Human Glucagon-like Peptide-1 Analogue Research Articles

ОЦЕНКА ЭФФЕКТИВНОСТИ ПРИМЕНЕНИЯ АНАЛОГА ЧЕЛОВЕЧЕСКОГО ГЛЮКАГОНОПОДОБНОГО ПЕПТИДА-1 ЛИРАГЛУТИДА У ПАЦИЕНТОВ С ПОДАГРОЙ И МЕТАБОЛИЧЕСКИ НЕЗДОРОВЫМ ФЕНОТИПОМ ОЖИРЕНИЯ

Introduction. Obesity is a global problem of the XXI century. The most important aspect of metabolic disorders that develop with obesity is a change in the level of serum uric acid (UA) in the blood and the development of gout. Currently, the dynamics of cardiovascular risk factors in patients with obesity on the background of drug therapy is being widely studied. The aim of our study is to study the level of UA, vaspin (VsP), visfatin (VF), omentin (ITLN1), retinol-binding protein-4 (RBP4) in patients with gout and metabolically unhealthy obesity (MNHO) during diet therapy and 3 months of treatment with the drug from the group of human glucagon-like peptide-1 analog (aGLP-1) Liraglutide. Materials and methods: 25 men with gout were examined, the average age was 43.6±7.3 years. Gout was diagnosed according to the classification criteria ACR/EULAR, 2015, Wallace S.L., 1977. Metabolic syndrome was established according to the criteria of GNCA (2013): abdominal obesity - waist circumference ≥ 94 cm in combination with any 2 from the following criteria - an increase in triglycerides (TG) ≥ 1.7 mmol / l; a decrease in high-density lipoproteins (HDL) < 1.0 mmol / l, an increase in low-density lipoproteins (LDL) ≥3.0 mmol / l, blood pressure (BP) ≥ 140/90 mm Hg; increase in plasma glucose ≥ 6.1 mmol / l. At the time of inclusion in the study, all patients had an interictal period of gout. Body mass index (BMI) was calculated using the Quetelet formula: body weight (kg)/height (m²). To assess the type of distribution of adipose tissue, the waist circumference (WT, cm) and hip circumference (HB) were measured with a flexible centimeter tape, with the calculation of the W/H ratio. The concentration of VsP, VF, ITLN1, RBP4 was studied using the enzyme-linked immunosorbent assay method using the kits; the concentration of the level of UA in blood serum and daily urine was studied using the colorimetric method. Liraglutide was injected into the subcutaneous fat of the anterior abdominal wall at a dose of 0.6 mg once a day for the first week. Escalation by 0.6 mg every week was then recommended until a dose of 18 mg per day was reached. Participants then received injections at a dose of 1.8 mg for 3 months. Thus, the observation period was 3 months. Laboratory studies and assessment of anthropometric parameters were carried out initially, as well as after 3 months. The control group consisted of 16 healthy men matched in age. Statistical data processing was carried out using the statistical software package Statistica 13.0. Results. 3 months after treatment, a statistically significant decrease in body weight, BMI and WC was noted (in all cases, p<0.01). Median BMI before treatment was ˗ 38.4 [35.4; 39.2] kg/m², against the background of ongoing therapy - 33.2 [31.4; 34.2] kg/m², and thus the loss of body weight was 23% (p<0.05). Serum UA level decreased by 30.1% (p<0.05) during therapy with a drug from the GLP-1 group. In patients with gout, BMI and regression of obesity were associated with a significant decrease in VsP by 17.2%, VF by 13.8% and RBP4 by 10.4%, and a significant increase in ITLN1 by 12.6%. A direct correlation was established between BMI and WC with the content of VsP, RBP4 and VF in blood serum (correlation coefficients from 0.44 to 0.57, p<0.05) and an inverse correlation with the content of ITLN1 (correlation coefficient -0.29, p<0.05). A direct correlation was found between the serum UA index and the content of VsP, VF, RBP4 (correlation coefficients from 0.31 to 0.49, p<0.05). Conclusion. Patients with gout in combination with MNZO showed a significant increase in serum levels of UA, VsP, RBP4 and VF, against the background of a decrease in the concentration of ITLN1. The use of diet therapy using a drug from the GLP-1 group showed a statistically significant decrease in BMI, WC, serum UA, pro-inflammatory adipokines (VsP, VF and RBP4), and a significant increase in anti-inflammatory cytokines (ITLN1).

Liraglutide ameliorates hepatic steatosis via retinoic acid receptor-related orphan receptor α-mediated autophagy pathway.

Liraglutide, an analog of human glucagon-like peptide-1 (GLP-1), has been found to improve hepatic steatosis in clinical practice. However, the underlying mechanism remains to be fully defined. Increasing evidence suggests that retinoic acid receptor-related orphan receptor α (RORα) is involved in hepatic lipid accumulation. In the current study, we investigated whether the ameliorating impact of liraglutide on lipid-induced hepatic steatosis is dependent on RORα activity and examined the underlying mechanisms. Cre-loxP-mediated, liver-specific Rorα knockout (Rora LKO) mice, and littermate controls with a Roraloxp/loxp genotype were established. The effects of liraglutide on lipid accumulation were evaluated in mice challenged with a high-fat diet (HFD) for 12 weeks. Moreover, mouse AML12 hepatocytes expressing small interfering RNA (siRNA) of Rora were exposed to palmitic acid to explore the pharmacological mechanism of liraglutide. The results showed that liraglutide treatment significantly alleviated HFD-induced liver steatosis, marked by reduced liver weight and triglyceride accumulation, improved glucose tolerance and serum levels of lipid profiles and aminotransferase. Consistently, liraglutide also ameliorated lipid deposits in a steatotic hepatocyte model in vitro. In addition, liraglutide treatment reversed the HFD-induced downregulation of Rora expression and autophagic activity in mouse liver tissues. However, the beneficial effect of liraglutide on hepatic steatosis was not observed in Rora LKO mice. Mechanistically, the ablation of Rorα in hepatocytes diminished liraglutide-induced autophagosome formation and the fusion of autophagosomes and lysosomes, resulting in weakened autophagic flux activation. Thus, our findings suggest that RORα is essential for the beneficial impact of liraglutide on lipid deposition in hepatocytes and regulates autophagic activity in the underlying mechanism.

Liraglutide on type 2 diabetes mellitus with nonalcoholic fatty liver disease: A systematic review and meta-analysis of 16 RCTs.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM). Our aim is to investigate the effects of liraglutide on T2DM with NAFLD. Relevant articles published from the earliest publication to March 2022 were selected from several databases. The Cochrane Collaboration's RevMan software was used for the analysis. Sixteen studies are selected for this meta-analysis, which includes totally 634 patients in the treatment group and 630 patients in the control group. As a result, 14 studies show that fasting plasma glucose levels of the experimental group are lower than that of the control group; 15 studies show that glycosylated hemoglobin A1c levels of the experimental group are lower than that of the control group; 13 studies show that triglyceride levels of the experimental group are lower than that of the control group; twelve studies show that total cholesterol levels of the experimental group are lower than that of the control group; 10 studies show that alanine aminotransferase levels of the experimental group is lower than that of the control group; 10 studies show that no significant difference in changes in aspartate transaminase between 2 groups; 13 studies show that low density lipoprotein cholesterol levels of the experimental group is lower than that of the control group; 9 studies show that no significant difference in changes in high density lipoprotein cholesterol between 2 groups; 7 studies mentioned adverse effects and the difference is significant. Liraglutide is potentially curative for T2DM with NAFLD.

Egg Microneedle for Transdermal Delivery of Active Liraglutide.

Liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, is promising for safely treating type 2 diabetes mellitus (T2DM), compared to insulin, by significantly reducing the risk of glucose-dependent hypoglycemia. Concerns related to injection prevent T2DM patients from taking liraglutide regularly, even though once-a-day subcutaneous (SC) injections. Dissolving microneedles (DMNs) are promising substitutes for SC injection and for improving patient convenience. However, there are two fundamental limitations: the low drug delivery due to incomplete insertion and loss of drug activity during DMN fabrication. Here, it is shown that an egg microneedle (EMN) designed with three functional layered structures can maintain the maximum activity of the loaded compound during DMN fabrication and deliver it completely into the skin, with the base layer allowing the complete delivery of liraglutide, and the shell layer maintaining the drug activity by mimicking the role of albumin in eggs. In a diabetic mouse model, liraglutide administration via EMN exhibited similar effect when compared to that of injection. Therefore, EMN-mediated liraglutide administration is a good potential option for replacing liraglutide injections in T2DM treatment.

Establishment of Stability-Indicating Purity Method Based on the Stress Degradation Behaviour of Human Glucagon-like Peptide-1 Analog Liraglutide using Reverse Phase-Liquid Chromatography

Establishment of Stability-Indicating Purity Method Based on the Stress Degradation Behaviour of Human Glucagon-like Peptide-1 Analog Liraglutide using Reverse Phase-Liquid Chromatography

Liraglutide and Exercise: A Possible Treatment for Obesity?

(1) Background: Obesity has become an important public health problem worldwide, and its characterization as a chronic disease reflects the impact of a complex and multifactorial condition. The treatment for obesity is based on lifestyle interventions that induce a negative energy balance. However, adherence to a lifestyle intervention is a challenge for many overweight and obese people. Thus, pharmacotherapy in the management of obesity is used to increase patient adherence to lifestyle changes and overcome the biological adaptations that occur with weight loss. Among these drugs, liraglutide stands out. Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1), a hormone that regulates glucose-dependent insulin secretion, and glucagon release. (2) Results: Liraglutide appears to be effective in weight reduction and glycemic control in diabetic and obese patients, and combination of liraglutide and exercise can also bring benefits in weight loss. Furthermore, the combination of liraglutide and physical exercise can prevent adverse effects observed in the administration of liraglutide. (3) Conclusions: liraglutide seems to contribute to cardiometabolic improvement in obese individuals with or without diabetes, and the combination of liraglutide and physical exercise can prevent adverse effects observed in the administration of liraglutide.

Obesity in Pediatric Transplant and the Use of Liraglutide

<h3>Introduction</h3> Obesity and metabolic disorders are associated with increased mortality post heart transplant. We report the case of a 17-year-old female with obesity pre and post transplant obesity whose body mass index (BMI) and metabolic profile improved with the GLP-1 analog, liraglutide. <h3>Case Report</h3> AG is a 17 year-old diagnosed with Dannon syndrome, an X-linked disorder, characterized by a triad of arrhythmia, muscle weakness and cardiomyopathy. Due to progressive decline in ventricular systolic function, she underwent heart transplantation. Her weight was 106.4 kg and BMI 34.35 kg/m² at the time of transplant. Post-transplant, despite healthy lifestyle recommendations, weight management and nutrition clinics, AG's hyperphagia persisted and her BMI continued to increase. AG was started on liraglutide and she lost 17kg over 6 months (Fig. 1). Her BMI improved from 38 kg/m² to 32 kg/m². Her HgbA1c normalized and lipid profile also improved. AGs only complaint was of nausea and vomiting however these symptoms were related to her immunosuppression medications and improved after adjusting her regimen. <h3>Summary</h3> Use of behavioral interventions to improve BMI pre- and post-transplant is of limited success in lowering BMI. The U.S. Food and Drug Administration approved liraglutide for chronic weight management among patients aged 12 and older with obesity. Liraglutide, a long-acting analog of human glucagon-like peptide-1, increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases B-cell growth/replication, and slows gastric emptying. This case demonstrated successful use of liraglutide to aid in weight loss in a post-transplant pediatric patient. Among motivated patients who maintain good communication with their clinician and adhere to a multidisciplinary approach, this regimen can improve previously unattainable weight loss goals. Close monitoring for side effects is crucial especially in populations where confounding regimens may require dose adjustments.

New practice in semaglutide on type-2 diabetes and obesity: clinical evidence and expectation.

Obesity is an important risk factor of type 2 diabetes (T2D), which has become an important factor threatening human health. However, no perfect drug choice for obesity exists. Semaglutide is a kind of human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion while inhibiting glucagon secretion through a glucose concentration-dependent mechanism. GLP-1 can also delay stomach emptying and suppress appetite to help lose weight. This review summarizes clinical evidence of the semaglutide effect on T2D and obesity and establishes expectations on future clinical trials for obesity treatment.

Effect of Various Dosing Conditions on the Pharmacokinetics of Oral Semaglutide, a Human Glucagon-Like Peptide-1 Analogue in a Tablet Formulation.

IntroductionOral semaglutide is a novel tablet formulation of the human glucagon-like peptide-1 analogue semaglutide. In two trials, the effects of prior food ingestion (food effect), post-dose fasting period and water volume with dosing (dosing conditions) on oral semaglutide pharmacokinetics were investigated.MethodsSubjects received once-daily oral semaglutide for 10 days. In the food-effect trial, 78 healthy subjects were randomised 1:1:1 to fed (meal 30 min pre-dose; 240 mL water with dosing), fasting (overnight until 4 h post-dose; 240 mL) or reference (fasting overnight until 30 min post-dose; 120 mL) arms. In the dosing conditions trial, 161 healthy men were randomised into eight dosing groups (overnight fasted with 50/120 mL water and 15/30/60/120 min post-dose fasting). Semaglutide plasma concentrations were measured frequently until 504 h after the 10th dose.ResultsIn the food-effect trial, limited or no measurable semaglutide exposure was observed in the fed arm, while all subjects in the fasting arm had measurable semaglutide exposure. Area under the semaglutide concentration–time curve (AUC0–24h,semaglutide,day10) and maximum semaglutide concentration (Cmax,semaglutide,day10) were numerically greater by approximately 40% for the fasting versus reference arm (p = 0.082 and p = 0.080, respectively). In the dosing conditions trial, AUC0–24h,semaglutide,day10 and Cmax,semaglutide,day10 were not different between water volumes (p = 0.541 and p = 0.676), but increased with longer post-dose fasting (p < 0.001).ConclusionAdministration of oral semaglutide in the fasting state with up to 120 mL water and at least 30 min post-dose fasting results in clinically relevant semaglutide exposure. These dosing conditions have been used in the oral semaglutide phase 3 trials and are part of the approved label.Trial RegistrationClinicalTrials.gov identifiers NCT02172313, NCT01572753.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01078-y.

Enhancing bile tolerance of Lactobacilli is involved in the hypolipidemic effects of liraglutide.

Liraglutide is an analog of human glucagon-like peptide-1 which play essential roles in regulation of glycolipid metabolism. To investigate role of lactic acid bacteria (LAB) in lipid-lowering effect of liraglutide, 40 mice were divided into normal food diet (NFD), high-fat food (HFD), 10.0 mg/kg/d simvastatin-treated HFD (SIM+HFD), 200 and 400 µg/kg/d liraglutide-treated HFD (LL+HFD and HL+HFD) groups for 5 weeks. We found that liraglutide could upregulate cholesterol 7α-hydroxylase (CYP7A1) and LDL-receptor (LDLR), whereas downregulate 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Besides, liraglutide enhance abundance of lactobacillaceae in gut of hyperlipidemic mice and increase bile tolerance ability of LAB by upregulating bile salt hydrolases, and the lysate of liraglutide-sensitive LAB could also directly downregulate HMGCR, the key enzyme in cholesterol synthesis, and inhibit hepatocyte steatosis. These findings might provide new theoretical guidance for clinical application of liraglutide and research and development of antiobesity, hypolipidemic, and cholesterol-lowering drugs or functional foods.

A narrative review of current trends in liraglutide: insights into the unmet needs in management of type 2 diabetes and obesity.

Liraglutide is a long-acting human glucagon-like peptide-1 (GLP-1) analogue and an effective treatment for patients with metabolic diseases including type 2 diabetes mellitus (T2DM) and obesity. This review focuses on the mechanism of action of liraglutide as a well-known glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with T2DM and obesity. The lower and the higher doses of GLP-1 RAs are used for glycaemic control in T2DM and in obesity respectively. GLP-1 RAs such as liraglutide enhance insulin secretion and inhibit glucagon release via the stimulation of glucagon-like peptide-1 receptors (GLP-1Rs). Liraglutide decreases hemoglobin A1c (HbA1c) in type 2 diabetes (T2D) patients when prescribes as monotherapy or in combination with one or more antidiabetic drugs. Usually, it is well tolerated with minor hypoglycemia in combination therapy. Liraglutide reduces cardiovascular events and related risk factors including improvement of lipid profile and control of blood pressure. Accordingly, it can be cost-effective and may be a budget neutral medication option by considering its protective effect on the cardiovascular system in long-term use in the health care plan. In the near future, by pharmacogenomics approach, prediction of the highest patient's response with the lowest adverse drug reactions and also rationality of drug development will be possible. Liraglutide can be used as a desirable medicine for glycemic control and obesity. It shows extensive evidence based benefits in diabetes complications. In this narrative review, we have summarized and evaluated studies related to the role of liraglutide in clinical practice.

Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis.

ContextNo head-to-head trials have directly compared once-weekly (OW) semaglutide, a human glucagon-like peptide-1 analog, with empagliflozin, a sodium–glucose co-transporter-2 inhibitor, in type 2 diabetes (T2D).ObjectiveWe indirectly compared the efficacy of OW semaglutide 1 mg vs once-daily (OD) empagliflozin 25 mg in patients with T2D inadequately controlled on metformin monotherapy, using individual patient data (IPD) and meta-regression methodology.Design, Setting, Participants, and InterventionsIPD for patients with T2D receiving metformin monotherapy and randomized to OW semaglutide 1 mg (SUSTAIN 2, 3, 8 trials), or to OD empagliflozin 25 mg (PIONEER 2 trial) were included. Meta-regression analyses were adjusted for potential prognostic factors and effect modifiers.Main Outcome MeasuresThe primary efficacy outcomes were change from baseline to end-of-treatment (~1 year) in HbA1c (%-point) and body weight (kg). Responder outcomes and other clinically relevant efficacy measures were analyzed.ResultsBaseline characteristics were similar between OW semaglutide (n = 995) and empagliflozin (n = 410). Our analyses showed that OW semaglutide significantly reduced mean HbA1c and body weight vs empagliflozin (estimated treatment difference: −0.61%-point [95% confidence interval (CI): −0.72; −0.49] and −1.65 kg [95% CI: −2.22; −1.08], respectively; both P < 0.0001). Complementary analyses supported the robustness of these results. A significantly greater proportion of patients on OW semaglutide vs empagliflozin also achieved HbA1c targets and weight-loss responses.ConclusionsThis indirect comparison suggests that OW semaglutide 1 mg provides superior reductions in HbA1c and body weight vs OD empagliflozin 25 mg in patients with T2D when added to metformin monotherapy.

Liraglutide Effect on Ventricular Transient Outward K + Channel and Connexin-43 Protein Expression.

Human glucagon-like peptide-1 analogue, Liraglutide, has shown cardioprotective effects in animal and clinical studies of type 2 diabetes mellitus. This study was conducted to assess the effect of Liraglutide on diabetes-induced myocardial electrical remodeling. A rat model of type 2 diabetes mellitus was induced by high-fat diet and low dose Streptozotocin (35 mg/kg). Diabetic rats were randomized into 4 subgroups (n=6-7): diabetic-untreated, diabetics treated with Liraglutide, diabetics treated with Ramipril, and diabetics treated with Metformin in addition to a control group. Changes in serum glucose, insulin, lipid profile and revised quantitative insulin sensitivity check index (QUICKI index) were assessed. QT and QTc intervals were measured and the degree of cardiac interstitial and perivascular fibrosis was examined. The expression of myocardial Ito channel α subunits, gap junction protein; Kv 4.2/4.3 and connexin 43 (Cx43) respectively, were assessed by western blotting and immunohistochemistry. Similar to Ramipril, both Liraglutide and Metformin effectively inhibited the diabetes-induced myocardial hypertrophy and fibrosis. However, Liraglutide treatment significantly improved Kv 4.2/4.3 and Cx43 expression/distribution and prevented diabetes-related QTc interval prolongation. We have shown that pathological alterations in myocardial Cx43 expression and distribution, in addition to reduced Ito channel expression, may underlie the QTc interval prolongation in high-fat diet/STZ rat model of type 2 diabetes mellitus. The beneficial effects of Liraglutide, as those of Ramipril, on cardiac electrophysiology could be at least attributed to its direct ability to normalize expression and distribution of Cx43 and Ito channels in the diabetic rat heart.

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes.

Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP‑1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials. In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20mg semaglutide co-formulated with 150-600mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40mg oral semaglutide (with 300mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40mg oral semaglutide (with 300mg SNAC), placebo, or placebo with SNAC. Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when co-formulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1week in all groups. The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing. CLINICALTRIALS. NCT01037582, NCT01686945.

Pharmacotherapy of obesity: what’s new?

The lifestyle change that underlies the treatment of such a prevalent chronic disease as obesity is often insufficient to successfully clinically relevant reduce body weight, especially in the presence of comorbid conditions and diseases (type 2 diabetes, atherogenic dyslipidemia, arterial hypertension, ischemic heart disease, hyperuricemia and gout, obstructive sleep apnea syndrome, polycystic ovary syndrome and other menstrual irregularities etc.). The availability in our country until recently, only two drugs for the treatment of obesity is extremely limited choice in the case of existing contraindications to this or another drug or the appearance of any side effects. The registration in Russia in 2016 of a new drug for the treatment of obese patients, including morbid or complicated concomitant diseases and conditions, an analogue of human glucagon-like peptide-1 — liraglutide in a dose of 3.0 mg, has replenished the arsenal of obesity pharmacotherapy and substantially extended capabilities of management of obesity and overweight including patients with severe comorbidities.

Efficacy of liraglutide 3 mig therapy in obesity and associated diseases

Obesity is a chronic disease associated with cardiometabolic risk factors, primarily cardiovascular diseases and type 2 diabetes mellitus. In 2016,Russiaregistered a new drug for treating obese patients liraglutide 3.0 mg, which is an analogue of human glucagon-like peptide-1. Given the urgency of the problem, we present a clinical case that shows the efficacy of therapy with liraglutide 3.0 mg daily in a patient with obesity, and its effect on metabolic risk factors.

Semaglutide: First Global Approval.

Novo Nordisk has developed a subcutaneous formulation of semaglutide (Ozempic®), a modified human glucagon-like peptide-1 (GLP-1) analogue, for the treatment of type 2 diabetes mellitus. It has been developed using Novo Nordisk's proprietary protein-acylation technology, and is administered using an injection device. Semaglutide lowers blood glucose by stimulating the release of insulin and also lowers body weight. Once-weekly subcutaneous semaglutide has recently been approved in the US, Puerto Rico and Canada, and has received a positive opinion in the EU for the treatment of patients with type 2 diabetes. It will be launched as the Ozempic® Pen, a pre-filled device. Semaglutide is also under regulatory review in Japan and Switzerland for the treatment of type 2 diabetes. Clinical development for obesity, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease is underway worldwide. This article summarizes the milestones in the development of semaglutide leading to this first approval for type 2 diabetes.

Long-Term Effectiveness of Liraglutide for Treatment of Type 2 Diabetes in a Real-Life Setting: A 24-Month, Multicenter, Non-interventional, Retrospective Study.

IntroductionThe aim of the study was to evaluate whether the reduction in glycated hemoglobin (HbA1c) observed in clinical trials with liraglutide in type 2 diabetes (T2D) could be attained in routine clinical practice.MethodsReaL was a multicenter, non-interventional, observational, retrospective, longitudinal study on the effectiveness of liraglutide, a human glucagon-like peptide-1 analog, in individuals with T2D treated in daily practice in Italy. Between 26 March and 16 November 2015, data were taken from clinical records of patients aged ≥ 18 years with treatment follow-up data of up to 24 months and who received their first prescription of liraglutide in 2011.ResultsA total of 1723 patients were included in the analysis. At baseline, mean age was 58.9 years, duration of diabetes was 9.6 years, and HbA1c was 8.3%. At 12 months, 36.1% of patients were prescribed the maximum 1.8 mg dose; 43.5% [95% confidence interval (CI): 40.9; 46.2] of patients attained the primary outcome of a reduction in HbA1c of ≥ 1% point at 12 months. At 24 months, 40.9% (95% CI 38.1; 43.7) of patients had attained the HbA1c target of ≤ 7%. Additionally, body weight significantly decreased by 3.4 kg (95% CI − 3.6; − 3.1, p < 0.0001).ConclusionIn this observational study conducted in routine clinical practice for up to 2 years, treatment with liraglutide improved HbA1c and reduced body weight in a similar fashion to that observed under randomized clinical trial conditions. The data support the use of liraglutide as an effective treatment for T2D in clinical practice.FundingNovo Nordisk S.p.A.Trial RegistrationClinicalTrials.gov identifier, NCT02255266.Electronic supplementary materialThe online version of this article (10.1007/s12325-017-0652-2) contains supplementary material, which is available to authorized users.

Effect of liraglutide in treatment of non-alcoholic fatty liver disease: mechanism of action and research advances

Non-alcoholic fatty liver disease is a common chronic liver disease closely associated with obesity, hyperlipidemia, and diabetes. It can gradually progress to liver cirrhosis or even hepatocellular carcinoma; however, there are still no specific therapeutic agents for this disease. Liraglutide is a human glucagon-like peptide-1 analogue and has a marked effect in the treatment of type 2 diabetes. At present, many studies indicate that liraglutide also has a certain therapeutic effect on non-alcoholic fatty liver disease during the treatment of type 2 diabetes, but its mechanism of action remains unknown. This article reviews the known mechanisms of action of liraglutide in the treatment of non-alcoholic fatty liver disease.

BPI-3016, a novel long-acting hGLP-1 analogue for the treatment of Type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) analogues have been commonly used as add-on medications for patients with Type 2 diabetes mellitus (T2DM). Currently, the development of long-acting GLP-1 analogues which allow the freedom and flexibility of once-weekly injections while maintaining their potency for a relatively long period has become the mainstream. Here, we successfully developed a long-acting human GLP-1(7–37) analogue (BPI-3016) with significantly extended half-life and increased resistance to dipeptidyl peptidase IV (DPP-IV) cleavage by structural modifications of human GLP-1. In vitro activity of BPI-3016 including GLP-1 receptor affinity and stimulation of cyclic adenosine monophosphate (cAMP) production was measured. In vivo activity of BPI-3016 such as its effects on glycemic control, β-cell mass and body weight was evaluated in ob/ob mice, db/db mice, and spontaneous diabetic cynomolgus monkeys. The results indicated that BPI-3016 preserved receptor affinity to GLP receptors, and was capable of stimulating cAMP production. In in vivo pharmacokinetic study, the half-life of BPI-3016 was more than 95h after single dosing in diabetic cynomolgus monkeys. Also, BPI-3016 reduced fasting and post-prandial plasma glucose levels for up to a week after a single dose; It reduced body mass index (BMI), body fat, improved glucose tolerance and showed insulinotropic effects after once-weekly injection for 7 weeks. In conclusion, BPI-3016 retains the effects of GLP-1 with significantly prolonged half-life, making it a promising therapy for type 2 diabetes with once-weekly treatment in the clinic.