**2. Methods**

The protocol of the review was developed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [62] and was designed to gather the results of clinical trials in patients with di fferent grades of PD and DM whose plasma levels of vitamin C were determined.

#### *2.1. Study Selection Criteria*

The population of interest for this review included patients with a current diagnosis of both chronic PD and DM (type 1 or type 2). All the studies which met the following inclusion criteria were included in this systematic review: (1) written in English; (2) published before 8 September 2019; (3) investigating association between vitamin C, PD and DM; (4) clinical trials conducted on adults; and (5) using quantitative methods of data collection. The design of the targeted studies, which were of interest, depended on the dosage and frequency of administration of ascorbic acid, both as therapeutic administration and as part of the patients' usual alimentation. Other types of studies, such as cohort, randomized and cross-sectional surveys were also included. Studies that included only plasmatic or salivary measurements of vitamin C were also of interest and included. Articles' exclusion criteria were: (1) written in a language other than English; (2) reviews and animal studies; (3) abstract only or no abstract; (4) not mentioning whether the patients had DM or not; or (5) not measuring ascorbic acid plasma/salivary levels.

## *2.2. Literature Search*

The electronic literature search was conducted by two independent authors (M.B. and A.D.M.) within the following databases: PubMed, Clinical Trials, Cochrane and Web of Science.

The inclusion criteria were defined according to the PICO model: population (P = "human adults"), intervention or exposure (I = "impact of vitamin C on patients with PD and DM"), comparison (C = "dosage and frequency of dosage for vitamin C, received as treatment or as part of alimentation; di fferent concentrations of plasmatic vitamin C"), and outcome (O = "measurement of periodontal status using specific disease parameters"). The following PICO question was used: "Is vitamin C associated with an improvement of periodontal status in patients with DM?"

Four types of searches in each database were performed with the exact term combination: type 1—"vitamin C AND periodontal disease AND diabetes mellitus" OR type 2—"ascorbic acid AND periodontal disease AND diabetes mellitus" OR type 3—"vitamin C AND periodontitis AND diabetes mellitus" OR type 4—"ascorbic acid AND periodontitis AND diabetes mellitus".

#### *2.3. Selection of Studies*

Both authors assessed the eligibility of all the studies and screened them, eliminating duplicates and removing all the studies that did not respect the selection criteria after assessing the content from titles and abstracts. The reviewers shared their independently obtained data and resolved decided any disagreements by general approval. The final titles were included for further data extraction and analysis.

#### *2.4. Data Extraction and Analysis*

The two authors independently extracted data from the final articles into an Excel template developed by the research team. The included elements were publication year, study type design, the country where the study was run, participants' characteristics (number, age and gender), periodontal status and type of measurement, type of intervention, along with diabetes status and type of measurement. The experimental design of the final list of studies was reported to cover the duration of the study, the administration (dosage and frequency) of vitamin C, the measurement of vitamin C and their main results.
