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Vol.:(0123456789)Journal of Endocrinological Investigation https:/doi.org/10.1007/s40618-024-02361-yCONSENSUS STATEMENTItalian guidelines forthemanagement ofadult individuals withoverweight andobesity andmetabolic comorbidities thatare resistant tobehavioral treatmentM.Chianelli L.Busetto R.Vettor B.Annibale A.Paoletta E.Papini,etal.full author details at the end of the articleReceived:6 December 2023/Accepted:9 March 2024 The Author(s),under exclusive licence to Italian Society of Endocrinology(SIE)2024AbstractAim This guideline(GL)is aimed at providing a clinical practice reference for the management of adult patients with over-weight or obesity associated with metabolic complications who are resistant to lifestyle modification.Methods Surgeons,endocrinologists,gastroenterologists,psychologists,pharmacologists,a general practitioner,a nutri-tionist,a nurse and a patients representative acted as multi-disciplinary panel.This GL has been developed following the Grading of Recommendations Assessment,Development and Evaluation(GRADE)approach.A systematic review and network meta-analysis was performed by a methodologic group.For each question,the panel identified potentially relevant outcomes,which were then rated for their impact on therapeutic choices.Only outcomes classified as“critical”and“impor-tant”were considered in the systematic review of evidence.Those classified as“critical”were considered for clinical practice recommendations.Consensus on the direction(for or against)and strength(strong or conditional)of recommendations was reached through a majority vote.Results The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI 27kg/m2 and 27 and 40kg/m2)and metabolic weight-related comorbidities(pre-diabe-tes,T2DM,NAFLD,dyslipidemia or hypertension)when behavioral treatments have proven ineffective?Patients with obesity may be deemed resistant to lifestyle interventions if Journal of Endocrinological Investigation they fail to achieve a weight loss of at least 5%of baseline weight after 6 months of properly prescribed and imple-mented diet and exercise.The panel formulated the ques-tion using the PICO(Population,Intervention,Comparison,Outcome)framework and established the criteria for study inclusion and exclusion(Appendix2).Selection ofoutcomesThe panel identified potentially relevant clinical outcomes and rated their importance on a nine-point scale,where 13 points indicated outcomes of limited relevance,46 points indicated important but not critical outcomes,and 79 points indicated critical outcomes.Only outcomes that were rated as critical or important were considered in the literature review and only the critical ones for the formulation of recommendations.Literature review andassessment ofquality ofevidenceWe conducted a comprehensive systematic literature search on the Medline/PubMed,Embase,and Cochrane Library databases from inception to May 16,2022,without language restrictions,to identify relevant evidence on the safety and efficacy of the treatments in question.The protocol for this systematic review was registered on the International Pro-spective Register of Systematic Reviews PROSPERO(num-ber CRD42022351409).We included randomized controlled trials(RCTs)only.Four authors independently screened titles and abstracts,full texts,and extracted data.We performed a network meta-analysis(NMA)using a frequentist approach and a random-effects model with graph theory for each outcome.We analyzed the data using STATA version 17 software.The risk of bias in the included studies was assessed using the tool described in the Cochrane Handbook for Systematic Reviews of Interventions(Version 5.1.0)38.Certainty of evidence was evaluated using the methodol-ogy developed by the GRADE working group,adapted for assessing the results of a NMA.We assessed confidence in effect estimates by considering the limitations of the stud-ies(risk of bias),heterogeneity of the meta-analytic result,direct applicability of literature findings to the PICO of inter-est,risk of publication-related bias,and imprecision,follow-ing a non-contextualized approach.We assigned four levels of certainty of evidence in accordance with the GRADE approach:high,moderate,low,and very low.Strength of recommendations was expressed as strong or conditional(in favor or against an intervention).Development ofrecommendationsDuring several web-based meetings,the ERT team presented the following items to the panel:the list and characteristics of identified studies,the list of excluded studies along with the reasons for their exclusion,the Evidence to Decision(EtD)framework as a tool for making recommendations,and a report on the economic analysis of treatments related to the clinical question.Subsequently,the panel discussed a draft of the recommendations and voted to judge their strength.Recommendations were categorized as either“strong”or“conditional”,based on factors such as the balance between effects,certainty of evidence,patients values and prefer-ences,economic resources,equity,acceptability,and feasi-bility of the intervention being considered(Table1).External reviewA multi-disciplinary group of experts conducted a thorough review of GL draft and provided summary judgments,criti-cisms,and suggestions to improve the document.The panel evaluated the reviewers feedback and operated the appro-priate amendments into the final text,when accepted and needed.UpdateThe recommendations outlined in this GL will remain valid for a maximum of 3 years from the publication date.Table 1 Categorization of recommendationsStrength of rec-ommendationStrongWeakFor cliniciansMost patients should follow the recommendation(benefits outweigh harms)Beneficial effects probably outweigh harmful effects,but there is still relevant uncertaintyFor patientsAlmost all properly informed patients behave as recommended A good proportion of properly informed patients behave as recommendedFor researchersThe recommendation is supported by reliable evidence or other convincing arguments.On some occasions,a strong recommendation may also be based on evidence with low or very low certaintyThe recommendation could be modified by subsequent studies Journal of Endocrinological InvestigationThereafter,AME will contact the Scientific Societies involved in the production of the document to update and revise it.Results:literature analysisPharmacological therapiesOrlistatThe analysis included 31 studies on orlistat,conducted between 1999 and 2009,involving a total of 6,699 patients(mean BMI 38.8kg/m2)with weight-related comorbidi-ties.Despite the low certainty of evidence,the studies showed that orlistat led to small improvements in differ-ent efficacy outcomes,such as weight reduction,waist circumference,HbA1c,fasting blood glucose,and ALT levels,and moderate results in triglyceride reduction.The side effects of orlistat were considered manageable,and thus were not considered a contraindication for its use in selected patients.A cost-effectiveness study demonstrated favorable results,although the high reference willingness-to-pay may pose sustainability issues.The lack of equi-table access to pharmacological treatment and the feasi-bility and acceptability of orlistat were not regarded as significant concerns.Overall,orlistat is suggested for use in patients with hyperlipidemia and hypertriglyceridemia covered by the GL 39,40.LiraglutideThe analysis included ten RCTs conducted from 2009 to 2021,focusing exclusively on liraglutide 3mg/day for treat-ment of people with obesity.Despite the low certainty of evidence,the results demonstrated small improvements in efficacy outcomes,such as weight reduction,waist circum-ference,HbA1c,systolic blood pressure,and QoL.Nota-bly,the reduction in HbA1c was small in studies involving patients without T2DM,but liraglutide has shown significant reductions in HbA1c in patients with T2DM with or without obesity at lower doses 41.The risk of undesirable effects,including death and serious adverse events,was considered negligible or small by the panel.The analysis did not provide sufficient data for a judgment on cost-effectiveness.Despite the potential equity issues related to out-of-pocket cost,the panel considered liraglutide acceptable and feasible.In con-clusion,despite the balance of effects and limited evidence,the panel suggests considering liraglutide for obese patients with pre-diabetes and T2DM due to its potential benefits on HbA1c reduction and glyco-metabolic control.SemaglutideThree studies,involving a total of two thousand one hun-dred seventeen patients(mean BMI 37.2kg/m2)with at least two comorbidities,were analyzed.Direct evidence with moderate certainty showed moderate improve-ments in various efficacy outcomes,including reduction of weight,waist circumference,fasting blood glucose,HbA1c,triglycerides,systolic blood pressure,and ALT.QoL improvement was considered large,while reductions in diastolic blood pressure were deemed as small.Unde-sirable effects were rated insignificant(as about death)or small(as about serious adverse events).The net balance of effects favored the intervention.Regarding cost-effec-tiveness,no Italian studies were available for semaglutide 2.4mg,but an American study considered it cost-effective 42.The panel expressed a favorable opinion based on the applicability of American data to the Italian market,pending the drugs availability in Italy.Equity considera-tions suggested that semaglutide could reduce equity,as current obesity drugs are fully out-of-pocket for patients and not reimbursable.Semaglutide-induced weight loss improves health status and QoL for patients with obesity.The use of semaglutide was deemed acceptable and fea-sible by patients and panel members.Based on this evi-dence,the panel recommends semaglutide use,particularly for patients with obesity and T2DM or pre-diabetes,con-tingent upon its availability in Italy 42.NaltrexonebupropionSix studies involving three thousand two hundred forty-one patients(mean BMI 36.3kg/m2)were analyzed.Despite the low certainty of evidence,the results showed improvements in various efficacy outcomes,including reduction of weight,waist circumference,HbA1c,and triglycerides,and improve-ment in QoL.The extent of these improvements was consid-ered small.Undesirable effects were rated insignificant(as about death),small(as about adverse events),and moderate(serious iatrogenic events),aligning with panel members clinical practice.Naltrexonebupropion,like other anti-obesity drugs,is out-of-pocket,reducing equitable access to treatment.It was considered probably acceptable by patients.While the balance of effects is neutral,naltrexonebupropion remains a useful aid in patients without contraindications,particularly those with emotional feeding.Its effect on food cravings is valuable in this subgroup.Starting this treatment and continuing it in patients with good tolerability is a rea-sonable option.Considering these aspects,the panel justi-fies and suggests the use of naltrexonebupropion in clinical practice,especially for patients with obesity and emotional eating 43.Journal of Endocrinological Investigation Surgical therapiesConsidering only RCTs,few studies on MBS were retrieved.This scarcity can be attributed to the ethical challenges asso-ciated with randomization in surgical procedures,leading to a predominant reliance on observational studies in the existing literature.Gastric banding(AGB)Considering both direct and indirect evidence,five studies on this procedure were included,published between 2006 and 2020,involving a total of 139 patients(mean BMI 34.3kg/m2)affected by comorbidities included in the PICO.Despite the low certainty of evidence,the results showed improvement in multiple efficacy outcomes(reduction of weight,waist circumference,HbA1c,fasting blood glu-cose,triglycerides),which were considered“moderate”by the panel.Regarding adverse effects,the panel could only assess the outcome of“death,”which was deemed numeri-cally“irrelevant,”while data on minor post-surgical com-plications are not available.Acceptability data are based on studies conducted on a small number of patients.The study by Roh etal.in 2020 44 showed that only 11.5%of patients preferred AGB due to awareness of long-term complications,the need for better compliance and frequent follow-up visits,and the perceived ineffectiveness of the treatment.As for healthcare professionals,31.2%of respondents preferred this approach in the study by Sarwer etal.in 2012 45.How-ever,on considering the implementation of more advanced surgical techniques,the panel downgrades the current appli-cability of this 10-year-old study.For this reason,the accept-ability is ranked as“variable.”The treatment is feasible and implementable in the national territory.The treatment is associated with high costs but,as all MBS procedures,is reimbursed by the national healthcare system,although approximately 50%of surgical treatments are performed in private practice.Based on these considerations,the panel expresses a conditional recommendation in favor of the intervention,considering the limited number of patients in the analyzed studies and the reduced utilization of the tech-nique in current clinical practice 44,45.Sleeve gastrectomyThe analysis included 10 studies on this technique,involv-ing a total of 302 patients(mean BMI 38.4kg/m2).Despite the low certainty of evidence,the results showed significant improvement in weight reduction,waist circumference,and HbA1c levels.Triglyceride reduction and QoL improve-ments were also observed but to a lesser extent.Adverse effects were considered minor,including post-surgical complications and mortality risk.Patient acceptability was high,with the majority preferring sleeve gastrectomy over other interventions.The treatment was deemed feasible and implementable.The panel strongly recommended sleeve gastrectomy,considering its substantial benefits and mini-mal adverse effects,while also being likely acceptable to all stakeholders and improving equity 44,45.RouxenY gastric bypass(RYGBP)The analysis included 10 RCTs on this technique,involv-ing 318 patients(mean BMI 37.2kg/m2)with comor-bidities such as T2DM and hypertension.The evidence showed significant improvement in multiple efficacy out-comes,including reduction of weight,waist circumference,HbA1c,triglycerides,and blood pressure.Adverse effects were assessed as small(mortality)or minor(post-surgical complications).The treatment was considered feasible and implementable,despite high costs,and was generally accepted by patients,although preferences varied among individuals.Based on these findings,the panel strongly rec-ommended the intervention due to its significant benefits and minor drawbacks,along with its feasibility and potential for improving equity 44,46,47.Other metabolic bypass proceduresThis section addresses surgi
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