, Meysam Zarezadeh 1,2,*
, Mahsa Malekahmadi 3, Parsa Jamilian 4, Parmida Jamilian 5, Roghayeh Molani-Gol 1,2, Alireza Ostadrahimi 21 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
2 Nutrition Research Center, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
3 Faculty of Nutrition and Diet Therapy, Tehran University of Medical Sciences, Tehran, Iran
4 Keele University School of Medicine, Keele University, Staffordshire, UK
5 School of Pharmacy and Bio Engineering, Keele University, Staffordshire, UK
Abstract
Obesity, one of the most frequent health risks, represents a global public health problem. The potential impact of L-carnitine, a vital nutrient for energy metabolism, on weight loss is worth considering. However, given the inconclusive results from recent meta-analyses on L-carnitine, we conducted an umbrella meta-analysis of placebo-controlled and controlled trials to evaluate the effect of L-carnitine on anthropometric indices.
Data synthesis: A comprehensive search approach using the relevant keywords was performed in PubMed, Web of Science, Scopus databases, and Google Scholar up to March 2023. Meta-analyses published in English that provided quantitative statistical analyses regarding the effects of L-carnitine on body weight, waist circumference (WC), and body mass index (BMI) were included. A random-effects model and subgroup analysis were performed based on the L-carnitine dosage and study population.
A total of 16,352 participants were included. Intervention durations ranged from 8 to 30 weeks, with L-carnitine dosages ranging between 150 and 4000 mg/day. The pooled results of the eight included meta-analyses indicated that L-carnitine supplementation can significantly decrease weight (effect size (ES) = –1.11; 95% confidence intervals (CIs): –1.90, –0.33, p = 0.005; I2 = 90.6%, p < 0.001), BMI (ES = –0.33; 95% CI: –0.61, –0.04, p = 0.026; I2 = 89.8%, p < 0.001), and WC (ES = –1.34; 95% CI: –1.83, –0.85, p < 0.001; I2 = 00.0%, p = 0.442).
The findings of this umbrella meta-analysis support that supplementation of L-carnitine supplementation can successfully manage weight, BMI, and WC reduction. Therefore, L-carnitine might help treat obesity.
CRD42022307951.
Keywords
- body weight
- body mass index
- waist circumference
- weight loss
- lipotropic supplementation
- anthropometric
Obesity, as one of the most frequent health risks, is a public health problem in the general population around the world [1]. Based on the World Health Organization (WHO) reports, 39% of worldwide adults were overweight and 13% were obese in 2016. Globally, the prevalence of obesity has nearly tripled from 1975 to 2016 [2]. Body mass index (BMI) and waist circumference (WC) are simple indices commonly used to classify overweight and obesity in adults and predict obesity-related health risks [3, 4]. Obesity is a chronic disorder that is associated with developing non-communicable diseases [5]. In fact, increased BMI is a major risk factor for diabetes, cardiovascular diseases, some cancers, and many other non-communicable diseases and play role in increasing premature death and disability in adulthood [6]. It also has been reported that medical costs for obese people are higher than people with healthy weight [7]. There are different approaches for obesity management such as lifestyle modifications and pharmacological or herbal interventions [8]. Although there are various dietary supplements for weight management on the market, there is not sufficient evidence regarding their effectiveness [9, 10]. L-carnitine is one of the supplements claimed to be efficacious on weight loss [11].
Carnitine or beta-hydroxy-gamma-methyl ammonium butyrate is a hydrophilic molecule which consists of two amino acids: lysine and methionine. Carnitine is a necessary nutrient for energy metabolism as it is necessary for the transfer of fatty acids into the mitochondria for beta-oxidation and energy production. It also has an important role in reactive oxygen species formation, energy production, trapping acetyl groups, and the metabolism of glucose [12], and through these, carnitine may be involved in weight loss or gain [13]. Dairy and animal proteins serve as primary sources of exogenous carnitine. Additionally, the kidneys and liver synthesize this essential nutrient [14, 15]. Research indicates that carnitine transported from the intestinal lumen into the enterocyte, then passes across the serosal membrane into the circulation through simple diffusion [16]. Studies have reported several benefits of carnitine supplementation including: reducing inflammation, improving lipid profile, improving quality of life, antioxidant effects, and weight control [17, 18, 19, 20, 21].
It has been shown in recent studies that L-carnitine supplementation plays a role in improving insulin resistance and appetite suppression by affecting hypothalamic carnitine palmitoyl transferase [22, 23]. L-carnitine has also demonstrated lipid-lowering activities and blood glucose control [24]. Through these proposed mechanisms, carnitine supplementation could be effective in obesity management and weight loss [22, 23, 24]. While some meta-analyses studies reported beneficial effects of L-carnitine supplementation on weight loss [11, 25, 26, 27, 28], conflicting findings have been observed in other studies [29, 30]. Ko et al. [31] were also unable to demonstrate a favourable impact of L-carnitine intervention on the reduction of body weight and BMI in their recent meta-analysis. The results of meta-analyses regarding the effects of L-carnitine on WC also present inconsistencies [25, 26]. Due to the contradictory results of studies, it seems necessary to determine the role of carnitine supplementation in weight control and achieve a definite result. Thus, the present umbrella meta-analysis was conducted to determine the overall role of carnitine supplementation on anthropometric indices including weight, WC and BMI.
This research adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane handbook for systematic reviews of interventions [32, 33]. Scientific databases including Scopus, PubMed, Web of Science, and Google Scholar were searched from inception up to March 2023. The applied MeSH terms and keywords were as the following: (carnitine) OR (acetylcarnitine) OR (ALCAR) OR (LCAR) OR (L-CAR) OR (L-car[tiab]) OR (Acetyl-L-Carnitine) OR (L-carnitine) OR (levocarnitine) OR (ACAL) OR (“acetyl carnitine”) AND (“waist circumference”) OR (“body weight”) OR (obesity) OR (anthropometry) OR (overweight) OR (“body mass index”) OR (“body size”) OR (“body composition”) OR (anthropometric) OR (BMI) AND (“meta-analysis”).
We included all meta-analysis studies investigating the effects of carnitine supplementation on weight, BMI, and WC in both diseased and healthy adult populations which have reported the effect sizes (ES) and corresponding confidence intervals (CI). In addition, we excluded in vivo, ex vivo, and in vitro studies, quasi-experimental studies, observational studies, controlled clinical trials, case reports, and studies with low-quality scores, and limited the studies to those written in English.
The screening process was conducted by two of the reviewers (FH and PJ) independently, and disagreements were resolved by discussion with the third reviewer (MZ). To ensure that all eligible articles were included in the study, the reference lists of all of the included meta-analyses were screened to identify relevant studies for systematic reviews. The first author’s name, year and location, sample size, the type and dosage of carnitine supplementation and supplementation duration, ESs, and CIs for weight, BMI, and WC were extracted from the included meta-analyses after screening. We also extracted data related to the quality of included studies to use in the AMSTAR questionnaire to evaluate quality of studies. The AMSTAR contains 11 items and the maximum score is 11 [34]. Scores of 8–11, 4–7, and 0–3 points are rated as high, medium, and low quality, respectively (Supplementary Table 1).
The overall effect sizes were calculated using ESs and CIs. We assessed heterogeneity based on I2 statistics and Cochrane’s Q-test. I2 value
In the initial search, 117 studies were obtained. After discarding duplicates and screening of remaining studies, overall, nine meta-analyses published between 2013 and 2021 were included in the umbrella meta-analysis. The flow chart of the selection process is summarized in Fig. 1. 16,352 participants were included in this review, and the age range of participants was between 18 and 82 years. Five studies were conducted in Iran [11, 27, 28, 29, 30], one in Korea [25], one in Spain [37], one in China [26], and one in the USA [31]. Nine studies were included in the qualitative synthesis and 8 studies were included in the quantitative synthesis. Gholipour’s meta-analysis study was not considered for quantitative analysis due to reporting the results in a different unit from the one reported in the rest of the studies [30]. Gholipur-Shahraki et al. [30], evaluated the effect of L-carnitine on patients with chronic kidney disease and reported no conclusive effect of carnitine on body weight and BMI [30]. The total number of registered clinical trials (RCTs) included in our meta-analyses was 118 studies. The mean duration of interventions varied from 8 to 30 weeks, and dosage range of L-carnitine was between 150 and 4000 mg/day. Of nine meta-analyses that evaluated the quality of included studies, three cases used the Jadad quality assessment scale and six cases used the Cochrane Risk of Bias Tool scale. Table 1 provides the details of included studies reviewed.
Fig. 1. Flow diagram depicting overview of the study-selection process.
| Author, year | No. of studies in meta-analysis | Duration | No. of participants in meta-analysis | Mean Age/range (year) | Study population/weight condition | Intervention/Dosage range (mg/day) | Measured variables | Type of study | Quality Assessment Scale |
| Talenezhad et al. 2020 | 37 | 3–48 wk | 2292 | 41/18–80 | Different conditions1/Mix of weight conditions | L-carnitine/250–4000 | Weight, BMI6, WC7 | Controlled trials/placebo-controlled trials | Yes (Cochrane) |
| Abolfathi et al. 2019 | 5 | 12–24 wk | 280 | 47/39–60 | NAFELD2/Not Reported (NR) | L-carnitine an carnitine orotate/300–2000 | Weight, BMI | Controlled trials/placebo-controlled trials | Yes (Jaded scale) |
| Gholipur et al. 2018 | 5 | 12–24 wk | 293 | NR | CKD3/NR | L-carnitine/750–1500 | Weight, BMI | Controlled trials/placebo-controlled trials | Yes (Cochrane) |
| Pooyandjoo et al. 2016 | 9 | 4–52 wk | 911 | 42/20–82 | Different conditions/Mix of weight conditions | L-carnitine/1000–4000 | Weight, BMI | Controlled trials/placebo-controlled trials | Yes (Jaded scale) |
| Askarpour et al. 2019 | 45 | 2–52 wk | 9596 | 42/23–82 | Different conditions /Overweight & Obese | L-carnitine/600–4000 | Weight, BMI, WC | Placebo-controlled trials | Yes (Cochrane) |
| Liao et al. 2021 | 6 | 12 wk | 672 | 27/24–31 | PCOS4/Overweight & Obese | L-carnitine/150–1000 | Weight, BMI, WC | Placebo-controlled trials | Yes (Cochrane) |
| Vidal-Casariego et al. 2013 | 3 | NR | NR | NR | DM5/NR | L-carnitine/2000–3000 | Weight, BMI | Placebo-controlled trials | Yes (Jaded scale) |
| Choi et al. 2020 | 2 | 8–12 wk | 155 | 48/41–68 | Metabolic Syndrome/NR | L-carnitine/750–3000 | WC | Placebo-controlled trials | Yes (Cochrane) |
| Ko et al. 2022 | 11 | 4–48 wk | 2153 | NR | DM/NR | L-carnitine/900–2000 | Weight, BMI | Controlled trials/placebo-controlled trials | Yes (Cochrane) |
1: Different Conditions like: DM, hepatitis c, NAFELD, etc.
2: Non-Alcoholic Fatty Liver Disease.
3: Chronic Kidney Disease.
4: Polycystic Ovary Syndrome.
5: Diabetes Mellitus.
6: BMI, Body Mass Index.
7: WC, Waist Circumference.
Based on the AMSTAR questionnaire, all included meta-analyses studies were evaluated as high quality. The quality score of seven studies was 11 and two cases had a quality score of 10 due to no assessment of publication bias. The results are presented in Supplementary Table 1.
The results from analysis of six studies indicated that the supplementation of carnitine significantly reduced weight (ES = –1.11 kg; 95% CI: –1.90, –0.33, p = 0.005; I2 = 90.6%, p
Fig. 2. Forest plot of the effects of L-carnitine supplementation on body weight detailing effect size (ES) and 95% confidence intervals (CIs).
| Effect size, n | ES (95% CI) | p – within | I2 (%) | P-heterogeneity | |||
| L-carnitine supplementation on weight | |||||||
| Overall | 6 | –1.11 (–1.90, –0.33) | 0.005 | 90.6 | |||
| Dose (mg/day) | |||||||
| 4 | –0.89 (–1.51, –0.27) | 0.005 | 78.8 | 0.003 | |||
| 2 | –1.54 (–3.50, 0.42) | 0.123 | 75.5 | 0.043 | |||
| Intervention duration (week) | |||||||
| 2 | –1.74 (–2.92, –0.66) | 0.004 | 93.8 | ||||
| 4 | –0.74 (–1.55, 0.07) | 0.072 | 77.1 | 0.004 | |||
| L-carnitine supplementation on BMI * | |||||||
| Overall | 7 | –0.33 (–0.61, –0.04) | 0.026 | 89.8 | |||
| Dose (mg/day) | |||||||
| 4 | –0.38 (–0.77, 0.00) | 0.051 | 93.9 | ||||
| 3 | –0.19 (–0.57, 0.19) | 0.330 | 50.5 | 0.133 | |||
| Intervention duration (week) | |||||||
| 3 | –0.39 (–0.94, 0.16) | 0.160 | 95.9 | ||||
| 4 | –0.24 (–0.50, 0.02) | 0.069 | 61.2 | 0.052 | |||
p-value
The pooled results of the seven meta-analyses showed that the supplementation of carnitine significantly decreased BMI values (ES = –0.33 kg/m2; 95% CI: –0.0.61, –0.04, p = 0.026; I2 = 89.8%, p
Fig. 3. The effects of L-carnitine supplementation on BMI. Forest plot (A) detailing ES and 95% CIs; Trim-and-fill analysis (B). ES, effect size; REML, restricted maximum likelihood method.
Four meta-analyses investigated effect of L-carnitine on WC and all of them were included in the analysis. The supplementation of L-carnitine significantly reduced WC (ES = –1.34; 95% CI: –1.83, –0.85, p
Fig. 4. Forest plot of the effects of L-carnitine supplementation on WC detailing ES and 95% CIs.
Obesity and overweight are growing health problems worldwide and are linked to several chronic diseases [38, 39, 40]. Various treatments have been studied and utilized in the treatment for obesity and overweight condition [41]. Effective and safe treatment plans for obesity commonly involve a change in lifestyle (i.e., behavioural, physical, and nutritional) and, in some cases, weight loss supplements are prescribed as a complementary treatment [42]. L-carnitine supplementation has been studied for its lipotropic effects under several disease states [24, 43], and, specifically, for its potential benefits in reducing weight in obese and overweight individuals [25, 26, 30].
This umbrella review supports the effects of supplementation with L-carnitine on reducing weight, BMI, and WC. Out of the six meta-analyses included in the analysis of the effect of L-carnitine on weight reduction, four concluded similar findings [11, 26, 27, 28], while two failed to demonstrate this effect [29, 31]. The same applies to BMI as well. Seven studies examined the effect of L-carnitine on BMI, of which four studies [11, 26, 27, 28] had consistent results with the present study and three of them [29, 31, 37] had inconsistent results.
One of the potential causes for these differences could be the study population: Abolfathi et al. [29], investigated L-carnitine supplementation on weight and BMI in individuals with nonalcoholic fatty liver disease (NAFLD), and participants in the studies by Ko et al. [31], and Vidal-Casariego et al. [37] were diabetic, and each study had a specific study population. In some meta-analysis [11, 27, 28], studies with different populations, including both healthy and diseased individual with normal weight or obesity were investigated. In the subgroup analysis of some included studies for present umbrella-meta analysis [28, 31], a tendency toward decreased weight with L-carnitine supplementation was observed, with an increase of BMI and body weight. Together, these indicate a potentially favorable impact of L-carnitine on patients with higher baseline body weight and BMI. Furthermore, in an interventional animal study conducted by Shoveller et al. [44], overweight cats in positive energy balance fed diets supplemented with L-carnitine exhibited lower body fat deposition than lean cats supplemented with L-carnitine. Therefore, it appears that L-carnitine supplementation may be more effective in obese and overweight individuals, and body fat mass or energy intake may influence outcomes.
According to the present study body weight in a subgroup of
Another potential cause for the discrepancy in the findings between the present study and the studies of Abolfathi et al. [29] and Vidal-Casariego et al. [37] could be the small number of analyzed RCTs and, as a result, the small sample size. Additionally, according to Abolfathi et al. [29], low-quality RCTs were included for data analysis, and carnitine deficiency at baseline was not evaluated among the studies. There are also some concerns regarding the study of Pooyandjoo et al. [11]. This study included RCTs with co-intervention in addition to L-carnitine. Therefore, the observed results might not reflect the pure effect of L-carnitine [45]. Additionally, one eligible study has been inadvertently excluded from the analysis due to using a different unit than that reported in the rest of the studies [30], which could affect the results. Additional studies are needed to validate these findings.
In the current study, the reduction in WC attributed to L-carnitine supplementation is supported by the results of the analysis. Two meta-analyses [25, 26] demonstrated the potential of L-carnitine to reduce WC, while the studies by Askarpour et al. [27] and Talenezhad et al. [28] failed to replicate this effect. In the subgroup analysis of the aforementioned studies, a significant reduction in WC was observed specifically in overweight and obese individuals. In this case, it appears that the variation in study results can be attributed to differences in the study populations. WC is one of the criteria for metabolic syndrome and is also directly related to diseases such as polycystic ovary syndrome [46, 47]. Therefore, interventions that aid in the reduction of WC could be effective in the improvement of various metabolic diseases under the metabolic syndrome.
The hypothesized mechanism for the reducing effect of L-carnitine on weight and BMI is shown schematically in Fig. 5. Fatty acids are stored in adipose tissue during periods of positive energy balance, and they are the major source of energy for vital organs of body [48]. Carnitine acetyltransferase enzymes (CATs) in the mitochondria, endoplasmic reticulum, and peroxisome use carnitine as a cofactor for transports of long-chain fatty acids across the inner mitochondrial membrane to stimulate
Fig. 5. Mechanisms of L-carnitine in weight lost and improving chronic diseases. CPTI-a, carnitine palmitoyltransferase I-a; A-FABP, adipose-specific fatty acid-binding protein; PPAR-
In accordance with existing recommendations, the established safe threshold for L-carnitine intake is up to 2000 mg/day. This limitation is imposed due to reported adverse effects, including nausea and stomach discomfort, as well as the formation of trimethylamine-N-oxide, a risk factor for the increased incidence of atherosclerosis [58, 59]. Our study findings supported the efficacy of a daily dosage of
To the best of our knowledge, the present study is the first umbrella meta-analysis investigating the effects of L-carnitine supplementation on weight, BMI, and WC. All of the included meta-analyses studies in this umbrella review had high quality. Nevertheless, there were some limitations. Due to the nature of this study, the primary studies included in the selected meta-analyses were not assessed in detail, while some of them were included in meta-analyses several times. This could introduce a potential source of bias, therefore, this limitation should be considered in the interpretation of the results. As previously mentioned, RCTs incorporating co-treatment alongside L-carnitine have been included in a meta-analysis [11], potentially influencing the outcomes, which were amended through sensitivity analysis. Additionally, due to high heterogeneity across the studies, subgroup analysis was implemented to identify the source of heterogeneity.
The results from the present umbrella meta-analysis supports L-carnitine supplementation in the management of obesity. According to the evidence, it seems that favorable impacts are achieved with dosages
FH, MM, and MZ designed the research and wrote the manuscript. ParsJ and ParmJ, RM conducted the systematic search. FH screened the articles and extracted the data. MZ and AO analyzed and interpreted the data. ParsJ and ParmJ drew the tables. FH and MZ had primary responsibility for the final content. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
The protocol of this study was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences (69438).
Not applicable.
This research received no external funding.
The authors declare no conflict of interest.
Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/IJVNR40033.
References
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