Development of the Italian Clinical Practice Guidelines on Bariatric and Metabolic Surgery: Design and Methodological Aspects

Development of the Italian clinical practice guidelines on bariatric and metabolic surgery, as well as design and methodological aspects. Background: Obesity and its complications are a growing problem in many countries. Italian Society of Bariatric and Metabolic Surgery for Obesity (Società Italiana di Chirurgia dell’Obesità e delle Malattie Metaboliche—SICOB) developed the first Italian guidelines for the treatment of obesity. Methods: The creation of SICOB Guidelines is based on an extended work made by a panel of 24 members and a coordinator. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology has been used to decide the aims, reference population, and target health professionals. Clinical questions have been created using the PICO (Patient, Intervention, Comparison, Outcome) conceptual framework. The definition of questions used the two-step web-based Delphi method, made by repeated rounds of questionnaires and a consensus opinion from the panel. Results: The panel proposed 37 questions. A consensus was immediately reached for 33 (89.2%), with 31 approved, two rejected and three which did not reach an immediate consensus. The further discussion allowed a consensus with one approved and two rejected. Conclusions: The areas covered by the clinical questions included indications of metabolic/bariatric surgery, types of surgery, and surgical management. The choice of a surgical or a non-surgical approach has been debated for the determination of the therapeutic strategy and the correct indications.


Introduction
Obesity and its complications are a growing public health concern in many countries, due an increasing prevalence, a relevant impact on the health of affected individuals and a growing related economic burden [1]. Treatments for obesity, which include lifestyle interventions and drug therapies, are often characterized by limited long-term efficacy [2]. Metabolic surgery, which has been developed for achieving a relevant weight loss in morbidly obese individuals, has also be shown to have a therapeutic potential for obesityrelated conditions, such as type 2 diabetes (T2D) [3,4] and obstructive sleep apnea [5]. However, the use of surgical approaches has been limited by organizational and economic limitations.
The development of rigorous guidelines is a relevant tool for the improvement of the quality of care, increasing the appropriateness of therapeutic choices. The Italian Society of Bariatric and Metabolic Surgery for Obesity (Società Italiana di Chirurgia dell'Obesità e delle Malattie Metaboliche-SICOB) recognized this need and decided to design and develop the first Italian guidelines, aimed at assisting healthcare professionals in the consideration of the surgical option for the treatment of obesity and related conditions. In the Italian national legal environment [6], the inclusion of guidelines in the National Guideline System is possible only after a careful methodological and formal revision by the National Center for Clinical Excellence of the Ministry of Health. In the development of national guidelines, the Center for Clinical Excellence recommends the use of Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology [7], which requires the identification of specific clinical questions and the definition of relevant outcomes for each one of those questions. The present paper reports the development of questions, the definition of outcomes for each question, and the description of search strategy and study inclusion criteria for each outcome.

Characteristics of the Panel Involved in the Development of the Guideline
Panel members, identified by SICOB in collaboration with other scientific societies Table S1, elected a coordinator and nominated the members of the evidence review team. The latter actively collects and analyses evidence, without participating in the definition of clinical questions, outcomes, and recommendations. The complete list of the 24 members of the panel, with their roles, and 10 from the evidence review team, is reported in Table S1. The mean age of panelists was 48.0 ± 11.9 years, with 46.1% aged less than 45 years.
All members of the panel and evidence review team compiled a declaration of potential conflicts of interest, which were collectively discussed to determine their relevance. In all cases, the reported conflicts were considered minimal or irrelevant; therefore, all components of the panel and of the evidence review team participated in the elaboration of all recommendations.

GRADE Methodology for the Development of Guidelines
The GRADE method [8] was developed to reduce the impact of personal opinions and prejudices on the recommendations of guidelines, inducing a greater adherence to evidence derived from methodologically valid studies. The first step of the development of guidelines, following this method, is the definition of a scoping document, defining aims, reference population, and target health professionals.
The following step is that of defining a series of clinical questions, using the PICO (Patient, Intervention, Comparison, Outcome) conceptual framework [7]. Each recommendation is developed as the answer to a question.
For each question, the panel defines a number of clinical outcomes, which are potentially relevant for the choice of different clinical options. Each outcome is then rated (from 1 to 9) for its importance; those receiving a rating of 7 or higher are classified as "critical" and represent the basis for the development of the recommendation.
For each critical outcome, the evidence review team will perform a systematic review of relevant studies, predefining search strategies and inclusion criteria, and performing meta-analyses whenever possible Table 1 and S2. Studies and related meta-analyses are assessed for methodological quality in order to verify the actual strength of available evidence. Further assessments include economic evaluations (usually based on cost-utility ratio, whenever possible), organizational impact, equity, acceptability, and feasibility. The final recommendation includes all those elements.

Delphi Process
The definition of questions was performed using a two-step web-based Delphi method, a structured technique aimed at obtaining, by repeated rounds of questionnaires, a consensus opinion from a panel of experts in areas wherein evidence is scarce or conflicting, and opinion is important [9].
Between June and October 2022, panelists were invited to propose questions with the PICO framework and to express their level of agreement or disagreement on each proposed question using a 5-point Likert scale, scored from 1 to 5 (1, strongly disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, strongly agree). Results were expressed as a percentage of respondents who scored each item as 1 or 2 (disagreement) or as 3, 4, or 5 (agreement). A positive consensus was reached in case of more than 66% agreement, a negative consensus in case of more than 66% disagreement, consensus was not reached when the sum for disagreement or agreement was below 66% [9]. For the statements on which consensus had not been achieved, panelists were asked to re-rate in a second round their agreement/disagreement, after internal discussion with all panelists.

Results
These guidelines will apply to adolescents (age > 13 years), adults, patients with Body Mass Index (BMI) > 30 kg/m 2 requiring bariatric or metabolic surgery. Healthcare systems, infrastructures, human and financial resources across Italian regions will be considered in developing these guidelines. Therefore, they are primarily intended to be applicable in Italy. The present guidelines will be used by healthcare professionals, including surgeons, obesity specialists, general practitioners, nutrition experts, psychologists, endocrinologists/diabetologists, and pediatricians.
The approved questions and their related approved critical outcomes are reported in Table 1. Proposed outcomes not reaching the rating for being considered critical are reported in Table S2.
The evidence review team identified the characteristics of relevant studies for each critical outcome, defining search strategy and study inclusion criteria, which are reported in Table S3. The search strategy used for all questions is: "obesity AND surgery" with an expected start date on 1st December, 2022.

Discussion
The areas covered by the clinical questions identified by panelists include indications of metabolic surgery, types of surgery, and pre-, peri-and post-surgical management of obese patients. The focus on indications is not surprising: the choice of a surgical or a nonsurgical approach for the treatment of obesity and related metabolic conditions is often debated, posing relevant issues for the determination of appropriateness of the therapeutic strategy. In addition, considering the current legislation on professional liability [6], a correct identification of proper indications can support clinicians in an environment characterized by increasing legal claims. In patients referred to surgical treatment, the choice of the most appropriate intervention is a major concern for surgeons; the collection and synthesis of available evidence from methodologically valid studies can be a more appropriate support for this decision than personal beliefs or experience.
The focus on procedures to be applied before, during and after the surgical procedure, is less obvious. Interestingly, the identification of those questions was performed by a panel mainly composed of surgeons, showing a clinical vision much broader than the surgical act per se.
Some questions were devoted to the application of surgical procedure for the treatment of obesity-related conditions, such as T2D. The possibility of using surgical techniques to treat T2D and other diseases associated with excess weight, even in patients with mild obesity, or not even properly obese, has been pursued by some authors [3,4]; promising preliminary evidences suggest that bariatric surgery has metabolic effects beyond weight loss, justifying the name of "metabolic surgery" [10]. However, the use of surgery in patients with relatively low BMI, even though affected by concomitant conditions, is still debated [11], and it is not recommended by most guidelines [12]. The systematic collection of evidence will depict a clearer picture of the effects of surgery in these conditions, thus completing existing guidelines on medical treatments for T2D [13,14] and other diseases.
Obese patients seeking treatment have expectations of weight loss. Conversely, health professionals have a greater attention to obesity-associated metabolic abnormalities, such as hyperglycemia, dyslipidemia, etc. The panelist planning the development of these guidelines reached one step further, recognizing the central role of longer-term hard outcomes, such as mortality, incident cardiovascular disease, and malignancies. The availability of sufficient evidence for a reliable assessment of the effects of surgery on those outcomes will be verified in the process of developing these guidelines. Appropriately sized, long-term studies on hard outcomes can be considered a priority for research.
The choice of a specific therapeutic strategy should be based on the assessment of the risk-benefit ratio, together with cost-utility analysis. This means that adverse events need to be systematically and carefully studied. In fact, safety outcomes have been included for most clinical questions, concurring to the development of recommendations.
Transparency in the development process is one of the main determinants of quality of guidelines [15][16][17][18][19] Potential conflicts of interest and some explanations on the data underlying recommendations are provided by most guidelines. The GRADE manual recommends the explicit publication of clinical questions, relevant outcomes, and summaries of evidence for each outcome [8]. We decided to go beyond the requirements of the GRADE manual, pre-emptively publishing in extenso the whole process leading to clinical questions and definition of critical outcomes. In addition, the search strategy and inclusion criteria for the systematic review and meta-analysis for each outcome has been reported in the present study, allowing the reproducibility of the whole process. It is the policy of this panel to publish extensively, and possibly on peer-reviewed journals, all systematic reviews and meta-analyses that will concur to the formulation of these guidelines.

Conclusions
The creation of SICOB Guidelines is based on an extended work. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology has been used to decide aims, reference population, and target health professionals. Clinical questions have been created using PICO (Patient, Intervention, Comparison, Outcome) conceptual framework. The GRADE manual recommends the explicit publication of clinical questions, relevant outcomes, and summaries of evidence for each outcome. The search strategy and inclusion criteria for the systematic review and meta-analysis for each outcome has been reported in the present study, allowing for the reproducibility of the whole process.
Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu15010189/s1, Table S1: Characteristics and tasks of all panelists; Table S2: PICO not reaching consensus and requiring a second Delphi round; *second round. Table S3: Main characteristics of studies for being included in metanalyses for each approved (≥ 7 points) outcome.