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. 2024 May 29;20(3):151–161. doi: 10.1080/14796678.2024.2349476

The effects of ursolic acid on cardiometabolic risk factors: a systematic review and meta-analysis

Pegah Rafiee a, Niloufar Rasaei b,c, Mohammad Reza Amini a,d, Reyhaneh Rabiee e, Zahra Kalantar f, Fatemeh Sheikhhossein f, Mohammad Gholizadeh g, Azita Hekmatdoost g,*
PMCID: PMC11216268  PMID: 38923885

Abstract

Aim: Ursolic acid (UA) has an important biological role in the fight against fat accumulation, insulin resistance, obesity and inflammation. Therefore, in the current review and meta-analysis work, we investigate the effects of UA (dosage range is 50.94 to 450 mg/day) on cardiometabolic risk factors. Materials & methods: After searching the studies up to February 2023, six articles were included in the study. Results: The pooled effect size showed that UA supplementation didn't significantly change body weight, body mass index, waist circumference, body fat percentage, lean body mass, systolic blood pressure, diastolic blood pressure, fasting blood glucose, insulin, triglyceride and high-density lipoprotein compared with control groups. Conclusion: UA supplementation had no significant effect on the cardiometabolic risk factors in adults.

Keywords: : cardiometabolic risk factors, meta-analysis, ursolic acid

Plain language summary

Cardiovascular disease (CVD) is a significant reason for morbidity and mortality. Ursolic acid (UA) has been shown to play important biological roles in the fight against fat accumulation, oxidative stress, insulin resistance via insulin-like growth factor 1, cancer, muscle atrophy, obesity and inflammation responsible for CVD. A systematic review and meta-analysis were conducted up to February 2023; six articles were included in the study and eleven cardiometabolic risk factors were identified. The pooled effect size showed that UA supplementation (dosage range is 50.94 to 450 mg/day) didn't significantly change body weight, body mass index, waist circumference, body fat percentage, lean body mass, systolic blood pressure, diastolic blood pressure, fasting blood glucose, insulin, triglyceride, and high-density lipoprotein compared with control groups.

TWEETABLE ABSTRACT

In the context of the six studies reviewed, ursolic acid supplementation did not affect the cardiometabolic risk factors in adults.

Plain language summary

Article highlights.

  • Cardiovascular disease (CVD) is a significant reason for morbidity and mortality.

  • Ursolic acid (UA) has been shown to play important biological roles in the fight against fat accumulation, oxidative stress, insulin resistance via IGF-1, cancer, muscle atrophy, obesity, and inflammation which are responsible for CVD.

  • We searched PubMed, Scopus, Cochrane Library, Web of Science, and Embase databases up to February 2023.

  • Data were pooled from six eligible studies comprising eight arms with a mean age of 23 to 61.1 years old.

  • We examined the effects of UA on cardiometabolic risk factors.

  • UA did not have any significant effects on body weight, body mass index, waist circumference, body fat percentage, lean body mass, systolic blood pressure, diastolic blood pressure, fasting blood glucose, insulin, triglyceride and high-density lipoprotein.

  • To address methodological issues including dosage, administration and the combined effect with other treatments, more research is required.

1. Background

Cardiovascular disease (CVD) is a significant reason for morbidity and mortality, representing 32% of all causes and 44% of all non-transferable disease deaths [1]. Heart disease, which affects about 610,000 people yearly in the US, is responsible for a quarter of all fatalities [2,3]. Additionally, it is estimated to be the leading cause of disability and the fourth leading reason for disability insurance benefits [4]. Nine key risk factors-hypertension, smoking, diabetes, alcohol consumption, obesity, lipids, diet, physical activity and psychosocial factors-were found to be responsible for more than 86% of CVD [5]. Furthermore, pharmacological treatment, dietary enhancements, functional food sources or dietary supplements, and nutraceutical items are progressively utilized for cardiovascular wellbeing [6–8].

Ursolic acid (UA) is a pentacyclic triterpene carboxylic acid that is found in saponins as a free acid or aglycone [9]. UA is tracked down in different plants, consumable vegetables and therapeutic herbs [10]. Although it was thought to be inactive, UA has been shown to play important biological roles in the fight against fat accumulation [11], oxidative stress [12], insulin resistance via IGF-1 [13], cancer [14], muscle atrophy [15], obesity [16] and inflammation [17]. UA has been shown to turn back ischemia in mice cardiovascular myocytes and ameliorate heart failure in animals [18,19]. However, most of this evidence is obtained from animal and cellular studies and the present study provides more evidence in this field by summarizing human studies. A human trial found that taking UA supplements significantly altered the components of metabolic syndrome (MetS). Because cardiovascular risk factors and MetS components are similar, these findings are significant [20]. On the other hand, other studies could not find any significant changes in body composition or other risk factors [21,22].

Although there are a number of review articles in the literature that discuss the cardioprotective effects of a single phytochemical compound or the general health benefits of phytochemical supplements, no comprehensive review or meta-analysis article has yet been published that focuses on the preclinical and clinical cardiovascular beneficial effects of UA. Therefore, in the current review and meta-analysis work, we have tried to fill this gap in the literature.

2. Methods

The guidelines of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) were used for the current systematic review and meta-analysis [23]. This was registered in PROSPERO (CRD42023428067) [24].

2.1. Search strategy

We conducted a comprehensive search of the PubMed, Scopus, Cochrane Library, Web of Science and Embase databases up to February 2023. Relevant research was detected based on the following keywords: (‘Ursolic Acid’) AND (intervention OR randomized OR randomized OR RCT OR random OR placebo OR randomly OR assignment OR trial OR trials OR ‘Double-Blind’ OR cross-over). In addition, we searched manually for the reference list of included studies to prevent missing related articles.

Two investigators (MRA, PR) independently identified eligible studies according to the inclusion/exclusion criteria. Any inconsistencies were resolved after consulting with a third author (AH).

2.2. Inclusion & exclusion criteria

We selected original studies that fulfilled the following criteria: Adults over 18 years old; the study was a randomized controlled trial (RCT) that used a placebo with either a parallel or crossover methodology; the baseline and end of the follow-up variations of cardiometabolic risk factors: body weight, body mass index (BMI), waist circumference (WC), body fat percentage (BFP), lean body mass (LBM), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), insulin, triglyceride (TG) and high-density lipoprotein (HDL); in intervention and control groups were delineated; the only difference between the intervention and control groups was US. We excluded studies that were: in vitro and animal studies; observational, conferences, letters, comments, books, unpublished data, reviews and meta-analyses; and studies on children and pregnant women; we were unable to determine the net effect of US.

2.3. Data extraction

Two investigators (MAR, PR) extracted the required data from eligible studies independently. Discrepancies between them were resolved by consulting third investigators (AH). The extracted data follows the first author's name, study location, the publication year of the study, study design, intervention (type, dose and duration of supplementation); participants' characteristics (age, gender and health status); sample size; including the mean of cardiometabolic risk factors at baseline and final of the study.

2.4. Outcomes

After searching the studies, 11 cardiometabolic risk factors were identified as suitable for meta-analysis. These included body weight, BMI, WC, BFP, LBM, SBP, DBP, FBG, insulin, TG and HDL. The outcomes of the current meta-analysis were the weighted mean differences (WMD) and 95% confidence intervals (CI) in these factors between UA supplementation and control groups.

2.5. Quality of assessment

The Cochrane Collaboration's tool was used to evaluate quality assessment and the risk of bias for selected studies [25]. The following domains for evaluation were: generation of random sequences; concealment of allocation; implementing blinding in participants and personnel; implementation blinding in outcome assessment; management of incomplete outcome data; prevention of selective reporting bias; and mitigation of other source bias. According to this scale, every domain was designed with a label indicating the presence of low risk, high risk or unknown risk of bias, representing the categories of yes, no and unclear risk of bias, respectively (Table 1).

Table 1. Risk of bias for randomized controlled trials, assessed according to the Revised Cochrane risk-of-bias tool for randomized trials (RoB 1).

Publications Random sequence generation Allocation concealment Selective reporting Blinding (participants and personnel) Blinding (outcome assessment) Incomplete outcome data Other sources of bias Ref.
1. Bang (2014) L U L U U L L [26]
2. Bang (2017) L U L U U L L [27]
3. Cho (2016) L L L L L L L [28]
4. Cione (2021) L L L L L L L [21]
5. Lobo (2021) L U L L U L H [22]
6. Ramírez-Rodríguez (2017) L L L L L L L [20]
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H: High risk of bias; L: Low risk of bias; U: Unclear risk of bias.

2.6. Statistical analysis

The present study employed WMD and 95% CI to determine and express treatment effects. We extracted the mean difference and standard deviation (SD) of the cardiometabolic risk factors pre- and post-intervention from periods for the ursolic acid and control groups. These measures were utilized to compute the net changes manifested within each group. When SD was not reported and a standard error of the mean (SEM) was represented instead of SD, we converted it to SD for analyses using the following formula: SDs = SEs × square root (n), where n represents the number of participants in each group. If medians and ranges or 95% CI were reported, the Hozo et al. method was used for estimating mean and SD values [29].

The existence of heterogeneity was evaluated through Cochran's Q-test (where a significance level of p < 0.1 was applied) and the I2 test, which determined the percentage of heterogeneity. If the I2 value was equal to 50% or more, it indicates significant heterogeneity. If there was heterogeneity, a random effects model was utilized; otherwise, the fixed-effects model was applied.

The sensitivity analysis was conducted by the leave-one-out method. Evaluating the influence of each study on the overall effect size can be accomplished by eliminating one trial and performing the analysis again. The presence of potential publication bias was detected through the use of a funnel plot, as well as Begg's rank correlation and Egger's weighted regression tests [30]. STATA software, version 14.0, was used for the current study. A p-value < 0.05 was considered statistically significant.

3. Results

3.1. Search strategy

Up to 9 February 2023, we identified 904 publications in the initial search 303 studies were removed due to duplication. After screening articles by titles and abstracts, 591 studies were discarded due to not being relevant or original studies (206), reviews (270) and animal studies (115). Therefore, ten studies remained for full-text review. After reading the full text, four studies were left out because they were irrelevant. Finally, six studies with eight treatment arms were incorporated into this systematic review and meta-analysis [20–22,26–28]. The flow chart of the search strategy is shown in Figure 1.

Figure 1.

Figure 1.

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Flow chart of the number of studies identified and selected for the meta-analysis.

3.2. Characteristics of included studies

Table 2 provides a summary of the characteristics of the studies that were included in the analysis. Data were obtained from six eligible investigations encompassing eight experimental arms, of which 158 participants had a mean age of 23 to 61.1 years old. Three studies were performed on men, two on both genders and one on females. The design of all the included studies was parallel. These studies were published between 2014 and 2021 and conducted in Korea, Brazil and Mexico. Two studies were performed on participants with MetS and other studies on healthy individuals. The duration of the intervention was eight weeks in four studies and 12 in the remaining studies. The dose of UA varies from 50.94 to 450 mg/day. Out of six studies that presented the effect of UA supplementation on cardiometabolic risk factors, five assessed weight, three BMI, three WC, five BFP, three LBM, two SBP and DBP, four glucose, three insulin, three TG and HDL.

Table 2. Demographic characteristics of the included studies.

First study (year) Location Study Design Health status Sex Sample size Duration (week) Mean age (year) Baseline BMI (kg/m2) Intervention group Comparator group Outcome Results Ref.
1. Bang (2014) Korean RCT, parallel Healthy Male 16 8 29.37 27.13 450 mg/day ursolic acid + resistance training Placebo + resistance training Weight/BMI/PBF/LBM/Glucose/Insulin PBF was significantly reduced and there was no significant effect on weight, BMI, LBM, glucose, or insulin [26]
2. Bang (2017) Korean RCT, parallel Healthy Male 16 8 33 Not reported 450 mg/day ursolic acid + resistance training Placebo + resistance training Weight/PBF/LBM There was no significant effect on weight, PBF and LBM [27]
3. Cho (2016) Korean RCT, double-blind, parallel Healthy Both 54 12 39.1 22.5 500 mg of loquat leaf extract (50.94 mg of ursolic acid) Placebo PBF/Glucose/Insulin/TG/HDL There was no significant effect on PBF, glucose, insulin, TG and HDL [28]
4. Cione (2021) Brazil RCT, double-blind, parallel Metabolic syndrome of postmenopausal women Female 26 8 61.1 32.2 450 mg/day ursolic acid + combined exercise program Placebo + combined exercise program Weight/PBF/WC/Glucose/Insulin/TG/HDL/SBP/DBP There was no significant effect on weight, PBF, WC, glucose, insulin, TG, HDL, SBP and DBP [21]
5. Lobo (2021) Brazil RCT, double-blind, parallel Healthy Male 22 8 23 22.7 400 mg/day ursolic acid + resistance training Placebo + resistance training Weight/BMI/PBF/WC/LBM There was no significant effect on weight, BMI, PBF, WC and LBM [22]
6. Ramírez-Rodríguez (2017) Mexico RCT, double-blind, parallel Metabolic syndrome Both 24 12 45 30.9 150 mg/day ursolic acid Placebo Weight/BMI/Glucose/TG/SBP/DBP Weight, BMI and glucose was significantly reduced and there was no significant effect on, TG, SBP and DBP [20]
7. Ramírez-Rodríguez (a) (2017) Mexico RCT, double-blind, parallel Metabolic syndrome Female 24 12 45 30.9 150 mg/day ursolic acid Placebo WC/HDL WC was significantly reduced [20]
8. Ramírez-Rodríguez (b) (2017) Mexico RCT, double-blind, parallel Metabolic syndrome Male 24 12 45 30.9 150 mg/day ursolic acid Placebo WC/HDL There was no significant effect on WC and HDL [20]
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BMI: Body mass index; DBP: Diastolic blood pressure; HDL: High-density lipoprotein; LBM: Lean body mass; PBF: Percentage body fat; RCT: Randomized controlled trial; SBP: Systolic blood pressure; TG: Triglyceride; WC: Waist circumference.

3.3. The effect of UA on anthropometric factors (weight, BMI, WC, BFP, LBM)

Combined data analysis showed that UA had no effect on weight (WMD: -0.94; 95% CI: -2.01, 0.14; p = 0.087) (I2 = 0%; p = 0.569) (Figure 2), BMI (WMD: -1.46; 95% CI:-4.46, 1.72; p = 0.367) (I2 = 91.4%; p < 0.001) (Figure 3), WC (WMD: -4.08; 95% CI: -8.91, 0.74; p = 0.097) (I2 = 89.8%; p < 0.001) (Figure 4), BFP (WMD: -0.49; 95% CI: -1.61, 0.62; p = 0.383) (I2 = 77.1%; p = 0.002) (Figure 5) and LBM (WMD: 0.84, 95% CI: -1.67,3.35; p = 0.551) (I2 = 0%; p = 0.86) (Figure 6). No significant effect of UA was seen in any factors between the intervention and control groups.

Figure 2.

Figure 2.

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Forest plot detailing weighted mean difference and 95% confidence intervals for the effect of ursolic acid on weight.

CI: Confidence interval; WMD: Weighted mean difference.

Figure 3.

Figure 3.

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Forest plot detailing weighted mean difference and 95% confidence intervals for the effect of ursolic acid on body mass index.

BMI: Body mass index; CI: Confidence interval; WMD: Weighted mean difference.

Figure 4.

Figure 4.

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Forest plot detailing weighted mean difference and 95% confidence intervals for the effect of ursolic acid on waist circumference.

CI: Confidence interval; WC: Waist circumference; WMD: Weighted mean difference.

Figure 5.

Figure 5.

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Forest plot detailing weighted mean difference and 95% confidence intervals for the effect of ursolic acid on body fat percentage.

CI: Confidence interval; WMD: Weighted mean difference.

Figure 6.

Figure 6.

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Forest plot detailing weighted mean difference and 95% confidence intervals for the effect of ursolic acid on lean body mass.

CI: Confidence interval; WMD: Weighted mean difference.

3.4. The effect of UA on blood pressure factors (SBP & DBP)

Pooled effect size showed that UA supplementation did not significantly change SBP (WMD: 0.37; 95% CI: -6.21, 6.95; p = 0.912) (I2 = 0%; p = 0.578) and DBP (WMD: 0.81; 95% CI: 4.47, 6.08; p = 0.765) (I2 = 23.7%; p = 0.252) compared with control groups (Supplementary Figures S1 & S2).

3.5. The effect of UA on blood sugar factors (glucose & insulin)

Pooled effect size demonstrated that UA supplementation had no effect on glucose (WMD: -1.93; 95% CI: -16.68, 12.81; p = 0.797) (I2 = 91.9%; p < 0.001) and insulin (WMD: 0.16; 95% CI: -1.14, 1.47; p = 0.806) (I2 = 0%; p = 0.846) (Supplementary Figures S3 & S4).

3.6. The effect of UA on lipid profiles (TG & HDL)

Pooled findings revealed no statistically significant in TG (WMD: 1.67; 95% CI: -13.37, 16.71; p = 0.827) (I2 = 0%; p = 0.569) and HDL (WMD: 0.03; 95% CI: -3.18, 3.25; p = 0.981) (I2 = 0%; p = 0.678) between intervention and control groups (Supplementary Figures S5 & S6).

3.7. Sensitive analysis

To evaluate the impact of each study on the overall effect size, we eliminated every study one by one from the analysis. Sensitivity analysis of cardiometabolic risk factors demonstrated that the ultimate estimates remained unchanged by the mission of any of the clinical trials encompassed in the study.

3.8. Publication bias

To assess the presence of publication bias, Egger's linear regression and Begg's rank correlation tests were employed. No significant publication bias was indicated for any factors (body weight (p = 0.839), BMI (p = 0.146), WC (p = 0.124), BFP (p = 0.567), LBM (p = 0.842), SBP (p = 0.317), DBP (p = 0.317), FBG (p = 0.749), insulin (p = 0.446), TG (p = 0.168) and HDL (p = 0.173).

4. Discussion

This is the first systematic review and meta-analysis that, to our knowledge, has evaluated the impact of UA intake on adult cardiometabolic risk variables. In this meta-analysis, we investigated the effects of UA on some anthropometric measurements, SBP, DBP, blood sugar factors, and lipid profiles. Six studies with eight treatment arms and 158 participants were included in the present systematic review and meta-analysis. The dose and intervention duration of the studies included in this systematic review and meta-analysis varies from 50.94 to 450 mg/day and 2–3 weeks, respectively, for healthy participants or patients with MetS. The results of the present study showed that the use of UA supplements has no significant effect on any of the cardiometabolic risk factors.

CVDs are one of the most important causes of death in the whole world, which will reach 23.6 million deaths by 2023 [31–34]. Numerous risk factors, such as hypertension, abnormal blood cholesterol levels, inflammation, insulin resistance and obesity, have an impact on the development of CVDs [35–39]. It has been observed in human research that taking UA for 8 weeks will improve serum irisin and BFP [26].

On the other hand, some previous double-blind, randomized, placebo-controlled trials did not find any significant association between UA supplementation and obesity indices, body composition and other CVD risk factors [21,22]. For example, another study found that consuming 450 mg/day of UA in addition to exercise had no beneficial effect on anthropometric measurements [27]. Also, another randomized, double-blinded and placebo-controlled trial indicated that the consumption of UA for 3 months has no beneficial effects on lipid and glucose profiles [28]. Cione et al.'s study showed that taking UA supplements for 2 months had no effect on improving the symptoms and components of MetS, including WC and metabolic profile, in postmenopausal women [21]. Moreover, in the trial of Lobo and colleagues, no significant effect on anthropometric measures was reported with 400 mg/day UA supplementation for 2 months [22].

On the other hand, the findings from another study revealed that consuming 150 mg/day of UA for 12 weeks caused a significant improvement in metabolic profile, including the levels of blood sugar and insulin resistance. Also, anthropometric measurements such as weight, WC and BMI decreased [20]. In relation to the effect of UA on cardiometabolic risk factors, few RCTs have been conducted on humans. On the other hand, the results of the few existing studies have contradictions [20,26,27,40].

Many biological activities of UA have been identified, including anti-inflammatory and antioxidant effects [41], preventing muscle wasting and adiposity [15], and increasing insulin sensitivity through the mediation of IGF-1 [13].

According to our data, taking ursolic acid did not significantly reduce body weight or other anthropometric measurements. Despite this, some papers imply that it has antiobesity properties [42]. One of the mechanisms mentioned in the studies that cause the reduction of fat accumulation by UA supplements is the activation of protein kinase A, which, as a result, increases the breakdown of fats and lipolysis, energy consumption and thermogenesis [43].

In our research, both DBP and SBP were unaffected by UA. The results of Somova et al.'s study on salt-sensitive hypertensive rats showed that taking UA supplements can reduce high blood pressure in rats. This can be due to the effects of UA supplementation on the reabsorption of sodium and potassium in the distal tubule of the renal [44].

The lipid profile, including HDL-c circulating concentrations, TG and total cholesterol, did not differ. However, the results of some studies have shown that the use of US supplements reduces the absorption of consumed fats, and this mechanism takes place through the reduction of the pancreatic lipase enzyme [43,45]. Serum lipids may differ significantly over a longer period of time during the intervention.

The results of experimental studies show that the improving effect of UA supplements on reducing insulin resistance is through the inhibiting protein tyrosine phosphatase 1B enzyme. This enzyme can increase the number of insulin receptors, activate existing insulin receptors by phosphorylation and stimulate glucose uptake [46,47].

According to the conflicting results of existing studies, it is important to take into consideration the different doses used, the differences in the intervention duration and the sample size of trials to explain the controversial results observed among the studies. Of course, it should be kept in mind that large clinical trials are necessary, particularly Phases I, II and III, which include dose-finding, toxicity, proof of concept, efficacy and safety, respectively.

Various studies have investigated the toxicity of UA. Somova and colleagues utilized a brine shrimp bioassay to demonstrate that administering UA to mice at a dosage of 60 mg/kg of body weight for 5 consecutive days did not result in any toxic effects [19]. In a recent investigation on repeated-dose toxicity, researchers examined the extended adverse effects of UA in Han-Wistar rats [48]. The research findings indicated that administering 1000 mg/kg/day of UA over 90 days did not result in any toxic effects. Consequently, the authors inferred that the no-observed-adverse-effect-level (NOAEL) for UA likely exceeds 1000 mg/kg/day. During a clinical study involving healthy adults, where single oral doses of UA up to 1000 mg were administered, researchers observed no significant adverse events, affirming the safety of UA within this dosage range [49]. Based on previous investigations, it's important to highlight that the oral administration of UA in humans was well-received, with either no adverse effects observed or those that did occur were not statistically significant [20,22,50]. These findings strongly suggest that UA demonstrates minimal toxicity in both rodents and humans [51]. Nonetheless, there is a possibility that UA is stored and builds up in tissues over time. Additional research is needed to investigate potential long-term toxic effects in living organisms [51].

As strengths, this is a comprehensive and the first systematic review and meta-analysis that included all RCTs that evaluated the effects of UA supplementation on cardiometabolic risk factors. There were not any limitations on date or language. There was a standardized methodology and precise search strategy in this study. We did not have any publication bias from statistical examinations. Finally, it is noteworthy that all included studies strictly adhered to the RCT design, thereby augmenting the reliability and robustness of the findings and most of the included studies were double-blind RCTs.

The limitations of this study are the small number and sample size of the included studies, the different kits used in studies to evaluate the metabolic profile, the lack of control over confounding factors such as physical activity and consumption of drugs, and the type of diet of the people in the studies. Due to all these limitations, more rigorous RCTs are needed to confirm the role of UA as a cardiometabolic risk factor in humans.

Further exploration is needed to systematically compare the efficacy of UA through head-to-head assessments in both RCTs and pragmatic controlled trials. The existing literature is deficient in such comparative data, emphasizing the importance of future research in this area. Additionally, there is a need for an extended approach involving a comprehensive network meta-analysis that combines findings from randomized controlled trials with real-world evidence. Such an inclusive strategy would contribute valuable insights to the existing knowledge base. The ability to ascertain treatment adherence was often compromised in the studies conducted, resulting in a scarcity of information regarding potential bias risks. To address this limitation, future studies that specifically investigate and measure adherence to treatments are essential. Such research endeavors would play a crucial role in affirming and reinforcing the conclusions drawn from the data obtained in these database studies.

5. Conclusion

The present systematic review and meta-analysis of six studies and eight arms suggest that UA supplementation (dosage range is 50.94 to 450 mg/day) did not have any significant improvement effect on the cardiometabolic risk factors in adults. However, further long-term and well-designed RCTs and mechanistic studies are needed to further evaluate and validate these results.

Supplementary Material

Supplementary Figures S1-S6
IFCA_A_2349476_SM0001.zip (70.5KB, zip)

Funding Statement

This study is related to project NO. 1401/59204 From Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/14796678.2024.2349476

Author contributions

MR Amini created the research. M Gholizade and P Rafiee carried out data screening and literature searches. MR Amini and F Sheikhhossein independently extracted the data and evaluated its quality. M Gholizade, P Rafiee, N Rasaei, R Rabiee and Z Kalantar wrote the text after data interpretation. A Hekmatdoost was the study's leader. All writers read and approved the final manuscript.

Financial disclosure

This study is related to project NO. 1401/59204 From Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran. We also appreciate the ‘Student Research Committee’ and ‘Research & Technology Chancellor’ at Shahid Beheshti University of Medical Sciences for their financial support of this study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

Writing assistance was provided by MR Amini and was funded by project NO. 1401/59204 From Student Research Committee, Shahid Beheshti University of Medical Sciences (Tehran, Iran).

Code availability

PROSPERO (CRD42023428067).

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