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Background: One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D)., Methods: PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks., Results: The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of -0.14% [95%CI -0.25; -0.03], p = 0.01, and I 2 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I 2 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I 2 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of -0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (-5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93])., Conclusion: Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients' education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680.

Aim: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification., Methods: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, 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 "important" 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 > 27 kg/m 2 and < 40 kg/m 2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m 2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative., Conclusion: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Aims: Glomerular hyperfiltration characterises the earliest stage of diabetic nephropathy and predicts adverse kidney and cardiovascular outcomes. We aimed to assess the prevalence and risk factors of glomerular hyperfiltration in a population-based contemporary cohort of individuals with type 2 diabetes (T2D)., Materials and Methods: The prevalence of unequivocal glomerular hyperfiltration (defined by an estimated glomerular filtration rate >120 mL/min/1.73 m 2 ) and its associated risk factors were identified in a cohort of 202,068 adult patients with T2D receiving specialist care in 2021-2022, whose center-aggregated data were automatically extracted from electronic medical records of 75 diabetes clinics in Italy., Results: Glomerular hyperfiltration was identified in 1262 (0.6%) participants. The prevalence of glomerular hyperfiltration varied widely across centers (0%-3.4%) and correlated with mean center age, HbA 1c , body mass index (BMI), and low-density lipoprotein cholesterol. Patients in centers with high glomerular hyperfiltration prevalence (>0.8%) were more often men and had lower age and BMI, but more frequent albuminuria and worse glucose, lipid, and blood pressure control, compared with low-normal prevalence centers., Conclusions: Unequivocal glomerular hyperfiltration can be identified in up to 3.4% of patients receiving up-to-date specialist diabetes care. Glomerular hyperfiltration prevalence varies across centers and substantially increases with suboptimal control of metabolic risk factors, which would require improved management to mitigate the negative health consequences of this pathological condition., (© 2024 John Wiley & Sons Ltd.)

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of 1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure, heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%) of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combination therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Compared to Immediate-Release (IR) metformin, Extended-Release (ER) metformin reduces side effects and pill burden while improving adherence; however, there is little real-life data on patient satisfaction with this innovative formulation to guide physicians toward a more holistic approach., Objective: Our goal is to train general practitioners on holistic patient management, with the aim of increasing patient satisfaction and treatment adherence, reducing side effects, and improving quality of life in patients with poor tolerance to metformin-IR., Materials and Methods: We designed an educational program for physicians called SlowDiab, aimed at establishing a holistic patient approach. In this context, adult patients with T2DM who experienced gastrointestinal discomfort with metformin-IR were enrolled and switched to metformin- ER. Data on glycemic control were collected at baseline and 2 months after switching. A survey was carried out on patients to assess their level of satisfaction., Results: In 69 enrolled patients (mean (min-max) age, 68.2 (41-90)), side effects decreased after switching from 61.8% to 16.2% (p < 0.01), and the mean perceived burden of adverse events on a scale of 1 to 10 also decreased (6.17 vs. 3.82; p < 0.05). Among patients previously intolerant to metformin-IR, 74.3% reported no longer experiencing any side effects after the switch. The mean number of tablets taken daily (2.28 vs. 1.66; p < 0.01) and mean plasma glycated hemoglobin (HbA1c) values (7.0% vs. 6.7%; p < 0.05) decreased, while 93.8% of patients were satisfied with the treatment change. Moreover, 84.2% reported an improvement in glycemic control after the switch., Conclusion: In a real-life setting, an educational program for general practitioners confirmed that metformin ER reduces side effects and improves pill burden, therapeutic adherence, and patient satisfaction compared to metformin IR., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Sarcopenia is an age-related clinical complaint characterized by the progressive deterioration of skeletal muscle mass and strength over time. Type 2 diabetes (T2D) is associated with faster and more relevant skeletal muscle impairment. Both conditions influence each other, leading to negative consequences on glycemic control, cardiovascular risk, general health status, risk of falls, frailty, overall quality of life, and mortality. PubMed/Medline, Scopus, Web of Science, and Google Scholar were searched for research articles, scientific reports, observational studies, clinical trials, narrative and systematic reviews, and meta-analyses to review the evidence on the pathophysiology of di-abetes-induced sarcopenia, its relevance in terms of glucose control and diabetes-related outcomes, and diagnostic and therapeutic challenges. The review comprehensively addresses key elements for the clinical definition and diagnostic criteria of sarcopenia, the pathophysiological correlation be-tween T2D, sarcopenia, and related outcomes, a critical review of the role of antihyperglycemic treatment on skeletal muscle health, and perspectives on the role of specific treatment targeting myokine signaling pathways involved in glucose control and the regulation of skeletal muscle metabolism and trophism. Prompt diagnosis and adequate management, including lifestyle inter-vention, health diet programs, micronutrient supplementation, physical exercise, and pharmaco-logical treatment, are needed to prevent or delay skeletal muscle deterioration in T2D.

Introduction: Obesity is a global pandemic and is cause of serious concern in all regions of the world. It is important to raise the attention of health care professionals in order to provide early treatment of patients with obesity. Obesity management, however, varies greatly amongst endocrinologists with respect to attitudes to diagnosis and treatment. Aim of this study was to identify practices and needs of Italian endocrinologists with respect to people with obesity., Methods: In this study, all members of the Italian Association of Clinical Endocrinologists (AME) were invited to participate in a web-based survey concerning the management of obesity., Results: The response rate was 24.1% (542/2248). Nutritional and obesity problems were reported as major areas of interest by 29.4% of the participants. A large proportion of patients seeking an endocrine consultation for other reasons are affected by obesity, but one in five respondents addressed the issue in 25% or less of the cases, while one in three always dealt with the problem. Obesity was managed personally/within a dedicated team by 42.6% of participants, while the remainders referred the patient to a dietician/nutritionist or a 2nd level center for obesity therapy. Metformin was used in a median of 30% of the patients (Interquartile range: 10-50) and liraglutide in 10% of the cases (IQR 0-30), while orlistat (median 0%; IQR 0-10) and naltrexone/bupropion (median 0%; IQR 0-5) were seldom prescribed. Cost of therapy was considered as the major limitation to the use of anti-obesity drugs, affecting adherence to long-term treatment. According to 41.9% of respondents, psychological support should be offered to all patients with obesity. Finally, 56% of participants believe that the availability of new drugs will increase the number of patients candidate to drug therapy., Discussion: In conclusion, it is of primary importance to raise the awareness of endocrinologists towards the problem of obesity and increase their confidence in managing this pathological condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chianelli, Busetto, Attanasio, Disoteo, Borretta, Persichetti, Samperi, Scoppola, Paoletta, Grimaldi, Papini and Nicolucci.)

A 24-years old female was admitted for acute renal failure, melanoderma, hyponatremia, and hyperkalemia. The clinical suspicion of Addison's disease was confirmed by laboratory test and the appropriate replacement therapy with corticosteroids and fludrocortisone was started. In the meantime primary hypothyroidism and diabetes mellitus type 1 were disclosed and treated, thus fulfilling a diagnosis of autoimmune polyendocrine syndrome type 2. Eighteen months later she was admitted for right-sided heart failure. The work-up allowed to diagnose pulmonary arterial hypertension. Here, we report the clinical course and discuss the putative link between these two rare diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)