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In phase 2 studies, efruxifermin, an Fc–FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1–F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. Adults (N = 31) with T2D and MASH fibrosis (F1–F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P <.0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA–mediated weight loss. The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. Clinicaltrials.gov , Number: NCT05039450. [Display omitted] [ABSTRACT FROM AUTHOR]

Liraglutide, a type2 diabetes mellitus (T2DM)-related treatment, improves glycemic control and reduces the risks of adverse cardiovascular events in T2DM patients. However, the underlying mechanisms of the above-mentioned beneficial effects of Liraglutide are not well understood. To have better understanding of these mechanisms, we aimed to study the metabolic impacts of Liraglutide on the metabolome and corresponding pathways in T2DM patients, especially metabolism plays a very fundamental role in health and diseases and is influenced by drugs. In this study, plasma samples collected from T2DM patients (n = 20) and taken pre- and post-Liraglutide treatment were used for untargeted metabolomics analyses, including metabolome profiling and metabolic pathway/network analyses. The metabolome profiling analyses identified 93 endogenous metabolites that were significantly affected by Liraglutide treatment where 49 and 44 metabolites were up and down regulated, respectively. Liraglutide caused metabolic alterations impacting metabolic pathways such as pentose and glucuronate interconversion and alanine, aspartate and glutamate metabolism in T2DM patients. Since the last-mentioned pathways are affected by Liraglutide, it could explain partially the overall beneficial effects of Liraglutide in T2DM, especially that glucuronate interconversion pathway is known by its important roles in eliminating toxic and undesirable substances from the human body to maintain good health status. In addition, the metabolism of amino acids induced by Liraglutide could improve the function of immune cells, strengthening the immunity of T2DM patients. Also, Liraglutide induced the level of other metabolites that help in the defense mechanism against oxidative events. Overall, the findings of this study provide a deeper understanding of the underlying mechanisms involved in the beneficial effects of Liraglutide in T2DM from the metabolic aspect.

Chronic kidney disease (CKD) is the 8th most common condition in the modern world. Unfortunately, it becomes more and more frequent and constitutes a significant global health problem, affecting millions of people worldwide. Therefore, its treatment is an important topic among researchers all over the world. It has been the subject of many trials, so it will eventually be as effective, secure, and comfortable for patients as it possibly can be. That is why updating and assembling current knowledge is the key to organizing information. This paper focuses on pharmacological treatment and nutritional guidelines for CKD pre-dialysis patients, as well as physical activity outcomes. It aims to summarize this knowledge, educate, and help doctors in their daily clinical work.

Summary: Background: Glucagon‐like peptide 1 (GLP‐1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly, GLP‐1 analog effects on AT distribution are unclear. Objectives: To investigate GLP1‐analog effects on adiposity distribution. Search methods: PubMed, Cochrane, and Scopus databases were screened for eligible randomized human trials. Pre‐defined endpoints included visceral AT (VAT), subcutaneous AT (SAT), total AT (TAT), epicardial AT (EAT), liver AT (LAT), and waist‐to‐hip ratio (W:H). Search was conducted until May 17, 2022. Data collection and analysis: Data extraction and bias assessment were performed by two independent investigators. Treatment effects were estimated using random effects models. Analyses were performed on Review Manager v5.3. Main results: Out of the 367 screened studies, 45 were included in the systematic review and 35 were used in the meta‐analysis. GLP‐1 analogs reduced VAT, SAT, TAT, LAT, and EAT, with non‐significant effects on W:H. Overall bias risk was low. Conclusions: GLP‐1 analog treatment reduces TAT, affecting most studied AT depots, including the pathogenic VAT, EAT, and LAT. GLP‐1 analogs may have significant roles in combating metabolic, obesity‐associated diseases via reductions of key AT depot volumes. [ABSTRACT FROM AUTHOR]

Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid β and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes.

Liraglutide, a type2 diabetes mellitus (T2DM)-related treatment, improves glycemic control and reduces the risks of adverse cardiovascular events in T2DM patients. However, the underlying mechanisms of the above-mentioned beneficial effects of Liraglutide are not well understood. To have better understanding of these mechanisms, we aimed to study the metabolic impacts of Liraglutide on the metabolome and corresponding pathways in T2DM patients, especially metabolism plays a very fundamental role in health and diseases and is influenced by drugs. In this study, plasma samples collected from T2DM patients (n = 20) and taken pre- and post-Liraglutide treatment were used for untargeted metabolomics analyses, including metabolome profiling and metabolic pathway/network analyses. The metabolome profiling analyses identified 93 endogenous metabolites that were significantly affected by Liraglutide treatment where 49 and 44 metabolites were up and down regulated, respectively. Liraglutide caused metabolic alterations impacting metabolic pathways such as pentose and glucuronate interconversion and alanine, aspartate and glutamate metabolism in T2DM patients. Since the last-mentioned pathways are affected by Liraglutide, it could explain partially the overall beneficial effects of Liraglutide in T2DM, especially that glucuronate interconversion pathway is known by its important roles in eliminating toxic and undesirable substances from the human body to maintain good health status. In addition, the metabolism of amino acids induced by Liraglutide could improve the function of immune cells, strengthening the immunity of T2DM patients. Also, Liraglutide induced the level of other metabolites that help in the defense mechanism against oxidative events. Overall, the findings of this study provide a deeper understanding of the underlying mechanisms involved in the beneficial effects of Liraglutide in T2DM from the metabolic aspect. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim Liraglutide, a long‐acting GLP‐1 analog, is approved for the treatment of obesity with improvements in fasting blood glucose, hemoglobin A1c, and cardiovascular health. Our aim was to measure the impact of liraglutide dose for obesity on hepatic steatosis measured by ultrasound. Methods A single‐center, randomized, double‐blind, placebo‐controlled pilot trial was undertaken in nondiabetic obese, otherwise healthy patients aged 18–65 years. Participants were randomly assigned to receive subcutaneous liraglutide (3.0 mg) or placebo over 16 weeks with dose escalation following US Food and Drug Administration guidelines. Both groups received standardized nutritional and behavioral counseling during the 16 weeks. Hepatic fat content was measured by ultrasound at baseline, 8 weeks, and 16 weeks as an attenuation coefficient (ACE). Effects of treatment were assessed using t‐test for the entire groups and for patient subgroup with baseline ACE >0.66 (indicating significant steatosis). Results Among 30 patients (93% female) enrolled, 16 were randomized to placebo and 14 to liraglutide. Baseline body mass indices (BMIs) and average age were similar in the two groups. After 16 weeks, the liraglutide group had a significant improvement in steatosis ACE scores (−0.068 ± 0.02 vs −0.0077 ± 0.02 placebo, P = 0.05). Change in steatosis was positively correlated with change in BMI (R2 = 0.402, P = 0.0007). Within the liraglutide group, patients with baseline ACE >0.66 had improvement in ACE (−0.134 ± 0.03) compared to those without significant steatosis (−0.041 ± 0.02, P = 0.05). Conclusions In this pilot trial, liraglutide, 3.0 mg over 16 weeks, reduced hepatic steatosis; a reduction in hepatic steatosis is correlated with BMI reduction, and effects are particularly evident in those with a significant degree of steatosis by ultrasound imaging.

Background and Aims: The growing use of GLP-1 analogs for type 2 diabetes mellitus (DM2) and obesity necessitates studies about their use in patients with inflammatory bowel diseases (IBD)., Methods: Data on patients with DM2 were retrieved from an Israeli nationwide cohort of patients with IBD (epi-IIRN), recording GLP-1 analog exposure for at least 6 months. Primary outcome was poor disease outcomes (i.e. composite of steroid-dependence, initiation of advanced IBD therapy, hospitalization, surgery, or death). Cox proportional hazard models with time-varying covariables were used to assess the impact of GLP-1 use on outcomes during follow-up., Results: We included 3,737 patients (24,338 patient-years) with IBD and DM2 [(50.4% ulcerative colitis (UC)], of whom 633 were treated with GLP-1 analogs. Accounting for demographics IBD/DM2 related variables, medication use, and laboratory measurements, GLP-1 analog use was associated with reduced composite outcome in the full cohort (adjusted Hazard Ratio (aHR) 0.74, 95%CI 0.62-0.89) and in each subtype [UC (aHR 0.71, 95%CI 0.52-0.96) and Crohn's disease (aHR 0.78, 95%CI 0.62-0.99)]. Similar trends were seen in multivariate analyses of each individual outcome, although only hospitalization was significant (aHR 0.74, 95%CI 0.61-0.91). The protective effect of GLP-1 analogs was seen in patients with obesity (aHR 0.61, 95%CI 0.50-0.77), but not in non-obese (aHR 0.94, 95%CI 0.67-1.31)., Conclusion: GLP-1 analogs are associated with improved outcomes in IBD, specifically in patients with obesity. The mechanisms of these effects require further investigation as well as their role in patients without DM2., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

GLP-1 analogs have been widely used to treat patients with type 2 diabetes in recent years and studies have found that GLP-1 analogs have multiple organ benefits. However, the role of GLP-1 analogs in diabetic retinopathy (DR), a common complication of diabetes mellitus (DM), remains controversial. Retinal ganglion cells (RGCs) are the only afferent neurons responsible for transmitting visual information to the visual center and are vulnerable in the early stage of DR. Protection of RGC is vital for visual function. The incretin glucagon-like peptide-1 (GLP-1), which is secreted by L-cells after food ingestion, could lower blood glucose level through stimulating the release of insulin. In the present study, we evaluated the effects of GLP-1 analog on RGCs both in vitro and in vivo. We established diabetic rat models in vivo and applied an RGC-5 cell line in vitro. The results showed that in high glucose conditions, GLP-1 analog alleviated the damage of RGCs. In addition, GLP-1 analog prevented mitophagy through the PINK1/Parkin pathway. Here we demonstrated the neuroprotective effect of GLP-1 analog, which may be beneficial for retinal function, and we further elucidated a novel mechanism in GLP-1 analog-regulated protection of the retina. These findings may expand the multi-organ benefits of GLP-1 analogs and provide new insights for the prevention of DR.

Background and Aim: Liraglutide, a long‐acting GLP‐1 analog, is approved for the treatment of obesity with improvements in fasting blood glucose, hemoglobin A1c, and cardiovascular health. Our aim was to measure the impact of liraglutide dose for obesity on hepatic steatosis measured by ultrasound. Methods: A single‐center, randomized, double‐blind, placebo‐controlled pilot trial was undertaken in nondiabetic obese, otherwise healthy patients aged 18–65 years. Participants were randomly assigned to receive subcutaneous liraglutide (3.0 mg) or placebo over 16 weeks with dose escalation following US Food and Drug Administration guidelines. Both groups received standardized nutritional and behavioral counseling during the 16 weeks. Hepatic fat content was measured by ultrasound at baseline, 8 weeks, and 16 weeks as an attenuation coefficient (ACE). Effects of treatment were assessed using t‐test for the entire groups and for patient subgroup with baseline ACE >0.66 (indicating significant steatosis). Results: Among 30 patients (93% female) enrolled, 16 were randomized to placebo and 14 to liraglutide. Baseline body mass indices (BMIs) and average age were similar in the two groups. After 16 weeks, the liraglutide group had a significant improvement in steatosis ACE scores (−0.068 ± 0.02 vs −0.0077 ± 0.02 placebo, P = 0.05). Change in steatosis was positively correlated with change in BMI (R2 = 0.402, P = 0.0007). Within the liraglutide group, patients with baseline ACE >0.66 had improvement in ACE (−0.134 ± 0.03) compared to those without significant steatosis (−0.041 ± 0.02, P = 0.05). Conclusions: In this pilot trial, liraglutide, 3.0 mg over 16 weeks, reduced hepatic steatosis; a reduction in hepatic steatosis is correlated with BMI reduction, and effects are particularly evident in those with a significant degree of steatosis by ultrasound imaging. [ABSTRACT FROM AUTHOR]

T2D is a potentially preventable disease that has been ranked the seventh leading cause of mortality in the United States. There is strong evidence demonstrating that preventing type 2 diabetes is, in many cases, attainable through lifestyle intervention. Unfortunately, prediabetes is mostly overlooked and awareness with diabetes prevention tools is lacking among primary care physicians. Nationally, efforts were not successful in reversing this epidemic even with an array of diabetes medications. Among the most effective medications for T2D are glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have been shown to reduce both A1C and body weight. Dulaglutide, liraglutide and injectable semaglutide also reduced cardiovascular events and cardiovascular mortality in patients with established cardiovascular disease or multiple cardiovascular risk factors. In this review, we will examine the first FDA approved oral GLP-1 RA; semaglutide. Moreover, this review will discuss the potential impact oral semaglutide may have on glycemic control, weight loss and cardiovascular comorbidities. It also examines the factors that may impact patient compliance, including cost, side effects and clinical issues. Finally, it deliberates the optimism surrounding the development of oral semaglutide in the treatment of diabetes as well as related conditions, such as obesity and non-alcoholic fatty liver disease (NAFLD). [ABSTRACT FROM AUTHOR]

Purpose: In East Asian patients, type 2 diabetes mellitus (T2DM) is characterized primarily by β-cell dysfunction, with lower insulin secretion than in Caucasian individuals. Therefore, bolus insulin and premixed insulin containing a bolus insulin component are important therapeutic tools in Japan, in addition to basal insulin. This subgroup analysis is stratified by insulin regimen and uses data from a phase 4, randomized, placebo-controlled, double-blind and subsequent open-label study in Japan to assess the efficacy and safety of once-weekly dulaglutide combined with various insulin therapies. Methods: This multicenter study enrolled Japanese patients with T2DM and inadequate glycemic control [glycated hemoglobin A1c (HbA1c) ≥ 7.5% to ≤ 10.5%] on insulin therapy [basal (B), premixed (PM), or basal bolus (BB)] in combination with or without one or two oral antidiabetic agents. Randomized participants received once-weekly dulaglutide 0.75 mg (n = 120) or placebo (n = 39) during a 16-week double-blind treatment period, and dulaglutide during a 36-week open-label extension. In this subgroup analysis, efficacy measures were changes from baseline in HbA1c, 7-point self-monitored blood glucose profiles, and body weight. Safety measures were incidence of adverse events and hypoglycemia during the first 16 weeks. Results: At week 16, least squares mean differences (95% CI) regarding changes from baseline in HbA1c for each insulin regimen versus placebo were: B: − 1.62% (− 1.96, − 1.28), PM: − 1.78% (− 2.25, − 1.30), and BB: − 1.15% (− 1.54, − 0.77); p < 0.001 dulaglutide vs. placebo for each subgroup. No significant differences in body weight changes were observed between dulaglutide and placebo for any insulin regimen. Gastrointestinal symptoms were the most commonly observed adverse events in dulaglutide-treated patients. Hypoglycemia incidence rates were: B: dulaglutide 38.5% vs. placebo 23.5%; PM: dulaglutide 38.5% vs. placebo 44.4%; BB: dulaglutide 50.0% vs. placebo 30.8%. Conclusions: Overall, dulaglutide was generally well tolerated and improved glycemic control significantly versus placebo, regardless of insulin regimen. Trial Registration: ClinicalTrials.gov identifier, NCT02750410. [ABSTRACT FROM AUTHOR]

Introduction: Although global studies have investigated the combination of dulaglutide with insulin in patients with type 2 diabetes mellitus (T2DM), differences in lean body mass and dulaglutide dosing can complicate the extrapolation of global study results to Japanese patients. This phase 4, randomized, placebo-controlled, double-blind, and subsequent open-label study aimed to assess the efficacy and safety of once-weekly dulaglutide 0.75 mg in combination with insulin therapy in patients with T2DM. Methods: Patients enrolled in this multicenter study were Japanese with T2DM who had inadequate glycemic control (HbA1c 7.5–10.5%) with insulin therapy (basal insulin, premixed insulin, or basal/mealtime insulin) in combination with or without one or two oral antidiabetic agents (OADs). Patients were randomized in a 3:1 ratio to dulaglutide or placebo. The first 16 weeks was the double-blind period with stable insulin dosing, and patients taking placebo were switched to dulaglutide for an additional 36-week open-label period in which all patients took dulaglutide (52 weeks total). Results: Patients (N = 159) were randomized to dulaglutide (n = 120) or placebo (n = 39). The least-squares (LS) mean changes from baseline in HbA1c at week 16 were dulaglutide − 1.45% and placebo 0.06%. The LS mean and 95% confidence interval for the difference were − 1.50% (− 1.73%, − 1.28%) and dulaglutide was superior to placebo. There were no significant differences between treatment groups in changes from baseline in body weight and insulin dose. The most frequently observed treatment-emergent adverse events in dulaglutide were nasopharyngitis, constipation, abdominal discomfort, nausea, and decreased appetite. The incidence rates of hypoglycemic events by week 16 were dulaglutide 42.5% and placebo 30.8% (P = 0.258). Conclusion: Once-weekly dulaglutide 0.75 mg was superior to once-weekly placebo in glycemic control improvement and well tolerated in patients with T2DM in combination with insulin therapy with or without OADs. Trial Registration: ClinicalTrials.gov, NCT02750410. Funding: Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists represent a class of treatments for type 2 diabetes that offer multifactorial benefits, including glycemic control, weight loss and low hypoglycemia risk. Once-weekly semaglutide is a novel GLP-1 analog that has been associated with improved glycemic control and reduced body mass index (BMI) versus once-weekly GLP-1 receptor agonist dulaglutide in SUSTAIN 7, which is reimbursed in patients with a BMI > 35 kg/m2 in Slovakia. The aim of the present study was to evaluate the long-term cost-effectiveness of once-weekly semaglutide 0.5 mg and 1 mg versus dulaglutide 1.5 mg in Slovakia.Methods: Clinical and cost outcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model. Baseline cohort characteristics and treatment effects were based on the sub-group of patients with a BMI > 35 kg/m2 in SUSTAIN 7. Patients were modeled to receive once-weekly semaglutide or dulaglutide for 3 years, after which treatment was intensified to basal insulin. Treatment effects associated with once-weekly semaglutide and dulaglutide were maintained for the first 3 years before HbA1c increased to 7.0% and BMI reverted to baseline. Costs were accounted from a healthcare payer perspective in Slovakia and expressed in euros (EUR). Utilities relating to quality of life were taken from published sources.Results: Once-weekly semaglutide 0.5 mg and 1 mg were associated with improvements in quality-adjusted life expectancy of 0.04 and 0.07 quality-adjusted life years (QALYs), respectively, versus dulaglutide 1.5 mg. Lifetime medical costs were similar, with cost savings of EUR 20 and EUR 140 per patient with once-weekly semaglutide 0.5 mg and 1 mg, respectively, versus dulaglutide 1.5 mg. Both doses of once-weekly semaglutide were therefore considered dominant versus dulaglutide 1.5 mg.Conclusion: Both doses of once-weekly semaglutide represent cost-saving treatment options versus dulaglutide 1.5 mg for obese patients with type 2 diabetes in Slovakia.Funding: Novo Nordisk A/S. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is associated with increased risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) in later life. We aimed to study the effect of liraglutide intervention on markers of VTE and CVD risk, in PCOS. In a double-blind, placebo-controlled, randomized trial, 72 overweight and/or insulinresistant women with PCOS were randomized, in a 2:1 ratio, to liraglutide or placebo 1.8 mg/day. Endpoints included between-group difference in change (baseline to follow-up) in plasminogen activator inhibitor-1 levels and in thrombin generation test parameters: endogenous thrombin potential, peak thrombin concentration, lag time and time to peak. Mean weight loss was 5.2 kg (95% CI 3.0–7.5 kg, P < 0.001) in the liraglutide group compared with placebo. We detected no effect on endogenous thrombin potential in either group. In the liraglutide group, peak thrombin concentration decreased by 16.71 nmol/L (95% CI 2.32–31.11, P < 0.05) and lag time and time to peak increased by 0.13 min (95% CI 0.01–0.25, P < 0.05) and 0.38 min (95% CI 0.09–0.68, P < 0.05), respectively, but there were no between-group differences. There was a trend toward 12% (95% CI 0–23, P = 0.05) decreased plasminogen activator inhibitor-1 in the liraglutide group, and there was a trend toward 16% (95% CI −4 to 32, P = 0.10) reduction, compared with placebo. In overweight women with PCOS, liraglutide intervention caused an approximate 5% weight loss. In addition, liraglutide affected thrombin generation, although not significantly differently from placebo. A concomitant trend toward improved fibrinolysis indicates a possible reduction of the baseline thrombogenic potential. The findings point toward beneficial effects of liraglutide on markers of VTE and CVD risk, which should be further pursued in larger studies.

Introduction: Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for the once-weekly treatment of type 2 diabetes. The objective of this 16-week, double-blind, single-center thorough QT study was to confirm that semaglutide treatment does not prolong cardiac repolarization versus placebo. Prolongation of the QT interval is a biomarker for ventricular tachyarrhythmia.Methods: In a parallel design, 168 healthy subjects were randomized to the treatment or placebo arms, of whom 166 were treated with subcutaneous semaglutide (N = 83; escalated to a supratherapeutic dose of 1.5 mg) or placebo (N = 83). The subjects (60% males) had a mean age of 38.2 years and body mass index of 25.1 kg/m2. To assess QT assay sensitivity, subjects in the placebo group received a single 400 mg moxifloxacin dose as positive control, and placebo in a crossover fashion. The primary endpoint was the time-matched change from baseline in QT interval corrected individually for heart rate (ΔQTcI), calculated from 11 electrocardiogram recordings from 0 to 48 h after the last 1.5 mg dose. Similar assessments were made for the therapeutic 0.5 and 1.0 mg semaglutide dose levels.Results: No QTcI prolongation occurred with any semaglutide dose; the upper limits of two-sided 90% confidence intervals of the placebo-subtracted ΔQTcI were < 10 ms at all doses and time points. Exposure-response analysis showed no dependence of QTcI on semaglutide concentration. QT assay sensitivity was confirmed. The semaglutide safety profile was similar to that of other GLP-1 receptor agonists.Conclusion: Based on investigations of QT/QTc, no concern with regard to ventricular arrhythmias was raised as semaglutide did not prolong the cardiac repolarization duration in healthy subjects.Trial Registration: ClinicalTrials.gov identifier: NCT 02064348.Funding: Novo Nordisk. [ABSTRACT FROM AUTHOR]

Introduction: Semaglutide, a new treatment option approved for the treatment of patients with type 2 diabetes mellitus, is a glucagon-like peptide-1 receptor agonist to be injected subcutaneously once weekly. This analysis used a population pharmacokinetic model of semaglutide to identify clinically relevant covariates for exposure.Methods: A total of 1612 patients with up to seven pharmacokinetic observations each were included in the analysis. All subjects had type 2 diabetes mellitus and were enrolled in one of five trials in the phase III development program for subcutaneous semaglutide once weekly (the SUSTAIN program). The treatment duration of the trials varied from 30 to 104 weeks.Results: No clinically relevant effects on the exposure were seen for sex, age, race, ethnicity, renal function, or injection site used, and semaglutide exposure was stable over time. Of the covariates chosen, only body weight had a relevant effect on the exposure of semaglutide. Few subjects developed semaglutide antibodies, and the antibodies had no effect on exposure. Dose proportionality was shown for the 0.5 mg and 1.0 mg maintenance doses of semaglutide.Conclusion: The population pharmacokinetic study showed that semaglutide exposure is not affected by covariates other than body weight at either a maintenance dose of 0.5 or 1.0 mg semaglutide. Therefore, we conclude that no semaglutide dose adjustments are needed in different populations. This finding is to be further explored in an exposure-response analysis.Trial Registration: The trials were registered at ClinicalTrials.gov (identifiers: NCT02054897, NCT01930188, NCT01885208, NCT01720446 and NCT02207374).Funding: Novo Nordisk A/S, Bagsværd, Denmark. [ABSTRACT FROM AUTHOR]

The article offers information on the methods to improve postprandial glucose (PPG) control in patients with type 1 diabetes, discussing the correlation between postprandial hyperglycemia and increased intraocular pressure, and the role of carbohydrates in postprandial hyperglycemia.

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is increasingly used in obese patients with type 2 diabetes mellitus (T2DM) in doses of up to 3.0 mg/day because of its attractive pharmacological profile. It is currently not known how to proceed with this medication during fasting for surgery. Discontinuation is likely to result in hyperglycaemia, while continuation might lead to hypoglycaemia, but, in view of its mode of action, continuation of GLP-1 analogs is likely to be safe. However, as evidence-based guidelines on GLP-1 management during perioperative fasting are not available, the safety of either policy needs to be confirmed on an individual basis. We therefore decided to perform a preoperative assessment of the glucose response to fasting during continuation of GLP-1 before giving a recommendation in individual cases. So far, 12 severely obese T2DM patients scheduled for bariatric surgery have been evaluated preoperatively by measuring glucose and insulin levels during a 32-hour fast with continuation of liraglutide. Hypoglycaemia was not observed. This suggests that liraglutide in doses of up to 3.0 mg can be safely continued during surgery without risking hypoglycaemia.

GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide) by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD) for 6 months to induce obesity and then subjected to supaglutide treatment (300 μg/kg, bi-weekly for 4 weeks), and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS). Cold tolerance test was performed to evaluate brown-adipose tissue (BAT) activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1) in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT) and aspartic transaminase (AST) content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that supaglutide increased tolerance of the mice to cold environment associated with up-regulation of Ucp1 in the inguinal fat. Furthermore, supaglutide improved glucose tolerance, and insulin sensitivity in the obese mice suggesting improved glucose and energy homeostasis. Our findings suggest that supaglutide exerts beneficial effect on established obesity through reducing energy intake and is associated with brown remodeling of white adipose tissue.

Semaglutide is a human glucagon-like peptide-1 analogue in clinical development for the treatment of type 2 diabetes. The absorption, metabolism and excretion of a single 0.5 mg/450 μCi [16.7 MBq] subcutaneous dose of [ 3 H]-radiolabelled semaglutide was investigated in healthy human subjects and compared with data from nonclinical studies. Radioactivity in blood, plasma, urine and faeces was determined in humans, rats and monkeys; radioactivity in expired air was determined in humans and rats. Metabolites in plasma, urine and faeces were quantified following profiling and radiodetection. The blood-to-plasma ratio and pharmacokinetics of both radiolabelled semaglutide-related material and of semaglutide (in humans only) were assessed. Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69–83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys. The metabolite profiles of semaglutide in humans appear to be similar to the profiles from the nonclinical species investigated. [ABSTRACT FROM AUTHOR]

Background: Reducing glycemic fluctuation is important for optimal diabetes management. This post hoc analysis examined glycemic fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone.Methods: We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients with type 2 diabetes (T2D), and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess glycemic fluctuation and day-to-day variability.Results: Compared with IDeg, IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (3.9-9.0 mmol/L) than IDeg for all pre- and postprandial values, and for the full nine-point profile (P < 0.05 for all). IDegLira also resulted in a greater reduction in the range of SMBG values over 24 h than IDeg (P ≤ 0.0001). CGM data showed that IDegLira provided greater reductions in interstitial glucose (IG) fluctuation (P = 0.0018) and postprandial IG increment (P = 0.0288) compared with IDeg. Compared with liraglutide, IDegLira brought a higher proportion of subjects within SMBG target ranges (all pre- and all postprandial values, and the full nine-point profile, P < 0.01 for all) and resulted in a greater reduction of time outside the IG target range (P = 0.0072). IDegLira also reduced mean IG more than liraglutide (P < 0.0001).Conclusions: Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than either IDeg or liraglutide alone. [ABSTRACT FROM AUTHOR]

GLP-1 is an incretin hormone that can effectively lower blood glucose, however, the short time of biological activity and the side effect limit its therapeutic application. Many methods have been tried to optimize GLP-1 to extend its in vivo half-time, reduce its side effect and enhance its activity. Here we have chosen the idea to dimerize GLP-1 with a C-terminal lysine to form a new GLP-1 analog, DLG3312. We have explored the structure and the biological property of DLG3312, and the results indicated that DLG3312 not only remained the ability to activate the GLP-1R, but also strongly stimulated Min6 cell to secrete insulin. The in vivo bioactivities have been tested on two kinds of animal models, the STZ induced T2DM mice and the db/db mice, respectively. DLG3312 showed potent anti-diabetic ability in glucose tolerance assay and single-dose administration of DLG3312 could lower blood glucose for at least 10 hours. Long-term treatment with DLG3312 can reduce fasted blood glucose, decrease water consumption and food intake and significantly reduce the HbA1c level by 1.80% and 2.37% on STZ induced T2DM mice and the db/db mice, respectively. We also compared DLG3312 with liraglutide to investigate its integrated control of the type 2 diabetes. The results indicated that DLG3312 almost has the same effect as liraglutide but with a much simpler preparation process. In conclusion, we, by using C-terminal lysine as a linker, have synthesized a novel GLP-1 analog, DLG3312. With simplified preparation and improved physiological characterizations, DLG3312 could be considered as a promising candidate for the type 2 diabetes therapy. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a progressive disease associated with significant morbidity and mortality. Even though progress have been accomplished in the management of type 2 diabetes, current treatment preferences for patients with this disease still fall short to address disease progression. With the present therapy, glycaemic control remains suboptimal and are often associated with weight gain and hypoglycaemia. Glucagon like peptide-1 (GLP-1) is an incretin hormone secreted from the small intestine that lowers fasting and postprandial glucose through multiple mechanisms including glucose-dependent insulin secretion, reduction of glucagon secretion, delaying gastric emptying and increased satiety. Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue is a treatment for T2DM that is administered as a once-daily subcutaneous injection. The efficacy and tolerability of liraglutide at doses of 0.6, 1.2, and 1.8 mg for T2DM, in combination with, and compared with, other T2DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD trial, treatment with liraglutide was associated with substantial improvements in glycaemic control and low risk of hypoglycaemia. In addition liraglutide significantly improved β-cell function, reduced systolic blood pressure (BP) and induced weight loss. Overall, liraglutide was well tolerated. Recent data on safety and efficacy of liraglutide from real-life clinical practice settings also reiterate the better therapeutic profile of this molecule. Based on results from the LEAD programme, and real-life clinical experience, liraglutide has been demonstrated as an effective therapeutic intervention even at the early stage of diabetes regardless of with what, it has been used.

GLP-1 has been clinically exploited for treating type 2 diabetes, while its short circulation half-life requires multiple daily injections to maintain effective glycemic control, thus limiting its widespread application. Here we developed a drug delivery system based on self-assembling polymer-amino acid conjugates (γ-PGA-PAE) to provide sustained release of GLP-1 analog (DLG3312). The DLG3312 loaded γ-PGA based nanoparticles (DLG3312@NPs) exhibited a spherical shape with a good monodispersity under transmission electron microscope (TEM) observation. The DLG3312 encapsulation was optimized, and the loading efficiency was as high as 78.4 ± 2.2 %. The transformation of DLG3312@NPs to network structures was observed upon treatment with the fresh serum, resulting in a sustained drug release. The in vivo long-term hypoglycemic assays indicated that DLG3312@NPs significantly reduced blood glucose and glycosylated hemoglobin level. Furthermore, DLG3312@NPs extended the efficacy of DLG3312, leading to a decrease in the dosing schedule that from once a day to once every other day. This approach combined the molecular and materials engineering strategies that offered a unique solution to maximize the availability of anti-diabetic drug and minimize its burdens to type 2 diabetic patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims To evaluate the impact of β-cell function on the efficacy of lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes (T2D). Materials and methods In this post hoc analysis, patients from the Phase 3 GetGoal-M and GetGoal-S clinical trials randomized to lixisenatide 20 μg once daily were stratified into quartiles by baseline β-cell function, as measured by the secretory units of islet in transplantation (SUIT) index. Results Patients ( N = 437) were distributed evenly among SUIT index quartiles 1 to 4 (lowest to highest β-cell function). Clinical outcomes improved from baseline across all SUIT quartiles; mean changes at week 24 were: glycated hemoglobin (HbA1c; % [mmol/mol]), − 0.99 (− 10.8), − 0.87 (− 9.5), − 0.86 (− 9.4), − 0.83 (− 9.1); and postprandial plasma glucose (PPG; mmol/L), − 7.9, − 5.6, − 5.5, − 4.3 (overall effect P < 0.0001). Furthermore, postprandial glucagon was reduced in all SUIT quartiles, while insulinogenic index improved only in patients with higher baseline SUIT (overall effect P = 0.0286). No severe symptomatic hypoglycemic events were reported. Conclusions Lixisenatide treatment resulted in reductions in HbA1c and PPG levels across all SUIT quartiles. This suggests that non-insulin-related actions of lixisenatide contribute to improved glycemic control in T2D. [ABSTRACT FROM AUTHOR]

GZR18 is a novel analog of glucagon-like peptide-1 (GLP-1). This study evaluates the pharmacology, pharmacokinetics, and efficacy of GZR18, and its potential for the treatment of Type 2 diabetes mellitus (T2DM). In vitro pharmacology and activity of GZR18 were characterized by a binding assay of GZR18 using human serum albumin (HSA), an activation assay in human GLP-1 receptor-expressing cell lines, and its effect on glucose-stimulated insulin secretion (GSIS) in primary mice islets. Pharmacokinetic profiling was performed in Sprague Dawley rats and cynomolgus monkeys, and efficacy evaluated using GZR18 single or repeated doses in db/db mice. GZR18 showed similar binding affinity for HSA and GLP-1 receptor compared with semaglutide and liraglutide. GZR18 increased GSIS, which was confirmed by dynamic islet perifusion and fluorescence imaging using PKZnR-5 for real-time detection. In cynomolgus monkeys, the average GZR18 maximal concentration was 527 nmol L−1, the terminal half-life (T 1/2) was 61.3 h, and the time to maximum concentration was 14 h. Single-dose GZR18 lowered blood glucose levels and reduced body weight over 72 h in db/db mice. GZR18 successive administration (every three days for 33 days, i.e. 11 doses) lowered nonfasting and fasting blood glucose levels (p < 0.05 versus control) and glycated hemoglobin, following the 11th dose. Food and water consumption in db/db mice was lowered following repeated doses of GZR18 (p < 0.05 versus control), without a reduction in body weight. These results demonstrate the potential of GZR18 as a long-acting GLP-1 analog for the treatment of T2DM. • The novel long-acting GLP-1 analog, GZR18, binds and activates GLP-1 receptor. • GZR18 improves glucose homeostasis in a genetic Type 2 diabetic mouse model. • GZR18 may have the potential to treat patients with Type 2 diabetes. • GZR18 could serve as a potential weekly long-acting GLP-1 analog. • First real-time PKZnR-5 fluorescence imaging of glucose-stimulated insulin secretion. [ABSTRACT FROM AUTHOR]

Background: Cardiomyocyte apoptosis is closely related to cardiac dysfunction in diabetic patients. Although GLP-1 analogs are used as anti-diabetic drugs, their effects on cardiomyocytes remain unclear. The aim of this study was to assess the effects of the GLP-1 analog liraglutide on high glucose-induced cardiomyocyte apoptosis. Methods: Wistar rats were divided into normal (N), diabetes mellitus (DM), and liraglutide (LIR) groups. H9c2 cardiomyocytes were divided into normal (NG) and high glucose (HG) groups, 4 liraglutide groups (Lir1-4), 3 Epac-1 agonist intervention groups (CPT1-3), and 2 Epac-1 shRNA transfection groups (sh21 and sh22). Apoptosis was measured using TUNEL assays, and the apoptotic indices were calculated. Intracellular ROS levels were measured using a DCFH-DA probe. Epac-1, Akt, and P-Akt (Ser473) expression were measured by immunoblotting. Results: The apoptotic index and intracellular ROS levels were higher in the HG than NG group (P<0.01). Liraglutide decreased both parameters in a dose- and time-dependent manner. Liraglutide increased the expression of Epac-1 in the myocardium of diabetic rats and H9c2 cells (P<0.05), and increased Akt phosphorylation in the myocardium of diabetic rats (P<0.05). Liraglutide treatment also increased the P-Akt (Ser473)/Akt ratio (P<0.05). An Epac-1 agonist increased Epac-1 expression (P<0.05) and the P-Akt (Ser473)/Akt ratio (P<0.05) in a dosedependent manner, and subsequently decreased apoptosis and intracellular ROS. Conversely, Epac-1shRNA knocked-down Epac-1 expression (P<0.01) and decreased the P-Akt (Ser473)/Akt ratio (P<0.05), but had no effect on apoptosis and intracellular ROS levels. Conclusions: Liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists, are the latest addition to the range of available medications for the management of patients with type 2 diabetes. The GLP-1 analog liraglutide has been approved for use in Europe and the US for over a year and has undergone evaluation in several pharmacokinetic/pharmacodynamics studies and in an extensive phase 3 clinical program. The aim of this review is to assess the pharmacokinetics, efficacy and safety of the phase 3 data. Methods: Data are presented from the pharmacokinetics/pharmacodynamics studies of liraglutide and from nine published phase 3 studies, including the six Liraglutide Effect and Action in Diabetes (LEAD) studies. Results: Liraglutide is effective at improving indices of glycemic control, and has a good tolerability and safety profile. Beneficial effects on weight (mean reduction of 1–3.4kg) and blood pressure (systolic blood pressure decreased by 2.1–6.7mmHg) are also observed. Conclusion: Liraglutide is an effective and well tolerated option for the treatment of type 2 diabetes. [Copyright &y& Elsevier]

Background: Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor agonist. Liraglutide is presently used in the treatment of selected patients with type 2 diabetes mellitus (T2DM). Objective: To assess efficacy and safety of liraglutide in, overweight and obese Indian patients with T2DM. Methods: A single center, prospective, open-labeled, single-arm, observational study for 24 weeks in a real-world setting. Fourteen overweight and obese patients with T2DM who were clinically suitable for liraglutide therapy received liraglutide injections. The starting dose of liraglutide (Victoza) injection was 0.6 mg/day for 3 days followed by 1.2 mg for next 10 days and finally 1.8 mg/day for 22 weeks. Patients were evaluated at baseline and after 12 and 24 weeks of therapy. Adverse events (AE) noted during course of therapy were recorded. A repeated measure analysis of variance was performed to assess statistical significance. Results: Fourteen patients were studied for 24 weeks. After 24 weeks of liraglutide therapy, mean fasting and postprandial plasma glucose decreased by 48.5 mg/dL and 66.71 mg/dL, respectively (P = 0.002 and P = 0004 over 24 weeks, respectively). A mean reduction of 2.26% of glycosylated hemoglobin was noted (P < 0.001 over 24 weeks). Mean decrease in body weight of 8.65 kg and mean decrease in body mass index of 3.26 kg/m2 was noted (P < 0.001 over 24 weeks for each parameter). Systolic blood pressure was reduced by 15.15 mm of Hg (P = 0.004). Significant improvement in total cholesterol, low-density lipoprotein, triglycerides, and serum creatinine was noted. Nine patients reported AEs. The AEs noticed were nausea (n = 6), feeling of satiety (n = 3), and vomiting (n = 1). No serious AE or hypoglycemic episodes were observed. Conclusion: Liraglutide once a day improved overall glycemic control and was well tolerated. Clinically significant reduction in body weight, systolic blood pressure and improvement in lipid profile were noticed with liraglutide therapy in addition to glycemic control. [ABSTRACT FROM AUTHOR]

Liraglutide is the first once-daily human glucagon-like peptide-1 analog available for use in clinical practice. It has recently been approved by the EMA and the US FDA for treatment of Type 2 diabetes mellitus (T2DM). Initial approval is for use in combination with either metformin or a sulfonylurea, or in combination with metformin plus a sulfonylurea or thiazolidinedione. Liraglutide monotherapy is approved in the USA. Results from the Liraglutide Effect and Action in Diabetes (LEAD) clinical trials program indicate that liraglutide significantly lowers glycosylated hemoglobin (HbA1c) with a low risk of hypoglycemia. Liraglutide is also associated with significant and sustained weight loss, decreased systolic blood pressure, and improvements in other markers of cardiovascular risk. Liraglutide also shows strong potential to preserve β-cell function. Maximum benefits may be achieved when liraglutide treatment is initiated early on in the course of T2DM. INSET: Key issues. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone, which has the regulatory function of stimulating the secretion of insulin to balance blood glucose levels. In this study, marker-free expression vector pX6 with a fusion gene of ten tandem repeated GLP-1 analog ([Ser8, Gln26 and Asp34]-GLP-1) genes was constructed and transformed into cucumbers by Agrobacterium tumefaciens-mediated transformation method. Four transgenic lines were obtained by PCR and Southern blotting analysis and two transgenic lines successfully expressed the fusion protein (named GLP-T), which was revealed by Western blotting analysis. The biological activity test results showed that the serum glucose level of diabetic rats was significantly decreased after oral administration of the fusion protein GLP-T extracted from the transgenic cucumber fruitage. These results suggest that this may provide a brand-new strategy to prevent and cure the diabetes with no pain. [ABSTRACT FROM AUTHOR]

Liraglutide, a new glucagon-like peptide-1 (GLP-1)-receptor agonist with 97% homology to human GLP-1, can be administered once/day independent of meals in patients with type 2 diabetes mellitus. Clinical trials have demonstrated its efficacy in controlling hyperglycemia, helping patients achieve hemoglobin Alc level goals; in facilitating weight loss, and in improving indexes of β-cell function when used alone or in combination with metformin, glimepiride, or rosiglitazone. These studies also suggest that liraglutide may be associated with modest improvements in systolic blood pressure. Data from a comparative trial of liraglutide and insulin glargine have suggested that liraglutide provides greater glycemic control with less weight gain, and another study demonstrated that liraglutide provides greater improvements in glycemic control with less hypoglycemia than exenatide and with comparable weight loss. Although liraglutide is well tolerated and is associated with low rates of hypoglycemia, transient and mild nausea can occur when therapy is initiated. However, rates of hypoglycemia appear to be lower and nausea appears to be less persistent with liraglutide than with exenatide. Even though data on the long-term use of liraglutide are still needed, this drug may provide a useful treatment option in patients poorly controlled with dietary modification and exercise and in those whose diabetes is inadequately controlled by oral antidiabetic agents. [ABSTRACT FROM AUTHOR]

GLP-1 analogs have been widely used to treat patients with type 2 diabetes in recent years and studies have found that GLP-1 analogs have multiple organ benefits. However, the role of GLP-1 analogs in diabetic retinopathy (DR), a common complication of diabetes mellitus (DM), remains controversial. Retinal ganglion cells (RGCs) are the only afferent neurons responsible for transmitting visual information to the visual center and are vulnerable in the early stage of DR. Protection of RGC is vital for visual function. The incretin glucagon-like peptide-1 (GLP-1), which is secreted by L-cells after food ingestion, could lower blood glucose level through stimulating the release of insulin. In the present study, we evaluated the effects of GLP-1 analog on RGCs both in vitro and in vivo. We established diabetic rat models in vivo and applied an RGC-5 cell line in vitro. The results showed that in high glucose conditions, GLP-1 analog alleviated the damage of RGCs. In addition, GLP-1 analog prevented mitophagy through the PINK1/Parkin pathway. Here we demonstrated the neuroprotective effect of GLP-1 analog, which may be beneficial for retinal function, and we further elucidated a novel mechanism in GLP-1 analog-regulated protection of the retina. These findings may expand the multi-organ benefits of GLP-1 analogs and provide new insights for the prevention of DR. [ABSTRACT FROM AUTHOR]