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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]

From clinical trials and observational data, oral semaglutide has proven to be the most effective second-line oral therapy for the management of patients with type 2 diabetes. This review aims to describe the perspective of an Italian expert panel that addressed the potential challenges arising during the use of oral semaglutide in the free-living conditions of routine clinical care. A group of Italian experts discussed and generated insights into the use of oral semaglutide in clinical practice. Key topics included the effectiveness of oral semaglutide in clinical practice, the positioning of the agent to optimize the treatment benefits, the possibility to adopt flexibility in the administration schedule, critical issues encountered, the role of patient communication and information in the importance of dose escalation and management of adverse events. Available data on efficacy and effectiveness of oral semaglutide from randomized clinical trials and real-world studies were reported, along with factors that determine tolerability and persistence on treatment. The debate over a fixed versus a flexible dosing schedule was critically addressed, providing anecdotical clues from a small case series and a real-world database. Additionally, a set of recommendations for clinicians to consider when prescribing oral semaglutide and during the process of patient monitoring were provided. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

On March 14, 2024, after more than 25 years of intense research and a long series of failures, the Food and Drug Administration approved resmetirom as first drug for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis (now Metabolic-Associated Steatotic Liver Disease – MASLD). The present review covers this difficult process, finally providing a drug to complement lifestyle intervention, that has long been the sole approved therapeutic intervention. However, the availability of a drug shown to reduce disease progression in advanced stages of diseases opens a series of questions that deserve even more intense research. How to continue ongoing trials? How to generate an appropriate use of resmetirom in the community, limiting treatment according to predefined criteria and according to individual risk assessment? How to guarantee that both hepatic and non-hepatic comorbidities are appropriately targeted? How to define cost-effective strategies that might prevent the generation of unacceptable differences within the population, given the high costs of novel drugs and the extremely high numbers of candidates to treatment? Only a close surveillance of drug use in the real world, generated by insurance databases and national healthcare system registries, might provide adequate answers to these compelling questions. [ABSTRACT FROM AUTHOR]

AbstractContextObjectiveMethodsResultsConclusionsPolycystic ovary syndrome (PCOS) is an endocrine gynaecological disorder that affects many women of childbearing age.To evaluate the efficacy and safety of glucose-like peptide-1 receptor agonists for obese women with PCOS.We searched the PubMed, Embase, WOS, and Cochrane Libarary databases up to June 2023. Studies were eligible if they were randomised controlled trials (RCTs) comparing GLP-1RAs against any other treatments for patients with PCOS.Overall, a total of 8 RCTs were included in this review, 7 of the RCTs compared GLP-1RAs with metformin, and 1 RCT compared GLP-1Ras with dapagliflozin. Compared with control group, GLP-1RAs were more effective at improving insulin sensitivity, reducing BMI, and resulting in a smaller waist circumference.GLP-1RAs may be a good option for obese women with PCOS, especially those with insulin resistance. However, high-quality studies are also needed in the future to assess the efficacy of GLP-1RAs in women with PCOS. [ABSTRACT FROM AUTHOR]

• Women with type 2 diabetes and ethnic minorities remain underrepresented across multiple GLP-1RA cardiovascular outcome trials. • GLP-1 receptor agonists significantly reduced MACE in both males and females with type 2 diabetes, among Asians and Whites, and in Asia and Europe. • There was no statistical difference in the reduction of MACE by GLP-1RAs among Blacks and Hispanics. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been pivotal in the management of type 2 diabetes mellitus (T2DM) and in the reduction of major adverse cardiovascular events (MACE). Notably, large cardiovascular outcomes trials (CVOTs) demonstrate significant disparities in inclusion, based on sex, race, ethnicity, and geographical regions. We examined the impact of GLP-1RA on MACE in patients with or without T2DM, based on sex, race, ethnicity, and geography. A literature search for placebo controlled randomized controlled trials on GLP-1RA treatment was conducted. Thorough data extraction and quality assessment were carried out, focusing on key outcome, and ensuring a robust statistical analysis using a random effects model to calculate log odds ratio (OR) with 95% confidence intervals (CIs). A total of 8 CVOTs comprising 71,616 patients were included. Compared with placebo, GLP-1RAs significantly reduced MACE in both sexes (females: logOR -0.19, (95% CI, -0.28 to -0.10), p < 0.01) versus (males: logOR -0.17, (95% CI, -0.23 to -0.10), p < 0.01), (p interaction NS), and among Asians (logOR -34 (95% CI, -0.53 to -0.15), p < 0.01), and Whites (logOR -17 (95% CI, -0.25 to -0.09), p < 0.01), with no difference in MACE among Blacks and Hispanics. Odds of MACE were also reduced in Asia (logOR -31 (95% CI, -0.50 to -0.11), p < 0.01), and Europe (logOR -27 (95% CI, -0.40 to -0.13), p < 0.01), but there was no statistical difference in MACE in North America and Latin America. Significant reductions in MACE with GLP-1RA treatment were demonstrated between both sexes and across certain ethnicities and certain geographical regions. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown efficacy in the treatment of metabolic disease-related complications, partially attributable to their anti-inflammatory properties. However, the specific cell types and pathways involved in these effects were not fully understood. A recent study by Wong et al. demonstrated the importance of the brain GLP-1R in mediating the anti-inflammatory effects of GLP-1RAs in Toll-like receptor and sepsis-mediated inflammation. In this discussion, we review the existing literature on the action of GLP-1RAs in inflammation and explore the implications of these recent findings. [ABSTRACT FROM AUTHOR]

Introduction: Lymphedema is a major public health issue for many women undergoing breast cancer treatment. Although weight loss has been reported to be beneficial in the treatment of lymphedema, no studies to date have examined the use of GLP-1RAs for the treatment of secondary lymphedema. This case report describes a patient who experienced significant resolution of her breast cancer-related lymphedema after initiation of a GLP-1RA for weight loss. Main symptoms and/or important clinical findings: Nine months postoperatively the patient developed arm swelling and disability. While on adjuvant chemo and hormonal therapy, her weight increased dramatically and peaked 4 years later. Corresponding to her weight gain was significant worsening of her symptoms. The main diagnoses, therapeutic interventions, and outcomes: Due to adjuvant cancer-related weight gain and inability to lose weight with diet and exercise, she was referred for evaluation and diagnosed with lymphedema. The patient started treatment with a Glucagon-like peptide 1 receptor agonist and lost 24% of her body weight over the next 13 months. The improvement in her lymphedema mirrored her weight loss. Her limb volume difference dropped from 10.3% down to 3.4% and she no longer required a compression garment. Her imaging demonstrated return of lymphatic pumping and she experienced a significant improvement in quality of life, assessed by a validated lymphedema-specific patient reported outcome (PROM). She remains on hormonal therapy, no longer needs compression and is back to regular exercise without impairment. Conclusions: GLP-1 RAs provide a potential medical option for many patients struggling with weight gain and lymphedema. We have observed by all objective measures a significant reduction in lymphedema and the elimination of compression in the case presented as a direct result of GLP-1 RA. This may also reduce a patient's BMI to the point where they become a good candidate for lymphovenous bypass or vascularized lymph node transplant when indicated. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a significant risk factor for stroke. Nevertheless, the evidence supporting stringent glycemic control to reduce macrovascular complications, particularly stroke, is not as clear as for microvascular complications. Presently, risk reduction strategies are based on controlling multiple risk factors, including hypertension, dyslipidemia, glycemia, smoking, and weight. Since 2008, new pharmacological therapies for treating T2DM have been required to undergo trials to ensure their cardiovascular safety. Remarkably, several novel therapies have exhibited protective effects against the combined endpoint of major cardiovascular events. Evidence from these trials, with stroke as a secondary endpoint, along with real-world data, suggests potential benefits in stroke prevention, particularly with glucagon-like peptide 1 receptor agonists. Conversely, the data on sodium–glucose cotransporter type 2 inhibitors remains more controversial. Dipeptidyl peptidase 4 inhibitors appear neutral in stroke prevention. More recent pharmacological therapies still lack significant data on this particular outcome. This article provides a comprehensive review of the evidence on the most recent T2DM therapies for stroke prevention and their impact on clinical practice. [ABSTRACT FROM AUTHOR]

Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2ipreceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: -3.5 ± 9.4 mL/min/1.73m2/year, post: -0.4 ± 6.3 mL/min/1.73m2/year, p < 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: -2.0 ± 10.9 mL/min/1.73m2/year, post: -1.8 ± 5.4 mL/min/1.73m2/year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits--especially annual eGFR decline--of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug. [ABSTRACT FROM AUTHOR]

Introduction: The pharmacological management of erectile dysfunction (ED) in type 2 diabetes (T2D) is challenging as ED has a multifactorial etiology. The therapeutic potential of certain antihyperglycemic medications, such as glucagon‐like peptide 1 receptor agonists (GLP‐1RAs), has yet to be entirely studied in this setting. Material and methods: A retrospective cohort study was conducted on 108 outpatients (median age 60 [56, 65] years) with T2D complaining of ED. Data were extracted from a database referring to patients with a 1‐year follow‐up on stable treatment with metformin alone (n = 45) and GLP‐1RAs as an add‐on to metformin (n = 63). Erectile function was assessed by the 5‐item International Index of Erectile Function (IIEF5) at baseline and after 1 year of stable treatment. Values were compared between baseline (T0) and after 12 months of treatment (T12). Results: ED was confirmed in all at baseline, with an IIEF5 score range between 13 and 19 points. After 12 months of treatment, glucose management was better in patients treated with GLP‐1RAs plus metformin (HbA1c T0: 8.3 ± 0.2 vs. HbA1c T12: 7% ± 0.3%, p < 0.0001) than in those on metformin alone (HbA1c T0: 7 ± 0.5 vs. HbA1c T12: 7.3 ± 0.4, p = 0.0007). GLP‐1RAs plus metformin over metformin alone resulted in a significant weight loss (−5.82 ± 0.69 kg, p < 0.0001), reduction in waist circumference (−4.99 ± 0.6 cm, p < 0.0001), improvement in HbA1c (−0.56% ± 0.13%, p < 0.0001), and fasting plasma glucose (−25.54 ± 3.09 mg/dL, p < 0.0001), increase in total (+41.41 ± 6.11 ng/dL, p < 0.0001) and free (0.44 ± 0.09 ng/dL, p < 0.0001) testosterone levels, and gain in self‐reported erectile function (IIEF5 score: +2.26 ± 0.26, p < 0.0001). The gain in the IIEF5 score was more relevant in patients with higher baseline IIEF5 score (estimated coefficient: 0.16 ± 0.08, p = 0.045), those having carotid stenosis (0.50 ± 0.24, p = 0.045), and showing weight loss from baseline (−0.08 ± 0.03, p = 0.013). The leading determinant of the final IIEF5 score was a 1‐year treatment with GLP‐1RAs plus metformin over metformin alone (2.74 ± 0.53, p < 0.0001). Discussion: GLP‐1RAs plus metformin over metformin alone improved ED regardless of different background characteristics of patients and partially irrespective of therapeutic targets achieved after 12 months of treatment. GLP‐1RAs may have induced positive vasculature effects, resulting in improved erectile function in T2D. Conclusion: Due to the retrospective nature of the study, a potential cause–effect relationship between the use of GLP‐1RAs plus metformin over metformin alone in improving ED cannot be verified and confirmed. Randomized clinical trials are needed to provide evidence supporting the use of GLP‐1RAs for treating ED in T2D. [ABSTRACT FROM AUTHOR]

Background: Multiple cardiovascular outcomes trials (CVOTs) have shown the efficacy of GLP-1RAs in reducing major adverse cardiovascular events (MACEs) for high-risk patients. However, some CVOTs failed to demonstrate cardiovascular benefits. Objectives: We analyzed the impact of GLP-1RA on cardiovascular and renal outcomes in patients with or without T2DM, with subgroup analysis based on sex, estimated glomerular filtration rate (eGFR), body mass index (BMI), and history of cardiovascular disease (CVD). Methods: A comprehensive database search for placebo-controlled RCTs on GLP-1RA treatment was conducted until April 2024. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with log odds ratios and 95 % confidence intervals (CIs). Results: A total of 13 CVOTs comprising 83,258 patients were included. GLP-1RAs significantly reduced MACE (OR 0.86, 95 % CI: 0.80 to 0.94, p < 0.01) all-cause mortality OR 0.87, 95 % CI: 0.82 to 0.93, p < 0.001, CV mortality (OR 0.87, 95 % CI: 0.81 to 0.94, p < 0.001), stroke (fatal: OR 0.74, 95 % CI: 0.56 to 0.96, p = 0.03; non-fatal: OR 0.87, 95 % CI: 0.79 to 0.96, p = 0.005), coronary revascularization (OR 0.86, 95 % CI: 0.74 to 0.99, p = 0.023), and composite kidney outcome (OR 0.76, 95 % CI: 0.67 to 0.85, p < 0.001. GLP-1RA significantly reduced MACE in both sexes. Furthermore, GLP-1RA reduced MACE regardless of CVD history, BMI, and eGFR level. Conclusion: Significant reductions in MACE, overall and CV mortality, stroke, coronary revascularization, and composite kidney outcome with GLP-1RA treatment were noted across all subgroups.

Abstract Objective To assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs. Methods We searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results In total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79–0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83–0.92; P

Aim: The results from the SUSTAIN‐6 trial generated some uncertainty regarding the association between incretin‐based drugs [dipeptidyl peptidase‐4 (DPP‐4) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs)] and the risk of diabetic retinopathy. Our objective was to synthesize the available evidence from observational studies regarding the use of incretin‐based drugs and the risk of diabetic retinopathy among individuals with type 2 diabetes. Materials and Methods: We systemically searched Cochrane Library, Embase and Medline to identify observational studies of interest. Risk of bias was assessed using the ROBINS‐I tool. Data from included studies were pooled using the DerSimonian and Laird random‐effect model with the Hartung‐Knapp extension. Results: We included 14 studies in the systematic review, with 10 examining DPP‐4 inhibitors and seven examining GLP‐1 RAs. Nine studies investigated incident diabetic retinopathy, six investigated diabetic retinopathy progression and two investigated both outcomes. Seven studies were at moderate risk of bias, four at serious risk of bias and three at critical risk of bias. Data pooled across studies showed no association between the use of DPP‐4 inhibitors (risk ratio: 0.98, 95% confidence interval: 0.83, 1.17) or GLP‐1 RAs (risk ratio: 0.87, 95% confidence interval: 0.56, 1.34) and the risk of diabetic retinopathy. Conclusion: This study suggests that the use of incretin‐based drugs is not associated with the risk of diabetic retinopathy among individuals with type 2 diabetes. However, these findings should be interpreted with caution considering the limited quality of some of the available evidence. [ABSTRACT FROM AUTHOR]

A small pilot study published in Clinical Autonomic Research suggests that new classes of glucose-lowering drugs, such as glucagon-like peptide 1 receptor agonists (GLP1ra) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), may reduce resting sympathetic nerve activity in patients with heart failure with preserved ejection fraction (HFpEF). HFpEF is associated with high morbidity, mortality, and economic cost, and current drug therapies have limited success in improving outcomes. The study compared resting muscle sympathetic nerve activity (MSNA) in patients with HFpEF taking GLP1ra or SGLT2i to those not taking these drugs and found that the drug group had significantly lower MSNA. The mechanisms behind this reduction in sympathetic activity are still unknown, and further research is needed to fully understand the impact of these drugs on sympathetic neural control in HFpEF patients. [Extracted from the article]

Objective: To assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs. Methods: We searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: In total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79–0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83–0.92; P < 0.001). For both drug classes, the effect on lowering the risk of MACE was restricted to approximately 14% in patients with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.82–0.90; P < 0.001), whereas no effect was observed in patients without established atherosclerotic cardiovascular disease (HR, 0.93; 95% CI, 0.85–1.02; P = 0.12). GLP1-RA reduced myocardial infarction, stroke and cardiovascular death more than finerenone (which appeared to have no effect). Only finerenone was beneficial for reducing the risk of HHF (HR, 0.78; 95% CI, 0.66–0.92; P = 0.003). Both finerenone (HR, 0.84; 95% CI, 0.77–0.92; P < 0.001) and GLP1-RA (HR, 0.81; 95% CI, 0.76–0.86; P < 0.001) reduced the risk of kidney disease progression, including macroalbuminuria, and finerenone was superior to GLP1-RA in delaying deterioration of kidney function. Conclusions: Finerenone and GLP1-RA lead to a risk reduction in MACE to a similar degree in patients with established atherosclerotic cardiovascular disease. For both drug classes, the effect on lowering the risk of progression of kidney disease was also in a similar magnitude in patients with T2DM, whereas only finerenone had a significant protective effect against HHF. Treatment decisions for patients with T2DM should consider the clinical benefit profiles of each drug. [ABSTRACT FROM AUTHOR]

We present a 42-year old male patient, with diabetic kidney disease, progressing proximal myotonic myopathy type 2 (PROMM MD2), metabolic syndrome and several comorbidities. Due to POMM MD2, the patient had a mixed restrictive-obstructive disorder of pulmonary ventilation, a large ventral hernia, along with weakening of the anterior abdominal wall musculature, relaxation of the paravertebral musculature, discopathy and radiculopathy of the lumbosacral spine. The patient had an extremely high cardiometabolic risk for cardiovascular and cerebrovascular accidents. The patient was treated with a glucagon-like peptide-1 (GLP-1) receptor agonist for cardio- and nephroprotection, along with treatment of all associated conditions, specific diet and adapted physical therapy. In the subsequent follow-ups at 3 and 6 months after the treatment start an improvement in several components of the metabolic syndrome and renal function was noted. The patient had a significant reduction in body weight, better glucoregulation, a significant reduction of proteinuria, maintained renal function, and better lipid profile. The overall cardiovascular risk was significantly reduced. GLP 1 receptor agonists could be used as effective cardiorenal protection in patients with progressive neuromuscular diseases. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood glucose levels, resulting in multi-organ dysfunction and various complications. Fusion proteins can form multifunctional complexes by combining the target proteins with partner proteins. It has significant advantages in improving the performance of the target proteins, extending their biological half-life, and enhancing patient drug compliance. Fusion protein-based drugs have emerged as promising new drugs in diabetes therapeutics. However, there has not been a systematic review of fusion protein-based drugs for diabetes therapeutics. Hence, we conducted a comprehensive review of published literature on diabetic fusion protein-based drugs for diabetes, with a primary focus on immunoglobulin G (IgG) fragment crystallizable (Fc) region, albumin, and transferrin (TF). This review aims to provide a reference for the subsequent development and clinical application of fusion protein-based drugs in diabetes therapeutics. [ABSTRACT FROM AUTHOR]

Purpose: Collateral drug benefits are hitherto unknown beneficial effects that might lead to repurposing of already marketed drugs. A randomized controlled trial has found liraglutide to be non‐inferior to colesevelam in reducing bile acid diarrhea. We hypothesized that this collateral drug benefit of liraglutide could have been detected using observational data. Methods: We performed a sequence symmetry analysis (SSA). In the SSA, we indexed individuals on the date of the first prescription of GLP1‐RA and restricted the analysis to all individuals who had a first prescription of bile acid sequestrants between 365 days prior to until 365 days after the index date. Sequence ratios (SR), that is, the ratio between counts of persons initiating GLP1‐RA first versus last, were calculated, and 95% confidence intervals were obtained. We adjusted for prescribing trends using null‐effect SR adjustment. Results: We included 158 individuals, with a median age of 58 years. The trend‐adjusted SR was 0.96 (95% confidence interval 0.70–1.31). When stratifying on the type of GLP1‐RA (liraglutide or semaglutide), we found results compatible with the previous trial (SRliraglutide 0.75, 0.51–1.10 and SRsemagltuide 1.23, 0.80–1.89). Since BAS also can be used as a cholesterol lowering drug, we repeated the main analysis while excluded statin users, resulting in a stronger association (SR 0.56, 0.33–0.96). Conclusion: Using the SSA methodology, we obtained estimates of a collateral drug benefit that were compatible with trial results. These results support the use of epidemiological analyses of observational data as instrument for detecting collateral drug benefits. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a prevalent and complex metabolic disorder associated with various complications, including cardiovascular diseases. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) have emerged as novel therapeutic agents for T2DM, primarily aiming to reduce blood glucose levels. However, recent investigations have unveiled their multifaceted effects, extending beyond their glucose-lowering effect. SGLT2i operate by inhibiting the SGLT2 receptor in the kidneys, facilitating the excretion of glucose through urine, leading to reduced blood glucose levels, while GLP1-RA mimic the action of the GLP1 hormone, stimulating glucose-dependent insulin secretion from pancreatic islets. Both SGLT2i and GLP1-RA have shown remarkable benefits in reducing major cardiovascular events in patients with and without T2DM. This comprehensive review explores the expanding horizons of SGLT2i and GLP1-RA in improving cardiovascular health. It delves into the latest research, highlighting the effects of these drugs on heart physiology and metabolism. By elucidating their diverse mechanisms of action and emerging evidence, this review aims to recapitulate the potential of SGLT2i and GLP1-RA as therapeutic options for cardiovascular health beyond their traditional role in managing T2DM. [ABSTRACT FROM AUTHOR]

Objective: To examine the evidence base for lifestyle and pharmacologic interventions to reduce the risk of cardiovascular events in patients with chronic kidney disease, with an emphasis on reporting available data in distinct subtypes. Data Sources: A PubMed search (origin to February 2023) was conducted and references for selected studies were reviewed to identify additional articles. Search terms included chronic kidney disease, major adverse cardiovascular events, and heart failure hospitalization. Study Selection and Data Analysis: English language studies reporting cardiovascular outcomes data in patients with chronic kidney disease were included. Data Synthesis: Much of the data on interventions to prevent cardiovascular events in patients with chronic kidney disease are derived from observational studies or subgroup analyses of trials of broader populations. Some common recommendations, such as weight loss, may be harmful in certain patients. Others may only offer benefits in subgroups, such as those with albuminuria. Newer agents, such as SGLT2 inhibitors and finerenone, have clearer evidence of cardiovascular benefit, but these may also apply only to specific subgroups. Relevance to Patient Care and Clinical Practice: Given the prevalence of chronic kidney disease and its attendant cardiovascular risk, it is important to understand which interventions offer the greatest benefit. Conclusions: Patients diagnosed with chronic kidney disease have markedly increased risk of cardiovascular events, including myocardial infarction, stroke, heart failure, and cardiovascular death. However, until recently, there were few cardiovascular outcome studies that targeted enrollment specifically to those patients. Certain drugs now have shown benefits to cardiovascular end points in this population. [ABSTRACT FROM AUTHOR]

Background: Atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), chronic kidney disease (CKD), and obesity are associated with increased morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Nonetheless, their prevalence among patients with T2DM in Saudi Arabia (SA) remains unknown. As current guidelines recommend, these comorbidities require adding certain antidiabetic agents with cardiorenal benefits. However, the prescribers' adherence to these recommendations remains unclear. Methods: A two-center retrospective cross-sectional study was conducted including adult patients (≥18 years) with T2DM admitted to hospital or seen at outpatient clinics between January and December 2020. Patients were classified into two groups based on the presence or absence of ASCVD. Patients with no prior ASCVD history were further classified based on the 10-year ASCVD risk estimation. Endpoints of interest included the prevalence of ASCVD, HF, CKD, and obesity in patients with T2DM. We also evaluated the characteristics of the utilized antidiabetic agents, statin, and aspirin therapies.. Results: Of the 1,218 included patients with T2DM, the majority were female (57.0 %), and aged 45–64 years (53.0 %) with a mean age of 59.3 ± 13.1 years. Hypertension and dyslipidemia were the most prevalent comorbidities (67.7 % and 69.0 %, respectively). Among all patients, 18.6 % had an established ASCVD and the prevalence of HF, CKD, and obesity were 5.1 %, 8.7 %, and 58.3 %, respectively. The most common types of ASCVD witnessed were revascularization (42.3 %), myocardial infarction (36.6 %), and stroke (33.9 %); with an increased prevalence of ASCVD as the age increases (52.8 % at age ≥ 65 years). In the non‐ASCVD group, the 10-year ASCVD risk was intermediate or high in 62.7 % of these patients. The rates of utilization of guidelines-recommended therapies were 83.6 % for metformin, 9.4 % for GLP-1 RA, 10.8 % for SGLT2i, 35.2 % for aspirin alone or in combination with clopidogrel, and 79.7 % for statin therapy. Conclusions: ASCVD, HF, CKD, and obesity are common complications in patients with T2DM in SA, with low overall utilization of the recommended guidelines-recommended medical therapies. Multimodal strategies should be utilized to assess T2DM and its complications, and to improve prescribers' adherence to guidelines-recommended therapies.

IntroductionLymphedema is a major public health issue for many women undergoing breast cancer treatment. Although weight loss has been reported to be beneficial in the treatment of lymphedema, no studies to date have examined the use of GLP-1RAs for the treatment of secondary lymphedema. This case report describes a patient who experienced significant resolution of her breast cancer-related lymphedema after initiation of a GLP-1RA for weight loss.Main symptoms and/or important clinical findingsNine months postoperatively the patient developed arm swelling and disability. While on adjuvant chemo and hormonal therapy, her weight increased dramatically and peaked 4 years later. Corresponding to her weight gain was significant worsening of her symptoms.The main diagnoses, therapeutic interventions, and outcomesDue to adjuvant cancer-related weight gain and inability to lose weight with diet and exercise, she was referred for evaluation and diagnosed with lymphedema. The patient started treatment with a Glucagon-like peptide 1 receptor agonist and lost 24% of her body weight over the next 13 months. The improvement in her lymphedema mirrored her weight loss. Her limb volume difference dropped from 10.3% down to 3.4% and she no longer required a compression garment. Her imaging demonstrated return of lymphatic pumping and she experienced a significant improvement in quality of life, assessed by a validated lymphedema-specific patient reported outcome (PROM). She remains on hormonal therapy, no longer needs compression and is back to regular exercise without impairment.ConclusionsGLP-1 RAs provide a potential medical option for many patients struggling with weight gain and lymphedema. We have observed by all objective measures a significant reduction in lymphedema and the elimination of compression in the case presented as a direct result of GLP-1 RA. This may also reduce a patient’s BMI to the point where they become a good candidate for lymphovenous bypass or vascularized lymph node transplant when indicated.

In October 2020, KDIGO (Kidney Disease: Improving Global Outcomes) published its first clinical practice guideline directed specifically to the care of patients with diabetes and chronic kidney disease (CKD). This commentary presents the views of the KDOQI (Kidney Disease Outcomes Quality Initiative) work group for diabetes in CKD, convened by the National Kidney Foundation to provide an independent expert perspective on the new guideline. The KDOQI work group believes that the KDIGO guideline takes a major step forward in clarifying glycemic targets and use of specific antihyperglycemic agents in diabetes and CKD. The purpose of this commentary is to carry forward the conversation regarding optimization of care for patients with diabetes and CKD. Recent developments for prevention of CKD progression and cardiovascular events in people with diabetes and CKD, particularly related to sodium/glucose cotransporter 2 (SGLT2) inhibitors, have filled a longstanding gap in nephrology's approach to the care of persons with diabetes and CKD. The multifaceted benefits of SGLT2 inhibitors have facilitated interactions between nephrology, cardiology, endocrinology, and primary care, underscoring the need for innovative approaches to multidisciplinary care in these patients. We now have more interventions to slow kidney disease progression and prevent or delay kidney failure in patients with diabetes and kidney disease, but methods to streamline their implementation and overcome barriers in access to care, particularly cost, are essential to ensuring all patients may benefit.

Hareer Fatima,1 Hussain Sohail Rangwala,1 Muhammad Saqlain Mustafa,1 Muhammad Ashir Shafique,1 Syed Raza Abbas,2 Azra Rizwan,3 Tagwa Kalool Fadlalla Ahmed,4 Ainan Arshad3 1Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan; 2Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan; 3Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan; 4Department of Medicine, Ahfad University for Women, Omdurman, Al-Khartum, SudanCorrespondence: Tagwa Kalool Fadlalla Ahmed, Department of Medicine, Ahfad University for Women, PO Box 167, Omdurman, Al-Khartum, Sudan, Tel +923412127759, Email tagwa.kalool@gmail.comIntroduction: Diabetes Mellitus (DM) is a significant global health concern, with Type 2 DM (T2DM) being highly prevalent. Glucagon-Like Peptide 1 receptor agonists (GLP-1RA), such as Danuglipron, offer potential benefits in T2DM management. This meta-analysis examines the safety and efficacy of Danuglipron, focusing on adverse outcomes and glycemic parameters.Methods: A systematic search was conducted in PubMed, Scopus, and Cochrane Library for RCTs involving Danuglipron till August 2023, following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. Adverse outcomes (diarrhea, nausea, vomiting, headache, decreased appetite, dyspepsia, dizziness) and glycemic parameters like changes in HbA1C, fasting plasma glucose (FPG), and body weight were analyzed.Results: Four RCTs published from 2021 to 2023 were included. Both doses of Danuglipron were associated with diarrhea (RR=2.66, 90% CI: 1.32 to 5.35, p=0.02), nausea (RR=5.5, 90% CI: 3.4 to 8.88, p< 0.00001), and vomiting (RR=5.98, 90% CI: 2.93 to 12.23, p=0.0001). The 120mg dose showed decreased appetite (RR=3.46, 90% CI: 1.57 to 7.62, p=0.01), dyspepsia (RR=4.04, 90% CI: 1.93 to 8.43, p=0.002), and dizziness (RR=5.08, 90% CI: 1.45 to 17.82, p=0.03). Reductions in HbA1C (SMD − 1.09, 90% CI − 1.39 to − 0.8, p < 0.00001), FPG (SMD − 1.10, 90% CI − 1.46 to − 0.75, p < 0.00001), and body weight (SMD − 1.08, 90% CI − 1.42 to − 0.74, p < 0.00001) were observed for both doses.Conclusion: Danuglipron demonstrates potential for glycemic control and weight reduction in T2DM. Adverse outcomes include diarrhea, nausea, vomiting, and decreased appetite, with dose-related effects. Clinicians must weigh benefits against side effects when considering Danuglipron for T2DM management.Keywords: diabetes mellitus, glucagon-like peptide 1 receptor agonists, Danuglipron, adverse outcomes, glycemic parameters

Alzheimer’s disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes, have been shown to have neuroprotective effects. This systematic review and meta-analysis evaluated the effects and potential mechanisms of GLP-1 RAs in AD animal models. 26 studies were included by searching relevant studies from seven databases according to a predefined search strategy and inclusion criteria. Methodological quality was assessed using SYRCLE’s risk of bias tool, and statistical analysis was performed using ReviewManger 5.3. The results showed that, in terms of behavioral tests, GLP-1 RAs could improve the learning and memory abilities of AD rodents; in terms of pathology, GLP-1 RAs could reduce Aβ deposition and phosphorylated tau levels in the brains of AD rodents. The therapeutic potential of GLP-1 RAs in AD involves a range of mechanisms that work synergistically to enhance the alleviation of various pathological manifestations associated with the condition. A total of five clinical trials were retrieved from ClinicalTrials.gov. More large-scale and high-quality preclinical trials should be conducted to more accurately assess the therapeutic effects of GLP-1 RAs on AD. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by increasing incidence and prevalence all-over the world. Current therapeutic management of type 2 diabetes is complex and is based not only on glycemic control, but also on cardiovascular and renal risks reduction. In previous years the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) increased in Russian Federation. Some manufacturers of the most widely used GLP-1 RA reported the supply decline in several countries. On Advisory board with participation of the Russian Endocrinology Association members the topics of SGLT2i and GLP-1 RA use in type 2 diabetes were discussed. The experts made conclusion that the decrease in access to GLP-1 RA does not pose serious risk for treatment of type 2 diabetes patients. SGLT2i show benefits in risk reduction of HF and CKD progression compering to GLP-1 RA, and in general show comparable efficacy in risk reduction of ACVD outcomes. SGLT2i show less glycemic efficacy in comparison with GLP-1 RA, and their replacement may need adding antidiabetic agents from other groups.

Type 2 diabetes mellitus (T2DM) is a significant risk factor for stroke. Nevertheless, the evidence supporting stringent glycemic control to reduce macrovascular complications, particularly stroke, is not as clear as for microvascular complications. Presently, risk reduction strategies are based on controlling multiple risk factors, including hypertension, dyslipidemia, glycemia, smoking, and weight. Since 2008, new pharmacological therapies for treating T2DM have been required to undergo trials to ensure their cardiovascular safety. Remarkably, several novel therapies have exhibited protective effects against the combined endpoint of major cardiovascular events. Evidence from these trials, with stroke as a secondary endpoint, along with real-world data, suggests potential benefits in stroke prevention, particularly with glucagon-like peptide 1 receptor agonists. Conversely, the data on sodium–glucose cotransporter type 2 inhibitors remains more controversial. Dipeptidyl peptidase 4 inhibitors appear neutral in stroke prevention. More recent pharmacological therapies still lack significant data on this particular outcome. This article provides a comprehensive review of the evidence on the most recent T2DM therapies for stroke prevention and their impact on clinical practice.

Aim: Glucagon‐like peptide 1 receptor agonists (GLP1‐RA) reduce atherosclerotic events in patients with type 2 diabetes (T2D) and a high cardiovascular risk. The effect of GLP1‐RA to reduce heart failure (HF) has been inconsistent across T2D trials, and individual trials were underpowered to assess the effect of GLP1‐RA according to HF history. In this meta‐analysis we aim to assess the effect of GLP1‐RA in patients with and without HF history in stable ambulatory patients with T2D. Methods: Random‐effects meta‐analysis of placebo‐controlled trials. The hazard ratio (HR) and 95% confidence intervals (95% CI) were extracted from the treatment effect estimates of HF subgroup analyses reported in each individual study. The primary outcome was a composite of HF hospitalization or cardiovascular death. Results: In total, 54 092 patients with T2D from seven randomized controlled trials were included, of whom 8460 (16%) had HF history. Compared with placebo, GLP1‐RA did not reduce the composite of HF hospitalization or cardiovascular death in patients with HF history: HR 0.96, 95% CI: 0.84‐1.08, but reduced this outcome in patients without HF history: HR 0.84, 95% CI: 0.76‐0.92. GLP1‐RA did not reduce all‐cause death in patients with HF history: HR 0.98, 95% CI: 0.86‐1.11, but reduced mortality in patients without HF history: HR 0.85, 95% CI: 0.79‐0.92. GLP1‐RA reduced atherosclerotic events regardless of HF history: HR 0.85, 95% CI: 0.75‐0.97 with HF, and HR 0.88, 95% CI: 0.83‐0.93 without HF. Conclusions: Treatment with GLP1‐RA did not reduce HF hospitalizations and mortality in patients with concomitant T2D and HF, but may prevent new‐onset HF and mortality in patients with T2D without HF. The reduction of atherosclerotic events with GLP1‐RA was not influenced by HF history status. [ABSTRACT FROM AUTHOR]

The management of diabetes and renal failure is changing thanks to the appearance of new drugs such as glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i) that have benefits in terms of survival and cardiorenal protection. Based on the potential mechanisms of GLP1-RA, kidney transplant recipients (KTRs) could benefit from their effects. However, high-quality studies are needed to demonstrate these benefits, in the transplant population, especially those related to cardiovascular benefits and renal protection. Studies with SGLT2i performed in KTRs are much less potent than in the general population and therefore no benefits in terms of patient or graft survival have been clearly demonstrated in this population to date. Additionally, the most frequently observed side effects could be potentially harmful to this population profile, including severe or recurrent urinary tract infections and impaired kidney function. However, benefits demonstrated in KTRs are in line with a known potential effects in cardiovascular and renal protection, which may be essential for the outcome of transplant recipients. Better studies are still needed to confirm the benefits of these new oral antidiabetics in the renal transplant population. Understanding the characteristics of these drugs may be critical for KTRs to be able to benefit from their effects without being damaged. This review discusses the results of the most important published studies on KTRs with GLP1-RA and SGLT2i as well as the potential beneficial effects of these drugs. Based on these results, approximate suggestions for the management of diabetes in KTRs were developed. [ABSTRACT FROM AUTHOR]

Tanzila S Razzaki,&ast; Alyson Weiner,&ast; Alpana P Shukla Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism Weill Cornell Medicine, New York, NY, USA&ast;These authors contributed equally to this workCorrespondence: Alpana P Shukla, Email aps2004@med.cornell.eduAbstract: Tirzepatide is a novel “twincretin” with glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist activity, which was recently approved by the Food and Drug Administration for the treatment of type 2 diabetes mellitus. In this review, we discuss preclinical and mechanistic human studies, which demonstrate improvements in insulin sensitivity and beta-cell function with the use of tirzepatide, as compared to placebo and glucagon-like peptide 1 receptor agonists. We then discuss SURPASS trials 1– 5, which evaluated the safety and efficacy of tirzepatide for type 2 diabetes mellitus as either monotherapy or combination therapy with other antidiabetic agents. The magnitude of tirzepatide’s effects and the efficacy relative to other anti-diabetes medications on weight, glycemic control, and beta-cell function may prove beneficial for the treatment of early type 2 diabetes mellitus. Further studies, including data on cardiovascular outcomes and long-term safety, will continue to elucidate the role of tirzepatide in the treatment algorithm of type 2 diabetes mellitus.Keywords: tirzepatide, type 2 diabetes mellitus, obesity, SURPASS trials, glucagon-like peptide 1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonist, “twincretin&#x201D

Abstract Background Characteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018. Methods We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018. Results Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%). Conclusion Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA.

Cardiovascular and microvascular disorders are serious complications of diabetes. Intensive glucose control is believed to hinder the pathological progression of these complications. In this review, we focus on the risk of diabetic retinopathy (DR) under intensive treatment with recently introduced glucose-lowering drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), sodium-glucose co-transporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs are more suitable for patients with diabetes at risk for, or established, cardiovascular complications, while SGLT2 inhibitors are more appropriate for complications of heart failure and chronic renal diseases. Accumulating evidence indicates that GLP-1RAs may provide a greater reduction in the risk of DR in patients with diabetes compared to DPP-4 inhibitors, sulfonylureas, or insulin. GLP-1RAs may be ideal antihyperglycemic drugs with direct benefits for the retina, since GLP-1R can be expressed in photoreceptors. Topical administration of GLP-1RAs induces direct retinal neuroprotection against DR by multiple mechanisms, such as preventing both neurodysfunction and retinal neurodegeneration; relieving the disruption of the blood-retinal barrier and associated vascular leakage, and inhibiting oxidative stress, inflammatory action, and neuronal apoptosis. Hence, it seems reasonable to utilize this strategy to treat patients with diabetes and early-stage DR, rather than exclusively using neuroprotective agents. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a prevalent and complex metabolic disorder associated with various complications, including cardiovascular diseases. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) have emerged as novel therapeutic agents for T2DM, primarily aiming to reduce blood glucose levels. However, recent investigations have unveiled their multifaceted effects, extending beyond their glucose-lowering effect. SGLT2i operate by inhibiting the SGLT2 receptor in the kidneys, facilitating the excretion of glucose through urine, leading to reduced blood glucose levels, while GLP1-RA mimic the action of the GLP1 hormone, stimulating glucose-dependent insulin secretion from pancreatic islets. Both SGLT2i and GLP1-RA have shown remarkable benefits in reducing major cardiovascular events in patients with and without T2DM. This comprehensive review explores the expanding horizons of SGLT2i and GLP1-RA in improving cardiovascular health. It delves into the latest research, highlighting the effects of these drugs on heart physiology and metabolism. By elucidating their diverse mechanisms of action and emerging evidence, this review aims to recapitulate the potential of SGLT2i and GLP1-RA as therapeutic options for cardiovascular health beyond their traditional role in managing T2DM.

Background and aims: Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque. Methods: In study A, we employed an electrical current to the carotid artery in ApoE−/− mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow. Results: Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% (p = 0.0002), respectively. Following cuff placement, expression of the pro-inflammatory marker osteopontin and macrophage marker Mac-2 was reduced (p

Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a potent antidiabetic agent with cardiorenal and weight-losing benefits in patients with type 2 diabetes (T2D). The combination of GLP-1 RA with basal insulin has been suggested in several clinical studies as a useful treatment for intensifying insulin therapy in T2D. However, there has been no real-world evidence study comparing the glycemic effects of GLP-1 RAs add-on to background treatment with and without insulin. A retrospective study was performed in 358 patients with T2D who initiated liraglutide or dulaglutide. Among them, 147 patients were prior and concurrent insulin users, and 211 patients were non-insulin users. After 12 months of GLP-1 RA treatment, the changes in hemoglobin A1c (HbA1C) and body weight were evaluated. The effectiveness of GLP-1 RAs on HbA1C reduction was greater in insulin users than non-insulin users at 12 months (−1.17% vs. −0.76%; p = 0.018). There was no significant difference in body weight change between insulin users and non-insulin users at 12 months (−1.42 kg vs. −1.87 kg; p = 0.287). The proportion of responders (decrease of HbA1C > 1%) in insulin users was much higher than that in non-insulin users (48% vs. 37 %; p = 0.04). In insulin users, those who had increased insulin dosage at 12 months had significantly less HbA1C reduction than that of non-increased patients (−0.62% vs. −1.57%; p = 0.001). GLP-1 RAs provide superior glucose-lowering effects in insulin-treated patients compared with non-insulin-treated patients with T2D without significant differences in body weight decrease. [ABSTRACT FROM AUTHOR]

Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) molecule approved for the treatment of both type 2 diabetes (T2D) and obesity. Semaglutide has a greater impact on glycated haemoglobin (HbA1c) reduction, compared to other GLP-1 RAs, and is the first molecule of this class available in oral formulation for T2D therapy, representing a useful option for subjects and physicians less prone to start an injective drug. Interestingly, due to its remarkable effects on weight reduction, higher than other GLP-1 RAs and very close to bariatric surgery, semaglutide is designated to change the approach to obesity therapy also in the subject not affected by diabetes. In addition to these favorable features, semaglutide, similarly to other GLP-1 RAs, offers beneficial effects on cardio-vascular (CV), renal, and liver protection, making this molecule an advantageous choice in the therapeutic management of “diabesity” (coexistence of both diabetes and obesity) and its co-morbidity.

Abstract Aims The cardioprotective effects of glucose‐lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose‐lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta‐analysis to evaluate the impact of various glucose‐lowering medications on the outcomes of non‐diabetic HF patients. Methods and results Medline and Embase were searched for RCTs investigating the use of glucose‐lowering medications in non‐diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre‐defined datasheet. Primary outcomes include serum N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO2). A Bayesian network meta‐analysis was performed to compare the effectiveness of different classes of glucose‐lowering medications in improving HF outcomes. Risk‐of‐bias was assessed using Cochrane Risk‐of‐Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium‐glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT‐proBNP, with the significant reduction in NT‐proBNP when compared with glucagon‐like peptide‐1 receptor agonists (GLP1‐RA) [mean differences (MD): −229.59 pg/mL, 95%‐credible intervals (95%‐CrI): −238.31 to −220.91], metformin (MD: −237.15 pg/mL, 95%‐CrI: −256.19 to −218.14), and placebo (MD: −228.00 pg/mL, 95%‐CrI: −233.99 to −221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1‐RA (MD: 8.09%, 95%‐CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%‐CrI: 4.37 to 7.84). SGLT2i and GLP1‐RA were more favourable to placebo in improving PVO2, with significant increase of PVO2 at a MD of 1.60 mL/kg/min (95%‐CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%‐CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo. Conclusions This Bayesian network meta‐analysis demonstrated that SGLT2i, when compared with GLP1‐RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO2 and NT‐proBNP in non‐diabetic HF patients. Further large‐scale prospective studies are needed to confirm these preliminary findings.

The treatment of diabetes mellitus type 2 (DM2) is becoming more complex as new medications are approved. Primary care providers must maintain their medical knowledge on emerging medications for best patient care. This review simplifies the non-insulin treatments of diabetes with an emphasis on the cardio-renal protectants, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1).

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are being investigated to slow the decline of kidney function in type 2 diabetics with chronic kidney disease (CKD). These agents have proven benefits on cardiac outcomes and all-cause mortality as well as in reducing the incidence of macroalbuminuria. Ours is a case of drug-associated acute interstitial nephritis requiring hemodialysis temporally related to a semaglutide dose increase. This case is unique as the index patient had no underlying CKD. Limited cases of acute kidney injury, superimposed on underlying CKD, in patients taking the GLP-1RA semaglutide have been reported. To our knowledge, there are no existing case reports in the literature of GLP-1RA-associated acute interstitial nephritis in a patient with baseline normal kidney function. Because our prescription of these agents is increasing and is anticipated to increase further with growing scientific evidence for their benefit, we sought to highlight this possible, important serious adverse effect of semaglutide.

Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus (DM), estimated to affect approximately one-third of the diabetic population, and the most common cause of preventable vision loss. The available treatment options focus on the late stages of this complication, while in the early stages there is no dedicated treatment besides optimizing blood pressure, lipid and glycemic control; DR is still lacking effective preventive methods. glucagon-like peptide 1 receptor agonists (GLP-1 Ras) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors have a proven effect in reducing risk factors of DR and numerous experimental and animal studies have strongly established its retinoprotective potential. Both drug groups have the evident potential to become a new therapeutic option for the prevention and treatment of diabetic retinopathy and there is an urgent need for further comprehensive clinical trials to verify whether these findings are translatable to humans. [ABSTRACT FROM AUTHOR]

Background: Characteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018. Methods: We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018. Results: Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%). Conclusion: Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists, increasingly used for diabetes management and weight loss, have been linked to lower readmission rates after knee and hip arthroplasty. However, their impact on total shoulder arthroplasty (TSA) outcomes remains unclear. This study investigates the effects of GLP-1 receptor agonists on major complications and revisions following TSA., Methods: A retrospective query of the TriNetX database from 2010 to 2023 was performed to identify patients who underwent anatomic or reverse TSA and were prescribed GLP-1 receptor agonists. GLP-1 receptor agonist users were 1:1 propensity score-matched to controls for demographic factors and comorbidities, yielding 1,259 patients in each group. Outcomes included 90-day postoperative medical complications and readmission and revision surgery at 2 years. Odds ratios (ORs), 95% confidence intervals, and P values were calculated. After Bonferroni correction, P < 0.005 was considered significant., Results: GLP-1 receptor agonist users (n = 1,259) experienced significantly higher rates of deep vein thrombosis (1.6% vs. 0.9%; OR 3.0; P = 0.001), myocardial infarction (1.60% vs. 0.9%; OR 2.84; P = 0.003), pneumonia (3.34% vs 1.50%; OR 2.25; P = 0.003), transfusion (7.1% vs. 4.3%; OR 1.7; P = 0.003), and readmission (8.1% vs 5.2%; OR 1.6; P = 0.004) in the 90-day postoperative period compared to patients not taking GLP-1 receptor agonists. There were no differences in the rates of stroke, pulmonary embolism, postoperative anemia, or renal failure. In patients with a minimum 2-year follow-up (n = 776), there was no difference in revision rate (3.2% vs 1.8%; OR 1.8; P = 0.07)., Conclusion: GLP-1 receptor agonist use during TSA was associated with an increased risk of deep vein thrombosis, myocardial infarction, pneumonia, need for transfusion, and readmission. Further investigation into the perioperative risk assessment and medical optimization of patients utilizing GLP-1 receptor agonists may be warranted., (Copyright © 2024. Published by Elsevier Inc.)

Background: Diabesity (diabetes as a consequence of obesity) has emerged as a huge healthcare challenge across the globe due to the obesity pandemic. Judicious use of antidiabetic medications including semaglutide is important for optimal management of diabesity as proven by multiple randomized controlled trials. However, more real-world data is needed to further improve the clinical practice., Aim: To study the real-world benefits and side effects of using semaglutide to manage patients with diabesity., Methods: We evaluated the efficacy and safety of semaglutide use in managing patients with diabesity in a large academic hospital in the United States. Several parameters were analyzed including demographic information, the data on improvement of glycated hemoglobin (HbA1c), body weight reduction and insulin dose adjustments at 6 and 12 months, as well as at the latest follow up period. The data was obtained from the electronic patient records between January 2019 to May 2023., Results: 106 patients (56 males) with type 2 diabetes mellitus (T2DM), mean age 60.8 ± 11.2 years, mean durations of T2DM 12.4 ± 7.2 years and mean semaglutide treatment for 2.6 ± 1.1 years were included. Semaglutide treatment was associated with significant improvement in diabesity outcomes such as mean weight reductions from baseline 110.4 ± 24.6 kg to 99.9 ± 24.9 kg at 12 months and 96.8 ± 22.9 kg at latest follow up and HbA1c improvement from baseline of 82 ± 21 mmol/mol to 67 ± 20 at 12 months and 71 ± 23 mmol/mol at the latest follow up. An insulin dose reduction from mean baseline of 95 ± 74 units to 76.5 ± 56.2 units was also observed at the latest follow up. Side effects were mild and mainly gastrointestinal like bloating and nausea improving with prolonged use of semaglutide., Conclusion: Semaglutide treatment is associated with significant improvement in diabesity outcomes such as reduction in body weight, HbA1c and insulin doses without major adverse effects. Reviews of largescale real-world data are expected to inform better clinical practice decision making to improve the care of patients with diabesity., Competing Interests: Conflict-of-interest statement: Authors have no conflicts of interests to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) treatment guidelines recommend sodium glucose cotransporter 2 inhibitor (SGLT2I) and glucagon-like peptide-1 agonist (GLP-1A) therapy in patients with type 2 diabetes mellitus (T2DM). SGLT2I improves the pathological condition of NAFLD/NASH in T2DM patients. However, cases of rebound during long-term SGLT2I treatment have been reported. This study investigated the efficacy of SGLT2I and GLP-1A combination therapy in diabetic patients with NAFLD by examining changes in computed tomography (CT)-based body composition and clinical outcomes. Methods Fifteen patients (5 men/10 women) with T2DM-associated NAFLD who had not responded to SGLT2I treatment and were being treated with GLP-1A combination therapy were included. Changes in the liver function, visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI) were compared using CT to evaluate the body composition. Results SGLT2I significantly improved alanine aminotransferase (28.0 to 13.0 IU/L), alkaline phosphatase (250.0 to 77.0 IU/L), and gamma glutamyl transpeptidase (23.0 to 12.0 IU/L) levels. The body mass index (BMI) decreased from 25.7 to 25.2 kg/m 2 . A CT-based analysis showed a significant improvement in SATI (80.9 to 66.1, p=0.002), with no significant change in VATI (53.2 to 51.5). GLP-1A addition improved the BMI (25.2 to 23.5 kg/m 2 ) and hemoglobin A1c (6.5% to 6.2%, p=0.001). A further analysis revealed additional improvement in SATI (66.1 to 56.6, p=0.007) and a significant decrease in VATI (51.5 to 48.3, p=0.001). Conclusion SGLT2I and GLP-1A combination therapy improved the liver function, body composition, and glycemic control in diabetic patients with NAFLD/NASH, as well as SATI and VATI. The optimal timing of combination therapy remains to be determined.