Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Effect of a multidisciplinary team approach in patients with diabetic foot ulcers on major adverse limb events (MALEs): systematic review and meta-analysis for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

The treatment of patients with diabetic foot ulcers (DFUs) is extremely complex, requiring a comprehensive approach that involves a variety of different healthcare professionals. Several studies have shown that a multidisciplinary team (MDT) approach is useful to achieve good clinical outcomes, reducing major and minor amputation and increasing the chance of healing. Despite this, the multidisciplinary approach is not always a recognized treatment strategy. The aim of this meta-analysis was to assess the effects of an MDT approach on major adverse limb events, healing, time-to-heal, all-cause mortality, and other clinical outcomes in patients with active DFUs. The present meta-analysis was performed for the purpose of developing Italian guidelines for the treatment of diabetic foot with the support of the Italian Society of Diabetology (Società Italiana di Diabetologia, SID) and the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD). The study was performed using the Grading of Recommendations Assessment, Development, and Evaluation approach. All randomized clinical trials and observational studies, with a duration of at least 26 weeks, which compared the MDT approach with any other organizational strategy in the management of patients with DFUs were considered. Animal studies were excluded. A search of Medline and Embase databases was performed up until the May 1st, 2023. Patients managed by an MDT were reported to have better outcomes in terms of healing, minor and major amputation, and survival in comparison with those managed using other approaches. No data were found on quality of life, returning-to-walking, and emergency admission. Authors concluded that the MDT may be effective in improving outcomes in patients with DFUs.

Offloading systems for the treatment of neuropathic foot ulcers in patients with diabetes mellitus: a meta-analysis of randomized controlled trials for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

AIM: To compare the effectiveness of commonly used offloading devices for the treatment of neuropathic foot ulcers in patients with diabetes mellitus. This meta-analysis (MA) has been performed for giving an answer to clinical questions on this topic of the Italian guideline on diabetic foot syndrome. METHODS: The present MA includes randomized controlled studies (duration > 12 weeks) comparing, in patients with diabetes mellitus and non-infected neuropathic foot ulcer: any offloading device vs either no offloading device or conventional footwear; removable versus non-removable offloading devices; surgical procedure vs other offloading approaches. The primary endpoint was ulcer healing. RESULTS: A total of 184 studies were identified, and 18 were considered eligible for the analysis. We found that: any plantar off-loading, when compared to the absence of plantar offloading device, is associated with a higher ulcer healing (MH-OR: 3.13 [1.08, 9.11], p = 0.04, I2 = 0%); total contact cast or nonremovable knee-high walker, compared to other offloading devices, had a higher ulcer healing rate (MH-OR: 2.64 [1.43, 4.89], p = 0.002, I2 = 51%); surgical offloading for active ulcers in combination with post-surgery offloading achieves higher ulcer healing rate when compared to offloading devices alone (MH-OR: 6.77 [1.64, 27.93], p = 0.008, I2 = 0%). CONCLUSIONS: Any plantar offloading, compared to the absence of plantar offloading device, is associated with a higher ulcer healing rate. Total contact cast or nonremovable knee-high walker, compared to other offloading devices, is preferable. Surgical offloading for active ulcers, in combination with post-surgery offloading devices, achieves a higher ulcer healing rate when compared to other offloading devices alone. Further studies with a larger cohort of patients with diabetic neuropathic foot ulcers and extended follow-up periods are necessary.

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. MATERIALS AND METHODS: In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. RESULTS: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). CONCLUSIONS: Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

Bypass surgery versus endovascular revascularization for occlusive infrainguinal peripheral artery disease: a meta-analysis of randomized controlled trials for the development of the Italian Guidelines for the treatment of diabetic foot syndrome.

To report a review and meta-analysis of all randomized controlled trials (RCTs) comparing bypass surgery (BS) and endovascular treatment (ET) in infrainguinal peripheral arterial disease (PAD) for several endpoints, such as major and minor amputation, major adverse limb events (MALEs), ulcer healing, time to healing, and all-cause mortality to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome (DFS). A MEDLINE and EMBASE search was performed to identify RCTs, published since 1991 up to June 21, 2023, enrolling patients with lower limb ischemia due to atherosclerotic disease (Rutherford I-VI). Any surgical BS or ET was allowed, irrespective of the approach, route, or graft employed, from iliac to below-the-knee district. Primary endpoint was major amputation rate. Secondary endpoints were amputation-free survival major adverse limb events (MALEs), minor amputation rate, all-cause mortality, ulcer healing rate, time to healing, pain, transcutaneous oxygen pressure (TcPO2) or ankle-brachial index (ABI), quality of life, need for a new procedure, periprocedural serious adverse events (SAE; within 30 days from the procedure), hospital lenght of stay, and operative time. Twelve RCTs were included, one enrolled two separate cohorts of patients, and therefore, the studies included in the analyses were 13. Participants treated with ET had a similar rate of major amputations to participants treated with BS (MH-OR 0.85 [0.60, 1.20], p = 0.36); only one trial reported separately data on patients with diabetes (N = 1), showing no significant difference between ET and BS (MH-OR: 0.67 [0.09, 5.13], p = 0.70). For minor amputation, no between-group significant differences were reported: MH-OR for ET vs BS: 0.83 [0.21, 3.30], p = 0.80). No significant difference in amputation-free survival between the two treatment modalities was identified (MH-OR 0.94 [0.59, 1.49], p = 0.80); only one study reported subgroup analyses on diabetes, with a non-statistical trend toward reduction in favor of ET (MH-OR 0.62 [0.37, 1.04], p = 0.07). No significant difference between treatments was found for all-cause mortality (MH-OR for ET vs BS: 0.98 [0.80, 1.21], p = 0.88). A significantly higher rate of MALE was reported in participants treated with ET (MH-OR: 1.44 [1.05, 1.98], p = 0.03); in diabetes subgroup analysis showed no differences between-group for this outcome (MH-OR: 1.34 [0.76, 2.37], p = 0.30). Operative duration and length of hospital stay were significantly shorter for ET (WMD: - 101.53 [- 127.71, - 75.35] min, p < 0.001, and, - 4.15 [- 5.73, - 2.57] days, p < 0.001 =, respectively). ET was associated with a significantly lower risk of any SAE within 30 days in comparison with BS (MH-OR: 0.60 [0.42, 0.86], p = 0.006). ET was associated with a significantly higher risk of reintervention (MH-OR: 1.57 [1.10, 2.24], p = 0.01). No significant between-group differences were reported for ulcer healing (MH-OR: 1.19 [0.53, 2.69], p = 0.67), although time to healing was shorter (- 1.00 [0.18, 1.82] months, p = 0.02) with BS. No differences were found in terms of quality of life and pain. ABI at the end of the study was reported by 7 studies showing a significant superiority of BS in comparison with ET (WMD: 0.09[0.02; 0.15] points, p = 0.01). The results of this meta-analysis showed no clear superiority of either ET or BS for the treatment of infrainguinal PAD also in diabetic patients. Further high-quality studies are needed, focusing on clinical outcomes, including pre-planned subgroup analyses on specific categories of patients, such as those with diabetes and detailing multidisciplinary team approach and structured follow-up.

Effectiveness of pneumococcal vaccination on hospitalization and death in the adult and older adult diabetic population: a systematic review.

INTRODUCTION: Diabetic patients are at a higher risk of getting pneumococcal disease and are therefore recommended to get vaccinated. The aim of our systematic review is the retrieval and analysis of all available evidence on the effect of pneumococcal vaccination on the risk of hospitalization and death in adult patients with diabetes. RESEARCH DESIGN AND METHODS: MEDLINEand EMBASE were searched from inception until January 2023. We included all studies investigating whether pneumococcal vaccination reduces the risk of dying or being hospitalized in diabetic patients. The Newcastle-Ottawa scale was used to assess risk of bias. RESULTS: Only two studies, encompassing a total of 68,246 subjects, were considered eligible for inclusion and of high quality. In both studies polysaccharide pneumococcal vaccination was associated with a reduction of the risk of hospitalization or death in adult diabetic patients (aHR: 0.76 in one study, aOR: 0.97 in the other one). However, in neither of the two included studies the lower risk was statistically significant. CONCLUSIONS: Further research is needed due to the potentially major clinical implications for diabetic patients. The results of this systematic review can serve as a foundation for future studies, indicating the importance of continuing research in this area to improve patient outcomes.

Bariatric Surgery for Patients with Overweight/Obesity. A Comprehensive Grading Methodology and Network Metanalysis of Randomized Controlled Trials on Weight Loss Outcomes and Adverse Events.

This study aims to compare different types of metabolic bariatric surgery (MBS) with lifestyle intervention/medical therapy (LSI/MT) for the treatment of overweight/obesity. The present and network meta-analysis (NMA) includes randomized trials. MBS was associated with a reduction of BMI, body weight, and percent weight loss, when compared to LSI/MT, and also with a significant reduction of HbA1c and a higher remission of diabetes. Meta-regression analyses revealed that BMI, a higher proportion of women, and a longer duration of trial were associated with greater effects of MBS. The NMA showed that all surgical procedures included (except greater curvature plication) were associated with a reduction of BMI. MBS is an effective option for the treatment of obesity. The choice of BMI thresholds for eligibility for surgery of patients with different complications should be performed making an evaluation of risks and benefits in each BMI category.

Polybrominated Diphenyl Ethers (PBDEs) and Human Health: Effects on Metabolism, Diabetes and Cancer.

There is increasing evidence of the role of endocrine disruptors (EDs) derived from commonly employed compounds for manufacturing and processing in altering hormonal signaling and function. Due to their prolonged half-life and persistence, EDs can usually be found not only in industrial products but also in households and in the environment, creating the premises for long-lasting exposure. Polybrominated diphenyl ethers (PBDEs) are common EDs used in industrial products such as flame retardants, and recent studies are increasingly showing that they may interfere with both metabolic and oncogenic pathways. In this article, a multidisciplinary panel of experts of the Italian Association of Medical Diabetologists (AMD), the Italian Society of Diabetology (SID), the Italian Association of Medical Oncology (AIOM), the Italian Society of Endocrinology (SIE) and the Italian Society of Pharmacology (SIF) provides a review on the potential role of PBDEs in human health and disease, exploring both molecular and clinical aspects and focusing on metabolic and oncogenic pathways.

Development of the Italian clinical practice guidelines for the treatment of diabetic foot syndrome: design and methodological aspects.

AIMS: Diabetic foot syndrome (DFS) and its complications are a growing public health concern. The Italian Society of Diabetology (SID) and the Italian Association of Clinical Diabetologists (AMD), in collaboration with other scientific societies, will develop the first Italian guidelines for the treatment of DFS. METHODS: The creation of SID/AMD Guidelines is based on an extended work made by 19 panelists and 12 members of the Evidence Review Team. 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 definition of questions has been performed using a two-step web-based Delphi methodology, 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. RESULTS: The mean age of panelists (26.3% women) was 53.7 ± 10.6 years. The panel proposed 34 questions. A consensus was immediately reached for all the proposed questions, 32 were approved and 2 were rejected. CONCLUSIONS: The areas covered by clinical questions included diagnosis of ischemia and infection, treatment of ischemic, neuropathic, and infected ulcers, prevention of foot ulceration, organization and education issues, and surgical management. The PICO presented in this paper are designed to provide indications for healthcare professionals in charge of diabetic foot treatment and prevention, primarily based on clinical needs of people with diabetic foot syndrome and considering the existing organization of health care.

Metabolic bariatric surgery as a therapeutic option for patients with type 2 diabetes: A meta-analysis and network meta-analysis of randomized controlled trials.

AIM: To compare different types of metabolic surgery with non-surgical therapy for the treatment of type 2 diabetes (T2D). METHODS: The present network meta-analysis (NMA) includes randomized clinical trials (duration ≥ 52 weeks) comparing different surgery techniques with non-surgical therapy in diabetes patients. The primary endpoints were endpoint HbA1c, body mass index (BMI) and diabetes remission. The secondary endpoints included fasting plasma glucose, lipid profile, blood pressure, arterial hypertension and dyslipidaemia remission, quality of life and surgical adverse events. Indirect comparisons of different types of surgery were performed by NMA. Mean and 95% confidence intervals for continuous variables, and the Mantel-Haenzel odds ratio for categorial variables, were calculated. RESULTS: The types of surgical procedure included laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD), greater curvature plication (GCP), one-anastomosis gastric bypass (OAGB) and Duodeno-Jejunal bypass. Thirty-six trials were included. Metabolic bariatric surgery (MBS) was associated with a significantly higher reduction of HbA1c, diabetes remission and BMI compared with medical therapy. In the NMA, a significant reduction of HbA1c was observed with OAGB and SG. Complete diabetes remission significantly increased with all surgical procedures in comparison with non-surgical therapy, except for GCP. In addition, only BPD, RYGB and OAGB were associated with a significant reduction of BMI. CONCLUSIONS: MBS is an effective option for the treatment of T2D in patients with obesity. Further long-term trials of appropriate quality are needed for assessing the risk-benefit ratio in some patient cohorts, such as those with a BMI of less than 35 kg/m2 and aged older than 65 years.

Autologous Peripheral Blood Mononuclear Cells in Patients with Small Artery Disease and Diabetic Foot Ulcers: Efficacy, Safety, and Economic Evaluation.

BACKGROUND: diabetic foot ulcers (DFU) represent the main cause of major amputations and hospitalisations in diabetic patients. The aim of this study was to assess the safety and cost-efficacy of intramuscular injection of peripheral blood mononuclear cells (PBMNCs) in diabetic patients with no-option chronic limb-threatening ischemia (CLTI) and small artery disease (SAD). METHODS: a retrospective study was carried out on a series of type 2 diabetic patients with DFU grade Texas 3 and no-option CLTI and SAD. All patients had undergone at least a previous revascularization and were allocated to a surgery waiting list for major amputation. The principal endpoint evaluated at 90 days was a composite of TcPO2 values at the first toe ≥30 mmHg and/or TcPO2 increase of at least 50% from baseline and/or ulcer healing. Secondary endpoints were individual components of the primary endpoint, any serious and non-serious adverse events, and direct costs at one year. RESULTS: the composite endpoint was achieved in nine patients (60.0%); one patient (6.7%) healed within ninety days and 26.7% and 46.7% showed TcPO2 ≥ 30 mmHg and a TcPO2 increase of at least 50% at ninety days, respectively. At one year, three (20.0%) patients underwent a major amputation (all diagnosed SAD grade III). One patient died after seven months, and seven patients (46.7%) healed. The overall median and mean cost per patient were EUR 8238 ± 7798 and EUR 4426 (3798; 8262), respectively. CONCLUSIONS: the use of PBMNCs implants in no-option CLTI diabetic patients with SAD seems to be of help in reducing the risk of major amputation.

Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials.

INTRODUCTION: An association between glucagon-like peptide-1 receptor agonists (GLP1-RA) and risk of pancreatitis and pancreatic cancer has been suggested. Since its first description, several new trials (including three cardiovascular outcome trials) have been published, substantially increasing the available data set. This suggests the need for an update of the previous meta-analysis. EVIDENCE ACQUISITION: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials, with duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The endpoints were pancreatitis, pancreatic cancer reported as serious adverse events. Mantel-Haenszel Odds Ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes defined above, on an intention-to-treat basis. EVIDENCE SYNTHESIS: A total of 43 trials fulfilling inclusion criteria (all reporting data on pancreatitis and pancreatic cancer) was identified. GLP-1 RA showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; P=0.13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; P=0.20). CONCLUSIONS: No clear evidence of risk for pancreatitis was observed, whereas data on pancreatic cancer are too scarce to draw any conclusion.

Effects of glucose-lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta-analysis of randomized controlled trials with external adjudication of events.

AIMS: To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. METHODS: A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow-up ≥52 weeks, in which glucose-lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All-cause mortality, 3-point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints. RESULTS: We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha-glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl-peptidase-4 inhibitors (n = 67), glucagon-like peptide-1 receptor agonists (n = 45) or sodium-glucose co-transporter-2 inhibitors (SGLT-2i; n = 42) and insulin (n = 18). Glucagon-like peptide-1 receptor agonist and SGLT-2i were associated with a significant reduction in all-cause mortality [Mantel-Haenszel odds ratio (MH-OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH-OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT-2i was associated with a reduced risk of HHF [MH-OR 0.68 (0.62; 0.75)], worsening albuminuria [MH-OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH-OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH-OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH-OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all-cause mortality [MH-OR 1.12 (1.01; 1.24)] and MACE [MH-OR 1.19 (1.02; 1.39)]. CONCLUSIONS: The results of this updated meta-analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose-lowering drugs on long-term glycaemic control.

Adherence to and early adverse events of COVID-19 vaccine in a cohort of 600 Italian breastfeeding and pregnant physicians.

Pregnant and breastfeeding women (PBW) have been excluded from COVID-19 vaccine registry and the majority of post-marketing trials, despite the recognized increased risk of severe infections and complications. The lack of efficacy and safety data prevented the formulation of specific indications/guidelines for vaccination and could have also contributed to increased vaccine hesitancy (VH) in PBW. The aim of this cross-sectional study is to assess the rate and predictors of VH, and early adverse events (AEFI) following COVID-19 vaccine in PBW with a cross-sectional study. In January 2021, a purposely designed questionnaire was administered to 600 PBW part of a Facebook group of physicians, immunized with two doses of Comirnaty®. Thirty-eight (29%) pregnant women and 13 (2.8%) breastfeeders were hesitant. The only statistically significant negative predictor of COVID-19 VH appeared to be having had the flu shot in 2020/2021 (OR: 0.35; 95% CI: 0.13-0.97; p = .044). Approximately 27% of PBW reported hesitancy toward the 2020/2021 season influenza vaccine. Among the vaccinated subjects, 51.6% of pregnant and 75.2% of breastfeeding women reported at least one symptom after the first, and 82.4% and 81.6%, respectively, after the second dose. Nausea/vomiting, fatigue, headache and arthralgia/myalgia were the most common symptoms; dizziness, shivering, syncope and limb paresthesia were rarely reported. Among infants of breastfeeding mothers, six experienced fever, five rash and four moderate and self-limiting diarrhea. Preliminary data on mRNA COVID-19 vaccine in PBW and in their infants are reassuring since AEFI, although frequent, are typically mild and similar to those occurring in the general population, and in PBW after other vaccines. Larger studies with longer follow-up after vaccination are strongly recommended to develop recommendations in these patients.

Major Amputation In Non-Healing Ulcers: Outcomes and Economic Issues. Data from a Cohort of Patients with Diabetic Foot Ulcers.

Background: Foot ulcers have a relevant economic impact on Health Care Systems and the cost-effectivenesseffectiveness of options is not clear. The aim of this study was the assessment of costs for ulcers treatment after 6, 12, and 18 months of follow-up, compared to those for major amputation. Methods: A retrospective study was carried out on 196 types 2 diabetic patients with foot ulcers. The principal endpoints were 1) the proportion of recovered patients among those with ulcers not healed after 6 and 12 months; 2) the assessment of direct costs for treatment of ulcers 6, 12, and 18 months of follow-up, as compared to the cost of major amputation. The economic evaluation was performed considering the perspective of the local health system. Results: Out of 196 patients, 85(46.2%), 131(71.6%), and 140(85.9%) healed within 6, 12, and 18 months, respectively. The average health cost during the 18-month follow-up was 5402€ per patient. We calculated hypothetical costs for three different scenarios, in which patients who did not heal within 6 months underwent a major amputation at 6, 1,2, or 18 months. Costs for the standard of care for all these scenarios (6,094, 7,256, and 7649€ for 6, 12, or 18 months, respectively) were significantly lower than that for major amputations (21,065€). Conclusions: A conservative approach appears more convenient than major amputations in ulcers not healing after 6 months, irrespective of the estimated risk of individual patients.

Effects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively). CONCLUSIONS: This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.