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

Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Metabolic Associated Fatty Liver Disease: A Systematic Review and Meta-analysis.

Clinical trials examining the therapeutic benefits of glucagon-like peptide-1 receptor agonists (GLP-1RA) on patients with metabolic associated fatty liver disease (MAFLD) have reported inconsistent results. The aim of this meta-analysis was to verify the role of GLP-1RA in the treatment of MAFLD patients. We searched PubMed, Embase, Medline, and the Cochrane Library for randomized controlled trials published that compared GLP-1RA with the control treatment in patients with MAFLD till to July 30, 2020. The effects of GLP-1RA on liver histology, body mass index, waist circumference (WC), aspartate aminotransferase, total cholesterol, triglycerides (TG), low-density lipoprotein and high-density lipoprotein were evaluated. Thirteen trials involving 704 patients were included in the meta-analysis. Compared with the control treatment, GLP-1RA treatment induced a greater resolution of steatohepatitis [RR=2.87; 95% confidence interval (CI): 0.89 to 9.23], delayed the progression of liver fibrosis (RR=3.83, 95% CI: 0.91 to 16.07) and reduced liver fat deposition (MD: -1.40; 95% CI: -2.75 to -0.05). In addition, it reduced the body mass index (MD: -1.15; 95% CI: -2.26 to -0.04), WC (MD: -3.33; 95% CI: -6.31 to -0.35) and improved serum aspartate aminotransferase (MD: -3.04; 95% CI: -5.93 to -0.16) and total cholesterol (MD: -0.20; 95% CI: -0.28 to -0.13). GLP-1RA improves liver steatosis and fibrosis. It is also beneficial to metabolic syndrome as it reduces BMI, WC, and hyperlipidemia.

A novel dual agonist of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors attenuates fentanyl taking and seeking in male rats

There has been a dramatic increase in illicit fentanyl use in the United States over the last decade. In 2018, more than 31,000 overdose deaths involved fentanyl or fentanyl analogs, highlighting an urgent need to identify effective treatments for fentanyl use disorder. An emerging literature shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the reinforcing efficacy of drugs of abuse. However, the effects of GLP-1R agonists on fentanyl-mediated behaviors are unknown. The first goal of this study was to determine if the GLP-1R agonist exendin-4 reduced fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, an animal model of relapse, in rats. We found that systemic exendin-4 attenuated fentanyl taking and seeking at doses that also produced malaise-like effects in rats. To overcome these adverse effects and enhance the clinical potential of GLP-1R agonists, we recently developed a novel dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs), GEP44, that does not produce nausea-like behavior in drug-naïve rats or emesis in drug-naïve shrews. The second goal of this study was to determine if GEP44 reduced fentanyl self-administration and reinstatement with fewer adverse effects compared to exendin-4 alone. In contrast to exendin-4, GEP44 attenuated opioid taking and seeking at a dose that did not suppress food intake or produce adverse malaise-like effects in fentanyl-experienced rats. Taken together, these findings indicate a novel role for GLP-1Rs and Y2Rs in fentanyl reinforcement and highlight a potential new therapeutic approach to treating opioid use disorders.

Safety and Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Children and Adolescents with Obesity: A Meta-Analysis

To determine the weight, body mass index (BMI), cardiometabolic, and gastrointestinal effects of glucagon-like peptide-1 (GLP-1) receptor agonists in children with obesity. Web of Science, PubMed/MEDLINE, and Scopus databases from 01/01/1994-01/01/2021 for randomized control trials examining the weight, BMI, cardiometabolic, or gastrointestinal effects of GLP-1 receptor agonists in children and adolescents with obesity. Data were extracted by 2 independent surveyors and a random effects model was applied to meta-analyze generic inverse variance outcomes. Primary outcomes were related to weight and cardiometabolic profile, and secondary outcomes of interest were gastrointestinal-related treatment-emergent adverse events. Nine studies involving 574 participants were identified, of which 3 involved exenatide and 6 involved liraglutide. GLP-1 receptor agonists use caused a modest reduction in body weight (mean difference [MD] -1.50 [-2.50,-0.50] kg, I2 64%), BMI (MD -1.24 [-1.71,-0.77] kg/m2, I2 0%), and BMI z score (MD -0.14 [-0.23,-0.06], I2 43%). Glycemic control was improved in children with proven insulin resistance (glycated hemoglobin A1c MD -1.05 [-1.93,-0.18] %, I2 76%). Although no lipid profile improvements were noted, a modest decrease in systolic blood pressure was detected (MD -2.30 [-4.11,-0.49] mm Hg; I2 0%). Finally, analysis of gastrointestinal-related treatment-emergent adverse events revealed an increased risk of nausea (risk ratio 2.11 [1.44, 3.09]; I2 0%), without significant increases in other gastrointestinal symptoms. This meta-analysis indicates that GLP-1 receptor agonists are safe and effective in modestly reducing weight, BMI, glycated hemoglobin A1c, and systolic blood pressure in children and adolescents with obesity in a clinical setting, albeit with increased rates of nausea. CRD42020195869.

Effects of GLP-1 receptor agonist on changes in the gut bacterium and the underlying mechanisms

There is a close relationship between the gut microbiota and metabolic disorders. In this study, acute administration of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide to mice increased the cecal levels of caseinolytic protease B, a component of Escherichia coli, and of norepinephrine. Chemical sympathectomy blocked these events. Norepinephrine was found to pass into the intestinal lumen in vitro. c-Fos staining of the intermediolateral nucleus was identified as indirect evidence of sympathetic nervous system activation of the intestinal tract by GLP-1RA. Under normal conditions, the increase in E. coli did not affect the host. However, in mice with colitis, bacterial translocation was observed with attenuation of tight junction gene expression. This is the first study to investigate the unique underlying mechanisms related the effects of GLP-1RA on changes in the gut bacterium.

Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Exacerbations Among Patients With Type 2 Diabetes.

Emerging data from animal and human pilot studies suggest potential benefits of glucagon-like peptide 1 receptor agonists (GLP-1RA) on lung function. We aimed to assess the association of GLP-1RA and chronic lower respiratory disease (CLRD) exacerbation in a population with comorbid type 2 diabetes (T2D) and CLRD. A new-user active-comparator analysis was conducted with use of a national claims database of beneficiaries with employer-sponsored health insurance spanning 2005-2017. We included adults with T2D and CLRD who initiated GLP-1RA or dipeptidyl peptidase 4 inhibitors (DPP-4I) as an add-on therapy to their antidiabetes regimen. The primary outcome was time to first hospital admission for CLRD. The secondary outcome was a count of any CLRD exacerbation associated with an inpatient or outpatient visit. We estimated incidence rates using inverse probability of treatment weighting for each study group and compared via risk ratios. The study sample consisted of 4,150 GLP-1RA and 12,540 DPP-4I new users with comorbid T2D and CLRD. The adjusted incidence rate of first CLRD admission during follow-up was 10.7 and 20.3 per 1,000 person-years for GLP-1RA and DPP-4I users, respectively, resulting in an adjusted hazard ratio of 0.52 (95% CI 0.32-0.85). For the secondary outcome, the adjusted incidence rate ratio was 0.70 (95% CI 0.57-0.87). GLP-1RA users had fewer CLRD exacerbations in comparison with DPP-4I users. Considering both plausible mechanistic pathways and this real-world evidence, potential beneficial effects of GLP-1RA may be considered in selection of an antidiabetes treatment regimen. Randomized clinical trials are warranted to confirm our findings.

GLP-1 Receptor Agonist Inhibited the Activation of RIPK1 for Alleviation the Neuronal Death and Neuroinflammation in APP/PS1 Mice

Alzheimer’s disease (AD) is characterized by neuronal necroptosis and neuroinflammation, retardation of these pathological development was considered to play crucial role in the treatment of AD. RIPK1, a receptor-interacting serine/threonine-protein kinase 1, was reported to be involved in the mediation of neuronal necroptosis and neuroinflammation. Previous investigations indicated that the agonists of glucagon like peptide-1 receptor (GLP-1R) such as Liraglutide, showed ameliorating effect against the development of Alzheimer’s disease on model mice, however, the mechanisms by which GLP-1R agonists function in AD remains elusive. The effect of Liraglutide on the retardation of the AD progression upon regulation of RIPK1 was studied using biochemical and immune-histochemical assays in model mice. Results in this study ascertained that the GLP-1R agonists possessed inhibitory effect on RIPK1-mediated necroptosis and microglial activation in vitro and in vivo. It was evidenced that the utility of GLP-1R agonist is capable to reduce RIPK1 activity significantly and the effect of GLP-1R agonist showed PKA depended manner. This study clarified the relationship of GLP-1R agonist and RIPK1 and demonstrating the physiological effect of GLP-1R agonist in amelioration of AD. This study provided a mechanism underlying the function of GLP-1R agonist in AD and suggested a potential therapeutic strategies for the treatment of AD.

The effects of glucagon like peptide-1 (GLP-1) on cardiac remodeling: exploring the role of medication and physiological modulation after metabolic surgery.

Obesity and associated comorbidities reach epidemic proportions nowadays. Several treatment strategies exist, but bariatric surgery has the only longstanding effects. Since a few years, there is increasing interest in the effects of gastro-intestinal hormones, in particular Glucagon-Like Peptide-1 (GLP-1) on the remission of Type 2 Diabetes (T2DM) and its effects on cardiac cardiovascular morbidity, cardiac remodeling, and mortality. In the past years several high quality multicenter randomized controlled trials were developed to assess the effects of GLP-1 receptor agonist therapy on cardiovascular morbidity and mortality. Most of the trials were designed and powered as non-inferiority trials to demonstrate cardiovascular safety. Most of these trials show a reduction in cardiovascular morbidity in patients with T2DM. Some follow-up studies indicate potential beneficial effects of GLP-1 receptor agonists on cardiovascular function in patients with heart failure, however the results are contradictory, and we need long-term studies to make firm conclusions about the pleiotropic properties of incretin-based therapies. However, it seems that GLP-1 receptor agonists have different effects than the increased GLP-1 production after bariatric surgery on cardiovascular remodeling. One of the hypotheses is that the blood concentrations of GLP-1 receptor agonists are three times higher compared to GLP-1 increase after bariatric and metabolic surgery. The purpose of this narrative review is to summarize the effects of GLP-1 on cardiovascular morbidity, mortality and remodeling due to medication but also due to bariatric and metabolic surgery. The second objective is to explain the possible differences in effects of GLP-1 agonists and bariatric and metabolic surgery.

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors in heart transplant patients with type 2 diabetes: Initial report from a cardiometabolic center of excellence

Type 2 diabetes mellitus (T2D) is a common comorbidity among patients who have undergone heart transplantation. Recently two classes of glucose-lowering medications (sodium-glucose cotransporter type-2 inhibitors [SGLT-2Is] and glucagon-like-peptide-1 receptor agonists [GLP-1RAs]), have been shown to significantly improve cardiovascular outcomes. There is a paucity of data regarding their use in immunosuppressed patients, with many studies specifically excluding this population. We retrospectively evaluated the safety and efficacy of GLP-1RAs and SGLT-2Is in patients who had undergone orthotopic heart transplant at a high-volume center. Among 21 patients, we found significant weight loss, reductions in insulin use, hemoglobin A1c, and low-density lipoprotein-cholesterol. Moreover, both SGLT-2Is and GLP-1RAs were well tolerated with no adverse events leading to discontinuation of either therapy. While larger studies of patients after solid organ transplant are needed, this small hypothesis-generating study demonstrates that SGLT-2Is and GLP-1RAs appear safe and effective therapies among patients with T2D after heart transplant.

The Antiobesity Effect of GLP-1 Receptor Agonists Alone or in Combination with Metformin in Overweight /Obese Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Objectives Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and metformin (MET) have markedly antiobesity effects in overweight/obese polycystic ovary syndrome (PCOS) patients. However, there was no literature to compare the antiobesity effects of these two medicines. Therefore, a systematic review and meta-analysis were conducted in our present study to evaluate the antiobesity effects of GLP-1RAs either as monotherapy or combined with MET in comparison with MET alone in overweight/obese PCOS patients. Methods All randomized controlled trials (RCTs) which reported the efficacy of GLP-1RAs and MET in overweight/obese PCOS patients in Medline (from Pubmed), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus databases were independently searched by two reviewers. The random-effect model was used to pool data extracted from the included literature. The weighted mean difference (WMD) and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD42020173199). Results A total of eight eligible RCTs were finally enrolled in our meta-analysis from the 587 retrieved literature. The results showed that GLP-1RAs alone or combined with MET was associated with a greater weight loss (N = 318, WMD = −2.61, 95% CI: −3.51 to −1.72, P ≤ 0.001, I2 = 77.5%), more obvious reduction of waist circumference (N = 276, WMD = −3.46, 95% CI: −4.36 to −2.56, P ≤ 0.001, I2 = 0.0%), and body mass index (BMI) (N = 318, WMD = −0.93, 95% CI: −1.60 to −0.26, P=0.007, I2 = 84.9%) in overweight/obese PCOS patients when compared with MET alone. Further sensitivity analysis demonstrated that the meta-analysis results of the efficacy differences in terms of body weight, waist circumference, and BMI were relatively stable and reliable. Conclusion Our meta-analysis demonstrated that the antiobesity effect of GLP-1RAs alone or combined with MET was superior to MET alone in terms of weight loss, the reduction of waist circumference, and BMI. More large-scale, high-quality RCTs are needed to further confirm these results in PCOS patients.

Decrease of coronary heart disease risk with GLP1-receptor agonists or SGLT2 inhibitors therapy in patients with type 2 diabetes in primary cardiovascular prevention: A 24 months follow-up study

AimsThe aim of this real-world study is to evaluate the effect of glucagon-like peptide1 receptor-agonist (GLP1 RA) and sodium-glucose co-transporter2 inhibitor (SGLT2i) on coronary heart disease (CHD) risk, in patients with type 2 diabetes (T2D) in primary cardiovascular prevention. MethodsData from 312 patients with T2D, without CHD history, starting treatment with GLP1 RA (n = 174) or SGLT2i (n = 138), were retrospectively collected. UKPDS-RE score was used to estimate 10-years risk for CHD before and 6, 12 and 24 months after prescription. ResultsThe 10-year CHD risk significantly decreased over 24 months in both GLP1 RA and SGLT2i groups (p = 0.037 and p < 0.001, respectively), with 3% and 7% CHD risk reduction already obtained after the first 6 months of GLP1 RA and SGLT2i therapy respectively (p < 0.001 in both groups. Analyses by categories of baseline CHD risk showed significant reductions of CHD risk in the severe risk categories of both groups (p < 0.001). CHD risk reduction obtained with SGLT2i was higher than with GLP1 RA at 6 and 12 months but not at 24 months. ConclusionThis real-world study shows that both GLP1 RA and SGLT2i reduce the 10-year risk for cardiovascular disease in patients with T2D in primary cardiovascular prevention.

Renoprotective effect of GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease in spontaneously diabetic Torii fatty rats.

The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders. Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague-Dawley rats (n = 7) were injected only with a vehicle. The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment. Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Hypoglycemia.

A relatively recent addition to the arsenal of antidiabetic drugs used for the treatment of type 2 diabetes mellitus (T2DM) has been the “incretin mimetics,” a group of drugs that work on the glucagon-like peptide-1 (GLP-1) receptor and enhance insulin secretion from the pancreatic β-cells in a glucose-dependent manner, more potently in hyperglycemic conditions, while suppressing glucagon secretion at the same time. Therefore, it was assumed that this class of drugs would have a lower risk of hypoglycemia than insulin secretagogues like sulphonylureas. However, GLP-1 receptor agonists have been proposed to cause hypoglycemia in healthy normoglycemic subjects implying that their action is not as glucose-dependent as once thought. Other studies concluded that they might not induce hypoglycemia and the risk is dependent on other individual factors. However, the FDA announced that the 12 GLP-1 receptor agonists currently available on the market had potential safety signs and evaluated the need for regulatory action. This review provides an overview of the studies that investigated the possible hypoglycemic effect of GLP-1 receptor agonists. In addition, the current review describes other adverse effects of GLP-1 receptor agonist treatment.

Effect of the glucagon-like peptide-1 analogue liraglutide versus placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial.

To examine how circulating glucagon-like peptide-1 (GLP-1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon-derived peptides (PGDPs), including endogenous GLP-1, glucagon-like peptide-2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control. Adults who were overweight/obese (body mass index 27-40 kg/m2 ) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist [GLP-1A]) and endogenous (GLP-1E) GLP-1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady-state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated for ISR, glucose and levels of PGDPs. Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean -3.6%, 95% CI [-5.2% to -2.1%]), SSPG (-32% [-43% to -22%]) and glucose AUC (-7.0% [-11.5% to -2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP-1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = -0.54) and SSPG (r = -0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP-1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP-1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP-1 receptor agonists to decrease their endogenous production in contrast to weight loss-dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells. Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.

Glucagon-like peptide-1 receptor agonist reduces di(2-ethylhexyl) phthalate-induced atherosclerotic processes in vascular smooth muscle cells.

Glucagon-like peptide-1 receptor (GLP1R) agonist is an incretin hormone and regulates glucose metabolism. However, phthalates, known as endocrine disruptors, can interfere with hormone homeostasis. In the present study, we aimed to estimate the impact of GLP1R agonist on di(2 ethylhexyl) phthalate (DEHP)-induced atherosclerosis. For this purpose, the effects of GLP1R agonist on various atherogenesis-related cellular processes and pathways were assessed in vascular smooth muscle cells (VSMCs). DEHP-induced cell proliferation and migration were significantly decreased by GLP1R agonist in VSMCs. Protein levels of matrix metalloproteinase (MMP)-2 and MMP-9 were significantly decreased in cells exposed to GLP1R agonist, compared with DEHP-treated cells. Expression levels of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were also reduced in GLP1R agonist-treated cells. Similarly, DEHP-associated phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2 was decreased in GLP1R agonist-treated cells, compared with DEHP-treated cells. Our findings suggest that treatment with GLP1R agonist counteracts the activation of pathways related to atherosclerosis.

Effects of GLP-1 Receptor Agonists and SGLT-2 Inhibitors in Heart Transplant Patients with Type 2 Diabetes: a Case Series

Background Type 2 diabetes mellitus (T2D) is common in post-heart transplant patients. Commonly used T2D medications, especially insulin, can promote weight gain and are not associated with cardiovascular (CV) benefits. Glucagon-like Peptide-1 receptor agonists (GLP-1 RA) and Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) are two drug classes that produce CV benefits in T2D and promote weight loss with minimal risk of hypoglycemia. Their use has not been previously evaluated in this particular group, and there have been theoretical concerns about safety in immunosuppressed patients. Methods Patients with T2D are sequentially referred by the Heart Transplant program to the Cardiometabolic Center of Excellence (CMCE) at our institution, allowing minimal selection bias. CMCE provides treatment algorithms that emphasize the use of cardioprotective T2D medications. We analyzed this initial series of transplant patients with T2D who have been on GLP-1 RA and/or SGLT-2i with at least two visits at CMCE. Results Among 15 patients, the mean age was 59.4 ± 2.6 years, 66.7% were males, 73.3% were Caucasians, 33.3% had history of ischemic cardiomyopathy and baseline eGFR was 53.5 ± 7.9 mL/min/1.73m2. The median time from transplant was 4.6 (1.6 - 10.5) years. The median follow-up time at CMCE was 5.4 (2.8 - 10.9) months. At baseline, 73% were on insulin, 40% on Metformin, 13% on Sulfonylurea, 13% on Dipeptidyl peptidase-4 inhibitors, and 7% on Thiazolidinediones. Following initiation of therapy at CMCE, 86.7% of patients were on a combination of GLP-1 RA and SGLT-2i, while the rest were taking only GLP-1 RA. Overall, the median total daily insulin requirements decreased substantially from 94 (40.5 - 124) to 34 (5 - 60) units at latest clinic visit; p = 0.003. Further, median hemoglobin A1c dropped from 7.7% (7.3 - 9.5) to 6.6% (6 - 8.5); p = 0.007. There was also a significant reduction in mean body weight (241.9 ± 35.8 at baseline vs. 217.1 ± 34.2 lbs at follow-up; p = 0.001), and mean body mass index (34.9 ± 4.5 vs. 31.1 ± 3.7; p = 0.001). Only one patient experienced side effects as one episode of severe nausea with Liraglutide that resolved when switched to Semaglutide. No infectious complications (including urinary tract or genital mycotic infections) were observed. Conclusions In this limited case series, combination therapy with GLP-1 RA and SGLT-2i was well tolerated in heart transplant patients and associated with favorable results in insulin requirement, hemoglobin A1c, and body weight. Type 2 diabetes mellitus (T2D) is common in post-heart transplant patients. Commonly used T2D medications, especially insulin, can promote weight gain and are not associated with cardiovascular (CV) benefits. Glucagon-like Peptide-1 receptor agonists (GLP-1 RA) and Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) are two drug classes that produce CV benefits in T2D and promote weight loss with minimal risk of hypoglycemia. Their use has not been previously evaluated in this particular group, and there have been theoretical concerns about safety in immunosuppressed patients. Patients with T2D are sequentially referred by the Heart Transplant program to the Cardiometabolic Center of Excellence (CMCE) at our institution, allowing minimal selection bias. CMCE provides treatment algorithms that emphasize the use of cardioprotective T2D medications. We analyzed this initial series of transplant patients with T2D who have been on GLP-1 RA and/or SGLT-2i with at least two visits at CMCE. Among 15 patients, the mean age was 59.4 ± 2.6 years, 66.7% were males, 73.3% were Caucasians, 33.3% had history of ischemic cardiomyopathy and baseline eGFR was 53.5 ± 7.9 mL/min/1.73m2. The median time from transplant was 4.6 (1.6 - 10.5) years. The median follow-up time at CMCE was 5.4 (2.8 - 10.9) months. At baseline, 73% were on insulin, 40% on Metformin, 13% on Sulfonylurea, 13% on Dipeptidyl peptidase-4 inhibitors, and 7% on Thiazolidinediones. Following initiation of therapy at CMCE, 86.7% of patients were on a combination of GLP-1 RA and SGLT-2i, while the rest were taking only GLP-1 RA. Overall, the median total daily insulin requirements decreased substantially from 94 (40.5 - 124) to 34 (5 - 60) units at latest clinic visit; p = 0.003. Further, median hemoglobin A1c dropped from 7.7% (7.3 - 9.5) to 6.6% (6 - 8.5); p = 0.007. There was also a significant reduction in mean body weight (241.9 ± 35.8 at baseline vs. 217.1 ± 34.2 lbs at follow-up; p = 0.001), and mean body mass index (34.9 ± 4.5 vs. 31.1 ± 3.7; p = 0.001). Only one patient experienced side effects as one episode of severe nausea with Liraglutide that resolved when switched to Semaglutide. No infectious complications (including urinary tract or genital mycotic infections) were observed. In this limited case series, combination therapy with GLP-1 RA and SGLT-2i was well tolerated in heart transplant patients and associated with favorable results in insulin requirement, hemoglobin A1c, and body weight.

β-catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet.

The hypoglycemic drug GLP-1 receptor agonist can ameliorate hepatic steatosis but the mechanism is not clear. Intake of high fructose leads to non-alcoholic fatty liver disease by stimulating lipid synthesis, and β-catenin is the key molecule for realizing GLP-1 function in extrahepatic tissues; with the discovery of GLP-1 receptor in liver, we speculate that β-catenin might mediate GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose. Wistar rats were fed with high fructose diet for 8 weeks and then treated with GLP-1 receptor agonist exenatide for 4 weeks; the changes of lipid synthesis pathway factors, the expression and nuclear translocation of β-catenin, and the hepatic steatosis of the rats were observed. After the intervention of exenatide, the hepatic steatosis induced by high fructose was improved, the nuclear translocation and expression of β-catenin were facilitated, and the mRNA and protein expression of the upstream regulator SREBP-1 and the downstream key enzymes ACC, FAS and SCD-1 of de novo lipogenesis were down-regulated. GLP-1 receptor agonist may ameliorate hepatic steatosis induced by high fructose by β-catenin regulating de novo lipogenesis pathway. GLP-1 receptor agonist may be a potential new drug for the treatment of non-alcoholic fatty liver disease, and the β-catenin may be an important target for the drug therapy.

Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection in β cells.

BACKGROUNDLong noncoding RNAs (lncRNAs) and mRNAs are widely involved in various physiological and pathological processes. The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a novel therapeutic strategy that could promote insulin secretion and decrease the rate of β-cell apoptosis in type 2 diabetes mellitus (T2DM) patients. However, the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated.AIMTo identify the lncRNAs and mRNAs that are involved in the protective effect of GLP-1RA in β cells, and their roles.METHODSRat gene microarray was used to screen differentially expressed (DE) lncRNAs and mRNAs in β cells treated with geniposide, a GLP-1RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs. Hub mRNAs were filtered using the STRING database and the Cytoscape plugin, CytoHubba. In order to reveal the regulatory relationship between lncRNAs and hub mRNAs, their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs, and competing endogenous RNA (ceRNA) mechanism was explored through miRanda and TargetScan databases.RESULTSWe identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of ≥ 1.5 and P value < 0.05. GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway, inflammatory response, calcium signaling pathway, positive regulation of cell proliferation, and ERK1 and ERK2 cascade. Pomc, Htr2a, and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin, CytoHubba. This result was further verified using SwissTargetPrediction tool. Through the co-expression network and competing endogenous (ceRNA) mechanism, we identified seven lncRNAs (NONRATT027738, NONRATT027888, NONRATT030038, etc.) co-expressed with the three hub mRNAs (Pomc, Htr2a, and Agtr1a) based on the Pearson coefficient of the expression levels. These lncRNAs regulated hub mRNA functions by competing with six miRNAs (rno-miR-5132-3p, rno-miR-344g, rno-miR-3075, etc.) via the ceRNA mechanism. Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs, suggesting that it is at a core position within the ceRNA network.CONCLUSIONWe have identified key lncRNAs and mRNAs, and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA in β cells.

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update.

Non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide. NAFLD progresses in some cases to non-alcoholic steatohepatitis (NASH), which is characterized, in addition to liver fat deposition, by hepatocyte ballooning, inflammation and liver fibrosis, and in some cases may lead to hepatocellular carcinoma. NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus (T2DM). Currently, lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in the management of T2DM and do not have major side effects like hypoglycemia. In patients with NAFLD, the GLP-1 receptor production is down-regulated. Recently, several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation, alleviating the inflammatory environment and preventing NAFLD progression to NASH. In this review, we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH. Finally, as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD, we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.

Tolerance develops toward GLP-1 receptor agonists’ glucose-lowering effect in mice

Glucagon-like peptide 1 (GLP-1) receptor agonists are popular antidiabetic drugs with potent glucose-lowering effects and low risk of hypoglycemia. Animal experiments and human data indicate that tolerance develops toward at least some of their effects, e.g., gastric motility. Whether tolerance develops toward the glucose-lowering effect of GLP-1 receptor agonists in mice has never been formally tested. The hypothesis of tolerance development in mice will be reported in this study. The direct glucose-lowering effect of the GLP-1 receptor agonists was measured in non-fasted mice and with intraperitoneal glucose tolerance test. Exenatide (10 μg/kg) and liraglutide (600 μg/kg) both substantially lost efficacy during the 18-day treatment as compared to the acute effect. We conclude that our results demonstrate development of tolerance toward GLP-1 receptor agonists’ glucose-lowering effect in mice.

GLP-1 receptor agonists for Parkinson's disease.

Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the off-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no effect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists.