Effects Of Glucagon-like Peptide-1 Receptor Agonists Research Articles

Effects of GLP-1 receptor agonists on cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease: Asystematic review and meta-analysis.

To evaluate the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD). We searched PubMed, Ovid MEDLINE, CINAHL, and Web of Science databases for randomized controlled trials reporting event rates for a composite cardiovascular outcome of cardiovascular death, myocardial infarction, and stroke in patients with T2DM and CKD receiving GLP1-RA or placebo. Studies were restricted to those reporting specific event rates for patients with CKD separately from the overall population. We conducted a meta-analysis using a random-effects model. This meta-analysis was registered on PROSPERO (CRD42022320157). A total of four studies comprising 7130 patients was included in our analysis. Four different GLP1-RA were assessed in a population with CKD defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 . Treatment with GLP1-RA was not associated with a significant reduction in the composite cardiovascular end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (odds ratio (OR) 0.80; 95% confidence interval (CI), 0.59-1.07; p=0.13) among patients with T2DM and CKD. Individual components of the composite cardiovascular end point were assessed in two trials and did not show evidence of an effect of GLP1-RA in reducing cardiovascular end points. Pooled analysis of clinical trials reporting separate cardiovascular events rates in patients with T2DM and CKD did not find GLP1-RA to be associated with a reduction in composite cardiovascular event rates. Select GLP1-RA may offer cardiovascular event reduction in patients with T2DM and CKD, but this does not appear to be a class effect. Use of GLP1-RA with demonstrated cardiovascular benefits should be preferred in patients with CKD and T2DM to further reduce cardiovascular risk.

Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been clinically proven to protect endothelial function. Previously, we demonstrated that endothelial NO synthase (eNOS) was activated by high-density lipoprotein (HDL) via its scavenger receptor of the B class/human homologue of SR-BI, CD36 and LIMPII analogous-1(hSR-BI/CLA-1). Here, we investigated the effect of GLP-1RA and exendin-4 on the expression of hSR-BI/CLA-1 in HUVECs. Our results confirmed that GLP-1R was expressed in HUVECs by PCR and exendin-4 significantly enhanced HDL-induced eNOS activation. Next, exendin-4 increased the expression of hSR-BI/CLA-1 and a blockade of GLP-1R cancelled this effect. Further, the hSR-BI/CLA-1 transcriptional activity was enhanced by exendin-4, which was diminished by the inhibition of AMPK or dominant-negative AMPK-α-subunit. Moreover, AMPK was phosphorylated by the activation of GLP-1R. Next, ChIP assay demonstrated that exendin-4 increased the FoxO1-binding in the hSR-BI/CLA-1 promoter by upregulation of FoxO1. Mutation of FoxO1-binding or silencing of FoxO1 cancelled the effect of exendin-4 on hSR-BI/CLA-1 expression. Exendin-4 reduced FoxO1 phosphorylation and induced its nuclear accumulation, while this effect was altered by the blocking of GLP-1R or inhibition of AMPK pathway. In summary, our results proved that exendin-4 increased hSR-BI/CLA-1 expression via the AMPK/FoxO1 pathway to activate eNOS, providing a basic mechanism underlining the protective effect of GLP-1RA on endothelial function.

GLP-1 RA Improves Diabetic Retinopathy by Protecting the Blood-Retinal Barrier through GLP-1R-ROCK-p-MLC Signaling Pathway.

GLP-1 receptor agonists (GLP-1RA) are common clinical agents that are clinically protective against diabetic complications, such as diabetic retinopathy (DR). Previous studies have shown that the RhoA/ROCK pathway plays an important role in the development of DR. However, the specific mechanism of action between GLP-1RA and DR remains unclear. The aim of this study was thus to investigate the main mechanism involved in the protective effect of GLP-1RA on DR. Type 2 diabetic mice were fed a high-sugar, high-fat diet. Changes in the retinal structure were observed via HE staining and transmission electron microscopy. The expression of retinal GLP-1R, blood-retinal barrier- (BRB-) related proteins, inflammatory factors, and related pathway proteins were studied via Western blot or immunohistochemistry/immunofluorescence analysis. GLP-1RA treatment reduced the blood glucose and lipid levels as well as the body weight of the diabetic mice while also improving retinal thickness, morphology, and vascular ultrastructure. Moreover, restored GLP-1R expression, increased Occludin and ZO-1 levels, and decreased albumin expression led to reduced retinal leakage and improved the BRB by inhibiting the RhoA/ROCK pathway. We found that the protective effect of GLP-1RA on the retina may be realized through the GLP-1R-ROCK-p-MLC signaling pathway.

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial.

BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.

Frequency of GLP-1 receptor agonists use in diabetic patients diagnosed with delayed gastric emptying and their demographic profile

Advances in the management of diabetes mellitus have come a long way in the 21st century. One of the most important developments in diabetes management has been the discovery of...

Effect of glucagon-like peptide-1 (GLP-1) agonists on the example of semaglutide on the cardiovascular system and their role in the treatment of obesity.

Obesity nowadays affects an increasing number of people. We can talk about it when the patient's BMI is ≥ 30.0 kg/m² (BMI 25.0-29.9 kg/m² - overweight). While obesity in itself may not be a problem for people suffering from it, its complications can be global and sometimes pose a serious threat to health or even life. Its main complications in the cardiovascular system include: hypercholesterolaemia, arterial hypertension, left ventricular hypertrophy, early atherosclerotic changes, heart and cerebral infarction. Treatment of obesity is based mainly on changing the patient's lifestyle - diet and physical activity, which can sometimes be problematic and difficult to apply.&#x0D; However, there is a new group of hypoglycaemic drugs - glucagon-like peptide-1 (GLP-1) agonists, which can make obesity treatment easier. These drugs use the incretin effect in the body to increase insulin secretion in response to a meal containing carbohydrates and prevent postprandial hyperglycemia. In this article, we will analyze the latest studies on the effects of GLP-1 receptor agonists, using semaglutide as an example, on the cardiovascular system and on weight loss in patients.

Therapeutic Potential of Glucagon-like Peptide-1 Agonists in Polycystic Ovary Syndrome: From Current Clinical Evidence to Future Perspectives.

Despite the continuous effort to understand the pathophysiology and determine potential therapeutic targets, PCOS treatment largely depends on lifestyle intervention and symptomatic management of individual signs and symptoms. International guidelines recognize the importance of weight reduction as a cornerstone for the achievement of better metabolic, reproductive, and cardiovascular outcomes in PCOS women who are overweight or obese. With its profound weight loss potential in patients with or without diabetes, the administration of GLP-1 receptor agonists has been investigated in overweight/obese women with PCOS in several single-center randomized control trials with considerable variation in the dosing regimen, follow-up duration, and outcome measurements over recent years. Most trials reported superior weight loss effects of GLP-1 receptor agonists compared to lifestyle changes or metformin, with additional metabolic, reproductive, and cardiovascular benefits in this population. However, their use is currently not widely accepted by the clinical community that treats this population. The major concern is how to balance the reproductive and metabolic treatment strategies since the use of GLP-1 receptor agonists requires effective contraception while on therapy and a washout period before pregnancy. Both approaches are not mutually exclusive, yet the best choice requires a careful assessment of the clinical context. Knowing a patient’s individual circumstances, precise clinical sub-phenotyping, and regular monitoring are crucial components for the safe and effective use of these new tools. In the present narrative review, we explore the current clinical evidence and provide the future perspectives and challenges for their implementation in PCOS management.

Effects of GLP-1 receptor agonists on arrhythmias and its subtypes in patients with type 2 diabetes: A systematic review and meta-analysis.

PurposeAn update of a systematic review and meta-analysis of the risk of arrhythmias and their subtypes in type 2 diabetic patients receiving glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trial(CVOT).MethodsRandomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetes mellitus patients published in full-text journal databases such as MEDLINE (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to March 1, 2022 were searched. We assessed the quality of individual studies by the Cochrane risk-of-bias algorithm. RevMan 5.4.1 software was use for calculating meta-analysis.ResultsA total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported no significant effect on total arrhythmia [RR=0.96, 95% CI (0.96, 1.05), p =0.36], and its subtypes such as atrial fibrillation [RR=0.96, 95% CI (0.86, 1.07), p =0.43], atrial flutter [RR= 0.82, 95% CI (0.57, 1.19), p =0.30], atrial tachycardia [RR=0.64, 95% CI (0.20, 2.01), p =0.44)], sinoatrial node dysfunction [RR=0.74, 95% CI (0.44, 1.25), p =0.26], ventricular preterm systole [RR=1.42, 95% CI (0.62, 3.26), p =0.41], second degree AV block [RR=0.96, 95% CI (0.53, 1.72), p =0.88], complete AV block [RR=0.75, 95% CI (0.49, 1.17), p =0.21], ventricular fibrillation [RR=1.00, 95% CI (0.50, 2.02), p =1.00], ventricular tachycardia [RR=1.37, 95% CI (0.91, 2.08), p =0.13] from treatment with GLP-1RA versus placebo. However, the risk of hypoglycemia was reduced by about 30% [RR=0.70, 95% CI (0.57, 0.87), p=0.001] and the risk of pneumonia by about 25% [RR=0.85, 95% CI (0.75, 0.97), p=0.01], both statistically significant differences.ConclusionIn type 2 diabetic patients, treatment with GLP-1RA has no significant effect on the risk of major arrhythmias but significantly reduces the risk of hypoglycemia and pneumonia.

Effects of GLP-1 Receptor Agonists on Biological Behavior of Colorectal Cancer Cells by Regulating PI3K/AKT/mTOR Signaling Pathway.

Colorectal cancer (CRC) has become one of the top ten malignant tumors with a high incidence rate and mortality. Due to the lack of a good CRC screening program, most of the CRC patients are being transferred at the time of treatment. The conventional treatment cannot effectively improve the prognosis of CRC patients, and the target drugs can significantly prolong the overall survival of patients in the advanced stage. However, the use of single drug may lead to acquired drug resistance and various serious complications. Therefore, combined targeted drug therapy is the main alternative treatment with poor effect of single targeted drug therapy, which has important research significance for the treatment of CRC. Therefore, this study intends to culture CRC cell lines in vitro at the cell level and intervene with the GLP-1 receptor agonist liraglutide. The effects of liraglutide on the PI3K/Akt/mTOR signal pathway and CRC cell proliferation, cycle, migration, invasion, and apoptosis are explored by detecting cell proliferation, cycle, migration, invasion, and apoptosis and the expression of related mRNA and protein. The results showed that liraglutide, a GLP-1 receptor agonist, could block the CRC cell cycle, reduce cell proliferation, migration, and invasion and promote apoptosis by inhibiting the PI3K/Akt/mTOR signal pathway.

The effect of glucagon like peptide-1 receptor agonist on behavioral despair and anxiety-like behavior in ovariectomized rats: Modulation of BDNF/CREB, Nrf2 and lipocalin 2

Ovariectomized (OVX) rodents show behavioral despair and anxiety-like behaviors. Glucagon-like peptide-1 receptor agonists (GLP-1RA) possess neuroprotective effects by reducing oxidative stress and neuroinflammation, thereby preventing synaptic loss. The objective of the present study is to evaluate the effect of GLP-1RA, namely liraglutide, on emotional behaviors, and to identify the level of oxidative stress, neuroinflammation, and BDNF signaling in the hippocampus of OVX rats. Forty female young Wistar rats were divided into 5 groups: Control, Control+liraglutide treated, OVX, OVX+fluoxetine, and OVX+liraglutide (150 µg/kg for 15 days, sc). Open field test and elevated plus-maze test were used to evaluate behaviors that are suggestive of anxiety. A forced swimming test was used to evaluate behavioral despair. At the end of the experiments, blood glucose level and body weight gain were measured. The levels of BDNF, CREB, Nrf2, and lipocalin 2 in the hippocampal tissue were measured by ELISA. Malondialdehyde (MDA) and glutathione levels were also evaluated. Statistical analysis was conducted through ANOVA and Bonferroni tests. Seven weeks post-OVX rats exhibited high anxiety related behavior and behavioral despair in comparison with the control groups. These behavioral changes were associated with increased lipocalin 2 and MDA levels in rats. Moreover, BDNF, CREB, and Nrf2 levels decreased significantly in the hippocampus of OVX rats. Liraglutide treatment limited the reduction of BDNF and Nrf2 levels in the hippocampus, maintaining them at the control levels. Liraglutide treatment also prevented the symptoms of behavioral despair and anxiety related behavior. As the main finding of the study GLP-1RA reduced behavioral despair and anxiety level and this may be related to the preservation of BDNF/Nrf2 levels and the decrease in oxidative stress and lipocalin 2 levels in the hippocampus.

Use of GLP-1 Receptor Agonists and Occurrence of Thyroid Disorders: a Meta-Analysis of Randomized Controlled Trials.

The association between glucagon-like peptide-1 (GLP-1) receptor agonists and the risk of various kinds of thyroid disorders remains uncertain. We aimed to evaluate the relationship between the use of GLP-1 receptor agonists and the occurrence of 6 kinds of thyroid disorders. We searched PubMed (MEDLINE), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science from database inception to 31 October 2021 to identify eligible randomized controlled trials (RCTs). We performed meta-analysis using a random-effects model to calculate risk ratios (RRs) and 95% confidence intervals (CIs). A total of 45 trials were included in the meta-analysis. Compared with placebo or other interventions, GLP-1 receptor agonists’ use showed an association with an increased risk of overall thyroid disorders (RR 1.28, 95% CI 1.03-1.60). However, GLP-1 receptor agonists had no significant effects on the occurrence of thyroid cancer (RR 1.30, 95% CI 0.86-1.97), hyperthyroidism (RR 1.19, 95% CI 0.61-2.35), hypothyroidism (RR 1.22, 95% CI 0.80-1.87), thyroiditis (RR 1.83, 95% CI 0.51-6.57), thyroid mass (RR 1.17, 95% CI 0.43-3.20), and goiter (RR 1.17, 95% CI 0.74-1.86). Subgroup analyses and meta-regression analyses showed that underlying diseases, type of control, and trial durations were not related to the effect of GLP-1 receptor agonists on overall thyroid disorders (all P subgroup > 0.05). In conclusion, GLP-1 receptor agonists did not increase or decrease the risk of thyroid cancer, hyperthyroidism, hypothyroidism, thyroiditis, thyroid mass and goiter. However, due to the low incidence of these diseases, these findings need to be examined further.Systematic Review RegistrationPROSPERO https://www.crd.york.ac.uk/prospero/, identifier: CRD42021289121.

452-P: Liraglutide Decreases Neointimal Growth in Control and Western Diet–Fed Mice, and Its Effect Is Insulin Dependent

Restenosis following percutaneous transluminal angioplasty and stenting is increased in subjects with insulin resistance and diabetes. Our preclinical models of restenosis show that insulin treatment is vasculoprotective in insulin sensitive conditions but insulin's effect is diminished or lost in Western diet induced insulin resistant conditions. Accordingly, early insulin treatment has not proven to provide cardiovascular disease (CVD) protection in subjects with dysglycemia, while the effect of intensive insulin treatment of type 2 diabetes (T2D) is debated. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a new class of antidiabetic drugs that reduce the CVD risk of T2D. Several animal studies have shown that GLP-1RA decrease neointimal growth in models of restenosis; however, the mechanisms of the CVD actions of these drugs remain elusive. GLP-1RA are insulin secretagogues, therefore their effect may be partly mediated by the insulin receptor (IR) . The objective of this study was to determine if insulin receptor (IR) deficiency in endothelial cells (EC) attenuates the effect of GLP-1RA to decrease neointimal growth after arterial injury. Endothelial deficient IR mice were generated by crossing IR floxed mice with mice expressing tamoxifen-inducible Cre recombinase under the control of Tie2 promoter. Mice were fed a low-fat (LFD) or a high-fat-high-sucrose (HFSD) Western diet and implanted with an osmotic pump delivering liraglutide, a GLP-1RA prototype (1mol/kg/day) , or vehicle prior to femoral artery wire injury. In LFD- as well as in HFSD-fed IR-floxed controls, liraglutide decreased neointimal area (NA) and intima-to-media ratio (I/M) . In LFD-fed endothelial IR deficient mice liraglutide had no effect. These data suggest that IR in ECs is important for the anti-restenotic effect of GLP1-RA, which is preserved in Western diet induced insulin resistant conditions unlike the effect of insulin. *First and second authors contributed equally Disclosure M.Gonzalez: None. Z.Liu: None. A.Giacca: None.

Glucagon-like peptide-1 (GLP-1) receptor agonists and cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of double-blind, randomized, placebo-controlled clinical trials

BackgroundThe cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.MethodsPubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.ResultsWe included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).ConclusionWe concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.

Effects of A GLP‑1 Receptor Agonist on Gastrointestinal Epithelial Cells

The number of people with diabetes worldwide has increased to 537 million, with a 3.6-fold increase occurring in the last 20 years. Various medications are used in the treatment of diabetes, and glucagon-like peptide-1 (GLP-1) receptor agonists have been recommended in major overseas guidelines. Although the main route of administration of GLP-1 receptor agonists is subcutaneous, orally administered GLP-1 receptor agonists were approved in 2019. Therefore, gastrointestinal epithelial cells are exposed to GLP-1 receptor agonists with poor bioavailability; however, it currently remains unclear whether this luminal approach damages these cells. The present study investigated the effects of GLP-1 receptor agonists on gastrointestinal epithelial cells. The gastrointestinal epithelial cell lines HGC-27, IEC-6, and Caco-2 were treated with Liraglutide, a GLP-1 receptor agonist. The protein expression of the GLP-1 receptor was confirmed in these cell lines, and Liraglutide did not significantly affect their proliferation. Although no inhibitory effects on oxidative stress were noted, Liraglutide appeared to alter the expression of drug absorption-regulating factors. In conclusion, since no significant changes were detected in the cell lines examined, even at higher concentrations of Liraglutide, there were no significant effects at the cellular level. However, since the present results were contradictory to previous findings, further studies using different conditions and cells are warranted.

Research Progress on the Cardiovascular Protective Effect of Glucagon-Like Peptide-1 Receptor Agonists.

The risk of cardiovascular diseases is closely related to diabetes. Macrovascular disease is the main cause of death and disability in patients with type 2 diabetes. In recent years, the glucagon-like peptide-1 receptor agonist (GLP-1RA), a new type of hypoglycemic drug, has been shown to regulate blood sugar levels, improve myocardial ischemia, regulate lipid metabolism, improve endothelial function, and exert a protective role in the cardiovascular system. This study reviewed the protective effects of GLP-1RA on the cardiovascular system.

GLP-1 receptor agonists in diabetic kidney disease: current evidence and future directions.

With the emergence of various classes of blood glucose-lowering agents, choosing the appropriate drug for each patient is emphasized in diabetes management. Among incretin-based drugs, glucagon-like peptide 1 (GLP-1) receptor agonists are a promising therapeutic option for patients with diabetic kidney disease (DKD). Several cardiovascular outcome trials have demonstrated that GLP-1 receptor agonists have beneficial effects on cardiorenal outcomes beyond their blood glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). The renal protective effects of GLP-1 receptor agonists likely result from their direct actions on the kidney, in addition to their indirect actions that improve conventional risk factors for DKD, such as reducing blood glucose levels, blood pressure, and body weight. Inhibition of oxidative stress and inflammation and induction of natriuresis are major renoprotective mechanisms of GLP-1 analogues. Early evidence from the development of dual and triple combination agents suggests that GLP-1 receptor agonists will probably become popular treatment options for patients with T2DM.

Glucagon-like Peptide-1 Receptor Agonists in the Management of Type 2 Diabetes Mellitus and Obesity: The Impact of Pharmacological Properties and Genetic Factors.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

Decreased Risk of Anxiety in Diabetic Patients Receiving Glucagon-like Peptide-1 Receptor Agonist: A Nationwide, Population-Based Cohort Study

Background: Previous findings on using Glucagon-like peptide-1 receptor agonist (GLP1-RA) as an antidepressant were conflicting, lacking large-scale studies. We used population-based data to investigate depression and anxiety risk in diabetic patients receiving the medication. Methods: From claims records of the National Health Insurance Research Database (NHIRD) of Taiwan, we identified cohorts of 10,690 GLP1-RA users and 42,766 propensity score-matched patients without GLP1-RA use from patients with diabetes mellitus (DM) diagnosed in 2011–2017, matched by age, gender, index year, occupation, urbanization, comorbidities, and medications. Incidence, hazard ratios (HR) and 95% confidence interval (CI) of depression and/or anxiety were estimated by the end of 2017. Results: The overall combined incidence of anxiety and/or depression was lower in GLP1-RA users than in non-users (6.80 versus 9.36 per 1,000 person-years), with an adjusted HR adjusted hazard ratio (aHR) of 0.8 (95% CI: 0.67–0.95) after controlling for covariates. The absolute incidence reduction was greater in anxiety (2.13 per 1,000 person-years) than in depression (0.41 per 1,000 person-years). The treatment effectiveness was significant for women. Patients taking GLP1-RA for longer than 180 days had the incidence of anxiety reduced to 2.93 per 1,000 person-years, with an aHR of 0.41 (95%CI: 0.27–0.61), compared to non-users. Dulaglutide could significantly decrease risks of both anxiety and depression. Conclusion: Patients with DM receiving GLP1-RA therapy have a greater reduction of the risk of anxiety than that of depression. Our findings strengthen previous research that advocated possible anti-depressant or anxiolytic effects of GLP1-RA and may lead to improved treatment adherence among patients with DM.

Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis.

Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes.

The Effect of GLP-1 Receptor Agonists on Postprandial Lipaemia.

To review the currently available data on the effect of Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on postprandial lipaemia. Out of the available studies that examined the respective lipid parameter, exenatide reduced postprandial triacyglycerol (TAG) in 4/6, apolipoprotein B-48 in 3/3, non-esterified fatty acids in 2/2, and apolipoprotein C-III and very low-density lipoprotein cholesterol (VLDL-C) in 1/1 studies. Liraglutide reduced postprandial TAG in 2/2, apolipoprotein B-48 in 3/3 and apolipoprotein C-III, chylomicron-TAG and VLDL1-TAG in 1/1 studies. Lixisenatide reduced postprandial chylomicron-TAG and apolipoprotein B-48 in 1 study. Semaglutide reduced postprandial TAG, apolipoprotein B-48 and VLDL in 1 study. Dulaglutide reduced postprandial apolipoprotein B-48 in 1 study. GLP-1 RAs have consistent beneficial effects on postprandial lipaemia with most of the data coming from studies with exenatide and liraglutide. Reduction of postprandial lipaemia might be one of the mechanisms behind the pleiotropic effects of GLP-1 RAs.