Combination Of Liraglutide Research Articles

Synergistic anti-tumor effects of Liraglutide, a glucagon-like peptide-1 receptor agonist, along with Docetaxel on LNCaP prostate cancer cell line

Docetaxel is a first line chemotherapy agent, which stabilizes microtubules in metastatic prostate cancer (PCa). Resistance to Docetaxel and its side effects remain as obstacle for its efficacy in monotherapy. Recently, combination with novel adjuvants have been emerged as a beneficial alternative strategy, which targets multiple important pathways and also requires lower therapeutic dosage, proposing as a strategy to overcome drug resistance. This study investigated whether Liraglutide, a Glucagon Like Peptide-1 Receptor agonist, can reinforce the effect of Docetaxel on LNCaP prostate cancer cell line.Cells were treated by Liraglutide and Docetaxel, alone and in combination. Cytotoxicity was evaluated by MTT assay. Compusyn and Combenefit softwares were used in order to evaluate synergistic efficacy. Apoptosis was determined by Cell cycle analysis and Annexin-V/Propidium iodide staining through flow cytometry. However, the mRNA level of pro-apoptotic gene “Bax” and anti-apoptotic “Bcl-2” were evaluated by quantitative Real-Time PCR. Also, phosphorylation level of ERK1/2 and AKT proteins was investigated by western blotting technique.The results showed that Docetaxel and Liraglutide decreased the viability of LNCaP cells synergistically, caused cell cycle arrest and induced apoptosis potentially. The key proteins’ evaluation in ERK/MAPK and AKT/PI3K pathways revealed a significant reduction in phosphorylation level of cells exposed to combination of drugs.Our results suggest that, the combination of Liraglutide and Docetaxel could be considered as a potent strategy in enhancing the efficacy of treatment, decreasing the Docetaxel therapeutic dose and thereby lowering systemic toxicities and resistances.

Postpartum treatment with liraglutide in combination with metformin versus metformin monotherapy to improve metabolic status and reduce body weight in overweight/obese women with recent gestational diabetes: A double-blind, randomized, placebo-controlled study

BackgroundGestational diabetes (GDM) imparts a high risk of developing diabetes postpartum. Insulin resistance appears to be the major contributor. Liraglutide, a glucagon-like peptide-1 analogue, improves peripheral glucose disposal and reduces body weight. We evaluated whether liraglutide in combination with metformin (MET-LIRA) is more effective than metformin monotherapy (MET-P) in improving insulin action and reducing body weight in overweight prior GDM (pGDM) women. MethodsWomen (n = 153; body mass index (BMI) ≥25 kg/m2; 18–45 y; GDM within 12 months) with metabolic abnormalities were randomized to MET-LIRA (MET-2000 mg, LIRA 1.8 mg SC QD) or MET-P (MET-2000 mg, Placebo QD). Study visits at baseline, 36–40, 56–60 and 80–84 weeks included body weight (BW), BMI, waist circumference and waist-to-height ratio measures. Oral glucose tolerance tests (OGTTs) were performed to assess glycemia, mean blood glucose (MBG), lipids, and compute insulin sensitivity and secretion measures. FindingsSeventy-two (47%) participants completed the study. MET-LIRA therapy was significantly better in improving MBG and insulin sensitivity indices [SIOGTT MET-LIRA from 4.6 (3.2) to 5.9 (2.9) vs. MET-P 5.5 (3.0) to 5.4 (3.2)] and reducing BW and central adiposity [BMI MET-LIRA from 37.2 (8.3) to 33.8 (5.2) vs MET-P 33.8(5.2) to 32.8(6)]. MET–LIRA therapy but not MET-P decreased triglycerides (TRG) and TRG/high density lipoprotein cholesterol (HDL-C) ratios. InterpretationMET-LIRA treatment demonstrated superior efficacy in correcting the metabolic status of pGDM women over 84 weeks of therapy. The addition of liraglutide to metformin therapy resulted in a more dramatic decrease in BW and central adiposity than metformin alone. FundationSupported by an unrestricted investigator initiated grant from Novo Nordisk, Inc. awarded to K.E.H. Meeting presentationThe results from preliminary analyses of this study were presented at 76th meeting of the American Diabetes Association, June 10–14, 2016 New Orleans, LA, and 77th meeting of the American Diabetes Association, June 9–12, 2017San Diego, CA.

RETRACTED ARTICLE: Effect of hCMSCs and liraglutide combination in ALI through cAMP/PKAc/β-catenin signaling pathway

BackgroundALI/ARDS is the major cause of acute respiratory failure in critically ill patients. As human chorionic villi-derived MSCs (hCMSCs) could attenuate ALI in the airway injury model, and liraglutide, glucagon-like peptide 1 (GLP-1) agonist, possesses anti-inflammatory and proliferation promotion functions, we proposed to probe the potential combinatory effect of hCMSCs and liraglutide on ALI.MethodsWe examined the time- and dose-dependent manner of GLP-1R, SPC, Ang-1, and FGF-10 with LPS via western blot and qRT-PCR. Western blot and chromatin immunoprecipitation assay detected the effects of liraglutide on GLP-1R, SPC, Ang-1, and FGF-10 through PKAc/β-catenin pathway and cAMP pathway. In the ALI animal model, we detected the effects of MSC and liraglutide combination on ALI symptoms by H&E staining, western blot, ELISA assays, calculating wet-to-dry ratio of the lung tissue, and counting neutrophils, leukocytes, and macrophages in mouse bronchoalveolar lavage fluid (BALF).ResultsThe data demonstrated that LPS reduced hCMSC proliferation and GLP-1R, SPC, Ang-1, and FGF-10 levels in a dose- and time-dependent manner. Liraglutide significantly dampened the reduction of GLP-1R, SPC, Ang-1, and FGF-10 and reversed the effect of LPS on hCMSCs, which could be regulated by GLP-1R and its downstream cAMP/PKAc/β-catenin-TCF4 signaling. Combination of hCMSCs with liraglutide showed more therapeutic efficacy than liraglutide alone in reducing LPS-induced ALI in the animal model.ConclusionsThese results reveal that the combination of hCMSCs and liraglutide might be an effective strategy for ALI treatment.

Effects of Liraglutide and Behavioral Weight Loss on Food Cravings, Eating Behaviors, and Eating Disorder Psychopathology.

This exploratory analysis examined the effects of intensive behavioral therapy (IBT) for obesity ("IBT-alone"), IBT plus liraglutide 3.0 mg/d ("IBT-liraglutide"), and IBT plus liraglutide 3.0 mg/d plus 12 weeks of a portion-controlled diet that provided 1,000 to 1,200 kcal/d ("Multicomponent") on changes in food cravings, eating behaviors, and eating disorder psychopathology at 24 and 52 weeks post randomization. Adults with obesity (mean age = 47.6 ± 11.8 years and BMI = 38.4 ± 4.9 kg/m2 ; 79.3% female; 54.0% non-Hispanic white; 44.7% black) were randomized to IBT-alone (n = 50), IBT-liraglutide (n = 50), or Multicomponent (n = 50). At weeks 24 and 52, liraglutide-treated groups reported significantly larger declines in weight concern relative to the IBT-alone group. At week 24, compared with IBT-alone, liraglutide-treated groups reported significantly greater reductions in dietary disinhibition, global eating disorder psychopathology, and shape concern. TheMulticomponent grouphad significantly greater reductions in binge eating at week 24 relative tothe IBT-alonegroup. However, differences among groups were no longer significant at week 52. Groups did not differ in total food cravings at week 24 or 52. The combination of liraglutide and IBT was associated with greater short-term improvements in dietary disinhibition, global eating disorder psychopathology, and shape concern than IBT alone.

Long-term efficacy and safety of combined insulin and glucagon-like peptide-1 therapy: Evidence from the LEADER trial.

AimGlucagon‐like peptide‐1 receptor agonist (GLP‐1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long‐term data are lacking. The aim was to assess the long‐term efficacy of the GLP‐1RA liraglutide in subgroups by insulin use in the LEADER trial.Materials and MethodsLEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal‐only insulin, other insulin or no insulin). Insulin was a non‐random treatment allocation as part of standard of care therapy.ResultsAt baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal‐only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no‐insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal‐only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal‐only and no‐insulin subgroups.ConclusionsIn patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.

Liraglutide in combination with metformin may improve the atherogenic lipid profile and decrease C-reactive protein level in statin treated obese patients with coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial

Background and aimsAtherosclerosis in obesity and type 2 diabetes (T2DM) is associated with low-grade inflammation (LGI) and dyslipidemia, where especially small, dense lipoprotein particles are atherogenic. The glucagon-like peptide-1 receptor agonist, liraglutide, reduces cardiovascular events by poorly understood mechanisms. We investigated the effect of liraglutide combined with metformin on LGI and lipoprotein density profiles in patients with stable coronary artery disease (CAD) and newly diagnosed T2DM. MethodsWe conducted a randomized, double-blind, placebo-controlled, cross-over trial over a 12 + 12-week period, with ≥2-week wash-out. Intervention: liraglutide/metformin vs. placebo/metformin. Lipoproteins were separated by continuous density gradient ultracentrifugation, and LDL divided into five subfractions between 226 and 270 Å, considering particle size ≤255 Å as the atherogenic pattern. Plasma C-reactive protein and tumor necrosis factor-α were assessed by the enzyme-linked immunosorbent-assay. Results28 out of 41 randomized patients completed all visits. Intention-to-treat analysis was performed but one patient had statin dosage and was excluded from the analysis. 95% of the patients were on statin therapy. Overall, liraglutide did not affect lipid subfractions or markers of LGI compared to placebo. The combination of liraglutide and metformin reduced the total LDL subfractions, primarily by reducing the most atherogenic subfraction LDL5, and reduced CRP but not TNF-α. Explorative analyses suggested that the subfraction LDL5 during the wash-out period rebounded significantly at least in a per-protocol analysis of the sub-group of patients starting the liraglutide therapy. ConclusionsIn patients with CAD and newly diagnosed T2DM on stable statin therapy, liraglutide combined with metformin may improve the atherogenic LDL lipid profile and CRP.

2130-P: Imeglimin Modulated ER Stress to Prevent ß-Cell Apoptosis Induced by High Glucose or Thapsigargin

Imeglimin, a tetrahydrotriazine anti-hyperglycemic agent, is thought to have effects on mitochondrial function of the liver, skeletal muscle, and pancreatic β-cells. However, the molecular mechanisms of imeglimin action have been still unclear. Treatment of mouse islets with 1.0 mM imeglimin significantly increased insulin release in response to glucose (2.1-fold, p&amp;lt;0.01 at 11.1 mM glucose; 1.9-fold, p&amp;lt;0.05 at 16.7 mM glucose, compared to 3.9 mM glucose). Treatment with a combination of liraglutide (100 nM) and imeglimin did not show an additional increase in insulin secretion compared to the treatment with liraglutide alone. Liraglutide and imeglimin significantly increased EdU-incorporated proliferating β-cells in the islets under 11.1 mM glucose (1.02% in vehicle control; 2.21% in liraglutide, p&amp;lt;0.01 vs. vehicle; 1.46% in 1.0 mM imeglimin, p&amp;lt;0.01 vs. vehicle). Imeglimin prevented β-cell apoptosis induced by high glucose (32% of control in imeglimin, p&amp;lt;0.01; 57% of control in liraglutide, p=0.068). We conducted gene expression microarray analysis of islets treated with imeglimin under high glucose and some ER stress-related gene expression were altered by imeglimin. Then, we examined the effects of imeglimin on ER stress-induced β-cell apoptosis in mouse islets. Imeglimin significantly reduced β-cell apoptosis induced by thapsigargin at 5.6 mM glucose (29% of thapsigargin, p&amp;lt;0.01). Imeglimin further upregulated the expression of C/EBP homologous protein (CHOP) under thapsigargin treatment and tended to decrease phosphorylation of eIF2-α. We also confirmed that imeglimin improved β-cell apoptosis induced by high glucose or thapsigargin in human islets. Collectively, imeglimin prevented β-cell apoptosis induced by high glucose or thapsigargin, in addition to increase in insulin secretion and β-cell proliferation. Imeglimin seemed to regulate CHOP/GADD34-mediated dephosphorylation of eIF2-α to recover from translational inhibition. Disclosure J. Li: None. J. Shirakawa: None. Y. Togashi: 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.

148-OR: IDegLira Improves Glycemic Control in Japanese Patients with Type 2 Diabetes (T2D) Uncontrolled on Premixed Insulin Therapy

Diabetes management is moving towards choosing therapies that reduce treatment burden, risk of hypoglycemia and weight gain. DUAL VII showed that IDegLira, a fixed-ratio insulin degludec (degludec)/liraglutide combination, had non-inferior A1C lowering, lower hypoglycemia rates, no weight gain and less treatment burden vs. basal-bolus therapy. In contrast, there are no trial data on the efficacy and safety of switching patients (pts) from premixed insulin therapy (with basal and bolus components) to a fixed-ratio combination such as IDegLira. DUAL II Japan (NCT02911948) - a 26 week phase 3a multicenter, randomized, double-blind, treat-to-target trial - compared the efficacy and safety of IDegLira vs. ≤50 U degludec in 210 Japanese pts with uncontrolled T2D (A1C 7.5-11.0%) on 20-50 U basal or premixed insulin therapy + metformin ± an oral antidiabetic drug. Primary analysis confirmed superior change in A1C with IDegLira vs. degludec ≤50, and post hoc analyses found the treatment effect was independent of insulin type at baseline (basal or premixed; interaction test, p=0.5229). This post hoc evaluation describes novel data in a subset of 39 pts who switched from premixed insulin to IDegLira. Mean (standard deviation [SD]) A1C was 8.3% (0.73) at baseline and 6.7% (0.93) at Week 26. Mean (SD) body weight reduced by 1.5 (2.9) kg. Daily insulin dose was 14.1 (3.4) U at baseline and 34.2 (11.5) U at Week 26. Rate of hypoglycemic events (defined as severe or plasma glucose &amp;lt;56 mg/dL) was 2.6 events/patient-year of exposure (52 events in 17 pts). No pts withdrew. This post hoc study is the first to evaluate the switch from premixed insulin to IDegLira, in pts with uncontrolled T2D. IDegLira initiation resulted in improved A1C and weight loss with most pts not experiencing hypoglycemic events. This study offers insight into the effectiveness and safety of switching pts from premixed insulin therapy to IDegLira, and provides a support for further investigation into this transition. Disclosure H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited. B.F. Agner: Employee; Self; Novo Nordisk A/S. A. Doshi: Advisory Panel; Self; Pfizer Inc. Employee; Self; PrimeCare Medical Group. R. Grøn: Employee; Self; Novo Nordisk A/S. M.F. Ranthe: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. L.K. Billings: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Funding Novo Nordisk A/S

OR22-1 Liraglutide as Add-on to SGLT2 Inhibitors in Patients with Inadequately Controlled Type 2 Diabetes (LIRA-ADD2SGLT2i): A 26-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce glycated hemoglobin (HbA1c), but randomized controlled trial data on their combined use are limited. The LIRA-ADD2SGLT2i trial compared the effect on glycemic control of liraglutide 1.8 mg/day (a GLP-1 analog) vs placebo as add-on to SGLT2i ± metformin in patients with type 2 diabetes (T2D). In this phase 3b trial, patients with T2D on a stable dose of SGLT2i ± metformin and with HbA1c 7.0-9.5% were randomized 2:1 to add either liraglutide 1.8 mg/day or placebo. Exclusion criteria included a history of diabetic ketoacidosis (DKA) while being treated with SGLT2i and/or estimated glomerular filtration rate <60 mL/min/1.73 m2. The primary endpoint was change in HbA1c from baseline at 26 weeks; also assessed after 26 weeks were change in body weight, the proportion of patients achieving HbA1c <7%, and safety. All were analyzed regardless of premature trial product discontinuation or initiation of glucoselowering rescue medication. Overall, 412 patients were screened, 303 were randomized and 280 (92.4%) completed treatment (92.1% with liraglutide, 93.0% with placebo). Baseline characteristics were balanced between treatment groups: mean HbA1c 8.0%, mean body weight 91.1 kg, mean duration of diabetes 9.9 years. At week 26, the mean change in HbA1c from baseline with liraglutide was 0.98% (n=203) vs 0.30% with placebo (n=100) (estimated treatment difference [ETD]: 0.68%, 95% confidence interval [CI]: 0.89, 0.48; p<0.001). The mean change in body weight from baseline with liraglutide was -2.81 kg vs 1.99 kg with placebo (ETD: 0.82 kg; 95% CI: -1.73, 0.09, p=0.077). In the liraglutide group, 51.8% of patients achieved HbA1c <7.0% vs 23.2% in the placebo group (odds ratio: 5.1, 95% CI: 2.67, 9.87; p<0.001). A higher proportion of patients in the liraglutide group reported ≥1 treatment-emergent adverse event (AE) than in the placebo group (66.3% vs 47.0%). Nausea was the most frequent AE, occurring in 26.2% of the liraglutide group and 6.0% of the placebo group, and it generally had early onset in the initial 4 weeks and was transient. Similar incidences of hypoglycemic episodes were reported in both groups (8.9% with liraglutide vs 8.0% with placebo); none were severe. The proportion of patients reporting serious AEs was low in both groups (liraglutide 2.5% vs placebo 1.0%). No fatalities occurred in either group and there were no reports of acute renal failure, DKA, diabetic foot ulcers or amputations with liraglutide in combination with SGLT-2i. In patients with T2D, the addition of liraglutide to SGLT2i therapy (± metformin) provided superior glycemic control vs placebo, and had a safety profile consistent with the known safety profile of both drug classes. The LIRA-ADD2SGLT2i is registered with ClinicalTrials.gov NCT02964247.

Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway.

Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.

Effects of liraglutide plus phentermine in adults with obesity following 1 year of treatment by liraglutide alone: A randomized placebo-controlled pilot trial

BackgroundThis pilot study evaluated whether adding phentermine to liraglutide would induce further weight loss in participants who had previously lost weight with liraglutide alone. Subjects/methodsParticipants were 45 adults with obesity (75.6% female, 55.6% white, body mass index = 34.3 ± 4.7 kg/m2) who had lost an average of 12.6 ± 6.8% of initial weight during a prior 1-year randomized trial with liraglutide and intensive behavioral treatment. Participants were re-randomized, in a double-blinded fashion, to liraglutide 3.0 mg plus phentermine 15.0 mg (liraglutide-phentermine) or liraglutide plus placebo (liraglutide-placebo). Participants also were provided with four, 15-minute counseling sessions during the 12-week extension study. ResultsAt week 12, the liraglutide-phentermine and liraglutide-placebo groups lost a mean (±SEM) of 1.6 ± 0.6% and 0.1 ± 0.5% of re-randomization weight, respectively (p = 0.073). Two (9.1%) liraglutide-phentermine participants and one (4.3%) liraglutide-placebo participant lost ≥5% of re-randomization weight; 19 (86.4%) and 16 (69.9%) participants, respectively, maintained their full weight loss achieved in the prior 1-year trial (p = 0.125). Liraglutide-phentermine participants generally reported larger reductions in hunger and food preoccupation than liraglutide-placebo participants during the first 8 weeks of the extension study. ConclusionsThe combination of liraglutide and phentermine appeared to be well-tolerated but did not produce additional clinically meaningful weight loss in individuals who had already lost 12.6% of initial weight with liraglutide alone. Trial registrationClinicalTrials.gov number, NCT02911818.

Determining the Effects of Combined Liraglutide and Phentermine on Metabolic Parameters, Blood Pressure, and Heart Rate in Lean and Obese Male Mice

Liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, and phentermine, a psychostimulant structurally related to amphetamine, are drugs approved for the treatment of obesity and hyperphagia. There is significant interest in combination use of liraglutide and phentermine for weight loss; however, both drugs have been reported to induce systemic hemodynamic changes, and as such the therapeutic window for this drug combination needs to be determined. To understand their impact on metabolic and cardiovascular physiology, we tested the effects of these drugs alone and in combination for 21 days in lean and obese male mice. The combination of liraglutide and phentermine, at 100 μg/kg/day and 10 mg/kg/day, respectively, produced the largest reduction in body weight in both lean and diet-induced obese (DIO) mice, when compared with both vehicle and monotherapy-treated mice. In lean mice, combination treatment at the aforementioned doses significantly increased heart rate and reduced blood pressure, whereas in DIO mice, combination therapy induced a transient increase in heart rate and decreased blood pressure. These studies demonstrate that in obese mice, the combination of liraglutide and phentermine may reduce body weight but only induce modest improvements in cardiovascular functions. Conversely, in lean mice, the additional weight loss from combination therapy does not improve cardiovascular parameters.

GDF15 acts synergistically with liraglutide but is not necessary for the weight loss induced by bariatric surgery in mice

ObjectiveAnalogues of GDF15 (Growth Differentiation Factor 15) are promising new anti-obesity therapies as pharmacological treatment with GDF15 results in dramatic reductions of food intake and body weight. GDF15 exerts its central anorexic effects by binding to the GFRAL receptor exclusively expressed in the Area Postrema (AP) and the Nucleus of the Solitary Tract (NTS) of the hindbrain. We sought to determine if GDF15 is an indispensable factor for other interventions that cause weight loss and which are also known to act via these hindbrain regions. MethodsTo explore the role of GDF15 on food choice we performed macronutrient intake studies in mice treated pharmacologically with GDF15 and in mice having either GDF15 or GFRAL deleted. Next we performed vertical sleeve gastrectomy (VSG) surgeries in a cohort of diet-induced obese Gdf15-null and control mice. To explore the anatomical co-localization of neurons in the hindbrain responding to GLP-1 and/or GDF15 we used GLP-1R reporter mice treated with GDF15, as well as naïve mouse brain and human brain stained by ISH and IHC, respectively, for GLP-1R and GFRAL. Lastly we performed a series of food intake experiments where we treated mice with targeted genetic disruption of either Gdf15 or Gfral with liraglutide; Glp1r-null mice with GDF15; or combined liraglutide and GDF15 treatment in wild-type mice. ResultsWe found that GDF15 treatment significantly lowered the preference for fat intake in mice, whereas no changes in fat intake were observed after genetic deletion of Gdf15 or Gfral. In addition, deletion of Gdf15 did not alter the food intake or bodyweight after sleeve gastrectomy. Lack of GDF15 or GFRAL signaling did not alter the ability of the GLP-1R agonist liraglutide to reduce food intake. Similarly lack of GLP-1R signaling did not reduce GDF15's anorexic effect. Interestingly, there was a significant synergistic effect on weight loss when treating wild-type mice with both GDF15 and liraglutide. ConclusionThese data suggest that while GDF15 does not play a role in the potent effects of VSG in mice there seems to be a potential therapeutic benefit of activating GFRAL and GLP-1R systems simultaneously.

Effects of liraglutide addition to multiple diabetes regimens on weight and risk of hypoglycemia for a cohort with type 2 diabetes followed in primary care clinics in Saudi Arabia

Context:Available therapies for type 2 diabetes mellitus (T2DM) do not adequately control glycemia in the long term as they do not address the issue of declining beta cell function and do not impact positively on weight or cardiovascular concerns associated with the disease.Aims:To measure changes in hemoglobin A1c, weight, and hypoglycemia after the addition of liraglutide to 3 therapeutic regimens of patients with T2DM.Settings and Design:An observational cohort study that was implemented in Al-Wazarat Health Center in Riyadh, Saudi Arabia.Methods and Materials:The study included 38 T2DM patients who were screened for initiation of liraglutide in combination with their treatment regimens; sulphonylurea, sulphonylurea with basal insulin (glargine), and multiple daily injections of insulin. The cohort was followed for 12 months, and the liraglutide was started with 0.6 mg dose that escalated to 1.2 and 1.8 mg. Glycemic level and weight were measured 3 times, whereas hypoglycemia was measured 2 times.Statistical Analysis Used:Quantitative continuous paired data were compared using a paired t-test and the nonparametric Wilcoxon signed rank test.Results:There was a statistically significant reduction of hemoglobin A1c with 1.2 mg dose (mean difference = 0.84%, P = 0.003). There were no statistically significant differences regarding the effect of liraglutide in addition to the 3 treatment regimens on patients’ weight (P = 0.08, 0.472, 0.08, respectively). Regarding hypoglycemia, liraglutide has showed minimal effect.Conclusions:Sustained effect of liraglutide on glycemic control in patients with T2DM without any major hypoglycemic episodes.

Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non-Alcoholic Steatohepatitis.

Although commonly associated with obesity, non-alcoholic fatty liver disease (NAFLD) is also present in the lean population representing a unique disease phenotype. Affecting 25% of the world's population, NAFLD is associated with increased mortality especially when progressed to non-alcoholic steatohepatitis (NASH). However, no approved pharmacological treatments exist. Current research focuses mainly on NASH associated with obesity, leaving the effectiveness of promising treatments in lean NASH virtually unknown. This study therefore aimed to evaluate the effect of liraglutide (glucagon-like peptide 1 analogue) and dietary intervention, alone and in combination, in guinea pigs with non-obese NASH. After 20 weeks of high-fat feeding (20% fat, 15% sucrose, 0.35% cholesterol), 40 female guinea pigs were block-randomized based on weight into four groups receiving one of four treatments for 4 weeks: continued high-fat diet (HF, control), high-fat diet and liraglutide treatment (HFL), chow diet (4% fat, 0% sucrose, 0% cholesterol; HFC) or chow diet and liraglutide treatment (HFCL). High-fat feeding induced NASH with severe fibrosis. Liraglutide decreased inflammation (p < 0.05) and hepatocyte ballooning (p < 0.05), while increasing hepatic α-tocopherol (p = 0.0154). Dietary intervention did not improve liver histopathology significantly, but decreased liver weight (p = 0.004), plasma total cholesterol (p = 0.0175), LDL-cholesterol (p = 0.0063), VLDL-cholesterol (p = 0.0034), hepatic cholesterol (p < 0.0001) and increased hepatic vitamin C (p = 0.0099). Combined liraglutide and dietary intervention induced a rapid weight loss, necessitating periodical liraglutide dose adjustment/discontinuation, limiting the strength of the findings from this group. Collectively, this pre-clinical study supports the beneficial effect of liraglutide on NASH and extends this notion to lean NASH.

GLP-1 Receptor Agonist Liraglutide Increased IVF Pregnancy Rates in Obese Women with PCOS and Previous Poor Response to First-Line Reproductive Treatments

Objective: GLP-1 has been investigated in regulation of reproductive system in animal models. Current observations suggest that it directly regulates kisspeptin and GnRH expression and that ovaries express GLP-1 mRNA. Aim: To evaluate the impact of low dose liraglutide in combination with metformin compared to metformin alone on IVF pregnancy rate (PR) and cumulatively PR (IVF and spontaneous) in infertile obese women with PCOS who had been previously poor responders regarding weight reduction with lifestyle modification and resistant to first line reproductive treatments. Design/Participants/Methods: A prospective randomized open-label study was conducted with 28 infertile obese PCOS patients (aged 31,07±4,75 years, BMI 36,7±3,5 kg/m2, mean ± SD). They were assigned to metformin (MET) 1000 mg BID or combined MET 1000 mg BID and low dose liraglutide 1.2 mg QD s.c. (COMBI) for 12 weeks. Ovarian stimulation protocol was started after 4-week medication free period. Results: Patients in MET lost on average 7,0±6,0 kg (P&amp;lt;0.001) compared with 7,5± 3,9 kg loss in COMBI group (P&amp;lt;0.001), with no significant between-treatment difference (P=0,103). All treatment interventions resulted in significant reduction of visceral adipose tissue as assessed by DXA and reduction of HOMA-IR (p&amp;lt;0.001), with no significant difference regarding the treatment employed. After intervention, PR per ET was significantly higher in COMBI (85,7%) compared with MET (28,6%) (P=0.03). Moreover, cumulatively PR in time frame of 12 months in COMBI was 69,2% compared to 35,7% in MET. Conclusion: Short-term preconception intervention with low dose liraglutide as an add on to metformin was superior to metformin alone in increasing PR per ET and cumulative PR in infertile obese PCOS, despite comparable weight reduction in both arms. Potential direct crosstalk between GLP-1 and reproductive system needs further exploration. Disclosure A. Janez: None. M. Jensterle: None.

Short Duration of Diabetes Should Be Associated with More Prominent Effect of Liraglutide—Titrated from Insulin Degludec plus Liraglutide Combination Therapy

Objective: In management of type 2 diabetes (T2DM), controlling HbA1c &amp;lt;7% is required. We examined effectiveness of insulin degludec (DEG) plus liraglutide (LIRA) combination therapy in Japanese T2DM patients. Methods: Hospitalized hyperglycemic 55 patients with T2DM who started this therapy were randomly recruited. Changes of HbA1c, Insulin doses, and ADRR in patients who did self-blood glucose monitoring (SMBG) were evaluated for a year after discharge. Since preserved β-cell function might influence the effect, effectiveness was compared by duration of T2DM ≤ 5 year (n=27) or ≥ 6 year (n=28). Results: 1) Baseline characteristics: Patients with short duration (SHORT) were younger (62±9.5 vs. 69.9±11.8 years old: p&amp;lt;0.05), had shorter duration (0.44±1.3 vs. 17.1±9.3 year:p&amp;lt;0.01), higher urinary C-peptide (91.1±4.6 vs. 47.0±30μg/day: p&amp;lt;0.01), higher HbA1c (12.4±2.5 vs. 11.0±2.3%: p&amp;lt;0.05), and lower final dose of liraglutide (0.68±0.18 vs. 0.78±0.17mg/day: p&amp;lt;0.05) compared with long duration (LONG) group. 2) Mean HbA1c in 55 patients have reached the target from 3rd month to 12th month. 3) Although daily glucose excursions at discharge and mean body weight were identical throughout a year in 2 groups, HbA1c in SHORT group dramatically improved after discharge. The average of HbA1c was maintained ≤ 6.0% from 4th month to 12th month. 4) Patients with HbA1c ≤ 6.0% using SMBG showed lower ADRR scores (1∼9). 5) The combined use of DEG and its dose gradually decreased in SHORT group, one third of patients could quit DEG at 6th month and over half at 12th month, but none in LONG group. 6) Although Long group had higher rates of chronic kidney disease (CKD) 46.4% and ischemic heart disease (IHD) 28.5%, SHORT group still had high rates of CKD 22.2% and IHD 18.5%. Conclusion: Since T2DM is a complex metabolic disorder, prominent effect of LIRA in the patients with short duration is supportive for GLP-1 receptor agonists as a first-line therapy. Disclosure K. Kashima: None. H. Shimizu: Speaker's Bureau; Self; Eli Lilly and Company, MSD K.K., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc.. M. Yamada: None.

Synergistic anti-tumor effects of liraglutide with metformin on pancreatic cancer cells.

Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively. RT-PCR and western blot analyses were used to determine the mRNA and protein levels of related molecules. Results showed that combination treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) significantly decreased cell viability and colony formation, caused cell cycle arrest, upregulated the level of pro-apoptotic proteins Bax and cleaved caspase-3, and inhibited cell migration in the cells, although their single treatment did not exhibit such effects. Combination index value for cell viability indicated a synergistic interaction of liraglutide and metformin. Moreover, the combined treatment with liraglutide and metformin could activate the phosphorylation of AMP-activated protein kinase (AMPK) more potently than their single treatment in the cells. These results suggest that liraglutide in combination with metformin has a synergistic anti-tumor effect on the pancreatic cancer cells, which may be at least partly due to activation of AMPK signaling. Our study provides new insights into the treatment of patients with type 2 diabetes and pancreatic cancer.

Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining β-cell function and the achievement of the glycated hemoglobin target 1 year after initiation.

Aims/IntroductionThe glucose‐lowering effects of the glucagon‐like peptide‐1 receptor agonist, liraglutide, have been shown to rely on remaining β‐cell function. However, the possible associations of remaining β‐cell function with the glucose‐lowering effects of liraglutide in combination with basal insulin remain unknown and warrant investigation.Materials and MethodsThis was a single‐center, retrospective, observational study carried out in a private hospital in Osaka, Japan. Type 2 diabetes patients who received a prescription change from insulin therapy, both multiple‐dose insulin and basal insulin‐supported oral therapy, to liraglutide and basal insulin combination and continued the therapy for 54 weeks without additional oral antidiabetic drugs or bolus insulin were retrospectively analyzed.ResultsAmong the 72 participants who received a prescription change from multiple‐dose insulin and basal insulin‐supported oral therapy to liraglutide and basal insulin combination, 57 continued the therapy for 54 weeks. Of those who continued the therapy without receiving additional oral antidiabetic drugs or bolus insulin, seven participants achieved glycated hemoglobin < 7.0% at 54 weeks, but 30 participants did not. The participants who achieved glycated hemoglobin < 7.0% at 54 weeks had a significantly higher C‐peptide immunoreactivity index, a β‐cell function‐related index frequently used in Japanese clinical settings. The receiver operating curve analysis showed that the C‐peptide immunoreactivity index cut‐off value for the achievement of glycated hemoglobin <7.0% at 54 weeks is 1.103.ConclusionsThe current findings show that the glucose‐lowering effects of liraglutide rely on remaining β‐cell function, even when used with basal insulin; and suggest that liraglutide and basal insulin combination might require additional bolus insulin to fully compensate insulin insufficiency in individuals with reduced β‐cell function.

Liraglutide and Metformin alone or combined therapy for type 2 diabetes patients complicated with coronary artery disease

BackgroundThis study is to compare the effects of Liraglutide and Metformin alone or combined treatment on the cardiac function in T2DM patients complicated with CAD.Methods120 T2DM patients were included at Endocrinology Department of Tianjin First Center Hospital (Tianjin, China) from April 2012 to September 2013. The study contained two sections. Section 1: 30 patients in group 1 was treated with Liraglutide (Novo Nordisk) (1.2 mg/d), and 30 patients in group 2 with Metformin (Shiguibao) (1500 mg/d) for 24 weeks. Section 2: 30 patients in group1 was treated with Liraglutide (1.8 mg/d) and 30 in group 2 with Liraglutide (1.2 mg/d) plus Metformin (1500 mg/d) for 24 weeks. Fasting blood glucose (FBG), postprandial glucose (PPG), glycated hemoglobin (HbA1c), body mass index (BMI), blood pressure (BP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), C reactive protein (CRP), left ventricular end-diastolic diameter (LVEDD), ejection fraction (EF) and the ratio of early (E) to late (A) ventricular filling velocities (E/A ratio) were measured before and after the 24-week treatment.ResultsAfter 24-week treatment, when blood glucose level was controlled in 4 groups, Liraglutide alone treatment showed better improvements than on all measuring except TG in Section 1, however, combined treatment of Liraglutide and Metformin showed better improvements on all measuring except BMI, TG and BP in Section 2.ConclusionsWith similar glycemic control, the Liraglutide (1.2 mg/d) monotherapy showed the better effects than either Metformin alone, or combination of Liraglutide and Metformin on lipid metabolism and cardiovascular function.Trial registrationThis trial was registered at Chinese Clinical Trial Registry (chictr.org.cn) # ChiCTR-IPR-16008578.