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BACKGROUND: In the process of exploring the mechanism of Alzheimer’s disease, the important role of bioinformatics for common target screening has been revealed, enabling the use of its screening results as a basis for exploring the therapeutic effects of drugs on the disease. OBJECTIVE: To predict the targets of liraglutide, a glucagon-like peptide-1 receptor agonist, in the treatment of Alzheimer’s disease by bioinformatics and molecular biology. METHODS: DisGeNET database and SEA database were used to obtain the common genes of Alzheimer’s disease and liraglutide. GO/KEGG enrichment analysis of common targets was conducted using DAVID online database. Protein-protein interaction networks were constructed using STRING database. The optimal dosage of liraglutide was determined using cell counting kit-8 assay. Expression of key proteins was analyzed using immunofluorescence and immunoblotting techniques. The mouse hippocampal neuron HT22 cell line was used for ex vivo experiments, and the cells were randomly divided into three groups: HT22 group, HT22+Aβ group, and HT22+Aβ+Lir group. No special treatment was done in the HT22 group, while Aβ1-42 was used to intervene in the HT22 cell line for 24 hours to construct an Aβ injury cell model in the HT22+Aβ group. In additional to modeling, liraglutide was added to the HT22+Aβ+Lir group for 12 hours. RESULTS AND CONCLUSION: A total of 3 333 genes associated with Alzheimer’s disease were screened from DisGeNET database. Then 147 potential targets of liraglutide were obtained from SEA database. Finally, 64 common targets of Alzheimer’s disease and Liraglutide were determined using R packets. GO/ KEGG analysis of common targets using DAVID online database suggested that common targets were mainly enriched in the following biological processes: neuroactive ligand-receptor interaction, renin-angiotensin system, bladder cancer, endopeptidase activity, peptide receptor activity, G protein-coupled peptide receptor activity, and transport vesicles. The obtained 64 common target proteins were imported into SRTING online database for protein-protein interaction network construction, and the top three genes, matrix metalloproteinases 2, 9 and interleukin 1β, were obtained. The activity of cultured cells was detected by the cell counting kit-8 kit. Liraglutide at 100 nmol/L was the optimal concentration for antagonizing Aβ1-42. In the western blot and immunofluorescence assays, the expression of matrix metalloproteinases 2, 9 and interleukin 1β was significantly increased in the HT22+Aβ group compared with the HT22 group (P < 0.05) but significantly decreased in the HT22+Aβ+Lir group compared with the HT22+Aβ group (P < 0.05). To conclude, the above bioinformatics data and secondary validation of differential genes in the GEO database suggest that both matrix metalloproteinases 2,9 and interleukin 1β could be potential targets of liraglutide in the treatment of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Aims: To conduct an updated systematic review and meta‐analysis to evaluate the efficacy of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) with regard to cardiac function and structure in people with or without type 2 diabetes mellitus (T2DM). Materials and Methods: We conducted a systematic search using the PubMed, Embase and ClinicalTrials.gov online databases. The primary outcome of interest was changes in mitral inflow E‐velocity to tissue Doppler e' velocity (E/e') ratio. Secondary outcomes included other indicators of cardiac reverse remodelling and functional capacity comprising changes in left ventricular mass (LVM), left ventricular global longitudinal strain, left ventricular end‐diastolic volume, left ventricular end‐systolic volume, left ventricular ejection fraction (LVEF), early to atrial mitral inflow velocity ratio, left atrial volume (LAV), N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels and 6‐min walk test (6MWT) results. Results: A total of 15 trials involving 898 patients were included in this analysis. GLP‐1RAs significantly improved E/e' ratio (mean difference [MD] = −0.73; 95% confidence interval [CI] −1.34, −0.13), LVM (MD = −3.86 g; 95% CI −7.60, −0.12), LAV (MD = −8.20 mL; 95% CI −12.37, −4.04), NT‐proBNP level (standardized MD = −0.27; 95% CI −0.47, −0.06), and 6MWT result (MD = +22.31 m; 95% CI 1.64, 42.99). However, GLP‐1RAs had no effect on LVEF (MD = +0.31%; 95% CI −1.02, 1.64). Conclusions: In this systematic review and meta‐analysis, GLP‐1RAs were found to have a positive impact on left ventricle diastolic function, hypertrophy, and exercise capacity, but had no effect on systolic function. [ABSTRACT FROM AUTHOR]

Aim: To investigate the real‐world utilization and comparative clinical outcomes of injectable and oral semaglutide in individuals with type 2 diabetes (T2D) with the aim of enhancing understanding of the practical implications associated with choosing between these formulations. Methods: New users of oral or injectable semaglutide were selected from a cohort of 14 079 initiators of glucagon‐like peptide‐1 receptor agonists. Propensity‐score matching (PSM) was employed to create balanced groups, ensuring comparability. The analysis encompassed dose exposure, drug persistence, and clinical outcomes, including changes in glycated haemoglobin (HbA1c) and body weight, with up to 18 months' follow‐up. Results: We analysed two matched groups of 107 participants each, who comprised on average 63.6% men, aged 64 years, with diabetes duration of approximately 10 years, body mass index of 29 kg/m2 and HbA1c level of 7.7–7.8% (61‐62 mmol/mol). The proportion of low, intermediate and high doses were similar with the oral and the injectable formulation. The change in HbA1c was similar between groups (−0.9% / ‐10 mmol/mol at 18 months) as was the proportion of individuals reaching HbA1c <6.5% (48 mmol/mol). The average change in body weight was similar in the two groups (−3.7 kg with injectable and −3.3 kg with oral at 18 months) but more new users of injectable semaglutide lost ≥5% body weight. Persistence on drug was longer with injectable than with oral semaglutide. Conclusion: In a real‐world setting, improvements in HbA1c and body weight were similar after initiation of oral or injectable semaglutide. These results may be specific to the features of the matched cohorts under investigation, with limited generalizability to populations with different characteristics. [ABSTRACT FROM AUTHOR]

This article discusses the effectiveness and safety of once-weekly subcutaneous semaglutide compared to other glucose-lowering agents in real-world patients with type 2 diabetes. The study included 502 participants treated with semaglutide and 511 participants treated with other agents. The results showed that semaglutide was associated with significant improvements in glycemic control, weight loss, and cardiovascular risk factors. Additionally, a higher proportion of patients in the semaglutide group achieved the target HbA1c level compared to the non-GLP-1RA group. The study concludes that semaglutide can be beneficial for the management of type 2 diabetes in routine clinical practice. [Extracted from the article]

A meta-analysis of randomized controlled trials was conducted to investigate the potential link between glucagon-like peptide-1 receptor agonists (GLP-1RA) and mental health. GLP-1 receptors are found in the central nervous system and have effects on neurocognitive functions, inflammation, stress response, and energy metabolism. The analysis included 31 studies with a total of 84,713 patients and found no significant difference in the incidence of psychiatric disorders, suicidal behavior, depression, or anxiety between GLP-1RA and placebo. However, the study acknowledged limitations, such as the exclusion of patients with severe mental illnesses in clinical trials and the need for further research on GLP-1RA effects in patients with pre-existing psychiatric disorders. [Extracted from the article]

Aim: The cardiovascular benefits provided by glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP‐lowering effects of GLP1‐RAs. Methods: A comprehensive database search for placebo‐controlled randomized controlled trials on GLP‐1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta‐regressions were done to account for covariates. Results: Compared with placebo, GLP‐1RAs modestly reduced SBP [semaglutide: MD −3.40 (95% CI −4.22 to −2.59, p <.001); liraglutide: MD −2.61 (95% CI −3.48 to −1.74, p <.001); dulaglutide: MD −1.46 (95% CI −2.20 to −0.72, p <.001); and exenatide: MD −3.36 (95% CI −3.63 to −3.10, p <.001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD −0.94 (95% CI −1.78 to −0.1), p =.03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. Conclusion: Patients on GLP‐1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP‐lowering is an indirect effect of GLP‐1RA and unlikely to be responsible for the benefits. [ABSTRACT FROM AUTHOR]

Despite its considerable and growing burden, there are currently no Food and Drug Administration‐approved treatments for metabolic dysfunction‐associated steatotic liver disease or its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH). Several glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all‐cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction‐associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP‐1RAs are Food and Drug Administration‐approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP‐1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP‐1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP‐1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta‐analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP‐1RAs. Large‐scale, phase 3 trials, which will provide definitive data on GLP‐1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH. [ABSTRACT FROM AUTHOR]

Aims: To assess the potential for precision medicine in type 2 diabetes by quantifying the variability of body weight as response to pharmacological treatment and to identify predictors which could explain this variability. Methods: We used randomized clinical trials (RCTs) comparing glucose‐lowering drugs (including but not limited to sodium‐glucose cotransporter‐2 inhibitors, glucagon‐like peptide‐1 receptor agonists and thiazolidinediones) to placebo from four recent systematic reviews. RCTs reporting on body weight after treatment to allow for calculation of its logarithmic standard deviation (log[SD], i.e., treatment response heterogeneity) in verum (i.e., treatment) and placebo groups were included. Meta‐regression analyses were performed with respect to variability of body weight after treatment and potential predictors. Results: A total of 120 RCTs with a total of 43 663 participants were analysed. A slightly larger treatment response heterogeneity was shown in the verum groups, with a median log(SD) of 2.83 compared to 2.79 from placebo. After full adjustment in the meta‐regression model, the difference in body weight log(SD) was −0.026 (95% confidence interval −0.044; 0.008), with greater variability in the placebo groups. Scatterplots did not show any slope divergence (i.e., interaction) between clinical predictors and the respective treatment (verum or placebo). Conclusions: We found no major treatment response heterogeneity in RCTs of glucose‐lowering drugs for body weight reduction in type 2 diabetes. The precision medicine approach may thus be of limited value in this setting. [ABSTRACT FROM AUTHOR]

Beneficial weight-loss properties of glucagon-like peptide-1 receptor agonists (GLP-1RA) in obese people, with corresponding improvements in cardiometabolic risk factors, are well established. OKV-119 is an investigational drug delivery system that is being developed for the long-term delivery of the GLP-1RA exenatide to feline patients. The purpose of this study was to evaluate the drug release characteristics of subcutaneous OKV-119 implants configured to release exenatide for 84 days. Following a 7-day acclimation period, five purpose-bred cats were implanted with OKV-119 protypes and observed for a 112-day study period. Food intake, weekly plasma exenatide concentrations and body weight were measured. Exenatide plasma concentrations were detected at the first measured timepoint (Day 7) and maintained above baseline for over 84 Days. Over the first 28 days, reduced caloric intake and a reduction in body weight were observed in four of five cats. In these cats, a body weight reduction of at least 5% was maintained throughout the 112-day study period. This study demonstrates that a single OKV-119 implant can deliver the GLP-1RA exenatide for a months long duration. Results suggest that exposure to exenatide plasma concentrations ranging from 1.5 ng/ml to 4 ng/ml are sufficient for inducing weight loss in cats. [ABSTRACT FROM AUTHOR]

Background: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. Materials and methods: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and β-glycerophosphate (β-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. Results: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/β-GP-induced VSMCs. In HG/β-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/β-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. Conclusion: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs. [ABSTRACT FROM AUTHOR]

Diabetes is one of the most prevalent diseases worldwide. In recent decades, type-2 diabetes has become increasingly common, particularly in younger individuals. Diabetes leads to many vascular complications, including atherosclerosis. Atherosclerosis is a cardiovascular disease characterized by lipid-rich plaques within the vasculature. Plaques develop over time, restricting blood flow, and can, therefore, be the underlying cause of major adverse cardiovascular events, including myocardial infarction and stroke. Diabetes and atherosclerosis are intrinsically linked. Diabetes is a metabolic syndrome that accelerates atherosclerosis and increases the risk of developing other comorbidities, such as diabetes-associated atherosclerosis (DAA). Gold standard antidiabetic medications focus on attenuating hyperglycemia. Though recent evidence suggests that glucose-lowering drugs may have broader applications, beyond diabetes management. This review mainly evaluates the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide and semaglutide in DAA. These drugs mimic gut hormones (incretins), which inhibit glucagon secretion while stimulating insulin secretion, thus improving insulin sensitivity. This facilitates delayed gastric emptying and increased patient satiety; hence, they are also indicated for the treatment of obesity. GLP-1 RAs have significant cardioprotective effects, including decreasing low-density lipoprotein (LDL) cholesterol and triglycerides levels. Liraglutide and semaglutide have specifically been shown to decrease cardiovascular risk. Liraglutide has displayed a myriad of antiatherosclerotic properties, with the potential to induce plaque regression. This review aims to address how glucose-lowering medications can be applied to treat diseases other than diabetes. We specifically focus on how nanomedicines can be used for the site-specific delivery of antidiabetic medicines for the treatment of diabetes-associated atherosclerosis. [ABSTRACT FROM AUTHOR]

The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism. [ABSTRACT FROM AUTHOR]

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1β, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3β, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists. [ABSTRACT FROM AUTHOR]

Aim/Introduction: Insulin glargine U100/lixisenatide and insulin degludec/liraglutide are fixed‐ratio combinations containing basal insulin and a glucagon‐like peptide‐1 receptor agonist capable of reducing both fasting and postprandial blood glucose levels with a single formulation. This study aimed to compare the time in range (TIR) and the time below range (TBR) level 1 using professional continuous glucose monitoring and to establish criteria for the differential use of the fixed‐ratio combinations. Materials and Methods: Thirty‐six outpatients with type 2 diabetes mellitus (24 men and 12 women; average age, 62.1 years) were randomly assigned to the groups. At 0 and 18 weeks, a device was worn to compare the TIR and TBR level 1. The correlation between the C‐peptide index at baseline and TIR at 18 weeks was assessed. Results: The TIR and TBR level 1 showed no significant differences between the two groups. Both groups showed significant positive correlations between the C‐peptide index and the TIR (P = 0.002, r = 0.679; P = 0.002, r = 0.681, respectively). The changes in glycemic variability, therapeutic indices, and body mass index were not significantly different among the groups (P > 0.05). The receiver operating curve analysis revealed that the cut‐off values of the C‐peptide index to achieve TIR of >70% at 18 weeks were 1.258 (sensitivity, 77.8%; specificity, 100%) and 1.099 (sensitivity, 57.1%; specificity, 90.9%) in the insulin glargine U100/lixisenatide and insulin degludec/liraglutide groups, respectively. Conclusions: A TIR of >70% was achieved for both fixed‐ratio combinations without significant differences. [ABSTRACT FROM AUTHOR]

The study addresses concerns about potential psychiatric side effects of Glucagon-like peptide-1 receptor agonists (GLP-1 RA). The aim of this work was to analyse adverse drug reports (ADRs) from the Food and Drug Administration Adverse Events Reporting System (FAERS) using metformin and orlistat as comparators. Descriptive and pharmacovigilance disproportionality analyses was performed. A total of 209,354 ADRs were reported, including 59,300 serious cases. Of those, a total of 5378 psychiatric disorder cases, including 383 'serious' cases related to selected ADRs were registered during 2005–2023. After unmasking, 271 cases where individual GLP-1 RA were implicated showing liraglutide (n = 90; Reported Odds Ratio (ROR) = 1.64), exenatide (n = 67; ROR = 0.80), semaglutide (n = 61; ROR = 2.03), dulaglutide (n = 45; ROR = 0.84), tirzepatide (n = 5; ROR = 1.76) and albiglutide (n = 2; ROR = 0.04). A greater association between these ADRs with metformin was observed, but not orlistat. With regards to selected preferred terms (PTs), 42 deaths including 13 completed suicides were recorded. Suicidal ideation was recorded in n = 236 cases for 6/7 GLP-1 RA (excluding lixisenatide). Suicide/self-injury reports pertaining to semaglutide; tirzepatide; and liraglutide were characterised, although lower than metformin. It is postulated that rapid weight loss achieved with GLP-1 RA can trigger significant emotional, biological, and psychological responses, hence possibly impacting on suicidal and self-injurious ideations. With the current pharmacovigilance approach, no causality link between suicidal ideation and use of any GLP-1 RA can be inferred. There is a need for further research and vigilance in GLP-1 RA prescribing, particularly in patients with co-existing psychiatric disorders. [ABSTRACT FROM AUTHOR]

Early initiation of intensive insulin therapy has been demonstrated to be effective in controlling glycemia and possibly preserving beta-cell function. Innovations in insulin formulations and delivery systems continue. However, we have seen an acceleration in the development of new classes of diabetes medications for individuals with type 2 diabetes and obesity, such as, for example, glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These formulations have been shown to confer significant benefits in achieving good glycemic control with reduced hypoglycemia risk, weight loss, and cardiorenal protection. Therefore, it is reasonable to question whether there is still a role for insulin therapy in the management of type 2 diabetes. However, there are clear limitations inherent to GLP-1 RA therapy, including high rates of suboptimal adherence and treatment discontinuation due to high cost and side effects, which diminish long-term efficacy, and supply issues. In addition, newer formulations have shown improvements in convenience and tolerability, and have been shown to be even more effective when used in conjunction with basal insulin. In this narrative review, we discuss current evidence that supports GLP-1 RA use in combination with insulin therapy and the potential pitfalls of reliance on GLP-1 RAs as a substitute for insulin therapy. [ABSTRACT FROM AUTHOR]

Introduction: People with type 2 diabetes are at heightened risk for severe outcomes related to COVID-19 infection, including hospitalization, intensive care unit admission, and mortality. This study was designed to examine the impact of premorbid use of glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy, sodium-glucose cotransporter-2 inhibitor (SGLT-2i) monotherapy, and concomitant GLP1-RA/SGLT-2i therapy on the severity of outcomes in individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods: Utilizing observational data from the National COVID Cohort Collaborative through September 2022, we compared outcomes in 78,806 individuals with a prescription of GLP-1RA and SGLT-2i versus a prescription of dipeptidyl peptidase 4 inhibitors (DPP-4i) within 24 months of a positive SARS-CoV-2 PCR test. We also compared concomitant GLP-1RA/SGLT-2i therapy to GLP-1RA and SGLT-2i monotherapy. The primary outcome was 60-day mortality, measured from the positive test date. Secondary outcomes included emergency room (ER) visits, hospitalization, and mechanical ventilation within 14 days. Using a super learner approach and accounting for baseline characteristics, associations were quantified with odds ratios (OR) estimated with targeted maximum likelihood estimation (TMLE). Results: Use of GLP-1RA (OR 0.64, 95% confidence interval [CI] 0.56–0.72) and SGLT-2i (OR 0.62, 95% CI 0.57–0.68) were associated with lower odds of 60-day mortality compared to DPP-4i use. Additionally, the OR of ER visits and hospitalizations were similarly reduced with GLP1-RA and SGLT-2i use. Concomitant GLP-1RA/SGLT-2i use showed similar odds of 60-day mortality when compared to GLP-1RA or SGLT-2i use alone (OR 0.92, 95% CI 0.81–1.05 and OR 0.88, 95% CI 0.76–1.01, respectively). However, lower OR of all secondary outcomes were associated with concomitant GLP-1RA/SGLT-2i use when compared to SGLT-2i use alone. Conclusion: Among adults who tested positive for SARS-CoV-2, premorbid use of either GLP-1RA or SGLT-2i is associated with lower odds of mortality compared to DPP-4i. Furthermore, concomitant use of GLP-1RA and SGLT-2i is linked to lower odds of other severe COVID-19 outcomes, including ER visits, hospitalizations, and mechanical ventilation, compared to SGLT-2i use alone. Graphical abstract available for this article. [ABSTRACT FROM AUTHOR]

Introduction: Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist. In the SURPASS-AP-Combo trial, once-weekly tirzepatide was associated with improved glycemic control and weight loss versus insulin glargine and was generally well tolerated in an Asia-Pacific, predominately Chinese, population with type 2 diabetes (T2D). This post hoc subgroup analysis of SURPASS-AP-Combo assessed the potential influence of patient baseline characteristics on the efficacy and safety of tirzepatide. Methods: Changes from baseline to week 40 in HbA1c, body weight, fasting serum glucose (FSG), and daily glucose average from self-measured blood glucose profiles were analyzed by potential influential factors including age (< 65, ≥ 65 years), sex, baseline HbA1c (≤ 8.5, > 8.5%), body mass index (BMI) (< 25, ≥ 25 kg/m2), body weight (< 75, ≥ 75 kg), duration of diabetes (< 10, ≥ 10 years), and concomitant oral antihyperglycemic medications (metformin, metformin plus sulphonylurea). Gastrointestinal adverse events and hypoglycemia were also evaluated. Results: At week 40, all tirzepatide doses were associated with reduced HbA1c, body weight, FSG, and daily glucose average from baseline in all subgroups. Greater HbA1c reductions were achieved in patients with higher baseline HbA1c across all tirzepatide doses, higher body weight with 10 mg and younger age with 15 mg tirzepatide. Greater reductions in body weight were observed in patients with higher body weight across all tirzepatide doses, lower baseline HbA1c with 5 mg and higher BMI with 5 mg tirzepatide. Conclusions: In this post hoc analysis, tirzepatide was associated with reduced blood glucose and body weight in a predominantly Chinese population with T2D across different subgroups, consistent with previous reports for tirzepatide. Clinical Trial Registration: NCT04093752. [ABSTRACT FROM AUTHOR]

Despite the availability of various antihyperglycaemic therapies and comprehensive guidelines, glycaemic control in diabetes management has not improved significantly during the last decade in the real-world clinical setting. Treatment inertia arising from a complex interplay among patient-, clinician- and healthcare-system-related factors is the prime reason for this suboptimal glycaemic control. Also, the key factor leading to inadequate glycaemic levels remains limited communication between healthcare professionals (HCPs) and people with type 2 diabetes (PwT2D). Early insulin administration has several advantages including reduced glucotoxicity, high efficacy and preserved β-cell mass/function, leading to lowering the risk of diabetes complications. The current publication is based on consensus of experts from the South-Eastern European region and Israel who reviewed the existing evidence and guidelines for the treatment of PwT2D. Herein, the experts emphasised the timely use of insulin, preferably second-generation basal insulin (BI) analogues and intensification using basal-plus therapy, as the most-potent glucose-lowering treatment choice in the real-world clinical setting. Despite an increase in the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the experts urged timely insulin initiation for inadequate glycaemic control in PwT2D. Furthermore, the combination of BI and GLP-1 RA addressing both fasting plasma glucose and post-prandial excursions as a free- or fixed-ratio combination was identified to reduce treatment complexity and burden. To minimise discontinuation and improve adherence, the experts reiterated quality, regular interactions and discussions between HCPs and PwT2D/carers for their involvement in the diabetes management decision-making process. Clinicians and HCPs should consider the opinions of the experts in accordance with the most recent recommendations for diabetes management. [ABSTRACT FROM AUTHOR]

Aim: Using a systematic review and meta‐analysis of placebo‐controlled cardiovascular outcome trials (CVOTs) of newer glucose‐lowering agents [sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is), glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), and dipeptidyl peptidase‐4 inhibitors (DPP‐4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes. Materials and Methods: Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study‐specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta‐regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions. Results: Twenty unique CVOTs (six SGLT‐2is, nine GLP‐1RAs, five DPP‐4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT‐2is, GLP‐1RAs and DPP‐4is with placebo, the hazard ratios (95% CIs) for 3‐point major adverse cardiovascular events were 0.88 (0.82‐0.94), 0.85 (0.79‐0.92) and 1.00 (0.94‐1.06), respectively. SGLT‐2is and GLP‐1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP‐4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3‐point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67‐1.06; p =.14; R2 = 14.2%), which was driven by the component of non‐fatal stroke (R2 = 100.0%; p =.094). There were non‐significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes. Conclusions: SGLT‐2is and GLP‐1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT‐2is and GLP‐1RAs in patients with T2D extend beyond mere glycaemic control. [ABSTRACT FROM AUTHOR]

Aim: Despite the increasing use of combination treatment with sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide‐1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. Materials and Methods: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co‐primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid‐femoral pulse wave velocity. Secondary outcomes included 24‐h blood pressure (BP), 24‐h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. Results: The carotid‐femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty‐four‐hour systolic BP was reduced by 10 mmHg (95% CI 6–14), p <.001 in the combination group, significantly superior to both placebo and monotherapy (p <.05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p <.001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4–57), p =.03 in the combination group compared with placebo. Conclusions: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24‐h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Postprandial glucose control can be challenging for individuals with type 1 diabetes, and this can be attributed to many factors, including suboptimal therapy parameters (carbohydrate ratios, correction factors, basal doses) because of physiological changes, meal macronutrients and engagement in postprandial physical activity. This narrative review aims to examine the current postprandial glucose‐management strategies tested in clinical trials, including adjusting therapy settings, bolusing for meal macronutrients, adjusting pre‐exercise and postexercise meal boluses for postprandial physical activity, and other therapeutic options, for individuals on open‐loop and closed‐loop therapies. Then we discuss their challenges and future avenues. Despite advancements in insulin delivery devices such as closed‐loop systems and decision‐support systems, many individuals with type 1 diabetes still struggle to manage their glucose levels. The main challenge is the lack of personalized recommendations, causing suboptimal postprandial glucose control. We suggest that postprandial glucose control can be improved by (i) providing personalized recommendations for meal macronutrients and postprandial activity; (ii) including behavioural recommendations; (iii) using other personalized therapeutic approaches (e.g. glucagon‐like peptide‐1 receptor agonists, sodium‐glucose co‐transporter inhibitors, amylin analogues, inhaled insulin) in addition to insulin therapy; and (iv) integrating an interpretability report to explain to individuals about changes in treatment therapy and behavioural recommendations. In addition, we suggest a future avenue to implement precision recommendations for individuals with type 1 diabetes utilizing the potential of deep reinforcement learning and foundation models (such as GPT and BERT), employing different modalities of data including diabetes‐related and external background factors (i.e. behavioural, environmental, biological and abnormal events). [ABSTRACT FROM AUTHOR]

Summary: Background/Aims: We examined the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) initiation on long‐term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction‐Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real‐world data from the MarketScan database. Methods: We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP‐1RAs initiation, modelled as time‐dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP‐1RAs and 4837 non‐GLP‐1RAs patients. Results: The non‐GLP‐1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP‐1RAs patients had 32 (7%) ALO over 586.6 person years – risk rate difference 13.5 (95% CI: 11.4–15.7) per 100 person‐years. The OPSW‐adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54–0.76) in patients with vs. without GLP‐1RAs initiation. GLP‐1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61–0.88), portal hypertension (HR: 0.73; 95% CI: 0.60–0.88), HCC (HR: 0.37; 95% CI: 0.20–0.63) and LT (HR: 0.24; 95% CI: 0.12–0.43). Conclusion: The use of GLP‐1RAs was associated with significant risk reductions in long‐term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. Methods: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. Results: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. Conclusion: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD. [ABSTRACT FROM AUTHOR]

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans. [ABSTRACT FROM AUTHOR]

Dietary salt has been associated with cognitive impairment in mice, possibly related to damaged synapses and tau hyperphosphorylation. However, the mechanism underlying how dietary salt causes cognitive dysfunction remains unclear. In our study, either a high-salt (8%) or normal diet (0.5%) was used to feed C57BL/6 mice for three months, and N2a cells were cultured in normal medium, NaCl medium (80 mM), or NaCl (80 mM) + Liraglutide (200 nM) medium for 48 h. Cognitive function in mice was assessed using the Morris water maze and shuttle box test, while anxiety was evaluated by the open field test (OPT). Western blotting (WB), immunofluorescence, and immunohistochemistry were utilized to assess the level of Glucagon-like Peptide-1 receptor (GLP-1R) and mTOR/p70S6K pathway. Electron microscope and western blotting were used to evaluate synapse function and tau phosphorylation. Our findings revealed that a high salt diet (HSD) reduced the level of synaptophysin (SYP) and postsynaptic density 95 (PSD95), resulting in significant synaptic damage. Additionally, hyperphosphorylation of tau at different sites was detected. The C57BL/6 mice showed significant impairment in learning and memory function compared to the control group, but HSD did not cause anxiety in the mice. In addition, the level of GLP-1R and autophagy flux decreased in the HSD group, while the level of mTOR/p70S6K was upregulated. Furthermore, liraglutide reversed the autophagy inhibition of N2a treated with NaCl. In summary, our study demonstrates that dietary salt inhibits the GLP-1R/mTOR/p70S6K pathway to inhibit autophagy and induces synaptic dysfunction and tau hyperphosphorylation, eventually impairing cognitive dysfunction. [ABSTRACT FROM AUTHOR]

BACKGROUND Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society--Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P=0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.) [ABSTRACT FROM AUTHOR]

Obesity is a significant risk factor for health issues like type 2 diabetes and cardiovascular disease. It often proves resistant to traditional lifestyle interventions, prompting a need for more precise therapeutic strategies. This has led to a focus on signaling pathways and neuroendocrine mechanisms to develop targeted obesity treatments. Recent developments in obesity management have been revolutionized by introducing novel glucagon-like peptide-1 (GLP-1) based drugs, such as semaglutide and tirzepatide. These drugs are part of an emerging class of nutrient-stimulated hormone-based therapeutics, acting as incretin mimetics to target G-protein-coupled receptors like GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon. These receptors are vital in regulating body fat and energy balance. The development of multiagonists, including GLP-1-glucagon and GIP-GLP-1-glucagon receptor agonists, especially with the potential for glucagon receptor activation, marks a significant advancement in the field. This review covers the development and clinical efficacy of various GLP-1-based therapeutics, exploring the challenges and future directions in obesity management. [ABSTRACT FROM AUTHOR]

Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern antiemetic medications. Similarly, antiobesity/diabetes medications that target the glucagon-like peptide-1 system, despite their remarkable metabolic success, also cause nausea and vomiting in a significant number of patients. These side effects hinder the ability to administer higher dosages for optimal glycemic and weight management and represent the major reasons for treatment discontinuation. Our inability to effectively control these side effects highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that drive and inhibit nausea and emesis. Here, we discuss clinical and preclinical evidence that highlights the glucose-dependent insulinotropic peptide receptor system as a novel therapeutic central target for the management of nausea and emesis. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases, including PD and type 2 diabetes mellitus (T2DM), suggesting a crucial interplay between the gut–brain axis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies is also very promising, enhancing the possibility of adding GLP1-R agonists to the current armamentarium of drugs available for PD treatment. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective medications for the treatment of type 2 diabetes and obesity. Pharmacological studies in rodents support an association between the use of GLP-1 RAs and the development of medullary thyroid cancer (MTC) resulting in a black box warning for these agents in patients at risk for this condition. Yet, the association between GLP-1 RAs and non-MTC remains controversial. Excessive worry about unproven thyroid cancer risk might lead to underutilizing GLP-1 RAs in patients who could otherwise experience substantial benefits. Unwarranted concerns about thyroid cancer could lead to unnecessary thyroid cancer screening and harms from overdiagnosis. Summary: The body of evidence assessing the association between GLP-1 RA use and thyroid cancer spans a wide range of methodologies, including basic and translational research investigating biological plausibility; randomized trials assessing clinical efficacy and providing the strongest evidence for causality; observational studies providing real-life outcome evaluation in larger populations but with limited evaluation of covariates or dependable outcome definitions; and pharmacovigilance studies that provide postmarketing assessments of a safety signal but do not address causality. There is biological plausibility supporting an association between GLP-1 RA and MTC in rodents, which is less clear for non-MTC in humans. Clinical evidence from randomized trials and associated meta-analysis suggest thyroid cancer as a rare event making effect estimates imprecise but without conclusive and consistent evidence of increase risk in those receiving GLP-1 RA. Observational studies at higher risk of bias also show low event rates for thyroid cancer, with effect estimates that are inconsistent among different studies. Pharmacovigilance studies consistently show a signal of increased reporting of thyroid cancer in patients treated with GLP-1 RA. Conclusions: Evidence from randomized controlled trials indicates occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 RA. Observational studies at higher risk of bias yield inconsistent results. Overall there is no conclusive evidence of elevated thyroid cancer risk. These findings can help clinicians when addressing patient's concerns about a potential yet unproven link between GLP-1 RA therapy and thyroid cancer. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions. Type 2 diabetes is a disease of elevated blood sugar levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type of medication used to treat type 2 diabetes that work on GLP-1 receptors in the body. Semaglutide and dulaglutide are examples of GLP-1 RAs, which lower blood sugar and body weight. Tirzepatide is a newer medication, which works on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. It reduces blood sugar and body weight in people living with type 2 diabetes. Healthcare professionals and patients are interested in how switching medication from semaglutide or dulaglutide to tirzepatide might change blood glucose levels and body weight. However, because tirzepatide is a newer medication, there is not much information available on this aspect. Data from clinical trials of these medications were used to predict the effects of switching from semaglutide or dulaglutide to tirzepatide. These model-based simulations showed that switching to tirzepatide may further reduce HbA1c (a measure of blood sugar) and body weight. This may provide useful information to healthcare professionals and patients when making decisions about treatment with these medications. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. RESEARCH DESIGN AND METHODS: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years' duration, HbA1c 6.8–8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined differences at 1 year and over the 3-year follow-up. RESULTS: Across treatments, diabetes distress (−0.24, P < 0.0001) and depressive symptoms (−0.67, P < 0.0001) decreased over 1 year. Diabetes distress was lower at 1 year for the glargine group than for the other groups combined (−0.10, P = 0.002). Diabetes distress was also lower for liraglutide than for glimepiride or sitagliptin (−0.10, P = 0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms. CONCLUSIONS: Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress. Glargine lowered diabetes distress modestly at 1 year rather than increasing it. Liraglutide also reduced diabetes distress at 1 year. Results can inform treatment decisions for adults with early T2DM. [ABSTRACT FROM AUTHOR]

Background: The efficacy of once-weekly (OW) glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been established in several trials in people with type 2 diabetes mellitus (T2DM); however, real-world evidence on their effectiveness is limited. This study evaluated the effectiveness of OW GLP-1RA regarding glycemic and weight outcomes, and relative to DPP-4i in a comparator analysis. Methods: This observational cohort study evaluated glycated hemoglobin (HbA1c) and weight outcomes in people with T2DM with two or more prescription claims for the same OW GLP-1RA using a pre-post study design (including for a semaglutide OW T2DM subgroup, hereafter referred to as semaglutide). Comparator analysis for the same outcome was performed for OW GLP-1RAs versus DPP-4i and semaglutide subgroup versus DPP-4i. A linked patient population from the IQVIA PharMetrics® Plus database and the Ambulatory Electronic Medical Records (AEMR) database was analyzed using data from January 2017 to April 2022. HbA1c and weight were assessed at baseline and at the end of the 12-month post-index period. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances in baseline patient characteristics in the comparator analysis. Results: In the pre-post analysis, a greater numerical reduction in HbA1c and weight was observed for the semaglutide subgroup (N = 354) relative to the OW GLP-1RA cohort (N = 921). In the semaglutide subgroup, 52.5% and 34.2% of patients achieved HbA1c of < 7.0% and ≥ 5% weight loss, respectively. For the comparator analysis, the OW GLP-1RAs (N = 651) were significantly more effective (p < 0.001) in reducing HbA1c (− 1.5% vs. − 1.0%) and weight (− 3.2 kg vs. − 1.0 kg) than the DPP-4is (N = 431). Similarly, the semaglutide cohort (N = 251) also displayed more effectiveness (p < 0.001) in reducing HbA1c (− 1.7% vs. − 0.9%) and weight (− 4.1 kg vs. − 1.3 kg) than the respective DPP-4i cohort (N = 417). Patients initiating OW GLP-1RAs, including the semaglutide cohort, were at least twice as likely to achieve HbA1c and weight outcomes as well as composite outcomes compared with those initiating DPP-4is. Conclusion: The study reinforces that OW GLP-1RAs are more effective in glycemic control and weight reduction compared with DPP-4is in people with T2DM in the real-world setting. These findings align with the recommendation in the current guidelines for utilizing glucose-lowering treatment regimens that support weight-management goals in people with T2DM. Plain Language Summary: In type 2 diabetes mellitus (T2DM), glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for managing blood sugar levels and major adverse cardiovascular event risk reduction. In clinical trials, once-weekly (OW) GLP-1RAs showed better control of blood sugar levels and body weight than those administered daily, as well as another class of daily T2DM medications called dipeptidyl peptidase-4 inhibitors (DPP-4is). However, there is limited evidence of OW GLP-1RAs-based routine care to confirm these findings. This study gathered prescription and outcomes data for people with T2DM (January 2017–April 2022) from two linked US databases. Body weight measurements and glycated hemoglobin (HbA1c) test results (measuring average blood sugar levels) were used to evaluate the effectiveness of OW GLP-1RAs (exenatide, dulaglutide, and semaglutide) via a pre-post analysis, and compare OW GLP-1RAs with DPP-4is. We found that treatment with semaglutide lowered body weight and blood sugar levels to a greater extent than OW GLP-1RAs in the pre-post analysis. In the comparator analysis, people receiving OW GLP-1RAs, including semaglutide, were at least twice as likely to achieve reduced HbA1c levels and body weight compared with those receiving DPP-4is. People receiving OW GLP-1RAs were three times more likely than those on DPP-4is to achieve the recommended target of HbA1c < 7.0% and weight loss ≥ 5%, while treatment with semaglutide increased this likelihood by > 4.6 times. This study shows clear benefits of OW GLP-1RAs, building on current evidence for integration of this treatment into overall management of T2DM. [ABSTRACT FROM AUTHOR]

Introduction: Semaglutide, the only glucagon-like peptide-1 receptor agonist (GLP-1 RA) available in subcutaneous and oral formulation for treatment of type 2 diabetes (T2D), has demonstrated clinically significant improvements in glycaemic control and weight in clinical trials. This study aimed to gain insights into the use of both formulations and evaluate their clinical effectiveness in a secondary care clinic in Wales. Methods: This was a retrospective observational analysis of adults with T2D initiated on oral or subcutaneous semaglutide. Changes from baseline in glycated haemoglobin (HbA1c), weight and other metabolic parameters were evaluated. Results: At baseline, participants (n = 103) had a mean age of 57.3 years, mean HbA1c of 79.1 mmol/mol (9.38%), mean weight of 111.8 kg and body mass index (BMI) of 39.6 kg/m2 (no statistically significant differences between oral and subcutaneous groups). At 6-month follow-up, statistically significant improvements in HbA1c (− 19.3 mmol/mol [− 1.77%] and − 20.8 mmol/mol [− 1.90%]), body weight (− 9.0 kg and − 7.2 kg), and BMI (− 3.3 kg/m2 and − 2.5 kg/m2) were observed for oral and subcutaneous semaglutide, respectively. No statistically significant differences between the formulations were observed, and safety profiles were comparable. Conclusions: Both formulations of semaglutide provided clinically and statistically significant reductions in HbA1c and weight in real-world practice. Oral GLP-1 RA may offer a practical and effective option for the management of T2D. [ABSTRACT FROM AUTHOR]

Introduction: Optimal glycemic management after diabetes onset remains a challenge in Hispanic/Latino adults with type 2 diabetes (T2D), often resulting in poor health outcomes and higher rates of diabetes-related complications. The aim of this study was to examine and compare demographic and clinical characteristics, glycemic outcomes, health care resource utilization (HCRU), and costs among injection-naïve Hispanic/Latino adults with T2D initiating dulaglutide or basal insulin. Methods: This retrospective, observational study used administrative claims data from the Optum Research Database. Hispanic/Latino adults with T2D were assigned to dulaglutide or basal insulin cohorts on the basis of pharmacy claims and were propensity-score matched on demographic and baseline characteristics. Measures of glycemic management included 12 month follow-up glycated hemoglobin (HbA1c) and change in HbA1c from baseline. Follow-up all-cause and diabetes-related HCRU and costs, including costs per 1% change in HbA1c, were compared between cohorts. Results: The final propensity-score matched sample included 2872 patients: 1436 patients in each cohort. Mean (SD) reduction in HbA1c from baseline to 12 month follow-up was greater in the dulaglutide cohort compared with the basal insulin cohort [−1.40% (1.88) versus −0.92% (2.07); p < 0.001]. The dulaglutide cohort had significantly lower proportions of patients with ≥ 1 all-cause and diabetes-related outpatient visits, emergency room visits, and inpatient stays compared with the basal insulin cohort (p < 0.05). The dulaglutide cohort had significantly lower all-cause total costs per 1% HbA1c reduction than the basal insulin cohort ($13,768 versus $19,128; p < 0.001). Diabetes-related costs per 1% reduction were numerically lower for the dulaglutide cohort, but the difference was not statistically significant ($9737 versus $11,403; p = 0.081). Conclusions: Dulaglutide demonstrated better glycemic outcomes and lower all-cause costs per 1% HbA1c reduction among Hispanic/Latino adults compared with those initiating basal insulin. Our real-world findings in the Hispanic/Latino population were consistent with results obtained from the overall population and confirm the glycemic benefits of dulaglutide observed in clinical settings. [ABSTRACT FROM AUTHOR]

Summary: Background: Growing evidence indicates that incretin‐based therapies (IBTs), glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), and dipeptidyl peptidase‐4 inhibitors (DPP4is) are effective and safe for treating pediatric obesity patients with or without type 2 diabetes. Therefore, we aimed to perform a systematic review and meta‐analysis for updating current evidence. Methods: We searched the PubMed, the Cochrane Library, and the EMBASE database for articles published until September 15, 2023, and limited to randomized control trials. The primary outcomes were changed from baseline in weight metrics and the cardiometabolic profile. A random effects model will be used, as high heterogeneity is expected. All analyses were performed using STATA 17.0. Results: Fifteen trials with a total number of 1286 participants were included in our meta‐analysis. Overall, the mean difference in weight change between the IBTs group and the control group was −2.89 kg (95% confidence interval, −5.12 to −0.65, p = 0.011). Additionally, IBTs significantly reduced the HbA1c level and fasting plasma glucose by 0.37% and 6.99 mg/dl, compared with control groups. IBTs showed a little increased risk of GI side effects and hypoglycemia events, but none of the severe hypoglycemia events were occurred in IBTs group. Conclusions: Our study results have proved that GLP‐1 RAs are safe, acceptable, and effective in weight reduction and sugar control for children with obesity. In addition, DPP‐4is seems to have no effect on glycemic control and weight loss in childhood obesity. Further research is needed to confirm these findings, especially in younger children. [ABSTRACT FROM AUTHOR]

This article explores the potential link between the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and suicidality. GLP-1RAs are commonly used to treat diabetes and obesity and have been effective in controlling blood sugar levels and promoting weight loss. However, recent reports have raised concerns about the potential risk of suicidality associated with these medications. The article emphasizes the need for further research and caution when prescribing GLP-1RAs, but also highlights that the benefits of these medications for diabetes and obesity generally outweigh the uncertain and rare risk of suicidality. Clinicians should monitor patients for mood changes or suicidality and follow regulatory guidance. [Extracted from the article]

Aim: Novel long‐acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin‐4‐IgG4‐Fc (E4F4) is a long‐acting glucagon‐like peptide‐1 receptor agonist. This first‐in‐human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. Methods: This single‐centre, randomized, double‐blind, placebo‐controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. Results: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose‐dependent relationship between frequency, severity or causality of treatment‐emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45‐14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose‐dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose‐response relationship in the 1.8‐10.35 mg dose range, with an increased response at the higher doses. Conclusion: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5‐10.35 mg once every 2 weeks. [ABSTRACT FROM AUTHOR]

Aim: To assess the short‐term, real‐world use and effectiveness of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) medications in the management of type 2 diabetes (T2D) in a diverse cohort of youth. Methods: This multicentre retrospective study analysed youth prescribed a GLP‐1RA for the management of T2D at two academic paediatric diabetes centres prior to June 2022. Change in HbA1c and insulin use from baseline to first (median 91 days) and second (median 190 days) follow‐up were evaluated for those taking a GLP‐1RA. Multivariable linear mixed effects models adjusting for baseline sex, age, race/ethnicity, insurance, insulin regimen, metformin regimen, GLP‐1RA dosing frequency and the body mass index Z‐score (BMI‐Z) examined the change in HbA1c for participants for up to 6 months after baseline. Results: A total of 136 patients with T2D (median age 16.1 [interquartile range 13.9‐18.0] years, 54% female, 56% non‐Hispanic Black, 24% Hispanic, 77% with public insurance) were prescribed GLP‐1RAs and taking them at first or second follow‐up. Median HbA1c decreased from 7.9% to 7.6% (P <.001) at a median follow‐up of 91 days (n = 109) and, among those with HbA1c available at baseline and second follow‐up (n = 83), from 8.4% to 7.4%. The proportion of patients prescribed insulin decreased from baseline to the first follow‐up visit (basal 69% to 60% [P =.008], prandial 46% to 38% [P =.03]). In multivariable analysis, there was a mean decrease in HbA1c by 0.09 percentage points per month (P =.005, 95% confidence interval −0.15, −0.03). Conclusions: Real‐world use of GLP‐1RAs in youth with T2D is associated with decreased HbA1c levels, despite challenges with access and adherence. GLP‐1RA treatment may reduce insulin doses for youth with T2D. [ABSTRACT FROM AUTHOR]

Aim: To determine the comparative effectiveness regarding major cardiovascular events of glucagon‐like peptide‐1 (GLP‐1) receptor agonists and sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Materials and Methods: We assembled a cohort of commercially insured adult patients with T2DM in the United States (derived from Optum Clinformatics DataMart 2003‐2021) who were new users of GLP‐1 receptor agonists or SGLT‐2 inhibitors. We compared risks of non‐fatal myocardial infarction or stroke in patients with and without CKD, and further categorized by CKD stage: stages G1 or G2 [estimated glomerular filtration rate (eGFR) ≥60 ml/min] and A2 (urine albumin to creatinine ratio 30 to <300 mg/g) or A3 (urine albumin to creatinine ratio ≥300 mg/g), stage G3a (eGFR 45 to <60 ml/min/1.73 m2) and stage G3b (eGFR 30 to <45 ml/min/1.73 m2). We used proportional hazards regression after inverse probability of treatment weighting to compute hazard ratios and 95% confidence intervals. Results: After accounting for the probability of treatment, patients with T2DM and CKD treated with SGLT‐2 inhibitors experienced a 14% lower risk of non‐fatal myocardial infarction or stroke (hazard ratio 0.86, 95% confidence interval 0.78‐0.94) relative to those treated with GLP‐1 receptor agonists. Conclusions: Recognizing the potential for residual confounding, selection bias and immortal time bias, commercially insured patients in the United States with T2DM and CKD treated with SGLT‐2 inhibitors experienced significantly lower risks of non‐fatal myocardial infarction or stroke relative to those treated with GLP‐1 receptor agonists. [ABSTRACT FROM AUTHOR]

Prescriptions and use of glucagon-like peptide-1 (GLP-1) receptor agonists are increasing dramatically, as indications are expanding from the treatment of diabetes mellitus to weight loss for people with obesity. As GLP-1 receptor agonists delay gastric emptying, perioperative healthcare practitioners could be concerned about an increased risk for pulmonary aspiration during general anaesthesia. We summarise relevant medical literature and provide evidence-based recommendations for perioperative care for people taking GLP-1 receptor agonists. GLP-1 receptor agonists delay gastric emptying; however, ongoing treatment attenuates this effect. The risk of aspiration during general anaesthesia is unknown. However, we advise caution in patients who recently commenced on GLP-1 receptor agonists. After over 12 weeks of treatment, standard fasting times likely suffice to manage the risk of pulmonary aspiration for most otherwise low-risk patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is an increasingly common long-term condition, and suboptimal perioperative glycaemic control can lead to postoperative harms. The advent of new antidiabetic drugs, in particular glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, has enabled perioperative continuation of these medicines, thus avoiding the harms of variable rate i.v. insulin infusions whilst providing glycaemic control. There are differences between medicines regulatory agencies and organisations on how these classes that are most often used to treat diabetes mellitus, (but also in the case of SGLT2 inhibitors chronic kidney disease and heart failure in those without diabetes) should be managed in the perioperative period. In this commentary, we argue that GLP-1 receptor agonists should continue during the perioperative period and that SGLT2 inhibitors should only be omitted the day prior to a planned procedure. The reasons for the differing advice advocated between regulatory agencies and what anaesthetic practitioners should do in the face of continuing uncertainty are discussed. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. Methods: A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. Results: Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40–0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. Conclusion: Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials and real-world studies suggest that combination therapy with sodium–glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is associated with improvement in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), systolic blood pressure (SBP), body mass index (BMI), and total cholesterol levels. However, a systematic review of available real-world evidence may facilitate clinical decision-making in the real-world scenario. This meta-analysis assessed the safety and effectiveness of combinations of SGLT2is + GLP-1RAs with a focus on their cardioprotective effects along with glucose-lowering ability in patients with type 2 diabetes mellitus (T2DM) in a real-world setting. Methods: Electronic searches were performed in the PubMed/MEDLINE, PROQuest, Scopus, CINAHL, and Google Scholar databases. Qualitative analyses and meta-analyses were performed using the Joanna Briggs Institute SUMARI software package and Review Manager v5.4, respectively. Results: The initial database search yielded 1445 articles; of these, 13 were included in this study. The analyses indicated that SGLT2is + GLP-1RAs combinations were associated with significantly lower all-cause mortality when compared with individual therapies (odds ratio [95% confidence interval [CI] 0.49 [0.41, 0.60]; p < 0.00001). Significant reductions in BMI (− 1.71 [− 2.74, − 0.67]; p = 0.001), SBP (− 6.35 [− 10.17, − 2.53]; p = 0.001), HbA1c levels (− 1.48 [− 1.75, − 1.21]; p < 0.00001), and FPG (− 2.27 [− 2.78, − 1.76]; p < 0.00001) were associated with the simultaneous administration of the combination. Changes in total cholesterol levels and differences between simultaneous and sequential combination therapies for this outcome were not significant. Conclusion: This systematic review and meta-analysis based on real-world data suggests that the combination of SGLT2is + GLP-1RAs is associated with lower all-cause mortality and favorable improvements in cardiovascular, renal, and glycemic measurements. The findings drive a call-to–action to incorporate this combination early and simultaneously in managing T2DM patients and achieve potential cardiovascular benefits and renal protection. [ABSTRACT FROM AUTHOR]

Background. Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the risk of cardiovascular events. The aim of the present systematic review and meta-analysis is to demonstrate the effects of GLP-1 RA and SGLT2is on intima-media thickness (IMT). Methods. PubMed, EMBASE, Web of Science, SCOPUS, and Google Scholar databases were searched from inception to September 9, 2023. All interventional and observational studies that provided data on the effects of GLP-1 RAs or SGLT2is on IMT were included. Critical appraisal was performed using the Joanna Briggs Institute checklists. IMT changes (preintervention and postintervention) were pooled and meta-analyzed using a random-effects model. Subgroup analyses were based on type of medication (GLP-1 RA: liraglutide and exenatide; SGLT2i: empagliflozin, ipragliflozin, tofogliflozin, and dapagliflozin), randomized clinical trials (RCTs), and diabetic patients. Results. The literature search yielded 708 related articles after duplicates were removed. Eighteen studies examined the effects of GLP-1 RA, and eleven examined the effects of SGLT2i. GLP-1 RA and SGLT2i significantly decreased IMT (MD = − 0.123 , 95% CI (-0.170, -0.076), P < 0.0001 , I 2 = 98 % and MD = − 0.048 , 95% CI (-0.092, -0.004), P = 0.031 , I 2 = 95 % , respectively). Metaregression showed that IMT change correlated with baseline IMT, whereas it did not correlate with gender, duration of diabetes, and duration of treatment. Conclusions. Treatment with GLP-1 RA and SGLT2i can lower IMT in diabetic patients, and GLP-1 RA may be more effective than SGLT2i. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to compare the effect of sodium–glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of diabetic retinopathy (DR) in patients with type 2 diabetes (DM2). Methods: We systematically searched the databases Pubmed, Embase, and Clinicaltrials up to October 2, 2023, for randomized clinical trials (RCTs) of drugs from the GLP-1RA, SGLT-2i, and DPP-4i groups, with at least 24 weeks duration, including adult patients with DM2 and reported ocular complications. A pairwise meta-analysis was performed to calculate the odds ratio (OR) of DR incidents. Results: Our study included 61 RCTs with a total of 188,463 patients and 2773 DR events. Pairwise meta-analysis showed that included drug groups did not differ in the risk of DR events: GLP1-RA vs. placebo (OR 1.08; CI 95% 0.94, 1.23), DPP-4i vs. placebo (OR 1.10; CI 95% 0.84, 1.42), SGLT2i vs. placebo (OR 1.02; CI 95% 0.76, 1.37). Empagliflozin may be associated with a lower risk of DR, but this sub-analysis included only three RCTs (OR 0.38; 95% CI 0.17, 0.88, p = 0.02). Conclusions: Based on currently available knowledge, it is challenging to conclude that the new antidiabetic drugs significantly differ in their effect on DR complications. [ABSTRACT FROM AUTHOR]

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics, glucagon-like peptide-1 receptor agonists (GLP-1ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2-in). Despite new guidelines, clinical inertia, which can be caused by physicians, patients or the healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient's overall situation in decision-making. We looked for the possible reasons for clinical inertia and the poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiatives in diabetes aim to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings. [ABSTRACT FROM AUTHOR]

Originally designed as anti-hyperglycemic drugs, Glucagon-Like Peptide-1 receptor agonists (GLP-1Ra) and Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated protective cardiovascular effects, with significant impact on cardiovascular morbidity and mortality. Despite several mechanisms have been proposed, the exact pathophysiology behind these effects is not yet fully understood. Cardiovascular imaging is key for the evaluation of diabetic patients, with an established role from the identification of early subclinical changes to long-term follow up and prognostic assessment. Among the different imaging modalities, CMR may have a key-role being the gold standard for volumes and function assessment and having the unique ability to provide tissue characterization. Novel techniques are also implementing the possibility to evaluate cardiac metabolism through CMR and thereby further increasing the potential role of the modality in this context. Aim of this paper is to provide a comprehensive review of changes in CMR parameters and novel CMR techniques applied in both pre-clinical and clinical studies evaluating the effects of SGLT2i and GLP-1Ra, and their potential role in better understanding the underlying CV mechanisms of these drugs. [ABSTRACT FROM AUTHOR]