Dose Of Liraglutide Research Articles

High dose of liraglutide impairs renal function in female hypertensive rats.

Glucagon-like peptide-1 (GLP-1) receptor agonists exhibit beneficial cardiovascular effects. However, the renal effects of different doses of liraglutide in an essential hypertension model have not yet been investigated. SHR female rats were treated for 30 days, twice a day, with saline (control) or liraglutide at low (0.06 mg/kg, LL) and high (0.6 mg/kg, LH) doses. Volume intake and excretion were monitored for a period of 24h. In renal tissue, nitrite-NO2-, nitrate-NO3-, advanced protein oxidation products-AOPP, collagen deposition, creatinine (Cr), urea (U), sodium, and potassium were analyzed. liraglutide reduced body weight gain in both groups. However, in the high dose, it increased urinary volume excretion and sodium/potassium ratio. Both doses reduced the urinary U/Cr ratio and LH increased the serum U/Cr ratio. AOPP was reduced only in LL. LH augmented collagen and early markers of kidney injury (blood urea nitrogen-BUN, BUN/Cr). LH increased NO3-, reduced NO2-, and caused an aberrant increase in GFR. Both doses' effects were independent of blood pressure and glycemic control. liraglutide appears to have distinct effects on the hypertensive female kidney depending on the dose, with higher doses impairing kidney function.

Renoprotective effect of liraglutide on diabetic nephropathy by modulation of Krüppel-like transcription factor 5 expression in rats.

Diabetic nephropathy (DN) is a serious consequence of diabetes that can develop through the lysophosphatidic acid axis. The purpose of this study was to determine whether the antidiabetic drug liraglutide can slow the development of diabetic kidney damage by altering the lysophosphatidic acid axis via KLF5. Wistar albino rats were divided into nondiabetic and diabetic rats (resulting from an intraperitoneal streptozotocin dose of 30mg/kg and a high-fat diet). These rats were further divided into four groups: nondiabetic control, liraglutide-treated nondiabetic, diabetic control, and liraglutide-treated diabetic. The nondiabetic and diabetic control groups received normal saline for 42 days, while the liraglutide-treated nondiabetic and diabetic groups received normal saline for 21 days, followed by a subcutaneous dose of liraglutide (200 μg/kg/day) for 21 days. Subsequently, serum levels of DN biomarkers were evaluated, and kidney tissues were histologically examined. The protein expression of PCNA, autotaxin, and KLF5 was detected. Liraglutide treatment in diabetic rats decreased DN biomarkers, histological abnormalities in kidney tissues, and the protein expression of PCNA, autotaxin, and KLF5. Liraglutide can slow the progression of DN by modulating KLF5-related lysophosphatidic acid axis. Thus, liraglutide may be an effective treatment for preventing or mitigating diabetes-related kidney damage.

6866 Real-world implications and limitations of GLP-1 prescriptions in adolescents

Abstract Disclosure: G. Castano: None. S. Sisley: None. Background: Glucagon-like-peptide-1 agonists (GLP1), approved for adolescents ≥ 10 years in 2019 for type 2 diabetes (T2D) and ≥ 12 years in 2020 for obesity, require adequate dose titration and have known side effects. There is little information on insurance approval, adherence to titration regimens, or the side effects of liraglutide in clinical practice. Methodology: We performed a retrospective review of all patients <18 years old who were prescribed GLP-1 at a large children’s hospital. We collected demographic information, prescription orders, insurance approval, and drug initiation dates. For individuals who completed at least 26±8 weeks of treatment, we also collected dose titration, side effects, and insulin doses. Results:599 patients were prescribed GLP-1 from 2019 to 2023, with a mean age of 14.99±2.1 years, 58% female, 58% public insurance, and 74% (n=442) with T2D. The cohort was comprised of 63% White, 30% Black, and 2.3% Asian individuals, with 52% of Hispanic ethnicity. 90% of prescriptions were for liraglutide, and 10% for other GLP1 analogs, including exenatide, dulaglutide, and semaglutide. Insurance denied 41% (n=244) of prescriptions, with more denials in those without T2D, 64% vs 32% in patients with T2D.Whereas private insurance denied more prescriptions than Medicaid in patients with T2D (54% vs 27%), the reverse was true for patients without T2D ( 55% private vs 69% Medicaid). Patients lost to follow-up in the first 3 months accounted for 22% (n=135) of the cohort, even though 48% (n=66) of those patients had insurance approval.Those who had insurance approval and took liraglutide for at least 26 weeks accounted for 34% (n=204) of the cohort. Of the patients with T2D, 50% (n=95) titrated to 1.8mg by their first follow-up appointment (1-3 months after prescription start), 33% (n=62) by 6 months, and 17% (n=32) never reached 1.8mg. In patients prescribed a higher dose of liraglutide (3.0 mg daily), 42% (n=8) titrated to 3mg over 5 weeks as prescribed, and 52% (n=10) never reached 3mg, with only one of them not reaching 1.8 mg.Most patients (82%, n=169) had no side effects documented in their charts. From those with side effects reported, GI problems (nausea, vomiting, diarrhea) were noted in 12% (n=25), and 2% (n=4) reported injection site reactions. Side effects that required medication discontinuation included hypoglycemia (n=1), mild pancreatitis (n=1), and severe pancreatitis (n=2). Conclusion: In clinical practice, despite FDA approval, insurance coverage of liraglutide is limited. Almost half of the patients require extra time to reach full doses of liraglutide, with one-third never reaching full treatment doses. Severe pancreatitis may be a previously unpublished side effect. More research is needed to understand how real-world adherence and side effects of liraglutide affect clinical outcomes. Presentation: 6/1/2024

The impact of GLP-1 receptor agonist liraglutide on blood pressure profile, hydration, natriuresis in diabetic patients with severely impaired kidney function

Chronic treatment with GLP-1R agonists may moderately lower blood pressure due to increased natriuresis and RAAS inhibition. Short-term effect of these drugs on blood pressure may be opposite and its mechanism remains unclear. We investigated the effect of a single dose of liraglutide on diurnal blood pressure profile, natriuresis, hydration and serum concentration of renin, aldosterone and atrial natriuretic peptide (ANP) in diabetic kidney disease (DKD). 17 patients with eGFR < 30 ml/min/1.73 m2 and 17 with > 60 ml/min/1.73 m2 received in a random order a single subcutaneous dose 1.2 mg liraglutide and placebo with subsequent 24 h blood pressure and natriuresis monitoring. Before and after each medication thoracic fluid index and plasma renin, aldosterone and ANP were also assessed. The blood pressure load in the daytime and nighttime were significantly increased after liraglutide compared to placebo in patients with eGFR < 30 ml/min/1.73 m2. In patients with eGFR > 60 ml/min/1.73 m2 the changes of arterial pressure were comparable, while the morning surge was significantly reduced after liraglutide compared to placebo. After liraglutide 24 h urine sodium excretion increased in both groups vs. placebo (p < 0.001), the effect was greatest in subjects with eGFR > 60 ml/min/1.73 m2. Plasma ANP increased after liraglutide in both groups, most in patients with eGFR < 30 ml/min/1.73 m2 group. Plasma aldosterone (p = 0.013) and thoracic fluid index (p = 0.01) decreased after liraglutide compared to placebo (p = 0.013 and p + 0.01, respectively. Plasma renin concentration remained unchanged. In severe chronic kidney disease liraglutide induces a transient increase of blood pressure due to reduced natriuresis. The natriuretic effect of liraglutide in DKD may be related to increased ANP and decreased aldosterone secretion.

Dose Response Effects of Liraglutide (Saxenda) on Weight Loss among Overweight and Obese Individuals: A Three Arm Randomized Controlled Trial

Introduction: The present is aimed to determine the effects of three different doses of Liraglutide (Saxenda) that are 0.6mg, 1.2mg and 1.8mg with and without exercises on obese population after 6 months of intervention. Methodology: A three arm randomized controlled trial was performed at Isra Univeristy Hospital, Hyderabad. A total of n=60 obese participants including both male and female were recruited and divided into two groups n=20 participants in each group. Each group was than further divided into two subgroups n=10 participants in each subgroup. Results: The analyses of the findings had revealed that n=22 participants included in the study were male whereas n=38 were female. The mean Body Mass Index (BMI) of the participants in group A at baseline was 29.95±1.35kg/m2, 30.21±1.56 kg/m2 and 29.54±2.33 kg/m2 in subgroup (i), (ii) and (iii) respectively whereas in group B the values of BMI at baseline were 30.25±1.56 kg/m2, 29.87±2.56 kg/m2 and 30.11±2.33 kg/m2 in subgroup (i), (ii) and (iii) respectively. In group C the values were 30.01±2.14 kg/m2, 28.59±2.22 kg/m2 and 30.58±1.98 kg/m2 in subgroup (i), (ii) and (iii) respectively. Conclusion: The findings revealed substantial differences in BMI and body fat percentage within each group from baseline through three and six months of intervention. Higher Liraglutide (Saxenda) dosages (1.8mg) resulted with greater decreases in BMI and body fat percentage than lower doses (0.6mg and 1.2mg). Keywords: obesity, body mass index, body fat percentage

O-16 Never too late: Delayed diagnosis of Prader-Willi syndrome

Abstract Introduction Prader-Willi syndrome (PWS) is the leading inherited cause of severe childhood obesity. The aim of this case report is to describe a case of delayed diagnosis of PWS and to emphasize the importance of early diagnosis of PWS. Clinical Case A 24-year-old young woman with a history of hyperphagia, severe obesity, and cognitive impairment was admitted to our department for glycemic control due to newly diagnosed type 2 diabetes mellitus. She also had obstructive sleep apnea, daytime sleepiness, scoliosis, short stature (148 cm), and impaired speech articulation. Central obesity (BMI:54.7 kg/m2, waist circumference 147 cm), cognitive impairment, and characteristic body and facial features (narrow bifrontal diameter, almond-shaped palpebral fissures, small hands and feet, strabismus) suggested a genetic disorder. Test results showed growth hormone 0.07 ng/mL (0-3.5) and IGF-1 46 ng/mL (191-478). Cytogenetic analysis was performed on GTG-banded metaphases obtained from peripheral blood lymphocyte culture. t(3;16)(p21;p13) was observed in the patient. Cytogenetic analysis of the parents showed that this translocation was of paternal origin. The SNRPN gene was amplified from the patient's genomic DNA by PCR using methylation-specific primers after bisulfite modification. PCR products were visualized by agarose gel electrophoresis. The methylation pattern was found to be consistent with PWS. Hypocaloric diet (1400 Kcal/day) metformin 2 g/day, liraglutide (dose gradually increased to 2.4 mg/day), and dapagliflozin 10 mg/day were started. During hospitalization, glycemic regulation was achieved and 5.4 kilograms of weight loss occurred. Conclusion Obesity-related complications (e.g. sleep apnea, type 2 diabetes) and behavioral problems contribute significantly to morbidity and mortality in individuals with PWS. Prevention and treatment of morbid obesity and related conditions in individuals with PWS and management of maladaptive behaviors are key goals that require long-term follow-up and attention to managing the process. In these adults with compulsive eating behaviors who lack the ability to make informed decisions, it is very challenging to ensure compliance with treatments such as obesity treatment and the use of assistive devices for sleep apnea, which require the patient's consent and compliance. The complexity of this multisystemic disease increases with age, and we emphasize the need for early diagnosis to reduce the morbidity and mortality associated with PWS.Figure 1.Used with the patient's and family's consent.

The GLP-1 analogue battle: effects of semaglutide 0,5 mg/weekly versus liraglutide 3 mg/daily on anthropometric parameters after 3 months in a real world-scenario

the prevalence of obesity is reaching a pandemic status. The SCALE trials showed that liraglutide 3 mg among people with obesity (PwO) was effective to reduce bodyweight and related complications. The fact that almost two-thirds of patients did not achieve the desired weight loss with the maximum dose of liraglutide made almost mandatory the development of other pharmacological options. The STEP 1-5 trials showed the effectiveness of semaglutide in reducing bodyweight in a dose-dependent manner. Moreover, the STEP 8 trial proved the superiority of semaglutide 2,4 mg/week versus liraglutide 3 mg/daily. We aimed to assess the effects of subcutaneous (s.c.) semaglutide 0.5 mg/weekly compared with s.c. liraglutide 3 mg/daily in PwO on anthropometric parameters in a real world-scenario for 3 months. we retrospectively evaluated 179 PwO (91.9 % ♀, 45.7 ± 10 years, and 33.3 ± 7 kg/m2) who received treatment with aGLP-1 as add-on therapy to lifestyle interventions. Patients were evaluated at baseline and after 3 months. Ninety-nine patients were prescribed s.c. semaglutide 0.5 mg/weekly with an off-label indication for weight reduction. These patients were compared with 80 patients treated with s.c. liraglutide 3 mg/daily. The main reason for prescribing of s.c. semaglutide was economic. Body composition was evaluated using a bioimpedance device (Tanita MC 580M®). baseline weight was significantly greater with semaglutide compared to liraglutide (97.19 ± 21.09 vs. 90.73 ± 21.88 kg; p < 0.01) as was fat mass (42.43 ± 15.04 vs. 34.84 ± 16.07 kg; p < 0.01), whereas baseline lean mass was lesser among subjects treated with semaglutide (31.62 ± 7.56 vs 45.69 ± 15.51 kg; p < 0.01). PwO experienced a significant reduction in weight using s.c. semaglutide 0.5 mg/weekly (96.67 ± 20.83 vs. 91.44 ± 19.6 kg; p < 0.01) or s.c. liraglutide 3 mg/daily (90.73 ± 21.88 vs. 80.13 ± 18.38 kg; p < 0.01) No significant differences were seen between the amount of weight lost (5.28 ± 4.22 vs 5.72 ± 1.62 kg; p = 0.5) in the two groups. Furthermore, both groups were comparable in fat mass (2.69 ± 5.34 vs 0.96 ± 4.22 kg; p = 0.3) and fat-free mass (0.86 ± 1.63 vs 1.03 ± 0.94 kg; p = 0.07) after 3 months of treatment with both aGLP1. Side effects were gastrointestinal and transient/comparable between groups Conclusions: subcutaneous semaglutide 0.5 mg and subcutaneous liraglutide 3 mg are effective treatments for reducing weight safely among PwO in a real-world scenario at short term and without a negative impact on fat-free mass. Moreover, low doses of semaglutide were similar to liraglutide 3 mg in reducing bodyweight at short term.

Label-free quantitative proteomic profiling reveals differential plasma protein expression in patients with obesity after treatment with liraglutide.

Treatment and management of obesity is clinically challenging. The inclusion of GLP-1 receptor agonists (GLP1RA) in the medical management of obesity has proven to be efficacious. However, mechanisms underlying the molecular changes arising from GLP1RA treatment in patients with obesity remain to be elucidated. A single-center, prospective study was undertaken to evaluate the changes in the plasma proteins after liraglutide 3 mg therapy in twenty patients (M/F: 7/13) with obesity (mean BMI 40.65 ± 3.7 kg/m2). Anthropometric and laboratory parameters were measured, and blood samples were collected at two time points: baseline, before initiating treatment (pretreatment group, PT), and after three months of receiving the full dose liraglutide 3 mg (posttreatment group, PoT). An untargeted label-free LC MSMS mass spectrometric approach combined with bioinformatics and network pathway analysis was used to determine changes in the proteomic profiles. The mean age of the study participants was 36.0 ± 11.1 years. A statistically significant change was observed in weight, BMI and HbA1c levels between the PT and PoT groups (paired t-test, P < 0.001). A significant dysregulation was noted in the abundances of 151 proteins (31 up and 120 downregulated) between the two groups. The potential biomarkers were evaluated using receiver operating characteristic (ROC) curves. The top ten proteins (area under the curve (AUC) of 0.999 (95% CI)) were identified as potential biomarkers between PT and PoT groups and included Cystatin-B, major vault protein, and plastin-3, which were upregulated, whereas multimerin-2, large ribosomal P2, and proline-rich acidic protein 1 were downregulated in the PoT group compared with the PT group. The top network pathway identified using ingenuity pathway analysis (IPA), centered around dysregulation of MAPK, AKT, and PKc signaling pathways and related to cell-to-cell signaling and interaction, cellular assembly and organization, cellular compromise and a score of 46 with 25 focus proteins. Through label-free quantitative proteomic analysis, our study revealed significant dysregulation of plasma proteins after liraglutide 3 mg treatment in patients with obesity. The alterations in the proteomic profile between the PT and PoT groups demonstrated a decrease in levels of proteins involved in inflammation and oxidative stress pathways. On the other hand proteins involved in the glycolytic and lipolytic metabolic pathways as well as those participating in cytoskeletal and endothelial reorganization were observed to be increased. Understanding actions of liraglutide at a molecular and proteomic levels provides a holistic look into how liraglutide impacts metabolism, induces weight loss and improves overall metabolic health.

Evaluation of the Effectiveness of Liraglutide on Metabolic Parameters in the Treatment of Obesity.

Background One of the essential chronic diseases is obesity, which negatively affects the individual and society. Liraglutide (LG) is an effective treatment for both obesity treatment and metabolic control. This study aims to show the effect of a 3.0 mg dose of LG, injected subcutaneously once a day, on weight loss and metabolic parameters. Methods This retrospective single-center study included 67 patients (60 women and seven men) with a BMI of at least 27 kg/m2 with comorbidities or a BMI of at least 30 kg/m2. Demographic characteristics, anthropometric measurements, and biochemical data of the participants were evaluated at the end of the four and 16 weeks. Results The mean body weight (BW) loss of patients using LG at 16 weeks was -11.71±2.21 kg. After the four and 16 weeks of beginning the LG use, the patients who lost more than 5% of initial BW were 38.8% vs. 76.1%, respectively (p=0.034). The mean baseline Homeostatic Model Assessment-Insulin Resistance Index, hemoglobin A1c, low-density lipoprotein, and triglycerides values were significantly higher than the 4 and 16 weeks (p<0.001). Twenty-two (32.8 %) patients experienced side effects (SE) after starting LG treatment, and the most common SE was found to be nausea (29.4%). Conclusion The use of LG, which is not covered by insurance, together with diet and exercise, has been shown to have clinically significant weight loss and a positive effect on glycemic values ​​and lipid profile.

Phase 3 efficacy and safety trial of proposed liraglutide biosimilar for reduction of glycosylated hemoglobin (HbA1c) in patients with Type 2 diabetes mellitus

Liraglutide is indicated for glycaemic control in adults with Type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise. A proposed biosimilar of liraglutide (Levim Liraglutide) was investigated for efficacy & safety in a phase 3 study against the originator reference liraglutide (Victoza®) manufactured by Novo Nordisk A/S, Denmark. Patients aged 18–65 years of age with glycosylated hemoglobin (HbA1c) between 7 and 10 %, among other criteria, were included in the study. Patients were randomized 1:1 to receive daily doses of either Levim liraglutide or reference liraglutide for 24 weeks. The least square mean (standard error, SE) for the primary efficacy endpoint of reduction in HbA1c% at Week 24 was −1.09 (0.15)% for Levim liraglutide group and −1.04 (0.14)% for reference liraglutide. The upper bound of the confidence interval for treatment difference was less than the non-inferiority margin of 0.4 % at one-sided alpha of 0.025 (P-value = 0.0003). The secondary endpoints for proportion of patients achieving reduction in HbA1c, glycaemic level and weight, changes in cardiovascular parameters and the overall safety profiles of the study drugs were comparable. Levim liraglutide demonstrated non-inferior efficacy and similar safety to reference liraglutide and may be an option in treatment of T2DM (CTRI.nic.in, no. CTRI/2022/02/040261).

Glucagon-like Peptide-1 Receptor Pathway Attenuates Platelet Activation in Aspirin-Exacerbated Respiratory Disease.

Platelets are key contributors to allergic asthma and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype involving platelet activation and IL-33-dependent mast cell activation. Human platelets express the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists decrease lung IL-33 release and airway hyperresponsiveness in mouse asthma models. We hypothesized that GLP-1R agonists reduce platelet activation and downstream platelet-mediated airway inflammation in AERD. GLP-1R expression on murine platelets was assessed using flow cytometry. We tested the effect of the GLP-1R agonist liraglutide on lysine-aspirin (Lys-ASA)-induced changes in airway resistance, and platelet-derived mediator release in a murine AERD model. We conducted a prospective cohort study comparing the effect of pretreatment with liraglutide or vehicle on thromboxane receptor agonist-induced invitro activation of platelets from patients with AERD and nonasthmatic controls. GLP-1R expression was higher on murine platelets than on leukocytes. A single dose of liraglutide inhibited Lys-ASA-induced increases in airway resistance and decreased markers of platelet activation and recruitment to the lung in AERD-like mice. Liraglutide attenuated thromboxane receptor agonist-induced activation as measured by CXCL7 release in plasma from patients with AERD and CD62P expression in platelets from both patients with AERD (n = 31) and nonasthmatic, healthy controls (n = 11). Liraglutide, a Food and Drug Administration-approved GLP-1R agonist for treatment of type 2 diabetes and obesity, attenuates invivo platelet activation in an AERD murine model and invitro activation in human platelets in patients with and without AERD. These data advance the GLP-1R axis as a new target for platelet-mediated inflammation warranting further study in asthma.

Glucagon-Like Peptide 1 Analogues as Adjunctive Therapy for Patients With Type 1 Diabetes: An Updated Systematic Review and Meta-analysis.

Concomitant obesity is common among patients with type 1 diabetes mellitus (T1DM), yet adjunctive therapy options are scarce. We assess the efficacy and adverse outcomes of glucagon-like peptide 1 (GLP-1) analogues when used as adjunctive therapy for T1DM. PubMed, EMBASE, Cochrane Central, and Scopus databases were searched for randomized controlled trials up to December 2022. Efficacy outcomes were A1c level, body weight, and total daily insulin (TDI) after ≥12 weeks of GLP-1 therapy. We also assessed 12 different adverse outcomes. Subgroup analysis was done for newly diagnosed or C-peptide positive (C-pos) patients. We report the certainty of evidence based on the GRADE assessment tool. A total of 24 studies using 4 different GLP-1 analogues with a total of 3377 patients were included. Liraglutide had the most substantial evidence with effect sizes on A1c (-0.09%/mg), weight (-2.2 kg/mg), and TDI (-4.32 IU/mg). Liraglutide dose was the greatest predictor of greater average weight loss and TDI decrease but was associated with higher odds of nausea (OR 6.5; 95% CI, 5.0-8.4) and ketosis (OR 1.8; 95% CI, 1.1-2.8). Odds of severe (OR 0.67; 95% CI, 0.43-1.04) or symptomatic hypoglycemia (OR 0.89; 95% CI, 0.53-1.51) were not significantly elevated. Among C-pos patients, greater A1c decrease (-0.51% vs -0.28%) but similar weight loss and TDI were seen. Effect sizes for exenatide were similar, but studies had higher risk of bias and safety data were sparse. Our meta-analysis supports therapeutic benefits of liraglutide for patients with T1DM mainly for weight loss and insulin dose reduction. Newly diagnosed or C-pos patients do not appear to experience greater weight loss benefits.

Low dose of liraglutide combined with metformin leads to a significant weight loss in Chinese Han women with polycystic ovary syndrome: a retrospective study

Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder with complex pathophysiological mechanism. It is reported that even a modest weight loss of 5–10% substantially may improve the reproductive and metabolic profile. This study aims to assess the efficacy of the low dose of liraglutide (0.6 mg QD) combined with metformin (0.85 mg BID) in weight loss in Chinese Han women with PCOS. Methods We included clinical data of 102 obese/overweight (≥18 years, body mass index ≥28 kg/m2 or ≥24 kg/m2) women who were diagnosed with PCOS from October 2016 to March 2018 in Wuhan Union Hospital initially. They were treated with dinae-35, low dose of liraglutide (0.6 mg QD) and metformin (0.85 mg BID) for 12 weeks. The demographic and clinical data were retrieved retrospectively, and weight loss was the main outcome measure. Student’s paired t-test and Wilcoxon rank sum test were used to compare the differences before and after therapy, p < 0.05 was considered statistically significant. Results Participants(n = 102)had lost a mean of 7.20 ± 3.42 kg of body weight (95%CI: 6.55–7.86, p < 0.001), and the mean reduction of BMI was 2.87 ± 1.36 kg/m2 (95%CI: 0.02–0.27, p < 0.001). A total of 88.24% of participants lost more than 5% of their body weight. Conclusion The combination of low dose of liraglutide and metformin was associated with significant reduction of body weight in Chinese Han women with PCOS. Additionally, a larger randomized double-blind multicenter controlled clinical trial is needed to confirm that. Trial registration The study was registered on http://www.chictr.org.cn as ChiCTR1900024384.

Liraglutide in adolescents with simple obesity and gastrointestinal comorbidities: treatment experience

BACKGROUND: Liraglutide was approved for treatment of obesity in children and adolescents since 12 years. Due to gastrointestinal (GI) side effects not all patients reach maximal dose; this can affect the efficacy of obesity treatment.AIM: To study efficacy and tolerability of liraglutide in adolescents with obesity.MATERIALS AND METHODS: We analyzed medical data of adolescents with simple obesity and GI comorbidities before and in 3 months after start of liraglutide (BMI SDS; obesity complications; liraglutide side effects, and maximal doses), duration of therapy, reasons for discontinuation, and BMI SDS in 3–6 months after discontinuation.RESULTS: Liraglutide was administered for 10 adolescents (7 girls, 3 boys) 15.4 (13.5; 16.2) years with BMI SDS 3.3 (2.9; 3.7). Three months of treatment led to significant (p=0.001) decrease of BMI SDS till 2.8 (2.6; 3.5). Maximal dose of liraglutide was 3.0 mg (6 patients), 2.4 mg (2), 1.8 mg (1), and 1.2 mg (1). No correlation between maximal dose and BMI ΔSDS was detected. While dose titration patients complained of nausea (9), diarrhea (3), obstipation (1), and flatulence (1). In majority of cases complains were not dose-dependent. Only in 1 patient nausea and diarrhea that did not allow to increase liraglutide dose above 1.2 mg; additional investigation after discontinuation of therapy revealed GI infection.Therapy was discontinued in 3 months by 2 patients (1 — side effects, 1 — satisfactory result), in 4–5 months by 3 patients (1 — relapse of excessive weight gain, 2 — financial reasons), in 6 months by 1 patient (satisfactory result); 4 continued therapies. In 3–6 months after discontinuation of therapy BMI SDS increased and did not significantly differ from basal.CONCLUSION: Liraglutide is effective for treatment of obesity in adolescents and well tolerated by majority of patients. In case of pronounced adverse events additional GI investigation is recommended. Patients can discontinue treatment not only due to side effects, but also when they achieve their goal, and due to financial reasons.

Abstract #1413680: Post-Bariatric Hypoglycemia (PBH) Refractory to Conventional Therapies: The Combined Effect of Very High Doses of Glucagon-Like Receptor Agonist (GLP1-RA) and a Low Dose of Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i)

As the number of bariatric surgeries in the United States plateaus at nearly 200,000, the prevalence of post-bariatric hypoglycemia (PBH) is escalating. Since the pathophysiology driving PBH is not fully understood, treatment for PBH can be challenging in the clinical practice. Most recently, the use of GLP1-RA or SGLT2i have been reported as monotherapy options for PBH. We are presenting the case of a patient without diabetes who failed conventional therapy for her persistent PBH and dumping syndrome but was successfully treated with very high doses of liraglutide and a low dose of empagliflozin. A 50-year-old Hispanic woman was referred to endocrinology with an 8-year history of recurrent syncope due to hypoglycemia. She was diagnosed with non-insulinoma pancreatogenic hypoglycemia complicated by PBH and dumping syndrome. She had a history of Roux-en-Y gastric bypass 10 years prior. Initially, she attempted diet modification, by eating less than 20 grams of carbohydrates per meal, with no improvement. Next, she trialed acarbose, which resulted in ongoing hypoglycemic events and gastrointestinal side effects. Intermittent-scanning Continuous Glucose Monitor (CGM) revealed 4% Target Below Range (TBR, <70 mg/dL) off of acarbose despite eating every 2 hours to avoid hypoglycemia. Her hypoglycemic events were confirmed with a glucometer. We started her on Octreotide 50 mcg sq twice daily (BID), which improved TBR to 1% but resulted in relentless constipation. To regulate her bowels, her Octreotide was adjusted to 25 mcg AM and 50 mcg PM, but her TBR increased to 3%. With the addition of Liraglutide 0.6 mg sq daily to Octreotide 50 mcg BID, her constipation was unbearable, and her TBR was 2%. She remained on Octreotide 50 mcg BID and Liraglutide was up-titrated to 1.2 mg daily (TBR 4%) and then 1.8mg daily (TBR 4%). Octreotide was discontinued. On liraglutide 2.4mg daily alone, she continued without nocturnal hypoglycemia. She noted improvement in both her gastrointestinal side effects and her post-prandial hypoglycemia (TBR 3%). The dose of Liraglutide was maximized to 3 mg daily. Her CGM was changed to real-time CGM, and her TBR was 2.4%. Empagliflozin 10 mg daily was added to Liraglutide 3 mg daily, and her hypoglycemia instantly, and completely resolved with a sustained TBR of 0%. Very high doses of Liraglutide combined with a low dose of empagliflozin corrected PBH to TBR 0% and resolved the dumping syndrome symptoms. This combination therapy should be considered in patients with PBH not responding to conventional anti-hypoglycemic monotherapies.

Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal pathway in rats

Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9–39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.

Effect of liraglutide on atherosclerosis in patients with impaired glucose tolerance: A double‑blind, randomized controlled clinical trial.

Glucagon-like peptide-1 receptor agonist liraglutide may have beneficial effects on atherosclerosis development in impaired glucose tolerance (IGT). To the best of our knowledge, however, little conclusive evidence from clinical trials has been presented. The present study aimed to investigate the effect of liraglutide on atherosclerosis progression in patients with IGT. The present study was a double-blind, randomized controlled clinical trial. A total of 39 of patients aged 20-75 years who were overweight or obese (BMI, 27-40 kg/m2) and presented IGT were randomized to receive liraglutide (n=17) or lifestyle interventions (n=22) for 6 months. Serum glucose and insulin (INS) levels, lipid profile, inflammatory biomarkers and carotid intima-media thickness (CIMT) were assessed at the start and end of each treatment. Side effects were also recorded. Liraglutide treatment was found to significantly improve glycaemia, including glycosylated hemoglobin, fasting and postprandial glucose as well as INS levels (all P<0.001). Liraglutide also significantly decreased serum total cholesterol and low-density lipoprotein levels (all P<0.001). Furthermore, serum levels of inflammatory biomarkers, as well as CIMT, were decreased following liraglutide treatment compared with those in the lifestyle intervention group (all P<0.001). Kaplan-Meier analysis showed that the risk of vasculopathy in the liraglutide group was lower than that in the lifestyle intervention group (log-rank test; P=0.041). The monitoring of drug-associated side effects indicated that the dose of liraglutide (0.6 to 1.2 mg/QD via subcutaneous injection) was safe and well-tolerated. The present study suggested that liraglutide may slow atherosclerosis development and improve inflammatory status as well as intimal function in patients with IGT with few side effects. The trial was registered through the Chinese Clinical Trial Registry (ChiCTR; trial registration no. ChiCTR2200063693; retrospectively registered) on Sep 14, 2022.

Metabolic effects of the liraglutide: a discussion of the results of clinical observations

Objective: to discuss the features of the use of the drug liraglutide for the treatment of patients with obesity, to analyze the metabolic parameters dynamic and the difficulties that arise during therapy, based on our own clinical observations.Materials and methods: the article provides an analysis of our own clinical observations of patients aged 54 and 47 years who received liraglutide therapy for exgenous constitutional obesity of the II degree. According to the examination results, both patients showed hyperinsulinemia and insulin resistance signs, lipid metabolism disorders. There were no episodes of acute pancreatitis in the past. Heredity for medullary thyroid cancer is not burdened, thyroid status is normal. Dose liraglutide escalation is recommended on a schedule 0.6 mg per week.Results: during therapy with liraglutide, patients under observation experienced a gradual progressive decrease in body weight against the background of a decrease in appetite and a decrease in the amount of food consumed. In the dynamics, there was a tendency to normalize the initial metabolic disorders: a decrease in insulin resistance and hyperinsulinemia, carbohydrate metabolismdisorders and lipid profile.Conclusion: the results of our own clinical observations indicate the effectiveness of the drug liraglutide use in the treatment of patients with obesity, not only to achieve the target weight loss indicators, but also to correct the initial disorders of the metabolic status.

Abstract 15922: Effect of Glp-1 Receptor Agonists on Systolic Blood Pressure in Patients With Overweight or Obesity: A Network Meta-Analysis

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to reduce weight in patients with overweight or obesity. However, their effect on systolic blood pressure (SBP) remains less well-established. We conducted a network meta-analysis to evaluate the effect of different drug-dose combinations of GLP-1 RAs on SBP in this population. Methods: Electronic databases were searched through January 2022 for RCTs which evaluated the efficacy of different doses of semaglutide, liraglutide, efpeglenatide, and exenatide in obese patients with and without T2DM. Systolic blood pressure (SBP) was chosen as the primary endpoint. A frequentist network meta-analysis using random-effects model was conducted, and pooled estimates were reported as mean differences (MD) with 95% confidence intervals (CI). Results: A total of 20 RCTs were included in the analysis. Among individuals with T2DM, liraglutide &lt;2 mg once daily (QD) showed the greatest reduction in SBP (MD: -3.78 [-5.63; -1.15]), followed by exenatide 10 ug twice daily (BID) (MD: -3.39 [-5.63; -1.15]), and semaglutide ≥1mg once weekly (QW) (MD: -3.28 [–5.68; –0.88]), when compared with placebo. Among individuals without diabetes, efpeglenatide ≤ 6 mg QW showed the greatest reduction in SBP (MD: -6.00 [-9.89; -2.11]), followed by semaglutide ≥ 1 mg QW (MD: -4.54 [–5.69; –3.39]), and semaglutide &lt;1mg QW (MD: -4.51 [–5.49; –3.54]). The figure shows how each drug/dose combination compares with others. Conclusions: This network meta-analysis suggests liraglutide &lt;2mg QD is the most efficacious GLP-1 RA in lowering SBP in obese patients with T2DM. For obese patients without diabetes, efpeglenatide ≤6mg QW is the most effective.

ODP222 Liragluitde Increased IL-1RA Concentrations in Obese Type 2 Diabetes: A Small Randomized Controlled Trial

Abstract Background Therapy with exenatide, exendin-4-based glucagon liked peptide-1 receptor agonist (GLP-1 RA) increased plasma interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein which protected pancreatic ß cells independent of glycemic and weight controlled. We hypothesized that liraglutide, long-acting GLP-1 analogue might contribute to a potential protective effect on ß cells in diabetes. Methods Twenty-four obese patients with type 2 diabetes receiving oral hypoglycemic agents with insulin therapy, except pioglitazone or incretin-based therapy, were randomly assigned to receive either maximum tolerate dose of liraglutide (n=12) or standard therapy (n=12) for twelve weeks. Results Among 24 participants who completed over 12 weeks of this study, median change was +258.7% (78.7, 656.6) and +101. 0% (-3.3, 189.4) of IL-1RA; P&amp;lt;0. 04, and -1.2% (-1.7, -0.8) and -0.4% (-1. 0, 0.3) of A1c; P&amp;lt;0. 03 in liraglutide and standard group, respectively. Percent changes of fasting plasma glucose, body weight, neck circumference and body mass index were all not statistically significant, when comparing between group. Pearson correlation between percent change of IL-1RA and percent change of A1c response to therapy were also not statistically significant. Conclusion Liraglutide might have anti-inflammatory effect independent of the glycemic control during initial short-term duration. Keywords: Liraglutide, Interleukin-1 receptor antagonist, obese type 2 diabetes. Presentation: No date and time listed