Cost-effectiveness analysis of once-weekly semaglutide vs. once-daily liraglutide administered subcutaneously in patients with overweight and obesity: a decision analysis.

OBJECTIVE: Obesity presents an enduring and multifaceted dilemma that impacts individuals, society, economies, and healthcare systems alike. Glucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide and semaglutide, have received FDA approval for obesity treatment. This study aims to present a cost-effectiveness analysis to compare the cost and clinical outcomes of semaglutide vs. liraglutide on weight loss in people with overweight and obesity. MATERIALS AND METHODS: A cost-effectiveness analysis was conducted to compare the cost and the clinical outcomes of adding weekly 2.4 mg SC semaglutide vs. daily 3.0 mg SC liraglutide or placebo to physical activity and diet control in overweight and obese patients. A clinical outcome of achieving ≥15% weight loss was chosen. A simple decision analysis model from a third-payer perspective was applied. Drug costs were based on the retail price of the USA market. One-way sensitivity analyses were performed. RESULTS: Results showed that 2.4 mg weekly semaglutide, when added to physical activity and diet control, was the most cost-effective choice in terms of ≥15% weight loss (ICER: $ 7,056/patient/68 weeks). The model was robust against the 50% increase in the unit cost of semaglutide and the 50% decrease in the unit cost of liraglutide, as well as the changes in probabilities by the corresponding 95% confidence intervals across the model. CONCLUSIONS: This cost-effectiveness analysis suggests that employing once-weekly 2.4 mg semaglutide emerges as a remarkably cost-effective option when contrasted with once-daily 3.0 mg liraglutide in patients with overweight and obesity when added to physical activity and diet control.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Methods: Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Results: Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Conclusions: GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.

Rare cutaneous adverse reactions associated with GLP-1 agonists: a review of the published literature.

Glucagon-like-peptide-1 (GLP-1) agonists are an emerging class of medications used to manage type 2 diabetes mellitus (T2DM) and weight loss, with demonstrated efficacy in reducing hemoglobin A1c levels, body mass index, and adverse cardiovascular events. While previous studies have reviewed notable cutaneous adverse effects with other antidiabetic medications, little is known about GLP-1 agonist-induced cutaneous reactions. Nevertheless, rare but significant cutaneous adverse reactions have been reported, including but not limited to dermal hypersensitivity reactions, eosinophilic panniculitis, bullous pemphigoid, and morbilliform drug eruptions. As GLP-1 induced cutaneous reactions are diverse, diagnosis requires clinical suspicion, thorough history-taking, and supportive histopathological findings when available. Management involves cessation of the offending agent with a tailored regimen to address inflammatory and/or immunogenic etiologies as well as irritative symptoms. This review aims to consolidate available information from case reports and case series regarding rare skin-related adverse outcomes due to GLP-1 use, aiming to provide a comprehensive overview of the presentation, pathogenesis, and management for dermatologists and other clinicians.

Liraglutide-associated depression in a patient with type 2 diabetes: A case report and discussion.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like liraglutide are primarily used for managing blood sugar levels in type 2 diabetes and aiding weight loss. Typically, their adverse effects are gastrointestinal, with limited exploration into their impact on mental health. CASE PRESENTATION: This report examines a 39-year-old male with type 2 diabetes who developed depressive symptoms after starting liraglutide for glycemic control and weight reduction. Symptoms included poor mood, irritability, decreased interest and energy, progressing to sadness, low self-esteem, and physical discomfort. A clinical diagnosis of a depressive episode was made, coinciding with the initiation of liraglutide. INTERVENTION AND OUTCOME: The patient depressive symptoms significantly improved within a week after discontinuing liraglutide and starting antidepressant therapy. This suggests a possible link between liraglutide and depression, despite considering other factors like diabetes-related stress. DISCUSSION: The report explores potential mechanisms, such as GLP-1RA effects on glucose fluctuations and dopamine modulation, which might contribute to depressive symptoms. The influence on the brain reward system and the reduction in cravings for addictive substances after GLP-1RA use is also discussed as a factor in mood regulation. CONCLUSION: This case highlights the necessity of being vigilant about potential psychiatric side effects, particularly depression, associated with GLP-1RAs. The rarity of such reports calls for more research to investigate and understand these implications further.

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus.

BACKGROUND: The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. METHOD: Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13). RESULTS: At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group. CONCLUSION: Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

No effect of liraglutide on high density lipoprotein apolipoprotein AI kinetics in patients with type 2 diabetes.

AIM: The catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia, insulin resistance and low plasma adiponectin levels. Since liraglutide is likely to partly correct these abnormalities, we hypothesized that it might have a beneficial effect on HDL apoAI kinetics in patients with T2D. METHODS: An in vivo kinetic study of HDL apoAI was performed in 10 patients with T2D before and after 6 months of treatment with 1.2 mg/day of liraglutide, using a bolus of l-[1-13C]leucine followed by a 16-hour constant infusion. RESULTS: Liraglutide reduced BMI (34.9 ± 4.7 vs 36.6 ± 4.9 kg/m2, P = 0.012), HbA1c (7.1 ± 1.1 vs 9.6 ± 2.6%, P = 0.003), HOMA-IR (5.5 ± 1.9 vs 11.6 ± 11.2, P = 0.003), fasting triglycerides (1.76 ± 0.37 vs 2.48 ± 0.69 mmol/l, P < 0.001) and triglycerides during kinetics (2.34 ± 0.81 vs 2.66 ± 0.65 mmol/l, P = 0.053). Plasma HDL cholesterol and adiponectin concentrations were unchanged (respectively 0.97 ± 0.26 vs 0.97 ± 0.19 mmol/l, P = 1; 3169 ± 1561 vs 2618 ± 1651 µg/l, P = 0.160), similar to triglyceride content in HDL (5.13 ± 1.73 vs 5.39 ± 1.07%, P = 0.386). Liraglutide modified neither HDL apoAI fractional catabolic rate (0.35 ± 0.11 vs 0.38 ± 0.11 pool/day, P = 0.375), nor its production rate (0.44 ± 0.13 vs 0.49 ± 0.15 g/l/day, P = 0.375), nor its plasma concentration (1.26 ± 0.19 vs 1.29 ± 0.14 g/l, P = 0.386). CONCLUSION: Six months of treatment with 1.2 mg/day of liraglutide had no effect on the kinetics of HDL apoAI in patients with T2D. The lack of decrease in triglyceride content in HDL related to an only moderate decrease in triglyceridemia, probably greatly explains these results. Insufficient improvement of insulin sensitivity and adiponectinemia may also be implied.

Glucagon-like peptide 1 agonists for type 2 diabetes, weight loss, or both?

ABSTRACT: Glucagon-like peptide 1 agonists (GLP1s) and the novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 agonist are effective drugs for reducing A1C and weight in patients with type 2 diabetes. However, clinicians may find it difficult to discern which drug to prescribe in specific clinical scenarios. This article discusses evidence-based clinical use of these drugs.

Liraglutide and Naringenin relieve depressive symptoms in mice by enhancing Neurogenesis and reducing inflammation.

Depression is a debilitating mental disease that negatively impacts individuals' lives and society. Novel hypotheses have been recently proposed to improve our understanding of depression pathogenesis. Impaired neuroplasticity and upregulated neuro-inflammation add-on to the disturbance in monoamine neurotransmitters and therefore require novel anti-depressants to target them simultaneously. Recent reports demonstrate the antidepressant effect of the anti-diabetic drug liraglutide. Similarly, the natural flavonoid naringenin has shown both anti-diabetic and anti-depressant effects. However, the neuro-pharmacological mechanisms underlying their actions remain understudied. The study aims to evaluate the antidepressant effects and neuroprotective mechanisms of liraglutide, naringenin or a combination of both. Depression was induced in mice by administering dexamethasone (32 mcg/kg) for seven consecutive days. Liraglutide (200 mcg/kg), naringenin (50 mg/kg) and a combination of both were administered either simultaneously or after induction of depression for twenty-eight days. Behavioral and molecular assays were used to assess the progression of depressive symptoms and biomarkers. Liraglutide and naringenin alone or in combination alleviated the depressive behavior in mice, manifested by decrease in anxiety, anhedonia, and despair. Mechanistically, liraglutide and naringenin improved neurogenesis, decreased neuroinflammation and comparably restored the monoamines levels to that of the reference drug escitalopram. The drugs protected mice from developing depression when given simultaneously with dexamethasone. Collectively, the results highlight the usability of liraglutide and naringenin in the treatment of depression in mice and emphasize the different pathways that contribute to the pathogenesis of depression.

Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

BACKGROUND: Liraglutide widely utilized in type 2 diabetes treatment, has elicited conflicting findings regarding its impact on cardiac function in patients with this condition. Therefore, The objective of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of liraglutide on cardiac function in patients diagnosed with type 2 diabetes. METHODS: We identified double-blind randomized trials assessing the effects of liraglutide compared to placebo on cardiac function in patients with type 2 diabetes. Data were synthesized with the fixed-effect models to generate standard mean differences (SMDs) with 95% confidence intervals (CIs) of each outcome for liraglutide versus placebo. The risk of bias would be assessed according to the Cochrane Risk of Bias Tool, while meta-analysis would be conducted using Revman 5.3.0 software. The evidence was graded based on the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: The meta-analysis encompassed 5 RCTs including 220 participants. Results revealed that liraglutide exhibited significant enhancements in left ventricular ejection fraction [SMD = -0.38, 95%CI(-0.70, -0.06), P = .02], cardiac index [SMD = -1.05, 95%CI(-1.52, -0.59), P < .0001], stroke volume [SMD = -0.67, 95%CI(-1.02, -0.32), P = .0002] and early diastolic filling velocity/late atrial filling velocity ratio [SMD = -0.52, 95%CI(-0.82, -0.22), P = .0006]. However, no statistically significant impact on cardiac output [SMD = -0.20, 95%CI(-0.53, 0.14), P = .26], early diastolic filling velocity/early diastolic annular velocity (E/Ea) ratio [SMD = -0.34, 95%CI(-0.75, 0.06), P = .10] and early diastolic filling velocity/early diastolic mitral annular velocity ratio [SMD = 0.21, 95%CI(-0.15, 0.56), P = .25] was observed. The Grading of Recommendations Assessment, Development and Evaluation evidence quality ratings indicated that all the outcome measures included in this study were evaluated as having low and very low quality. CONCLUSION: The available evidence suggested that liraglutide may exert a favorable impact on cardiac function in patients with type 2 diabetes. Consequently, the utilization of liraglutide as a preventive measure against heart failure incidents in individuals with type 2 diabetes represents a promising strategy. However, robust evidence support requires the conduct of large-scale, multicenter high-quality RCTs.

Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease: The STARDUST Randomized Clinical Trial.

Importance: Peripheral artery disease (PAD) in diabetes may lead to diabetic foot ulcer and lower-extremities amputation. Glucagon-like peptide 1 receptor agonists have proven cardiovascular benefits in trials of people with type 2 diabetes at high cardiovascular risk. Objective: To examine the effect of liraglutide on peripheral perfusion measured as peripheral transcutaneous oxygen pressure (TcPo2) in individuals with type 2 diabetes and PAD. Design, Setting, and Participants: This open-label randomized clinical trial was conducted between February 1, 2021, and June 30, 2022, with a final follow-up on December 30, 2022, at University of Campania "Luigi Vanvitelli," Naples, Italy. Fifty-five individuals with type 2 diabetes, PAD, and TcPo2 between 30 and 49 mm Hg were included. Interventions: Patients were randomized to receive 1.8 mg of subcutaneous liraglutide or conventional treatment of cardiovascular risk factors (control group) for 6 months. Main Outcomes and Measures: Coprimary outcomes were the change from baseline of peripheral perfusion between groups and the comparison of the proportion of individuals who reached 10% increase of TcPo2 from baseline in each group. Results: Fifty-five participants (mean [SD] age, 67.5 [8.5] years; 43 [78%] male) were randomized (27 to the liraglutide group and 28 to the control group) and analyzed. Participants had a median (IQR) hemoglobin A1c level of 6.9% (6.5%-7.8%) and a mean (SD) TcPo2 of 40.3 (5.7) mm Hg. Transcutaneous Po2 increased over time in both groups, with significant differences favoring the liraglutide group after 6 months (estimated treatment difference, 11.2 mm Hg; 95% CI, 8.0-14.5 mm Hg; P < .001). The 10% increase of TcPo2 occurred in 24 participants (89%) in the liraglutide group and 13 (46%) in the control group (relative risk, 1.91; 95% CI, 1.26-2.90; P < .001). Compared with the control group, individuals in the liraglutide group had a significant reduction of C-reactive protein (-0.4 mg/dL; 95% CI, -0.7 to -0.07 mg/dL; P = .02), urinary albumin to creatinine ratio (-119.4 mg/g; 95% CI, -195.0 to -43.8 mg/g; P = .003), and improvement of 6-minute walking distance (25.1 m; 95% CI, 21.8-28.3 m; P < .001). Conclusions and Relevance: In this randomized clinical trial of people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion detected by TcPo2 measurement during 6 months of treatment. These results support the use of liraglutide to prevent the clinical progression of PAD in individuals with type 2 diabetes. Trial Registration: ClinicalTrials.gov Identifier: NCT04881110.

Effect of Liraglutide combined with Jinlida granules on glycolipid metabolism and islet function of type 2 diabetes mellitus.

To investigate whether Liraglutide combined with Jinlida granules affects glycolipid metabolism and islet function in the treatment of type 2 diabetes mellitus (T2DM), a control group and an observation group were established with 90 T2DM patients. The control group was given Jinlida treatment and the observation group was given liraglutide combined treatment for 12 weeks. The clinical efficacy, glycolipid metabolism, bone metabolism, islet function, and endothelial function. The curative effect of the observation group was better than that of the control group. After treatment, FBG, 2hPG, HbAlc, TC, TG, and LDL-C in the observation group were lower and HDL-C was higher than those in the control group (P < 0.05). After treatment, the observation group showed higher bone mineral density, osteocalcin, FINS, and HOMA-ß and lower HOMA-IR than the control group (P < 0.05). After treatment, endothelin-1 level in the observation group was lower than that in the control group, and the NO level was higher (P < 0.05). No significant difference was found in the incidence of adverse reactions between the two groups (P > 0.05). Liraglutide combined with Jinlida in T2DM can improve glucose, lipid, and bone metabolism, promote the recovery of islet function, and enhance vascular endothelial function.

Effects of GLP-1 receptor agonists on the degree of liver fibrosis and CRP in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: A systematic review and meta-analysis.

BACKGROUND: Based on the rapidly growing global burden of non-alcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), in order to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of NAFLD or NASH this paper presents a systematic review and meta-analysis of randomized controlled trials(RCTs). METHODS: In this systematic review and meta-analysis, We searched PubMed, Medline, Web of Science and The Cochrane Library databases. All randomized controlled trials involving GLP-1RAs and NAFLD or NASH were collected since the database was established. A meta-analysis of proportions was done with the generalised linear mixed model. Continuous variables were represented by Mean and Standard Deviation (SD), and binary variable were represented by Relative Risk (RR) and 95% Confidence Interval (CI) as effect indicators. The research results were presented by Revman 5.4. This study is registered with PROSPERO (CRD42023390735). FINDING: We included 16 placebo-controlled or active drug-controlled randomized controlled trials (involving 2178 patients) that used liraglutide, exenatide, dulaglutide, or semaglutie in the treatment of NAFLD or NASH, as measured by liver biopsy or imaging techniques. This study found that the effect of GLP-1RAs on histologic resolution of NASH with no worsening of liver fibrosis (n=2 RCTs; WMD:4.08, 95%CI 2.54-6.56, p < 0.00001) has statistically significant. At the same time, GLP-1RAs affected CRP (n = 7 RCTs; WMD:-0.41, 95% CI-0.78 to -0.04, p =0.002) and other serological indicators were significantly improved. CONCLUSION: This study evaluated the efficacy of GLP-1RAs in patients with NAFLD and NASH. These results suggest that GLP-1RAs may be a potential and viable therapeutic approach as a targeted agent to intervene in disease progression of NAFLD and NASH.

Exploring the association between suicidal thoughts, self-injury, and GLP-1 receptor agonists in weight loss treatments: Insights from pharmacovigilance measures and unmasking analysis.

INTRODUCTION: The study addresses concerns about potential psychiatric side effects of Glucagon-like peptide-1 receptor agonists (GLP-1 RA). AIM: The aim of this work was to analyse adverse drug reports (ADRs) from the Food and Drug Administration Adverse Events Reporting System (FAERS) using metformin and orlistat as comparators. METHODS: Descriptive and pharmacovigilance disproportionality analyses was performed. RESULTS: A total of 209,354 ADRs were reported, including 59,300 serious cases. Of those, a total of 5378 psychiatric disorder cases, including 383 'serious' cases related to selected ADRs were registered during 2005-2023. After unmasking, 271 cases where individual GLP-1 RA were implicated showing liraglutide (n = 90; Reported Odds Ratio (ROR) = 1.64), exenatide (n = 67; ROR = 0.80), semaglutide (n = 61; ROR = 2.03), dulaglutide (n = 45; ROR = 0.84), tirzepatide (n = 5; ROR = 1.76) and albiglutide (n = 2; ROR = 0.04). A greater association between these ADRs with metformin was observed, but not orlistat. With regards to selected preferred terms (PTs), 42 deaths including 13 completed suicides were recorded. Suicidal ideation was recorded in n = 236 cases for 6/7 GLP-1 RA (excluding lixisenatide). DISCUSSION: Suicide/self-injury reports pertaining to semaglutide; tirzepatide; and liraglutide were characterised, although lower than metformin. It is postulated that rapid weight loss achieved with GLP-1 RA can trigger significant emotional, biological, and psychological responses, hence possibly impacting on suicidal and self-injurious ideations. CONCLUSIONS: With the current pharmacovigilance approach, no causality link between suicidal ideation and use of any GLP-1 RA can be inferred. There is a need for further research and vigilance in GLP-1 RA prescribing, particularly in patients with co-existing psychiatric disorders.

Liraglutide 3.0 mg in the treatment of adults with obesity and prediabetes using real-world UK data: A clinical evaluation of a multi-ethnic population.

UK guidelines recommend liraglutide 3.0 mg in adults treated within specialist weight management services with BMI ≥35 kg/m2, prediabetes and high cardiovascular disease risk. We aimed to clinically evaluate liraglutide 3.0 mg in specialist weight management services. We evaluated liraglutide 3.0 mg in weight management services at Guys and St Thomas' NHS Foundation Trust. Objective body weight (BW) was measured at baseline and 4 months, allowing classification as 'responders' (≥5% BW reduction) and 'non-responders' (<5% BW reduction). One hundred and twenty-one patients were evaluated. At 4 months, 76.0% attended follow-up (82.6% responders, 17.4% non-responders); BW (-8.6 kg, 95%CI:-9.8, -7.4 kg), BMI (-3.2 kg/m2, 95%CI: -3.6, -2.8) and %-BW (-6.6%, IQR: -8.8%, -5.2%) significantly reduced. In responders, HbA1c reduced by -5.0 mmol/mol (IQR: -7.0. -4.0 mmol/mol). In responders BW continued to reduce up to 12 months (4 m: -10.2 kg, p < .0001; 6 m: -15.6 kg, p < .0001; 9 m: -16.5 kg, p < .0001; 12 m: -16.7 kg, p < .01). Those of Black African and Caribbean ethnicity experienced less BW loss than those of white ethnicity (4.12 kg, p = .017) and had a greater attrition rate. In adults with obesity and prediabetes who are treated within specialist weight management services, liraglutide 3.0 mg reduces BW and HbA1c. Those of Black African and Caribbean ethnicity experienced less BW reduction and greater attrition at 4 months. Further evaluation of the ethnic differences in response to obesity pharmacotherapy is required.

Liraglutide prevents cellular senescence in human retinal endothelial cells (HRECs) mediated by SIRT1: an implication in diabetes retinopathy.

Diabetes mellitus (DM) is a chronic metabolic disorder affecting millions of people worldwide, characterized by dysregulated glucose homeostasis and hyperglycemia. Diabetic retinopathy (DR) is one of the serious multisystemic complications. Aging is an important risk factor for DR. Endothelial sirtuin 1 (SIRT1) plays an important role in regulating the pathophysiology of glucose metabolism, cellular senescence, and aging. Liraglutide, an analog of Glucagon-like peptide 1 (GLP-1), has been widely used in the treatment of DM. However, the effects of Liraglutide on DR are less reported. Here, we investigated whether treatment with Liraglutide has beneficial effects on high glucose (HG)-induced injury in human retinal microvascular endothelial cells (HRECs). First, we found that exposure to HG reduced the expression of glucagon-like peptide 1 receptor 1 (GLP-1R). Additionally, Liraglutide ameliorated HG-induced increase in the expression of vascular endothelial growth factor-A (VEGF-A) and interleukin 6 (IL-6). Importantly, Liraglutide ameliorated cellular senescence and increased telomerase activity in HG-challenged HRECs. Liraglutide also reduced the levels of p53 and p21. Mechanistically, Liraglutide restored the expression of SIRT1 against HG. In contrast, the knockdown of SIRT1 abolished the protective effects of Liraglutide in cellular senescence of HRECs. Our findings suggest that Liraglutide might possess a benefit on DR mediated by SIRT1.

Glucagon-Like Peptide-1 Receptor Agonists in Post-bariatric Surgery Patients: A Systematic Review and Meta-analysis.

BACKGROUND: A significant number of patients face the issue of weight gain (WG) or inadequate weight loss (IWL) post-bariatric surgery for obesity. Several studies have been published evaluating the role of glucagon-like peptide-1 receptor agonists (GLP1RA) for weight loss post-bariatric surgery. However, no systematic review and meta-analysis (SRM) till date has evaluated the efficacy, safety and tolerability of GLP1RA in this clinical scenario. Hence, this SRM aimed to address this knowledge gap. METHODS: Databases were searched for randomized controlled trials (RCTs), case-control, cohort and observational studies involving use of GLP1RA in the intervention arm post-bariatric surgery. Primary outcome was weight loss post at least 3 months of therapy. Secondary outcomes were evaluation of body composition parameters, total adverse events (TAEs) and severe adverse events (SAEs). RESULTS: From initially screened 1759 articles, 8 studies (557 individuals) were analysed. Compared to placebo, patients receiving liraglutide had significantly greater weight loss after 6-month therapy [MD - 6.0 kg (95% CI, - 8.66 to - 3.33); P < 0.001; I2 = 79%]. Compared to liraglutide, semaglutide had significantly greater percent reduction in body weight after 6-month [MD - 2.57% (95% CI, - 3.91 to - 1.23); P < 0.001; I2 = 0%] and 12-month [MD - 4.15% (95% CI, - 6.96 to - 1.34); P = 0.004] therapy. In study by Murvelashvili et al. (2023), after 12-month therapy, semaglutide had significantly higher rates of achieving > 15% [OR 2.15 (95% CI, 1.07-4.33); P = 0.03; n = 207] and > 10% [OR 2.10 (95% CI, 1.19-3.71); P = 0.01; n = 207] weight loss. A significant decrease in fat mass [MD - 4.78 kg (95% CI, - 7.11 to - 2.45); P < 0.001], lean mass [MD - 3.01 kg (95% CI, - 4.80 to - 1.22); P = 0.001] and whole-body bone mineral density [MD - 0.02 kg/m2 (95% CI, - 0.04 to - 0.00); P = 0.03] was noted with liraglutide. CONCLUSION: Current data is encouraging regarding use of GLP1RAs for managing WG or IWL post-bariatric surgery. Deterioration of bone health and muscle mass remains a concern needing further evaluation. TRIAL REGISTRATION: The predefined protocol has been registered in PROSPERO having registration number of CRD42023473991.

Utilization of Anti-obesity Medications After Bariatric Surgery: Analysis of a Large National Database.

PURPOSE: A significant proportion of patients experience insufficient weight loss or weight regain after bariatric surgery. There is a paucity of literature describing anti-obesity medication (AOM) use following bariatric surgery. We sought to identify prevalence and trends of AOM use following bariatric surgery. MATERIALS AND METHODS: We utilized the IBM Explorys® database to identify all adults with prior bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy). Those prescribed AOMs (semaglutide, liraglutide, topiramate, phentermine/topiramate, naltrexone/bupropion, orlistat) within 5 years of surgery were further identified. Data was analyzed to characterize AOM utilization among different age, demographic, and comorbid populations. RESULTS: A total of 59,160 adults with prior bariatric surgery were included. Among AOMs studies, prevalence of use was highest for topiramate (8%), followed by liraglutide (2.9%), phentermine/topiramate (1.03%), naltrexone/bupropion (0.95%) semaglutide (0.52%), and orlistat (0.17%). Age distribution varied, with the highest utilization among those age 35-39 years for topiramate, 40-44 years for phentermine/topiramate and naltrexone/bupropion, 45-49 years for semaglutide, and 65-69 years for liraglutide and orlistat. African American race was associated with higher utilization across all AOMs. Among comorbidities, hypertension, hyperlipidemia, and diabetes mellitus were most associated with AOM use. CONCLUSION: Despite a relatively high incidence of weight regain, AOMs are underutilized following bariatric surgery. It is imperative that barriers to their use be addressed and that AOMs be considered earlier and more frequently in patients with insufficient weight loss or weight regain after bariatric surgery.

Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK-3ß/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model.

The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-ß deposition, glycogen synthase kinase 3 beta (GSK3ß), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3ß/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10 weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200 µg/kg/day sc) or liraglutide (0.6 mg/kg/day sc) for 6 weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3ß/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms.

Glucagon-like peptide-1 receptor agonists modestly reduced blood pressure among patients with and without diabetes mellitus: A meta-analysis and meta-regression.

AIM: The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP-lowering effects of GLP1-RAs. METHODS: A comprehensive database search for placebo-controlled randomized controlled trials on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta-regressions were done to account for covariates. RESULTS: Compared with placebo, GLP-1RAs modestly reduced SBP [semaglutide: MD -3.40 (95% CI -4.22 to -2.59, p < .001); liraglutide: MD -2.61 (95% CI -3.48 to -1.74, p < .001); dulaglutide: MD -1.46 (95% CI -2.20 to -0.72, p < .001); and exenatide: MD -3.36 (95% CI -3.63 to -3.10, p < .001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD -0.94 (95% CI -1.78 to -0.1), p = .03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. CONCLUSION: Patients on GLP-1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP-lowering is an indirect effect of GLP-1RA and unlikely to be responsible for the benefits.

The role of glucagon-like peptide-1 receptor agonists in metabolic dysfunction-associated steatohepatitis.

Despite its considerable and growing burden, there are currently no Food and Drug Administration-approved treatments for metabolic dysfunction-associated steatotic liver disease or its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all-cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction-associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP-1RAs are Food and Drug Administration-approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP-1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP-1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP-1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta-analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP-1RAs. Large-scale, phase 3 trials, which will provide definitive data on GLP-1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH.