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BACKGROUND: We examined the real-world comparative safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. other newer anti-glycemic medications (dipeptidyl peptidase-4 inhibitors [DPP4i], glucagon-like peptide-1 receptor agonists [GLP1a]) in patients with and without chronic kidney disease (CKD). METHODS: Among US Veterans with diabetes receiving care from the Veterans Affairs (VA) healthcare system over 2004-19, we identified incident users of SGLT2i vs. DPP4i vs. GLP1a monotherapy. In analyses stratified by CKD status, defined by estimated glomerular filtration rate and albuminuria, we examined associations of SGLT2i vs. DPP4i vs. GLP1a use with risk of infection-related (primary outcome) and genitourinary infection hospitalizations (secondary outcome) using multivariable Cox models. FINDINGS: Among 92,269 patients who met eligibility criteria, 52% did not have CKD, whereas 48% had CKD. In the overall and non-CKD cohorts, compared to DPP4i use, SGLT2i use was associated with lower infection-related hospitalization risk (HRs [95% CIs] 0.74 [0.67-0.81] and 0.77 [0.67, 0.88], respectively), whereas GLP1a use demonstrated comparable risk. However, in the CKD cohort SGLT2i and GLP1a use were each associated with lower risk (HRs [95% CIs] 0.70 [0.61, 0.81] and 0.91 [0.84, 0.99], respectively). Propensity score-matched analyses showed similar findings in the non-CKD and CKD cohorts. In the overall, non-CKD, and CKD cohorts, SGLT2i use was associated with lower genitourinary infection hospitalization risk whereas GLP1a use showed comparable risk vs. DPP4i use. INTERPRETATION: In a national cohort of Veterans with diabetes, compared with DPP4i use, SGLT2i use was associated with lower infection-related and genitourinary infection hospitalization risk. FUNDING: VA Health Services Research and Development, USA.

PURPOSE: Data are limited on sodium glucose co-transport 2 inhibitors (SGLT2-is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among real-world cohorts of underrepresented patients. We examined these therapies and glycemic control in US adults with diabetes mellitus (DM) by atherosclerotic cardiovascular disease (ASCVD) risk and sociodemographic factors. METHODS: In the NIH Precision Medicine Initiative All of Us Research Program, we categorized DM as (1) moderate risk, (2) high risk, and (3) with ASCVD. We examined proportions on DM therapies, including SGLT2-i or GLP-1 RA, and at glycemic control by sociodemographic factors and CVD risk groups. RESULTS: Our 81,332 adults aged ≥ 18 years with DM across 340 US sites included 22.3% non-Hispanic Black, 17.2% Hispanic, and 1.8% Asian participants; 31.1%, 30.3%, and 38.6% were at moderate risk, high risk, or with ASCVD, respectively. Those with DM and ASCVD were most likely on SGLT2-i (8.6%) or GLP-1 RA (11.9%). SGLT2-i use was

Aims Methods and results Conclusions Glucagon‐like peptide‐1 receptor agonists reduce major adverse cardiovascular events (MACE) and cardiovascular mortality in people with type 2 diabetes (T2D). However, previous studies suggest the effects on heart failure outcomes vary according to left ventricular ejection fraction (LVEF). We aimed to evaluate the effects of exenatide on cardiovascular events according to LVEF in people with T2D.Post‐hoc analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial evaluating the effects of once‐weekly exenatide (EQW) versus placebo on cardiovascular outcomes according to baseline LVEF (<40% or ≥40%). Outcomes were also evaluated according to New York Heart Association (NYHA) class and obesity. The main outcome was hospitalization for heart failure (HHF). A treatment‐by‐LVEF interaction was used. In EXSCEL (n = 14 752), 4749 participants had LVEF available at baseline; 455 (10%) with LVEF <40%, 4294 (90%) with LVEF ≥40%. LVEF modified the EQW effect on hHF: hazard ratio (HR) = 1.52 (95% confidence interval [CI] = 0.95–2.43) in participants with LVEF < 40% and HR = 0.74 (95% CI = 0.55–1.01) in those with LVEF ≥ 40% (p‐interaction = 0.012). No significant treatment‐by‐LVEF interactions (p‐interaction >0.10) were observed for MACE, cardiovascular death or all‐cause mortality. The risk of HHF was also modified by baseline NYHA class (HR 0.91, 95% CI 0.65–1.27 for NYHA class I/II; HR 1.84, 95% CI 0.95–3.59 for NYHA class III/IV; p‐interaction = 0.062), mostly driven by the LVEF <40% subgroup. Obesity did not modify the effects of EQW on HHF.The EQW effect on HHF was influenced by LVEF, with a potentially decreased risk in participants with LVEF ≥40% and increased risk in those with LVEF <40%. The risk of HHF was particularly high in participants with LVEF <40% and NYHA class III/IV. LVEF did not modify the effect of EQW on atherosclerotic outcomes. [ABSTRACT FROM AUTHOR]

Aim: To investigate the efficacy and safety of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 (SGLT2) inhibitors in liver transplant (LT) recipients with diabetes. Methods: A single‐centre, retrospective analysis of prospectively collected data from an LT recipient database (1990–2023) was conducted. We included adults with pre‐existing diabetes and post‐transplant diabetes, newly started on GLP‐1RAs and/or SGLT2 inhibitors after LT. Metabolic and biochemical parameters and outcomes were collected for up to 12 months after starting medications and were compared to those in patients receiving dipeptidyl peptidase‐4 (DPP‐4) inhibitors. Statistical analysis included descriptive statistics and linear mixed models. Results: We included participants on GLP‐1RAs (n = 46), SGLT2 inhibitors (n = 87), combination therapy (n = 12), and a DPP‐4 inhibitor comparator (n = 217). Both GLP‐1RAs and combination therapy decreased mean glycated haemoglobin (HbA1c) levels, and combination therapy remained significant when adjusted for DPP‐4 inhibitor treatment (−3.5%, 95% CI [−6.1, −0.95]; p = 0.0089) at 12 months. All three groups had significant decreases in mean weight and body mass index, but these remained significant in the GLP‐1RA (−5.2 kg, 95% CI [−8.7, −1.7], p = 0.0039 and 1.99 kg/m2, 95% CI [−3.4, −0.6], p = 0.0048) and combination therapy groups (−5.4 kg, 95% CI [−10.5, −0.36], p = 0.04 and −3.4 kg/m2, 95% CI [−5.5, −1.3], p = 0.0015) when adjusted for DPP‐4 inhibitor treatment at 12 months. Alanine aminotransferase levels decreased with GLP‐1RA and combination therapy. There were two (1.4%) cases of graft rejection. Conclusion: We found that GLP‐1RAs, SGLT2 inhibitors, and their combination, led to significant weight loss in LT recipients with diabetes. Combination therapy, in particular, lowered HbA1c and alanine aminotransferase levels compared to DPP‐4 inhibitors. Further studies are needed to assess long‐term safety and efficacy. [ABSTRACT FROM AUTHOR]

Diabetes mellitus and obesity are growing health concerns. New pharmacologic interventions have recently begun to play a more notable role in the treatment pathway of these separate but related conditions. In particular, glucagon-like peptide-1 receptor agonists, such as semaglutides (Ozempic, Wegovy) and tirzepatide (Mounjaro), and sodium glucose co-transporter 2 inhibitors, such as dapagliflozin (Farxiga) and empagliflozin (Jardiance), have emerged as treatment options. Multiple clinical trials have demonstrated their efficacy in regulating metabolism, improving glycemic control, and managing long-term weight reduction. However, glucagon-like peptide-1 receptor agonists have also been associated with gastrointestinal side effects, including delayed gastric emptying as well as regurgitation and aspiration during general anesthesia or deep sedation, and sodium glucose co-transporter 2 inhibitors have been associated with severe diabetic ketoacidosis. Therefore, discontinuation of these medications before surgery is imperative. Given the popularity of these medications among the general public, it is essential for hand surgeons, to understand how to appropriately manage them perioperatively. The objective of this article was to review these new diabetes mellitus and weight loss medications, including their mechanisms of action, indications for use, and perioperative management guidelines. Additionally, we will take this opportunity to review perioperative guidelines for other common medications relevant to patients undergoing procedures involving the hand and upper extremity such as antithrombotic medications and rheumatoid arthritis-related immunosuppressive medications. Finally, we will describe how the electronic medical record system can be used to optimize perioperative medication management in this population. [ABSTRACT FROM AUTHOR]

Introduction: Despite the technological advancements in catheter ablation strategies, the recurrence of atrial fibrillation (AF) post-ablation remains a concern that requires further investigation. Glucagon-like peptide 1 (GLP-1) receptor agonists have shown a significant effect on weight reduction, which in turn is associated with freedom from AF recurrence in both patients who are obese and not obese undergoing ablation. Therefore, we aimed to summarize the available evidence on the efficacy of GLP-1 receptor agonists in maintaining sinus rhythm post-ablation. Methods: Medline, Cochrane Library, and Scopus were searched until June 9, 2024. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled using DerSimonian-Laird random effects meta-analysis. Results: Three propensity score-matched studies (n = 6031 participants) were analyzed. Over a 12-months follow-up, the use of GLP-1 receptor agonists was associated with a significant reduction in AF recurrence compared to controls, hazard ratio (HR) = 0.549, 95% confidence interval (CI) = [0.315, 0.956], P = 0.034; I2 = 57%. No significant heterogeneity was observed (Q statistic = 4.6, heterogeneity P = 0.1). Conclusion: The use of GLP-1 receptor agonists is associated with a lower risk of AF recurrence in patients receiving AF ablation therapy. Further large-scale randomized trials are necessary to explore the efficacy of GLP-1 receptor agonists in maintaining ablation outcomes over the long term. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Registration Number While randomized controlled trials data on the long‐term effect of glucose‐lowering drugs (GLDs) on liver‐related outcomes are lacking, population‐based studies have evaluated the associations of GLDs with liver‐related outcomes in individuals with type 2 diabetes (T2D). we aimed to conduct a systematic review of population‐based studies evaluating the effects of GLDs on liver‐related outcomes in people with T2D.PubMed, Web of Science, and Embase databases were systematically searched for population‐based studies testing the associations of GLDs with liver‐related outcomes in individuals with T2D and no liver disease other than non‐alcoholic fatty liver disease (NAFLD) from inception to 23 February 2024. GLDs included SGLT2is, TZDs, insulin, GLP‐1 RAs and dipeptidyl peptidase‐4 inhibitors (DPP4Is).Ten cohort studies, comprising 1,274,641 participants, met the inclusion criteria. The median follow‐up period ranged from 8.9 to 76 months. Of all the GLDs under investigation, SGLT2is were associated with the strongest reduction in NAFLD incidence, cirrhosis, and composite liver‐related events compared to other medications. TZDs were associated with a reduced risk of developing NAFLD and cirrhosis but were not significantly associated with a lower incidence of hepatocellular carcinoma. GLP‐1 RAs demonstrated a significant association with reduced liver‐related mortality.Observational data from population‐based studies suggest that GLDs such as SGLT2is are associated with beneficial long‐term liver‐related outcomes in T2D patients with NAFLD. Additional studies, including randomized controlled trials with long‐term follow‐up, are needed to confirm these findings.PROSPERO CRD442024536872. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a retrospective multicenter national study examining the risk of gastric and esophageal cancer in patients with type 2 diabetes who were receiving glucagon-like peptide receptor agonists. We used propensity score matching analysis to account for confounders. We assessed the risk of the outcomes in a seven-year timeframe. We add to the most recent literature findings that debunk the risk of cancers with their use. Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming more popular in managing type 2 diabetes mellitus (T2DM). Concerns linger over potential links to malignancies like pancreatic and thyroid cancers, requiring more research to clarify their safety profiles. Additionally, evidence suggests GLP-1 RAs may lower colorectal and pancreatic cancer risk, especially in obese and overweight individuals, indicating a protective effect beyond weight loss. Current studies leave a gap in comprehensively understanding cancer risks associated with GLP-1 RAs, which prompts further research to enhance our understanding of their overall safety. Methods: We queried the US Collaborative Network (63 health care organizations) of the TriNetX research database. Patients with T2DM were identified and divided into two cohorts: patients on GLP-1 RAs and patients not on GLP-1 RAs. We excluded tobacco use and alcohol use disorders, obese patients with a body mass index (BMI) of >25 kg/m2, and those with a family history of gastrointestinal malignancy, infectious mononucleosis, chronic gastritis, pernicious anemia, helicobacter pylori infection, or gastroesophageal reflux disease (GERD). We used a 1:1 propensity score matching (PSM) model using patients' baseline characteristics, medications, labs, and genetics. We compared the rate of gastric cancer and esophageal cancer at the seven-year mark. Results: A total of 2,748,431 patients with T2DM were identified. Of those, 6% (n = 167,077) were on a GLP-1 RA and 94% (n = 2,581,354) were not on a GLP-1 RA. After PSM, both cohorts included 146,277 patients. Patients with T2DM who were on a GLP-1 RA, compared to those who were not, had a statistically significant lower risk of both gastric cancer (0.05% vs. 0.13%, p < 0.0001) and esophageal cancer (0.04% vs. 0.13%, p < 0.0001) at the seven-year mark. Conclusion: The use of GLP-1 RAs in patients with T2DM does not significantly increase the risk of gastric or esophageal cancer. This finding supports the continued use of GLP-1 analogues as a therapeutic option in managing T2DM, considering their well-established benefits and low risk of complications. Based on the study results, these medications may even have a protective effect against these malignancies. [ABSTRACT FROM AUTHOR]

Background: Despite all the technological advances in treatment of patients with type 1 diabetes (T1D), glucose control remains suboptimal in most patients. In addition, a relatively high percentage of patients with T1D, including children, have obesity. Therefore, new interventions are required that focus their effects on weight loss, in order to help with associated insulin resistance and improve glycemic control. Summary: GLP-1 receptor agonists (GLP-1 RAs) have proven to be effective and safe in adults with T1D, showing improvement in glycemic control, body weight and cardiorenal protection. GLP-1 RAs are also approved for children with obesity (above the age of 12 years) or type 2 diabetes (above the age of 10 years). However, currently these medications are not approved for use in children with T1D. Only a few published studies have evaluated their efficacy and safety for this indication. Key Message: This review presents the rationale and experience of add-on GLP-1 RA therapy to pediatric and adolescent patients with T1D, otherwise treated, from RCTs and real-world data. Results of studies of GLP-1 RA in children with T1D are still pending, while large multicenter randomized controlled trials (RCTs) in this population are lacking. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The aim of this study was to examine contemporary trends in the use of, time to, and type of first add‐on anti‐hyperglycaemic therapy to metformin in Australia.We used the dispensing records of a 10% random sample of Pharmaceutical Benefits Scheme (PBS) eligible people. We included people aged 40 years and older initiating metformin from 1 January 2018 to 31 December 2020. Our primary outcome was first add‐on anti‐hyperglycaemic medicine within 2 years of metformin initiation. We analysed time to dispensing of first add‐on therapy. All analyses were stratified by metformin initiation year.Overall, 38 747 people aged 40 years and older initiated metformin between 2018 and 2020. Approximately one‐third (n = 12 946) of people received add‐on therapy with the proportion increasing slightly by year of metformin initiation (32.3% in 2018 to 34.8% in 2020). Amongst people with add‐on therapy following metformin initiation, sodium‐glucose cotransporter 2 inhibitor (SGLT2i) use increased from 28.8% (2018) to 35.0% (2020), and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) increased from 3.0% to 9.6%, respectively. Dipeptidyl peptidase‐4 inhibitors and sulfonylureas as first add‐on therapy decreased and insulin remained stable. One‐third of people with add‐on therapy initiated the therapy on the same day metformin was initiated, i.e. initial combination therapy.Amongst people initiating metformin from 2018 to 2020, there was an increasing proportion of SGLT2i and GLP‐1 RA being used as first add‐on therapy. However, the overall prevalence of add‐on therapy was low. Advocacy to promote add‐on therapy with cardiorenal beneficial medicines is critical to reduce type 2 diabetes morbidity and mortality. [ABSTRACT FROM AUTHOR]

GLP-1 receptor agonists, which were initially intended to treat type 2 diabetes patients, have demonstrated promise as an adjuvant therapy for type 1 diabetes (T1D). These medications can manage T1D by improving β-cell function, reducing glucose fluctuation, and providing cardioprotective effects. Recent research suggests that boosting cell proliferation and lowering apoptosis can help maintain the bulk of β-cells. Furthermore, GLP-1 receptor agonists have potent anti-inflammatory characteristics, improving immunological control and lowering systemic inflammation, both of which are critical for reducing autoimmune damage in T1D. Beyond glucose control, these agonists have neuroprotective qualities and aid in weight management. Combining these medications with insulin could significantly change how T1D is managed. The clinical data and biological mechanisms discussed in this review support the potential use of GLP-1 receptor agonists in T1D. [ABSTRACT FROM AUTHOR]

There are three components to diabetes care. These are prevention, treatment and management. Linda Nazarko explains how nurses are increasingly adopting a holistic model of diabetes care. Until recently the focus in diabetes care was on managing blood glucose – a glucocentric view. This is changing to a more holistic model aimed at prevention, treatment and management through lifestyle interventions as well as medication. An estimated 5 million people in the UK are living with diabetes, most have type 2 diabetes which is associated with obesity. Type 2 diabetes can be prevented, treated with diet and weight loss, or managed with medication. The number of people with diabetes has reached epidemic proportions. To manage diabetes well and reduce complications of poorly managed diabetes, management of the condition can no longer be restricted to endocrinologists and diabetes specialist nurses. This article provides guidance on how glucagon-like peptide-1 receptor agonists can be used in the management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

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Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for glycemic control, with many also demonstrating cardiovascular (CV) benefit, in people with type 2 diabetes (T2D). This study aimed to find a consensus on the barriers and strategies for the optimal use of GLP-1 RAs in people with T2D and high CV risk or established cardiovascular disease (CVD) in Spain. Methods: A two-round Delphi survey (53 questions) was conducted among members of four national scientific societies in Spain, including physicians experienced in the management of people with T2D. The degree of consensus was evaluated with a 7-point Likert scale, establishing consensus when ≥ 70% of the panelists agreed (6–7) or disagreed (1–2). Results: A total of 97 physicians participated in the first round (endocrinology: 34%, family and community medicine: 21%, internal medicine: 23%, and cardiology: 23%), and 96 in the second round. The main barriers identified were: therapeutic inertia and late use of GLP-1 RAs; lack of a comprehensive approach to CV risk; lack of knowledge on the usefulness of GLP-1 RAs in CVD prevention and treatment; and economic/administrative barriers. Strategies with a highest consensus included: the need to establish simple protocols that integrate awareness of CV risk monitoring; training professionals and patients; and the use of new technologies. Conclusion: Physicians identified clinical, healthcare, and economic/administrative barriers that limit the use of GLP-1 RAs in people with T2D and high CV risk or established CVD in Spain, highlighting the importance of integrating these therapies according to clinical practice guidelines. [ABSTRACT FROM AUTHOR]

Background: Obstructive Sleep Apnea (OSA) is a prevalent disorder characterized by repetitive upper airway obstructions during sleep, leading to intermittent hypoxia and sleep fragmentation. Current treatments, particularly Continuous Positive Airway Pressure (CPAP), face adherence challenges, necessitating novel therapeutic approaches. Methods: This review explores the potential of Glucagon-like Peptide-1 receptor agonists (GLP-1RA), commonly used for type 2 diabetes and obesity, in managing OSA. GLP-1RA promotes weight loss, enhances insulin sensitivity, and exhibits anti-inflammatory and neuroprotective properties, potentially addressing key pathophysiological aspects of OSA. Results: Emerging evidence suggests that these agents may reduce OSA severity by decreasing upper airway fat deposition and improving respiratory control. Clinical trials have demonstrated significant reductions in the Apnea-Hypopnea Index (AHI) and improvements in sleep quality with GLP-1 therapy. Conclusions: Future research should focus on elucidating the mechanisms underlying GLP-1 effects on OSAS, optimizing combination therapies, and identifying patient subgroups that may benefit the most. Integrating GLP-1RA into OSAS management could revolutionize treatment by addressing both the metabolic and respiratory components of the disorder, ultimately enhancing patient outcomes. [ABSTRACT FROM AUTHOR]

The increasing prevalence of obesity imposes significant health challenges, particularly in women undergoing menopause. Effective obesity management is essential to mitigate associated comorbidities and improve quality of life. The pillars of obesity treatment encompass lifestyle modifications, pharmacotherapy and surgical interventions. Pharmacotherapy may be considered for women who do not achieve adequate weight loss through lifestyle changes alone and have obesity or overweight with risk factors. Bariatric surgery is reserved for individuals with severe obesity or those with obesity-related complications. During menopause, hormonal changes contribute to weight gain and fat redistribution, complicating obesity management. Tailored treatment strategies are necessary to address the unique challenges faced by this population. The role of physicians and gynecologists is pivotal in the multidisciplinary approach to obesity management during menopause. Gynecologists are often the primary health-care providers for menopausal women and are in a unique position to offer guidance on weight management. They can provide personalized counseling, coordinate with nutritionists, endocrinologists and bariatric specialists, and monitor the effects of obesity and its treatment on reproductive health. By integrating obesity management into routine gynecological care, gynecologists can significantly impact the overall health and well-being of menopausal women. [ABSTRACT FROM AUTHOR]

Add-on of basal insulin (BI) to intensify the ongoing therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended, but it is unclear if free or fixed combination of BI and GLP-1 RA produce similar outcomes. A retrospective comparative effectiveness analysis of the add-on of glargine 300 U/mL (Gla-300) to ongoing GLP-1 RA vs. switch to fixed ratio combination of degludec and liraglutide (iDegLira) was performed. Real-world data collected in electronic medical records by 32 Italian diabetes clinics. Propensity score (PS) adjustment was applied to assess changes in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight, and BI dose after 6 months from Gla-300 or iDegLira initiation. Compared to iDegLira group (N = 260), Gla-300+GLP-1 RA group (N = 255) had older age and higher levels of HbA1c (9.1 vs. 8.9%). After 6 months, statistically significant greater FBG improvement [estimated mean difference and 95% confidence intervals: −24.05 mg/dl (−37.04; −11.06; p = 0.0003) and BI dose increase [+0.03 U/kg (95%CI 0.00; 0.06); p = 0.009] were found in the free vs. fixed combination group, although low doses of BI (0.2 U/kg) were reached in both groups. Trends of larger HbA1c and body weight reductions with the free combination were also found, without reaching the statistical significance. Although inertia in insulin initiation and titration was documented in both groups, higher benefit on FBG control was obtained with free vs. fixed combination, likely due to a better titration of BI and GLP-1 RA. • Addition of basal insulin (BI) to GLP-1 RA is a recommended intensification approach. • It is unclear if starting BI in free or fixed combination with GLP-1 RA produce similar results. • Larger benefit on fasting blood glucose was obtained with free vs. fixed combination. • A better titration of BI and GLP-1 RA was documented with the free combination. • Clinical inertia in titration was documented in both approaches. [ABSTRACT FROM AUTHOR]

Purpose: Effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in type-2 diabetes mellitus (T2DM) with or without prior heart failure (HF) have been inconsistent across cardiovascular outcome trials. This study aimed to investigate the impact of HF history at baseline on cardiovascular effects of GLP-1 RAs in T2DM. Methods: PubMed, Embase, Web of Science, and clinical trial registries were searched for randomized controlled trials (RCTs) or post hoc analyses (≥ 24 weeks) reporting HF hospitalizations and/or cardiovascular death (HHF/CVD), major adverse cardiovascular events (MACE) comprising of cardiovascular death, myocardial infarction, and stroke in adults with T2DM with or without HF history (PROSPERO:CRD42022367633). Hazard ratios (HRs) in GLP-1RAs versus placebo arms were pooled together using the generic inverse variance method in fixed-effects model. Subgroup analysis was performed. Results: We identified 5 eligible studies, pooling data retrieved from six RCTs and 48,489 individuals with T2DM. On pooled analysis, GLP1RA treatment versus placebo significantly reduced risk of HHF/CVD in only T2DM without HF history (HR = 0.84; 95%CI, 0.77–0.91; I2 = 14%; p < 0.001), but not in those with HF history (HR = 0.96; 95%CI, 0.85–1.08; I2 = 14%; p = 0.4) (p-interaction < 0.1). GLP-1RAs reduced incident HHF in T2DM with or without HF history (HR = 0.89; 95%CI, 0.80–0.98; I2 = 41%; p < 0.05) (p-interaction = 0.28). Sensitivity analysis excluding REWIND trial accentuated the impact of baseline HF history on both HHF/CVD and HHF (p-interaction < 0.05). Benefits on MACE with GLP-1RAs were consistently seen in T2DM regardless of HF history (p-interaction = 0.8). Conclusion: GLP-1RAs consistently prevented HF hospitalizations and MACE in T2DM regardless of baseline HF history, whereas significant attenuation of benefits on composite HHF/CV death were observed in those with HF history. [ABSTRACT FROM AUTHOR]

Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP-1RAs) emerged as a primary treatment for type-2 diabetes mellitus (T2DM), however, their multifaceted effects on various target organs beyond glycemic control opened a new era of treatment. We conducted a comprehensive literature search using databases including Scopus, Google Scholar, PubMed, and the Cochrane Library to identify clinical, in-vivo, and in-vitro studies focusing on the diverse effects of GLP-1 receptor agonists. Eligible studies were selected based on their relevance to the varied roles of GLP-1RAs in T2DM management and their impact on other physiological functions. Numerous studies have reported the efficacy of GLP-1RAs in improving outcomes in T2DM, with demonstrated benefits including glucose-dependent insulinotropic actions, modulation of insulin signaling pathways, and reductions in glycemic excursions. Additionally, GLP-1 receptors are expressed in various tissues and organs, suggesting their widespread physiological functions beyond glycemic control potentially include neuroprotective, anti-inflammatory, cardioprotective, and metabolic benefits. However, further scientific studies are still underway to maximize the benefits of GLP-1RAs and to discover additional roles in improving health benefits. This article sought to review not only the actions of GLP1RAs in the treatment of T2DM but also explore its effects on potential targets in other disorders. [ABSTRACT FROM AUTHOR]

Raz Muhammed HamaSalih Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Slemani, Kurdistan Region, IraqCorrespondence: Raz Muhammed HamaSalih, College of Pharmacy, University of Sulaimani, Town Campus, Slemani, Kurdistan Region, 46001, Iraq, Tel +9647700591984, Email raz.hamasalih@univsul.edu.iqBackground: Doxorubicin (DOX) is used to treat various types of cancers. However, its use is restricted by cardiotoxicity, a leading cause of morbidity and mortality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may be associated with cardioprotective properties.Purpose: This study aims to determine the protective effects of different semaglutide (SEM) doses on DOX-induced cardiotoxicity in a rat model.Methodology: Thirty-five female Wistar rats were divided into five groups. The first group received distilled water as a negative control (NC); the positive control (PC) group received distilled water plus DOX; the third group (SL) received a low dose of SEM (0.06 mg/kg) plus DOX; the fourth group (SM) received a moderate dose of SEM (0.12 mg/kg) plus DOX; and the fifth group (SH) received a high dose of SEM (0.24 mg/kg) plus DOX. Blood samples were collected on day 8 to assess serum troponin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total lipid profile, and vascular cell adhesion molecule 1 (VCAM-1). Cardiac tissue was sent for histopathological analysis.Results: DOX increased the total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), LDH, and CKP levels. Moderate and high doses of semaglutide significantly reduced serum cholesterol levels (&ast;p = 0.0199), (&ast;&ast;p = 0.0077), respectively. A significant reduction (&ast;&ast;&ast;p = 0.0013) in total body weight after treatment with SEM was observed in the SL group and a highly significant reduction (&ast;&ast;&ast;&ast;p < 0.0001) was observed in the SM and SH groups. SEM at all doses reduced CPK levels. The SL group showed a significant reduction in troponin level (&ast;p=0.0344). Serum LDH levels were reduced by all three SEM doses. The histopathological findings support the biochemical results.Conclusion: Semaglutide may possess cardioprotective properties against DOX-induced cardiotoxicity in a rat model by decreasing serum biochemical markers of cardiotoxicity.Keywords: cardioprotection, GLP-1 receptor agonists, anthracycline, rodents

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are employed extensively in the management of type 2 diabetes and obesity. However, there is a paucity of real-world data on their safety and tolerability for metabolic and nutritional adverse events in large sample populations. This study aimed to analyse the metabolic and nutritional safety signatures of different GLP-1 RAs by exploring the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: AEs data were extracted from the FDA Adverse Event Reporting System database for each GLP-1 RA from the time of its launch until the second quarter of 2023. The reported odds ratio (ROR), proportional reporting ratio (PRR), Empirical Bayesian Geometric Mean and Bayesian Confidence Propagation Neural Network were employed to identify AE signals. Results: A system organ class of metabolism and nutrition disorders was employed to filter AE reports, resulting in the identification of 10,450 reports for exenatide, 2,860 reports for liraglutide, 240 reports for albiglutide, 4,847 reports for dulaglutide, 2,905 reports for semaglutide, 1,089 reports for tirzepatide, and 13 reports for lixisenatide. Semaglutide (ROR, 3.34; 95%CI, 3.22), liraglutide (ROR, 2.78; 95%CI, 2.69), and exenatide (ROR, 2.15; 95%CI, 2.11) were associated with metabolism and nutrition disorders. The number of AE signals detected were as follows: albiglutide (n = 1), lixisenatide (n = 2), tirzepatide (n = 11), exenatide (n = 12), liraglutide (n = 16), semaglutide (n = 20), dulaglutide (n = 22). Dehydration was the most frequent AE contributing to serious outcomes for liraglutide (n = 318, 23.93%), dulaglutide (n = 434, 20.90%), semaglutide (n = 370, 25.10%) and tirzepatide (n = 70, 32.86%). The time to onset (TTO) of AE was statistically different between exenatide and the other GLP-1 RAs (p < 0.001), and the Weibull parameters for dehydration for liraglutide, dulaglutide, and semaglutide analyses all showed an early failure-type profile. Conclusion: Our study suggests that exenatide, liraglutide, and semaglutide are more susceptible to metabolic and nutritional AEs than other GLP-1 RAs. Liraglutide, dulaglutide, semaglutide, and tirzepaptide's potential to induce dehydration, necessitates special attention. Despite certain deficiencies, GLP-1 RAs have considerable potential for the treatment of eating disorders. [ABSTRACT FROM AUTHOR]

This article presents a study conducted in China that explores the treatment satisfaction of individuals with type 2 diabetes who were treated with dulaglutide, a medication used to lower blood sugar levels. The study found that participants reported high levels of satisfaction with dulaglutide, indicating that it may be a beneficial treatment option for individuals with type 2 diabetes in the Chinese population. Factors such as longer treatment duration, lower HbA1c levels, weight loss, absence of adverse events, and the convenience and ease of use of the medication were associated with higher treatment satisfaction. The study suggests that high treatment satisfaction may lead to improved adherence and better clinical outcomes for individuals with type 2 diabetes. [Extracted from the article]

Summary Pregnancy during or soon after treatment with weight loss medication, particularly glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), is contraindicated due to potential teratogenicity. The aim of this scoping review is to investigate what is known about the use of weight loss medication in women of childbearing age in relation to reproductive health outcomes, focusing on the three medications licenced in the United Kingdom at the time of the search. A systematic search of studies that assessed reproductive health outcomes in women taking either orlistat, liraglutide or semaglutide was undertaken in July 2023 and updated in January 2024 across MEDLINE, Embase, CINAHL, Scopus, ClinicalTrials.gov, PROSPERO, Epistemonikos and OpenGrey. Studies focused on polycystic ovarian syndrome, diabetes or animals were excluded. Titles and abstracts were screened, and data from included articles were extracted. After removal of duplicates, 341 titles remained, of which 318 were excluded. Of the final 18 articles included, there were five interventional trials, one retrospective case‐control study, six narrative reviews, two systematic reviews, three systematic review protocols and one registry protocol yet to start recruitment. All five interventional trials involved orlistat given preconceptionally, showing no improvement in live birth rate, despite improvement in reproductive hormone levels. There were no studies with primary data about GLP‐1 RAs. There were no qualitative studies. There is an absence of primary data about the role of GLP‐1 RAs on the reproductive health of women of childbearing age without polycystic ovarian syndrome. Future research should explore short‐ and long‐term effects on reproductive health, pregnancy outcomes and experiences. [ABSTRACT FROM AUTHOR]

Our understanding of type 2 diabetes (T2D) has evolved dramatically. Advances have upended entrenched dogmas pertaining to the onset and progression of T2D, beliefs that have prevailed from the early era of diabetes research—and continue to populate our medical textbooks and continuing medical education materials. This review article highlights key insights that lend new governing principles for gold standard management of T2D. From the historical context upon which old beliefs arose to new findings, this article outlines evidence and perspectives on beta cell function, the underlying defects in glucoregulation, the remediable nature of T2D, and, the rationale supporting the shift to complication-centric prescribing. Practical approaches translate this rectified understanding of T2D into strategies that fill gaps in current management practices of prediabetes through late type 2 diabetes. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is involved in a range of central and peripheral pathways related to appetitive behavior. Hence, this study explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on substance and behavioral addictions, including alcohol, caffeine, nicotine, cannabis, psychostimulants, compulsive shopping, and sex drive/libido. Data were collected from various social platforms. Keywords related to GLP-1 RAs and substance/behavioral addiction were used to extract relevant comments. The study employed a mixed-methods approach to analyze online discussions posted from December 2019 to June 2023 and collected using a specialized web application. Reddit entries were the focus here due to limited data from other platforms, such as TikTok and YouTube. A total of 5859 threads and related comments were extracted from six subreddits, which included threads about GLP-1 RAs drugs and associated brand names. To obtain relevant posts, keywords related to potential substance use and compulsive behavior were selected. Further analysis involved two main steps: (1) manually coding posts based on users' references to the potential impact of GLP-1 RAs on substance use and non-substance habits, excluding irrelevant or unclear comments; (2) performing a thematic analysis on the dataset of keywords, using AI-assisted techniques followed by the manual revision of the generated themes. Second, a thematic analysis was performed on the keyword-related dataset, using AI-assisted techniques followed by the manual revision of the generated themes. In total, 29.75% of alcohol-related; 22.22% of caffeine-related; and 23.08% of nicotine-related comments clearly stated a cessation of the intake of these substances following the start of GLP-1 RAs prescription. Conversely, mixed results were found for cannabis intake, and only limited, anecdotal data were made available for cocaine, entactogens, and dissociative drugs' misuse. Regarding behavioral addictions, 21.35% of comments reported a compulsive shopping interruption, whilst the sexual drive/libido elements reportedly increased in several users. The current mixed-methods approach appeared to be a useful tool in gaining insight into complex topics such as the effects of GLP-1 RAs on substance and non-substance addiction-related disorders; some GLP-1 RA-related mental health benefits could also be inferred from here. Overall, it appeared that GLP-1 RAs may show the potential to target both substance craving and maladaptive/addictive behaviors, although further empirical research is needed. [ABSTRACT FROM AUTHOR]

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management. [ABSTRACT FROM AUTHOR]

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin‐angiotensin system with angiotensin‐converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium‐glucose cotransporter‐2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon‐like peptide‐1 (GLP‐1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase‐4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD. [ABSTRACT FROM AUTHOR]

Aims: To compare weight loss outcomes between patients starting semaglutide who had previously been on another anti‐obesity medication (AOM) compared to those who were AOM‐naïve. Materials and Methods: We performed a retrospective study in patients with overweight or obesity taking semaglutide for weight loss for a duration of 3 to 12 months. Our primary endpoint was assessment of percentage of total body weight loss (TBWL) in patients who started semaglutide as their first AOM (AOM‐naïve) compared to those who started semaglutide and had previously taken another AOM (non‐AOM‐naïve). The secondary outcome was a comparison of the proportions of patients achieving ≥5%, ≥10%, ≥15% and ≥20% TBWL between the groups. Our endpoints were analysed using independent t‐tests and ANOVA/ANCOVA for continuous variables and Pearson's test for categorical variables. Results: This study included 305 patients. Outcomes of semaglutide treatment were superior in AOM‐naïve patients (n = 231) compared to non‐AOM‐naïve patients (n = 74) at 3 (6.3% vs. 3.8%), 6 (10.6% vs. 6.7%), 9 (14.0% vs. 9.1%) and 12 months (14.3% vs. 10.6%; p < 0.0001 at 3, 6 and 9 months, and p = 0.01 at 12 months). A greater proportion of patients in the AOM‐naïve group achieved a TBWL ≥ 15% (48% vs 21%; p = 0.02) and ≥20% (27% vs 4% p < 0.01) at 12 months. Conclusion: The use of semaglutide in patients with previous intake of other AOMs was associated with inferior weight loss outcomes in comparison to patients who were AOM‐naïve. [ABSTRACT FROM AUTHOR]

Summary: UK guidelines recommend liraglutide 3.0 mg in adults treated within specialist weight management services with BMI ≥35 kg/m2, prediabetes and high cardiovascular disease risk. We aimed to clinically evaluate liraglutide 3.0 mg in specialist weight management services. We evaluated liraglutide 3.0 mg in weight management services at Guys and St Thomas' NHS Foundation Trust. Objective body weight (BW) was measured at baseline and 4 months, allowing classification as 'responders' (≥5% BW reduction) and 'non‐responders' (<5% BW reduction). One hundred and twenty‐one patients were evaluated. At 4 months, 76.0% attended follow‐up (82.6% responders, 17.4% non‐responders); BW (−8.6 kg, 95%CI:‐9.8, −7.4 kg), BMI (−3.2 kg/m2, 95%CI: −3.6, −2.8) and %‐BW (−6.6%, IQR: −8.8%, −5.2%) significantly reduced. In responders, HbA1c reduced by −5.0 mmol/mol (IQR: −7.0. −4.0 mmol/mol). In responders BW continued to reduce up to 12 months (4 m: −10.2 kg, p <.0001; 6 m: −15.6 kg, p <.0001; 9 m: −16.5 kg, p <.0001; 12 m: −16.7 kg, p <.01). Those of Black African and Caribbean ethnicity experienced less BW loss than those of white ethnicity (4.12 kg, p =.017) and had a greater attrition rate. In adults with obesity and prediabetes who are treated within specialist weight management services, liraglutide 3.0 mg reduces BW and HbA1c. Those of Black African and Caribbean ethnicity experienced less BW reduction and greater attrition at 4 months. Further evaluation of the ethnic differences in response to obesity pharmacotherapy is required. [ABSTRACT FROM AUTHOR]

Summary: Hypothalamic obesity does not respond well to conventional interventions for obesity. GLP‐1 receptor agonists have mechanisms independent of the hypothalamus which may be potentially beneficial for managing hypothalamic obesity. This systematic review summarizes the efficacy and safety of GLP‐1 receptor agonists use in hypothalamic obesity. A PRISMA‐compliant systematic review was performed. Data was extracted from included studies and analysed based on change in weight, body mass index, glycaemic control, satiety, and safety profile with GLP‐1 receptor agonist use. Ten studies comprising 5 case reports, 4 case series and 1 randomized‐controlled trial included 54 patients (24 males, 30 females) with mean age of 25.2 (range 13–71) years with hypothalamic obesity who had received GLP‐1 receptor agonists (exenatide = 48, liraglutide = 5 and dulaglutide = 1) over a mean duration of treatment of 12 (range 3–51) months. Mean weight reduction of 7.4 (SD 7.92) kg was observed in patients in whom weight was reported, with 85.7% of patients experiencing weight loss. All patients on liraglutide had weight reduction post‐therapy. The sole trial had reported a non‐significant reduction in BMI post‐exenatide. Glycaemic control had either improved/maintained in all patients in whom this was measured. The main side effects of GLP‐1 receptor agonist in individuals with hypothalamic obesity were nausea and vomiting; there were no major safety concerns. Based on limited published experience, GLP‐1RA may be effective and safe for weight control in hypothalamic obesity, with the added benefit of improved glycaemic control in those with concurrent diabetes mellitus. [ABSTRACT FROM AUTHOR]

Although good glycemic control in patients with type 2 diabetes (T2D) can prevent cardiovascular complications, many diabetic patients still have poor optimal control. A new class of antidiabetic drugs (e.g., glucagon-like peptide-1-GLP-1 receptor agonists, sodium-glucose co-transporters-SGLT2 inhibitors), in addition to the low hypoglycemic effect, exert multiple beneficial effects at a metabolic and cardiovascular level, through mechanisms other than antihyperglycemic agents. This review aims to discuss the effects of these new antidiabetic drugs, highlighting cardiovascular and metabolic benefits, through the description of their action mechanisms as well as available data by preclinical and clinical studies. Moreover, new innovative tools in the T2D field will be described which may help to advance towards a better targeted T2D personalized care in future. [ABSTRACT FROM AUTHOR]

Purpose: Metformin has been the first-line treatment for type 2 diabetes mellitus as monotherapy or concomitantly with other glucose-lowering therapies due to its efficacy, safety, and affordability. Recent studies on the cardioprotective and renoprotective benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have influenced guidelines on diabetes management to consider these newer agents as alternative first-line therapies. This paper explores the literature supporting the use of these newer medications alone as a first-line agent in place of metformin. Methods: A review of citations from the most recent guidelines along with a literature search via PubMed was completed to review (1) what, historically, made metformin first-line (2) if newer agents' benefits remain when used without metformin (3) how newer agents compare against metformin when used without it. Results: Evaluation of the historical literature was completed to summarize the key findings that support metformin as a first-line therapy agent. Additionally, an assessment of the literature reveals that the benefits of these two newer classes are independent of concomitant metformin therapy. Finally, studies have demonstrated that these newer agents can be either non-inferior or sometimes superior to metformin when used as monotherapy. Conclusion: GLP-1 RA and SGLT-2i can be considered as first line monotherapies for select patients with high cardiovascular risks, renal disease, or weight loss requirements. However, pharmacoeconomic considerations along with lesser long-term safety outcomes should limit these agents' use in certain patients as the management of diabetes continues to transition towards shared-decision making. [ABSTRACT FROM AUTHOR]

Simple Summary: This is a retrospective national cohort study that aims to assess the risk of developing pancreatic cancer in patients with type 2 diabetes mellitus (T2DM) who are being treated with Glucagon-like Peptide-1 receptor agonists. We exclude patients with multiple risk factors for pancreatic cancer from our study. We retrospectively follow the patients for 7 years after the initiation of treatment. Current evidence is controversial about their use and the possible risk of pancreatic disease. We aim to revoke the association of pancreatic cancer with their use in support of their continued use due to their beneficial cardiovascular and renal effects. Background: GLP-1 RAs are widely used for T2DM treatment due to their cardiorenal and metabolic benefits. This study examines the risk of pancreatic cancer with GLP-1 RA use in patients with T2DM. Methods: We analyzed TriNetX's deidentified research database using the U.S. Collaborative Network comprising 62 healthcare organizations across the U.S.A. Patients with T2DM were split into two cohorts: one receiving GLP-1 RAs, and one not receiving GLP-1 RAs. We excluded patients with known risk factors for pancreatic cancer, including pancreatic cysts, a personal or family history of BRCA1, BRCA2, CDKN2A, KRAS, MEN1, MLH1, MSH2, NOTCH1, PALB2, PMS2, and PRSS1S genes, family history of pancreatic cancer, and VHL syndrome. Using a 1:1 propensity score-matching model based on baseline characteristics and comorbidities, we created comparable cohorts. We then compared the rate of pancreatic cancer between the two cohorts at a 7-year interval. Results: Out of 7,146,015 identified patients with T2DM, 10.3% were on a GLP-1 RA and 89.7% were not. Post-PSM, 721,110 patients were in each group. Patients on GLP-1 RAs had a 0.1% risk compared to a 0.2% risk of pancreatic cancer in the 7-year timeframe. Conclusion: The use of GLP-1 RAs in patients with type 2 diabetes mellitus (T2DM) does not appear to substantially elevate the risk of pancreatic cancer; in fact, it may potentially exert a protective effect. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease is a chronic condition that often copresents with type 2 diabetes and obesity. Glucagonlike peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. Although the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight into the antiatherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent preclinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, which include systemic inflammation, monocyte recruitment, proinflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development. [ABSTRACT FROM AUTHOR]

Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation. [ABSTRACT FROM AUTHOR]

BackgroundType 2 diabetes mellitus (T2DM) is linked to a heightened likelihood of experiencing fractures. It is crucial to ascertain whether medications used to lower blood sugar levels can elevate the risk of fractures. We aimed to investigate and compare the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA), Dipeptidyl Peptidase-4 Inhibitors (DPP-4i), and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) on the fracture risk in patients with T2D in the real world.MethodsA network meta-analysis conducted an inclusive literature search in PubMed, Scopus, Web of Science, and Cochrane Library to select appropriate population-based cohort studies that investigated the risk of bone fractures of (GLP-1RA), (DPP-4i) or (SGLT-2i) in the real world. A network meta-analysis (NMA) was performed using R software to investigate the risk of total fractures as a primary outcome among patients who used (GLP-1RAs), (SGLT-2i) or (DPP-4i) versus each other or other glucose-lowering medications (GLMs). The odds ratio (OR) and 95% confidence interval (CI) were summarized overall network and for each pairwise direct and indirect comparison. The surface under the cumulative ranking curve (SUCRA) with the P-scores was calculated for each treatment in the network meta-analysis to detect their cumulative ranking probabilities in lowering the risk of total fractures.ResultsIn our NMA, we identified a set of 13 population-based cohort studies comprising a total of 1,064,952 patients. The risk of fracture was identified with the follow-up duration for each class. We found a significant decrease in the fracture risk by about 87% associated with patients who used SGLT2 inhibitors in combination with other glucose-lowering medications, followed by SGLT2 inhibitors alone by about 67%, then GLP-1 receptor agonists by about 60%, and at last DPP-4 inhibitors by about 55%.ConclusionOur study’s collective findings suggest a significant association of the low risk of fracture with the use of SGLT2i with other GLMs combination, SGLT2i alone, GLP-1RA, and DPP-4i, respectively. This population-based analysis offers the best available evidence and might be helpful for clinicians in the decision of the most suitable T2DM treatment strategies, especially for elderly type 2 diabetic patients, as they may be safe in terms of fracture.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023448720.

BackgroundThe escalating global economic burden of ischemic stroke poses a significant public health challenge amid global aging trends. The broad therapeutic efficacy of new antidiabetic drugs may offer new options in the prevention and treatment of ischemic stroke. Consistent conclusions regarding the relationship between novel antidiabetic agents and the risk of ischemic stroke remain elusive, and the causal relationship deserves further investigation.Materials and methodsThree novel antidiabetic drug targets were selected, and cis-expression quantitative trait loci (cis-eQTL) were screened as instrumental variables. Genetic association data for ischemic stroke were obtained from the Genome-wide Association Study (GWAS) database. Mendelian randomization (MR) analysis, facilitated by R software, calculated MR estimates for each single nucleotide polymorphism (SNP), and meta-analysis was performed using five methods. To ensure robustness, sensitivity analyses, heterogeneity analyses, horizontal pleiotropy analyses, and co-localization analyses were conducted for significant MR associations.ResultsThree eQTLs for antidiabetic drug genes served as instrumental variables, utilizing a GWAS dataset comprising 34,217 cases and 406,111 controls for ischemic stroke. Genetic variants in glucagon-like peptide-1 receptor agonists (GLP-1 RA) targets exhibited a positive correlation with ischemic stroke risk (OR 1.06, 95% CI 1.04–1.08, P = 0.000), while genetic variation in dipeptidyl peptidase 4 inhibitors (DPP-4i) targets showed a negative association with ischemic stroke risk (OR 0.93, 95% CI 0.89–0.97, P = 0.003). Sensitivity analyses supported robust conclusions, revealing no heterogeneity or horizontal pleiotropy.ConclusionThis study found that GLP-1 RA and DPP-4i were associated with an increased risk of ischemic stroke by MR analysis. Although sensitivity analyses provide support for this result, it contradicts previous knowledge. Therefore, the results of this study still need to treated with caution. Updated and more in-depth GWAS data and high-quality real-world data are expected to validate the results.

Background: To evaluate the weight loss outcomes of the large US cohort of patients undergoing endoscopic sleeve gastroplasty (ESG) with or without concomitant anti-obesity (AOM) use. Methods: We performed a retrospective analysis of adult patients who underwent ESG from seven different sites, from January 1, 2020 to November 30, 2022. Percent total body weight loss (%TBWL) and %excess weight loss (%EWL) were calculated based on baseline weight at the procedure. Medication use was considered if the subject received a prescribed AOM during the study period. SPSS (version 29.0) was used for statistical analyses. Results: A total of 1506 patients were included (1359 (90.2 %) no AOM use and 147 (9.8 %) AOM use). Patients who were on an active AOM at the time of the procedure had a significantly lower TBWL% as compared to patients not on AOMs at 6 months. At the 24-month visit, patients who were prescribed AOMs after the 12-month visit had a significantly higher TBWL% and EWL% as compared to patients who were on active AOM at the time of the procedure. There was no significant difference between classes of medications at any time point, however, patients on a GLP-1RA had a trend towards improved weight loss at 18 and 24 months. Conclusion: In this large, real-world cohort of patients from the United States, data signal that with the use of pharmacotherapy at the appropriate time, patients can achieve optimal results.

ABSTRACT Obesity is a prevalent chronic disease. The management of extreme obesity – i.e., body mass index (BMI) ≥ 50 kg/m2 or obesity class IV and V – is still far from ideal. Individuals with extreme obesity have a high risk of surgical complications, mortality, comorbidities, and reduced weight loss following bariatric surgery. Although lifestyle changes and anti-obesity medications are recommended for all patients with extreme obesity as adjuvants to weight loss, these measures are less effective than bariatric surgery. As a first step, sleeve gastrectomy or an inpatient very-low-calorie diet should be incentivized to enhance weight loss before definitive surgery. Although malabsorptive procedures lead to greater weight loss, they are associated with an increased risk of early complications and malnutrition. Nonstandard techniques employed in clinical trial protocols, such as transit bipartition, may be performed as they maintain a weight loss potency comparable to that of the classic duodenal switch but with fewer nutritional problems. Anatomical causes should be investigated in patients with postoperative suboptimal clinical response or recurrent weight gain. In these cases, the initiation of anti-obesity drugs, endoscopic therapies, or a conversion procedure might be recommended. More studies are needed to address the specific population of patients with extreme obesity, as their outcomes are expected to be distinct from those of patients with lower BMI.

Summary: Background: We examined the real-world comparative safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. other newer anti-glycemic medications (dipeptidyl peptidase-4 inhibitors [DPP4i], glucagon-like peptide-1 receptor agonists [GLP1a]) in patients with and without chronic kidney disease (CKD). Methods: Among US Veterans with diabetes receiving care from the Veterans Affairs (VA) healthcare system over 2004–19, we identified incident users of SGLT2i vs. DPP4i vs. GLP1a monotherapy. In analyses stratified by CKD status, defined by estimated glomerular filtration rate and albuminuria, we examined associations of SGLT2i vs. DPP4i vs. GLP1a use with risk of infection-related (primary outcome) and genitourinary infection hospitalizations (secondary outcome) using multivariable Cox models. Findings: Among 92,269 patients who met eligibility criteria, 52% did not have CKD, whereas 48% had CKD. In the overall and non-CKD cohorts, compared to DPP4i use, SGLT2i use was associated with lower infection-related hospitalization risk (HRs [95% CIs] 0.74 [0.67–0.81] and 0.77 [0.67, 0.88], respectively), whereas GLP1a use demonstrated comparable risk. However, in the CKD cohort SGLT2i and GLP1a use were each associated with lower risk (HRs [95% CIs] 0.70 [0.61, 0.81] and 0.91 [0.84, 0.99], respectively). Propensity score-matched analyses showed similar findings in the non-CKD and CKD cohorts. In the overall, non-CKD, and CKD cohorts, SGLT2i use was associated with lower genitourinary infection hospitalization risk whereas GLP1a use showed comparable risk vs. DPP4i use. Interpretation: In a national cohort of Veterans with diabetes, compared with DPP4i use, SGLT2i use was associated with lower infection-related and genitourinary infection hospitalization risk. Funding: VA Health Services Research and Development, USA.

Chuanhao Xiong,1,&ast; Jingzhu Wu,1,&ast; Yuhang Ma,1,&ast; Na Li,1 Xuejiao Wang,1 Yao Li,2 Xiaoying Ding1 1Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoying Ding, Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, People’s Republic of China, Email xiaoyingding@126.com Yao Li, Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, People’s Republic of China, Email yao.li@shsmu.edu.cnPurpose: Polycystic ovary syndrome (PCOS) is a frequent cause of infertility in reproductive-age women. Our work aims to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on gut microbiota, with metabolic parameters including body weight and the hormone profile in PCOS.Patients and Methods: Dehydroepiandrosterone (DHEA)-induced PCOS mice were established and then treated with two GLP-1RAs: liraglutide and novel form semaglutide for four weeks. Changes in body weight and metabolic parameters were measured. Fecal samples were collected and analyzed using metagenomic sequencing.Results: Liraglutide and semaglutide modulated both alpha and beta diversity of the gut microbiota in PCOS. Liraglutide increased the Bacillota-to-Bacteroidota ratio through up-regulating the abundance of butyrate-producing members of Bacillota like Lachnospiraceae. Moreover, liraglutide showed the ability to reverse the altered microbial composition and the disrupted microbiota functions caused by PCOS. Semaglutide increased the abundance of Helicobacter in PCOS mice (p < 0.01) which was the only bacteria found negatively correlated with body weight. Moreover, pathways involving porphyrin and flavonoids were increased after semaglutide intervention.Conclusion: Liraglutide and semaglutide improved reproductive and metabolic disorders by modulating the whole structure of gut microbiota in PCOS. The greater efficacy in weight loss compared with liraglutide observed after semaglutide intervention was positively related with Helicobacter. The study may provide new ideas in the treatment and the underlying mechanisms of GLP-1RAs to improve PCOS.Keywords: PCOS, GLP-1 receptor agonists, gut microbiota, metabolism

Introduction and Objective: Obesity, as one of the diseases of civilization, has become a significant problem in our time. Although the first ways of treating it appeared many years ago, pharmacotherapy of obesity has been developing significantly in recent years. The purpose of this article is to introduce the obesity drugs that have been registered for the treatment of obesity in Poland and to describe a new substance called tirzepatide, which, although it does not have such registration yet, is one of the most promising medications of the near future. State of Knowledge: Obesity is an urgent and growing problem. In Poland, about 25% of adults are obese, and this number is increasing over the years. [1] [2] In Europe, four drugs belonging to three different groups are registered for the treatment of obesity: orlistat, a combined drug that includes naltrexone hydrochloride and bupropion hydrochloride, liraglutide, and semaglutide. Although the last drug achieves the best results in studies and is the substance most favored by doctors and patients, there is still much research on new substances and formulations, which would bring even better results and health benefits. One of these substances is tirzepatide, a drug registered in 2022 for the treatment of type 2 diabetes. Summary: Nowadays in Poland, there are four drugs registered for obesity. Two of them are representatives of the group of GLP-1 analogues. Pharmacological treatment of obesity has good results and is a relatively safe process that should be implemented in conjunction with lifestyle changes. The fifth substance described in this article is tirzepatide, a drug that, although not registered for the treatment of obesity yet, is for now one of the most promising substances among the new drugs. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide 1 receptor agonists (GLP-1) elicit substantial reductions in glycemia and body weight in people with type 2 diabetes (T2D) and obesity, but existing data suggest the therapy must be continued indefinitely to maintain clinical improvements. Given the high cost and poor real-world persistence of GLP-1, an effective therapy that enables deprescription with sustained clinical improvements would be beneficial. Thus, the purpose of this real-world study was to assess the effect of GLP-1 deprescription on glycemia and body weight following co-therapy with carbohydrate restricted nutrition therapy (CRNT) supported via telemedicine in a continuous remote care model. Methods: A retrospective, propensity score matched cohort study among patients with T2D at a telemedicine clinic was conducted. Patients in whom GLP-1 were deprescribed (DeRx; n = 154) were matched 1:1 with patients in whom GLP-1 were continued (Rx). HbA1c and body weight at enrollment in clinic (pre-CRNT), at date of deprescription or index date (derx/ID), and at 6 and 12 months (m) post-derx/ID were utilized in this study. Results: No regression in weight was observed following deprescription with > 70% maintaining ≥ 5% weight loss 12 m post-derx/ID. HbA1c rose 6 m and 12 m post-derx/ID in both DeRx and Rx cohorts, but most patients maintained HbA1c < 6.5%. HbA1c and body weight measured 6 m and 12 m following derx/ID did not significantly differ between cohorts and were improved at derx/ID and at follow-up intervals compared to pre-CRNT. Conclusion: These results demonstrate the potential for an alternate therapy, such as CRNT supported via telemedicine, to enable maintenance of weight loss and glycemia below therapeutic targets following discontinuation of GLP-1 therapy. [ABSTRACT FROM AUTHOR]

Overloaded glucose levels in several metabolic diseases such as type 2 diabetes (T2D) can lead to mitochondrial dysfunction and enhanced production of reactive oxygen species (ROS). Oxidative stress and altered mitochondrial homeostasis, particularly in the cardiovascular system, contribute to the development of chronic comorbidities of diabetes. Diabetes-associated hyperglycemia and dyslipidemia can directly damage vascular vessels and lead to coronary artery disease or stroke, and indirectly damage other organs and lead to kidney dysfunction, known as diabetic nephropathy. The new diabetes treatments include Na+-glucose cotransporter 2 inhibitors (iSGLT2) and glucagon-like 1 peptide receptor agonists (GLP-1RA), among others. The iSGLT2 are oral anti-diabetic drugs, whereas GLP-1RA are preferably administered through subcutaneous injection, even though GLP-1RA oral formulations have recently become available. Both therapies are known to improve both carbohydrate and lipid metabolism, as well as to improve cardiovascular and cardiorenal outcomes in diabetic patients. In this review, we present an overview of current knowledge on the relationship between oxidative stress, mitochondrial dysfunction, and cardiovascular therapeutic benefits of iSGLT2 and GLP-1RA. We explore the benefits, limits and common features of the treatments and remark how both are an interesting target in the prevention of obesity, T2D and cardiovascular diseases, and emphasize the lack of a complete understanding of the underlying mechanism of action. [Display omitted] • T2D induces mitochondrial dysfunction and oxidative stress, fostering chronic comorbidities. • iSGLT2 and GLP-1RA enhance glycemic, carbohydrate, and lipid control in T2D. • iSGLT2 and GLP-1RA prevent cardiovascular, kidney diseases, and death. • iSGLT2 and GLP-1RA ease mitochondrial function, oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Summary: Type 2 diabetes (T2D), obesity, and nonalcoholic fatty liver disease/nonalacoholic steatohepatitis (NAFLD/NASH) share mutual causalities. Medications that may offer clinical benefits to all three conditions are being developed. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are approved for the management of T2D and obesity and there is great interest in evaluating higher doses of available GLP‐1RAs and developing novel GLP‐1RA‐based co‐agonists to provide greater reductions in glycated hemoglobin (HbA1c) and body weight as well as modifying NAFLD/NASH complications in clinically meaningful ways. High‐dose GLP‐1RAs and multi‐hormonal strategies including GLP‐1R agonism have either already been approved or are in development for managing T2D, obesity, or NASH. We provide a mechanistic outline with a detailed summary of the available clinical data and ongoing trials that are adjudicating the impact of high‐dose GLP‐1RAs, unimolecular, and multimolecular GLP‐1R‐based co‐agonists in populations living with T2D, obesity, or NASH. The available trial findings are aligned with preclinical observations, showing clinical efficacy and safety thus providing optimism for the expansion of GLP‐1R‐based drug classes for managing the triad of T2D, obesity and NASH. Development, access, and wide‐spread utilization of these new therapeutic approaches will offer important opportunities to markedly improve the collective global burden of T2D, obesity, and NASH. [ABSTRACT FROM AUTHOR]