**4. Discussion**

Our systematic review and meta-analysis aimed to investigate the association between a low and high level of adherence to MD and risk parameters of MetS, according to the NCEP-ATP III criteria. The present study, examining 41 observational studies, revealed a positive impact of MD on the five components of MetS, including WC, HDL, TG, FG and BP. Although a previous meta-analysis conducted by Kastorini et al. [30] explored the effect of MD on MetS prevalence, including its components, this is the first meta-analysis estimating the impact of the level of adherence to MD on each parameter of MetS according to evidence obtained by MD adherence scores.

With regards to abdominal obesity, our results showed a significant inverse association between WC and adherence to MD. Only one study [40] did not find any statistical difference in WC between the different levels of adherence to MD groups, which could be attributed to the underlying health condition of participants (CKD patients). Increased WC, which was detected in the low adherence to MD subjects, along with the accumulation of visceral fat, have been linked to the presence of low-grade systemic inflammation, increased oxidative stress and overexpression of pro-inflammatory cytokines, including CRP, IL-6 and TNF-a [109,110]. These metabolic abnormalities have a direct impact on other biochemical risk markers of MetS, and more specifically HDL, TG and FG, which consequently stimulate atherogenesis and mediate insulin resistance [111]. The high content of antioxidants, polyphenols and fiber found in MD have been previously associated with decreased systemic inflammation and central obesity, which could explain its beneficial effect [112,113]. Moreover, an enhanced with nuts MD was found to be helpful regarding the maintenance of body weight status [114,115].

A significantly positive correlation was also found between high adherence to MD and HDL cholesterol concentration. Our findings are consistent with previously reported data from randomized controlled trials (RCTs), in which a Mediterranean dietary pattern improved HDL cholesterol concentration and the overall lipid profile [116–118]. Increased intake of olive oil, polyphenols, antioxidants as well as an optimal ratio of MUFA:SFA, through the adherence to MD, seemed to have a synergistic effect on various mechanisms of lipid metabolism by promoting changes on the overall composition of HDL cholesterol particles, increased antioxidant and cholesterol efflux capacity [117,119]. Furthermore, a higher HDL concentration observed in high MD adherers could potentially be a secondary effect closely related to lower mean values of central obesity, as aforementioned, and improved cardiometabolic risk markers.

According to our results, an inverse significant association was observed between TGs concentration and adherence to MD. In a large network meta-analysis performed by Tsartsou et al. [108], the protective effect of MD on the overall lipid profile, including TGs, was also demonstrated. These findings were mainly attributed to the high content of olive oil polyphenols and oleic acid as part of the MD [108]. Another meta-analysis of RCTs, investigating the effect of plant oils on blood lipids, had also reported a decrease in TG concentration from the use of diets rich in olive oil [120]. Notwithstanding, it was demonstrated that oils rich in omega-3-fatty acids (n-3 FAs) caused a greater decrease in TGs than olive oil [120]. The metabolic mechanisms responsible for these changes are related to the types of fatty acids, i.e., MUFAS and n-3 FAs, which have the ability to suppress postprandial TGs, enhance TG clearance, decrease the activity of TG lipase and the overall TG synthesis [121–123].

Taking the above into consideration, where the mean values of WC, HDL cholesterol and serum TG concentration were significantly closer to normal in the high adherence to MD groups compared to the low adherence group, we conclude that the level of adherence to MD could play an important role to ameliorate the obesity level and the impaired lipid profile, in combination or not with appropriate pharmacological treatment.

With respect to FBG, an inverse correlation was demonstrated between MD levels of adherence and FBG, which, however, was not statistically significant. A possible explanation for that could be the high number of individuals diagnosed with diabetes or at diabetic risk who participated in the studies [49,61,65,68–71,74,81,92], along with other confounding factors (e.g., age, BMI, medication, etc.). However, the fact that mean values of FBG in both high and low adherers were within the normal range led us to the conclusion that MD adherence can have a positive impact on glycemic control regardless of the level of adherence. Sufficient evidence exists supporting the positive effect of adherence to MD so as to improve glycemic control and decrease the overall risk of T2DM [124]. A systematic review of 17 studies assessing the effect of MD on the incidence of T2DM revealed that high adherence to MD was significantly correlated with improved FBG concentration and HbA1c in diabetic patients [125]. Additionally, both RCTs and prospective cohort studies have also confirmed the benefits of MD on glycemic control over other diets among different subgroups of the population, including healthy individuals, individuals with high CVD/T2DM risk or diabetic patients [65,126,127]. These outcomes have been closely related to the composition of MD, which is rich in anti-inflammatory compounds, as well as to its enhanced activity of glucagon-like peptide (GLP-1) hormone and to changes in gu<sup>t</sup> microbiome caused by MD [48]. Notwithstanding, a meta-analysis by Ajala et al. on 20 RCTs demonstrated that not only MD but also low-carbohydrate, low-glycemic-index and high protein diets could enhance the cardiometabolic profile [128].

Regarding SBP and adherence to MD level, we have also found an inverse but nonstatistically significant association. Hypertension is considered a major risk factor for endothelial dysfunction and the development of CVDs [129]. It has been previously demonstrated that prolonged adherence to MD can decrease both SBP and DBP [130].

According to our included studies, in a vast majority, the mean SBP was <130 mmHg in both low and high adherence to MD groups. Consequently, we can conclude that even a poor adherence to MD can positively influence SBP. This conclusion is in accordance with existing data from previously published studies that have reported a significant inverse correlation between adherence of MD and BP [131,132]. Moreover, two recent meta-analyses showed that MD could significantly reduce BP when compared to control diets [133,134]. In addition, a greater decrease in BP was recorded for subjects presented with higher BP at baseline and in studies with a longer duration of the intervention [133]. Various nutrients included in MD exerted beneficial effects through improved vasodilation and endothelial function such as nitric oxides, flavonoids and minerals [135].

The benefits of MD adherence are not limited to the five parameters of MetS [136]. MiRNAs were found to be better regulated in obese patients following an MD [137]. Recent studies have shown that an MD reduces serum inflammatory markers as well as the incidence of stroke, CVD and breast cancer [138,139]. Moreover, MD was recommended as a diet that can help women with menopause-related symptoms and needs [140].

Our study can be characterized by several strengths. According to our knowledge, this is the first systematic review and meta-analysis that aimed to examine the impact of the level of adherence to an MD on the parameters of MetS. Moreover, the grea<sup>t</sup> number of the studies included and the subjects examined (*n* = 74,058), whose origin covered a significant part of the world, made our results quite representative. Furthermore, publication biases were not detected in our study, except from the studies included for the TG parameter in which the *p*-value of Egger's test was not rounded up 0.04598. In addition, the fact that we have included studies that used validated MD adherence scores in order to assess the level of adherence to MD increased the accuracy of our conclusions. The limitations of our study mainly concerned the heterogeneity in the included studies. High heterogeneity was detected for all parameters of MetS, which was potentially due to the different types of population (i.e., ethnicity) and health status (i.e., healthy, obese/overweight and diagnosed conditions) across all included studies, as well as to the difference between sample sizes and the use of a variety of MDS. The presence of high heterogeneity in population samples and the fact that subjects under pharmacological treatment were not excluded do not allow for inference of our results regarding the role of MD. Over and above, the variety of MDSs used to assess adherence among studies introduces biases due to the different ways of classification and quantification of food components. Furthermore, levels of adherence to MD may be perceived differently, depending on the geographical location and, thus, produce additional bias. For example, high adherers living in Mediterranean regions might have a greater intake of specific foods when compared to high adherers residing in non-Mediterranean regions. Moreover, the conversion of data whenever necessary for unification of the quantitative analysis adds to our study's limitations. Moreover, we have included studies published in English and Spanish; therefore, studies published in a different language were not a part of this study.
