Glucagon-like peptide-1 receptor (GLP-1R) agonists prevent tributyltin-induced muscle atrophy/wasting via restoring GLP-1R signaling in vitro and in mice.

Certain antidiabetic agents may prevent dementia in patients with type 2 diabetes mellitus (T2DM). The purpose of this study is to elucidate the relative effect of antidiabetic agents on reducing dementia risk in patients with T2DM. PubMed, Cochrane Library and Igaku Chuo Zasshi-Web from inception to 31 December 2023 were searched. Trials reported in English or Japanese language that assessed the effects of glucose-lowering drugs on dementia were selected. Overall, 67 trials (4 088 683 individuals) assessing nine antidiabetic agent classes were included. Studies comprised monotherapies versus control (no use of antidiabetic agents or placebo) (three trials), monotherapies versus add-on therapies (one trial) and real-world database studies (63 trials). The analysis showed that the risk of dementia decreased with sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), thiazolidinediones (TZD) and dipeptidyl peptidase-4 inhibitors (DPP4i) compared with the reference (placebo, no use of antidiabetic agents or other antidiabetic agents). Conversely, insulin was associated with an increased risk of dementia, whereas no significant association was found with the use of metformin, sulfonylureas, glinides and α-glucosidase inhibitors. Analyses of treatment rankings further revealed the relative effect on reducing dementia risk in the following order: SGLT2i > GLP1-RA > TZD > DPP4i; insulin ranked the lowest. The most effective antidiabetic agent in reducing dementia risk in T2DM is SGLT2i, followed by GLP1-RA, TZD and DPP4i, whereas insulin is associated with an elevated risk of dementia.

Understanding the real-world impact of treatment with empagliflozin and glucagon-like peptide-1 receptor agonists (GLP-1RA) on healthcare resource utilization (HCRU) and costs could help inform clinical decision-making and healthcare policy. We conducted a comparative-effectiveness cohort study comparing HCRU and costs following empagliflozin versus GLP-1RA treatment in adults with type 2 diabetes (≥18 years) using US Medicare and commercial claims (08/2014-09/2019). We estimated rate ratios (RR) for HCRU outcomes using zero-inflated negative binomial regression and cost differences per member per year (PMPY) using gamma regression after adjusting for 143 baseline covariates via propensity score matching. We identified 146,341 matched pairs across all databases. After matching, the rates of hospital days, hospitalizations, emergency department (ED) visits, and physician office visits were similar between treatments. Empagliflozin had lower rates of dispensed medication classes versus GLP-1RA across most databases (RRs ranged from 0.91 to 0.95, RDs from -1246 to -709 per 1000 PY, reflecting varying degrees of precision). Total costs of care were lower with empagliflozin versus GLP-1RA. PMPY ratios ranged from 0.93 to 0.97 and differences from -$1425 to -$847. Inpatient and outpatient costs were comparable between treatments. Empagliflozin had lower pharmacy costs than GLP-1RA, mainly driven by glucose-lowering medications (PMPY ratios ranging from 0.91 to 0.95; PMPY differences from -$799 to -$441). Among adults with diabetes, empagliflozin was associated with similar rates of inpatient days, hospitalizations, ED, and office visits, with lower dispensed medication rates compared with GLP-1RA. Empagliflozin initiators incurred lower total costs, driven by lower glucose-lowering medication costs.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) effectively reduce hypoglycemia and offer additional clinical benefits such as weight loss. However, their high costs impose a significant economic burden on both patients and payers. Health care expenditures associated with GLP-1 RA use have not been adequately examined in previous studies. To examine the excess expenditures (total, payer, and out-of-pocket) associated with GLP-1 RA use compared with nonuse among adults with diabetes in the United States. The study design was cross-sectional using data on adults (aged ≥18years) with diabetes from multiple years (2016, 2018, and 2020) of the Medical Expenditure Panel Survey. Any GLP-1 RA use was derived from prescription medication files. Dependent variables included total, payer, and out-of-pocket health care expenditures. Excess expenditures associated with GLP-1 RAs were estimated using a multivariable generalized linear model (GLM) with gamma distribution and log link. The model adjusted for age, sex, race and ethnicity, social determinants of health, obesity, physical activity, and comorbid conditions. The study sample consisted of 7,670 adults with diabetes, representing approximately 28.6 million individuals in the United States. Overall, 7.5% of adults with diabetes used GLP-1 RAs, with rates increasing from 4.3% in 2016 to 10.6% in 2020. GLP-1 RA users had higher total ($22,029 vs $15,165, P < 0.001), payer ($20,023 vs $13,758, P < 0.001), and out-of-pocket ($2,006 vs $1,407, P < 0.001) expenditures compared with nonusers. Multivariable GLMs indicated that GLP-1 RA users incurred an adjusted excess of $5,417 (P < 0.001), $4,764 (P < 0.001), and $436 (P = 0.001) for total, payer, and out-of-pocket expenditures, respectively. One in 13 adults used GLP-1 RAs. GLP-1 RA users had greater overall, third-party, and out-of-pocket expenditures. These findings underscore the growing economic impact of GLP-1 RA use and highlight the importance of developing strategies that balance the proven clinical advantages of GLP-1 RAs against their financial burden.

Weight loss from glucagon-like peptide-1 receptor agonists by genetic factors in adults with type 2 diabetes.

FABP4, marker of worse prognosis in cardiovascular disease, induces neutrophil's proatherogenic phenotype which is modulated by semaglutide.

GLP-1 Receptor Agonists and Cardiovascular Outcomes in Adults With Diabetes and Peripheral Artery Disease: An Updated Systematic Review and Meta-Analysis.

Efficacy and safety of finerenone in Asian patients with type 2 diabetes and chronic kidney disease: A FIDELITY analysis by baseline kidney function.

Efficacy of GLP-1 receptor agonists in obese patients with heart failure with preserved ejection fraction: A systematic review and meta-analysis of randomized trials and propensity score-matched cohorts.

Association between glucagon-like peptide-1 receptor agonists and nonfusion risk after single-level anterior cervical discectomy and fusion.

Rationale: The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has advanced diabetes management. Nevertheless, frequent administration remains a challenge, even with weekly formulations. Herein, we developed a sustained-release hydrogel-based delivery system for Efsubaglutide Alfa (Suba), an IgG-conjugated GLP-1RA, designed to alleviate treatment burden and enhance patient adherence. Methods: A series of biodegradable poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers were synthesized, and a thermosensitive PLGA-PEG-PLGA hydrogel with suitable sol-gel transition temperature and in vivo degradation profile was selected for the fabrication of the Suba-loaded hydrogel system (Suba@T-gel). The pharmacokinetic and pharmacodynamic profiles following subcutaneous administration of Suba@T-gel were evaluated in multiple rodent models. Results: In vivo non-invasive imaging and pharmacokinetic studies showed that a single subcutaneous injection of Suba@T-gel enabled sustained release of Suba for over three weeks. This prolonged release profile is attributed to moderate Suba-polymer interactions and the large molecular size of Suba, which facilitate sustained drug release through a carrier degradation-controlled mechanism. In diabetic murine models, a single administration of Suba@T-gel achieved stable glycemic control for three weeks. Furthermore, the continuous liberation of Suba remarkably enhanced insulin secretion, reduced glycosylated hemoglobin levels, and improved pancreatic function in diabetic mice. Additionally, this system ameliorated diabetes-related complications by improving lipid metabolism, reversing hepatic steatosis and enhancing nerve fiber density. Conclusions: The Suba@T-gel system represents a promising strategy for long-acting management of diabetes and substantial improvement in patient compliance.

In patients with advanced chronic kidney disease (CKD), risk factor reversals occur where obesity and elevated LDL cholesterol paradoxically associate with improved survival. This review synthesizes recent advances in understanding these obesity and lipid paradoxes, integrating insights from body composition, inflammation, and metabolism. Observational studies have shown stage-specific survival advantages of obesity, mainly in hemodialysis populations and among patients with inflammation. The lipid paradox is also largely explained by the confounding effects of inflammation, which suppresses cholesterol levels. Beyond quantitative assessment, emerging evidence emphasizes that assessments of body composition and lipid quality are stronger predictors of clinical outcomes. For severely obese patients, integrative strategies using lifestyle, nutritional therapy, and pharmacologic agents may modulate inflammation, reducing the risk of protein-energy wasting. Weight loss from GLP-1 receptor agonists or bariatric surgery may improve kidney transplant eligibility but requires careful individual assessment to balance this benefit with the risk of malnutrition. The obesity and lipid paradoxes in CKD are not merely anomalies nor statistical fallacies to be adjusted for, but manifestations of CKD's distinct metabolic milieu. Their recognition highlights the need for individualized approaches beyond conventional risk factor modification. By integrating assessment of body composition, nutrition, and inflammation, precision nephrology can provide tailored interventions that improve prognosis.

The COVID-19 pandemic, caused by SARS-CoV-2, has had a profound global impact. Diabetes mellitus is a major comorbidity associated with higher infection risk, severe disease, and mortality in COVID-19 patients. This review examines the bidirectional relationship between COVID-19 and diabetes, focussing on immunometabolic mechanisms, post-COVID metabolic effects, and therapeutic implications. A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science for articles published until May 2025 using the terms "COVID-19," "SARS-CoV-2," "diabetes," and "immunometabolism." Peer-reviewed studies addressing clinical, molecular, or therapeutic interactions between the two diseases were included. Evidence shows that SARS-CoV-2 infection aggravates metabolic dysfunction through immune dysregulation, cytokine-mediated inflammation, and β-cell injury. Hyperglycemia promotes viral replication and inflammatory damage, creating a vicious cycle that worsens outcomes. Reports also indicate an increased risk of new-onset and post-COVID diabetes. Certain antidiabetic agents, such as metformin and GLP-1 receptor agonists, may improve prognosis via anti-inflammatory and metabolic effects. Diabetes significantly amplifies the severity of COVID-19 through intertwined metabolic and immune mechanisms. Understanding these interactions provides new insights into disease management and supports the development of targeted immunometabolic therapies for improving outcomes in diabetic patients affected by COVID-19.

Heart Failure With Preserved Ejection Fraction and Chronic Kidney Disease: From Pathophysiology to Treatment.

A GLP-1 receptor agonist semaglutide attenuates cardiac microvascular injury in HFD/STZ-induced diabetic mice.

Development and validation of an LC-MS/MS method for Tirzepatide, a dual GIP/GLP-1 receptor agonist, in rat plasma for application to a pharmacokinetic study.

Comprehensive identification and characterization of in vitro and in vivo metabolites of the novel GLP-1 receptor agonist danuglipron using UHPLC-QToF-MS/MS.

Type 2 diabetes is associated with worsened stroke outcome and lasting disability. The underlying mechanisms are undetermined, and no therapy is available. We experimentally investigated whether pharmacologically targeting obesity, which is highly prevalent in type 2 diabetes, before stroke enhances neurological recovery in type 2 diabetes. To induce weight loss, we employed the glucagon-like peptide1 receptor (GLP-1R) agonist semaglutide and the neuropeptideY receptor Y2 (NPY2R) agonist BI8271, which potentiates GLP-1R-mediated weight loss. We also investigated potential acute neuroprotective effects induced by these treatments, independently of metabolic regulation. C57BL/6J mice were fed with a high-fat diet for 5 months to induce obesity and features of type 2 diabetes (i.e. hyperglycaemia and insulin resistance). Weight loss was induced by 4-week administration of semaglutide and/or BI8271. As a control for the effect of weight loss, a vehicle (PBS)-treated group was switched to standard diet to achieve the same weight range and the same percentage weight loss within the same time frame as those receiving semaglutide/BI8271. Thereafter, mice were subjected to stroke by transient middle cerebral artery occlusion (tMCAO). Stroke recovery (the primary outcome) was assessed by measuring the recovery of grip strength and the lateralised sensorimotor integration. Brains and serum were collected, and stroke volume and serum IGF-1 levels were quantified (secondary outcomes). In additional studies, type 2 diabetic mice were subjected to tMCAO and injected with semaglutide and/or BI8271 1 and 24h after reperfusion. Acute neuroprotection (the primary outcome) was assessed by a grip strength test and by quantifying stroke volume and the number of surviving neuronal nuclear marker (NeuN)-positive neurons. We report that pre-stroke weight loss by GLP-1R activation, and more potently by dual co-activation of GLP-1 and NPY2 receptors, is a pharmacologically targetable mechanism, upstream of glycaemic regulation, through which post-stroke recovery is achieved. Moreover, we show that post-stroke recovery in type 2 diabetes is inversely associated with peripheral IGF-1 levels. Finally, GLP-1R and NPY2R activation can also improve stroke recovery through acute neuroprotection if they are given acutely after stroke, independently of their metabolic effects. The diabetes and obesity epidemics are increasing the incidence of stroke, and consequently the need for treatments to improve stroke outcome. Our results indicate that clinically used type 2 diabetes treatments could be employed in a preventive role to improve stroke outcome by exerting dual pharmacological action: weight loss and acute neuroprotection. These findings could have novel therapeutic implications for many people.

Single-cell RNA sequencing reveals beneficial mechanisms of Exendin-4 in autoimmune uveitis.

To compare treatment persistence and augmentation in adults with type 2 diabetes initiating glucagon-like peptide-1 receptor agonist versus sodium-glucose cotransporter-2 inhibitor therapy, including subgroups with cardiovascular disease and obesity. Using Humana Healthcare Research claims data, we identified adults with type 2 diabetes newly initiating GLP-1 RA or SGLT2i therapy between 1 January, 2018, and 30 June 2022. Eligible patients had >12 months of continuous enrollment before and after the index date (first GLP-1 RA or SGLT2i claim). Persistence was measured over 12 months post-index, defined by a therapy gap <45 days, with additional 30- and 90-day gap assessments. Days on therapy until discontinuation were calculated. Augmentation was defined as the initiation of a new glucose-lowering class not used pre- or at-index. The 1:1 matched cohort included 22 167 GLP-1 RA and 22 267 SGLT2i initiators (mean age 68.2 years; 52.2% female; 73.4% White; 18.6% Black). At 1 year, persistence was 37.6% for GLP-1 RA versus 47.0% for SGLT2i (p <0.001). Augmentation occurred in 23.4% versus 27.4%, respectively (p <0.001). GLP-1 RA users were more likely to discontinue (HR = 1.39, p <0.001) therapy. Cardiovascular and obesity subgroup findings were consistent with overall study findings. A higher percentage of patients were persistent with increasing allowable gap (30-day: 31.4% vs. 41.1%; 90-day: 50.1% vs. 59.1%, GLP-1 RA vs. SGLT2i, respectively). At 1 year, SGLT2i users showed higher persistence and augmentation than GLP-1 RA users. This may reflect better tolerance, fewer side effects, improved glucose control, preferences for oral medications, lower patient costs, and easier access to SGLT2i medications. Providers may support improved persistence by addressing patient-specific factors influencing therapy choices.