The effectiveness of 0.5 mg and 1mg of semaglutide in patients with type two diabetes and predictors of response: a retrospective cohort study.

Background: Semaglutide is a glucagon-like peptide-1 receptor agonists (GLP-1-RAs) approved for the treatment of type 2 diabetes mellitus (T2DM) at doses up to 1 mg. The results from randomized control trials and real-world studies revealed that weekly semaglutide was associated with significant improvements in HbA1c and body weight. To our knowledge, no study assessed the effectiveness of using semaglutide for patients with T2DM in the Saudi population. We aim to assess the effectiveness of once weekly SC 0.5 and 1 mg of semaglutide on HbA1c and weight reduction in patients with T2DM in the Saudi population within 12 months of use, evaluate the predictors of response, and compare the effect of the two doses. Method: This is a retrospective cohort study conducted at Security Force Hospital in Riyadh, Saudi Arabia. Using electronic medical records of patients with type two diabetes who received semaglutide 0.5 or 1 mg for a total duration of at least 12 months of use. Results: Within the study period of semaglutide use, HbA1c significantly decreased from baseline by -2.1% (-2.3 to -1.91, 95% CI) (P <0.001). While the mean change in weight was -6.19 kg (-6.66 to -5.72, 95% CI) (P<0.001). Moreover, BMI, FBG, total cholesterol, LDL, and TG all decreased significantly from baseline (p<0.001). When comparing the sub-groups of 0.5 and 1 mg doses, although results were numerically favorable of 1 mg, there were no statistically significant differences in HbA1c % (-2.1 ± 1.8 vs. -2.1 ± 1.9, p-value= 0.934, respectively), and weight (-6.1 ± 5 vs. -6.2 ± 4.4 kg, p-value=0.837, respectively). Significant predictors of HbA1c reduction were the duration of DM, baseline HbA1c, and insulin therapy. While the significant predictor for weight reduction was insulin therapy. Conclusion: This study is document the effectiveness of once-weekly SC semaglutide on glycemic control and weight loss in real-world practice. We recommend a starting goal dose of 0.5 mg and gradual increase of dose based individual patient response. further studies are needed to assess the effectiveness and tolerability of various semagltude doses.

Nanoparticles targeting the intestinal Fc receptor enhance intestinal cellular trafficking of semaglutide.

Semaglutide is the first oral glucagon-like peptide-1 (GLP-1) analog commercially available for the treatment of type 2 diabetes. In this work, semaglutide was incorporated into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NPs) to improve its delivery across the intestinal barrier. The nanocarriers were surface-decorated with either a peptide or an affibody that target the human neonatal Fc receptor (hFcRn), located on the luminal cell surface of the enterocytes. Both ligands were successfully conjugated with the PLGA-PEG via maleimide-thiol chemistry and thereafter, the functionalized polymers were used to produce semaglutide-loaded NPs. Monodisperse NPs with an average size of 170 nm, neutral surface charge and 3% of semaglutide loading were obtained. Both FcRn-targeted NPs exhibited improved interaction and association with Caco-2 cells (cells that endogenously express the hFcRn), compared to non-targeted NPs. Additionally, the uptake of FcRn-targeted NPs was also observed to occur in human intestinal organoids (HIOs) expressing hFcRn through microinjection into the lumen of HIOs, resulting in potential increase of semaglutide permeability for both ligand-functionalized nanocarriers. Herein, our study demonstrates valuable data and insights that the FcRn-targeted NPs has the capacity to promote intestinal absorption of therapeutic peptides.

Liraglutide Attenuates Diabetic Cardiomyopathy via the ILK/PI3K/AKT/PTEN Signaling Pathway in Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus.

One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 µg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM.

Exploiting the biological effect exerted by lipid nanocapsules in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global adult population and can progress to end-stage liver disease with life-threatening complications; however, no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNCs) are a very versatile platform, easy to produce, and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being extensively studied in clinical trials in the context of NAFLD. Our nanosystem provides with increased levels of GLP-1, triggered by the nanocarrier itself, and by the plasmatic absorption of the encapsulated synthetic analog (exenatide). Our goal in this study was to demonstrate a better outcome and a greater impact on the metabolic syndrome and liver disease progression associated with NAFLD with our nanosystem than with the subcutaneous injection of the GLP-1 analog alone. To that end, we studied the effect of chronic administration (one month) of our nanocarriers in two mouse models of early NASH: a genetic model (foz/foz mice fed a high fat diet (HFD)) and a dietary model (C57BL/6J mice fed with a western diet plus fructose (WDF)). Our strategy had a positive impact in promoting the normalization of glucose homeostasis and insulin resistance in both models, mitigating the progression of the disease. In the liver, diverging results were observed between the models, with the foz/foz mice presenting a better outcome. Although a complete resolution of NASH was not achieved in either model, the oral administration of the nanosystem was more efficient at preventing the progression of the disease into more severe states than the subcutaneous injection. We thus confirmed our hypothesis that the oral administration of our formulation has a stronger effect on alleviating the metabolic syndrome associated with NAFLD than the subcutaneous injection of the peptide.

Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A subgroup analysis by baseline variables in the PIONEER 9 and PIONEER 10 trials.

AIMS/INTRODUCTION: To assess the impact of baseline characteristics on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: In the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 9 and 10 trials, Japanese patients were randomized to once-daily oral semaglutide (3, 7, or 14 mg) or a comparator (placebo or once-daily subcutaneous liraglutide 0.9 mg in PIONEER 9; once-weekly subcutaneous dulaglutide 0.75 mg in PIONEER 10) for 52 weeks, with 5 weeks of follow up. An exploratory analysis grouped patients in each trial according to baseline glycated hemoglobin (HbA1c ; ≤8.0, >8.0-≤9.0, or >9.0%), body mass index (<25, ≥25-<30, or ≥30 kg/m2 ) and, for PIONEER 10 only, by background medication (sulfonylurea, glinide, thiazolidinedione, α-glucosidase inhibitor, sodium-glucose cotransporter 2 inhibitor). Efficacy (changes from baseline to week 26 in HbA1c and bodyweight) and safety were assessed. RESULTS: Seven hundred and one patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). In both trials, HbA1c reductions increased as baseline HbA1c increased; there were no other apparent patterns between the variables investigated and HbA1c or bodyweight changes. There was one statistically significant subgroup interaction between baseline HbA1c and estimated treatment differences in bodyweight change for oral semaglutide 14 mg versus placebo in PIONEER 9 (P = 0.0286). Baseline HbA1c , baseline body mass index and background medication did not appear to affect the proportions of patients reporting adverse events. CONCLUSIONS: Oral semaglutide is effective across a range of baseline subgroups of Japanese patients with type 2 diabetes, with no unexpected safety findings.

Anti-obesity Medications for the Management of Nonalcoholic Fatty Liver Disease.

PURPOSE OF REVIEW: Obesity is closely associated with nonalcoholic fatty liver disease (NAFLD), a highly prevalent disease without any approved medication. The aim of this review was to summarize the evidence on the effect of anti-obesity medications on NAFLD, especially focusing on hepatic histology. RECENT FINDINGS: Orlistat and some glucagon-like peptide-1 receptor analogs, including liraglutide and semaglutide, have beneficial effects on hepatic steatosis and inflammation, but not fibrosis. Other anti-obesity medications, including lorcaserin, setmelanotide, phentermine hydrochloric, phentermine/topiramate, and naltrexone/bupropion, have been minimally investigated in NAFLD. Furthermore, medications like sodium-glucose cotransporter-2 inhibitors and farnesoid X receptor have shown beneficial effects in both NAFLD and obesity, but they have not been licensed for either disease. Liraglutide, semaglutide, and orlistat may be currently used in selected patients with obesity and NAFLD. Further research is warranted, since targeting obesity may provide additional benefits on its comorbidities, including NAFLD.

Expression of human globular adiponectin-glucagon-like peptide-1 analog fusion protein and its assay of glucose-lowering effect in vivo.

In this study, human globular adiponectin-glucagon-like peptide-1 analog (gAd-GLP-1-A) fusion protein was expressed and its glucose-lowering effect was measured in vivo. We constructed a prokaryotic expression vector PET28a-gAd-GLP-1-A and transformed the vector into Escherichia coli BL21 (DE3). A recombinant fusion protein of about 25KD was expressed from BL21 (DE3) cells after isopropylthio-ß-D-galactoside induction. This protein was N-terminal His-tagged gAd-GLP-1-A fusion protein. Most of the protein was expressed in inclusion body. The fusion protein in inclusion body was purified by using High-Affinity Nickel Iminodiacetic Acid Resin and refolded in urea gradient refolding buffer. The refolded protein was incubated with enterokinase to remove the N-terminal His-tag. The fusion protein without His-tag is gAd-GLP-1-A fusion protein, which exhibited significant glucose-lowering effect in diabetic mice.

Liraglutide, a glucagon-like peptide-1 analog, inhibits high glucose-induced oxidative stress and apoptosis in neonatal rat cardiomyocytes.

Cardiomyocyte apoptosis serves an important role in diabetic cardiomyopathy. Liraglutide, a glucagon-like peptide-1 analog, has been indicated to exert a cardioprotective effect. However, the role of liraglutide on cardiomyocyte apoptosis in hyperglycemia is not fully understood. The aim of the current study was to assess whether liraglutide protects against high glucose (HG)-induced cardiomyocyte apoptosis in vitro. Sprague-Dawley neonatal rat cardiomyocytes were cultured in Dulbecco's modified Eagle's medium, supplemented with 5.5 or 25 mmol/l D-glucose or 5.5 mmol/l D-glucose + 19.5 mmol/l mannitol, in the presence or absence of liraglutide (10 or 100 nmol/l). Cell viability was assessed via an MTT assay and early apoptosis rates were assessed via flow cytometry. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in cell supernatants were measured. Bcl-2 associated X (Bax), B-cell lymphoma-2 (Bcl-2) and cleaved/full caspase-3 protein levels were determined via western blotting. The results revealed that liraglutide effectively inhibited the HG-induced increase in early apoptosis and MDA content and markedly increased SOD activity. Furthermore, liraglutide markedly inhibited the HG-induced increase in Bax and cleaved caspase-3 protein expression, and upregulated the expression of Bcl-2. The present study demonstrated that liraglutide suppressed HG-induced oxidative stress and cardiomyocyte apoptosis. Thus, the anti-apoptotic actions of liraglutide may be attributable, in part, to the inhibition of Bax, the inhibition of caspase-3 activation and the upregualtion of Bcl-2.

Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia.

Rationale Post-stroke hyperglycemia occurs in up to 50% of patients presenting with acute ischemic stroke. It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical outcomes. Insulin-based therapies have generally not been beneficial in treating post-stroke hyperglycemia as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worsen clinical outcomes. Exenatide may be a safer, simpler, and more effective alternative to insulin in acute ischemic stroke. Design TEXAIS is a three year, Phase 2, multi-center, prospective, randomized, open label, blinded end-point trial comparing exenatide to standard of care. It aims to recruit 528 patients with a primary end point of major neurological improvement at 7 days defined as a ≥8-point improvement in NIHSS score, or NIHSS 0-1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive exenatide 5 µg subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose. Conclusion TEXAIS aims to show that exenatide is safe and effective in the treatment of post-stroke hyperglycemia. It has been designed to be highly generalizable with an ability to enroll a large percentage of patients with acute ischemic stroke, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycemia. Trial registration: ClinicalTrials.gov/ANZCTR NTA1127.

Effects of glucagon-like peptide 1 analogs in combination with insulin on myocardial infarct size in rats with type 2 diabetes mellitus.

AIM: To evaluate the effects of glucagon-like peptide-1 analogs (GLP-1a) combined with insulin on myocardial ischemia-reperfusion injury in diabetic rats. METHODS: Type 2 diabetes mellitus (T2DM) was induced in male Wistar rats with streptozotocin (65 mg/kg) and verified using an oral glucose tolerance test. After anesthesia, the left coronary artery was occluded for 40 min followed by 80 min reperfusion. Blood glucose level was measured during surgery. Rats were randomized into six groups as follows: (1) control rats; (2) insulin (0.1 U/kg) treated rats prior to ischemia; (3) insulin (0.1 U/kg) treated rats at reperfusion; (4) GLP-1a (140 mg/kg) treated rats prior to ischemia; (5) GLP-1a (140 mg/kg) treated rats at reperfusion; and (6) rats treated with GLP-1a (140 mg/kg) prior to ischemia plus insulin (0.1 U/kg) at reperfusion. Myocardial area at risk and infarct size was measured planimetrically using Evans blue and triphenyltetrazolium chloride staining, respectively. RESULTS: There was no significant difference in the myocardial area at risk among groups. Insulin treatment before ischemia resulted in a significant increase in infarct size (34.7% ± 3.4% vs 18.6% ± 3.1% in the control rats, P < 0.05). Post-ischemic administration of insulin or GLP-1a had no effect on infarct size. However, pre-ischemic administration of GLP-1a reduced infarct size to 12% ± 2.2% (P < 0.05). The maximal infarct size reduction was observed in the group treated with GLP-1a prior to ischemia and insulin at reperfusion (8% ± 1.6%, P < 0.05 vs the control and GLP-1a alone treated groups). CONCLUSION: GLP-1a pre-administration results in myocardial infarct size reduction in rats with T2DM. These effects are maximal in rats treated with GLP-1a pre-ischemia plus insulin at reperfusion.

Discovery of a long-acting glucagon-like peptide-1 analog with enhanced aggregation propensity.

In the course of our search for new GLP-1 analogs, we screened a number of [Ser8]-GLP-1 analogs using the C-terminal helix 3 of the albumin binding domain 3 of protein G from bacterial Streptococcal G strain 148 (G148-ABD3) as appendage. Our efforts led to the discovery of [Ser8]-GLP-1 (7-35)-GVKALIDEILAA-NH2, peptide 6, as a long-acting GLP-1 analog with enhanced self-associated aggregation. Peptide 6 showed enhanced stability in rat and human plasma and an extended half-life of 5.4 h with good bioavailability in rats and subsequently prolonged therapeutic effects in diabetic mice. Analytical ultracentrifugation and TLC suggest that 6 remains oligomeric in the circulation, which accounts for its extended in vivo half-life. The present work shows the possible enhancement of medium-sized oligopeptides aggregation propensity and highlights the potential advantages of peptide aggregates for long-acting peptide drugs.

Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy: a systematic literature review and network meta-analysis.

OBJECTIVE: Treatment intensification with additional anti-diabetic agents is recommended in type 2 diabetes (T2D) for patients inadequately controlled on metformin monotherapy. The present network meta-analysis (NMA) evaluated comparative efficacy and safety of once-weekly semaglutide and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) in T2D patients inadequately controlled with metformin. METHODS: Randomized controlled trials with ≥20 weeks duration were searched in EMBASE, MEDLINE, and CENTRAL. Primary efficacy outcomes were: change from baseline in HbA1c, weight, systolic blood pressure (SBP), post-prandial blood glucose (PPG), and fasting blood glucose (FPG). Treatment effects at 26 (±4) weeks were compared using Bayesian NMAs. Meta-regression and sensitivity analysis were used to address the trial heterogeneity. RESULTS: Eight trials were found eligible for this NMA. Statistically significant reductions in HbA1c were observed with both 1.0 mg and 0.5 mg doses of once-weekly semaglutide when compared to SGLT-2is. The mean differences in change from baseline in HbA1c for once-weekly semaglutide 1.0 mg vs SGLT-2is ranged from -0.66% for canagliflozin 300 mg (95% Credible Intervals [CrI]: -0.82, -0.50%) to -1.11% for dapagliflozin 5 mg (95% CrI: -1.37, -0.85%). Once-weekly semaglutide 1.0 mg performed significantly better than all SGLT-2is of interest in reducing weight and improving FPG levels: however, SBP reduction was not statistically differentiable. Results of sensitivity analysis and meta-regressions aligned with base-case results. NMAs were not possible for PPG and safety outcomes, due to lack of data. CONCLUSION: Once-weekly semaglutide treatment is significantly better compared to SGLT-2is in achieving adequate glycemic control in T2D patients inadequately controlled with metformin monotherapy.

Safety and efficacy of liraglutide treatment in Japanese type 2 diabetes patients after acute myocardial infarction: A non-randomized interventional pilot trial.

BACKGROUND: Glucagon-like peptide 1 analogs are expected to exert a cardio-protective action due to their effective glucose-lowering action and favorable potency on multifactorial metabolic pathways. However, the safety and tolerability of liraglutide treatment after a recent acute coronary syndrome (ACS) in Japanese patients with type 2 diabetes mellitus (T2DM) have yet to be fully established. METHODS: A total of eight T2DM patients were recruited within 2 weeks after the onset of a ST-elevation myocardial infarction (STEMI) followed by successful percutaneous coronary intervention (PCI). The patients continued to receive liraglutide (up to 0.9mg once daily) for 24 weeks after the ACS combined with standard treatment such as a statin or beta-blocker. Changes in various metabolic parameters from pre-liraglutide treatment values were evaluated 24 weeks after liraglutide treatment, and included glycemic and lipid profiles, and cardiac systolic and diastolic function assessed by cardiac ultrasonography. RESULTS: Twenty-four weeks of treatment with liraglutide reduced body weight (67.0±5.8kg to 62.0±7.8kg, p=0.003) and HbA1c level (6.6±0.5% to 5.9±0.5%, p=0.006) and increased the level of 1,5-anhydroglucitol (12.8±6.9µg/mL to 18.7±8.2µg/mL, p=0.008) without development of hypoglycemia. There were no significant changes over 24 weeks in left ventricular systolic or diastolic function assessed by cardiac ultrasonography. No participant developed a major adverse cardiac event during the 24 weeks of liraglutide treatment, defined as cardiac death, new onset or recurrence of myocardial infarction, or needing target lesion revascularization. CONCLUSIONS: The present trial demonstrated that liraglutide treatment after onset of STEMI was well-tolerated in Japanese patients with T2DM over 24 weeks, and provided the first evidence to support clinical application of liraglutide treatment even just after ACS in Japanese high-risk T2DM patients.

Patient preference and tolerability of a DPP-4 inhibitor versus a GLP-1 analog in patients with type 2 diabetes mellitus inadequately controlled with metformin: a 24-week, randomized, multicenter, crossover study.

OBJECTIVE: The present study aimed to assess the patient preference and tolerability of oral dipeptidyl peptidase-4 inhibitor (vildagliptin) versus injectable glucagon-like peptide-1 analog (liraglutide) in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy. METHODS: This 24-week, randomized, multicenter, crossover study, patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy with hemoglobin A1c (HbA1c) ⩾6.5% and ⩽9.0% were randomized in a crossover manner to receive either vildagliptin/metformin single-pill combination (SPC) 50/1000 mg twice daily (n = 32) or 1.2 mg liraglutide as an add-on to metformin (0.6 mg [weeks 0-1] followed by 1.2 mg [weeks 2-12] once daily/1000 mg twice daily) (n = 30) for the first 12 weeks. RESULTS: Patient preference at week 24 was similar, with 51.7% (n = 31) patients preferring vildagliptin/metformin SPC compared with 48.3% (n = 29) preferring liraglutide as an add-on to metformin therapy (p = 0.449). Post hoc analyses showed that more elderly patients (⩾65 years) preferred vildagliptin (65%; n = 13) over liraglutide (35%; n = 7) therapy. Liraglutide was associated with better improvement in fasting plasma glucose (-21.5 mg/dl versus -3.4 mg/dl) and HbA1c (-0.5% versus -0.3%) levels. Fewer adverse events were reported with vildagliptin/metformin SPC (n = 16) compared with liraglutide as add-on to metformin treatment (n = 46). CONCLUSIONS: In this pilot study, although both vildagliptin and liraglutide therapies were preferred similarly by the patients and showed effective control of glycemia over 12 weeks, vildagliptin was associated with fewer adverse events and was preferred more by elderly patients.

Use of flash glucose-sensing technology in patients with type 2 diabetes treated with liraglutide combined with CSII: a pilot study

Glycemic variability (GV) may be linked to the development of diabetic complications by inducing inflammation, oxidative stress, and endothelial dysfunction. Flash glucose monitoring (FGM) provides a novel method of continuously monitoring interstitial glucose levels for up to 14 days. This study randomly assigned poorly controlled type 2 diabetes mellitus patients treated with metformin and multiple daily injections of insulin (n=60) to either continuous subcutaneous insulin infusion (CSII) treatment or CSII in combination with liraglutide (CSII+Lira) treatment for 14 days during hospitalization. GV was assessed using a FGM system; weight and cardiometabolic biomarkers were also evaluated. The coefficient of variation was significantly reduced in the CSII+Lira group (P<0.001), while no significant change was observed in the CSII group. The changes differed significantly between the two groups in mean amplitude of glycemic excursions (P=0.004), standard deviation (P=0.006), and the percentage of time in the target range (4-10 mmol/L, P=0.005 and >10 mmol/L, P=0.028). The changes in mean of daily differences, interquartile range, and percentage of time in hypoglycemia (<3.3 mmol/L) and hyperglycemia (>13.9 mmol/L) identified by FGM showed no difference. Treatment with liraglutide increased serum adiponectin [33.5 (3.5, 47.7) pg/mL, P=0.003] and heme oxygenase-1 levels [0.4 (-0.0, 1.8) ng/mL, P=0.001] and reduced serum leptin levels [-2.8 (3.9) pg/mL, P<0.001]. Adding the glucagon-like peptide-1 analog liraglutide improved GV, weight, and some cardiometabolic risk markers. The FGM system is, therefore, shown to be a novel and useful method for glucose monitoring.