Effects of Astaxanthin Supplementation on Glycemic Control and Lipid Profile in Patients With Prediabetes and Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Abstract

Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, and its prevalence is increasing worldwide. Oxidative stress has a crucial role in T2DM development. Astaxanthin is a carotenoid compound that has antioxidant, anti-inflammatory, anti-apoptotic, and anti-diabetic effects. The current meta-analysis was conducted to evaluate the available evidence and provide an accurate estimate of the overall effects of astaxanthin supplementation in patients with prediabetes and T2DM. PubMed, Scopus, Web of Science, and Google Scholar databases were searched using relevant keywords and MeSH terms until January 2025. A meta-analysis was performed using the random-effects model and STATA 17 software. In addition, the included studies’ quality and the evidence’s overall strength were assessed using the Cochrane and GRADE tools, respectively. In total, 9 randomized controlled trials, including 403 patients with prediabetes and T2DM, were included in this review. The findings showed that astaxanthin supplementation significantly reduced serum levels of fasting blood sugar (WMD: –16.126 mg/dl (95%CI: −28.968 to −3.285), P = .014), glycated hemoglobin (WMD: −0.338 (95%CI: −0.598 to −0.079), P = .011), triglyceride (WMD: –20.872 mg/dl, (95%CI: –38.205 to 3.540), P = .018), total cholesterol (WMD: –12.174 mg/dl, (95% CI:−19.839 to −4.509), P = .002), and low-density lipoprotein cholesterol (WMD: –9.409 mg/dl (95% CI: −15.287 to −3.531), P = .002) and increased serum high-density lipoprotein cholesterol levels (WMD: 3.021 mg/dl, (95%CI: 2.000-4.042) compared to the control group. However, astaxanthin administration had no significant effect on HOMA-IR, body weight, and body mass index of patients. The findings indicate the beneficial effects of astaxanthin supplementation on improving glycemic indices and lipid profiles in patients with prediabetes and T2DM. The non-significant effects of astaxanthin on weight and body mass index warrant high-quality research to confirm these findings and clarify the effects of astaxanthin in patients with prediabetes and T2DM.

Keywords

astaxanthin prediabetes diabetes obesity meta-analysis

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition characterized by high blood sugar levels. This condition may arise from a lack of insulin production, reduced insulin response in the body, or both.^1-3 The worldwide diabetes prevalence keeps rising; currently, more than 415 million people suffer from the disease according to the International Diabetes Federation (IDF). It is projected that this number will rise to over 600 million by 2040.^4-6 Prediabetes is characterized by blood glucose levels exceeding the normal range but below the threshold for a diabetes diagnosis that defined as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). The prevalence of prediabetes is increasing around the world, and it is expected that 6.5% (414 million) and 10.0% (638 million) of the population will have IFG and IGT by 2045, respectively. Every year, an estimated 5% to 10% of individuals with prediabetes will progress to developing T2DM.^7,8 If diabetes is not managed correctly, it raises the chances of comorbidities such as cardiovascular disease, kidney disease, neuropathy, retinopathy, liver dysfunction, and mortality rates.^4,9-11 The risk factors for T2DM involve a mix of genetic and metabolic elements contributing to its widespread occurrence. Factors that cannot be changed include ethnicity, family history, a history of gestational diabetes, and advancing age. Additionally, factors that can be modified, such as obesity, poor dietary habits, level of physical activity, and smoking, also play a role in the onset of T2DM.^2,12-15 Based on conducted studies, lifestyle interventions have the most significant impact on preventing the progression of diabetes.^16-18 Controlling blood glucose levels and diabetes significantly depends on keeping track of dietary habits.^19,20

Nutritional supplements are recommended to enhance diabetes control and maintain a proper diet. Astaxanthin is a powerful antioxidant and naturally occurs in various microorganisms and seafood as a carotenoid compound belonging to the xanthophyll family.²¹ As oxidative stress is one of the main factors in the pathogenesis and progression of diabetes and its associated comorbidities,²² antioxidants may help protect the body from oxidative stress. This red xanthophyll carotenoid is also found in several species, such as salmon, shrimp, yeasts, crustaceans, trout, microalgae, and birds.^23,24 In addition to the anti-diabetic effects of astaxanthin, it has an important role in preventing cardiovascular diseases and neurodegenerative diseases, protecting the retina, anticancer, counteracting skeletal injuries, anti-apoptotic, and enhancing immunity.^25-28 Astaxanthin, with its antioxidant and anti-inflammatory effects, can help decrease insulin resistance and improve insulin sensitivity. It attenuates inflammation by reducing circulating interleukin-6 (IL-6) levels in patients with T2DM.²⁵

Glycemic biomarkers such as fasting blood sugar (FBS) and glycated hemoglobin (HbA1c) are major indicators of glycemic control and are strongly associated with the risk of microvascular and macrovascular complications in both prediabetes and T2DM.^26,27 Insulin resistance plays a pivotal role in the pathophysiology linking hyperglycemia and lipid abnormalities.²⁸ Dyslipidemia represents a major contributor to cardiovascular morbidity in diabetic populations.²⁹ Therefore, evaluating the effects of astaxanthin supplementation on these glycemic and lipid biomarkers provides clinically meaningful insight into its potential role in metabolic risk reduction. Some studies assessed the effects of astaxanthin in patients with prediabetes and T2DM; however, their results are controversial.^16,24,29 Moreover, to our knowledge, there is currently no comprehensive study that systematically reviews the effects of astaxanthin supplementation on patients with prediabetes and T2DM and reports quantitative findings. Therefore, this meta-analysis aims to summarize the existing literature on the effects of astaxanthin supplementation on metabolic factors in patients with these conditions.

Method

Data Sources and Search Strategy

This study examined the effects of astaxanthin supplementation on patients with prediabetes and T2DM, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines³⁰ (Supplemental Table 1). The protocol of this study has been registered in PROSPERO (ID: CRD420251029618). A comprehensive search was conducted in the electronic databases, including PubMed, Scopus, and Web of Science, and Google Scholar, until 1/18/2025. The search was conducted using a combination of the following Medical Subject Heading (MeSH) and non-MeSH keywords (PubMed search strategy is shown in Supplemental Table 2): (“Astaxanthin” OR “E-Astaxanthin” OR “Astaxanthine”) AND (Diabetes OR T2DM OR Glycemic OR “gestational” OR “adult-onset diabetes mellitus” OR “adult onset diabetes mellitus” OR “hyperglycem” OR “hyperglycaem” OR “prediabetes” OR “prediabetic state” OR “prediabetic states” OR “prediabetic” OR “pre-diabetes” OR “pre diabetes” OR “pre-diabetic” OR “pre-diabetics” OR “pre diabetic” OR “pre diabetics”). To further identify relevant studies, the reference lists of related reviews in this field were manually examined.

Eligibility Criteria

The literature was systematically searched, and all randomized controlled trials (RCTs) with full-text English-language articles that addressed the effects of supplementation with astaxanthin in adult patients with T2DM or prediabetes were investigated and included in the review.

PICOS criteria for this systematic review and meta-analysis were as follows: Population: all patients with prediabetes and T2DM; Intervention: astaxanthin; Comparison: placebo or control group; Outcome: metabolic factors and anthropometric measures; Study design: randomized controlled trials. Observational studies, book chapters, conference publications, letters, posters, editorials, commentaries, editorials, theses, and review articles were not included. Also, Studies without accessible full texts and studies investigating the effects of astaxanthin in combination with other dietary supplements were excluded from the review.

Selection of the Studies

Literature was downloaded to EndNote software (Version 21) to manage citations and facilitate review, and duplicate studies were removed. Using the Rayyan software, 2 authors (SB and RM-G) independently screened the retrieved articles based on eligibility criteria. The titles and abstracts of the articles were evaluated according to the established inclusion and exclusion criteria. The full-text versions of the studies that met the eligibility criteria were collected for a more detailed review. Studies with inadequate data or those failing to satisfy the predefined criteria were excluded from the review. Discrepancies between the authors were resolved by the third author (MR).

Data Extraction

The following information was manually extracted from the selected studies: study first author, year of publication, study population, sample size, age, gender, supplement dose, time of intervention, Mean, and standard deviation (SD) for before and after the supplementation for the intervention and placebo groups.

The Risk of Bias and Certainty of Evidence Assessments

The included RCT studies’ quality was assessed using the Cochrane risk of bias tool (Version 5.1.0), which includes assessing the randomization process, intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Each trial was evaluated across these bias domains, and a summary risk-of-bias score was assigned for each one. The Cochrane Collaboration’s tool examines bias across 6 domains and gives rating systems with “low”, “high” and “unclear” levels to evaluate risk levels. Studies can be classified as “low risk of bias” by showing minimal risk throughout all 3 key assessment areas (selection, detection and performance). An assessment of “unclear risk of bias” occurs when uncertainty exists in any of the key domains while “high risk of bias” exists when high risk factors are detected across the domains. This assessment determined an overall classification, categorizing the trials as having a low risk, some concerns, or a high risk of bias. Each of the included studies was reviewed by 2 authors, who assessed each possible source of bias and rated the risk as high, low, or unclear. Any disagreements were resolved through discussion or adjudication with a third reviewer. In addition, the overall strength of the evidence was assessed using the GRADE tool.

Statistical Analysis

Meta-analysis was performed using STATA 17 software. Effect sizes were determined using the change score approach. The mean change in each group was calculated by: mean value at the end of follow-up-mean value at the baseline. The SD changes were calculated using the following formula: SD ¼ square root [(SD pre-treatment)² (SD post-treatment)² – (2R SD pre-treatment SD post-treatment)], where the correlation coefficient (R-value) was considered .8.²⁵ When an SEM or SE was reported instead of SD, the SD was calculated based on the following formula: SD¼ SEM √n (n ¼ sample size in each group). The random-effect model utilizing the restricted maximum likelihood (REML) approach was used to pool the included studies’ results and express weighted mean differences (WMD) and 95% confidence intervals (CI). Given the expected clinical heterogeneity across studies in terms of population characteristics, astaxanthin dose, intervention duration, and baseline metabolic status, random-effects models were applied for all analyses irrespective of statistical heterogeneity. The heterogeneity of included studies was assessed using Cochrane’s Q test (with a significant P-value <.1) and I-square test (I² greater than 50%, showing significant heterogeneity).

A subgroup analysis was conducted on the year of publication, sex of participants, sample size, intervention form, and population of the included studies. The sensitivity analysis evaluated the effect of each study on the overall effect size by removing a single trial and repeating the analysis. The funnel plot, as well as the Begg or Egger tests, was used to determine the publication bias. To adjust for the impact of publication bias, the trim and fill method was applied. The statistical significance was set at P < .05.

Results

Search Results

The detailed process of the study selection is shown in Figure 1. Our initial search identified 717 studies (PubMed [n = 132], Scopus [n = 349], Web of Science [n = 197], and Google Scholar [n = 39]). After removing 328 duplicate articles, we screened the remaining 389 articles based on their titles and abstracts. We excluded 378 articles for being animal studies, review articles, or unrelated studies. Among 11 full-text articles that were screened further, 2 RCTs were excluded because they did not report the required data. Ultimately, 9 RCTs were eligible for this systematic review and meta-analysis.^{16,21,23,24,29,31-33}

Figure 1.

The process of study selection for this systematic review (PRISMA diagram).

The Studies’ Characteristics

The overall characteristics of the eligible studies are summarized in Table 1. These studies, conducted in Iran (n = 4), the USA (n = 1), China (n = 1), and Japan (n = 1), were published between 2019 and 2024. The supplementation durations varied from 8 to 24 weeks. The astaxanthin intervention dosage in the included studies ranged from 8 to 12 mg/day. The study design in all studies was parallel. All of the studies were performed on both sexes of subjects. The sample sizes of the eligible trials ranged from 18 to 34 participants. Overall, 403 subjects were enrolled in these trials, with 173 individuals assigned to the astaxanthin group and 230 to the control group. The participants’ mean age ranged from 18 to 75 years. Participants in these studies were patients with prediabetes and T2DM.

Table 1.

Characteristics of the Included Studies.

First author, year of publication/country	Population	No. of participants (intervention/control)	Gender of patients	Age range (mean age)	Intervention dose (mg/day)	Intervention duration (week)
Ciaraldi, 2023/USA	Patients with prediabetes and dyslipidemia	22/12	M (n = 24) and F (n = 10)	18-75	12	12 and 24 wk
Sokri Mashhadi, 2018/Iran	T2DM patients (with no insulin therapy)	22/22	M (n = 17) and F (n = 27)	30-60	8	8 wk
Shari-Rigi, 2024/Iran	T2DM patients	25/25	M (n = NM) and F (n = NM)	20-60	10	12 wk
Urakaze, 2021/Japan	Patients with prediabetes	23/21	M (n = 15) and F (n = 29)	20-74	12	12 wk
Roustaei Rad, 2024/Iran	T2DM patients	24/22	M (n = 22) and F (n = 25)	20-60	10	12 wk
Chan, 2019/China	T2DM patients	18/18	M (n = 22) and F (n = 14)	40-75	6 and 12	8 wk
Shari-Rigi, 2023/Iran	T2DM patients	30/30	M (n = 35) and F (n = 25)	30-60	10	12 wk
Sokri Mashhadi, 2020, Iran	T2DM patients	22/22	M (n = 17) and F (n = 27)	30-60	8	8 wk
Taghiyar, 2023, Iran	T2DM patients	34/33	M (n = NM) and F (n = NM)	40-65	10	12 wk

Abbreviations: F, female; M, male; NM, not mentioned; T2DM, type 2 diabetes mellitus.

Quality Assessment of the Included Studies and Certainty of the Evidence

Based on the results of the included studies’ quality assessment using the Cochrane Collaboration scale (Supplemental Table 3), the included studies had a low risk of bias. Some of the studies did not consider the allocation concealment. Moreover, using the GRADE tool, the quality of the obtained evidence was rated as low for HbA1c, high for HDL-C, and moderate for the rest (Table 2).

Table 2.

Summary of Results and Quality of Evidence Assessment Using the GRADE Approach.

	Summary of findings		Quality of evidence assessment (GRADE)
Outcome measures	No. of patients/RCTs	WMD (95%CI)	Risk of bias^a	Inconsistency^b	Indirectness^c	Indirectness^d	Publication bias^e	Quality of evidence^f
Glycemic indices
FBS	292/6	–16.126 mg/dl (−28.968 to −3.285)	Not serious	Serious	Not serious	Not serious	Not serious	Moderate
HbA1c	292/6	−0.338 (−0.598 to −0.079)	Not serious	Serious	Not serious	Not serious	Serious	Low
HOMA-IR	84/2	−0.950 (−2.061 to 0.161)	Not serious	Serious	Not serious	Not serious	Not Serious	Moderate
Lipid profiles
TG	276/6	–20.872 mg/dl (–38.205 to 3.540)	Not serious	Serious	Not serious	Not serious	Not serious	Moderate
LDL-C	276/6	–9.409 mg/dl (−15.287 to −3.531)	Not serious	Serious	Not serious	Not serious	Not serious	Moderate
HDL-C	222/5	3.021 mg/dl (2.000 to4.042)	Not serious	Not serious	Not serious	Not serious	Not serious	High
TC	1276/6	–12.174 mg/dl (−19.839 to −4.509)	Not serious	Serious	Not serious	Not serious	Not serious	Moderate
Anthropometric measures
Weight	84/2	6.952 kg (−8.031 to 21.935)	Not serious	Serious	Not serious	Not serious	Serious	Moderate
BMI	128/3	–0.090 kg/m² (−0.503 to 0.322	Not serious	Serious	Not serious	Not serious	Not serious	Moderate

Abbreviations: BMI, body mass index; FBS, fasting blood sugar; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.

Risk of bias based on the Cochrane results.

Downgraded if there was a substantial unexplained heterogeneity (I² > 50%, P < .10) that was unexplained by meta-regression or subgroup analyses.

Downgraded if there were factors present relating to the participants, interventions, or outcomes that limited the generalizability of the results.

Downgraded if optimal information size was not met, or the 95%CI include the null value lower and upper bounds of the 95%CI were <0.95 and >1.05, respectively.

Downgraded if there was an evidence of publication bias using funnel plot.

Since all included studies were meta-analyses of randomized clinical trials, the certainty of the evidence was graded as high for all outcomes by default and then downgraded based on prespecified criteria. Quality was graded as high, moderate, low, very low.

Outcomes

Effect of Astaxanthin Intervention on Glycemic Indices

The impact of astaxanthin supplementation on fasting blood sugar (FBS) levels was assessed in 6 RCTs, including 292 patients. Pooled analysis showed a significant reduction in FBS levels (WMD: –16.126 mg/dl (95%CI: −28.968- −3.285), P = .014) with a high amount of heterogeneity (I-squared = 98.3% P_{heterogeneity} < .001); Figure 2A). The results of subgroup analysis showed that a similar significant effect on FBS was seen in trials that had sample size ⩾50 (WMD: –17.046 mg/dl (95%CI: −26.788-−7.305) and astaxanthin dosage <12 mg/day (WMD: –14.214 mg/dl (95%CI: −19.630-−8.798); Supplemental Table 3). Sensitivity analysis indicated that removing each study did not change the results (Supplemental Figure 1A). Begg’s test results indicated no publication bias (P = .348), however, there was partial asymmetry in the funnel plot (Figure 2B). Thus, the trim and fill method was applied so that no study was imputed (Supplemental Figure 1B).

Figure 2.

Forest plot (A) and funnel plot (B) of the effect of astaxanthin supplementation on fasting blood sugar levels.

Combined the results of 6 eligible studies comprising 292 patients showed that astaxanthin intervention significantly decreased glycated hemoglobin (HbA1c; WMD: −0.338 (95%CI: −0.598-−0.079), P = .011) with a high heterogeneity among the studies (I-squared = 93.6% P_{heterogeneity} < .001; Figure 3A). In addition, the subgroups results showed that impact of astaxanthin on HbA1c in studies with sample size ⩾50 (WMD: −0.557 (95%CI: −0.873 to −0.241)) and intervention duration <12 mg/day (WMD: −0.338 (95%CI: −0.598 to −0.079); Table 3). Sensitivity analysis indicated that removing the Sharifi-Rigi et al. study changed the results (WMD: −0.228 (95%CI: −0.458 to −0.001); Supplemental Figure 2A). Begg’s test results indicated no publication bias (P = .188), however, there was partial symmetry in the funnel plot (Figure 3B). Thus, the trim and fill method was applied and by imputing 2 studies the results became non-significant (WMD: −0.165 (95%CI: −0.506 to 0.176); Supplemental Figure 2B). The trim-and-fill analysis suggests potential publication bias influencing this outcome.

Figure 3.

Forest plot (A) and funnel plot (B) of the effect of astaxanthin supplementation on HbA1c.

Table 3.

Subgroup Analyses for the Effects of Astaxanthin on Patients with Prediabetes and T2DM.

Subgroups	Effect size (n)	ES (95%CI)^a	P-within^b	I² (%)^c	P-heterogeneity^d
Astaxanthin on FBS
Sample size (n)
<50	2	−15.542 (−45.204, 14.120)	.304	98.0	.003
⩾50	4	−17.046 (−26.788, −7.305)	.001	90.5	<.001
Intervention duration (weeks)
<12	4	−14.214 ( −19.630, −8.798)	<.001	31.8	.221
⩾12	2	−14.604 (−39.417, 10.209)	.249	99.6	<.001
Dosage (mg/day)
<12	2	−27.402 (−30.187, −24.617)	<.001	0.0	.614
⩾12	4	−9.715 (−17.418, −2.011)	.013	87.2	<.001
Astaxanthin on HbA1c
Sample size (n)
<50	2	0.011 (−0.032, 0.055)	.611	0.0	.881
⩾50	4	−0.557 (−0.873, −0.241)	.001	79.9	.002
Dosage (mg/day)
<12	3	−0.513 (−0.889, −0.138)	.007	86.0	.001
⩾12	3	−0.061 (−0.234, 0.111)	.485	78.2	.010
Astaxanthin on LDL-C
Sample size (n)
<50	3	−5.721 (−13.484, 2.042)	.149	95.2	.086
⩾50	3	−13.193 (−23.311, −3.075)	.011	85.6	.001
Intervention duration (weeks)
<12	2	−8.840 (−22.942, 5.262)	.219	86.2	.007
⩾12	4	−9.275 (−17.348, −1.202)	.024	74.4	.008
Dosage (mg/day)
<12	3	−8.502 (−21.384, 4.380)	.196	81.1	.005
⩾12	3	−11.496 (−16.984, −6.007)	<.001	71.4	.030
Astaxanthin on TG
Sample size (n)
<50	3	−14.233 (−25.155, −3.312)	.011	18.6	.293
⩾50	3	−23.435 (−49.915, 3.044)	.083	89.4	<.001
Intervention duration (weeks)
<12	2	−44.510 (−51.219, −37.800)	<.001	0.0	.688
⩾12	4	−11.652 (−18.404, −4.899)	.001	0.0	.988
Dosage (mg/day)
<12	3	−15.416 (−29.030, −1.802)	.026	12.2	.320
⩾12	3	−22.868 (−49.044, 3.309)	.087	94.9	<.001
Astaxanthin on HDL-C
Sample size (n)
<50	3	2.834 (1.347, 4.321)	<.001	0.24	.268
⩾50	2	2.715 (−0.769, 6.200)	.127	0.0	.514
Dosage (mg/day)
<12	2	1.498 (−0.583, 3.580)	.158	0.0	.667
⩾12	3	3.503 (2.331, 4.674)	<.001	0.0	.905
Astaxanthin on TC
Sample size (n)
<50	3	−7.126 (−12.288, −1.963)	.007	6.4	.344
⩾50	3	−16.926 (−25.949, −7.902)	<.001	72.0	.028
Intervention duration (week)
<12	2	−20.231 (−23.635, −16.828)	<.001	3.6	.308
⩾12	4	-8.542 to 15.269, −1.816)	.013	47.0	.129
Dosage (mg/day)
<12	4	−16.448 (−23.658, −9.237)	<.001	61.9	.049
⩾12	2	−6.095 (−11.179, −1.012)	.019	0.0	.328

Abbreviations: BMI, body mass index; CI, confidence interval; ES, effect size; FBS, fasting blood sugar; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.

Obtained from the Random-effects model.

Refers to the mean (95%CI).

Inconsistency, percentage of variation across studies due to heterogeneity.

Obtained from the Q-test.

The bold values are clinically significant.

Pooling the results of 2 included RCTs indicated that homeostasis model assessment of insulin resistance (HOMA-IR) did not alter after astaxanthin supplementation (WMD: −0.950 (95%CI: −2.061 to 0.161), P = .094; Figure 4). Only one included RCT¹⁶ assessed the effects of astaxanthin on serum insulin levels in patients with prediabetes and reported that 24 weeks of astaxanthin supplementation significantly improved serum insulin levels.

Figure 4.

Forest plot of the effect of astaxanthin supplementation on HOMA-IR.

Effect of Astaxanthin Intervention on Lipid Profile

Pooling the findings of 6 included studies including 276 patients based on the random-effects model, showed that low-density lipoprotein cholesterol (LDL-C) levels significantly decreased after astaxanthin supplementation (WMD: −9.409 mg/dl (95%CI: −15.287 to −3.531), P = .002) with a high heterogeneity among the studies (I-squared = 79.9%, P_{heterogeneity} < .001; Figure 5A). The results of the sub-group analysis have demonstrated that astaxanthin intake had significant effect on reducing LDL-C levels in studies with sample size ⩾50 (WMD: –9.409 mg/dl, (95%CI; −15.287 to −3.531)), intervention dose ⩾12 mg/day (WMD: –26.00 mg/dl, (95%CI; −45.491 to –6.509)), and supplement duration ⩾12 weeks (WMD: –9.275 mg/dl (95%CI; −17.348 to −1.202); Table 3). Moreover, sensitivity analysis indicated that removing each study did not change the results (Supplemental Figure 3A). Begg’s test results indicated no publication bias (P = .851), however, there was a partial asymmetry in the funnel plot (Figure 5B). Thus, the trim and fill method was applied with imputing one studies that the results did not change (Supplemental Figure 3B).

Figure 5.

Forest plot (A) and funnel plot (B) of the effect of astaxanthin supplementation on low-density lipoprotein levels.

The results of 6 RCTs including 276 patients combined and showed that astaxanthin significantly decreased serum triglycerides (TG) levels (WMD: –20.872 mg/dl, (95%CI: −38.205 to 3.540), P = .018) with a relatively high heterogeneity among the studies (I-squared = 89.1%, P_{heterogeneity} < .001; Figure 6A). The subgroup results showed that astaxanthin intake had a significant impact on TG levels in studies with sample size <50 (WMD: –14.233 mg/dl (95%CI: −25.155 to −3.312)) and intervention dose <12 mg/day (WMD: –15.416 mg/dl (95%CI: −29.030 to −1.802); Table 3). Sensitivity analysis indicated that after removing the Mashhadi et al. study, the results be non-significant (WMD: –18.470 mg/dl (95%CI: −37.442 to 0.502); Supplemental Figure 4A). Begg’s test results indicated no publication bias (P = .348), however, there was a partial asymmetry in the funnel plot (Figure 6B). Thus, the trim and fill test was conducted, which did not indicate a study (Supplemental Figure 4B).

Figure 6.

Forest plot (A) and funnel plot (B) of the effect of astaxanthin supplementation on triglyceride levels.

The meta-analysis of 5 eligible studies comprising 222 participants showed that astaxanthin intake significantly increased serum high-density lipoprotein cholesterol (HDL-C) levels (WMD: 3.021 mg/dl, (95%CI, 2.000-4.042), P < .001) with a low heterogeneity among the studies (I-squared = 0.0%, P_{heterogeneity} = .543); Figure 7A). Subgroup analyses results showed that astaxanthin intake had a significant impact on HDL-C levels in studies with sample size <50 (WMD: 2.834 mg/dl (95%CI: 1.347-4.321)) and intervention dosage ⩾12 mg/day (WMD: 3.503 mg/dl (95%CI: 2.331-4.674); Table 3). Sensitivity analysis indicated that removing each study did not change the results (Supplemental Figure 5A). Begg’s test results indicated no publication bias (P = .624), however, there was partial asymmetry in the funnel plot (Figure 7B). Thus, the trim and fill method was done, which did not impute a study (Supplemental Figure 5B).

Figure 7.

Forest plot (A) and funnel plot (B) of the effect of astaxanthin supplementation on high-density lipoprotein cholesterol levels.

The findings of 6 RCTs including 276 patients were pooled by a random effect model and indicated that astaxanthin supplementation significantly reduced serum total cholesterol (TC) levels (WMD: –12.174 mg/dl, (95%CI: −19.839 to −4.509), P = .002) with high heterogeneity among the studies (I-squared = 82.7%, P_{heterogeneity} = .190; Figure 8A)). Based on the subgroup analysis, the results did not alter by the included studies sample size and intervention dose and duration. Sensitivity analysis indicated that removing each RCT did not impact the results (Supplemental Figure 6A). Begg’s test results indicated no publication bias (P = .851), however, there was partial asymmetry in the funnel plot (Figure 8B). Thus, the trim and fill method was applied with no imputing a study (Supplemental Figure 6B).

Figure 8.

Forest plot (A) and funnel plot (B) of the effect of astaxanthin supplementation on total cholesterol levels.

Effect of Astaxanthin Intervention on Anthropometric Parameters

Pooling the results of 2 included RCTs showed that astaxanthin had no significant impact on the weight of patients (WMD: 6.952 kg, (95%CI: –8.031 to 21.935), P = .363; Figure 9A). Moreover, 3 eligible studies with 128 patients reported the effects of astaxanthin on body mass index (BMI) of patients that combining their results indicated that astaxanthin intervention did not change significantly the BMI of participants (WMD: –0.090 kg/m², (95%CI: −0.503 to 0.322), P = .667; Figure 9B).

Figure 9.

Forest plot of the effect of astaxanthin supplementation on body weight (A) and body mass index (B).

Other Outcomes

One of the included RCTs reported that astaxanthin supplementation may have antioxidant and anti-inflammatory effects, as it was beneficial for improving circulating malondialdehyde (MDA) and interleukin-6 (IL-6) levels and down-regulating microRNA-146a.³²

Another included study indicated that astaxanthin could modify the serum levels of saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA), and increase the expression and activity levels of SIRT1 and AMP-activated protein kinase (AMPK), respectively.³¹

Discussion

This systematic review and meta-analysis summarize the findings on the effects of astaxanthin supplementation in patients with prediabetes and T2DM. The meta-analysis results demonstrated that astaxanthin supplementation significantly improved several key metabolic parameters in these patients. Specifically, there was a notable reduction in FBS, HbA1c, LDL-C, TC, and TG, accompanied by a significant increase in HDL-C. Interestingly, despite these improvements, astaxanthin did not significantly impact HOMA-IR, body weight, or BMI, which may be due to the small number of included studies. Although the obtained improvement may not be enough to be clinically effective, the significant heterogeneity and different intervention dose and duration likely prevented reaching the minimal clinically important differences, and if the intervention continued, the changes in the studied variables would be clinically meaningful. The substantial heterogeneity observed across most outcomes likely reflects true clinical heterogeneity rather than methodological limitations alone. Differences in baseline glycemic control, astaxanthin dose (6-12 mg/day), intervention duration (8-24 weeks), sample size, and population metabolic characteristics contribute to variability in effect estimates. While random-effects models are appropriate under such conditions, findings should be interpreted with caution. Moreover, the subgroup analyses results should be considered with caution due to the small number of RCTs in each group and the lack of correction for multiple comparisons. Additionally, about HbA1c that the results became non-significant based on the trim-and-fill adjustment indicates that the apparent reduction in HbA1c may be overestimated due to publication bias and should be interpreted cautiously. Regarding the intervention dose, it should be noted that no clear dose–response relationship was observed across studies, as higher doses of astaxanthin did not consistently produce greater metabolic improvements. This may suggest a threshold or saturation effect rather than linear dose dependency.

There are some previous meta-analyses in this regard that reported various findings. For example, Xia et al revealed that astaxanthin consumption did not change the serum levels of FBS, HbA1c, TC, LDL-C, and TG, but increased HDL-C levels in the general population.³⁴ Moreover, astaxanthin intervention had no significant effect on the body weight and BMI of participants. BMI, BW, DBP, and SBP.³⁴ Another meta-analysis demonstrated a significant attenuating effect on TC, but not on FBS, TG, LDL-C, and HDL-C levels and body weight of adults at risk of metabolic syndrome.³⁵ Moreover, the meta-analysis by Laurindo et al reported the positive effects of astaxanthin on HDL-C and TG levels in the general population. However, astaxanthin does not appear to significantly influence LDL-C and TC levels.³⁶

Some possible mechanisms explain the astaxanthin effects. Astaxanthin, as a xanthophyll carotenoid with antioxidant properties, has been reported to enhance insulin sensitivity and reduce oxidative stress, which are key contributors to insulin resistance and β-cell dysfunction in T2DM.^37,38 There are several mechanisms for these effects of astaxanthin in these patients. It was suggested that adiponectin-mediated mechanisms may be crucial in astaxanthin’s insulin-sensitizing effects. Adiponectin enhances fatty acid oxidation and glucose uptake through activation of AMPK and PPAR-α, which could explain improvements in HOMA-IR and lipid profiles independent of weight loss.^21,39 Another mechanistic insight is astaxanthin’s anti-inflammatory effects. It was reported that astaxanthin significantly reduced IL-6 and MDA, and downregulated miR-146a expression, a microRNA involved in nuclear factor-kappa B (NF-κB)-mediated inflammation.^32,40 This indicates that astaxanthin may mitigate chronic inflammation, a key driver of insulin resistance and vascular complications in T2DM. In addition, astaxanthin’s antioxidant properties are notably stronger than those of other carotenoids, attributed to its unique molecular structure, which allows membrane-spanning antioxidant action.^40,41 It neutralizes reactive oxygen species (ROS), protects β-cells from glucotoxicity, and enhances mitochondrial function, all of which are essential in preserving insulin sensitivity and preventing oxidative damage in T2DM.⁴² Therefore, astaxanthin could improve insulin sensitivity via downregulation of pro-inflammatory cytokines and miRNAs,^32,40 enhancement of adiponectin secretion, which activates AMPK/PPAR-α pathways,^21,39 increasing GLUT4 expression and translocation that enhance glucose uptake in muscle and adipose tissue,^43,44 and inhibition of oxidative stress and improvement of β-cells function.⁴² The lack of a statistically significant improvement in HOMA-IR may be attributable to limited statistical power, as only 2 trials assessed this outcome, as well as the possibility that astaxanthin primarily improves glycemic control through antioxidant and β-cell protective mechanisms rather than directly enhancing peripheral insulin sensitivity. Moreover, although astaxanthin has been shown to activate pathways such as AMPK and adiponectin signaling, the absence of significant changes in body weight or BMI suggests that its metabolic benefits may occur independently of weight loss, particularly over short intervention periods. On the other hand, the intervention duration of 8 to 24 weeks may be insufficient to detect significant changes in body weight or BMI, as anthropometric outcomes typically require longer-term interventions to manifest. Therefore, higher intervention duration, more than 12 weeks, is suggested to reach a meaningful reduction in body weight of patients with diabetes.

According to the findings, astaxanthin supplementation had a significant effect on lipid profile improvements that may be attributed to its role in upregulating lipid metabolism-related genes and enhancing mitochondrial function, thereby reducing lipid accumulation and promoting fatty acid oxidation.¹⁶ The enhanced catabolism of very low-density lipoprotein (VLDL) through increased lipoprotein lipase and VLDL receptor expression related to improved insulin resistance was considered as the mechanism underlying the reduction in the serum TG concentration following astaxanthin supplementation.^45,46 Additionally, it was suggested that increased HDL-C levels may be related to the adiponectin enhancement, as changes in the adiponectin concentration were positively associated with changes in the HDL-C levels.^21,45,47 Increasing HDL-C and adiponectin concentrations following astaxanthin supplementation was reported by the studies.^21,45,47

Limitations

Despite the compelling evidence, some limitations persist. The relatively small number of included studies, variability in intervention dosage duration across studies, and the lack of reporting data about the adverse effects were the main limitations of this review. The meta-analysis included a relatively small number of RCTs with limited sample sizes, included only the English language articles, and nearly half of the included studies were conducted in Iran, which may be because of limited geographic diversity restrict the generalizability of findings to other populations. Furthermore, there is a high amount of heterogeneity among the studies, which was explained by the subgroup analyses. In addition, potential publication bias, particularly affecting HbA1c outcomes, reduces confidence in the pooled estimates.

Conclusion

In conclusion, astaxanthin supplementation may improve glycemic indices and lipid profiles in patients with prediabetes and T2DM, though substantial heterogeneity and potential publication bias limit confidence in these findings. The lack of effects on anthropometric measures and the limited number of studies warrant cautious interpretation. Well-designed, adequately powered trials are needed to confirm these preliminary findings and establish optimal dosing and duration.

Supplemental Material

sj-docx-1-nmi-10.1177_11786388261432862 – Supplemental material for Effects of Astaxanthin Supplementation on Glycemic Control and Lipid Profile in Patients With Prediabetes and Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Supplemental material, sj-docx-1-nmi-10.1177_11786388261432862 for Effects of Astaxanthin Supplementation on Glycemic Control and Lipid Profile in Patients With Prediabetes and Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials by Roghayeh Molani-Gol, Sanaz Bohlouli Sardroudi and Maryam Rafraf in Nutrition and Metabolic Insights

Supplemental Material

sj-docx-2-nmi-10.1177_11786388261432862 – Supplemental material for Effects of Astaxanthin Supplementation on Glycemic Control and Lipid Profile in Patients With Prediabetes and Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Supplemental material, sj-docx-2-nmi-10.1177_11786388261432862 for Effects of Astaxanthin Supplementation on Glycemic Control and Lipid Profile in Patients With Prediabetes and Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials by Roghayeh Molani-Gol, Sanaz Bohlouli Sardroudi and Maryam Rafraf in Nutrition and Metabolic Insights

Footnotes

Acknowledgements

We would like to thank the Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran, for their financial support (grant number: 39064).

ORCID iD

Maryam Rafraf

Author Contributions

RMG analyzed data and wrote the main manuscript text, and SB contributed to data collection. MR contributed to revising the manuscript. All authors read the manuscript and approved the final version.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The research protocol was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran (grant number: 39064).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

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