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SYSTEMATIC REVIEW
published: 08 November 2021
doi: 10.3389/fnut.2021.748075
Frontiers in Nutrition | www.frontiersin.org 1November 2021 | Volume 8 | Article 748075
Edited by:
Clelia Madeddu,
University of Cagliari, Italy
Reviewed by:
Sidney B. Peres,
State University of Maringá, Brazil
Marco Vacante,
University of Catania, Italy
*Correspondence:
Dong-Dong Wang
13852029591@163.com
Su-Mei He
hehe8204@163.com
You-Mei Wang
wym15861703855@163.com
†These authors have contributed
equally to this work
Specialty section:
This article was submitted to
Clinical Nutrition,
a section of the journal
Frontiers in Nutrition
Received: 07 August 2021
Accepted: 11 October 2021
Published: 08 November 2021
Citation:
Wang D-D, Wang T-Y, Yang Y, He S-M
and Wang Y-M (2021) The Effects of
L-Carnitine, Acetyl-L-Carnitine, and
Propionyl-L-Carnitine on Body Mass
in Type 2 Diabetes Mellitus Patients.
Front. Nutr. 8:748075.
doi: 10.3389/fnut.2021.748075
The Effects of L-Carnitine,
Acetyl-L-Carnitine, and
Propionyl-L-Carnitine on Body Mass
in Type 2 Diabetes Mellitus Patients
Dong-Dong Wang 1
*†, Tian-Yun Wang 2†, Yang Yang 3†, Su-Mei He 4
*and You-Mei Wang 2
*
1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University,
Xuzhou, China, 2Department of Pharmacy, Huaian Hospital of Huaian City, Huaian, China, 3Department of Pharmacy, The
Affiliated Changzhou Children’s Hospital of Nantong University, Changzhou, China, 4Department of Pharmacy, The Affiliated
Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, China
Purpose: The study aimed to explore the effects of l-carnitine, acetyl-l-carnitine, and
propionyl-l-carnitine on Body Mass in type 2 diabetes mellitus (T2DM) patients.
Methods: Randomized controlled trial (RCT) studies of l-carnitine, acetyl-l-carnitine, and
propionyl-l-carnitine in T2DM patients were searched. The change rates of Body Mass
index (BMI) from baseline values were used as an evaluation indicator. The maximal
effect (Emax) model by non-linear mixed-effect modeling (NONMEM) was used as the
evaluation method.
Results: A total of 10 RCT studies, 1239 T2DM patients were included for
analysis, including eight studies of l-carnitine, one study of acetyl-l-carnitine, and
one study of propionyl-l-carnitine. The study found that l-carnitine could reduce the
Body Mass of T2DM patients. Based on only one study each for acetyl-l-carnitine
and propionyl-l-carnitine, no significant effects were found in acetyl-l-carnitine or
propionyl-l-carnitine. In addition, in order to achieve a plateau of efficacy (80% Emax),
2 g/day l-carnitine was required for at least 2 weeks.
Conclusions: Two g/day l-carnitine was required for at least 2 weeks to affect Body
Mass in T2DM patients, and no significant effects were found in acetyl-l-carnitine
or propionyl-l-carnitine.
Keywords: l-carnitine, acetyl-l-carnitine, propionyl-l-carnitine, Body Mass, type 2 diabetes mellitus
HIGHLIGHTS
- The present study analyzed the effects of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine
on Body Mass in T2DM patients.
- L-carnitine could reduce the Body Mass of T2DM patients, in which 2 g/day l-carnitine was
required for at least 2 weeks.
- No significant effects on Body Mass were found from acetyl-l-carnitine or propionyl-l-carnitine
in T2DM patients.
Wang et al. Carnitine Effects on BMI in T2DM
INTRODUCTION
Type 2 diabetes mellitus (T2DM), a chronic degenerative disease
where the pancreas cannot produce enough insulin and/or
the insulin produced is inefficient, causing hyperglycemia, is
a major health problem and one of the top 10 causes of
mortality worldwide (1). According to the International Diabetes
Federation (IDF) (2019), 9.3% of adults around the world,
amount to 463 million people, have T2DM (1). This number
is expected to increase increase to 700 million people by 2045,
which is equivalent to 10.90% of the adult population worldwide
(1). In addition, T2DM is also an important risk factor for chronic
kidney disease, cardiovascular disease, and mortality (2).
From a clinical point of view, T2DM patients are often
accompanied by obesity, atherosclerotic disease, dyslipidemia,
and hypertension (3,4), in which more than 50% of T2DM
patients have been reported to be obese (3,5). Overweight or
obesity in T2DM can increase the cardiovascular disease risk
and further increase the risk of death, which are important
determinants of the prognosis in T2DM patients (5,6). Therefore,
intensive therapy for T2DM patients with overweight or obesity
is crucial (2).
At present, many drugs have been used to control blood
glucose and Body Mass in T2DM patients, among which Wang et
al. report the quantitative efficacy of l-carnitine supplementation
on glycemic control in T2DM patients (7). However, the effects
of l-carnitine, as well as its other forms of existence, acetyl-
l-carnitine, and propionyl-l-carnitine on Body Mass in T2DM
patients are still unclear. The present study is to explore the
effects of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine
on Body Mass in T2DM patients.
METHODS
Literature Search and Data Extraction
We searched and extracted the Pubmed database (https://
pubmed.ncbi.nlm.nih.gov/) with the deadline of April 2021.
Only English publications were included. The terms “l-carnitine,”
“acetyl-l-carnitine,” “propionyl-l-carnitine,” and “type 2 diabetes
mellitus” were used in the present search strategy. Inclusion
criteria included: (I) randomized controlled trial (RCT), (II)
with Body Mass Index (BMI) information, (III) exact dose
and duration of l-carnitine, acetyl-l-carnitine, and propionyl-l-
carnitine. Source, country, grouping, sample size, age, duration of
treatment et al were extracted from the above-included studies.
In order to eliminate the potential baseline effect, the efficacy
of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine were
evaluated using BMI change rate from the baseline value. The
Formula (1) was as follows:
E% =Et−Eb
Eb
×100% (1)
Et, the value of BMI at time t; Eb, the value of BMI at baseline.
Model Establishment
The Emax model was used to evaluate the effects of l-carnitine,
acetyl-l-carnitine or propionyl-l-carnitine on Body Mass in
T2DM patients. In addition, in order to acquire the actual effects
on BMI from l-carnitine, acetyl-l-carnitine, and propionyl-l-
carnitine, the control effects need to be subtracted from the sum
effects. The Formulas (2) and (3) were as follows:
ED,i,j =EI,i,j −EC,i,j (2)
ED,i,j =Emax, i, j ×Time
ET50, i, j +Time +εi, j
qNi, j
100
(3)
EI,i,j, the sum effects on BMI from l-carnitine, acetyl-l-carnitine
or propionyl-l-carnitine, including actual effects and control
effects; ED,i,j, the actual effects on BMI; EC,i,j , the control effects on
BMI; i, different studies; j, the time point of every study; Emax, the
maximal effects on BMI; ET50, the treatment duration to reach
half of the maximal effects on BMI; εi,j, the residual error of study
i with j time; Ni,j, the sample size in study i with time point j. εi,j
was weighted by sample size, assumed to be normally distributed,
with a mean of 0 and variance of σ2/(Ni,j/100).
The inter-study variability was described by exponential error
or additive error models. The Formulas (4)–(7) were as follows:
Emax,i,j =Emax ×exp(η1,i) (4)
ET50,i,j =ET50 ×exp(η2,i) (5)
Emax,i,j =Emax +η1,i (6)
ET50,i,j =ET50 +η2,i (7)
η1,i,η2,i were the inter-study variabilities, when available, they
would be added into Emax, and ET50 , respectively. η1,i,η2,i
were assumed to be normally distributed, with a mean of 0 and
variance of ω1,i2,ω2,i 2, respectively.
In addition, continuous covariates and categorical covariates
were evaluated by Formulas (8)–(9) and (10):
Pp=PT+(COV −COVm)·θc(8)
Pp=PT×(COV/COVm)θc(9)
Pp=PT+COV ×θc(10)
Pp, the parameter for a patient with a covariate value of COV;
PT, the typical value of the parameter; COV, covariate; COVm,
the median value of covariable in the population. θc, a correction
coefficient of the covariate to the model parameter.
The model development was done using non-linear mixed-
effect modeling (NONMEM, edition 7, ICON Development
Solutions, Ellicott City, MD, USA). When a basic model was
built, potential covariates were considered for adding into Emax.
The change of objective function value (OFV) was used as the
covariate inclusion criteria. When the decrease of OFV was >3.84
(χ2,α=0.05, d.f. =1), it was considered sufficient for inclusion.
When the increase of OFV was >6.63 (χ2,α=0.01, d.f. =1), it
was considered sufficient for significance in the final model (8).
Model Validation and Prediction
The goodness-of-fit plots of the model (individual predictions
vs. observations), distribution of conditional weighted residuals
(CWRES) for the model (density vs. CWRES, and quantiles
Frontiers in Nutrition | www.frontiersin.org 2November 2021 | Volume 8 | Article 748075
Wang et al. Carnitine Effects on BMI in T2DM
of CWRES vs. quantiles of normal), and individual plots
from different studies were used to estimate the final model.
Prediction-corrected visual predictive check (VPC) plots were
FIGURE 1 | Overview of the strategy for literature review.
used to assess the predictive performance of the final model.
In addition, the medians and 2.5th−97.5th percentiles of the
results from bootstrap (Simulation, n=1,000) were used to
compare with final model parameters. The efficacy prediction of
l-carnitine on BMI in T2DM patients was simulated by the Monte
Carlo method.
RESULTS
Included Studies
Figure 1 was the retrieval process and a total of 10 RCT
studies, comprising 1,239 T2DM patients were included for
analysis, including 8 studies of l-carnitine (9–16), 1 study of
acetyl-l-carnitine (17), and 1 study of propionyl-l-carnitine (18).
The dosages of l-carnitine, acetyl-l-carnitine, and propionyl-l-
carnitine were 2–3, 2, and 2 g/day, respectively, in the included
studies, and the details were shown in Table 1, and part of
the literature was retrieved from the previous study (7). The
risk of bias analysis was shown in Figure 2. As both acetyl-l-
carnitine, and propionyl-l-carnitine had only 1 study, model-
based meta-analysis (MBMA) could not be performed at this
time for them. Further analysis found that no significant effects
on BMI in acetyl-l-carnitine or propionyl-l-carnitine in T2DM
patients. Therefore, the following MBMA analysis was mainly
aimed at l-carnitine.
Modeling and Validation
The actual drug effects of l-carnitine on BMI in T2DM patients
is shown in Table 2, the Emax of l-carnitine on BMI in T2DM
patients was −1.51% and the ET50 of l-carnitine on BMI
in T2DM patients was 0.5 weeks. In addition, no covariate
TABLE 1 | Included randomized controlled studies.
Study Country Group Sample size Age Duration
Intervention Control Intervention Control Intervention Control
El-Sheikh
et al. (16)
Egypt 2 g/day L-carnitine +4 mg/day
glimepiride
4 mg/day
glimepiride
31 27 50.9 ±8.6 50.3 ±8.8 6 months
Derosa et al.
(14)
Italy 2 g/day L-carnitine +360 mg/day
orlistat
360 mg/day
orlistat
132 126 51.0 ±4.0 53.0 ±6.0 12 months
Derosa et al.
(15)
Italy 2 g/day L-carnitine +10 mg/day
sibutramine
10 mg/day
sibutramine
129 125 54.0 ±5.0 51.0 ±4.0 12 months
Malaguarnera
et al. (13)
Italy 2 g/day L-carnitine +20 mg/day
simvastatin
20 mg/day
simvastatin
40 40 47.0 ±13.0 45.0 ±12.0 12 weeks
Malaguarnera
et al. (12)
Italy 2 g/day L-carnitine +placebo placebo 41 40 49.0 ±13.0 48.0 ±11.0 3 months
Galvano et al.
(11)
Italy 2 g/day L-carnitine +20 mg/day
simvastatin
20 mg/day
simvastatin
38 37 52.1 ±8.1 51.4 ±7.6 4 months
Derosa et al.
(10)
Italy 2 g/day L-carnitine +Placebo Placebo 46 48 52.0 ±6.0 50.0 ±7.0 6 months
Liang et al. (9) China 3 g/day L-carnitine +Placebo Placebo 23 23 59.4 ±1.7 57.9 ±2.6 12 weeks
Parvanova
et al. (17)
Italy 2 g/day Acetyl-L-
carnitine
+Placebo Placebo 109 110 64.9 ±7.7 64.6 ±7.5 6 months
Santo et al.
(18)
Italy 2 g/day
Propionyl-L-carnitine
+Placebo Placebo 37 37 61.75 ±3.03 61.26 ±1.6 12 months
Part of the literature was retrieved from the previous study (7).
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Wang et al. Carnitine Effects on BMI in T2DM
FIGURE 2 | Risk of bias analysis.
TABLE 2 | Parameter estimates of final model and 95% confidential interval.
Parameter Estimate Simulation (n=1,000) Bias (%)
Median 95% confidence interval
Emax, % −1.51 −1.51 [−8.82, −0.62] 0
ET50, week 0.5 0.5 [0.5, 37.2] 0
ωEmax 1.345 1.200 [0.003, 6.982] −10.781
ωET50 0.003 0.003 [0.003, 9.798] 0
ε0.414 0.415 [0.159, 0.789] 0.242
95% confidential interval was showed with 2.5th, 97.5th percentile; Emax was the maximal
effects; ET50 was the treatment duration to reach half of Emax;ωEmax was the inter-study
variability of Emax;ωET 50 was the inter-study variability of ET50;εwas the residual error;
Bias =(Median-Estimate)/Estimate ×100%.
(in particular dosage) was incorporated into the Emax model,
showing there was no significant dose-dependence from l-
carnitine efficacy on BMI in T2DM patients in the present study.
The Emax model of l-carnitine on BMI in T2DM patients was
shown in Formulas (11):
E=−1.51% ×Time
0.5 +Time (11)
E, efficacy of l-carnitine on BMI; Time, l-carnitine
treatment duration.
The visual inspection of routine diagnostic plots, and
individual predictions vs. observations, are shown in Figure 3A.
The distribution of CWRES for model (density vs. CWRES,
and quantilies of CWRES vs. quantiles of normal) are shown
in Figures 3B,C. Individual plots from different studies are
shown in Figure 3D. As we could see, there were good linear
relationships between individual predictions and observations,
and individual plots were also consistent meaning the good fitting
of the final models. At the same time, the distribution of the
model also satisfied the normal distribution.
The VPC plots are shown in Figure 4, and most observed
data were included in the 95% prediction intervals produced
by simulation data, which shows the predictive power of the
final models.
Prediction
We also simulated the curve of the final model for the effect of
l-carnitine on BMI via the Monte Carlo method. The trend of
the efficacy of l-carnitine on BMI in T2DM patients is shown
in Figure 5. As we could see from the curve, the efficacy of l-
carnitine on BMI at 0.5 weeks was 50% of the Emax, at 2 weeks
was 80% of the Emax (plateau stage), at 4.5 weeks was 90% of
the Emax, at 9.5 weeks was 95% of the Emax . In the current study,
the dose range was 2–3 g/day and there was no significant dose-
dependence from l-carnitine efficacy on BMI in T2DM patients,
so the lower dose of 2 g/day was selected as recommended dose.
In addition, in order to achieve a plateau of efficacy (80% Emax),
2 g/day l-carnitine was required for at least 2 weeks.
DISCUSSION
Carnitine is derived from amino acids and is found in almost
all cells in the body (19). Its name comes from the Latin
carnus, meaning meat, because the compound is extracted
from meat (19). Carnitine is a generic term, which includes l-
carnitine, acetyl-l-carnitine, and propionyl-l-carnitine (20). L-
carnitine plays an important role in energy metabolism (21).
It transfers long-chain fatty acids to cell mitochondria for
oxidation, which produces energy needed by the body (21,
22). It also transports harmful substances out of the organelle,
preventing them from accumulating in the cell (21). Because
of these functions, carnitine is found in high concentrations in
skeletal muscle and cardiac muscle cells, which allow them to
use fatty acids as an energy source (20). For most people, the
body can make enough to meet its needs, but for some people,
because of genetic or pharmaceutical reasons, the body cannot
produce enough, it is, therefore, an essential nutrient for these
individuals (23).
As is well-known, l-carnitine can adjust many events,
such as metabolism of glucose and fatty acids, and has the
Frontiers in Nutrition | www.frontiersin.org 4November 2021 | Volume 8 | Article 748075
Wang et al. Carnitine Effects on BMI in T2DM
FIGURE 3 | Model evaluation. (A) individual predictions vs. observations for the model from the effect of l-carnitine on BMI. (B) distribution of conditional weighted
residuals (CWRES) for model (density vs. CWRES). (C) distribution of CWRES for model (quantiles of CWRES vs. quantiles of normal). (D) individual plots for the
model from the effect of l-carnitine on BMI.
FIGURE 4 | Visual predictive check of the model from the l-carnitine effect on
BMI. Median, 2.5% CI and 97.5% CI were simulated by Monte Carlo (n=
1,000); CI, confidence interval; From a to h were studies come form El-Sheikh
et al. (16), Derosa et al. (14), Derosa et al. (15), Malaguarnera et al. (13),
Malaguarnera et al. (12), Galvano et al. (11), Derosa et al. (10), Liang et al. (9),
respectively.
potential to protect these cellular events in several manners
including decreasing the production of reactive oxygen species
at different points and maintaining mitochondrial functions
FIGURE 5 | Model prediction.
(24). In addition, it has been reported that l-carnitine had
many important pharmacological actions (24–31), for example,
l-carnitine has a potential therapeutic effect in treating insulin
resistance (32). It is also reported that l-carnitine can improve
glycemia in T2DM patients (33). Wang et al.’s report provides
valuable quantitative information for the efficacy of l-carnitine
supplementation on glycemic control in T2DM patients (7).
Frontiers in Nutrition | www.frontiersin.org 5November 2021 | Volume 8 | Article 748075
Wang et al. Carnitine Effects on BMI in T2DM
They find that for the efficacy of l-carnitine on fasting plasma
glucose (FPG), 2 g/day l-carnitine is required for at least 36.1
weeks; For the efficacy of l-carnitine on glycated hemoglobin
(HbA1c), 2 g/day l-carnitine is required for at least 106 weeks
(7). However, the effects of l-carnitine, as well as its other
forms of existence, acetyl-l-carnitine, and propionyl-l-carnitine
on Body Mass in T2DM patients are still unclear. The purpose
of this study is to explore the effects of l-carnitine, acetyl-l-
carnitine, and propionyl-l-carnitine on Body Mass in T2DM
patients by MBMA.
In the present study, a total of 10 RCT studies comprising
1,239 T2DM patients were included for analysis, including 8
studies of l-carnitine (9–16), 1 study of acetyl-l-carnitine (17),
and 1 study of propionyl-l-carnitine (18). The dosages of l-
carnitine, acetyl-l-carnitine, and propionyl-l-carnitine were 2–
3, 2, and 2 g/day, respectively, in the included studies. Of
course, when investigating the efficacy of a drug on Body Mass,
important factors should be stable such as diet, antiglycemic
drugs, and duration of T2DM. Fortunately, since our study
was from RCTs, conditions in the intervention group and the
control group were similar in each study. In this way, the control
group effects were deducted from the intervention group, and
the actual l-carnitine drug effects were obtained. In addition,
we also considered the impact of various indicators in different
studies on baseline values. In addition, as for both acetyl-l-
carnitine, and propionyl-l-carnitine had only 1 study, MBMA
analysis could not be performed at this time for them. Further
analysis found no significant effects on BMI in acetyl-l-carnitine
or propionyl-l-carnitine in T2DM patients.
In further analysis of the effects of l-carnitine on Body Mass
in T2DM patients, we found the Emax of l-carnitine on BMI
in T2DM patients was −1.51% and the ET50 of l-carnitine
on BMI in T2DM patients was 0.5 weeks. In addition, no
covariate (in particular dosage) was incorporated into the Emax
model, showing there was no significant dose-dependence from l-
carnitine efficacy on BMI in T2DM patients. In the current study,
the dose range was 2–3 g/day, there was no significant dose-
dependence from l-carnitine efficacy on BMI in T2DM patients,
so the lower dose of 2 g/day was selected as recommended
dose. In addition, in order to achieve a plateau of efficacy (80%
Emax), 2 g/day l-carnitine was required for at least 2 weeks.
From the current view, l-carnitine could play an important
role in glucose metabolism and increase energy expenditure,
meanwhile, l-carnitine had a role in lipid metabolism as well
(34–36). For these two reasons, l-carnitine helps Body Mass
loss by increasing energy expenditure (36). However, this
study had some limitations. The number of studies currently
included was limited, and additional studies were needed in
the future.
CONCLUSIONS
Two gram per day l-carnitine was required for at least 2 weeks
to affect Body Mass in T2DM patients, and no significant effects
were found in acetyl-l-carnitine or propionyl-l-carnitine.
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
AUTHOR CONTRIBUTIONS
D-DW, S-MH, and Y-MW conceived and designed the study. D-
DW, T-YW, YY, and S-MH collected and analyzed data. D-DW
wrote the paper. S-MH reviewed and edited the manuscript. All
authors read and approved the final manuscript.
FUNDING
This work was supported by the Initializing Fund of Xuzhou
Medical University (No. RC20552111), the Fusion Innovation
Project of Xuzhou Medical University (No. XYRHCX2021011),
the Xuzhou Special fund for promoting scientific and
technological innovation (No. KC21257), the Suzhou
Science & Technology Town Hospital pre-research fund
project (No. 2019Y01), the Suzhou Science and Technology
Development Plan Project (No. S YSD2019076), and the Jiangsu
Pharmaceutical Society-Tianqing Hospital Pharmaceutical Fund
Project (No. Q202024).
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