Glucagon-like Peptide-1 Receptor Agonists Research Articles

Comparison of GLP-1RAs vs Other Pharmacotherapy for Obesity

Background: The Centers for Disease Control and Prevention (CDC) reports that 42% of adults in the United States (US) are obese, and 10% are severely obese. Obesity has many known associated health risks, and successful treatment decreases those risks. Management always includes diet and lifestyle changes and drug therapy can improve weight loss. The current United States Food and Drug Administration (FDA) approved pharmaceutical therapy choices for long-term use include a combination of phentermine-topiramate, combination bupropion-naltrexone, orlistat, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual action GLP-1RAs and gastric inhibitory peptide agonists (GIP). Objectives: This review will summarize evidence comparing the safety and efficacy of GLP-1RAs or GLP-1RAs/GIP agonists with other pharmacologic treatments to achieve and maintain weight loss, improve quality of life, and reduce morbidity in obese adults. Methods: We completed a literature review of multiple databases, including PubMed, Embase, Google Scholar, and Cochrane databases, to identify studies about pharmacologic treatment for overweight or obese adults with or without T2DM and reporting outcomes of mean percentage body weight loss. An emphasis was placed on choosing meta-analyses and primary studies in patients without T2DM. We excluded articles older than 5 years or published in a language other than English. 19 meta-analyses and 2 randomized controlled trials (RCTs) were chosen, and 13 meta-analyses were excluded based on not meeting the inclusion criteria. 6 meta-analyses and 2 RCTs were included. Results: The literature showed that over 52 weeks, liraglutide reduced mean body weight percentage by 4.81% (95% CI: 4.23%-5.39%). Between a 12-68 week period in patients receiving semaglutide, three meta-analyses reported reduced weight by 12.57% [97% CI 10.35%-14.80%,) 10.55% (95% CI 6.96%-14.13%,) and 10.09% (95% CI: 8.33%-11.84%.) Tirzepatide, a novel GLP-1RA and GIP agonist, recently completed a phase-3 RCT, which showed that over 72 weeks, the mean weight percentage decrease was 18.4% (95% CI: 18.5%-23.2%) vs a 3.1% weight gain with placebo, a change of 21.8%. Each of the GLP-1RA agents (including tirzepatide) improved cardiometabolic risk factors. Phentermine-topiramate reduced mean body weight percentage by 8.45% (95% CI, 7.89%–9.01%) after 52-56 weeks. Bupropion-naltrexone reduced mean body weight percentage by 3.01% (95% CI, 2.47%–3.54%) over 56 weeks. Finally, orlistat reduced mean body weight percentage by 2.78% (95% CI, 2.36%–3.20%) after 1-4 years. Semaglutide is a well-established drug with weight loss, but tirzepatide shows the most promise in being the superior agent. Conclusion: It is well known that pharmacotherapy with diet and exercise is more effective than diet and exercise alone in achieving weight loss. The GLP-1RAs are effective for weight loss, with semaglutide more effective than phentermine-topiramate, bupropion-naltrexone, orlistat, and liraglutide. Tirzepatide shows promise as a superior agent, but more comprehensive studies need to be done. When choosing pharmacotherapy, utilizing a GLP-1RA (semaglutide) or a dual GLP-1RA/GIP agonist (tirzepatide) can improve cardiometabolic risk factors and quality of life and is more effective than any other FDA-approved agent. ?

Quantitative Comparison of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Adults: A Systematic Review and Model-Based Meta-Analysis.

The objective of this study is to quantitatively compare the weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adult patients with no diabetes and type 2 diabetes (T2D). PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase have been used as data sources from database inception to January 6, 2024. A total of 137 trials, encompassing 310 treatment arms, 17 GLP-1RAs, and 56,683 patients, were included in the analysis. The included trials were divided into three groups based on the characteristics of the populations: nondiabetic overweight or obesity group (NDOOG), type 2 diabetes Caucasian group (T2DCG), and type 2 diabetes Asian group (T2DAG). The effects of covariates were further evaluated, patients with a higher baseline body weight tend to have better weight loss outcomes, and patients with a higher baseline glycated hemoglobin (HbA1c) tend to achieve better blood sugar control. Five mathematical models were subjected to longitudinal analysis. In terms of Δ body weight, retatrutide (12 mg qw) was the most effective treatment (mean difference = -26.56% [95% confidence interval: -43.89% to -3.01%]). Tirzepatide (15 mg qw) demonstrated good weight loss ability in all three ΔBW models, ΔBW-NDOOG (-22.76% [-26.45% to -18.50%]), ΔBW-T2DCG (-11.09% [-12.39% to -9.44%])), and ΔBW-T2DAG (-4.97% [-5.84% to -4.12%]). In the aspect of ΔHbA1c, tirzepatide (10 mg qw) and oral orforglipron (10 mg qd) were the most effective drug, respectively. GLP-1RAs demonstrated effective weight management in both nondiabetic and T2D populations. Retatrutide achieved the most pronounced weight reduction, followed by tirzepatide. GLP-1RAs also significantly improved glycemic control for patients with T2D, with tirzepatide performing the best for glycemic control.

Glucagon-Like Peptide 1 Receptor Agonists and Venous Thromboembolism in Type 2 Diabetes: A Target Trial Emulation.

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are anti-diabetes agents recently approved for weight loss. Obesity is an established risk factor for venous thromboembolism (VTE). Moreover, preclinical studies have shown that GLP1-RA may attenuate thromboxaneinduced platelet activation. Therefore, we hypothesized that GLP1-RA use may reduce the risk of VTE. We performed a target trial emulation using a population-based database of electronic health records to evaluate whether GLP1-RA use is associated with a reduction in VTE in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidas e-4 inhibitors (DPP4i). Patients who were newly initiated on GLP1-RA were propensity scorematched to patients who were newly initiated on DPP4i. We evaluated the primary outcome, composite VTE, identified using ICD-10 codes, within 12 months of the initiation of GLP1-RA or DPP4i. The study cohort comprised 540,258 patients with 270,129 individuals receiving either GLP1-RA or DPP4i. Over 12 months of follow-up, patients who received GLP1-RA had a lower incidence of VTE compared with patients who received DPP4i (6.1 vs. 7.6 events per 1000 patient-years, hazard ratio [HR], 0.78 [95% CI: 0.73-0.83]). This was similar for PE (2.9 vs. 3.8 events per 1000 patient-years, HR, 0.74 [95% CI: 0.68-0.82]) and DVT (3.9 vs. 4.7 events per 1000 patient-years, HR, 0.81 [95% CI: 0.75-0.88]). In this propensity scorematched, target trial emulation study, patients with T2DM who received a GLP1-RA had a lower risk of VTE at one year compared with patients who received DPP4i.

Comparison of the efficacy and safety of GLP-1 receptor agonists on cardiovascular events and risk factors: A review and network meta-analysis.

This study aims to systematically evaluate and perform a systematic review and network meta-analysis comparing the comprehensive cardiovascular protective effects of various glucagon-like peptide-1 receptor agonists (GLP-1RAs), focusing on cardiovascular events and risk factors. We searched PubMed, Embase, Cochrane Library and Web of Science from inception to December 15, 2024. Included studies were published randomized controlled trials (RCTs) comparing GLP-1RAs to placebo or other GLP-1RAs. Missing data were standardized, and network meta-analysis was performed using Stata 17.0. Study heterogeneity, publication bias and evidence quality were assessed using the Cochrane Risk of Bias tool and Confidence in Network Meta-Analysis (CINeMA). As of December 15, 2024, a total of 18 313 articles were retrieved. Based on the inclusion and exclusion criteria, 156 high-quality studies were included, incorporating 144 782 patients and 14 different GLP-1RAs. The network meta-analysis demonstrated low heterogeneity, ensuring the reliability of the results. Comprehensive analysis revealed the following: Efpeglenatide was the most effective in reducing major adverse cardiovascular events. Oral semaglutide shows more significant advantages in reducing all-cause mortality and cardiovascular mortality. Orforglipron excelled in glycaemic control and weight reduction. SC-Semaglutide showed the greatest efficacy in lowering both systolic blood pressure and diastolic blood pressure, Liraglutide showed the greatest efficacy in lowering total cholesterol, Noiiglutide in triglycerides and Taspoglutide in low-density lipoprotein cholesterol, but no GLP-1RAs in high-density lipoprotein cholesterol. GLP-1RAs did not significantly increase the incidence of adverse events, but Orforglipron and Taspoglutide significantly increased the incidence of gastrointestinal adverse events compared with placebo. This study compared the cardiovascular benefits of different GLP-1RAs, including reductions in cardiovascular events and improvements in multiple cardiovascular risk factors. However, due to limitations in the quantity and quality of the included studies, the conclusions should be interpreted with caution. Future large-scale, high-quality clinical trials are needed to validate these findings and further optimize comprehensive cardiovascular management strategies for patients.

Diabetic Ketoacidosis and the Use of New Hypoglycemic Groups: Real-World Evidence Utilizing the Food and Drug Administration Adverse Event Reporting System

Background: Diabetic ketoacidosis (DKA), a life-threatening complication, can occur in individuals with type 2 diabetes during illness, stress, or medication use. This study examines DKA signals in type 2 diabetes, focusing on sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors. Methods: DKA reports from Q1 2019 to Q3 2024 were retrieved from the FDA Adverse Event Reporting System (FAERS). Associations between primary exposure and outcomes were ascertained using four key metrics: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Component (IC). Results: SGLT2 inhibitors exhibited the higher DKA risk in 2019–2021 (ROR: 314.86 [95% CI 301.76–328.53], PRR of 245.69 [95% CI 235.47- 256.36], IC of 6.90, and EBGM of 120), declining in 2022–2024. GLP-1 receptor agonists showed an ROR increase from 2.88 [95% CI 2.56–3.25] in 2019–2021 to 4.64 [95% CI 4.06–5.29] in 2022–2023, slightly declining to 3.95 [95% CI 3.27–4.74] in 2024. DPP-4 inhibitors exhibited a steady ROR rise from 6.81 [95% CI 5.52–8.40] in 2019–2021 to 8.57 [95% CI 6.24–11.76] in 2022–2023 and further to 11.02 [95% CI 6.71–18.10] in 2024. PRR, EBGM, and IC values followed similar trends. The age groups 41–60 and 61–91 years were the most affected, with hospitalization at its highest rate for DPP4-inhibitors in Q1-Q3 of 2024. Hospitalizations were also observed with GLP-1 receptor agonists and SGLT2 inhibitors. Life-threatening events and fatalities were also reported, with physicians contributing to most reports. Conclusions: DKA signals were observed for all three drug classes, particularly among elderly patients, highlighting the need for careful monitoring, especially during periods of illness or stress. However, the risk was higher in the SGLT2 inhibitor group than in the other groups.

Research progress and future prospects of small-molecule glucagon-like peptide-1 receptor agonists (GLP-1RAs)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are key agents in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Small-molecule GLP-1RAs offer the advantage of oral administration while demonstrating efficacy comparable to that of peptide drugs. Despite synthetic challenges and solubility issues, compounds such as Pfizer’s PF-06882961 (Danuglipron), Eli Lilly’s LY3502970 (Orforglipron), and Hengrui Pharma’s HRS-7535 have shown potential to reduce glycosylated hemoglobin A1c (HbA1c) levels and body weight in Phase I-II trials, with mild to moderate gastrointestinal adverse effects, suggesting that they may be promising therapeutic options in the future.

Design considerations for future renoprotection trials in the era of multiple therapies for chronic kidney disease.

Nephrology has benefited from conducting increasingly large high-quality trials in the last 5-10 years. In addition to the long-standing known benefits of renin-angiotensin system inhibitors, we now have multiple pharmacotherapies that provide kidney and/or cardiovascular protection for certain types of patient with chronic kidney disease (CKD). These include sodium-glucose co-transporter 2 inhibitors (SGLT2i), a non-steroidal mineralocorticoid receptor antagonist and a glucagon-like peptide-1 receptor agonist. Trials of SGLT2i have had particularly important impact, as wide eligibility criteria in pivotal trials have enabled safety and efficacy across a wide range of causes of CKD to be demonstrated. These findings support the concept of final common pathways of CKD progression and should encourage similar trial designs recruiting broad ranges of patients at risk of CKD progression. This is important as these new drugs do not completely arrest CKD progression nor do they mitigate the full excess of cardiovascular disease. In the current era of multiple therapies to manage risk of CKD progression, trial design and conduct also need to consider new challenges. These include falling event rates, establishing standard of care for participants pre-randomization and improving the inclusion of trial participants understudied in previous trials. Streamlining trial design and conduct and reducing participation burden for patients and clinicians is increasingly important to facilitate larger sample sizes and to optimize adherence to study interventions and follow-up. Potential other solutions include maintaining a focus on wide generalizability (to include understudied patient groups) and empowering patients to volunteer for trials (through public and patient involvement and large-scale invitation methods), as well as innovations in trial design (including use of pre-randomization run-in periods to implement standard of care and factorial or platform trials to assess multiple treatments simultaneously).

Exploring the Putative Involvement of MALAT1 in Mediating the Beneficial Effect of Exendin-4 on Oleic Acid-Induced Lipid Accumulation in HepG2 Cells

Background/Objectives: The reduction of oleic acid (OA)-induced steatosis in HepG2 cells observed upon treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) Exendin-4 (Ex-4) is associated with the modulation of the expression of several microRNAs, long non-coding RNAs (lncRNAs), and mRNAs. Notably, MALAT1, an lncRNA, shows significant downregulation in the presence of Ex-4 as compared to OA alone. In this study, we aimed to explore the role of MALAT1 in the positive impact of Ex-4 on OA-induced lipid accumulation in HepG2 cells. Methods: Steatosis in HepG2 cells was induced by treating them with 400 µM OA. The effect of Ex-4 on steatosis was examined by treating the steatotic cells with 200 nM of EX-4 for 3 h. MALAT1 was silenced with siRNA, while gene expression was quantified using qRT-PCR. Results: In the presence of Ex-4, the silencing of MALAT1 did not exert any discernible influence on de novo lipogenesis genes such as PPARγ and SREBP1. However, MALAT1 silencing significantly affected, to varying degrees, the expression levels of several lipid metabolism genes such as FAS, ACADL, CPT1A, and MTTP. Conclusions: Further investigations are warranted to fully decipher the role of the Ex-4-MALAT1 in the positive impact of GLP-1RAs on steatosis.

Upcoming drug targets for kidney protective effects in chronic kidney disease.

Despite recent advancements in the treatment of chronic kidney disease (CKD), identifying novel therapies beyond guideline-directed therapies that reduce residual cardiorenal risk remains imperative. In this review, we highlight the clinical evidence supporting emerging therapies for CKD, including glucagon-like peptide-1 receptor agonists (GLP1RA) and other incretin-based therapies, aldosterone synthase inhibitors (ASI), endothelin receptor antagonists (ERA), soluble guanylate cyclase (sGC) agonists and anti-inflammatory drugs. Long-acting GLP1RA are already recommended for glycemic control in patients with CKD and type 2 diabetes and the large, dedicated kidney outcome trial FLOW was recently stopped early for efficacy. Emerging clinical trial evidence supports the concept that ASI also provide additional benefit on top of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which remain a cornerstone of CKD treatment. Next, we consider the use of sGC agonists, which target nitric oxide bioavailability and thereby reduce albuminuria. Finally, we explore the therapeutic potential of ERA, which act through hemodynamic and anti-fibrotic mechanisms, thereby addressing a common final pathway in the development of CKD. Accordingly, our review highlights the changing therapeutic landscape for CKD with promising agents to further prevent the progression of kidney disease.

The Efficacy of Glucagon-like Peptide-1 (GLP-1) Receptor Agonists for Insufficient Weight Loss or Regain After Metabolic/Bariatric Surgery: A Systematic Review and Meta-analysis

The Efficacy of Glucagon-like Peptide-1 (GLP-1) Receptor Agonists for Insufficient Weight Loss or Regain After Metabolic/Bariatric Surgery: A Systematic Review and Meta-analysis

Semaglutide reprograms macrophages via the GLP-1R/PPARG/ACSL1 pathway to suppress papillary thyroid carcinoma growth.

The use of glucagon-like peptide-1 receptor (GLP-1R) agonists such as semaglutide, a novel class of antidiabetic medications, has raised concerns about potential adverse effects, particularly a possible association with thyroid cancer (TC). This study aims to evaluate whether semaglutide influences the progression of TC by modulating tumor-associated macrophages (TAMs). Semaglutide was administered to human papillary thyroid carcinoma (PTC) xenograft mouse models, co-culture systems consisting of human THP-1 macrophage cells and PTC cells, and primary murine peritoneal macrophages. Assessments included tumor size, M1/M2 macrophage ratio, PTC cell proliferation, and polarization marker expression. Semaglutide did not significantly impact the proliferation of PTC cells but reduced tumor size and inhibited the proliferation of PTC cells in co-culture systems. It increased M1 and decreased M2 macrophages, reprogramming polarization by downregulating PPARG expression. Co-treatment with semaglutide and a PPARG agonist in the co-culture system confirmed the upregulation of downstream genes RSAD2, ACSL1, and PLA2G7. Silencing ACSL1 inhibited lipid accumulation in THP-1 cells and promoted polarization towards the M2 macrophage phenotype. Semaglutide modulates macrophage lipid metabolism through the GLP-1R/PPARG/ACSL1 signaling pathway. This modulation promotes the conversion of TAMs to the M1 macrophage phenotype, enhancing their anticancer activity. These findings suggest that semaglutide may improve therapeutic strategies, reduce unnecessary thyroid nodule screenings, and broaden its clinical applications.

Comparing Glucagon-Like Peptide-1 Receptor Agonists to Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure With Preserved Ejection Fraction: A Systematic Review

Comparing Glucagon-Like Peptide-1 Receptor Agonists to Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure With Preserved Ejection Fraction: A Systematic Review

A System-Based Review on Effects of Glucagon-Like Peptide-1 Receptor Agonists: Benefits vs Risks

A System-Based Review on Effects of Glucagon-Like Peptide-1 Receptor Agonists: Benefits vs Risks

Effect of iGlarLixi on continuous glucose monitoring-measured time in range in insulin-naive adults with suboptimally controlled type 2 diabetes.

People with type 2 diabetes (T2D) and glycated haemoglobin (HbA1c) ≥9% may benefit from fixed-ratio combination therapies such as iGlarLixi (insulin glargine 100 U/mL and lixisenatide 33 μg/mL). Use of continuous glucose monitoring (CGM) is recommended, but data are lacking to assess the impact of iGlarLixi in individuals with HbA1c ≥9%. Soli-CGM (NCT05114590) was a 16-week, multicentre, open-label study evaluating the efficacy of once-daily iGlarLixi using blinded CGM-based metrics in insulin-naive adults with HbA1c ≥9%-13% who were receiving ≥2 oral antihyperglycaemic agents (OADs) ± glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The primary outcome was the change from baseline to week 16 in percent time in range (TIR; 70-180 mg/dL). Secondary outcomes included change in mean daily blood glucose (BG), maximum postprandial glucose 4 h post-breakfast (PPG-4 h), and time above range (TAR; >180 mg/dL). On-treatment hypoglycaemia was assessed. The study enrolled 124 participants (mean age, 55.6 years; HbA1c, 10.2%). Sixteen weeks of treatment with iGlarLixi improved TIR (+26.2%), mean BG (-52.5 mg/dL), maximum PPG-4 h (-73.7 mg/dL), and TAR (-28.7%); all p < 0.001. Rates of American Diabetes Association level 1 (BG <70 but ≥54 mg/dL) and level 2 (BG <54 mg/dL) hypoglycaemia were reported as 1.4 and 0.6 events per person-year, respectively. No level 3 events (requiring assistance) were reported. In people with T2D suboptimally controlled on ≥2 OADs ± GLP-1 RAs, 16 weeks of treatment with iGlarLixi significantly improved TIR and reduced TAR without severe hypoglycaemia.

GLP-1 and SGLT2 Therapies in Type 2 Diabetes Mellitus. Cutting-Edge Approaches to Advancing Diabetes Care

Type 2 diabetes mellitus (T2DM) is a multifactorial disease characterized by insulin resistance, beta-cell dysfunction, and chronic hyperglycemia. Despite the availability of conventional therapies, significant unmet needs persist in achieving optimal glycemic control and reducing long-term complications. GLP-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors represent two novel classes of antidiabetic agents that have transformed the therapeutic landscape. This paper explores their mechanisms of action, clinical benefits, and potential synergistic effects, emphasizing their impact on cardiovascular and renal outcomes. Challenges and future directions for these agents in personalized diabetes care are also discussed.

Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes: A Network Meta-Analysis.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors improve hyperglycemia, and SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACEs) among individuals with type 2 diabetes. It is not clear whether efficacy varies by age or sex. To assess whether age or sex are associated with differences in the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors. The MEDLINE and Embase databases and US and Chinese clinical trial registries were searched for articles published from inception to November 2022; in August 2024, the search was updated to capture the trial results. Two reviewers screened for randomized clinical trials of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors vs a placebo or active comparator in adults with type 2 diabetes. Individual participant data and aggregate data were used to estimate age × treatment interactions and sex × treatment interactions in multilevel network meta-regression models. Hemoglobin A1c (HbA1c) and MACEs. Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA1c; mean age, 58.9 [SD, 10.8] years; 42.3% were female and 23 trials with 168 489 participants reported MACEs; mean age, 64.0 [SD, 8.6] years; 35.3% were female), individual participant data were obtained for 103 trials (103 reported HbA1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% [95% credible interval {CrI}, 0.10% to 0.38%] per 30-year increment in age), for dual therapy (AR, 0.17% [95% CrI, 0.10% to 0.24%]), and for triple therapy (AR, 0.25% [95% CrI, 0.20% to 0.30%]). The use of GLP-1 receptor agonists was associated with greater HbA1c lowering with increasing age for monotherapy (AR, -0.18% [95% CrI, -0.31% to -0.05%] per 30-year increment in age) and for dual therapy (AR, -0.24% [95% CrI, -0.40% to -0.07%]), but not for triple therapy (AR, 0.04% [95% CrI, -0.02% to 0.11%]). The use of DPP4 inhibitors was associated with slightly better HbA1c lowering in older people for dual therapy (AR, -0.09% [95% CrI, -0.15% to -0.03%] per 30-year increment in age), but not for monotherapy (AR, -0.08% [95% CrI, -0.18% to 0.01%]) or triple therapy (AR, -0.01% [95% CrI, -0.06% to 0.05%]). The relative reduction in MACEs with use of SGLT2 inhibitors was greater in older vs younger participants per 30-year increment in age (hazard ratio, 0.76 [95% CrI, 0.62 to 0.93]), and the relative reduction in MACEs with use of GLP-1 receptor agonists was less in older vs younger participants (hazard ratio, 1.47 [95% CrI, 1.07 to 2.02]). There was no consistent evidence for sex × treatment interactions with use of SGLT2 inhibitors and GLP-1 receptor agonists. The SGLT2 inhibitors and GLP-1 receptor agonists were associated with lower risk of MACEs. Analysis of age × treatment interactions suggested that SGLT2 inhibitors were more cardioprotective in older than in younger people despite smaller reductions in HbA1c; GLP-1 receptor agonists were more cardioprotective in younger people.

Population profile and glycemic control following initiation or switch of injectable therapies in Tianjin, China: A real-world retrospective cohort study of adults with type 2 diabetes.

To evaluate characteristics and glycemic outcomes in individuals with type 2 diabetes using injectable therapies in real-world clinical practice in Tianjin, China. Data from inpatients and outpatients receiving injectable therapies between January 2015 and December 2019 were collected from the Tianjin regional electronic medical records and retrospectively analyzed. Seven cohorts were identified, including individuals initiating injectable therapies (premixed insulin [n = 4,687], basal insulin [4,177], or glucagon-like peptide-1 receptor agonists [541]) or switching injectable therapies (premixed insulin to basal insulin [1,298], basal insulin to premixed insulin [1,457], basal insulin to basal + bolus insulin [1,772], or glucagon-like peptide-1 receptor agonists to basal insulin ± glucagon-like peptide-1 receptor agonists [82]). In participants initiating therapy, glycated hemoglobin and fasting plasma glucose were highest in the basal insulin cohort, while among participants switching therapy, the highest values were in the basal insulin ± glucagon-like peptide-1 receptor agonists cohort. Initiating therapy with premixed or basal insulin and switching from basal insulin to basal + bolus insulin improved glycemic control over 12 months. A mean delay in initiating therapy of up to 13 months after oral glucose-lowering drug failure was observed, with 60% having a delay of >6 months. This delay was associated with a lower proportion achieving glycemic control 3 months after initiation. Effectiveness was not observed at all time points in all cohorts, suggesting some treatments were not used in the appropriate population. Delays in initiating injectable therapies were observed and were associated with poor glycemic control.

GLP-1 Receptor Agonist Medications Alter Outcomes of Spine Surgery: A Study Among Over 15,000 Patients.

retrospective cohort study. To investigate the relationship between perioperative Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) and postoperative outcomes after spinal fusion in obese and diabetic patient populations. GLP-1 RAs have been shown to be beneficial when used perioperatively in clinical orthopaedic arthroplasty literature. Minimal evidence exists showing efficacy with respect to spinal fusion. This retrospective, multi-center study accessed the TriNetX platform, using the research database to identify diabetic patients who underwent spinal fusion between 2008 and 2022. Cohorts were created based on Body-Mass-Index (BMI) and GLP-1 RA usage. Propensity score matching was employed to create balanced cohorts utilizing BMI, Hemoglobin A1c (HbA1c), surgical intervention, as well as other demographic characteristics. Orthopedic outcomes were compared between GLP-1 RA users and non-users. The primary outcomes included post-operative infection, readmission, revision surgery, and quality of life metrics. After matching, the study cohort consisted of 2,263 patients, with 1,560 classified as obese. GLP-1 RA use was associated with significantly reduced post-operative infection rates (obese: HR=0.168 (0.086, 0.328), not obese: HR=0.250 (0.102, 0.612)), fewer revisions (obese: HR=0.505 (0.368, 0.693), not obese: HR=0.439 (0.272, 0.708)), decreased postoperative readmission rates (obese: HR=0.283 (0.243, 0.329), not obese: HR=0.241 (0.193, 0.301)), and reduced mobility abnormalities (obese: HR=0.355 (0.230, 0.549), not obese: HR=0.508 (0.269, 0.959)). No significant differences were observed in rates of fracture rates between GLP-1 RA users and non-users. GLP-1 RA use in spinal fusion patients was associated with improved post-operative outcomes, including lower infection rates, fewer revisions, and better quality of life metrics. These findings suggest that GLP-1 RAs may be a valuable adjunctive therapy in managing surgical outcomes in diabetic and obese patients undergoing spinal fusion. Further prospective and animal-based studies are needed to confirm these findings and explore the underlying mechanisms.

Abstract TMP104: Association of GLP-1 Receptor Agonist Use with Clinical Outcomes in Diabetic Patients Hospitalized for Ischemic Stroke

Background and Purpose: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown cardiovascular benefits in patients with type 2 diabetes mellitus (T2DM). We aimed to evaluate the association of GLP-1RA use with clinical outcomes in diabetic patients admitted for acute ischemic stroke (AIS). Methods: This single-center retrospective study included diabetic patients aged ≥18 years admitted for AIS from 2015-2023. GLP-1RA use was defined as a history of taking GLP-1RA at admission or being prescribed GLP-1RA at discharge. The primary outcome was the incidence of new ischemic stroke within 1 year. Secondary outcomes included functional independence (modified Rankin Scale score 0-2) and mortality at 90 days. Propensity score weighting was used to balance covariates between groups. Logistic regression was used to estimate log odds ratios (LORs) for outcomes. Results: Of 123 patients, 35 (28%) used GLP-1RA. The GLP-1RA group had lower incidence of new ischemic stroke at 1 year (2.9% vs 6.8%; adjusted LOR -1.13, 95% CI -3.21-0.95, p=0.28) and higher rates of functional independence at 90 days (67% vs 40%; adjusted LOR 2.38, 95% CI -0.12-4.87, p=0.06) compared to the non-GLP-1RA group, but these differences were not statistically significant. Mortality at 90 days was similar between groups (25% vs 26%; adjusted LOR 0.078, 95% CI -1.51-1.67, p=0.92). Conclusions: In this cohort of diabetic patients admitted for AIS, GLP-1RA use showed trends toward reduced incidence of recurrent stroke and improved functional outcomes, although not statistically significant. Larger prospective studies are needed to further evaluate the potential neuroprotective effects of GLP-1RAs in ischemic stroke.

Effect of acute treatment with the glucagon-like peptide-1 receptor agonist, liraglutide, and estrus phase on cue- and drug-induced fentanyl seeking in female rats.

Opioid use disorder (OUD) is a crisis in the USA. Despite advances with medications for OUD, overdose deaths have continued to rise and are largely driven by fentanyl. We have previously found that male rats readily self-administer fentanyl, with evident individual differences in fentanyl taking, seeking, and reinstatement behaviors. We also have shown that acute treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can reduce fentanyl seeking behavior in male rats. However, given that females are significantly more vulnerable to drug-related cues, drug cravings, and to the development of OUD compared to males, it is imperative that we investigate the biological risk factors on fentanyl use disorder. Further, preclinical models report that females in estrus have increased fentanyl intake, more rapid development of OUD, and enhanced relapse vulnerability compared to those in a non-estrus phase. Thus, we aimed here to understand the effect of estrus phase on our model of OUD and on the effectiveness of acute liraglutide treatment. Herein, we show that female rats readily self-administer fentanyl (1.85 μg/infusion) intravenously, with marked individual differences in fentanyl taking behavior. Additionally, rats in the estrus phase exhibited greater fentanyl intake compared with those in a non-estrus phase, greater cue-induced fentanyl seeking, and greater drug-induced reinstatement of fentanyl seeking. Finally, acute liraglutide treatment (0.3 mg/kg s.c.) reduced cue-induced fentanyl seeking and blocked drug-induced reinstatement of fentanyl seeking, particularly when tested in estrus. Overall, these data support the broad effectiveness of acute GLP-1R agonists as a promising non-opioid treatment for OUD.