Glucagon-like Peptide-1 Receptor Agonist Treatment Research Articles

GLP-1 receptor agonist attenuates tubular cell ferroptosis in diabetes via enhancing AMPK-fatty acid metabolism pathway through macropinocytosis

Kidney tubules are mostly responsible for pathogenesis of diabetic kidney disease. Actively reabsorption of iron, high rate of lipid metabolism and exposure to concentrated redox-active compounds constructed the three main pillars of ferroptosis in tubular cells. However, limited evidence has indicated that ferroptosis is indispensable for diabetic tubular injury. Glucagon-like peptide-1 receptor agonist (GLP-1RA) processed strong benefits on kidney outcomes in people with diabetes. Moreover, GLP-1RA may have additive effects by improving dysmetabolism besides glucose control and weight loss. Therefore, the present study aimed at exploring the benefits of exendin-4, a high affinity GLP-1RA on kidney tubular dysregulation in diabetes and the possible mechanisms involved, with focus on ferroptosis and adenosine 5′-monophosphate-activated protein kinase (AMPK)-mitochondrial lipid metabolism pathway. Our data revealed that exendin-4 treatment markedly improved kidney structure and function by reducing iron overload, oxidative stress, and ACSL4-driven lipid peroxidation taken place in diabetic kidney tubules, along with reduced GPX4 expression and GSH content. AMPK signaling was identified as the downstream target of exendin-4, and enhancement of AMPK triggered the transmit of its downstream signal to activate fatty acid oxidation in mitochondria and suppress lipid synthesis and glycolysis, and ultimately alleviated toxic lipid accumulation and ferroptosis. Further study suggested that exendin-4 was taken up by tubular cells via macropinocytosis. The protective effect of exendin-4 on tubular ferroptosis was abolished by macropinocytosis blockade. Taken together, present work demonstrated the beneficial effects of GLP-1RA treatment on kidney tubular protection in diabetes by suppressing ferroptosis through enhancing AMPK-fatty acid metabolic signaling via macropinocytosis.

Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes

Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Treatment with GLP-1RA was compared with basal insulin. Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. ClinicalTrials.gov Identifier: NCT02072902.

GLP-1 Receptor Agonists for Treatment of Obesity

GLP-1 Receptor Agonists for Treatment of Obesity

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity.

N-acylethanolamines (NAEs) include endocannabinoid (EC) and EC-related molecules that impact the anti-obesity and anti-diabetic efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) in animal studies. However, the clinical relevance of these findings remains to be determined. Here, we tested whether GLP-1RA treatment affects circulating NAE levels and whether NAEs may predict the efficacy of GLP-1RA treatment in humans with obesity undergoing weight loss maintenance. We profiled plasma levels of NAEs in participants with obesity undergoing weight loss maintenance with (n = 23)/or without (n = 20) treatment with the GLP-1RA liraglutide. NAE levels were measured at three different time points: before the start of the study, at the end of the diet-induced weight loss, and after 52-weeks treatment. Linear regression analyses were used to investigate whether pharmacological responses could be predicted by NAEs levels. Liraglutide treatment reduced plasma concentrations of the NAE and oleoyl-ethanolamide (OEA), without altering arachidonoyl-ethanolamide (AEA) levels and palmitoyl-ethanolamide (PEA) levels. High pre-treatment levels of OEA were predictive of superior compound-mediated effects on fasting insulin and triglyceride levels. High pre-treatment PEA and AEA levels were also predictive of superior Liraglutide-mediated effects on triglyceride levels. Our data suggests that specific NAEs such as OEA and AEA are promising biomarkers of GLP-1RA metabolic efficacy in humans with obesity during weight loss maintenance. Plasma profiling of EC-related molecules may be a promising strategy to tailor GLP-1R-based therapies to individual needs in obesity and diabetes management.

Glucagon-like Peptide-1 Receptor Agonist Treatment in Type 1 Diabetes

Type 1 diabetes (T1D) is characterized by a progressive decline of insulin production due to a marked destruction of pancreatic B cells. Intensive insulin therapy is the pillar of T1D management. More recently, continuous glucose monitoring devices, closed-loop systems (CLS) and smarter connected insulin pen systems have all significantly helped individuals to improve glycemic control. Despite these advances, however, more than three-quarters of the adult T1D population does not achieve recommended glycemic targets. In addition, aggressive insulin intensification potentiates weight gain and the risk of recurrent hypoglycemic events. Recent significant increase in rates of obesity has also led to a sharp increase in T1D patients who concurrently have adiposity-based chronic disease, increasing their insulin resistance and predisposition for cardiovascular events. While insulin will remain the basis of T1D management, there is an unmet need for individualized adjunctive therapeutic approaches focusing on the prevention of diabetic complications in addition to glycemic control. One such adjunctive therapy currently being explored in T1D are the glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a popular and robust approach in Type 2 diabetes (T2DM) to mimic the natural endogenous GLP-1 incretin. This brief review will focus on the rationale and existing evidence for the use of GLP-1 RAs in the management of T1D.

Effect of tirzepatide on glycaemic control and weight loss compared with other glucagon-like peptide-1 receptor agonists in Japanese patients with type 2 diabetes mellitus.

To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.

Exploratory Study Analyzing the Urinary Peptidome of T2DM Patients Suggests Changes in ECM but Also Inflammatory and Metabolic Pathways Following GLP-1R Agonist Treatment.

Type II diabetes mellitus (T2DM) accounts for approximately 90% of all diabetes mellitus cases in the world. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased capability to target directly or indirectly six core defects associated with T2DM, while the underlying molecular mechanisms of these pharmacological effects are not fully known. This exploratory study was conducted to analyze the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients. Urine samples of thirty-two T2DM patients from the PROVALID study ("A Prospective Cohort Study in Patients with T2DM for Validation of Biomarkers") collected pre- and post-treatment with GLP-1R agonist drugs were analyzed by CE-MS. In total, 70 urinary peptides were significantly affected by GLP-1R agonist treatment, generated from 26 different proteins. The downregulation of MMP proteases, based on the concordant downregulation of urinary collagen peptides, was highlighted. Treatment also resulted in the downregulation of peptides from SERPINA1, APOC3, CD99, CPSF6, CRNN, SERPINA6, HBA2, MB, VGF, PIGR, and TTR, many of which were previously found to be associated with increased insulin resistance and inflammation. The findings indicate potential molecular mechanisms of GLP-1R agonists in the context of the management of T2DM and the prevention or delaying of the progression of its associated diseases.

Treatment intensification following glucagon-like peptide-1 receptor agonist treatment in type 2 diabetes: The RESTORE-G real-world study

Background and aimsTo assess intensification approaches with basal insulin (BI) following glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment in type 2 diabetes (T2D). Methods and resultsReal-world data were collected in electronic medical records by 32 Italian diabetes clinics between 2011 and 2021. Primary endpoint was the proportion of insulin-naïve T2D patients treated with GLP-1 RA who initiated (add-on or switch) BI. Secondary endpoints were: treatment approaches, mean time to BI start, effectiveness and safety.Among 7,962 eligible patients, BI was prescribed to 3,164 (39.7%; 95%CI 38.7; 40.8): 67.6% switched to BI (22.1% also starting 1–3 injections of short-acting insulin), 22.7% added BI while maintaining GLP-1 RA, and 9.7% switched to a fixed-ratio combination of GLP-1 RA and BI (FRC). Median time since the first GLP-1 RA to BI/FRC prescription was 27.4 (IQ range 11.8–53.5) months. In this study 60.3% of patients did not start BI/FRC, among whom 15.2% intensified GLP-1 RA therapy with other oral agents. Effectiveness and safety were documented in all intensification approaches with BI/FRC, but HbA1c level at intensification time of ≥9.0% and suboptimal BI titration suggested clinical inertia. Use of second generation BI and add-on to GLP-1 RA schemes increased over time and effectiveness improved. ConclusionClinical inertia should be overcome using innovative insulin options. Timely combination therapy of BI and GLP-1 RA is a valuable choice.

GLP-1RAs caused gastrointestinal adverse reactions of drug withdrawal: a system review and network meta-analysis.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) significantly reduce postprandial blood glucose, inhibit appetite, and delay gastrointestinal emptying. However, it is controversial that some patients are intolerant to GLP-1RAs. PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) using GLP-1RAs with documented withdrawal due to gastrointestinal adverse reactions (GI AEs) from their inception to September 28, 2022. After extracting the information incorporated into the studies, a random-effects network meta-analysis was performed within a frequentist framework. 64 RCTs were finally enrolled, which included six major categories of the GLP-1RA. The sample size of the GLP-1RAs treatment group was 16,783 cases. The risk of intolerable gastrointestinal adverse reactions of Liraglutide and Semaglutide was higher than that of Dulaglutide. Meanwhile, the higher the dose of the same GLP-1RA preparation, the more likely to cause these adverse reactions. These intolerable GI AEs were not significantly related to drug homology or formulations and may be related to the degree of suppression of the appetite center. Dulaglutide caused the lowest intolerable GI AEs, while Liraglutide and Semaglutide were the highest. For Semaglutide, the higher the dose, the more likely it is to drive GI AEs. Meanwhile, the risk of these GI AEs is independent of the different formulations of the drug. All these findings can effectively guide individualized treatment. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359346, identifier CRD42022359346.

Exendin-4 protects against high glucose-induced mitochondrial dysfunction and oxidative stress in SH-SY5Y neuroblastoma cells through GLP-1 receptor/Epac/Akt signaling

Mitochondrial dysfunction under diabetic condition leads to the development and progression of neurodegenerative complications. Recently, the beneficial effects of glucagon-like peptide-1 (GLP-1) receptor agonists on diabetic neuropathies have been widely recognized. However, molecular mechanisms underlying the neuroprotective effects of GLP-1 receptor agonists against high glucose (HG)-induced neuronal damages is not completely elucidated. Here, we investigated the underlying mechanisms of GLP-1 receptor agonist treatment against oxidative stress, mitochondrial dysfunction, and neuronal damages under HG conditions mimicking a diabetic hyperglycemic state in SH-SY5Y neuroblastoma cells. We revealed that treatment with exendin-4, a GLP-1 receptor agonist, not only increased the expression of survival markers, phospho-Akt/Akt and Bcl-2, but also decreased the expression of pro-apoptotic marker, Bax, and reduced the levels of reactive oxygen species (ROS) defense markers (catalase, SOD-2, and HO-1) under HG conditions. The expressions of mitochondrial function associated genes, MCU and UCP3, and mitochondrial fission genes, DRP1 and FIS1, were decreased by exendin-4 compared to non-treated levels, while the protein expression levels of mitochondrial homeostasis regulators, Parkin and PINK1, were enhanced. In addition, blockade of Epac and Akt activities was able to antagonize these neuroprotective effects of exendin-4. Collectively, we demonstrated that stimulation of GLP-1 receptor propagates a neuroprotective cascade against the oxidative stress and mitochondrial dysfunction as well as augments survival through the Epac/Akt-dependent pathway. Therefore, the revealed mechanisms underlying GLP-1 receptor pathway by preserving mitochondrial homeostasis would be a therapeutic candidate to alleviate neuronal dysfunctions and delay the progression of diabetic neuropathies.

Characteristics predicting the efficacy of SGLT-2 inhibitors versus GLP-1 receptor agonists on major adverse cardiovascular events in type 2 diabetes mellitus: a meta-analysis study

BackgroundRecent large clinical trials have demonstrated cardiovascular benefits of similar overall magnitude for sodium–glucose cotransporter-2 inhibitor (SGLT-2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy in subjects with type 2 diabetes. We sought to identify subgroups based on baseline characteristics with a differential response to either SGLT-2i or GLP-1RA.MethodsPubMed, Cochrane CENTRAL, and EMBASE were searched from 2008 to 2022 for SGLT-2i or GLP-1RA randomized trials that reported 3-point major adverse cardiovascular events (3P-MACE). Baseline clinical and biochemical characteristics included age, sex, body mass index (BMI), HbA1c, estimated glomerular filtration rate (eGFR), albuminuria, preexisting cardiovascular disease (CVD), and heart failure (HF). Absolute and relative risk reductions (ARR and RRR) regarding incidence rates for 3P-MACE with a 95% confidence interval were calculated. The association of average baseline characteristics in each study with the ARR and RRR for 3P-MACE was investigated by meta-regression analyses (random-effects model, assuming inter-study heterogeneity). Meta-analysis was also conducted to investigate whether the efficacy of SGLT-2i or GLP-1RA on 3P-MACE reduction could differ according to the patient’s characteristics (e.g., HbA1c above/below cutoff).ResultsAfter a critical assessment of 1,172 articles, 13 cardiovascular outcome trials with a total of 111,565 participants were selected. In meta-regression analysis, the more patients with reduced eGFR in the studies, the greater ARR by SGLT-2i or GLP-1RA therapy. Similarly, in the meta-analysis, SGLT-2i therapy tended to be more effective in reducing 3P-MACE in people with eGFR < 60 ml/min/1.73 m2 than in those with normal renal function (ARR − 0.90 [–1.44 to − 0.37] vs. − 0.17 [–0.34 to − 0.01] events/100 person-years). Furthermore, people with albuminuria tended to respond better to SGLT-2i therapy than those with normoalbuminuria. However, this was not the case for the GLP-1RA treatment. Other factors including age, sex, BMI, HbA1c, and preexisting CVD or HF did not affect the efficacy of either SGLT-2i or GLP-1RA treatment on the ARR or RRR of 3P-MACE.ConclusionsBecause decreased eGFR [significant] and albuminuria [trend] were found to predict a better efficacy for SGLT-2i in 3P-MACE reduction, this class of drug should be preferred in such patients. However, GLP-1RA may be considered for patients with normal eGFR because it showed better efficacy than SGLT-2i in this subgroup [trend].

795-P: Elucidating the Role of Weight Loss and Glycemia with Observed Benefits of GLP-1 Receptor Agonist Treatment in Patients with T2D

Weight loss has been associated with reduced cardiovascular disease (CVD) risk in people with type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RA) are an advancement in T2D treatment that can regulate glycemia and promote weight loss. However, the impact of weight loss, independent of glycemic control, on real-world clinical outcomes is not well understood. Here, the Cleveland Clinic electronic health record system was utilized to investigate the independent contributions of glycemic control and body mass index (BMI) change on clinical outcomes such as CVD, chronic kidney disease (CKD), hypertension, dyslipidemia, and time to insulin initiation in patients with T2D treated with GLP-1RA. Patients (n=4161) with T2D seen at the Cleveland Clinic between 8/2/2005 and 12/31/2021 who initiated GLP-1RA treatment without documented congestive heart failure, insulin use, and/or an estimated glomerular filtration rate &amp;lt;30 mL/min at the time of treatment initiation were retrospectively analyzed. Patients were required to be receiving GLP-1RA treatment for ≥12 months and have &amp;lt;18 months between physician encounters. Independent of glycemic control, each 1% reduction in BMI was associated with a 4% reduction in CVD risk (P=.008) and a 3% reduction in insulin initiation risk (P=.002). Independent of BMI change, each 1% reduction in HbA1c was associated with a 4% reduction in CKD risk (P=.001) and a 16% reduction in insulin initiation risk (P&amp;lt;.0001). Associations between BMI variability and CVD (HR=1.12, P&amp;lt;.0001) and osteoarthritis (HR=1.09, P=.014) and between HbA1c variability and CKD (HR=1.73, P=.032) and hypertension (HR=1.07, P&amp;lt;.0001) were observed. Durable BMI reduction was associated with a 28% decrease in CKD risk (P=.016) and a 61% reduction in hypertension risk (P=.005). In the real-world setting, decreased BMI was independently associated with reduced risk of CVD, CKD, hypertension, osteoarthritis, and insulin initiation. Disclosure A.Sharma: None. B.Burguera: Research Support; Novo Nordisk. M.Kattan: Consultant; Renalytix, Verici, Research Support; Novo Nordisk, Bayer Inc. A.D.Misra-hebert: Research Support; Bayer Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk. K.M.Pantalone: Consultant; AstraZeneca, Bayer Inc., Corcept Therapeutics, Diasome, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi, Research Support; Bayer Inc., Merck &amp; Co., Inc., Novo Nordisk, Twin Health, Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Merck &amp; Co., Inc., Novo Nordisk. D.M.Rotroff: Research Support; Novo Nordisk, Stock/Shareholder; Clarified Precision Medicine. A.Mariam: None. E.Zacherle: None. A.Milinovich: Research Support; Novo Nordisk, Merck &amp; Co., Inc., AbbVie Inc., Amgen Inc., Bayer Inc., Eli Lilly and Company, Twin Health. J.Bauman: None. D.S.Sugano: None. J.Noone: Employee; Novo Nordisk. J.R.Rajpura: Employee; Novo Nordisk. R.S.Zimmerman: Speaker's Bureau; Xeris Pharmaceuticals, Inc.

207-OR: Myostatin Inhibition Synergizes with GLP-1R Agonism to Accelerate Weight Loss in Male, Obese Nonhuman Primates

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become standard-of-care for the pharmacological treatment of obesity by inducing clinically meaningful weight loss through a reduction in appetite. While these agents potently reduce fat mass, the caloric restriction also reduces skeletal muscle mass. Strategies to preserve skeletal muscle in the presence of caloric restriction are needed to improve weight loss quality in obese patents. Trevogrumab (∝-MSTN) and garetosmab (∝-ActA) are fully human monoclonal antibodies that potently inhibit two mediators of skeletal muscle atrophy: myostatin (MSTN) and activin A (ActA). We first tested the effects of ∝-MSTN, ∝-ActA and GLP-1RA (Semaglutide [Sema]) on body composition of diet-induced obese mice either alone or in combination. Sema (-29.8%) and ∝-MSTN/∝-ActA (-23.4%) produced significant reduction in fat mass after 4 weeks of treatment vs baseline. Adding MTSN and ActA blockade to Sema produced an additive effect on fat mass (-54.2%). This combination also increased lean mass by 9.8% vs a 1.9% loss with Sema alone. To test this in primates, we performed a 20-week study with the combined administration of either Sema + ∝-MSTN or Sema + ∝-MSTN and ∝-ActA in obese male cynomolgus monkeys. The combination of ∝-MSTN + Sema was sufficient to cause an additive effect on fat mass -43.9% vs -25.1% for Sema alone. The addition of ∝-ActA to the combination produced a similar reduction in fat (-49.6%). The Sema control group also lost -2.5% lean mass after 20 weeks; despite the significant reduction in fat mass, the addition of ∝-MSTN to Sema slightly increased lean mass over the same period (0.5%); the addition of ∝-ActA increased lean mass even further (6.2%). These data suggest the blockade of MSTN and ActA to GLP-1RA treatment could greatly improve the quality of weight loss with this class of anti-obesity agents. Disclosure J.Mastaitis: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. D.Gomez: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. V.Le rouzic: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. M.Stec: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. N.Khan: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. E.Na: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. T.Mcwilliams: None. S.Min: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. M.Sleeman: Employee; Regeneron Pharmaceuticals Inc. Funding Regeneron Pharmaceuticals Inc.

Effects of repeated developmental GLP-1R agonist exposure on young adult behavior and hippocampal structure in mice

Glucagon-like peptide-1 receptor (GLP-1R) agonists are common type 2 diabetes medications that have been repurposed for adult chronic weight management. Clinical trials suggest this class may also be beneficial for obesity in pediatric populations. Since several GLP-1R agonists cross the blood–brain barrier, it is important to understand how postnatal developmental exposure to GLP-1R agonists might affect brain structure and function later in life. Toward that end, we systemically treated male and female C57BL/6 mice with the GLP-1R agonist exendin-4 (0.5 mg/kg, twice daily) or saline from postnatal day 14 to 21, then allowed uninterrupted development to young adulthood. Beginning at 7 weeks of age, we performed open field and marble burying tests to assess motor behavior and the spontaneous location recognition (SLR) task to assess hippocampal-dependent pattern separation and memory. Mice were sacrificed, and we counted ventral hippocampal mossy cells, as we have recently shown that most murine hippocampal neuronal GLP-1R is expressed in this cell population. We found that GLP-1R agonist treatment did not alter P14-P21 weight gain, but modestly reduced young adult open field distance traveled and marble burying. Despite these motor changes, there was no effect on SLR memory performance or time spent investigating objects. Finally, we did not detect any changes in ventral mossy cell number using two different markers. These data suggest developmental exposure to GLP-1R agonists might have specific rather than global effects on behavior later in life and that extensive additional study is necessary to clarify how drug timing and dose affect distinct constellations of behavior in young adulthood.

Association of glucagon-like peptide-1 receptor agonist treatment with gastric residue in an esophagogastroduodenoscopy.

Previous studies have reported that the glucagon-like peptide-1 receptor agonist (GLP-1RA) delays gastric emptying, and gastric emptying was assessed by the 13 C breath test or paracetamol absorption technique. However, neither of them is clinically familiar in real-world clinical practice. The purpose of the present study was to investigate the association between GLP-1RA treatment and gastric residue in an esophagogastroduodenoscopy. This study was a matched pair case-control study. The study population consisted of 1,128 individuals with diabetes who had esophagogastroduodenoscopy at our clinic between July 2020 and June 2022. To account for differences in characteristics, such as age, sex, insulin treatment and glycated hemoglobin, we carried out a one-to-one nearest neighbor propensity score matching analysis between diabetes patients with and without GLP-1RA treatment. After matching, we compared the presence of gastric residue in an esophagogastroduodenoscopy by the McNemar test between patients with and without GLP-1RA treatment. After the propensity score matching, we selected 205 pairs. In the propensity score-matched comparison, the proportion of gastric residue was statistically significantly higher in the GLP-1RA treatment group (0.49% vs 5.4%, P=0.004). The details of GLP-1RA prescribed for the 11 patients with gastric residue were liraglutide once daily 1.8 mg (n=2), dulaglutide once weekly 0.75 mg (n=5), semaglutide once weekly 0.5 mg (n=2) and semaglutide once weekly 1.0 mg (n=2). GLP-1RA treatment is associated with gastric residue in an esophagogastroduodenoscopy in patients with diabetes.

Glucagon-Like Peptide-1 Receptor Agonist Protects Against Diabetic Cardiomyopathy by Modulating microRNA-29b-3p/SLMAP.

Our aims were to investigate the pathogenesis of diabetic cardiomyopathy (DCM) and to explore the protective effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) on DCM. After 12 weeks of treatment with exenatide-loaded microspheres, a long-acting GLP-1RA, in DCM mice, cardiac structure and function were evaluated by plasma B-type natriuretic peptide (BNP), echocardiography, H&E, oil red and Sirius staining. The expression of glucagon-like peptide-1 receptor in mouse heart tissue was determined by immunofluorescence staining. The label-free proteomic analysis of cardiac proteins was conducted among control, DCM and DM+GLP-1RA groups. Then, quantitative real-time PCR, Western blotting and dual-luciferase reporter assay were performed to verify the regulation of target protein by the upstream microRNA (miRNA). GLP-1RA treatment obviously improved serum BNP, myocardial fibrosis, lipid deposition of the myocardium and echocardiography parameters in DCM mice. Sarcolemmal membrane-associated protein (SLMAP) was one of 61 differentially expressed cardiac proteins found in three groups by proteomic analysis. Up-regulation of microRNA-29b-3p (miR-29b-3p) and down-regulation of SLMAP were found in the ventricular myocardium of GLP-1RA-treated DCM mice. SLMAP was a target of miR-29b-3p, while GLP-1RA regulated SLMAP expression through miR-29b-3p. Furthermore, inhibition of glucagon-like peptide-1 receptor (GLP-1R) in cardiomyocytes reversed the effects of GLP-1RA on miR-29b/SLMAP. SLMAP may play roles in the pathogenesis of DCM and may be a target of GLP-1RA in protecting against DCM. After binding to myocardial GLP-1R, GLP-1RA can regulate the expression of myocardial SLMAP through miR-29b-3p.

Vitreous hemorrhage during GLP-1 receptor agonist treatment

BackgroundThe purpose of this case report is to describe a case of vitreous hemorrhage in a patient with a history of diabetic retinopathy and receiving dulaglutide for the management of type 2 diabetes mellitus (T2DM). Case summaryA 64-year-old African American male with a past medical history of T2DM and severe diabetic retinopathy for 4 years was restarted on dulaglutide 1.5 mg weekly after being off therapy for 3 months. Baseline laboratory test results included hemoglobin A1c (HbA1c) of 8.8% and random blood glucose (BG) of 280 mg/dL. In addition, the patient had an average fasting BG of 150 mg/dL. In absence of intolerance, the dulaglutide dose was gradually maximized to 4.5 mg weekly and HbA1c decreased to 7.3% and random BG to 121 mg/dL at week 12 since reinitiation. At week 17 of therapy, the patient presented to the emergency department with a 1-day history of vision loss in the left eye and was diagnosed as having vitreous hemorrhage. The etiology for vitreous hemorrhage is unclear and may be a spontaneous episode. In discussion with the patient and the ophthalmologist, dulaglutide was restarted at 1.5 mg once weekly. After 4 weeks of reinitiation, the patient denied any recurrent symptoms of vitreous hemorrhage or worsening diabetic retinopathy. The most recent ophthalmology evaluation indicated no change in diabetic retinopathy. Practice implicationsThis case report adds to the limited body of evidence available for the incidence of vitreous hemorrhage in the setting of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) therapy and pre-existing diabetic retinopathy. The case report illustrates that a history of diabetic retinopathy should not automatically preclude the use of GLP-1 RAs.

Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial

BackgroundIdentifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss.MethodsThis was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: placebo, moderate-to-vigorous exercise (minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination of both), the GLP-1 RA liraglutide 3.0 mg/day, or a combination (exercise + liraglutide). A total of 166 participants completed the trial. We assessed the prespecified secondary outcome metabolic syndrome severity z-score (MetS-Z), abdominal obesity (estimated as android fat via dual-energy X-ray absorptiometry), and inflammation marker high-sensitivity C-reactive protein (hsCRP). Statistical analysis was performed on 130 participants adherent to the study interventions (per-protocol population) using a mixed linear model.ResultsThe diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (− 0.37, 95% CI − 0.58 to − 0.16, P < 0.001) and the combination treatment (− 0.48, 95% CI − 0.70 to − 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03).ConclusionThe combination of adherent exercise and liraglutide treatment reduced metabolic syndrome severity, abdominal obesity, and inflammation and may therefore reduce cardiometabolic risk more than the individual treatments.Trial registration EudraCT number: 2015-005585-32, ClinicalTrials.gov: NCT04122716

Effect of Glucagon-like Peptide-1 Receptor Agonists on Cardio-Metabolic Risk Factors among Obese/Overweight Individuals Treated with Antipsychotic Drug Classes: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) constitute a drug class primarily developed for the treatment of subjects with type 2 diabetes, although they have also provided significant benefit for subjects with obesity without underlying diabetes. Individuals with psychotic disorders who are receiving antipsychotic treatment are a patient population at risk of developing obesity, which is linked to other metabolic disturbances. We searched PubMed and the Cochrane Library from inception to 1 December 2022, for randomized controlled trials (RCTs) enrolling obese or overweight adult subjects with an underlying psychotic disorder treated with antipsychotic drugs, randomized either to GLP-1RAs or a control. We set as the primary efficacy outcome the change in body weight and as secondary efficacy outcomes the change in body mass index (BMI) and in waist circumference, along with indices of glycemia, lipid profile, and blood pressure. We pooled data from 4 trials (2 with liraglutide and 2 with exenatide) in a total of 199 enrolled subjects. GLP-1RA treatment, compared to control, resulted in a significant decrease in body weight by 3.8 kg [mean difference (MD) = -3.80, 95% CI; -6.35 to -1.24, I2 = 64%]. In addition, GLP-1RA treatment led to a significant decrease in BMI, compared to control, of 1.04 kg/m2 (MD = -1.04, 95% CI; -1.92 to -0.17, I2 = 35%). However, no significant effect on waist circumference was shown (MD = -3.2, 95% CI; -6.47 to 0.08, I2 = 88%). A significant improvement in glycemia and lipid profiles was also demonstrated with GLP-1RAs. No subgroup difference between liraglutide and exenatide was shown, and the use of GLP-1RAs did not increase the risk for treatment discontinuation compared to the control group. Treatment with GLP-1RAs can significantly improve weight loss and other cardiometabolic risk factors in obese people taking antipsychotic medications.