Effects Of Glucagon-like Peptide-1 Agonists Research Articles

Effects of GLP-1 agonists on proportion of weight loss in obesity with or without diabetes: Systematic review and meta-analysis

To determine effects of glucagon-like peptide-1 (GLP-1) receptor agonists on ≥5% or ≥10% weight loss in overweight or obese patients with or without type 2 diabetes mellitus (T2DM). A systematic review and meta-analysis of placebo-controlled, randomized clinical trials (RCTs) ≥12 weeks’ duration. Registries were searched from inception to October 10, 2021. Sixty RCTs with 24,969 patients were included; 22 trials (median duration 39 weeks) with 17,183 patients (median age, 54.9y; 64% female; median baseline weight, 96.2kg) included data on ≥5% or ≥10% weight loss. Among GLP-1 receptor agonist-treated participants, 50.2% had ≥5% weight loss versus 17.1% placebo [odds ratio (OR), 5.03; 95% CI, 3.996.32]; 17.5% had ≥10% weight loss on agonists versus 3.1% placebo (OR, 5.31; 95% CI, 3.907.22). Highest proportion of ≥5% weight loss was achieved by semaglutide subcutaneous (SQ) 2.4mg (OR 8.32, 95% CI 4.59–15.09), semaglutide SQ < 2.4 mg (OR 7.1, 95% CI 4.6–10.95), and liraglutide SQ > 1.8mg (OR 4.28, 95% CI 3.37–5.43). Non-T2DM achieved significantly greater mean absolute weight loss than T2DM participants (coefficient: 2.47kg, 95% CI: 4.12 to −0.82). Nausea was associated with greater mean absolute weight loss (coefficient: 0.12, 95% CI: 0.06–0.17). GLP-1 receptor agonists are efficacious in inducing ≥5% or ≥10% weight loss in T2DM and non-T2DM with overweight or obesity. • A previous systematic review and network meta-analysis documented the weight loss relative to baseline as a continuous measure, and the relative efficacy of different medications in this class. • In 22 trials with 17,183 patients, 50.2% and 17.5% of those treated with GLP-1 receptor agonists had ≥5% and ≥10% weight loss respectively (both significant relative to placebo). • Participants without type 2 diabetes mellitus (T2DM) achieved significantly greater mean weight loss than those with T2DM. • Since highest proportions of >5% weight loss were achieved by semaglutide subcutaneous (SQ) 2.4 mg, semaglutide SQ < 2.4 mg, and liraglutide SQ > 1.8 mg, these appear to be the treatments of choice. • Nausea was associated with greater mean weight loss; development of nausea is a clinical indicator of treatment efficacy.

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.

Effect of Glucagon-like peptide-1 agonist (liriglutide) on weight and glycemic control among adults with type 2 diabetes mellitus attending primary care center at security forces hospital in Riyadh, Saudi Arabia.

Introduction:Liraglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist), also known as incretin mimetics. This is the new approach for management of weight among diabetic patients along with glycemic controls. The study aims to explore the efficacy of Liraglutide on weight (body mass index) and glycemic control (HbA1C) among adult patients with type 2 diabetes mellitus in primary care center.Methods:Retrospective chart review of 149 adult patients with type II diabetic taking Liraglutide as a monotharepy for 6 months and more were included in the study. Analysis was done in SPSS version 22.Results:Total 149 chart reviews were done. The mean age of participants were 55.52 (SD: 8.167). Of total 58.4% were female and 70% were on insulin. Paired sample statistics reported that pre- and post-change in BMI and weight was significantly different with P value < 0.001. However pre- and post-change in the value of HBA1c was not significantly different with P value 0.561.Conclusion:Through this retrospective study we can conclude that Liraglutide has important effect on weight loss and reduction in BMI. However, further longitudinal studies with large sample size and multi-center randomized controlled trials are needed to generalize the effectiveness of Liraglutide among Saudi population.

Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin.

The incretin hormone, glucagon-like peptide-1 (GLP-1), is known for responding to dietary fat and carbohydrate. It elicits effects on pancreas, gut, and brain to stabilize blood glucose levels. We have previously reported that the GLP-1 agonist, exenatide, vasodilates the kidney and suppresses proximal reabsorption. The present study was undertaken to determine whether the renal effects of exenatide are mediated by nitric oxide (NO) and/or prostaglandins. Inulin clearance (glomerular filtration rate, GFR) and urine flow rate (UV) were measured in anesthetized rats before and during exenatide infusion (1 nmol/h iv). Animals were pretreated with cyclooxygenase (COX) inhibitor (meclofenamate), NO synthase (NOS) inhibitor (NG-monomethyl-l-arginine, l-NMMA), NO clamp (l-NMMA + sodium nitroprusside), or placebo. Effectiveness of COX inhibition was tested by measuring urinary prostaglandin E2 (UPGE2). Effectiveness of NOS blockade and NO clamp was determined by urinary NO degradation products (UNOx). Exenatide increased GFR, UV, UPGE2, and UNOx. Pretreatment with meclofenamate reduced UPGE2 by 75% and reduced the effect of exenatide on UPGE2 by 30% but did not modify the effects of exenatide on GFR or UV. Pretreatment with l-NMMA reduced UNOx and the impact of exenatide on GFR and UV by 50%. Pretreatment by NO clamp did not prevent UNOx from increasing during exenatide but blunted the effects of exenatide on GFR and UV. In conclusion, exenatide is a potent renal vasodilator and diuretic in the rat. These effects of exenatide are insensitive to COX inhibition but are mediated, in part, by NO.

Effect of glucagon-like peptide-1 agonist on insulin signaling pathway in skeletal muscle of mice with insulin resistance

Objective To study the effect of glucagon-like peptide-1 agonist(exendin-4)on insulin signaling pathway in skeletal muscle of mice with insulin resistance(IR). Methods Thirty male KM mice were divided into normal control group(NC group, n=10)and IR group(n=20). The mice in NC group and IR group were fed with routine diet and high-fat diet for 16 weeks, respectively. After IR models were successfully established, 10 mice in IR group were treated with exendin-4(Ex group, 3 μg·kg-1·d-1)for 4 weeks. NC group and IR group were given the same dose of normal saline. Body weight, fasting blood glucose(FBG), and fasting insulin(FINS)were measured before and after the intervention, and homeostasis model assessment for insulin resistance(HOMA-IR)was calculated. The muscle glycogen content were measured by Periodic Acid-Schiff Stain(PAS). The expressions of insulin receptor(IRC), insulin receptor substrate-1(IRS-1), and phosphatidylinositol 3-kinase(PI3K)in the skeletal muscle were measured by Western blot and immunohistochemistry. Results Before intervention, the body weight, FBG, and HOMA-IR of IR group and Ex group were higher compared with NC group(all P 0.05). Compared with before intervention, the body weight of three groups after intervention were all increased, but increased more significantly in the IR group. After intervention, the FBG and HOMA-IR in Ex group decreased, compared with IR group and Ex group of non-intervention (all P 0.05). The skeletal muscle cells in NC control were colored extensively and more colored granules, while IR group were less colored, and Ex group were between NC group and IR group. Compared with NC group, the expressions of IRC, IRS-1, and PI3K in the skeletal muscle of IR group were significantly decreased(P 0.05). Compared with IR group, the expressions of IRC, IRS-1 and PI3K in Ex group were higher(P<0.05). Conclusions Exendin-4 improves insulin resistance by up-regulating the expressions of IRC, IRS-1, and PI3K in the skeletal muscle and promoting the synthesis of muscle glycogen. (Chin J Endocrinol Metab, 2016, 32: 315-320) Key words: Glucagon-like peptide-1 agonist; Insulin resistance; Skeletal muscle; Insulin receptor

Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists.

Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function.

Incretin-Based Therapies, Glucometabolic Health and Endovascular Inflammation

Incretin peptides are a group of gastrointestinal hormones that play a prominent role in the regulation of glucose metabolism. Incretin-based therapies (IBTs) have recently emerged as an important treatment option for patients with type 2 diabetes mellitus (T2DM). These pharmaceutical agents may be specially well suited for patients who are overweight or obese with primarily post-meal glucose peaks, and in whom traditional first-line oral agents have failed to maintain adequate glycemic control. There are 2 classes of IBTs: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide 1 (GLP-1) receptor agonists. The ultimate effect of both types of agents is to augment GLP-1 signaling, which results in enhanced glucose-dependent insulin secretion, inhibition of glucagon secretion and decreased appetite. This leads to improved regulation of glucose homeostasis accompanied by either no increase in body weight (with DPP-4 inhibitors) or a reduction (with GLP-1 receptor agonists). GLP-1 inhibits food intake and the increased GLP-1 response may contribute as a satiety signal. Although data regarding the effect of GLP-1 agonists and DPP-4 inhibitors on levels of peptides involved in the regulation of food intake in T2DM are few, an indirect effect of IBT on weight loss is possible (e.g. Exendin-4 induces adiponectin secretion in vitro). Results from animal models indicate reduction of food intake and body weight by GLP-1 agonists, but follow-up studies are required. A growing amount of evidence suggests that these peptides may also impact the cardiovascular system, including beneficial effects on myocardial cells, lipid profiles and blood pressure as well as reduced markers of systemic inflammation and improved endothelial dysfunction. The potential role of these agents in improving components of the metabolic syndrome and retardation of atherosclerosis needs to be fully elucidated. Although IBTs are currently recommended only for use in the early treatment of T2DM, the 'non-glycemic' actions of these drugs may have far reaching therapeutic implications. It is hoped that future studies will elucidate their potential strengths and weaknesses for use in various metabolic conditions.

Effect of alogliptin on blood pressure in patients with type 2 diabetes mellitus

In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.

PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist

There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.

Abstract 9654: Dipeptidyl Peptidase-4 Inhibitors May Reduce the Risk of Major Adverse Cardiovascular Events and All-cause Mortality In Patients With Type 2 Diabetes: Meta-analyses Oof Randomized Controlled Trials

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, both of which have an incretin effect, represent novel, effective therapeutic approaches to treating hyperglycemia in type 2 diabetes mellitus (T2DM). Their impact on cardiovascular (CV) outcomes, however, is still under investigation. Hypotheses: We assessed the impact of DPP-4 inhibitors and GLP-1 agonists on the risk of a composite of cardiovascular death, myocardial infarction, and stroke (MACE), and on all-cause mortality (ACM) in T2DM. Methods: We searched Medline, EMBASE, and Cochrane Library for randomized controlled trials (RCTs) published up to February 2010 that compared an incretin agent versus usual care, placebo, or other active agents for patients with T2DM, and reported a pre-specified CV outcome. We also searched a major trial registry, FDA and EMEA databases, and contacted authors about unclear CV outcome information. We undertook Der-Simonian and Laird random effect meta-analyses of MACE and all-cause mortality, using inverse-variance weights and continuity correction of 0.005. We excluded total-zero-event trials. We conducted subgroup analyses using a small number of pre-specified hypotheses, including study duration, type of control, treatment mode, and risk of bias. Results: Of 61 eligible trials, data on MACE was available in 33 trials of DPP-4 inhibitors (107 events /24341 patients), and 9 of GLP-1 agonists (12/3745), and ACM in 20 trials of DPP-4 inhibitors (45/17317), and 3 of GLP-1 (3/1404). There was a significant reduction in MACE (RR 0.53, 95% CI 0.33 to 0.85) between DPP-4 inhibitors and control, and a non-significant reduction in ACM (RR 0.46, 95% CI 0.19 to 1.07). No significant differences were found between GLP-1 agonists and control in MACE (RR 0.77, 95% CI 0.13 to 4.61) or ACM (RR 3.53,0 to &gt;999). There was no significant heterogeneity detected in all analyses (p&gt;0.1). Subgroup analyses did not show any significant differences in treatment effect, except that the effect on all-cause mortality differs by treatment mode (monotherapy vs. combination/add-on therapy, interaction p=0.04). Conclusion: DPP-4 inhibitors may reduce the risk of MACE and ACM. The effect of GLP-1 agonists on CV outcomes remains uncertain.