Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type 2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group.

The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in ß-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.

Sex- and Gender-Related Differences in Obesity: From Pathophysiological Mechanisms to Clinical Implications.

Obesity, primarily characterized by excessive fat accumulation, is a multifactorial chronic disease with an increasing global prevalence. Despite the well-documented epidemiology and significant advances in understanding its pathophysiology and clinical implications, the impact of sex is typically overlooked in obesity research. Worldwide, women have a higher likelihood to become obese compared to men. Although women are offered weight loss interventions more often and at earlier stages than men, they are more vulnerable to psychopathology. Men, on the other hand, are less likely to pursue weight loss intervention and are more susceptible to the metabolic implications of obesity. In this narrative review, we comprehensively explored sex- and gender-specific differences in the development of obesity, focusing on a variety of biological variables, such as body composition, fat distribution and energy partitioning, the impact of sex steroid hormones and gut microbiota diversity, chromosomal and genetic variables, and behavioural and sociocultural variables influencing obesity development in men and women. Sex differences in obesity-related comorbidities and varying effectiveness of different weight loss interventions are also extensively discussed.

Pegvaliase-induced immediate hypersensitivity reaction after the discontinuation of antihistamine therapy in a patient with phenylketonuria - Case report.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism, resulting from the deficient activity of phenylalanine hydroxylase that converts Phe to tyrosine in the liver, leading to elevated levels of Phe. Pegvaliase is an innovative and effective enzyme replacement therapy for reducing Phe concentration, but it has been associated with severe drug-induced hypersensitivity adverse events (HAEs). Limited data is available on the management of these HAEs, thus, we aimed to present a case report of a successful management strategy. The patient was a 28-year-old Caucasian male with classical PKU, who was otherwise healthy. Due to poor metabolic control, the pegvaliase treatment was initiated. The titration phase was uneventful, with transient and mild side effects, localized to the injection site. After the patient was on a maintenance dose of pegvaliase and had no reactions to the drug, we discontinued the H1-antihistamine. In the following days, within minutes after receiving the pegvaliase injection, an acute hypersensitivity reaction occurred that required emergency treatment. H1-antihistamine treatment was reintroduced. Four days after the incident he received pegvaliase under medical supervision and did not experience any symptoms. In conclusion, cautious reintroduction of pegvaliase in a hospital setting can be safely performed after HAE due to the discontinuation of H1-antihistamines. HAEs could be successfully mitigated by scheduling daily antihistamines administration closer to the pegvaliase injection. This approach can enable PKU patients to maintain their access to an effective and quality-of-life-improving therapy.

The maintenance of long-term weight loss after semaglutide withdrawal in obese women with PCOS treated with metformin: a 2-year observational study.

Background: Withdrawal of semaglutide is frequently followed by weight regain due to compensatory biological changes that prevent the maintenance of long-term weight loss. There are some studies implying that metformin might attenuate weight regain. The weight trajectory after discontinuation of short-term semaglutide treatment in obese women with PCOS who continued metformin treatment has not yet been evaluated. Aims: We explored changes in body weight, cardiometabolic and endocrine parameters in obese women with PCOS who continued treatment with metformin 2 years after discontinuation of short-term intervention with semaglutide. Methods: 25 women with PCOS and obesity, aged 33.7 ± 5.3 years (mean ± SD), were treated with once-weekly subcutaneous semaglutide 1.0 mg as an adjunct to metformin 2000 mg/day and lifestyle intervention for 16 weeks. At week 16, semaglutide was discontinued. Treatment with metformin 2000 mg/day and promotion of lifestyle intervention were continued during the 2-year follow-up period. Weight change, cardiometabolic, and endocrine parameters were assessed 2 years after semaglutide discontinuation. Results: During semaglutide treatment phase, weight decreased from 101 (90-106.8) kg to 92 (83.3-100.8) kg. Two years after semaglutide withdrawal, weight was 95 (77-104) kg. The net weight loss 2 years after discontinuation of semaglutide remained significant when compared to baseline (p=0.003). At the end of the study, 21 out of 25 subjects had lower body weight compared to baseline. Improvements in cardiometabolic parameters including decrease in total and LDL cholesterol, fasting glucose, and glucose after OGTT that had been seen during semaglutide-treatment phase reverted towards baseline two years after semaglutide cessation. Free testosterone levels significantly decreased during semaglutide treatment from 6.16 (4.07-9.71) to 4.12 (2.98-6.93) nmol/l, (p= 0.012) and did not significantly deteriorate after semaglutide discontinuation. Conclusion: Two years after semaglutide withdrawal, women with PCOS who continued with metformin regained about one-third of the semaglutide-induced weight loss. At the end of the follow up, 84% of women had a lower body weight than at baseline.

The Current and Emerging Role of Statins in the Treatment of PCOS: The Evidence to Date.

Polycystic ovary syndrome (PCOS) manifests a multifactorial pathology characterized by polycystic ovaries, menstrual cycle disorders, varying degrees of hyperandrogenism, and an ad-verse metabolic risk profile. The position of hyperandrogenism in this syndrome has been extensively studied. A multitude of mechanisms place it in the position of cause but also of consequence; therefore, ongoing research efforts are focused on identifying medications that can effectively reduce levels of androgens in women with PCOS. Moreover, lipid abnormalities are common in this population, with up to 70% of patients having dyslipidemia. Statins may have potential therapeutic benefits for women with PCOS, as they have been shown to improve insulin resistance and reduce the risk of cardiovascular disease. In addition, their role in accelerated steroidogenesis by limiting one source of cholesterol, influencing enzymatic activity, and providing several other beneficial mechanisms is widely investigated. This review aimed to provide a comprehensive overview of the pathogenesis of androgen excess and dyslipidemia in PCOS, as well as the therapeutic potential of statins.

New-Onset Diabetes Mellitus in COVID-19: A Scoping Review.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic became superimposed on the pre-existing obesity and diabetes mellitus (DM) pandemics. Since COVID-19 infection alters the metabolic equilibrium, it may induce pathophysiologic mechanisms that potentiate new-onset DM, and we evaluated this issue. METHOD: A systematic review of the literature published from the 1 January 2020 until the 20 July 2023 was performed (PROSPERO registration number CRD42022341638). We included only full-text articles of both human clinical and randomized controlled trials published in English and enrolling adults (age > 18 years old) with ongoing or preceding COVID-19 in whom hyperglycemia was detected. The search was based on the following criteria: "(new-onset diabetes mellitus OR new-onset DM) AND (COVID-19) AND adults". RESULTS: Articles on MEDLINE (n = 70) and the Web of Science database (n = 16) were included and analyzed by two researchers who selected 20 relevant articles. We found evidence of a bidirectional relationship between COVID-19 and DM. CONCLUSIONS: This link operates as a pathophysiological mechanism supported by epidemiological data and also by the clinical and biological findings obtained from the affected individuals. The COVID-19 pandemic raised the incidence of DM through different pathophysiological and psychosocial factors.

Prolactin in Polycystic Ovary Syndrome: Metabolic Effects and Therapeutic Prospects.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine and metabolic disorder in premenopausal women, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Patients frequently present comorbidities, including obesity, insulin resistance, and impaired glucose and lipid metabolism. The diverse clinical presentation may mimic various endocrine disorders, making the diagnosis challenging in some clinical circumstances. Prolactin (PRL) is a recommended biomarker in the initial diagnostic workup to rule out hyperprolactinemia (HPRL). The traditional role of PRL is linked to lactation and the reproductive system. Recent research highlights PRL's emerging role in metabolic homeostasis. PRL influences metabolism directly by interacting with the pancreas, liver, hypothalamus, and adipose tissue. Its influence on an individual's metabolism is intricately tied to its serum concentration. While deficient and very high levels of PRL can negatively affect metabolism, intermediate-normal to moderately high levels may promote metabolic health. In women with PCOS, PRL levels may be altered. Research results on different aspects of the relationship between PCOS and the impact of various levels of PRL on metabolic homeostasis are limited and inconsistent. In this narrative literature review, we comprehensively examined data on serum PRL levels in PCOS patients. We investigated the correlation between a favorable metabolic profile and serum PRL levels in this population. Furthermore, we explored the concept of beneficial PRL effects on metabolism and discussed the potential therapeutic application of dopamine agonists in PCOS treatment. Lastly, we emphasized several promising avenues for future research in this field.

Case Report: Multiple prolactinomas in a young man with Kallmann syndrome and familial hypocalciuric hypercalcemia.

Introduction: The occurrence of prolactinomas in sex hormone treated patients with central hypogonadism is extremely rare. Case presentation: We present a Caucasian male patient who was diagnosed with Kallmann syndrome (KS) at age 15 years. Testosterone treatment was started. At age 26 the patient presented with mild headache. MRI revealed two separate pituitary adenomas along with the absence of the olfactory bulbs. Given the presence of marked hyperprolactinemia (17x upper limit of the reference range) the diagnosis prolactinoma was made and treatment with cabergoline was started which resulted in a complete biochemical response and in marked reduction of both adenomas in size. Hypogonadism persisted and testosterone replacement therapy was continued. Genetic testing of genes associated with pituitary tumors, Kallmann syndrome and idiopathic hypogonadotropic hypogonadism was negative. Mild concomitant hypercalcemia in accordance with familial hypocalciuric hypercalcemia (FHH) prompted mutation analysis of the calcium receptor (CASR) gene which yielded a pathogenic inactivating variant. Discussion/conclusion: The presence of two separate prolactinomas in a patient with KS has not yet been reported in the literature. The effect of sex hormone treatment of KS patients on the possible development of prolactinoma is unknown at present. The occurance of multiple prolactinomas in our patient suggests increased susceptibility. Although CaSR is expressed in GnRH neurons in mouse brain and CaSR deficient mice have a reduced hypothalamic GnRH neuronal population, the relevance of the CASR gene variant in our patient for the KS phenotype is unclear at present.

Efficacy, safety, and patient satisfaction with oral semaglutide: first single-centre clinical experience.

OBJECTIVE: To explore the effects of oral semaglutide on glycaemic parameters, body weight, and satisfaction in the first recipient patients with type 2 diabetes mellitus in Slovenia, in a real-world clinical practice setting. METHODS: The first consecutive adult patients with type 2 diabetes who were eligible for oral semaglutide treatment were included in this prospective, open-label interventional study. Patients received increasing doses of oral semaglutide and were evaluated at inclusion, at 1 month, then 3-5 months after starting treatment. Fasting blood glucose, glycosylated haemoglobin (HbA1c), body weight, patient satisfaction with oral semaglutide treatment (using the validated Treatment Satisfaction Questionnaire for Medication), and adverse effects, were analysed. Statistical analyses were performed using one-way analysis of variance, and, when significant interactions were found, Bonferroni post-hoc test. A P-value <0.05 was considered statistically significant. RESULTS: Twenty patients (11 male: 9 female; mean age, 59.9 ± 1.5 years; mean diabetes duration, 8.5 ± 1.4 years) were included. Oral semaglutide (7 and 14 mg) significantly decreased HbA1c (from 9.4 ± 0.3% to 8.2 ± 0.2% and 7.8 ± 0.2%, respectively) and fasting plasma glucose (from 11.2 ± 0.5 mmol/L to 9.2 ± 0.7 mmol/L and 8.9 ± 0.4 mmol/L, respectively). Oral semaglutide (14 mg) significantly decreased body weight (from 100.9 ± 2.7 kg to 92.7 ± 2.4 kg). Patients reported that treatment was easy to use and expressed high global satisfaction. Mild and transient, mostly gastrointestinal, adverse effects were reported in 10 patients. CONCLUSIONS: Oral semaglutide, the first oral glucagon-like peptide 1 receptor agonist, was effective and safe, and associated with high patient satisfaction, in its first recipients in Slovenia. The results are important for daily clinical practice involving patients with type 2 diabetes, however, due to the small study population, lack of placebo control, and short exposure to oral semaglutide, the effectiveness of oral semaglutide in clinical practice requires further investigation.

Cardiometabolic Risk, Peripheral Arterial Disease and Cardiovascular Events in Polycystic Ovary Syndrome: Time to Implement Systematic Screening and Update the Management.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder in women of reproductive age. It presents with gynaecologic, metabolic, and psychologic manifestations. The dominant drivers of pathophysiology are hyperandrogenism and insulin resistance. Both conditions are related to cardiometabolic risk factors, such as obesity, hypertension, dyslipidaemia, hyperglycaemia, type 2 and gestational diabetes, nonalcoholic fatty liver disease and obstructive sleep apnoea. Women with PCOS of reproductive age consistently demonstrated an elevated risk of subclinical atherosclerosis, as indicated by different measurement methods, while findings for menopausal age groups exhibited mixed results. Translation of subclinical atherosclerosis into the increased incidence of peripheral arterial disease and major cardiovascular (CV) events is less clear. Although several expert groups have advised screening, the CV risk assessment and prevention of CV events are frequently underdiagnosed and overlooked aspects of the management of PCOS. A combination of lifestyle management and pharmacotherapy, including the promising new era of anti-obesity medicine, can lead to improvements in cardiometabolic health.

Health-Related Quality of Life Assessment in Older Patients with Type 1 and Type 2 Diabetes.

Type 1 (T1D) and type 2 diabetes (T2D) are determinants of health-related outcomes including health-related quality of life (HRQOL). We aimed to determine differences in HRQOL between older adults with T1D and T2D and specific factors influencing HRQOL in this age group. This study used a cross-sectional design with 56 age- and HbA1c-matched T1D and T2D patients (aged 68.9 ± 7.8 years; 55% had T2D). We employed several validated questionnaires (Short Form-36 (SF-36) and the EuroQol-5 Dimensions/Visual Analog Scale (VAS)) to investigate the relationships between HRQOL domains and diabetes type, glycemic control, complications, and comorbidities. T1D was associated with better self-reported general health (assessed with the SF-36 general health domain (p = 0.048) and the EuroQol-5 VAS (p = 0.002), whereas no significant differences in the other SF-36 domains, self-reported diabetes distress, anxiety, or depression were found. Most HRQOL domains were not associated with HbA1c or the presence of diabetes complications. The most significant reduction in HRQOL was experienced by patients with higher BMIs, irrespective of the diabetes type. The obtained HRQOL data could be used in clinical settings for evidence-based patient education focused on specific subgroups of patients, as well as in national healthcare policies, e.g., interventions designed to alleviate obesity.

The Effect of Additional Treatment with Empagliflozin or Semaglutide on Endothelial Function and Arterial Stiffness in Subjects with Type 1 Diabetes Mellitus-ENDIS Study.

We investigated the effect of additional treatment with newer antidiabetic drugs on endothelium function and arterial stiffness in subjects with type 1 diabetes mellitus (T1DM) without cardiovascular diseases. A total of 89 participants, all users of CGMS (continuous monitoring glucose system), were randomized into three comparable groups, receiving empagliflozin (E; n = 30), receiving semaglutide (S; n = 30), and a control group (C; n = 29). At baseline and 12 weeks post treatment, we measured FMD (brachial artery flow-mediated dilation) and FBF (forearm blood flow as reactive hyperemia assessed with strain gauge plethysmography) as parameters of endothelial function, as well as pulse wave velocity (PWV) and peripheral resistance as parameters of arterial stiffness. Improvement in FMD was significant in both intervention groups compared to controls (E group 2.0-fold, p = 0.000 and S group 1.9-fold, p = 0.000), with no changes between those two groups (p = 0.745). During the evaluation of FBF, there were statistically insignificant improvements in both therapeutic groups compared to controls (E group 1.39-fold, p = 0.074 and S group 1.22-fold, p = 0.701). In arterial stiffness parameters, improvements were seen only in the semaglutide group, with a decline in peripheral resistance by 5.1% (p = 0.046). We can conclude that, for arterial stiffness, semaglutide seems better, but both drugs positively impact endothelial function and, thus, could also have a protective role in T1DM.

The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials.

Type 2 Diabetes Mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are part of metabolic syndrome and share multiple causal associations. Both conditions have an alarmingly increasing incidence and lead to multiple complications, which have an impact on a variety of organs and systems, such as the kidneys, eyes, and nervous and cardiovascular systems, or may cause metabolic disruptions. Sodium-glucose cotransporter 2-inhibitors (SGLT2-i), as an antidiabetic class with well-established cardiovascular benefits, and its class members have also been studied for their presumed effects on steatosis and fibrosis improvement in patients with NAFLD or non-alcoholic steatohepatitis (NASH). The MEDLINE and Cochrane databases were searched for randomized controlled trials examining the efficacy of SGLT2-i on the treatment of NAFLD/NASH in patients with T2DM. Of the originally identified 179 articles, 21 articles were included for final data analysis. Dapagliflozin, empagliflozin, and canagliflozin are some of the most used and studied SGLT2-i agents which have proven efficacy in treating patients with NAFLD/NASH by addressing/targeting different pathophysiological targets/mechanisms: insulin sensitivity improvement, weight loss, especially visceral fat loss, glucotoxicity, and lipotoxicity improvement or even improvement of chronic inflammation. Despite the considerable variability in study duration, sample size, and diagnostic method, the SGLT2-i agents used resulted in improvements in non-invasive markers of steatosis or even fibrosis in patients with T2DM. This systematic review offers encouraging results that place the SGLT2-i class at the top of the therapeutic arsenal for patients diagnosed with T2DM and NAFLD/NASH.

A Critical View over the Newest Antidiabetic Molecules in Light of Efficacy-A Systematic Review and Meta-Analysis.

The increase in life expectancy without a decrease in the years lived without disability leads to the rise of the population aged over 65 years prone to polypharmacy. The novel antidiabetic drugs can improve this global therapeutic and health problem in patients with diabetes mellitus (DM). We aimed to establish the efficacy (A1c hemoglobin reduction) and safety of the newest antidiabetic drugs (considered so due to their novelty in medical practice use), specifically DPP-4i, SGLT-2i, GLP-1 Ra, and tirzepatide. The present meta-analysis followed the protocol registered at Prospero with the CRD42022330442 registration number. The reduction in HbA1c in the DPP4-i class for tenegliptin was 95% CI -0.54 [-1.1, 0.01], p = 0.06; in the SGLT2-iclass for ipragliflozin 95% CI -0.2 [-0.87, 0.47], p = 0.55; and for tofogliflozin 95% CI 3.13 [-12.02, 18.28], p = 0.69, while for tirzepatide it was 0.15, 95% CI [-0.50, 0.80] (p = 0.65). The guidelines for treatment in type 2 DM are provided from cardiovascular outcome trials that report mainly major adverse cardiovascular events and data about efficacy. The newest antidiabetic non-insulinic drugs are reported to be efficient in lowering HbA1c, but this effect depends between classes, molecules, or patients' age. The newest antidiabetic drugs are proven to be efficient molecules in terms of HbA1c decrease, weight reduction, and safety, but more studies are needed in order to characterize exactly their efficacy and safety profiles.

Effect of semaglutide versus other glucagon-like peptide-1 receptor agonists on cardio-metabolic risk factors in patients with type 2 diabetes: A systematic review and meta-analysis of head-to-head, phase 3, randomized controlled trials.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a cornerstone treatment for type 2 diabetes mellitus (T2DM). The aim of the present meta-analysis was to assess whether semaglutide exerts greater effects on glycemia and other cardio-metabolic risk factors compared to other GLP-1RAs. METHODS: PubMed and Cochrane Library databases, along with grey literature sources, were searched form inception to 8th February 2023, in order to retrieve head-to-head, phase 3 randomized controlled trials (RCTs) assessing the effect of semaglutide versus other GLP-1RAs on glycemia and other cardio-metabolic risk factors in T2DM. RESULTS: We finally pooled data from 5 RCTs in a total of 3760 randomized participants. Semaglutide compared to other GLP-1RAs provided a significantly greater reduction in HbA1c levels by 0.44 %, in fasting plasma glucose by 0.48 mmol/L, in body weight by 2.53 kg and in body mass index by 0.91 kg/m2. Subjects receiving semaglutide experienced significantly greater odds for achieving target and optimal HbA1c, along with significantly greater odds for weight loss >5 % and 10 %. However, subjects randomized to semaglutide also experienced significantly greater odds for gastrointestinal adverse events and treatment discontinuation. CONCLUSION: Semaglutide is more effective than rest GLP-1RAs, in terms of improvement in glycemia and other cardio-metabolic risk factors, among individuals with T2DM.

Telemedicine for diabetes management during COVID-19: what we have learnt, what and how to implement.

The past two decades have witnessed telemedicine becoming a crucial part of health care as a method to facilitate doctor-patient interaction. Due to technological developments and the incremental acquisition of experience in its use, telemedicine's advantages and cost-effectiveness has led to it being recognised as specifically relevant to diabetology. However, the pandemic created new challenges for healthcare systems and the rate of development of digital services started to grow exponentially. It was soon discovered that COVID-19-infected patients with diabetes had an increased risk of both mortality and debilitating sequelae. In addition, it was observed that this higher risk could be attenuated primarily by maintaining optimal control of the patient's glucose metabolism. As opportunities for actual physical doctor-patient visits became restricted, telemedicine provided the most convenient opportunity to communicate with patients and maintain delivery of care. The wide range of experiences of health care provision during the pandemic has led to the development of several excellent strategies regarding the applicability of telemedicine across the whole spectrum of diabetes care. The continuation of these strategies is likely to benefit clinical practice even after the pandemic crisis is over.

Brown Adipose Tissue: A New Potential Target for Glucagon-like Peptide 1 Receptor Agonists in the Treatment of Obesity.

Adipose tissue can be divided into white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, according to the differences in morphology. WAT acts as a buffer for increased energy intake and decreased energy expenditure during the development of obesity, resulting in visceral and ectopic WAT accumulation. These WAT depots are strongly associated with chronic systemic inflammation, insulin resistance, and cardiometabolic risk related to obesity. They represent a primary weight loss target in anti-obesity management. Second-generation anti-obesity medications glucagon-like peptide-1 receptor agonists (GLP-1RAs) cause weight loss and improve body composition by reducing visceral and ectopic fat depots of WAT, resulting in improved cardiometabolic health. Recently, the understanding of the physiological significance of BAT beyond its primary function in generating heat through non-shivering thermogenesis has been expanded. This has raised scientific and pharmaceutical interest in the manipulation of BAT to further enhance weight reduction and body weight maintenance. This narrative review focuses on the potential impact of GLP-1 receptor agonism on BAT, particularly in human clinical studies. It provides an overview of the role of BAT in weight management and highlights the need for further research to elucidate the mechanisms by which GLP-1RAs affect energy metabolism and weight loss. Despite encouraging preclinical data, limited clinical evidence supports the notion that GLP-1RAs contribute to BAT activation.

Effects of Mindfulness-Based Therapy on Clinical Symptoms and DNA Methylation in Patients with Polycystic Ovary Syndrome and High Metabolic Risk.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting women of reproductive age. Research has shown that epigenetic alterations such as DNA methylation may play a role in the development and progression of abnormal ovarian function and metabolic disorders in PCOS. Studies have identified specific genes (related with insulin signaling and steroid hormone metabolism) that are methylated in women with PCOS. DNA methylation appears to respond to various interventions aimed at altering health and lifestyle factors. We tested the efficacy of a mindfulness-based stress reduction program (MBSR) in PCOS patients. We examined its effects on anthropometric measurements, mental health and wellbeing, and alterations in DNA methylation in peripheral blood. MBSR was associated with a reduction in body mass index, waist circumference and blood glucose level, an improvement in subjectively perceived general health, emotional role limitation, and levels of pain, as well as mindfulness-like traits. MBSR reduced the expression of anxious symptomatology and subjectively perceived stress. Methylation changes were observed in four genes: COMT, FST, FKBP51, and MAOA. We conclude that MBSR may be a useful supplementary therapy to mitigate the deleterious effects of PCOS on mental health.

Effectiveness and Safety of iGlarLixi in People with Type 2 Diabetes in Adriatic Region Countries: ENSURE-ADR, a Real-World Study.

INTRODUCTION: The efficacy of iGlarLixi, a fixed-ratio combination of basal insulin glargine 100 units/mL (iGlar) and the short-acting GLP-1 RA lixisenatide (Lixi), was established in people with type 2 diabetes (T2D) who were advancing therapy from oral antidiabetic drugs (OADs) and basal insulin (BI). This retrospective study aimed to evaluate the effectiveness and safety of iGlarLixi using real-world data from people with T2D in the Adriatic region countries. METHODS: This was a non-interventional, retrospective, multicenter, cohort study with the collection of pre-existing data at iGlarLixi initiation and after 6 months of treatment in real-world clinical and ambulatory settings. The primary outcome was the change in glycated hemoglobin (HbA1c) at 6 months after iGlarLixi initiation. Key secondary outcomes included the proportion of people achieving HbA1c < 7.0%, the effect of iGlarLixi on fasting plasma glucose (FPG), body weight and body mass index (BMI). RESULTS: In this study, 262 participants (130 in Bosnia and Herzegovina, 72 in Croatia and 60 in Slovenia) initiated treatment with iGlarLixi. The participants had a mean ± SD age of 66.2 ± 7.9 years and the majority were women (58.0%). The mean baseline HbA1c was 8.9 ± 1.7% and the mean body weight was 94.3 ± 18.0 kg. After 6 months of treatment, the reduction in the mean HbA1c was statistically significant (1.11 ± 1.61%, 95% confidence internal [CI] 0.92, 1.31; p < 0.001), and the proportion of participants who achieved HbA1c < 7.0% had significantly increased from baseline (8.0-26.0%, p < 0.001). The change in mean FPG (mmol/L) levels was significant (2.7 ± 4.4 [95% CI 2.1, 3.2; p < 0.001]). The mean ± SD body weight and BMI were significantly reduced by 2.9 ± 4.3 kg (95% CI 2.3, 3.4; p < 0.001) and 1.3 ± 4.4 kg/m2 (95% CI 0.7, 1.8; p < 0.001), respectively. Two serious hypoglycemia episodes and one adverse gastrointestinal effect (nausea) were registered. CONCLUSIONS: This real-world study demonstrated the effectiveness of iGlarLixi for improving glycemic control and decreasing body weight in people with T2D who need to advance therapy from OADs or insulin.