec- men and women. At 1 year, C-reactive protein (CRP) fell by
ommended replacing some carbohydrate with protein. The 37% and 12% in the Mediterranean diet and low-fat diet
target of 30% protein was achieved in only 12 of the 207 groups, respectively and the between-group difference
(6%) participants in the high-protein group [48]. This re- was significant [0.8, (95% CI: 1.3 to 0.3 mg/L)] while
view suggests that LCDs in a real-world setting may be adiponectin rose by 43% in the Mediterranean diet group
difficult to sustain. In line with our observations, meta- and 11% in the low-fat diet group [difference between
analyses have shown that LCDs were more effective in groups: 1.9 lg/mL, (95% CI: 0.8e3.0 lg/mL)] [60].This re-
HbA1c and body weight reduction in the short-term view suggests that the adoption of vegetarian or Medi-
compared to other diets, whereas no superiority was terranean dietary patterns can be an effective strategy for
observed in the long-term [49,50]. Another meta-analysis managing diabetes. The TMD is an example of a mostly but
revealed that a moderate carbohydrate reduction seems not exclusively plant-based diet which is healthy,
to be a more realistic approach in improving glycemic economically affordable [61] and environmentally sus-
control in patients with T2DM compared to a very low- tainable [62]. It encourages consumption of a variety of
carbohydrate intervention [51]. palatable foods, optimising adherence and sustainability
Furthermore, the overall effect on long-term athero- and therefore is considered an effective approach for
sclerosis risk is not clear. Although LCD are focused on management of T2DM [63e65]. Moreover a 2018 Sys-
improving glycemic control in T2DM, the negative conse- tematic review and meta e analysis has shown that olive
quences of severely restricting carbohydrate is often a oil intake, an integral part of the Mediterranean diet, may
concomitant increase in saturated fats which in turn can be associated with a decreased risk for developing T2DM
increase atherosclerosis risk. Low carbohydrate diets high in as well as improving glucose metabolism [66]. The find-
saturated fat may accelerate the progression of coronary ings of our review are consistent with a recent meta e
artery disease (CAD) through increases in lipid deposition analysis that assessed the comparative efficacy of various
and inflammatory and coagulation pathways [52,53]. As dietary patterns on glycaemic control in patients with
seen in a study of two cohorts the high animal protein/low- T2DM. The network meta e analysis revealed that the
carbohydrate score was associated with higher all-cause Mediterranean diet is the most effective and efficacious
mortality, cardiovascular mortality and cancer mortality dietary approach to improve glycaemic control in T2DM
whereas a higher vegetable low-carbohydrate score was patients [67]. In addition the ADA and the European As-
associated with lower all-cause and cardiovascular mortal- sociation for the Study of Diabetes (EASD) report suggests
ity [54]. Wycherley et al. revealed that maintaining a rela- the Mediterranean eating pattern as the greatest in
tively low level of saturated fat as part of a LCD could improving glycemic control compared to low-
possibly mitigate potential impairments in vascular func- carbohydrate, low glycemic index, high-protein diets, and
tion as measured by flow mediated dilatation and the the Dietary Approaches to Stop Hypertension (DASH) diet
associated increased cardiovascular disease (CVD) risk [55]. [5]. Besides, the Mediterranean dietary pattern results in
However, there is a growing convergence of scientific lower environmental footprints due to the greater
evidence that an optimal diet is mostly plant-based, con- emphasis on plant-over animal-derived products [62].
taining a host of food and nutrients known to have inde- Another possible approach in managing diabetes may
pendent health benefits. Both vegetarian diets and be IF and macrobiotic diets. IF regimens have gained
prudent diets (diets characterised by increased consump- considerable popularity in recent years, as some people
tion of plant foods and small amounts of red meat in find these diets easier to follow than a daily or continuous
addition to fish and dairy products) are associated with energy restriction [68]. Despite the recent popularity of IF,
reduced risk of chronic diseases, particularly CAD and the supporting evidence base in humans remains small
T2DM. Evidence linking red meat intake, particularly therefore more research is required, in particular, long-
processed meat, and increased risk of CAD, cancer and term RCTs, before robust conclusions can be reached. In
T2DM is convincing and provides indirect support for regards to macrobiotic diets as there is only one long term
consumption of a plant-based diet [34,56]. Results from intervention in T2DM management further research is
the Attica study in Greece showed that meat and meat needed to validate the effectiveness of this dietary pattern.
products, among all food groups, were the ones mostly It is noteworthy to mention that the majority of pa-
associated with poor insulin resistance and hyper- tients with T2DM have reported difficulties in adhering to
insulinemia [57]. There are various reasons for suspecting conventional low fat diets. Nine out of thirteen trials with
that a plant-based diet can reduce the risk for other major sufficient nutrition data show a fat intake >30% at the end
complications of diabetes - retinopathy, nephropathy, and of the intervention. This supports the view that guidelines
macrovascular disease - independent of its tendency to should focus more on dietary pattern-based approaches
improve glycemic control in diabetic patients [58]. Re- for the management of T2DM rather than nutrient-based
searchers from the Melbourne Collaborative Cohort Study approaches.
showed that adherence to a Mediterranean diet may
reduce total and CVD mortality risk associated with dia- Conclusion
betes [59]. Maria Ida Maiorino et al. examined the influ-
ence of a Mediterranean diet compared to a low-fat diet on LCDs have demonstrated beneficial effects on short-term
the inflammatory milieu in T2DM for 215 newly diagnosed weight reduction for obese individuals without diabetes,
A systematic review of selected dietary RCTs in T2DM 541
but the evidence for long-term efficacy on individuals with guidelines for nutrition therapy in diabetes. Can J Diabetes 2013
T2DM is inconclusive. Thus, a possible explanation might Feb;37(1):51e7.
[8] Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group.
be that people are unable to achieve a strictly prescribed Preferred reporting items for systematic reviews and meta-
carbohydrate intake. Moreover, our review suggests that analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097.
vegetarian and Mediterranean dietary patterns may be [9] Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD,
et al. Cochrane bias methods group; Cochrane statistical methods
more effective in improving glycemic control and selected group. The Cochrane collaboration’s tool for assessing risk of bias in
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accelerate the progression of CAD, strategies aiming to McDuffie JR. The effect of a low-carbohydrate, ketogenic diet
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public health interest. Nevertheless, further long-term carbohydrate Mediterranean diet improves cardiovascular risk
factors and diabetes control among overweight patients with type
intervention trials are needed to validate the beneficial
2 diabetes mellitus: a 1-year prospective randomized intervention
effects of plant-based diets for diabetes management. study. Diabetes Obes Metab 2010 Mar;12(3):204e9.
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Conflicts of interest Gicchino M, et al. Effects of a Mediterranean-style diet on the need
for antihyperglycemic drug therapy in patients with newly diag-
nosed type 2 diabetes: a randomized trial. Ann Intern Med 2009
The authors have no relevant conflict of interest to
Sep 1;151(5):306e14. Erratum in: Ann Intern Med. 2009 Oct 20;
disclose. 151(8):591.
[15] Toobert DJ, Glasgow RE, Strycker LA, Barrera Jr M, Radcliffe JL,
Wander RC, et al. Biologic and quality-of-life outcomes from the
Acknowledgements Mediterranean Lifestyle Program: a randomized clinical trial.
Diabetes Care 2003 Aug;26(8):2288e93.
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currently completing her doctorate (PhD) at La Trobe diet in the treatment of type 2 diabetes: a randomized, controlled,
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with Type 2 diabetes. Diabet Med 2011 May;28(5):549e59.
[18] Soare A, Del Toro R, Khazrai YM, Di Mauro A, Fallucca S,
Supplementary data to this article can be found online at Angeletti S, et al. A 6-month follow-up study of the randomized
https://doi.org/10.1016/j.numecd.2019.02.004. controlled Ma-Pi macrobiotic dietary intervention (MADIAB trial)
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