Lira Group Research Articles

BJS-06 LAPAROSCOPIC INTRACORPOREAL RECTUS APONEUROPLASTY (LIRA) TECHNIQUE VERSUS INTRAPERITONEAL ONLAY MESH CLOSING THE DEFECT (IPOM PLUS) FOR VENTRAL HERNIA REPAIR: COMPARATIVE RESULTS AT MEDIUM FOLLOW-UP

Abstract Background The primary aim of this prospective study is to compare the postoperative outcomes between LIRA technique and IPOM plus, in terms of recurrence and bulging rates at one-year follow-up; the secondary aim is to compare the postoperative complications, seroma and pain at 30 days and one-year after surgery. Methods Patients with midline ventral hernia of 4–10 cm in width were included. Seromaand recurrence was evaluated by Computed tomography scan 1 month and 1 year after surgery. Pain was evaluated using the visual analogue scale score. Results Forty-five and forty-seven patients underwent LIRA and IPOM plus, respectively. Preoperatively, smoke habitus rate was statistically significantly higher in LIRA group (20 patients, 44.4%) in comparison to IPOM group (5 patients, 10.6%) (p=0.0001). Statistically significant differences were not considering the intraoperative variables. Two bulgings (4.4%) occurred in the LIRA group, while in the IPOM group occurred 10 bulgings (21.3%) and three recurrences (6.4%) (p=0.017 and p=0.085, respectively). Postoperatively, seven (15.6%, Clavien-Dindo I) and four complications (8.5%, two Clavien-Dindo I and two Clavien-Dindo III-b) occurred in the LIRA and in the IPOM group, respectively (p=0.298). One month after surgery, clinical seroma, occurred in five (11.1%) and eight patients (17%) in the LIRA and in the IPOM group, respectively (p=0.416). During follow-up, pain reduction occurred, without statistically significant differences. Conclusions LIRA showed lower bulging and recurrence rates in comparison to IPOM plus at one-year follow-up. Further prospective studies, with a large sample of patients and longer follow-up are required to draw definitive conclusions.

Liraglutide inhibits the progression of prediabetes in rats by reducing Raf-1 kinase inhibitor protein.

BackgroundThe cleavage product of Raf-1 kinase inhibitor protein (RKIP), hippocampal cholinergic neurostimulating peptide (HCNP) is involved in the promotion of insulin secretion. Studies have shown that liraglutide can inhibit the progression of prediabetes. This study aims to investigate whether the above effects of liraglutide are related to RKIP and HCNP.MethodsInsulin-1 (INS-1) cells were divided into control group (CON), HCNP group, and HCNP + darifenacin group (H-DAR). The three groups were cultured with Roswell Park Memorial Institute (RPMI) 1640, synthetic HCNP (50 pg/mL) and RPMI 1640, and HCNP + RPMI 1640 + darifenacin respectively. Subsequently, twelve 12- to 14-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were randomly divided into 2 groups: the placebo group (PBO) and the liraglutide treatment group (LIRA). Six Long Evans Tokushima Otsuka (LETO) rats were used as the control group (CON). The LIRA group was given liraglutide 200 µg/kg intraperitoneally twice a day. After 12 weeks, body weight, fasting blood glucose, 2 hours postprandial blood glucose, and insulin resistance index were recorded. Western blot was used to detect expression level of C-RKIP, N-RKIP, and extracellular signal-regulated kinase of phosphorylation (p-ERK). Real-time quantitative polymerase chain reaction (qRT-PCR) to detect pancreatic tissue choline acetyltransferase (ChAT) and M3 cholinergic receptor (M3R) gene expression levels.ResultsAt glucose concentrations of 5.6 and 16.7 mmol/L, the insulin content in the HCNP group was higher than that in the CON and H-DAR groups (all P<0.01). The body weight and fasting serum insulin (FINS) of rats in the PBO group were higher than those in the LIRA group and the CON group (P<0.01). The relative content of C-RKIP protein in the PBO group was higher than that in the LIRA and CON groups (P<0.01). The relative content of N-RKIP protein and p-ERK protein was lower than that in the LIRA and CON group (P<0.05 and P<0.01, respectively). ChAT and M3R gene expression levels in PBO group were lower than those in LIRA and CON group (P<0.01).ConclusionsLiraglutide promotes the production of HCNP, can increase ChAT activity, activate M3R, and further promote the secretion of insulin.

Comparison of insulin degludec (IDeg)/insulin Aspart (IAsp) co-formulation therapy twice-daily with free combination of GLP-1 receptor agonist liraglutide plus insulin degludec in Tochigi: IDEAL Trial.

We compared the efficacy and safety of insulin degludec/insulin aspart co-formulation (IDegAsp) twice-daily to a free combination of basal insulin degludec and GLP-1 receptor agonist liraglutide (IDeg+Lira) once-daily for patients with inadequately controlled type 2 diabetes on insulin therapy and oral antidiabetic drugs. Eligible patients were randomly allocated at a 1:1 ratio to receive either the once-daily dual injection of IDeg+Lira (n=24) or twice-daily single injection of IDegAsp (n=28). The primary endpoints were as follows: HbA1c changes over 52weeks of treatment and the percentage of participants achieving HbA1c<7.0% at week 52. After 52weeks, HbA1c decreased by 0.3% in the IDegAsp group and by 0.7% in the IDeg+Lira group. The HbA1c reduction was greater in the IDeg+Lira group than in the IDegAsp group. 19% of patients on IDegAsp versus 40% on IDeg+Lira achieved HbA1c<7.0%. Pre-breakfast and pre-dinner blood glucose at 52weeks were significantly lower in the IDeg+Lira group than in the IDegAsp group. The reduction in body mass index (BMI) was greater in the IDeg+Lira group than in the IDegAsp group throughout the study period. The confirmed hypoglycaemia rates were 1.32 and 0.69 per patient/year of exposure to IDegAsp and IDeg+Lira, respectively. In patients with inadequately controlled type 2 diabetes on insulin therapy and oral antidiabetic drugs, treatment with the once-daily dual injection of IDeg+Lira compared with the twice-daily single injection of IDegAsp showed no significant difference in glycaemic control but statistically superior weight loss.

2186-PUB: Comparison of Insulin Degludec (IDeg)/Insulin Aspart (IAsp) Coformulation Therapy Twice Daily with Free Combination of GLP-1 Receptor Agonist Liraglutide plus Insulin Degludec in Tochigi: IDEAL Trial

Objective: To compare the efficacy and safety of insulin degludec/insulin aspart co-formulation (IDegAsp) twice daily with free combination of basal insulin degludec and GLP-1 receptor agonist liraglutide once daily in type 2 diabetic patients inadequately controlled on insulin therapy with oral antidiabetic drugs. Subjects and Methods: Eligible patients were randomly allocated at a 1:1 ratio to receive once-daily IDeg plus liraglutide given separately (n=24) or twice daily IDegAsp (n=28). IDeg+Lira were separately administered before breakfast. The primary endpoints were the change in HbA1c from baseline to 52 weeks of treatment, as well as the percentage of participants achieving HbA1c less than 7.0% at 52 weeks. Results: After 52 weeks, HbA1c was decreased by 0.3% in the IDegAsp group and by 0.7% in the IDeg+Lira group. Reduction in HbA1c tended to be greater in the IDeg+Lira group than in the IDegAsp group (P=0.070). Nineteen percent of patients on IDegAsp versus 40% on IDeg+Lira achieved HbA1c&amp;lt;7.0%. Pre-breakfast and -dinner FBP at 52 weeks were significantly lower in the IDeg+Lira group than in the IDegAsp group. A reduction in body mass index (BMI) was greater in the IDeg+Lira group than in the IDegAsp group throughout the study period. In the IDeg+Lira group, mean insulin degludec and liraglutide at 52 weeks were 15.1 U and 0.84 mg, respectively. Conclusions: In patients with inadequately controlled type 2 diabetes on insulin and oral antidiabetic drugs, treatment with insulin degludec and liraglutide separately injections compared with IDegAsp co-formation twice daily showed no significant difference in glycemic control, but with somewhat greater reduction in HbA1c at 52 weeks, and a statistically superior weight loss. Disclosure Y. Aso: None. T. Jojima: None. S. Sakurai: None. T. Iijima: None. T. Tomaru: Research Support; Self; Merck &amp; Co., Inc., Teijin Pharma Limited. I. Usui: None.

Liraglutide improved inflammation via mediating IL-23/Th-17 pathway in obese diabetic mice with psoriasiform skin

Objectives The purpose of this study was to investigate the effect of liraglutide on obesity diabetic mice with psoriasiform skin inflammation. Methods Wild-type mice and db/db mice were randomly divided into five groups (n = 6): including the control group which received Vaseline, the imiquimod (IMQ)-induction group and the liraglutide-treatment group. The advanced treatment with liraglutide (0.3 mg/kg/d) for 4 weeks before IMQ induced psoriatic skin inflammation in the db/db + IMQ + Lira group. Basic parameters of diabetes, PASI, histopathology of skin, the expression of IL-17A, IL-23, IL-22, and TNF-α in the skin of back were measured. Results After IMQ induction, the psoriatic skin inflammation and pathological changes in the db/db + IMQ group were more serious than those in the WT + IMQ group. The glucose metabolism and insulin resistance of in the db/db + IMQ + Lira group were significantly improved, Psoriasis Area and Severity Index (PASI) was significantly reduced, and the protein and mRNA expressions of IL-23, IL-17, IL-22, and TNF-α in the back skin tissues were decreased. Conclusions Liraglutide can improve psoriasis skin lesions of obese diabetic mice, and the mechanism may be related to the inhibition of the expression of IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway.

Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice

In vivo beta-cell neogenesis may be one way to treat diabetes. We aimed to investigate the effect of glucagon-like peptide-1 (GLP-1) on beta-cell neogenesis in type 2 diabetes mellitus (T2DM). Male C57BL/6J mice, 6 wk old, were randomly divided into three groups: Control, T2DM, and T2DM + Lira. T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin (40 mg/kg/d for 3 d). At 8 wk after streptozotocin injection, T2DM + Lira group was injected intraperitoneally with GLP-1 analog liraglutide (0.8 mg/kg/d) for 4 wk. Apparently for the first time, we report the appearance of a primitive bud connected to pancreas in all adult mice from each group. The primitive bud was characterized by scattered single monohormonal cells expressing insulin, GLP-1, somatostatin, or pancreatic polypeptide, and four-hormonal cells, but no acinar cells and ductal epithelial cells. Monohormonal cells in it were small, newborn, immature cells that rapidly proliferated and expressed cell markers indicative of immaturity. In parallel, Ngn3+ endocrine progenitors and Nestin+ cells existed in the primitive bud. Liraglutide facilitated neogenesis and rapid growth of acinar cells, pancreatic ducts, and blood vessels in the primitive bud. Meanwhile, scattered hormonal cells aggregated into cell clusters and grew into larger islets; polyhormonal cells differentiated into monohormonal cells. Extensive growth of exocrine and endocrine glands resulted in the neogenesis of immature pancreatic lobes in adult mice of T2DM + Lira group. Contrary to predominant acinar cells in mature pancreatic lobes, there were still a substantial number of mesenchymal cells around acinar cells in immature pancreatic lobes, which resulted in the loose appearance. Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud, which liraglutide facilitates in adult T2DM mice. To our knowledge, this is the first time such a phenomenon has been reported.

113-LB: Effects of Liraglutide and Empagliflozin Add-On to Insulin Therapy in Patients with Type 2 Diabetes: ELLENA-IT, a Randomized Controlled Study

Liraglutide (Lira) and empagliflozin (Empa) have been reported to suppress cardiovascular events in large-scale clinical trials. However, reports of their long-term combined use with insulin therapy or direct comparisons of both drugs are limited. This open-label, parallel-group, randomized controlled trial aimed to compare the effects of Lira and Empa used in combination with insulin therapy in patients with type 2 diabetes (T2D). Adult outpatients with T2D undergoing stable insulin therapy with HbA1c level of 7.0%-9.5% were eligible for participation. Subjects received 0.9 mg/day Lira or 10 mg/day Empa for 24 weeks. The primary endpoint was the change in HbA1c levels from baseline to week 24. Body composition was assessed using the dual energy X-ray absorptiometry method (UMIN-CTR 000027614). Overall, 66 insulin-treated patients with T2D were randomized to receive Lira or Empa; 57 patients completed 24 weeks of weekly administration of Lira (n = 29) or Empa (n = 28). HbA1c and glycated albumin (GA) levels were lower in the Lira group than in the Empa group (HbA1c, Lira, −1.23 ± 0.85% vs. Empa, −0.32 ± 0.68%, p &amp;lt; 0.001; GA, Lira, −4.3 ± 3.1% vs. Empa, −2.2 ± 2.9%, p = 0.01). There was no difference between the two groups in terms of change in body weight (∆BW: Lira, −1.4 ± 1.9 kg vs. Empa, −1.4 ± 1.9 kg, p = 0.97) or in body fat mass/lean tissue mass. There was no difference between the groups in terms of change in urinary albumin excretion [∆UAE (median, IQR): Lira, −6.2 (−63.5, −10.1) mg/g-creatinine vs. Empa, −20.4 (−69.7, −2.0) mg/g-creatinine, p = 0.28]. There was no significant difference in the frequency of hypoglycemia between the groups over 24 weeks (p = 0.46). In conclusion, the addition of Lira to ongoing insulin therapy significantly reduced HbA1c and GA levels to a larger extent than the addition of Empa in patients with inadequately controlled T2D. Disclosure H. Nakaguchi: None. Y. Kondo: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.

The osteogenic effect of liraglutide involves enhanced mitochondrial biogenesis in osteoblasts

Liraglutide (Lira), a long-acting glucagon-like peptide 1 receptor (GLP1R) agonist reduces glycosylated hemoglobin in type 2 diabetes mellitus patients. Lira is reported to have bone conserving effect in ovariectomized (OVX) rats. Here, we investigated the osteoanabolic effect of Lira and studied the underlying mechanism. In established osteopenic OVX rats, Lira completely restored bone mass and strength comparable to parathyroid hormone (PTH 1-34). Body mass index normalized bone mineral density of Lira was higher than PTH. The serum levels of osteogenic surrogate pro-collagen type 1 N-terminal pro-peptide (P1NP) and surface referent bone formation parameters were comparable between Lira and PTH. GLP1R, adiponectin receptor 1 (AdipoR1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) levels in bones were downregulated in the OVX group but restored in the Lira group whereas PTH had no effect. In cultured osteoblasts, Lira time-dependently increased GLP1R, AdipoR1 and PGC1α expression. In osteoblasts, Lira rapidly phosphorylated AMP-dependent protein kinase (AMPK), the cellular energy sensor. Exendin 3, a selective GLP1R antagonist and PKA inhibitor H89 blocked Lira-induced increases in osteoblast differentiation, and expression levels of AdipoR1 and PGC1α. Furthermore, H89 inhibited Lira-induced phosphorylation of AMPK and dorsomorphin, an AMPK inhibitor blocked the Lira-induced increases in osteoblast differentiation and AdipoR1 and PGC1α levels. Lira increased mitochondrial number, respiratory proteins and respiration in osteoblasts in vitro and in vivo, and blocking mitochondrial respiration mitigated Lira-induced osteoblast differentiation. Taken together, our data show that Lira has a strong osteoanabolic effect which involves upregulation of mitochondrial function.

Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease.

Type 2 diabetes mellitus (T2DM) complicated with non-alcoholic fatty liver disease (NAFLD) is difficult to treat. The present study explored the efficacy of (liraglutide) Lira in treating T2DM complicated with NAFLD. A total of 127 patients suffering from T2DM complicated with NAFLD were enrolled in the present study, and randomly assigned to a Lira group (liraglutide injection: 0.6–1.2 mg/day, 12 weeks, n=52) or a Metformin (Met) group (oral metformin: 1000–1500 mg/day, 12 weeks, n=75). During the treatment phase, the values for fasting plasma glucose (FPG), 2 h plasma glucose (2hPG), glycated hemoglobin (HbA1c), aspartate aminotransferase (AST)/alanine aminotransferase (ALT), and adiponectin (APN) decreased in both the Lira and Met groups, and the levels of Δ2hPG, ΔAST/ALT, and ΔAPN in the Lira group were significantly lower than those in the Met group. The values for total cholesterol (TC), triglycerides (TG), low-and high-density lipoproteins (LDL and HDL), ALT, AST, weight, body mass index (BMI), waist to hip ratio (WHR), and C-reactive protein were markedly increased in both groups, and levels of ΔAST, ΔALT, Δweight, ΔBMI, ΔWHR, and ΔCRP (C-reactive protein) in the Lira group were significantly higher than those in the Met group. An analysis of treatment efficacy showed that liraglutide was better than metformin in its ability to significantly decrease the ALT levels in patients with combined T2DM and NAFLD. Furthermore, liraglutide was more effective than metformin at ameliorating the severity of T2DM complicated with NAFLD, and produced its effects by alleviating liver inflammation and improving liver function.

Liraglutide improves myocardial fibrosis after myocardial infarction through inhibition of CTGF by activating cAMP in mice.

To study the role and mechanism of liraglutide in myocardial fibrosis after myocardial infarction (MI). A total of 72 C57/BL male mice were randomly divided into sham operation group (Sham group), myocardial infarction group (MI group), and liraglutide intervention group (Lira group). The left anterior descending coronary artery (LAD) of the mice in MI group and Lira group was ligated to establish the MI model. One week after the operation, the mice in Lira group were intraperitoneally injected with 100 μg/kg of liraglutide once a day for 4 weeks. The mice in Sham group and MI group were injected with the equal volume of normal saline. At the 5th week after the operation, the cardiac morphologic indexes and cardiac function indexes were measured by echocardiography. After an ultrasound, the heart specimens of the mice were immediately harvested by thoracotomy, and histomorphological hematoxylin-eosin (HE) staining, collagen fiber Masson staining, and immunohistochemical staining were performed. The infarction zone and the non-infarction zone were isolated from another heart specimen; the cyclic adenosine monophosphate (cAMP) and hydroxyproline content were determined; and the expression levels of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) were detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting. Liraglutide improved the cardiac function of mice after myocardial infarction. Liraglutide improved the myocardial fibrosis in mice after myocardial infarction. Liraglutide increased cAMP in myocardial cells of mice after myocardial infarction. Liraglutide did not change the TGF-β1 expressions while reduced the CTGF expressions in infarct and non-infarct area of mice after myocardial infarction. Liraglutide, through increasing the level of cAMP, could decrease the deposition of collagen fibers in myocardial tissues of mice after MI, reduce the degree of infiltration of collagen fibers in the infarction zone into the myocardium in the non-infarction zone and inhibit the adverse ventricular remodeling in the non-infarction zone, thus improving the cardiac function after MI.

Actions of Liraglutide on Vascular Endothelial Cells Play a Central Role in the Suppression of Atherosclerosis in Diabetic Mice

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to exert direct anti-atherosclerotic effects through multiple actions on various cells. However, it is unclear which action is crucial. We investigated the role of the anti-atherogenic effects of liraglutide (Lira) on vascular endothelial cells (VECs) in vivo. Methods: Streptozotocin-induced diabetic apolipoprotein E-null mice (male, 20 weeks) were randomly assigned to treatment with saline or Lira (17 nmol/kg/d) and underwent femoral artery (FA) wire injury to remove VECs. Thioglycolate-exudated peritoneal macrophages and vascular samples (aorta, FA, and right brachiocephalic artery [RBCA]) were collected 4 weeks after treatment. Results: In the Lira group, active GLP-1 levels were significantly higher (4.7 ± 1.1 vs. 2.8 ± 0.3 pmol/L) and levels of HbA1c (8.9 ± 0.4% vs. 8.3 ± 0.5%) and total cholesterol (492 ± 8 vs. 457 ± 19 mg/dL) were significantly lower than in controls. Lira significantly reduced the atherosclerotic plaque (oil red O [ORO]-stained area) on the surface of the whole aorta by 36% and the plaque volume and intraplaque macrophage infiltration in the aortic root by 56% and 55%, respectively. Additionally, Lira suppressed the expression of inflammatory cytokines in macrophages by 40-45% (p &amp;lt; 0.05) and the expression of inflammatory cytokines in the RBCAs, which are prone to lesion, plaque formation, and rupture. In FA, no plaque was observed in uninjured lesions, while severe plaque formation occurred in injured lesions. In contrast, Lira failed to suppress plaque volume or neointimal thickening in FAs where the VECs were removed (ORO-stained area/vascular wall area: 0.51 ± 0.vs. 0.55 ± 0.08, neointimal area/medial area: 2.4 ± 1.2 vs. 2.6 ± 0.7), indicating that Lira cannot suppress atherosclerosis independent of VECs. Conclusions: Of the multiple actions on various cells, VECs play a central role in the suppression of atherosclerosis mediated by Lira. Disclosure M. Hiromura: None. Y. Mori: None. M. Koshibu: None. H. Kushima: None. K. Kohashi: None. M. Terasaki: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca.

Protective effects of combining human umbilical cord mesenchymal stem cells and glucagon like peptide-1 receptor agonist on the islet inflammatory injury in rat model of type 2 diabetes mellitus

Objective To investigate the effects and mechanism of combining human umbilical cord mesenchymal stem cells and liraglutide on the islet function of type 2 diabetes mellitus SD rats. Method Type 2 diabetes mellitus rats were established by giving high carbonhydrate and fat diet for 4 weeks to SD rats, and then 30 mg/kg streptozotocin was injected intraperitoneally. Type 2 diabetes mellitus rats were randomly divided into four groups according the table of random number: Type 2 diabetes mellitus group(T2DM group), umbilical cord mesenchymal stem cells treatment group(T2DM+ UC-MSCs group), liraglutide treatment group(T2DM+ LIRA group)and liraglutide combined umbilical cord mesenchymal stem cells treatment group(T2DM+ LIRA+ UC-MSCs group). Each group included 10 rats, and rats were given the appropriate drug therapy for 8 weeks. HbA1C, insulin, C-peptide, and glucagon levels were measured. The expressions of insulin and glucagon in pancreas tissue were measured through immunohistochemistry analysis. The apoptosis status of the islet cells in pancreas tissue were evaluated through TUNEL. And the expressions of the nuclear factor-κB(NF-κB)and Toll-like recpter 4(TLR4)protein in pancreas tissue were determined by Western blot. Result After 8 weeks treatment, compared with T2DM group, HbA1C of T2DM+ UC-MSCs group、T2DM+ LIRA group and T2DM+ LIRA+ UC-MSCs group decreased significantly, and it was lowest in T2DM+ LIRA+ UC-MSCs group [(9.1±0.4)% vs (7.2±0.4)%, (3.9±0.3)%, (3.1±0.3)%, respectively, P <0.05]. The insulin and C-peptide of T2DM+ UC-MSC group were significantly increased(P<0.05). The insulin and C-peptide were increased while the glucagon was significantly decreased in T2DM+ LIRA group and T2DM+ LIRA+ UC-MSCs group(P<0.05). The ratio of insulin positive area in pancreas tissue was obviously rised, while the ratio of glucagon positive area in pancreas tissue was clearly descended in T2DM+ LIRA+ UC-MSCs group. And the same difference in valuating islet cells apoptosis by TUNEL could be observed(P<0.05). The expression of NF-κB and TLR4 protein in pancreas tissue of T2DM+ LIRA+ UC-MSCs group were the least among the four groups [(0.75±0.10) vs(0.60±0.08), (0.47±0.08), (0.31±0.04), P<0.05]and [(1.24±0.12) vs (0.93±0.10), (0.95±0.09), (0.74±0.07), P<0.05]. Conclusion The combined treatment of liraglutide with umbilical cord mesenchymal stem cells is superior over a single treatment of liraglutide or umbilical cord mesenchymal stem cells in improving the islet function in type 2 diabetes mellitus models, which may be related to the down modulating the TLR4/NF-κB inflammatory signaling pathway. (Chin J Endocrinol Metab, 2016, 32: 1003-1009) Key words: Diabetes mellitus, type 2; Liraglutide; Mesenchymal stem cells; Islet function; TLR4/NF-κB pathway

Effects of Liraglutide Combined with Short-Term Continuous Subcutaneous Insulin Infusion on Glycemic Control and Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A Pilot Study.

The objective of this paper is to investigate the effects of liraglutide in combination with short-term continuous subcutaneous insulin infusion (CSII) therapy on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Thirty-nine eligible newly diagnosed T2DM patients were recruited and randomized to receive either of two therapies: short-term CSII alone (CSII alone group) or CSII in combination with liraglutide (CSII + Lira group) for 12 weeks. Blood glucose control, homeostasis model assessment (HOMA) indices, and acute insulin response (AIR) were compared between the two groups. The patients in CSII + Lira group achieved euglycemia with equivalent insulin dosage in shorter time (1 (0) versus 2 (3) days, P = 0.039). HbA1c at the end of study was comparable between two groups (6.3 ± 0.7% versus 6.0 ± 0.5%, for CSII alone group and CSII + Lira group, resp., P = 0.325). The increment of AIR was higher in CSII + Lira group (177.58 (351.57) μU·min/mL versus 58.15 (51.30) μU·min/mL, P < 0.001). However, after stopping liraglutide, its effect on beta cell function disappeared completely. Liraglutide combined with short-term CSII was effective in further improving beta cell function, but the beneficial effects did not sustain after suspension of the therapy.

19. Efficacy and Safety of Liraglutide Added to Insulin in Type 1 Diabetes: The LIRA-1 Trial (277-OR)

Weight gain and hypoglycemia are common side effects to insulin therapy in type 1 diabetes (T1D). The combination of insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy has proven effective in reducing weight gain and insulin dose in type 2 diabetes. This 26-week trial is the first randomized, double-blinded, placebo controlled study to evaluate efficacy and safety of GLP-1RA treatment in poorly controlled, overweight patients with T1D. One hundred patients with T1D, HbA1c > 64 mmol/mol and BMI > 25 kg/m2, were randomized to liraglutide 1.8 mg (LIRA) or placebo added to intensive insulin therapy. Mean baseline characteristics were similar between groups (LIRA; placebo ± SD) age 47 ± 13; 49 ± 12 years, HbA1c 73 ± 8;73 ± 8 mmol/mol, daily insulin dose 75 ± 30; 74 ± 26 IU/day and body weight 93.4 ± 14.2; 94.0 ± 12.5 kg except diabetes duration 20 ± 12; 25 ±12 years. After 12 weeks, LIRA reduced HbA1c, body weight and daily insulin dose compared with placebo. At end of treatment no difference in HbA1c between groups was found. Body weight and daily insulin dose remained reduced in the LIRA group. Frequency of hypoglycemia did not differ between groups. Nausea occurred more frequently with LIRA than placebo (48% vs. 7%). In conclusion, LIRA added to insulin treatment reduced body weight and daily insulin dose in overweight, poorly controlled patients with T1D, but did not improve HbA1c compared with placebo at end of treatment.

The efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes with glycosylated hemoglobin A1c > 9

To evaluate the efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes mellitus (T2DM) with glycosylated hemoglobin A1c (HbA1c) > 9%. This was an open-labelled, randomized, parallel-group, treat-to-target trial. Newly diagnosed T2DM patients with HbA1c > 9% were enrolled. These patients were treated with metformin with repaglinide and randomized to receive once-daily liraglutide (LIRA, n=25) or the insulin glargine (IGla, n=24) at bedtime. Efficacy and safety were assessed and compared after 18-month treatment. (1) Compared with the baseline, patients with LIRA had significantly reduced mean body weight,BMI and waist circumference (P < 0.01), whereas, the above indexes were increased (P < 0.01) in patients treated with IGla. (2) After 18 months of treatment, fasting plasma glucose (FPG), 2-hour plasma glucose after a 75g oral glucose load (2hPG) and HbA1c were significantly improved in all patients (P < 0.01), with 2hPG, mean blood glucose (MBG), the largest amplitude of glycemic excursions (LAGE), mean amplitude of glycemic excursions (MAGE) were significantly lower in LIRA group than in IGla group (all P < 0.05). (3) HOMA-IR decreased in both groups (P < 0.05). However, ΔI30/ΔG30, AUCCP180 and Matsuda index were only significantly increased in patients treated with LIRA (respectively, 4.88 ± 1.55 vs 7.60±1.91, 9.23 ± 2.66 vs 13.18 ± 2.72, 39.28 ± 20.35 vs 54.64 ± 23.34, all P < 0.01), while HOMA-IR reduced (4.41 ± 1.58 vs 3.52 ± 1.44, P < 0.05). But in IGla group only HOMA-IR was reduced (4.92 ± 1.84 vs 4.57 ± 1.80, P < 0.05). The index of ΔI30/ΔG30, AUCCP180 and Matsuda index in LIRA group are higher than those of indexes in IGla group(respectively, 7.60 ± 1.91 vs 4.18 ± 1.00, 13.18 ± 2.72 vs 10.53 ± 2.68,54.64 ± 23.34 vs 41.65 ± 17.84, all P < 0.05), while HOMA-IR is lower (3.52 ± 1.44 vs 4.57 ± 1.80, P< 0.05). (4) The rate of HbA1c ≤ 6.5% and the dosages of oral anti-diabetic drugs in LIRA group were significantly better than that in IGla group. (5) No significant differences were observed in hypoglycemic episodes and adverse events between two groups. It seems that liraglutide is superior to insulin glargine in newly diagnosed T2DM patients with HbA1c > 9% in improving beta-cell function, insulin sensitivity and glucose homeostasis.

Significantly Better Glycemic Control and Weight Reduction with Liraglutide, a Once-daily Human GLP-1 Analog, Compared with Insulin Glargine: All as Add-on to Metformin and a Sulfonylurea in Type 2 Diabetes.

A 26-week, randomized trial compared the efficacy and safety of liraglutide (lira; 1.8 mg, QD), lira placebo (plb) and open label insulin glargine (glar), all as add-on to metformin (met; 1 mg, BID) and glimepiride (glim; 2–4 mg QD). 581 subjects were randomized (mean age 57.5±9.9; mean BMI 30.5±5.3 kg/m2 mean HbA1c 8.2±0.9 %). Lira+met+glim reduced HbA1c more than glarg and plb in combination with met and glim (ANCOVA, p=0.0015; p<0.0001) and more of the subjects in the lira group reached HbA1c ≤6.5% (p<0.0001). Estimated weight difference between lira and glar groups was −3.4 kg (p<0.0001) and −1.4 kg between lira and plb groups (p=0.0001). Glar was individually titrated according to a patient-driven algorithm, and the average dose of glar was 24 IU/day at end of trial. Most common AEs in the lira group were GI disorders (mainly nausea). Nausea occurred in ~15% of subjects in the lira group, but was transient. Frequency of minor hypoglycemic episodes (<56 mg/dL) were similar for the lira and glar groups and more frequent than in the plb group. Five subjects reported major hypoglycemic events in the lira group (only one required medical assistance; none resulted in coma or seizure). Presence of lira antibodies was 9.8%. Lira+met and a sulfonylurea (SU) was generally well tolerated and statistically significantly improved glycemic control, and reduced body weight in comparison to met and an SU alone and to glar added to met and an SU. Tabled 1 lira1.8+met+glim plb+met+glim glar+met+glim Final HbA1c, % (SE)Change HbA1c, % (SE) 7.0 (1.0)-1.33 (0.09)*^ 8.1 (1.3)-0.24 (0.11) 7.2 (0.9)-1.09 (0.09) % HbA1c S6.5% 37.1*^ 10.9 23.6 Weight change, kg (SE) −1.81 (0.33)*^ −0.42 (0.39) 1.62 (0.33) Final FPG, mg/dL (SE)Change FPG, mg/dL 137.7 (39.3)-27.92* 180.2 (51.4)9.56 133.2 (38.1)-32.16 % reporting minor hypo events 27.4 16.7 28.9 % reporting nausea 13.9 3.5 1.3 Week 26 FPG titration targets reached: 100 mg/dL (% subjects)120 mg/dL (% subjects) 47 (20.26)93 (40.09) *Statistically significant compared to: *met+glim; ^glar+met+glim Open table in a new tab *Statistically significant compared to: *met+glim; ^glar+met+glim