International Journal of

Environmental Research
and Public Health

Review
Ketogenic Diet Benefits to Weight Loss, Glycemic Control, and
Lipid Profiles in Overweight Patients with Type 2 Diabetes
Mellitus: A Meta-Analysis of Randomized Controlled Trails
Chong Zhou 1,† , Meng Wang 2,† , Jiling Liang 3 , Guomin He 4, * and Ning Chen 3, *

1 School of Journalism and Communication, Wuhan Sports University, Wuhan 430079, China
2 Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China
3 Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of
Exercise Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan 430079, China
4 School of Economics and Management, Wuhan Sports University, Wuhan 430079, China
* Correspondence: 1988012@whsu.edu.cn (G.H.); 2011030@whsu.edu.cn (N.C.); Tel.: +86-27-8719-1486 (G.H.);
+86-27-6784-6140 (N.C.)
† These authors contributed equally to this work.

Abstract: A ketogenic diet, characterized by low calories with high levels of fat, adequate levels of
protein, and low levels of carbohydrates, has beneficial effects on body weight control in overweight
patients. In the present study, a meta-analysis was conducted to investigate the role of a ketogenic
diet in body weight control and glycemic management in overweight patients with type 2 diabetes
Citation: Zhou, C.; Wang, M.; Liang,
mellitus (T2DM). In summary, we systematically reviewed articles from the Embase, PubMed, Web
J.; He, G.; Chen, N. Ketogenic Diet of Science and Cochrane Library databases and obtained eight randomized controlled trials for
Benefits to Weight Loss, Glycemic meta-analysis. The results show that a ketogenic diet had significantly beneficial effects on the loss of
Control, and Lipid Profiles in body weight (SMD, −5.63, p = 0.008), the reduction of waist circumference (SMD, −2.32, p = 0.04),
Overweight Patients with Type 2 lowering glycated hemoglobin (SMD, −0.38, p = 0.0008) and triglycerides (SMD, −0.36, p = 0.0001),
Diabetes Mellitus: A Meta-Analysis and increasing high-density lipoproteins (SMD, 0.28, p = 0.003). Overall, these results suggest that
of Randomized Controlled Trails. Int. a ketogenic diet may be an effective dietary intervention for body weight and glycemic control, as
J. Environ. Res. Public Health 2022, 19,
well as improved lipid profiles in overweight patients with T2DM. Hence, a ketogenic diet can be
10429. https://doi.org/10.3390/
recommended for the therapeutic intervention of overweight patients with T2DM.
ijerph191610429

Academic Editors: Zbigniew Keywords: glycemic management; body weight control; very low-carbohydrate diet; glycated
Adamczewski and Magdalena hemoglobin; high-density lipoprotein; therapeutic intervention
Stasiak

Received: 29 June 2022

Accepted: 19 August 2022
Published: 22 August 2022
1. Introduction
Type 2 diabetes mellitus (T2DM) is a high-incidence chronic metabolic disorder, with
Publisher’s Note: MDPI stays neutral
high mortality and morbidity rates worldwide due to its multiple complications [1]. Patients
with regard to jurisdictional claims in
published maps and institutional affil-
with T2DM are more likely to suffer from cardiovascular diseases, diabetic neuropathy, and
iations.
many other complications, as the major causes of diabetes-related deaths [2]. Although
medication therapy, such as metformin, gliquidone, and acarbose, can reduce the fluctuation
in blood glucose levels, lifestyle interventions, especially medical nutrition, are an effective,
recommended, non-pharmacological intervention [3].
Copyright: © 2022 by the authors. A ketogenic diet, characterized by low calories with high-level fat, moderate-level
Licensee MDPI, Basel, Switzerland. protein, and very low-level carbohydrate (usually less than 50 g/d), has been introduced
This article is an open access article as a nutrition-based intervention for the treatment of epilepsy through energy supply from
distributed under the terms and ketone bodies, which mimics metabolic starvation due to the strict restriction of carbo-
conditions of the Creative Commons hydrates [4,5]. There are four types of ketogenic diet, including standard ketogenic diet,
Attribution (CC BY) license (https:// cyclical ketogenic diet, targeted ketogenic diet, and high-protein ketogenic diet [6]. Among
creativecommons.org/licenses/by/ them, standard ketogenic diet, which typically contains 70 percent fat, 20 percent protein
4.0/).

Int. J. Environ. Res. Public Health 2022, 19, 10429. https://doi.org/10.3390/ijerph191610429 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2022, 19, 10429 2 of 12

and only 10 percent carbohydrates, is the most studied and recommended. Under the con-
dition of reduced carbohydrate consumption, ketone bodies produced by the breakdown of
fats in the liver, is an alternative source of energy to glucose, especially the central nervous
system [7]. Recently, this diet has been reported to have great potential in the body weight
control of patients with obesity [8–10]. A previous review has documented that obesity is a
risk factor for T2DM and its complications, such as chronic cardiovascular diseases [11].
Although previous meta-analyses and systematic reviews have demonstrated the efficacy of
a ketogenic diet in body weight control [12,13], conflicting findings have been reported with
regard to changes in glycemic and lipid profiles of T2DM patients under this dietary inter-
vention. A randomized controlled trial (RCT) reported that a ketogenic diet could mitigate
insulin resistance and reduce glycemic responses, thereby improving the glycemic profiles
of T2DM patients [14]. Conversely, other evidence indicates that a low-carbohydrate and
high-fat diet is associated with deteriorated lipid profiles [15,16]. The mechanisms that
underlie the associations between ketogenic diet and T2DM are still a subject of debate,
and gut microbiota might play a significant role in the relationship between very low-
carbohydrate ketogenic diet (VLCKD) and reducing obesity [17]. The appropriateness of
ketogenic diets in overweight T2DM patients on body weight control, and glycemic and
lipid profile management, is still not firmly established. Therefore, in the present study, to
validate the effect of a ketogenic diet on overweight patients with T2DM, we conducted
a meta-analysis based on comprehensive metabolic parameters including body weight
changes, glycemic control, and lipid profiles of overweight patients with T2DM in the
presence of ketogenic diet intervention, relative to other types of dietary interventions.

2. Materials and Methods

2.1. Data Sources and Search Strategy
This meta-analysis was conducted based on the standard Cochrane protocols. Briefly,
two independent reviewers systematically searched for relevant literature in the PubMed,
Embase, Cochrane Library, and Web of Science databases, according to the guidelines
of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).
Specifically, we targeted RCTs that investigated and evaluated the effects of a ketogenic
diet on body weight change, glycemic control, and lipid profile in overweight T2DM
patients, which were published until 30 April 2022. To identify relevant studies, the
reviewers used the following search terms: (“Diet, Ketogenic” [MeSH] OR “Ketogenic*”
[Title/Abstract]) AND (“Diabetes Mellitus, Type 2” [MeSH] OR “Non-Insulin-Dependent
Diabetes*” [Title/Abstract] OR “Type II Diabetes*” [Title/Abstract]) AND (“Overweight”
[MeSH] OR “Obesity” [MeSH]). The search filter was set as “clinical trials”, and eligible
RCTs were also obtained from reference lists of relevant review articles. A ketogenic diet
was defined as a dietary intake comprising high fats, moderate proteins, and very low
carbohydrates (less than 50 g/d).

2.2. Selection Criteria

Articles were included in the meta-analysis according to the Participants, Intervention,
Comparison, Outcomes, and Study design (PICOS) principle (Table 1). The inclusion
criteria were as follows: (a) studies written and published in English; (b) the participants
were patients diagnosed with T2DM in terms of glycated hemoglobin (HbA1c) or fasting
glucose; (c) the participants were overweight with a body mass index (BMI) of not less
than 25 kg/m2 ; (d) the dietary intervention was a ketogenic diet (the intervention group)
alongside other types of diets (the control group); (e) the main outcomes included body
weight change, glycemic control, and lipid profile; and (f) studies were RCTs. Alternatively,
studies were excluded if: (a) they were case reports, meta-analyses, or reviews; (b) they
were animal studies; (c) they had no control group; and (d) they had no or insufficient data
for calculating mean differences and standard errors, or 95% confidence intervals before
and after interventions.
Int. J. Environ. Res. Public Health 2022, 19, 10429 3 of 12

Table 1. PICOS criteria for inclusion and exclusion of studies.

Parameters Inclusion Criteria

Population Overweight T2DM patients
Intervention Ketogenic diet; very low-carbohydrate diet
Comparison Any comparisons
Outcomes Body weight change, glycemic control, lipid profile
Study design Randomized controlled trials

2.3. Data Extraction and Quality Assessment

Two reviewers independently screened the titles and abstracts, based on the afore-
mentioned inclusion and exclusion criteria. Full texts were then retrieved and carefully
reviewed. Any discrepancies and controversies between them were evaluated by a third
author, and resolved by consensus. Data extraction was also independently performed
by two reviewers using Microsoft Excel, with missing raw data obtained from the corre-
sponding authors via email. Information retrieved included the name of the first author,
year of publication, country, study design, type and duration of intervention, inclusion
and exclusion criteria, number of patients, and outcomes. The outcomes are mainly body
composition parameters (body weight, BMI, and waist circumference), glycemic control
(fasting glucose, fasting insulin, HbA1c, and homeostatic model assessment index of insulin
resistance (HOMA-IR)), and lipid profiles (total cholesterol, high-density lipoprotein (HDL),
low-density lipoprotein (LDL), and triglycerides).
The quality of the included RCTs was assessed according to the recommendations
of the Cochrane Handbook. These were based on the following processes: random se-
quence generation, allocation concealment, blinding participants and personnel, blinding
of outcome assessment, incomplete outcome data, selective reporting, and other bias. Con-
sequently, the risk of bias in randomized studies is classified into three scores, namely:
“low”, “high”, and “unclear”. Any disagreements during the analysis of the risk of bias
and quality of evidence were resolved by consensus, involving a third reviewer.

2.4. Statistical Analysis

Statistical analyses were performed using Review Manager software (Version 5.4, the
Cochrane Collaboration). Briefly, sample sizes, means and standard deviations (SD) of
continuous variables, before and after intervention, were extracted from each group and
presented as the means ± SD (M ± SD). The effects of ketogenic diets on overweight
T2DM patients were estimated by weighted standardized mean differences (SMDs), with
corresponding 95% confidence intervals (CIs) for each selected study. Heterogeneity among
studies was quantitatively evaluated by Cochrane’s Q test and I2 test. The I2 value, with a
value >50%, is considered high heterogeneity based on a random-effect model. Otherwise, a
fixed-effect model was implemented. All tests were two-tailed, and a statistically significant
difference was considered at p < 0.05. Begg’s funnel plots and Egger’s linear regression tests
were used for the detection of publication bias, and a symmetric funnel plot is considered a
low risk of publication bias.

3. Results
3.1. Study Selection
A summary of study selection in this meta-analysis is presented using the flow chart
shown in Figure 1. Initial screening of the aforementioned databases resulted in 481 articles,
with 83, 262, 95, and 41 articles from PubMed, Embase, Web of Science, and Cochrane
Library, respectively. Next, 156 duplicated studies were excluded, and the remaining
325 articles, whose titles and abstracts were subsequently screened, were included accord-
ing to the aforementioned selection criteria. Among them, 14 full-text articles remained
for eligibility assessment. Finally, eight RCTs remained for meta-analysis after carefully
reviewing the full texts [18–25].
 cles, with 83, 262, 95, and 41 articles from PubMed, Embase, Web of Science, and
Cochrane Library, respectively. Next, 156 duplicated studies were excluded, and the
remaining 325 articles, whose titles and abstracts were subsequently screened, were in-
cluded according to the aforementioned selection criteria. Among them, 14 full-text arti-
Int. J. Environ. Res. Public Health 2022,cles
19, 10429 4 of 12
remained for eligibility assessment. Finally, eight RCTs remained for meta-analysis
after carefully reviewing the full texts [18–25].

Figure 1. Flow chart of literature selection.

3.2. Study Characteristics

3.2. Study Characteristics
Details of the eight eligible studies are shown in Table 2. Briefly, these RCTs included a
Details of the eight eligible studies are shown in Table 2. Briefly, these RCTs in-
total of 611 participants diagnosed with T2DM, of which 331 participants were administered
cluded a total of 611 participants diagnosed with T2DM, of which 331 participants were
ketogenic diets comprising a daily dietary intake of carbohydrates less than 50 g. The
administered ketogenic diets comprising a daily dietary intake of carbohydrates less than
intervention duration varied from 3 months to 2 years. Notably, four trials were conducted
50 g. The intervention duration varied from 3 months to 2 years. Notably, four trials were
in the USA, two in Australia, and one each in Spain and Kuwait. All eight studies reported
conducted in the USA, two in Australia, and one each in Spain and Kuwait. All eight
the effects of post-intervention of ketogenic diets versus baseline on body weight change,
studies reported the effects of post-intervention of ketogenic diets versus baseline on
glycemic control, and lipid profiles in overweight T2DM patients.
body weight change, glycemic control, and lipid profiles in overweight T2DM patients.
3.3. Quality of the Included Trials
Table 2. Characteristics of included studies.
A summary of the risk of bias for each RCT is shown in Figure 2. One of the RCTs
First Au- Study exhibited
Interventiona high risk of performance bias, while another had a high risk of reporting bias
Inclusion
Country Exclusion Criteria Interventions N Outcomes
thor/Year Design because
Duration
data onCriteria
glycemic control and lipid profile are presented as linear graphs. Moreover,
one study had a high risk ofT2DM duration
detection bias,longer VLCKD:
while another had <50
a g/d
high risk of other bias due
45 body weight,
than 10
to the involvement of a Scientific years; insulin
Advisory carbohydrates
Board. Nevertheless, the included studies were
BMI, waist cir-
of high quality, with an therapy;risk
acceptable HbA1cof ≥ 9%;
bias.
Age: 30–65 cumference,
fasting C-peptide < 1
years old; LCD: a daily energy fasting plasma
Goday 3.4. Effects of Ketogenic Diet on Bodyng/mL.
Weight Change
Spain RCT 4 months BMI: 30–35 restriction of 500– glucose, HbA1c,
(2016) [21] All eight studies In addition: impaired
kg/m2;reported parameters in body 1000 weight
kcal,change, with44the fasting
<30% fat, resultsinsulin,
demon-
strating that T2DM patientsrenal or liver
exposed to function,
a ketogenic diet were more likely to record a higher
T2DM 10–20% protein, 45– HOMA-IR, total
body weight loss (SMD, −alcohol intake
5.63; 95% CI,≥ −409.76
g/d to
for−1.49; I2 = 60%; moderate heterogeneity,
60% carbohydrates. cholesterol, TG,
Figure 3A) and a reduction men and ≥circumference
in waist 24 g/d for (SMD, −2.32; 95% CI, −4.58 −0.06;
LDL,toHDL
2 women, pregnancy, lacta-
I = 52%; moderate heterogeneity, Figure 3B) when compared to those on other types of
diets. Notably, we found no statistical significance in SMD of BMI reduction (p = 0.14,
Figure 3C).
Int. J. Environ. Res. Public Health 2022, 19, 10429 5 of 12

Table 2. Characteristics of included studies.

First Study Intervention

Country Inclusion Criteria Exclusion Criteria Interventions N Outcomes
Author/Year Design Duration
T2DM duration longer than 10 years; insulin therapy; VLCKD: <50 g/d carbohydrates 45 body weight, BMI, waist
Age: 30–65 years old; HbA1c ≥ 9%; fasting C-peptide < 1 ng/mL. circumference, fasting plasma
Goday (2016) Spain In addition: impaired renal or liver function, alcohol intake LCD: a daily energy restriction of glucose, HbA1c, fasting insulin,
RCT 4 months BMI: 30–35 kg/m2 ;
[21] ≥ 40 g/d for men and ≥ 24 g/d for women, pregnancy, 500–1000 kcal, <30% fat, 10–20% 44 HOMA-IR, total cholesterol, TG,
T2DM
lactation, sever eating or psychiatric disorder. protein, 45–60% carbohydrates. LDL, HDL
HbA1c, LDL, HDL, TG, fasting
Age: >18 years old; BMI: ≥25 kg/m2 ; insulin or more than 3 glucose-lowering agents; oral LCKD: 20–50 g/d carbohydrates 16
Saslow (2014) glucocorticoids or weight loss medications; pregnancy; glucose and insulin, HOMA-IR,
[20] USA RCT 3 months T2DM (HbAc1 ≥ 6.5) or prediabetes
breastfeeding; weight loss surgery; vegan body weight, BMI,
(HbAc1 ≥ 6.0) MCCRD: 45–50% carbohydrates. 18 waist circumference
HbA1c, LDL, HDL, TG, fasting
Age: >18 years old; BMI: ≥ 25 kg/m2 ; LCKD: 20–50 g/d carbohydrates 16
Saslow insulin or more than 3 glucose-lowering agents glucose and insulin, HOMA-IR,
(2017a) [23] USA RCT 12 months T2DM (HbAc1 ≥ 6.5) or prediabetes
body weight, BMI,
(HbAc1 ≥ 6.0) MCCRD: 45–50% carbohydrates. 18 waist circumference
Age ≥ 18 years old; LCKD: 20–50 g/d carbohydrates 12
Saslow BMI ≥ 25 kg/m2 ; any diabetes medication other than metformin HbA1c, LDL, HDL, TG; body
(2017b) [25] USA RCT 32 weeks American Diabetes Associations’
T2DM (HbA1c 6.5–9.0) 13 weight, BMI, waist circumference
“Create Your Plate” diet
LCD: 14% carbohydrates (<50 g/d),
28% protein, 58% fat 58
Age: 35–68 years old; T1DM; impaired renal or liver function; overt (35% monounsaturated fat and HbA1c, LDL, HDL, total
BMI: 26–45 kg/m2 ; endocrinopathy; history of malignancy; respiratory 13% polyunsaturated fat) cholesterol, TG, fasting glucose and
Tay (2015) [18] Australia RCT 52 weeks
T2DM (HbA1c ≥ 7.0 and/or disease, gastrointestinal disease, or CVD; pregnancy or HCD: 53% carbohydrates, insulin, HOMA-IR, body weight,
antidiabetic treatment) lactation; history of or current eating disorder or smoking. 17% protein, 30% fat (15% BMI, waist circumference
57
monounsaturated fat and 9%
polyunsaturated fat)
LCD: 14% carbohydrates (<50 g/d),
Age: 35–68 years old; T1DM; renal, hepatic, respiratory, gastrointestinal, or 58 HbA1c, LDL, HDL, total
28% protein, 58% fat cholesterol, TG, fasting glucose and
Tay (2018) [19] Australia RCT 2 years BMI: 26–45 kg/m2 ; cardiovascular disease; history of malignancy; any
T2DM (HbA1c ≥ 7.0 and/or significant endocrinopathy; pregnancy/lactation; history HCD: 53% carbohydrates, insulin, HOMA-IR, body weight,
57 BMI, waist circumference
antidiabetic treatment) of or current eating disorder or smoking. 17% protein, 30% fat
Age: 18–65 years old; unstable or serious medical condition; significant HbA1c, fasting glucose, fasting
Westman
(2008) [24]
USA RCT 24 weeks BMI: 27–50 kg/m2 ; co-morbid illnesses such as liver disease, kidney disease, LCKD: <20 g/d carbohydrates 48 insulin, body weight, BMI, waist
T2DM > 1 year (HbA1c > 6.0); cancer; pregnancy; or nursing mothers. circumference

Age ≥ 18 years; body weight, BMI, waist

Hussain renal insufficiency, liver disease, or unstable circumference, HbA1c, fasting
(2012) [22] Kuwait RCT 24 weeks BMI > 25 kg/m2 ; LCKD: <20 g/d carbohydrates 78
cardiovascular disease. glucose, TG, total cholesterol,
fasting serum glucose > 6.9 mM. LDL, HDL.
Note: BMI: body mass index; T2DM: type 2 diabetes mellitus; TG: triglycerides; HbA1c: glycosylated hemoglobin; HOMA-IR: homeostasis model assessment of insulin resistance;
VLCKD: very low-carbohydrate ketogenic diet; LCKD: low-carbohydrate ketogenic diet; MCCRD: medium carbohydrate, low fat, calorie-restricted diet; HCD: high-carbohydrate diet;
LCD: low-carbohydrate diet; LGID: low-glycemic index diet.
 3.3. Quality of the Included Trials
A summary of the risk of bias for each RCT is shown in Figure 2. One of the RCTs
exhibited a high risk of performance bias, while another had a high risk of reporting bias
because data on glycemic control and lipid profile are presented as linear graphs.
Moreover, one study had a high risk of detection bias, while another had a high risk of
Int. J. Environ. Res. Public Health 2022, 19, 10429
other bias due to the involvement of a Scientific Advisory Board. Nevertheless, the in- 6 of 12
cluded studies were of high quality, with an acceptable risk of bias.

Int. J. Environ. Res. Public Health 2022, 19, x FOR PEER REVIEW 7 of 14

a higher body weight loss (SMD, −5.63; 95% CI, −9.76 to −1.49; I2 = 60%; moderate heter-
ogeneity, Figure 3A) and a reduction in waist circumference (SMD, −2.32; 95% CI, −4.58 to
−0.06; I2 = 52%; moderate heterogeneity, Figure 3B) when compared to those on other
types of diets. Notably, we found no statistical significance in SMD of BMI reduction (p =
Figure 2. Risk of bias summary.
2. Risk
0.14, Figure
Figure of bias summary.
3C).
3.4. Effects of Ketogenic Diet on Body Weight Change
All eight studies reported parameters in body weight change, with the results
demonstrating that T2DM patients exposed to a ketogenic diet were more likely to record

Figure 3.
Figure 3. Forest
Forestplots
plotsfor for
the the
effects of post-intervention
effects versus versus
of post-intervention baseline baseline
on weight
onchange in change in
weight
overweight T2DM patients. (A) Changes in body weight; (B) Changes in waist circumference; (C)
overweight T2DM patients. (A) Changes in body weight; (B) Changes in waist circumference;
Changes in BMI. The green squares represent individual effect sizes, and the black diamonds rep-
(C) Changes
resent pooling in BMI.
effect The green squares represent individual effect sizes, and the black diamonds
sizes.
represent pooling effect sizes.
3.5. Effects of Ketogenic Diet on Glycemic Control
Seven of the eight trials included studies reporting glycemic parameters, including
fasting glucose, HbA1c, fasting insulin, and HOMA-IR. With regard to HbA1c, we ob-
served a slightly higher decrease between the ketogenic and non-ketogenic diet groups
(SMD, −0.38; 95% CI, −0.61 to −0.16; I2 = 27%; low heterogeneity, Figure 4A) at baseline
 Int. J. Environ. Res. Public Health 2022, 19, 10429 7 of 12

3.5. Effects of Ketogenic Diet on Glycemic Control

Seven of the eight trials included studies reporting glycemic parameters, including
fasting glucose, HbA1c, fasting insulin, and HOMA-IR. With regard to HbA1c, we observed
a slightly higher decrease between the ketogenic and non-ketogenic diet groups (SMD,
−0.38; 95% CI, −0.61 to −0.16; I2 = 27%; low heterogeneity, Figure 4A) at baseline and
post-intervention. However, we found no significant differences in the overall effect for
fasting glucose (p = 0.74, Figure 4B), fasting insulin (p = 0.07, Figure 4C), and HOMA-IR
(p = 0.14, Figure 4D) between the intervention and control groups. Notably, the reduction
iron. Res. Public Health 2022, 19, x FOR PEER REVIEW
in fasting insulin approached borderline significance in favor of the8 ketogenic
of 14 diet group,
2
albeit with no significant heterogeneity (I = 0, Figure 4C).

Figure 4. Forest plots

Figurefor4.the effects
Forest of for
plots post-intervention versus baseline on
the effects of post-intervention glycemic
versus control
baseline in
on glycemic control in
overweight T2DMoverweight
patients. (A) Changes in HbA1c; (B) Changes in fasting glucose; (C) Changes
T2DM patients. (A) Changes in HbA1c; (B) Changes in fasting glucose; in (C) Changes in
fasting insulin; (D) Changes in HOMA-IR. The green squares represent individual effect sizes, and
fasting insulin; (D) Changes in HOMA-IR. The green squares represent individual effect sizes, and
the black diamonds represent pooling effect sizes.
the black diamonds represent pooling effect sizes.
3.6. Effects of Ketogenic Diet of
3.6. Effects onKetogenic
Lipid Profiles
Diet on Lipid Profiles
The results fromThesubgroup
results analysis, in the seven
from subgroup studies
analysis, that
in the reported
seven lipid
studies thatprofiles,
reported lipid profiles,
revealed that the ketogenic diet was associated with a significantly higher reduction
revealed that the ketogenic diet was associated with a significantly higher in reduction in
triglyceride levels (SMD, −0.36;
triglyceride 95%
levels CI, −0.55
(SMD, −0.36;to95%
−0.18;
CI,I −=0.55
2 2
0%;tohomogeneity,
−0.18; I = 0%; Figure 5A)
homogeneity, Figure 5A)
and an increaseandin HDL levels (SMD,
an increase in HDL 0.28; 95%(SMD,
levels CI, 0.09
0.28;to 95%
0.46;CI,
I2 =0.09 0.46; I2 = 0%; homogeneity,
0%;tohomogeneity,
Figure 5B). However,
Figurewe found
5B). no significant
However, we founddifferences withdifferences
no significant regard to changes in total
with regard to changes in total
cholesterol and LDL levels between
cholesterol and LDLthe ketogenic
levels between and
thenon-ketogenic
ketogenic anddiet groups (p = diet
non-ketogenic 0.97 groups (p = 0.97
and p = 0.26, respectively, Figure 5C,D), despite a lack of heterogeneity in both lipid pa-
rameters between the groups.
 Int. J. Environ. Res. Public Health 2022, 19, 10429 8 of 12

on. Res. Public Health 2022, 19, x FOR PEER REVIEW 9 of 14

and p = 0.26, respectively, Figure 5C,D), despite a lack of heterogeneity in both lipid
parameters between the groups.

Figure 5. Forest plots for the

Figure effects
5. Forest of post-intervention
plots versus baseline versus
for the effects of post-intervention on lipid profiles
baseline onin over-
lipid profiles in overweight
weight T2DM patients. (A) Changes in fasting triglycerides; (B) Changes in HDL; (C) Changes in
T2DM patients. (A) Changes in fasting triglycerides; (B) Changes in HDL; (C) Changes in total
total cholesterol; (D) Changes in LDL. The green squares represent individual effect sizes, and the
cholesterol; (D) Changes in LDL. The green squares represent individual effect sizes, and the black
black diamonds represent pooling effect sizes.
diamonds represent pooling effect sizes.
4. Discussion 4. Discussion
In the present meta-analysis,
In the present the results from eight
meta-analysis, studies
the results reporting
from the effect
eight studies of a the effect of a
reporting
ketogenic diet onketogenic
patients with T2DM revealed that this diet is an effective intervention
diet on patients with T2DM revealed that this diet is an effective intervention for
for lowering body weightbody
lowering and weight
glycemicandlevels, as levels,
glycemic well asasimproving lipid profiles
well as improving in
lipid profiles in overweight
overweight diabetic patients.
diabetic Notably,
patients. the the
Notably, ketogenic dietdiet
ketogenic exhibited excellent
exhibited excellentbenefits in in reducing body
benefits
reducing body weight,
weight, waist circumference, HbA1c,
waist circumference, HbA1c,and andtriglycerides,
triglycerides, as as
wellwell as in-
as increasing HDL.
creasing HDL. Obesity, which is highly prevalent in patients with T2DM, has been associated with
Obesity, which is highly
chronic prevalentstatuses,
inflammation in patients
suchwith T2DM, has been
as mitochondrial associatedendoplasmic
dysfunction, with reticulum
chronic inflammation statuses, such as mitochondrial dysfunction, endoplasmic reticu-
stress, and hyperinsulinemia [26]. Body weight control is considered an effective inter-
lum stress, and hyperinsulinemia
vention strategy for [26]. Body weight
attenuating control
insulin is considered
resistance induced by anobesity
effective[27,28]. Numerous
intervention strategy for attenuating
meta-analyses insulinhave
and reviews resistance induced
investigated the by obesity
effect [27,28]. Nu-
of a ketogenic diet on body weight
merous meta-analyses
controland
andreviews
found thathave investigated
nutritional the is
ketosis effect of a ketogenic
a beneficial process diet on weight manage-
in body
mentand
body weight control [29–31].
found Similarly, the results
that nutritional from is
ketosis thea present study
beneficial demonstrated
process in body that a ketogenic
weight management [29–31]. Similarly, the results from the present study demonstrated
that a ketogenic diet is a significantly superior intervention over other diets with regard
to reducing body weight in obese T2DM patients (Figure 3). Additionally, ketogenic di-
Int. J. Environ. Res. Public Health 2022, 19, 10429 9 of 12

diet is a significantly superior intervention over other diets with regard to reducing body
weight in obese T2DM patients (Figure 3). Additionally, ketogenic diet-based interven-
tion was associated with a significant reduction in waist circumference, a parameter of
central obesity that has been shown to be an important risk factor for the progression and
prognosis of diabetes and related complications [32]. Moreover, there was no significant
difference between the groups in terms of BMI reduction, which is the most commonly
used parameter for assessing obesity. The observed significant reduction in body weight
after ketogenic diet intervention (Figure 3A) might be due to attenuation of decreased
resting energy expenditure modulation, as previously reported [33]. However, the exact
mechanisms of a ketogenic diet on body weight loss remain unclear. For instance, some
mechanistic studies have indicated that a ketogenic diet can suppress appetite by either
directly affecting ketone bodies [34] or regulating appetite control hormones [35]. On the
other hand, other evidence has demonstrated a great metabolic efficiency of fat consump-
tion by reducing the resting respiratory quotient in patients assigned to a ketogenic diet [36].
Moreover, other findings have suggested that the high consumption of fat after ketogenic
diets might be due to reduced lipogenesis, increased lipolysis, and increased metabolic
costs of gluconeogenesis [37]. Regardless of the underlying mechanism of action, it is
evident that a ketogenic diet exerts a remarkable effect on body weight loss in overweight
patients with T2DM.
Extreme restriction of daily dietary intake of carbohydrates causes a decline in the
absorption of monosaccharides, reduces blood glucose levels, and limits blood glucose
fluctuations, indicative of positive regulation of glucose metabolism [38,39]. Consequently,
this phenomenon may contribute to the benefit of a ketogenic diet on glycemic control
in T2DM patients. HbA1c levels can reflect average blood glucose concentrations in the
past 2–3 months in patients with T2DM; hence, it has been recommended as an effective
parameter for monitoring long-term glycemic regulation and a risk predictor [40]. The
results of the present meta-analysis revealed that the consumption of a ketogenic diet was
likely to induce a greater reduction in HbA1c in overweight patients with T2DM than in
those under other types of diets (Figure 4). Moreover, the intervention duration of the
included studies was at least 3 months; thus, the change in HbAlc between baseline and
post-intervention can be used to effectively evaluate the efficacy of a ketogenic diet for
controlling blood glucose levels. This result was consistent with those reported in other
systemic reviews and meta-analyses, in which a ketogenic diet was found to remarkably
improve glycemic profiles [41]. Furthermore, accumulating evidence has demonstrated
a strong relationship between insulin resistance and the ketogenic diet [42,43]. A mild in-
crease in ketosis in peripheral blood, induced by a ketogenic diet, might improve peripheral
insulin sensitivity, relieve hyperinsulinemia-related stress, reduce external insulin require-
ments, and inhibit its secretion, thereby improving glycemic profiles and mitigating insulin
resistance [44]. Moreover, ketone bodies can increase the concentration of intracellular
glucose and generate metabolic effects similar to those of insulin, but without activating the
insulin signaling pathway, which allows for a therapeutic effect of mild ketosis in insulin
resistance states [42]. In the present meta-analysis, although we found no evidence that
such an intervention could significantly affect fasting insulin levels in diabetic patients, the
reduction in insulin levels approached borderline significance in favor of the ketogenic diet
group, with excellent homogeneity, suggesting that this diet has potential health benefits
on insulin profiles.
The majority of daily calories are from fat intake in a ketogenic diet, and increasing
fat consumption may improve lipid profiles in obese diabetic patients, as previously
described [45]. Interestingly, the consumption of a ketogenic diet could result in the
improved lipid profiles and remarkably improved glucose metabolism [41]. In the current
meta-analysis, seven out of the eight clinical trials reported the analysis of lipid profiles,
including triglycerides, total cholesterol, HDL, and LDL. Our results revealed statistically
significant changes in triglycerides and HDL levels after ketogenic diet consumption,
which may be attributed to the inclusion criteria used to select the participants (Figure 5).
Int. J. Environ. Res. Public Health 2022, 19, 10429 10 of 12

Notably, the recruited individuals were overweight T2DM patients, with a BMI > 25 kg/m2 ,
and who’s glycemic and lipid profiles were in a total mess. In addition, the basal lipid
biomarkers were much higher than that of healthy controls, suggesting the possibility that
a strict diet intervention might induce significant changes [46]. Since the components of
diabetic dyslipidemia were mostly related to insulin resistance [47], the improvement of
dysfunctional lipid profiles could reduce the risks of cardiovascular diseases in diabetic
patients [48]. Although we did not explore the cardioprotective effects of a ketogenic
diet in overweight patients with T2DM, the potential therapeutic effects of such dietary
management on cardiovascular diseases cannot be ignored. Previous mechanistic studies
have shown that the improvement of dyslipidemia induced by a ketogenic diet may not
only benefit the regulation of insulin sensitivity, but also control and prevent the occurrence
and progression of related complications [49,50].
Similarly, this study has some limitations. First, only eight studies were enrolled in
our meta-analysis, owing to a limited number of studies that have evaluated the effect of a
ketogenic diet on T2DM patients. Second, the included studies did not have some data on
body weight change, glycemic control, or lipid profile, which may generate biases toward
the overall effect. Third, none of these studies were carried out in East Asian countries, and
the included individuals were more likely to be Caucasians, which may generate population
bias. Fourth, although the Cochrane risk approach is the most recommended method for
analyzing the risk of bias in RCTs, it has been associated with limitations, especially
when assessing some complicated and complex interventions involved in behavior or
lifestyle [51].

5. Conclusions
The results of the current meta-analysis reveal that ketogenic diet intervention has
remarkable benefits on body weight and glycemic control, as well as the improvement
of lipid profiles in overweight T2DM patients. Specifically, a ketogenic diet can reduce
body weight, waist circumference, HbA1c, and triglycerides, and increase HDL levels.
Thus, the ketogenic diet intervention for overweight T2DM patients could be considered.
Moreover, the ketogenic diet could reveal more benefits to the improved body compositions
for mitigating the development and progression of T2DM due to overweight or obesity
by lowering body weight, reducing glycemic levels, and improving lipid profiles. In the
future, comprehensive mechanistic studies need to be conducted to underpin associations
between ketogenic diets and overweight patients with T2DM, and even confirmed by
experimental exploration.

Author Contributions: Conceptualization, N.C. and G.H.; methodology, C.Z. and M.W.; formal
analysis, C.Z., M.W. and J.L.; investigation, C.Z. and M.W.; data curation, C.Z., M.W. and J.L.;
writing—original draft preparation, C.Z. and M.W.; writing—review and editing, N.C., G.H., C.Z.
and M.W. All authors have read and agreed to the published version of the manuscript.
Funding: This study was funded by the National Natural Science Foundation of China under Grant
(No. 31771318) to N.C., and the Fundamental Research Funds for the Central Universities under
Grant (2021yjsCXCY095) to M.W., as well as the Chutian Scholar Program and Innovative Start-Up
Foundation from Wuhan Sports University to N.C.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data that support the findings of this study are available from the
corresponding author upon reasonable request.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Environ. Res. Public Health 2022, 19, 10429 11 of 12

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