1. Introduction

Metabolic syndrome poses a significant public health concern because of its increasing incidence globally and its association with serious life-threatening illnesses [1, 2]. Many metabolic risk factors in the same individual characterize the metabolic syndrome [2, 3]. The initial unified agreement about the definition of metabolic syndrome was drawn up during a meeting hosted by the International Diabetes Federation in 2005. As stated in this, the main contributing factor is obesity, determined by waist circumference and BMI [3]. The prevalence of metabolic syndrome depends on age, gender, race, and ethnicity worldwide, ranging from 10% to 84%. It is estimated that 20%–25% of the world’s adult population, including Indonesian people, have metabolic syndrome [2].

The contributing factors that cause metabolic syndrome are internal and external to the human body. Internal means genes or hereditary, whereas external means lifestyle [2, 3]. Describing lifestyle factors is eating unhealthy food. Patients with metabolic syndrome must avoid food and beverages with high sugar (sucrose and fructose), fat, and carbohydrate contents [4]. Metabolic syndrome has multiple underlying causes [2, 3]. These risk factors are called metabolic syndrome, including abdominal obesity, increased triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol concentrations, elevated blood pressure, and hyperglycemia [5]. Metabolic syndrome increases the risk of cardiovascular disease, Type 2 diabetes, cancer (liver, pancreas, breast, and bladder), kidney dysfunction, pancreatic dysfunction, coronary or peripheral atherosclerosis, and heart failure [2, 3]. Moreover, metabolic syndrome is associated with several other systemic issues that impact many organs and systems, including fatty liver disease, respiratory disorders, osteoarthritis, and cancer [3].

Metabolic syndrome and obesity are closely linked, with each condition often exacerbating the other. Obesity, characterized by excessive accumulation of body fat, is a significant risk factor for developing metabolic syndrome, a group of disorders that include high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels. The excess adipose tissue in obese individuals contributes to insulin resistance, inflammation, and dyslipidemia, which are critical components of metabolic syndrome. Conversely, the presence of metabolic syndrome can further promote weight gain and obesity by disrupting normal metabolic processes and increasing appetite. This bidirectional relationship highlights the importance of treating both conditions simultaneously to reduce the risk of associated health complications such as cardiovascular disease and Type 2 diabetes [4, 5].

The connection between metabolic syndrome and hypertension is significant because hypertension is a common component and consequence of metabolic syndrome. Metabolic syndrome encompasses a group of disorders, including insulin resistance, central obesity, dyslipidemia, and elevated blood glucose levels, all of which contribute to the development and exacerbation of hypertension. Insulin resistance and obesity, in particular, lead to several physiological changes, such as increased sympathetic nervous system activity, sodium retention, and changes in blood vessel function that increase blood pressure. Additionally, the inflammatory condition associated with metabolic syndrome can damage blood vessels, promoting artery stiffness and further increasing blood pressure. Effective treatment of metabolic syndrome through lifestyle changes and medical interventions is crucial for controlling high blood pressure and reducing the risk of cardiovascular events and other related health problems [2, 4].

Hyperglycemia is a critical component of metabolic syndrome. Metabolic syndrome is characterized by some disorders, including insulin resistance, central obesity, dyslipidemia, hypertension, and elevated fasting blood glucose levels. Insulin resistance, a hallmark of metabolic syndrome, impairs the body’s ability to use glucose effectively, leading to elevated blood sugar levels or hyperglycemia. Chronic hyperglycemia, in turn, increases insulin resistance and contributes to further metabolic disorders. The interaction of these diseases creates a vicious circle that can lead to the development of Type 2 diabetes and increase the risk of cardiovascular disease. Managing hyperglycemia through lifestyle interventions such as diet, exercise, and medical treatments is critical to breaking this cycle and mitigating the health impairments associated with metabolic syndrome [1, 3, 5].

The relationship between metabolic syndrome and hyperlipidemia is complicated and mutually reinforcing. Hyperlipidemia, characterized by increased levels of lipids in the blood, including cholesterol and triglycerides, is a common feature of metabolic syndrome. Metabolic syndrome includes a range of conditions, such as insulin resistance, central obesity, hypertension, and hyperglycemia, all of which contribute to lipid abnormalities. In particular, insulin resistance and obesity lead to increased production of very low-density lipoprotein (VLDL) and decreased clearance of triglycerides from the bloodstream, leading to hyperlipidemia. In addition, metabolic syndrome is often accompanied by a proinflammatory condition that can further disrupt lipid metabolism. This dyslipidemia increases the risk of atherosclerosis and cardiovascular disease, which is why control of lipid levels is crucial in treating metabolic syndrome. Addressing hyperlipidemia through lifestyle changes, dietary modifications, and pharmacological interventions is critical for reducing cardiovascular risks associated with metabolic syndrome [3, 5].

Macronutrients and micronutrients are essential in protecting the body against metabolic syndrome. Carbohydrates, lipids, and proteins are the body’s main energy sources. Elevated blood sugar levels after consuming simple carbohydrates can raise the risk of metabolic syndrome. People with metabolic syndrome are recommended to choose complex carbohydrates and reduce their intake of simple carbohydrates, ingest enough protein, and choose to consume mono- and polyunsaturated fatty acids [6]. Vitamins and minerals are nutrients that the body needs in trace levels. Micronutrients are vital in protecting the body from metabolic syndrome. Vitamin and mineral deficiencies in vitamins B complex, C, and D, and Mg and K can elevate the risk of metabolic syndrome [7].

Spirulina is frequently utilized as a dietary supplement because it has the characteristics of high nutrients and bioactive components and is safe for human consumption [8–10]. Approximately 55%–69% proteins, 6%–7% lipids (rich in polyunsaturated fatty acids, or PUFAs), 15%–24% carbohydrates, and minerals and antioxidants are all present in high concentrations in Spirulina [11]. Several micronutrients are rich in Spirulina, including beta-carotene, B vitamins, and minerals [12]. Spirulina also has phycocyanin as a major pigment with significant advantages for humans [10, 13].

Spirulina is a blue-green microalgae from phylum Cyanobacteria that flourishes in aquatic environments, and species of Spirulina have been isolated from tropical waters to the North Sea [8, 10]. The most well-known species of Spirulina in other studies are S. platensis, S. maxima, and S. fusiformis [8, 13]. Spirulina, a nutrient-dense cyanobacterium, shows significant potential as a complementary therapy for chronic conditions such as obesity, diabetes, and dyslipidemia. It aids in weight reduction by decreasing body weight, fat percentage, and waist circumference while controlling appetite through phenylalanine-induced release of cholecystokinin and improved leptin sensitivity. Spirulina enhances glycemic control and insulin sensitivity by increasing insulin production, improving hemoglobin levels, and reducing inflammatory mediators. Additionally, it improves lipid profiles by lowering total cholesterol and triglycerides through its action on HMG-CoA reductase and lipid metabolism. Another mechanism for improving the lipid profile of S. platensis is the inhibition of HMG-CoA reductase activity and activation of the lecithin cholesterol acyl transferase (LCAT) enzyme [14]. Its anti-inflammatory and antioxidant properties, attributed to compounds like C-phycocyanin and β-carotene, reduce oxidative stress and inflammation. Spirulina high-protein content further aids in weight management and cardiovascular health by reducing oxidative stress and managing endothelial dysfunction [9, 11, 13, 15–17].

Several clinical studies have examined the effects of Spirulina on food intake and energy expenditure. A double-blind, placebo-controlled study in 52 obese adults found that 12 weeks of spirulina supplementation significantly reduced food intake and body weight compared with placebo [18]. This decrease in food intake is associated with increased release of the hormone GLP-1, which induces satiety. Another study in 40 athletes showed that spirulina supplementation for four weeks increased energy expended during exercise compared to placebo [19]. This increase in energy expenditure correlates with increased fat oxidation, indicating a potential effect of spirulina in improving metabolism. In a clinical trial on 78 Type 2 diabetes patients, spirulina supplementation for 12 weeks significantly reduced food intake and body weight [20]. This effect is attributed to the inhibition of appetite by spirulina.

Spirulina has been studied in combination with conventional drugs related to metabolic syndrome, such as antidiabetics [21]. In a study on streptozotocin-induced diabetic rats, spirulina showed comparable hypoglycemic effects to glibenclamide, a sulfonylurea antidiabetic drug [22]. When combined, Spirulina and glibenclamide produced a more significant reduction in blood glucose than either treatment alone. A clinical trial in patients with Type 2 diabetes found that spirulina supplementation improved glycemic control and insulin sensitivity when added to metformin [23]. With many uses of Spirulina as a dietary supplement, this systematic review aims to get an overview of the effect of supplementation on human-specific metabolic syndrome.

2. Method

The method used for this review is a systematic review using references from Khan et al. [24]. The systematic review strategy begins with a clearly stated problem, locates relevant research, rates the quality of those studies, and uses a clear methodology to compile the evidence. Systematic reviews are different from other reviews and commentaries because of their clear and rigorous process [25].

(8) include more in-depth research results from each article in the results section, and (9) discuss in more depth the discussion of each article and additions from other more concrete articles following the discussion.

3. Result

3.1. Search Result

After searching the article from the database that has been determined, the next step is to perform screening by analyzing the inclusion criteria of each article against the specified review topics in Figure 1. A total of 527 articles were located using the given keywords. After the screening was completed, nine articles were found which were duplicates of the others. In assessing eligibility, 453 articles were disqualified because they addressed animal tests, in vitro, in silico, reviews, and theoretical articles. A total of 65 articles were screened again, and it was determined that 52 articles did not match the topic of metabolic syndrome. The number of articles that addressed the topic of discussion was 13 articles, which were used for systematic review (Table 2).

Table 2. The result of the Spirulina supplementation review on humans.

Author	Year	Location	Design	Duration of trial	Inclusion criteria	Supplementation form species	Dose	Participant	Age (years)	Result
Rajabzadeh et al. [26]	2023	Iran	Randomized, double-blind, placebo-controlled	90 days	Type 2 diabetic mellitus patient	Spirulina platensis capsules	2 g/day	n = 68 men and women	25 to 50	Spirulina supplementation reduced fasting blood sugar, triglycerides, total cholesterol, and LDL-C levels and increased HDL-C levels in Type 2 diabetic patients
Mohammad et al. [27]	2022	Iran	Single-blind, quasiexperimental	60 days	Overweight and obese men, BMI > 25 kg/m2	Spirulina capsules	1 g/day	n = 60 men	30 to 55	Spirulina supplementation decreased weight and fasting blood sugar levels in overweight and obese males
Koite et al. [8]	2022	France	Controlled, randomized, double-blind, placebo-controlled	90 days	Patient with metabolic syndrome	Spirulina platensis liquid	20 mg/day	n = 40 22 men 18 women	18 to 65	Spirulysat did not change the plasma triglycerides, cholesterol, and LDL-C and boosted HDL-C in metabolic syndrome patients
van den Driessche et al. [28]	2020	Netherlands	Randomized, placebo-controlled, double-blind	17 days	BMI 18–30 kg/m2	Spirulina capsules	4.8 g/day	n = 35 15 men 20 women	18 to 70	Spirulina consumption did not lower plasma blood glucose in overweight individuals. At the same time, daily consumption in non-hypercholesterolemic men and women also did not affect plasma indicators of intestinal cholesterol absorption or serum lipid concentrations
Gomez-Tellez et al. [13]	2020	Mexico	Double-blind randomized controlled trial	90 days	Abdominal obesity patient	Spirulina maxima capsules	266 mg/day	n = 50 men and women	18 to 60	S. maxima supplementation made significant effects on the systolic blood pressure in obese people
Hernández-Lepe et al. [15]	2019	Mexico	Double-blind, randomized, crossover, controlled trial	90 days	Adults with BMI > 25 kg/m2	Spirulina maxima capsules	4.5 g/day	n = 52 men	26 ± 5	Spirulina maxima supplementation enhances BMI and HDL, and also decrease total cholesterol, triglycerides, and LDL cholesterol in males with excess body weight and dyslipidemia
Hernández-Lepe et al. [19]	2019	Mexico	Randomized, crossover controlled trial	45 days	BMI ≥ 25 kg/m2	Spirulina maxima capsules	4.5 g/day	n = 52 men	18 to 35	Spirulina maxima supplementation improves the BMI and HDL but decrease total cholesterol, triglycerides, and LDL in men with extra body weight and dyslipidemia
Hernández-Lepe et al. [29]	2018	Mexico	Randomized, double-blind, placebo-controlled, and counterbalanced crossover trial	90 days	BMI ≥ 25 kg/m2	Spirulina maxima capsules	4.5 g/day	n = 52 men	26 ± 5	Spirulina maxima supplementation improves the body fat percentage in overweight, but mostly in individuals with obesity
Martínez-Sámano et al. [30]	2018	Mexico	Single-blind, randomized, placebo-controlled	90 days	Systemic arterial hypertension patient	Spirulina maxima capsules	4.5 g/day	n = 16 men and women	20 to 60	On Spirulina supplementation, there were significantly reductions in systolic blood pressure but insignificantly in diastole blood pressure
Yousefi, Mottaghi, and Saidpour [31]	2018	Iran	Randomized, double-blind, placebo-controlled clinical trial	90 days	BMI 25–40 kg/m2	Spirulina platensis tablets	2 g/day	n = 38 men and women	20 to 60	Spirulina supplementation significantly reduced body weight, waist circumference, body fat, and BMI
Zeinalian et al. [18]	2017	Iran	Randomized double-blind placebo-controlled trial	90 days	Obese individuals, BMI ≥ 30 kg/m2	Spirulina capsules	1 g/day	n = 64	20 to 50	Spirulina supplementation had a decrease in BMI and appetite
Szulinska et al. [20]	2017	Poland	Randomized, double-blind placebo-controlled study	90 days	Individuals with hypertension and obesity, BMI ≥ 30 kg/m2	Spirulina maxima capsules	2 g/day	n = 50 25 men 25 women	25 to 60	Spirulina supplementation significantly reduced blood glucose and increased insulin sensitivity
Miczke et al. [32]	2016	Poland	Double-blind, placebo-controlled, randomized trial	90 days	Hypertension patient	Spirulina maxima capsules	2 g/day	n = 40 21 men 19 women	40 to 60	Spirulina supplementation had a significantly reduction in SBP and stiffness index

4. Discussion

The results of this review were obtained through data analysis from various articles published up to 2023. As the primary debate, 13 articles on the subject of Spirulina supplementation were utilized. The results show that Spirulina supplementation improves metabolic syndrome in humans. With consumption at a dose of 20 mg to 6 g and within a period of 14 days to 1 year, Spirulina supplementation is effective in the treatment of metabolic syndrome. Obesity, hypertension, hyperglycemia, and hyperlipidemia are among them.

Spirulina supplementation affects body weight and BMI by reducing fat content and limiting lipid accumulation and appetite [11, 13, 19, 29, 31]. Spirulina reduces lipid accumulation in the liver by reducing macrophage infiltration of visceral fat [35]. Phycocyanin from S. maxima extract decreased the adipogenic proteins C/EBPα, PPARγ, and aP2, as well as the lipogenic proteins SREBP1, ACC, FAS, LPAATβ, Lipin1, and DGAT1 in 3T3-L1 and C3H10T1/2 cells. These proteins contribute to increased fat accumulation; fat accumulation is low when their expression is suppressed [36]. The role of essential amino acids in spirulina, such as L-phenylalanine, is one of the factors for weight loss by influencing neurotransmitters such as dopamine and norepinephrine [37]. In appetite suppression, phenylalanine concentration increases the release of cholecystokinin [31]. Phenylalanine plays a role in increasing the feeling of satiety by inhibiting gastric emptying. This amino acid can increase cholecystokinin secretion, with the secretion of this hormone inhibiting gastric emptying to reduce energy intake and blood glucose levels [38].

In hypertension, Spirulina, which contains the bioactive component, inhibits angiotensin-converting enzyme I and activates angiotensin-converting enzyme II, and also increases the expression of endothelial nitric oxide synthase (eNOS) [20, 30]. The reduction in SBP and DBP is due to the stimulation of phycocyanin in Spirulina [13, 32, 33]. This pigment is present in spirulina and causes a decrease in blood pressure levels by promoting the production of eNOS. A study of phycocyanin administration over 25 weeks in spontaneous hypertensive rats (SHR) showed that administration lowered blood pressure by increasing eNOS expression and that the nitric oxide produced could relax blood vessels [39]. A tripeptide from Spirulina, namely, Ile-Gln-Pro (IQP), also shows antihypertensive effects. The peptide can inhibit angiotensin-converting enzyme I and activate angiotensin-converting enzyme II. Treatment with the tripeptide in SHR rats at 10 mg/kg per day for 14 weeks [40] and 8 weeks [41] lowers the blood pressure of these rats by inhibiting angiotensin-converting enzyme I and activating angiotensin-converting enzyme II.

In hyperglycemia, treatment with spirulina reduced blood glucose concentrations. Phycocyanin has the potential to act as a protein that mimics insulin or stimulates Langerhans B cells by increasing insulin synthesis. The pigment also improves insulin sensitivity. Administration of phycocyanin at 200 mg/kg over 4 weeks increased insulin secretion in diabetic mice with alloxan induction. The pigment increases the Ca²⁺ and K⁺ channels opening on the pancreatic beta cell membrane, stimulating insulin release [42]. Another study showed that treating KKAy mice with 100 mg/kg for 3 weeks improved insulin sensitivity. The increased glucose uptake occurs by shifting the Glu transporter to the cell membrane by activating the IRS/PI3K/Akt pathway [43].

Spirulina is known to reduce the body’s lipid profile by increasing lipoprotein lipase and pancreatic lipase, decreasing cholesterol and triglyceride synthesis, and increasing HDL synthesis [8, 17, 19, 26, 33, 34]. The bioactive compounds of this microalgae that play a role in improving the blood lipid profile include phycocyanin, gamma-linolenic acid, and glycolipid H-b2. Administration of phycocyanin 50 mg/kg for 30 days was able to decrease total triglycerides, total cholesterol, and LDL and increase HDL [44], while administration of phycocyanin 1.25% to hamsters fed a hypercholesterolemic diet for 2 months was able to lower TG, T-Chol, and LDL (increased mRNA level of LDL receptor) [45]. Administration of 2% GLA for 8 weeks lowered TG and cholesterol in hypercholesterolemic rats [46]. This essential fatty acid can lower cholesterol 170 times more than linoleic acid [47]. At a dose of 250 mg/kg, this compound can lower the TAG level of hypercholesterolemic mice by inhibiting pancreatic lipase activity [48]. Glycolipid H-b2, a type of glycolipid found specifically in spirulina, also plays a role in lowering hypercholesterolemia in mice.

5. Limitations

The review highlights several challenges in determining the optimal dosage and form of Spirulina for treating metabolic syndrome. Firstly, the studies used a wide range of dosages (20 mg–6 g) and forms (capsules, tablets, liquids, and sauces), making establishing a consistent treatment protocol difficult. Secondly, the trial durations varied significantly, from as short as 17 days to as long as 1 year, with shorter durations possibly insufficient to observe long-term effects. Additionally, the participant characteristics varied, including healthy individuals and those with metabolic syndrome, diabetes, hypertension, and obesity, affecting the results’ generalizability. The review also included both randomized and nonrandomized clinical trials, with nonrandomized trials being more prone to bias, impacting the reliability of the findings. Moreover, there was variability in the outcomes measured, such as BMI, waist circumference, blood pressure, fasting blood glucose, and lipid profiles, complicating direct comparisons or meta-analyses. Inconsistent results were reported, with some studies showing significant benefits of Spirulina supplementation. In contrast, others did not observe substantial changes, such as no significant impact on plasma blood glucose in overweight individuals despite high dosages. Lastly, the review concludes that further research is needed to determine Spirulina’s optimal dosage and form. By addressing these limitations, future studies can better clarify the role of Spirulina in managing metabolic syndrome and provide more definitive recommendations for its use.

6. Strengths

The strengths of this study are numerous and noteworthy. Firstly, the study’s comprehensive scope ensures that it captures a wide range of data and insights by covering a broad spectrum of studies on Spirulina supplementation, considering variations in dosage, trial duration, and participant demographics. This comprehensive approach enhances the robustness and applicability of the findings across different populations and settings. Secondly, the rigorous methodology employed in the review, which involves systematic searches in reputable databases like Scopus and PubMed, enhances the credibility and reliability of the study by ensuring the inclusion of relevant and high-quality studies. Thirdly, the large initial pool of 527 articles narrowed down to 13 suitable human clinical studies indicates a thorough and careful selection process, further ensuring the relevance and rigor of the included studies. Additionally, the diverse range of dosages (20 mg–6 g) and treatment durations (17–360 days) covered in the included studies aids in understanding the effects of Spirulina across different usage patterns and provides insights into optimal dosages and treatment periods for various metabolic conditions. By focusing specifically on human clinical studies, the review ensures that its findings directly apply to human health, increasing the practical relevance of the conclusions drawn. Furthermore, the review highlights Spirulina’s rich nutritional and bioactive composition, which includes macro- and micronutrients, vitamins, minerals, and bioactive compounds, supporting its multifaceted benefits in improving metabolic syndrome. The findings also indicate multiple health benefits of Spirulina supplementation, such as reductions in overweight, obesity, BMI, hypertension, hyperglycemia, and dyslipidemia, making it a valuable supplement for managing metabolic syndrome holistically. The review provides specific mechanistic insights into how components like tripeptides, gamma-linolenic acid, and glycolipids contribute to lowering blood pressure and improving lipid profiles, enhancing the scientific foundation for the observed health benefits. Lastly, the overall findings demonstrate consistent positive clinical outcomes. Spirulina supplementation significantly improves various aspects of human metabolic syndrome, thereby strengthening the evidence supporting its efficacy in managing this condition.

7. Conclusion

Spirulina supplementation in humans has a positive effect on metabolic syndrome. It is due to phycocyanin, Ile-Gln-Pro, gamma-linolenic acid, and the glycolipid H-b2. Spirulina supplementation may benefit weight management, blood pressure placebo, blood sugar, and lipid profile regulation in humans. Spirulina may help reduce body weight and BMI by decreasing fat accumulation and appetite. It appears to achieve this by influencing fat-storing proteins and hormones involved in satiety. Spirulina contains components that inhibit enzymes that raise blood pressure and promote nitric oxide production, a molecule that relaxes blood vessels. This may contribute to lowering blood pressure. Spirulina may help regulate blood sugar by stimulating insulin production. It may also improve insulin sensitivity, allowing cells to absorb glucose more effectively. Spirulina contains pigment and bioactive that inhibit enzymes that promote bad cholesterol and induce good cholesterol production. However, the form of use, dosage, and treatment should be further researched to determine the right amount for each metabolic syndrome problem.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding

This study was funded by the Directorate General of Higher Education, Research and Technology of the Ministry of Education, Culture, Research and Technology, Republic of Indonesia (Fundamental Research Project: DIPA-023.17.1.690523/2023).