BACKGROUND:The obesity pharmacotherapy landscape is evolving rapidly, with several approved incretin-based therapies and an expanding pipeline of investigational compounds targeting multiple metabolic pathways. Conventional evidence syntheses often struggle to accommodate differences in dose selection, treatment duration and stage of clinical development. To describe a methodological framework for a series of systematic reviews and network meta-analyses aimed at comparing approved and investigational obesity management medications (OMMs). METHODS:This article presents the methodological framework for a series of systematic reviews and network meta-analyses that will be conducted according to PRISMA 2020, PRISMA-NMA and PRISMA-P recommendations. Separate reviews and network meta-analyses will be performed for individual pharmacological classes of OMMs. Treatment nodes will be defined as molecule-dose combinations, selecting the highest approved dose for marketed therapies and the highest tested dose for investigational agents. Eligible studies will include randomised Phase 1-4 trials conducted in adults with overweight or obesity, with or without Type 2 diabetes. The primary outcome will be percentage total body weight loss at approximately 24-26 weeks. Risk of bias and certainty of evidence will be assessed using RoB 2 and CINeMA. RESULTS:The framework identifies 40 obesity investigational molecules that have completed at least Phase 1 development and groups them into 13 major mechanistic classes and nine approved therapies for the treatment of obesity. The present framework, therefore, encompasses 49 molecules which will serve as candidate interventions for future class-specific network meta-analyses. CONCLUSIONS:This paper presents a dose-informed methodological framework for future evidence syntheses in obesity pharmacotherapy, supporting comparative evaluation and contextual positioning of next-generation OMMs. TRAIL REGISTRATION:PROSPERO-CRD420261425340.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to obesity and insulin resistance, and sustained weight loss is associated with histological improvement. Whether different obesity-management modalities exert weight-independent hepatic effects remains uncertain. METHODS:We conducted a systematic review and network meta-analysis (NMA) of randomised controlled trials evaluating lifestyle intervention, obesity management medications, endoscopic sleeve gastroplasty and metabolic and bariatric surgery in adults with BMI ≥ 27 kg/m2 and biopsy-confirmed MASH. The primary endpoint was MASH resolution without worsening of fibrosis. Study-level meta-regressions explored associations between total body weight loss (TBWL%) and histologic outcomes. RESULTS:Six RCTs (n = 1379) met inclusion criteria. Tirzepatide, semaglutide, sleeve gastrectomy and Roux-en-Y gastric bypass were superior to placebo or standard care for achieving MASH resolution. Because the network was weakly connected and largely placebo-anchored, indirect estimates were imprecise. Across study arms, greater TBWL% was associated with higher rates of MASH resolution and fibrosis improvement; however, these associations were strongly influenced by a small number of high-weight-loss surgical arms. CONCLUSIONS:Weight loss was consistently associated with histologic improvement across available RCTs. However, the limited evidence base, sparse network structure and ecological nature of the meta-regression preclude causal inference. These findings should be considered exploratory and hypothesis-generating, underscoring the need for adequately powered head-to-head trials.

INTRODUCTION:Diabetic foot (DF) disease, including ulcerations, amputations, and infections, represents a major cause of morbidity and mortality in individuals with diabetes mellitus (DM). Despite their substantial clinical, social, and economic burden, robust global epidemiological estimates remain limited due to fragmented evidence and heterogeneous methodologies. This systematic review and meta-analysis aimed to provide reliable pooled estimates of incidence and prevalence of DF disease, to explore geographic and demographic variations, and to assess the types of data sources available for epidemiological research. METHODS:Following PRISMA guidelines (PROSPERO registration CRD42025640944), PubMed, Embase, CINAHL Plus, and Cochrane Library were systematically searched from inception to December 21, 2024, for observational studies in adults (≥ 18 years) with DM reporting epidemiological measures of DF disease. Data extraction and quality appraisal (Joanna Briggs Institute checklists) were independently performed by four reviewers. Random-effects meta-analyses were conducted using generalised linear mixed-effects models to calculate pooled complication-specific prevalence and incidence rates among patients with diabetes. Heterogeneity among study estimates was assessed using Cochran's Q test, I2 statistic, and the between-study variance (τ2). To identify sources of heterogeneity, meta-regression analyses were performed considering study-level covariates (modifiers). RESULTS:Eighty-nine studies were included (18 prospective cohorts, 33 retrospective cohorts, 38 cross-sectional), enrolling between 92 and 29,650,811 participants, with data from Europe (N = 29, 32.6%), Asia (N = 25, 28.1%), Africa (N = 16, 18.0%), America (N = 16, 18.0%), and Oceania (N = 3, 3.4%). Pooled global incidence rates were 10.93 cases/1000 person-years (95% CI, 6.67-17.91) for ulcerations, 3.58 (95% CI, 1.93-6.63) for amputations, and 19.11 (95% CI, 4.81-75.97) for infections. Pooled prevalence estimates were 54.57 cases/1000 persons (95% CI, 37.63-78.52) for active ulcerations, 72.63 (95% CI, 48.21-108.02) for past ulcerations, 14.75 (95% CI, 9.52-22.77) for amputations, and 39.17 (95% CI, 6.81-195.07) for infections. Substantial heterogeneity (I2 > 90%) was observed, with significant modifiers including geographical region, diabetic foot identification method, data source, study setting, age, diabetes duration, and length of follow-up. Rates in America and Africa were generally above the global pooled average, whereas those in Europe, Asia, and Oceania were below. CONCLUSIONS:Globally, DF disease is common and severe, with incidence and prevalence rates underscoring its important public health impact. Heterogeneity across studies highlighted the influence of geography, methodology, and data sources. These findings may support future clinical and pharmacoepidemiological studies that evaluate new interventions and monitor temporal trends using large-scale data.

OBJECTIVE:This review compared antiobesity strategies-obesity management medications (OMM), endoscopic bariatric procedures (EBP), and metabolic bariatric surgery (MBS)-with lifestyle intervention, placebo, or no therapy (LSI/Pbo/NT). METHODS:This network meta-analysis included randomized clinical trials comparing OMM, EBP, and MBS versus LSI/Pbo/NT or active comparators in adults with obesity. MEDLINE and Embase were searched up to December 1, 2024. The primary endpoint was total body weight loss percentage (TBWL%), analyzed at 26-52, 53-104, 105-156, and ≥ 156 weeks. This study was registered with PROSPERO (CRD42024623707). RESULTS:Of 139 RCTs, 54 evaluated MBS (n = 61,961), 21 EBP (n = 2934), and 64 OMM (n = 5991). At 26-52 weeks, most treatments showed significant effects versus the reference. TBWL% exceeded 10% with most surgeries and tirzepatide. Long-term data were lacking for most OMM and all EBP. Most treatments maintained their efficacy over time, except greater curvature plication. EBP and MBS were generally associated with a higher SAE risk than OMM; BPD showed the highest long-term SAE incidence. CONCLUSIONS:MBS appears superior in the long term (particularly for higher-efficacy procedures, such as RYGB, SG, SADI, and BPD). EBP, except ESG, was less effective than newer OMM. Semaglutide and tirzepatide showed no inferior short-term results in comparison with MBS.

AIMS:Health literacy (HL) is a key determinant of diabetes self-management and clinical outcomes in type 2 diabetes mellitus (T2DM). The Diabetes Health Literacy Scale (DHLS) is a 14-item instrument assessing informational, numeracy, and communicative HL, with established validity in Korean, Persian, Malay, and Chinese populations. This study aimed to translate and culturally adapt the DHLS into Italian and evaluate its structural validity, internal consistency, construct validity, and measurement invariance across Italian-born and foreign-born adults with T2DM. METHODS:A total of 300 adults with T2DM were recruited from two outpatient diabetology clinics in Florence, Italy. DHLS translation followed ISPOR guidelines with cognitive debriefing. Psychometric evaluation followed COSMIN recommendations and included confirmatory factor analysis, McDonald's omega, Pearson's correlations with comparator instruments, and multigroup confirmatory factor analysis (CFA). RESULTS:CFA supported the three-factor second-order structure (CFI = 0.921, RMSEA = 0.077). Internal consistency was satisfactory across domains (ω = 0.759-0.868) and excellent for the total scale (ω = 0.940; ωH = 0.770). All convergent validity hypotheses were supported. Multigroup CFA demonstrated configural but only partial metric invariance across birthplace groups. CONCLUSIONS:The DHLS-IT is a valid and reliable instrument for assessing diabetes HL in Italian adults with T2DM. Partial metric invariance cautions against direct latent score comparisons between Italian-born and foreign-born patients.

BACKGROUND AND AIM:To retrospectively evaluate accuracy of screening tests for peripheral artery disease (PAD) in patients with diabetic foot ulcers (DFUs) and analyze the variation of these parameters when combining more tests together. METHODS AND RESULTS:PAD was diagnosed using Duplex-Ultrasound Scan (DUS). The following screening tests were evaluated: ankle systolic pressure, ABI (Ankle-Brachial Index), TP (Toe Pressure), TBI (Toe-Brachial Index), and wave-form analysis (WFA). Sensitivity, specificity, PLR, NLR (Positive and Negative Likelihood Ratio), and accuracy were calculated for each test and for multiple combinations (considering positive those cases in which at least one test was positive). Out of 97patients, 64 had PAD. TBI, TP, and WFA sensitivity (1.0, 1.0, and 0.83, respectively) and specificity (0.57, 0.43, and 1.0, respectively) were superior to those obtained with ABI (0.82 and 0.64). Among combination of two tests, those of pedal pulses with either TBI or WFA had a better performance than that with ABI. The combination of three tests further increased sensitivity, without reducing specificity. CONCLUSIONS:DUS is the golden standard for diagnosing PAD in patients with DFU. The use of combinations of tests (in particular, WFA + ABI or WFA + TBI) as a first-step can be a valid alternative in case of limited resources.

AIMS:To assess if there is a difference in the oncogenic risk between GLP-1 RA and comparators in randomized controlled trials. MATERIALS AND METHODS:A meta-analysis of randomized controlled trials comparing GLP-1RA to any comparators for diabetes and/or obesity, lasting at least 52 weeks. The endpoints included the incidence of overall cancers and single malignancies. RESULTS:Fifty trials were included. GLP-1RA treatment was not associated with a significant difference in risk for overall cancer (MH-OR 1.05, 95% confidence interval [CI] [0.98, 1.13]). Uterine cancer was significantly reduced in the GLP-1RA arm in trials performed in subjects with obesity (MH-OR 0.24, 95% CI [0.06, 0.94]), but not in those aimed at diabetes treatment (MH-OR 0.92, [0.58, 1.47]). We detected an increase in the risk for thyroid cancer (MH-OR 1.55, [1.05, 2.27]), more evident in longer-term trials, and in the risk for colorectal cancer (MH-OR 1.27 [1.03, 1.57]), which, conversely, was significant only in shorter-term trials. No significant difference in the risk was detected for any other cancer. CONCLUSIONS:GLP-1 RA do not appear to produce an effect on most malignancies in clinical trials. A reduction of very close obesity-associated cancers seems possible, whereas a risk signal for thyroid cancer was observed, prompting the need for further specific studies. On the other hand, the small increase observed in colorectal cancer in shorter-term trials may be the effect of a disproportionate increase in diagnostic procedures in the GLP-1 RA arm, because of the suspicion raised by common side effects of GLP-1 RA.

BACKGROUND:Diabetic foot osteomyelitis (DFO) is associated with a considerably high risk of incident major amputations, disability and mortality. To assess the effects of a local antibiotic delivery system on the incidence of post-surgical infective complications in patients with DFO. METHODS:This is a double-blind, placebo-controlled, parallel series, randomized controlled trial (RCT) aimed at verifying the efficacy and safety of a local calcium-sulphate bio-absorbable antibiotic delivery (either with tobramycin or vancomycin) in patients with DFO treated with surgical procedures. The trial enrolled adult patients with diabetes and Texas 3 grade ulcers complicated by osteomyelitis and accompanied by deep tissues infection. The primary end-point was the percentage of infective complications (composite end-point of dehiscence, infection, DFO recurrence and new DFO in adjacent sites) at 12 weeks. RESULTS:The study was prematurely terminated after the completion of the first 20 cases, because of the significant superiority of the active treatment arm. After 12 weeks of treatment, five of 20 wounds (25%) achieved the primary composite end-point. All post-surgical infective complications occurred in the placebo group, with a significant between-group difference (unadjusted p = 0.010). No between-group differences in overall costs were observed. CONCLUSIONS:This is the first RCT in patients with DFO showing that the use of antibiotic-impregnated calcium-sulphate granules is economically sustainable and has the potential of improving the prognosis of DFO.

AIMS:We aimed at comparing different approved strategies (obesity management medications-OMM, endoscopic bariatric procedures-EBP, and metabolic bariatric surgery-MBS) with lifestyle intervention/placebo/no therapy (LSI/Pbo/NT) for the treatment of different BMI-based classes of obesity (i.e., overweight-BMI: 25-29.9 kg/m2; class I-BMI: 30-34.9 kg/m2; class II-BMI: 35-39.9 kg/m2; class III-BMI >39.9 kg/m2). MATERIALS AND METHODS:This systematic review (SR) and network meta-analysis (NMA) included randomised clinical trials (RCTs) comparing OMM, EBP, and MBS versus either LSI/Pbo/NT or active comparators in individuals with overweight or obesity. A Medline and Embase search was performed up to 31st January 2025 for RCTs on EMA (European Medicines Agency)-approved weight-loss interventions in adults with overweight/obesity. The primary endpoint was total body weight loss (TBWL%), analysed at different time points: 26-52, 53-104, 105-156, and ≥156 weeks. Secondary endpoints included all-cause mortality, quality of life, and serious adverse events (SAE). Weighted mean difference and 95% confidence intervals (WMD, 95% CI) for continuous variables and Mantel-Haenszel odds ratio (MH-OR, 95% CI) for categorical variables were calculated using random effect models. The study was registered on the PROSPERO website (CRD42024625338). RESULTS:In trials enroling subjects in class I of obesity, tirzepatide resulted in equal effectiveness to both OAGB and RYGB, and it was significantly superior to all the other comparisons. In trials on class II of obesity, tirzepatide was significantly superior to all the other comparisons and inferior to both OAGB and RYGB. Semaglutide was associated with a higher TBWL% than the other OMMs (with the notable exception of tirzepatide), and it was equally effective to EBP, GCP, and LAGB. In trials enroling patients with a mean BMI >40 kg/m2, the procedure with the highest estimated weight loss was BPD. Semaglutide was statistically less effective than SG and gastric bypass, but not inferior to GCP and LAGB. Both RYGB and OAGB were superior to SG. CONCLUSION:In patients affected by mild to moderate obesity, newer OMMs (i.e., tirzepatide and semaglutide) appear to be valid alternatives to EBP and MBS. They could be preliminarily chosen as a first-line option based on similar efficacy and greater safety and tolerability. Higher degrees of obesity could be more effectively treated with MBS, the efficacy of which, with the notable exception of LAGB and GCP, appears superior to other treatments, especially in the long term.

BACKGROUND AND AIM:To verify the prevalence of positive Fibrosis-4 (FIB-4) score, a screening test for metabolic-associated liver disease, in a large population-based sample in the Tuscany Italian Region, and to identify sub-populations at higher risk which could be targeted by specific screening programs. METHODS AND RESULTS:Population-based survey performed in the Italian region of Tuscany, with Tuscany health informative system's administrative data. We included 594,923 subjects, of which 32% had available data for the FIB-4 calculation. The overall proportion of subjects with an FIB-4 value > 1.3, was 41.6% of those with available exams, and 12,8% of the whole population, whereas 5.4% and 1.7% had FIB-4 >2.67. In those younger than 80 years, FIB >1.3 had a 33.1% and 9.4%. People with diabetes mellitus had higher figures (52.8.% and 28.9% for FIB>1.3). Among subjects aged 70 years or over, 74.9% of those with available data and 38.4% of the general population had a FIB-4>1.3, whereas 32% and 16% had a FIB-4 > 2. CONCLUSIONS:The relevant proportion of FIB-4 positivity in the general population poses a significant burden for further screening with liver elastography. Targeting people with diabetes, excluding people older than 80 years and/or adopting a FIB-4 threshold of 2 in those aged more than 70 years could increase the cost-effectiveness of the screening procedures.

We thank Dr Ma and Yan for their appreciation of our work [ [1] Mannucci E. Bonifazi A. Monami M. Comparison between different types of exercise training in patients with type 2 diabetes mellitus: a systematic review and network metanalysis of randomized controlled trials. Nutr, Metabol, and Cardiovasc Dis : NMCD. 2021; 31 (In eng): 1985-1992https://doi.org/10.1016/j.numecd.2021.02.030 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ]. We totally agree on the potential relevance of intensity of exercise as a possible moderator of the efficacy of [ [2] Liu Y. Ye W. Chen Q. Zhang Y. Kuo C.H. Korivi M. Resistance exercise intensity is correlated with attenuation of HbA1c and insulin in patients with type 2 diabetes: a systematic review and meta-analysis. Int J Environ Res Public Health. 2019; 16 (In eng)https://doi.org/10.3390/ijerph16010140 Crossref Scopus (63) Google Scholar ]. Other potentially relevant elements include duration of aerobic exercise, type of aerobic exercise, use of behavioral/motivational in interventions to increase adherence to prescribed exercise regimens, etc. Our systematic review was aimed at providing an updated estimate of the effects of different types of exercise (i.e., aerobic, resistance, or mixed), and not at comprehensively assessing all characteristics of exercise interventions in type 2 diabetes. In fact, this meta-analysis was designed in order to answer to a specific question raised in the development of the new Italian guidelines for the treatment of type 2 diabetes [ [3] Mannucci E. Candido R. Delle Monache L. Gallo M. Giaccari A. Masini M.L. et al. Italian guidelines for the treatment of type 2 diabetes. Nutr, Metabol, and Cardiovasc Dis : NMCD. 2022; (In eng)https://doi.org/10.1016/j.numecd.2022.01.027 Abstract Full Text Full Text PDF Scopus (2) Google Scholar , [4] Mannucci E. Candido R. Monache L.D. Gallo M. Giaccari A. Masini M.L. et al. Italian guidelines for the treatment of type 2 diabetes. Acta Diabetol. 2022; 59 (In eng): 579-622https://doi.org/10.1007/s00592-022-01857-4 Crossref PubMed Scopus (1) Google Scholar ].

Diabetes is a chronic condition that can be worsened by complications such as seasonal influenza virus infections. The aim of the present meta-analysis is the systematic retrieval and analysis of all available evidence on the effects of an influenza vaccine on diabetic patients. We conducted a systematic review and meta-analysis by searching MEDLINE, Embase and the Cochrane databases from inception until April 2019. We included all types of studies reporting on the effectiveness of influenza vaccination in adult and elderly patients with type 1 and type 2 diabetes. The Newcastle-Ottawa scale was used to assess risk of bias, the GRADE methodology was used to assess the evidence for each outcome. A total of 2261 studies were identified, of those, 6 studies completely fulfilled the inclusion criteria. In the 6 studies included in the analysis, influenza vaccination was associated with a lower mortality rate (Mantel Haenszel Odds Ratio (MH-OR), 95% CI: 0.54 (0.40; 0.74), p < 0.001). Patients who received influenza vaccination showed a lower risk of hospitalization for pneumonia (MH-OR, 95% CI: 0.89; (0.80; 0.98), p = 0.18). A sensitivity analysis using fixed effect model confirmed the results (MH-OR, 95% CI: 0.91; (0.87; 0.96); p = 0.001). The results of this meta-analysis are clinically relevant and support the recommendation for all persons with diabetes to receive influenza vaccination.