**1. Introduction**

Metabolic Syndrome (MetS), also known as the syndrome X, belongs to the group of non-communicable diseases (NCDs) [1]. The prevalence of MetS has been closely related to socioeconomic factors, as well as lifestyle changes deriving from the impact of westernization on diet and health behavior [1]. Thereby, this transition has led to an increase in morbidity and mortality rates, forcing health systems to introduce more effective strategies so as to prevent the expansion of this epidemic [2]. According to the National Health and Nutrition Examination Survey (NHNES), the prevalence of MetS in US adults reached 34.2% during 2007–2012, with the highest rates observed in non-Hispanic white males and elderly >70 years of age [3]. A large analysis of cohort studies in European countries from 2000 to 2013 revealed that the prevalence of MetS ranged from 42.7%–78.2% for males and 24%–68.4% for females [4].

Metabolic syndrome has been characterized by health professionals and scientists as a cluster of predefined metabolic conditions, namely, hyperglycemia, dyslipidemia, hypertension and central obesity [5]. Chronic low-grade inflammation is considered another important risk factor present in the pathogenesis of MetS [6]. Increased adipose tissue and circulation of inflammatory mediators triggered by excess intake of specific micronutrients comprise the two primary components, which induce proinflammatory responses [6]. Consequently, MetS has been linked to not only the development but also

**Citation:** Bakaloudi, D.R.; Chrysoula, L.; Kotzakioulafi, E.; Theodoridis, X.; Chourdakis, M. Impact of the Level of Adherence to Mediterranean Diet on the Parameters of Metabolic Syndrome: A Systematic Review and Meta-Analysis of Observational Studies. *Nutrients* **2021**, *13*, 1514. https://doi.org/10.3390/nu13051514

Academic Editor: Dolores Corella

Received: 30 March 2021 Accepted: 28 April 2021 Published: 30 April 2021

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to the progression of other NCDs, such as cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), chronic respiratory diseases, etc. [7,8]. More specifically, it has been demonstrated that metabolic syndrome can increase the risk of CVD and mortality by 78% [9].

Currently, the most popular criteria used for the diagnosis of the MetS come from three different organizations, the World Health Organization (WHO) [10], the National Cholesterol Education Program in Adult Treatment Panel III (NCEP-ATP III), established slightly different criteria for the identification of MetS, excluding insulin resistance and using waist circumference, which are the most commonly applied criteria in clinical practice [11], and the International Diabetes Federation (IDF) that has also published similar definitions with regards to the MetS, however, diagnosis relies mainly on central obesity [12]. A summary of the diagnostic criteria of MetS can be found in Table 1.

**Table 1.** Published definitions and criteria for the diagnoses of MetS by the WHO, NCEP-ATP III and IDF.


WHO: World Health Organization, NCEP-ATP III: National Cholesterol Education Program in Adult Treatment Panel III, IDF: International Diabetes Federation, HDL: High-Density Lipoprotein, TG: Triglycerides and FBG: Fasting Blood Glucose. a Ethnic-specific WC values: Europe ≥94 cm for males and ≥80 cm for females; South Asia and China ≥90 cm for males and ≥80 cm for females; Japan ≥85 cm for males and ≥90 cm for females.

Lifestyle modifications, focusing on dietary patterns and physical activity, may improve markers of MetS and further reduce the risk of development of NCDs [13]. Among various types of dietary treatments, there has been a grea<sup>t</sup> deal of evidence with regards to the potential benefits of the Mediterranean diet (MD) in the field of nutritional epidemiology [14]. The traditional MD can be characterized as a plant-based diet containing high amounts of monosaturated fats, omega-3 fatty acids, polyphenols, vitamins and antioxidants, and low amounts of saturated fats and ethanol. With respect to nutrient content, the MD provides approximately 35%–45% fats (of which about 20% derives from monounsaturated fatty acids (MUFAs), 5% from polyunsaturated fatty acids (PUFAs) and 9% from saturated fatty acids (SFAs)), 15% protein and 45% carbohydrates [15]. However, what makes the MD distinct from other dietary patterns is the presence of various food components, including unrefined cereals, legumes, fish, vegetables, fruit, nuts, moderate

amounts of wine and, most importantly, olive oil, which is considered the traditional symbol of MD [16].

Over the years, different dietary index scores have been developed for assessing the degree of adherence to the MD [17]. These composite scores aim to measure overall dietary quality with the use of validated food frequency questionnaires (FFQs) [17,18]. Data obtained from FFQs are combined within specific groups, food combinations or nutrients found typically in the MD, in which a specific value is assigned based on a predefined calculation [19]. Ratings resulting from MD scores (MDSs) from all groups are often categorized as low, moderate or high, reflecting the adherence level to MD for each subject [17,18]. As there is no specific rule or consensus as to how the adherence level of different MDSs should be interpreted, low scores indicate poor adherence, whereas higher scores indicate good adherence to MD or otherwise described by the authors. In general, high adherence is the result of frequent consumption in adequate quantities of beneficial components, such as fruits, vegetables, legumes, fish, nuts, whole grain products and olive oil, whereas there is a low intake of alcohol, meat and SFA [20,21].

Several studies have revealed an inverse association between adherence to MD and risk of obesity, CVDs, T2DM as well as all-cause mortality [22–27]. The potential advantages relate to the synergic effect and mechanisms of specific nutrients that have a direct impact on all risk markers of MetS, namely, WC, HDL, TG, FBG, BP, as well as systemic inflammation [28]. Even though the positive impact of MD on risk and occurrence of MetS has been previously confirmed [29,30], there have not been any analyses evaluating how different levels of adherence to MD could favorably impact each parameter of MetS.

Therefore, the purpose of this study was to examine the impact of low and high adherence to MD on the parameters of MetS.

#### **2. Materials and Methods**

This study is a systematic review and a meta-analysis which was conducted according to the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) statement (Supplementary File S1). The protocol of this systematic review and meta-analysis was submitted in the OSF platform (https://osf.io/n4ja8/ accessed on 5 March 2021).

## *2.1. Literature Search*

A systematic literature search was conducted in the following electronic databases PubMed, EMBASE, Google Scholar, Scopus, Web of Science and Cochrane Central Registry of Clinical Trials (until 11 January 2021) in all fields option using the following search string: ("Mediterranean diet") AND (Adherence) for the PubMed database, which was modified accordingly for the other search engines (search terms and keywords of our search strategy can be found in Supplementary File S2). Additional relevant studies were searched by references screening of the articles retrieved.

#### *2.2. Study Selection-Eligibility Criteria*

Eligible studies for inclusion to systematic review were original observational studies that investigated the impact of MD adherence on three or more parameters of MetS (WC, HDL, TG, SBP and FBG), according to the revised criteria NCEP ATP III [11], in the adult population, using a validated tool or scoring algorithm. MDSs developed by Panagiotakos et al. [31], Sofi et al. [32] and Trichopoulou et al. [21], as well as the PREDIMED MD Adherence Screener (MEDAS) score [33], the short MDS produced by Martinez Gonzalez et al. [34] the serving MDS [35], the Mediterranean-Style Dietary Pattern Score (MSDPS) by Rumawas et al. [36], the MD quality index [37], the relative MD system [38], and modified versions of MDSs [39–49], were used in our included studies. A summary of the diagnostic criteria of MetS can be found in Table 1. Studies that were not published as original papers (e.g., abstracts, conference papers, editorials and commentaries, etc.) were excluded. Additionally, manuscripts that did not provide adequate data regarding low and

high adherence to MD were also excluded from this analysis. Only studies in English and Spanish language were part of our review.

## *2.3. Data Extraction*

Records of our search results were imported into a reference managemen<sup>t</sup> software (Endnote X9 for windows-by Clarivate Analytics USA) and two reviewers (LC, DB), after the removal of duplicates, assessed the studies for eligibility. Any disagreements were solved by a third reviewer (EK). Data extraction was performed independently by the abovementioned two reviewers using a pre-specified standardized Microsoft® excel form and was checked for accuracy by a third reviewer (EK). In cases of missing data, corresponding authors were contacted by email in order to retrieve any additional data.

The primary outcome of our study was to investigate the impact of high adherence to MD compared to low adherence to MD on the five parameters of MetS according to the NCEP ATP III [11] revised criteria for diagnosis.

#### *2.4. Quality Assessment of Included Studies*

The quality of the eligible studies was assessed using the Newcastle Ottawa Scale (NOS) adjusted version for cross-sectional studies by two independent authors (LC and DB) [50]. Any disagreements that arose were solved by consensus and by the involvement of a third author (EK). Sensitivity analysis was further performed after the exclusion of low-quality studies (NOS < 7).
