Dose Of Liraglutide Research Articles

Practice pearl: liraglutide and cardiovascular and renal events in type 2 diabetes

ABSTRACTReview of:Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375: 311–322.Mann J, Orsted D, Brown-Frandsen K, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med 2017; 377: 839–848.This comprehensive research project, LEADER, led to two reports, one focusing on the effect of liraglutide on cardiovascular events, and the second one reporting on the renal effects on the same study population. The study group included 9340 patients with type 2 diabetes. Patients were required to have type 2 diabetes and an age 50 with a previous cardiovascular problem or chronic heart failure, or an age of 60 with at least one cardiovascular risk factor. Patients were randomized to 1.8 mg (or the maximum tolerated dose) of liraglutide, or placebo. The median follow up was 3.8 years. The primary cardiovascular outcome, a combined endpoint of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, was seen in 13% (608 of 4668 patients) treated with liraglutide versus 14.9 % (694 of 4672 patients) in the placebo patients (HR 0.87; 95% confidence interval [CI] 0.78 to 0.97; P = 0.01 for superiority). Death from cardiovascular disease and death from any cause were also lower in the liraglutide group. The rates for nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were not significantly reduced. In the renal report, the renal outcome was reduced in the liraglutide versus the placebo group (268 of 4668 versus 337 out of 4672 in the placebo group; HR 0.78; CI 0.67 to 0.92; p = 0.003). This improvement was mainly driven by a lower rate of the new onset of persistent macroalbuminuria in the liraglutide patients (161 vs 215 patients; HR 0.74; 95% CI, 0.60 to 0.91; p = 0.004), while the rates of other renal adverse events were similar in both groups. When taken together these two reports are the first data to show that the glucagon-like peptide 1 (GLP-1) analogue liraglutide can reduce cardiovascular events and halt progression to macroalbuminuria in patients with Type 2 diabetes.

Liraglutide repairs the infarcted heart: The role of the SIRT1/Parkin/mitophagy pathway.

Liraglutide is glucagon-like peptide-1 receptor agonist used for treating patients with type 2 diabetes mellitus. The present study aimed to investigate the role and mechanism of liraglutide in repairing the infarcted heart following myocardial infarction. The results of the present study demonstrated that amplification of the dose of liraglutide for ~28 days was able to reduce cardiac fibrosis, inflammatory responses and myocardial death in the post-infarcted heart. In vitro, liraglutide protected cardiomyocyte mitochondria against the chronic hypoxic damage, inhibiting the mitochondrial apoptosis pathways. Mechanistically, liraglutide elevated the expression of NAD-dependent protein deacetylase sirtuin-1 (SIRT1), which increased the expression of Parkin, leading to mitophagy activation. Protective mitophagy reversed cellular adenosine 5′-triphosphate production, reduced cellular oxidative stress and balanced the redox response, sustaining mitochondrial homeostasis. Notably, following blockade of glucagon-like peptide 1 receptor or knockdown of Parkin, the beneficial effects of liraglutide on mitochondria disappeared. In conclusion, the results of the present study illustrated the protective role of liraglutide in repairing the infarcted heart via regulation of the SIRT1/Parkin/mitophagy pathway.

Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects.

IntroductionMetformin and glucagon‐like peptide‐1 (GLP‐1) agonists are widely used for treating type two diabetes mellitus (T2DM). While recent studies suggest these drugs might modify the gastrointestinal tract (GIT) microbiome, further confirmation is required from human clinical trials.Materials and methodsHere, we compare, in patients with T2DM, the effects of metformin (n = 18 subjects) and liraglutide (n = 19), a GLP‐1 agonist, on their GIT microbiomes over a 42 day period (n = 74 samples) using 16S ribosomal RNA (rRNA) sequencing.ResultsWe found that these drugs had markedly different effects on the microbiome composition. At both baseline and Day 42, subjects taking metformin had a significant increase (Baseline adj. P = .038, Day 42 adj. P = .041) in the relative abundance of the bacterial genus Sutterella, whereas liraglutide dosing is associated with a significant increase (Baseline adj. P = .048, Day 42 adj. P = .003) in the genus Akkermansia, a GIT bacteria positively associated with gut barrier homoeostasis. Bacteroides and Akkermansia relative abundances were also significantly associated with duration of subject diabetes (adj P < .05). Specifically, there was a significantly higher abundance of Akkermansia in subjects with short and medium durations than those with long duration of diabetes.DiscussionTo our knowledge, this is the first report of GLP‐1 agonist‐associated changes in the human microbiome and its differentiating effects to metformin. Our study suggests that modulation of the GIT microbiome is a potentially important component in the mechanism of action of these drugs.

Featured article: Structure moderation of gut microbiota in liraglutide-treated diabetic male rats.

The change of gut microbiome is associated with a serious of metabolic disorders, such as diabetes. As a glucagon-like peptide 1 analogue, liraglutide is a potent antidiabetic drug in clinical practice. However, the effect of liraglutide on the community of gut microbiota is still unknown. We aimed to determine the influence of liraglutide on fecal microbiota in diabetic male rats. Five-week-old male Sprague-Dawley rats were fed with a control diet or a high-fat diet for four weeks. By injecting streptozotocin, the diabetic rat model was performed. Diabetic male rats were injected subcutaneously with a low dose of liraglutide (liraglutide 0.2 mg/kg/day), a high dose of liraglutide (liraglutide 0.4 mg/kg/day), or normal saline for 12 weeks. Our data showed that liraglutide effectively prevented the development of diabetes in male rats. Pyrosequencing of the V3-V4 region of 16S rRNA genes manifested a remarkable transfer of gut microbiota construction in liraglutide-treated male rats compared with that of the diabetic male rats. Further analysis identified 879 liraglutide-treated specific operational taxonomic units. Some short-chain fatty acid (SCFA)-producing bacteria, including Bacteroides, Lachnospiraceae, and probiotic bacteria, Bifidobacterium, were selectively enhanced in liraglutide-treated diabetic male rats. Lactobacillus was negatively correlated with fasting blood glucose. To sum up, our findings propose that the prevention of diabetes by liraglutide in the diabetic male rats may be associated with the structural change of the gut microbiota, inflammation alleviation, and abundantly elevated SCFA-producing bacteria in the intestine. Impact statement Our findings suggest that significant changes in gut microbiota are associated with liraglutide treatment on the diabetic male rats, including enrichment of short-chain fatty acid producers and probiotic bacteria. This may help alleviate systemic inflammation and contribute to the beneficial effects of liraglutide against diabetes.

Liraglutide acutely suppresses glucagon, lipolysis and ketogenesis in type 1 diabetes.

In view of the occurrence of diabetic ketoacidosis associated with the use of sodium-glucose transport protein-2 inhibitors in patients with type 1 diabetes (T1DM) and the relative absence of this complication in patients treated with liraglutide in spite of reductions in insulin doses, we investigated the effect of liraglutide on ketogenesis. Twenty-six patients with inadequately controlled T1DM were randomly divided into 2 groups of 13 patients each. After an overnight fast, patients were injected, subcutaneously, with either liraglutide 1.8 mg or with placebo. They were maintained on their basal insulin infusion and were followed up in our clinical research unit for 5 hours. The patients injected with placebo maintained their glucose and glucagon concentrations without an increase, but there was a significant increase in free fatty acids (FFA), acetoacetate and β-hydoxybutyrate concentrations. In contrast, liraglutide significantly reduced the increase in FFA, and totally prevented the increase in acetoacetate and β-hydroxybutyrate concentrations while suppressing glucagon and ghrelin concentrations. Thus, a single dose of liraglutide is acutely inhibitory to ketogenesis.

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females and is often associated with a number of cardiometabolic disorders such as central obesity, dyslipidaemia, hypertension, insulin resistance, hyperinsulinaemia, glucose intolerance and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a gut hormone secreted after a meal, enhances glucosestimulated insulin secretion and additionally suppresses appetite and gastric motility. Most studies found impaired GLP-1 kinetics in obese individuals, whereas small studies in PCOS reported reduced, normal or even elevated GLP-1 levels. Apart from their efficacy in patients with T2DM, some GLP-1 receptor agonists (GLP-1 RAs) have been successfully tested in terms of both efficiency and safety in obese individuals without diabetes and liraglutide 3 mg once daily has been approved as an antiobesity drug in the USA and the European Union. Recently, some small trials of short duration using GLP-1 RAs as monotherapy or combined with metformin in obese PCOS women showed positive results regarding weight reduction and a decrease in testosterone levels but without significant effects on insulin levels, insulin sensitivity and menstrual patterns. Longer term studies with more patients and higher doses of liraglutide (as this drug is already approved for obese individuals) are required to determine the precise indications of GLP-1 RAs in PCOS and to evaluate safety issues.

Addition of Metformin to Liraglutide, A GLP-1 Receptor Agonist, Improves Glycemic Control in Patients with Type 2 Diabetes Mellitus

Background: The maximum permissible dose of liraglutide, a GLP-1 receptor agonist, under the Japanese Heath Insurance system is 0.9 mg/day. We determined the effects of adding metformin to liraglutide therapy in Japanese patients with type 2 diabetes.Material and Methods: This observational retrospective study included 47 patients with type 2 diabetes who were treated with liraglutide alone or in combination with sulfonylureas. Metformin was added at a dose ranging from 250 to 500 mg/day based on inadequate glycemic control. Liraglutide and metformin doses were converted from mg/day to mg/kg body weight/day before analysis of the correlation between the dose and changes in glycated hemoglobin (HbA1c) and body mass index (BMI).Results: Both HbA1c and BMI decreased significantly after 24 weeks of the combination treatment. Mild gastrointestinal adverse events were reported by 21% of the patients. Only the dose of metformin, but not that of liraglutide, expressed in mg/kg body weight was correlated significantly with decrease in HbA1c and BMI.Conclusions: The addition of metformin to the maximum permissible dose of liraglutide helps secure glycemic control and reduce BMI in Japanese patients with type 2 diabetes who exhibit inadequate response to liraglutide.

Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial

BackgroundLiraglutide 3 mg was recently approved as an anti-obesity drug. Metformin is weight neutral, yet it could enhance the therapeutic index of GLP-1 agonist. We compared weight-lowering potential of liraglutide 1.2 mg in combination with metformin to liraglutide 3 mg monotherapy in obese PCOS.MethodsThirty obese women with PCOS (aged 33.1 ± 6.1 years, BMI 38.3 ± 5.4 kg/m2) were randomized to combination (COMBO) of metformin (MET) 1000 mg BID and liraglutide 1.2 mg QD (N = 15) or liraglutide 3 mg (LIRA3) QD alone (N = 15) for 12 weeks. The primary outcome was change in anthropometric measures of obesity.ResultsBoth treatments led to significant weight loss (−3.6 ± 2.5 kg, p = 0.002 in COMBO vs −6.3 ± 3.7 kg, p = 0.001 in LIRA3). BMI and waist circumference reduction in LIRA3 was greater than in COMBO (−2.2 ± 1.3 vs −1.3 ± 0.9 kg/m2,p = 0.05 and −4.2 ± 3.4 vs −2.2 ± 6.2 cm, p = 0.014, respectively). Both interventions resulted in a significant decrease of post-OGTT glucose levels. COMBO significantly reduced total testosterone and was associated with less nausea.ConclusionsShort-term interventions with COMBO and LIRA3 both led to significant improvement of measures of obesity in obese PCOS, LIRA3 being superior to COMBO. However, COMBO further improved androgen profile beyond weight reduction and was associated with better tolerability.Trial registrationThe study was retrospectively registered with ClinicalTrials.gov (NCT02909933) on 16th of September 2016.

Liraglutide Versus SGLT-2 Inhibitors in People with Type 2 Diabetes: A Network Meta-Analysis.

IntroductionFor people with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs (OADs), evidence from both randomized controlled trials (RCTs) and real-world studies has demonstrated that treatment intensification with liraglutide offers effective glycemic control, weight reduction, and a lower risk of hypoglycemia compared to treatment intensification with insulin or additional OADs. Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a new class of OADs that have also been shown to be effective in T2DM patients inadequately controlled with OADs. Currently there are no head-to-head RCTs comparing these to liraglutide.MethodsWe aimed to evaluate the relative efficacy, using network meta-analysis (NMA), of treatment intensification with liraglutide and SGLT-2 inhibitors people with T2DM who have been treated with metformin (alone or in combination with SU, DPP-4, and TZD). We performed a systematic literature review to identify relevant RCTs comparing liraglutide (1.2 and 1.8 mg), canagliflozin (100 and 300 mg), empagliflozin (10 and 25 mg), or dapagliflozin (5 and 10 mg) to placebo. To strengthen the indirect evidence base, we also included non-placebo RCTs where sitagliptin (100 mg) was the active comparator. Bayesian NMA was performed on the following outcomes to assess the relative efficacy and safety of interventions: reduction (change) in HbA1c, weight, and fasting plasma glucose (FPG) as well as proportion reaching target HbA1c (<7%), and risk of hypoglycemia. Doses for each intervention were considered separately.ResultsA total of 16 RCTs were identified. All trials were similar with respect to important baseline characteristics and study design. Both doses of liraglutide were generally statistically significantly superior to the SGLT-2s with respect to change from baseline in HbA1c and FPG as well as odds of reaching target HbA1c <7%. For weight, canagliflozin 300 mg was superior to liraglutide 1.2 mg, and SGLT-2s were generally associated with larger change from baseline in weight. For risk of major or minor hypoglycemia, no differences were found between treatments.ConclusionsCompared to SGLT-2 inhibitors, liraglutide offers improvement in HbA1c and FPG. Reductions in weight are likely comparable between liraglutide and SGLT-2s. Liraglutide did not differ from SGLT-2s in terms of risk of hypoglycemia. Given the lack of head-to-head evidence, this analysis provides valuable insight into the comparative outcomes of liraglutide versus SGLT-2 inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0217-4) contains supplementary material, which is available to authorized users.

Current drugs for weight loss

Current drugs for weight loss

GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation.

Beneficial roles for glucagon-like peptide 1 (GLP-1)/GLP-1R signaling have recently been described in diseases, where low-grade inflammation is a common phenomenon. We investigated the effects of GLP-1 in Brunner's glands and duodenum with abundant expression of GLP-1 receptors, as well as GLP-1 effect on colonic inflammation. RNA from Brunner's glands of GLP-1R knockout and wild-type mice were subjected to full transcriptome profiling. Array results were validated by quantitative reverse transcription polymerase chain reaction in wild-type mice and compared with samples from inflammatory bowel disease (IBD) patients and controls. In addition, we performed a detailed investigation of the effects of exogenous liraglutide dosing in a T-cell driven adoptive transfer (AdTr) colitis mouse model. Analyses of the Brunner's gland transcriptomes of GLP-1R knockout and wild-type mice identified 722 differentially expressed genes. Upregulated transcripts after GLP-1 dosing included IL-33, chemokine ligand 20 (CCL20), and mucin 5b. Biopsies from IBD patients and controls, as well as data from the AdTr model, showed deregulated expression of GLP-1R, CCL20, and IL-33 in colon. Circulating levels of GLP-1 were found to be increased in mice with colitis. Finally, the colonic cytokine levels and disease scores of the AdTr model indicated reduced levels of colonic inflammation in liraglutide-dosed animals. We demonstrate that IL-33, GLP-1R, and CCL20 are deregulated in human IBD, and that prophylactic treatment with 0.6 mg/kg liraglutide improves disease in AdTr colitis. In addition, GLP-1 receptor agonists upregulate IL-33, mucin 5b, and CCL20 in murine Brunner's glands. Taken together, our data indicate that GLP-1 receptor agonists affect gut homeostasis in both proximal and distal parts of the gut.

Glucagon-like peptide-1 analogue, liraglutide, in experimental cerebral malaria: implications for the role of oxidative stress in cerebral malaria

BackgroundCerebral malaria from Plasmodium falciparum infection is major cause of death in the tropics. The pathogenesis of the disease is complex and the contribution of reactive oxygen and nitrogen species (ROS/RNS) in the brain is incompletely understood. Insulinotropic glucagon-like peptide-1 (GLP-1) mimetics have potent neuroprotective effects in animal models of neuropathology associated with ROS/RNS dysfunction. This study investigates the effect of the GLP-1 analogue, liraglutide against the clinical outcome of experimental cerebral malaria (ECM) and Plasmodium falciparum growth. Furthermore the role of oxidative stress on ECM pathogenesis is evaluated.MethodsECM was induced in Plasmodium berghei ANKA-infected C57Bl/6j mice. Infected Balb/c (non-cerebral malaria) and uninfected C57Bl/6j mice were included as controls. Mice were treated twice-daily with vehicle or liraglutide (200 μg/kg). ROS/RNS were quantified with in vivo imaging and further analyzed ex vivo. Brains were assayed for cAMP, activation of cAMP response element binding protein (CREB) and nitrate/nitrite. Plasmodium falciparum was cultivated in vitro with increasing doses of liraglutide and growth and metabolism were quantified.ResultsThe development and progression of ECM was not affected by liraglutide. Indeed, although ROS/RNS were increased in peripheral organs, ROS/RNS generation was not present in the brain. Interestingly, CREB was activated in the ECM brain and may protect against ROS/RNS stress. Parasite growth was not adversely affected by liraglutide in mice or in P. falciparum cultures indicating safety should not be a concern in type-II diabetics in endemic regions.ConclusionsDespite the breadth of models where GLP-1 is neuroprotective, ECM was not affected by liraglutide providing important insight into the pathogenesis of ECM. Furthermore, ECM does not induce excess ROS/RNS in the brain potentially associated with activation of the CREB system.

LEADER and the new ‘cardiovascular’ glucose‐lowering agents

<scp>LEADER</scp> and the new ‘cardiovascular’ glucose‐lowering agents

Single dose and repeated administrations of liraglutide alter energy metabolism in the brains of young and adult rats.

Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue that was recently approved to treat obesity in some countries. Considering that liraglutide effects on brain energy metabolism are little known, we evaluated the effects of liraglutide on the energy metabolism. Animals received a single or daily injection of saline or liraglutide during 7 days (25, 50, 100, or 300 μg/kg i.p.). Twenty-four hours after the single or last injection, the rats were euthanized and the hypothalamus, prefrontal cortex, cerebellum, hippocampus, striatum, and posterior cortex were isolated. Our results demonstrated that a single dose of liraglutide in young rats increased the activity of complexes and inhibited creatine kinase activity. Repeated administrations of liraglutide in young rats reduced the activity of complexes and activated creatine kinase activity. In adult rats, a single dose of liraglutide reduced the activity of complex I and creatine kinase and increased the activity of complexes II and IV. Repeated administrations of liraglutide in adult rats increased the activity of complexes I and IV and reduced the activity of complex II and creatine kinase. We concluded that liraglutide may interfere in energy metabolism, because analysis of different times of administrations, concentrations, and level of brain development leads to divergent results.

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.

Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17days each (0.6mg for 7days, 1.2mg for 7days, and 1.8mg for 3days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3mg) recently approved for obesity. ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Abstract 12630: Cardiovascular Safety of Liraglutide: Pooled Analysis of Major Adverse Cardiovascular Events across Weight Management and Type 2 Diabetes Development Programs

The cardiovascular safety of liraglutide in individuals with overweight/obesity and those with type 2 diabetes (T2D) is unknown. A meta-analysis of five phase II/III liraglutide (dose up to 3.0 mg) weight management (WM) trials was performed. Additional sensitivity meta-analyses of 21 liraglutide T2D trials (dose up to 1.8 mg) and a pre-specified pooled analysis of all WM and T2D trials (27 trials; WM+T2D) were also conducted. The primary endpoint was first occurrence of adjudicated major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke or cardiovascular death) with liraglutide (any dose) or pooled total comparator (placebo, active) and analysis was using a Cox proportional hazards model stratified by trial. Prospective adjudication (blinded, independent) was implemented in three of the WM trials; post-hoc adjudication was conducted for all other trials. For WM trials, the observation period was from the first drug dose to the last drug dose plus a 30-day follow-up; for the SCALE Obesity and Prediabetes trial, data to October 1, 2014 were included. For WM trials (liraglutide: n=3,872; comparator: n=2,036), baseline characteristics were: 71% women; history of CV disease, 9%; mean age, 47 yrs; mean BMI, 38 kg/m 2 . For T2D trials (liraglutide: n=5,511; comparator: n=2,748): 43% women; history of CV disease, 13%; mean age, 56 yrs; mean BMI, 30 kg/m 2 . In WM trials (n=20 events), the hazard ratio (HR) [95% confidence interval (CI)] for MACE (liraglutide/comparator) was 0.45 [0.18; 1.10] (Figure 1A). In T2D trials (n=49 events), the HR was 0.64 [0.35, 1.15] (Figure 1A). For the WM+T2D analysis (n=69 events), the HR was 0.57 [0.35, 0.94] (Figure 1B). In a pooled analysis of WM+T2D trials, MACE was significantly lower in patients treated with liraglutide. The dedicated cardiovascular outcomes trial, LEADER, will provide further insights into the cardiovascular safety of liraglutide.

Effects of dose escalating liraglutide from 1.2 to 1.8 mg in clinical practice: a case-control study.

Randomized trials show that liraglutide 1.8 mg is more effective than 1.2 mg in reducing HbA1c, but dose escalation is neither routinely considered nor recommended by some guidelines. We report real world data on the effects of dose-escalating liraglutide from 1.2 to 1.8 mg. In a pseudo-prospective, case-control study, patients who underwent liraglutide dose escalation to 1.8 mg for not having met individualized targets while on the 1.2 mg dose (n = 52) were compared to matched patients who remained on 1.2 mg (n = 52) for having shown good response, as defined by the patient's own diabetologist. HbA1c was recorded at ≤6-month intervals until the end of observation. The two groups were matched for all clinical characteristics, including baseline HbA1c (8.5 %). During a 12-month follow-up, patients who remained on liraglutide 1.2 mg showed a maximal HbA1c reduction of 1.29 ± 0.15 %. Patients who escalated to 1.8 mg showed a lower HbA1c reduction during therapy with 1.2 mg than controls (0.58 ± 0.16 %; p = 0.0017). Escalation to 1.8 mg resulted in a further HbA1c reduction of 0.62 ± 0.17 %. During a total 18-month follow-up, patients who escalated to 1.8 mg showed a total maximal HbA1c reduction of 0.84 ± 0.22 %. At the end of the observation, HbA1c was 7.54 ± 0.17 % in patients who remained on 1.2 mg and 7.92 ± 0.21 in patients who escalated to 1.8 mg (p = 0.13). Escalation to 1.8 mg also helped further body weight reduction. Escalating liraglutide dose to 1.8 mg in patients who responded less than expected to 1.2 mg helps in reducing HbA1c and reaching therapeutic targets.

Abstract P006: Liraglutide Attenuates Cardiac Fibrosis and Vascular Dysfunction in a Non-diabetic Angiotensin II-infusion Model via Anti-inflammatory and Anti-oxidant Mechanisms

Glucagon-like peptide-1 (GLP-1) based therapies are used to treat type II diabetes via increasing insulin secretion and inhibiting glucagon production. Recent evidence suggests that activating the GLP-1 receptor may also mediate direct vaso-protective effects. Therefore the objective of the study was to determine whether GLP-1R stimulation conferred cardio- and vaso-protection in a non-diabetic setting using the angiotensin (Ang) II infusion model of hypertension and cardiovascular dysfunction. Male C57Bl/6J mice (4-6 months) were assigned to one of the following 4 week treatment protocols: 1) vehicle (saline), 2) Ang II (800ng/kg/day), 3) Ang II + liraglutide (30μg/kg/day), 4) Ang II + liraglutide (300μg/kg/day). All treatments were administered via osmotic mini-pumps (s.c). After 4 weeks the effect of liraglutide treatment on blood pressure, vascular function and cardiac remodelling was examined. Liraglutide (both doses) attenuated Ang II-induced increase in systolic blood pressure (Ang II: 175.3 ± 8.6mmHg vs Ang II+Lirag (30) 150.2 ± 6.4 mmHg or Ang II+Lirag (300): 145.4 ± 6.9 mmHg) without affecting blood glucose levels. Liraglutide (both doses) completely prevented Ang II-induced endothelial dysfunction (% maximum relaxation: Ang II=50.7 ± 7.8%; Ang II+Lirag (30)=82.7 ± 5.8; Ang II+Lirag (300)=81.5 ± 6.1%). In the heart, liraglutide prevented Ang II-induced cardiomyocyte hypertrophy (n=7-10; p&lt;0.05) and reduced collagen deposition (% collagen expression: Ang II=4.4 ± 0.5 vs Ang II+Lirag(300)=2.9 ± 0.3; n=7-9; p&lt;0.01). This anti-fibrotic effect was attributed to reduced fibroblast/myofibroblast expression as well as decreased inflammation with reduced NFκB and MCP-1 expression and decreased oxidative stress with a significant reduction in superoxide production using high dose of liraglutide. Overall, stimulation of GLP-1R in a non-diabetic setting protected against Ang II-mediated cardiac hypertrophy, cardiac fibrosis and vascular dysfunction, indicating potential for use of GLP-1 based therapies in treatment of cardiovascular disease independent of diabetes.

Effectiveness and Persistence with Liraglutide Among Patients with Type 2 Diabetes in Routine Clinical Practice—EVIDENCE: A Prospective, 2-Year Follow-Up, Observational, Post-Marketing Study

IntroductionThe aim of this study was to investigate whether the efficacy of liraglutide observed in randomized controlled trials translates into therapeutic benefits in the French population during routine clinical practice.MethodsThis observational, prospective, multicenter study included 3152 adults with type 2 diabetes who had recently started or were about to start liraglutide treatment. During 2 years of follow-up, an evaluation of the reasons for prescribing liraglutide, maintenance dose of liraglutide, changes in combined antidiabetic treatments, level of glycemic control, change in body weight and body mass index (BMI), patient satisfaction with diabetes treatment and safety of liraglutide were investigated. The primary study endpoint was the proportion of patients still receiving liraglutide and presenting with HbA1c <7.0% after 2 years of follow-up.ResultsAt the end of the study, 29.5% of patients maintained liraglutide treatment and reached the HbA1c target. Mean (±SD) HbA1c, fasting plasma glucose concentration, body weight and BMI were significantly reduced from baseline [8.46% (±1.46) to 7.44% (±1.20); 180 (±60) to 146 (±44) mg/dL; 95.2 (±20.0) to 91.1 (±19.6) kg; 34.0 (±7.2) to 32.5 (±6.9) kg/m2; respectively, all P < 0.0001]. Patient treatment satisfaction increased, with the mean diabetes treatment satisfaction questionnaire status version score increasing from 22.17 (±7.64) to 28.55 (±5.79), P < 0.0001. The main adverse event type was gastrointestinal, with a frequency of 10.9%, and the percentage of patients suffering ≥1 hypoglycemic episode decreased from 6.9% to 4.4%.ConclusionThe results of the EVIDENCE study suggest that the effectiveness of liraglutide in real-world clinical practice is similar to that observed in randomized controlled trials.FundingNovo Nordisk A/S.Trial RegistrationClinicalTrials.gov identifier, NCT01226966.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0245-x) contains supplementary material, which is available to authorized users.

Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice

Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pre-treatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro. The cAMP/PKA/pCREB pathway appears to play an important role in this neuroprotective activity of liraglutide. Furthermore, our findings in cell culture were well-translated in a weight drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI when evaluated 7 and 30 days post trauma. These data cross-validate former studies of exendin-4 and suggest that liraglutide holds therapeutic potential for the treatment of mTBI. Exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of traumatic brain injury (TBI). Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pretreatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro, likely involving the cAMP/PKA/pCREB pathway. Our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI.