Glucagon-like Peptide-1 Analogue Research Articles

Obesity management for the pre–liver transplant and post–liver transplant patient

Obesity management for the pre–liver transplant and post–liver transplant patient

Sindrome progeroide atipica con lipodistrofia parziale familiare, dovuta alla mutazione missenso c.1045 C > T (p.Arg349Trp) in eterozigosi del gene LMNA, e diabete mellito di tipo 2

Familial partial lipodystrophy (FPLD) associated with LMNA gene mutations is a rare form of lipodystrophy disorder characterized by partial absence of subcutaneous adipose tissue and predisposition to develop metabolic complications related to insulin-resistance inclu-ding type 2 diabetes mellitus (T2D). Recently, this peculiar phenotype has been associated to atypical progeroid syndrome (APS). We present a case of 31-year-old woman with progeria features, partial lipodystro¬phy, type 2 diabetes mellitus (T2D), hypertriglyceridemia and hepatic steatosis. The baseline insulin sensitivity and secretion assessment showed strong insulin-resistance with hyperglycemia and elevated insulin secretion. Genetic analysis revealed a missense heterozygous LMNA mutation c.1045 C > T (p. Arg349Trp) that established APS diagnosis with FPLD, so far studied and described in only 10 patients worldwide. The patient was initially treated with metformin, fenofi¬brate, omega-3 and low carb and low fat diet with optimal results on metabolic control related to glycemic and lipid profile; later, liragluti¬de (Glucagon-Like Peptide-1 analog, GLP-1) therapy was added. Du¬ring the 6 month follow-up the anthropometric parameters improved, in particular a significant improvement in body composition with redi¬stribution of fat mass and a reduction of visceral fat and liver volume were observed. The improvements obtained were consolidated and maintained in the following years. However, with disease progression, focal segmental glomerulosclerosis (FSGS) and peripheral neuropathy developed. This case highlights the clinical and metabolic characteristics of this rare form of lipodystrophy and proposes an innovative therapeutic approach to manage the disease.

GLP-1 analogs and regional adiposity: A systematic review and meta-analysis.

Glucagon-like peptide 1 (GLP-1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly, GLP-1 analog effects on AT distribution are unclear. To investigate GLP1-analog effects on adiposity distribution. PubMed, Cochrane, and Scopus databases were screened for eligible randomized human trials. Pre-defined endpoints included visceral AT (VAT), subcutaneous AT (SAT), total AT (TAT), epicardial AT (EAT), liver AT (LAT), and waist-to-hip ratio (W:H). Search was conducted until May 17, 2022. Data extraction and bias assessment were performed by two independent investigators. Treatment effects were estimated using random effects models. Analyses were performed on Review Manager v5.3. Out of the 367 screened studies, 45 were included in the systematic review and 35 were used in the meta-analysis. GLP-1 analogs reduced VAT, SAT, TAT, LAT, and EAT, with non-significant effects on W:H. Overall bias risk was low. GLP-1 analog treatment reduces TAT, affecting most studied AT depots, including the pathogenic VAT, EAT, and LAT. GLP-1 analogs may have significant roles in combating metabolic, obesity-associated diseases via reductions of key AT depot volumes.

Glucagon-like peptide-1 analog therapy in rare genetic diseases: monogenic obesity, monogenic diabetes, and spinal muscular atrophy.

Implementing genetic analyses have unraveled rare alterations causing early-onset obesity and complications, in whom treatment is challenging. We aimed to report on the effects of adjuvant off-label therapy with liraglutide, glucagon-like peptide-1 analogue (GLP-1a), in rare genetic diagnoses. Case scenarios and review of the literature. Case 1: Nine-year-old boy with early-onset severe obesity and nonalcoholic fatty liver disease (NAFLD) due to a homozygous mutation in the MC4R gene deteriorated under lifestyle change and metformin therapy [at 10.5 years: body mass index (BMI) 51.2kg/m2, 226% of the 95th percentile, fat percentage (FP) 65% and muscle-to-fat ratio (MFR) z-score of -2.41]. One year of liraglutide treatment halted progressive weight gain [BMI 50.3kg/m2, 212% of the 95th percentile, 63.7% FP and MFR z-score of -2.34], with biochemical improvement. Case 2: Twelve-year-old boy with obesity presented with diabetes and progressive NAFLD. Exome analysis revealed two heterozygous mutations compatible with monogenic diabetes (HNF1A) and familial hypercholesterolemia (LDLR). Lifestyle modifications resulted in clinical and laboratory improvement (BMI 87th percentile, 32.8% FP, MFR z-score of -1.63, HbA1c 5.5%) without the expected recovery in liver transaminases. Liraglutide treatment augmented the improvement in weight status (BMI 68th percentile, 22.6% FP, MFR z-score of -1.13) with normalization of liver transaminases. Case 3: Nineteen-year-old male with spinal muscular atrophy type 3 presented with sarcopenic obesity and comorbidities. Treatment strategy included dietary counseling and multiple drug therapies (metformin, anti-hypertensive and statins). Liraglutide therapy led to a gradual recovery of metabolic complications allowing tapering-down other medications. Considering the pleiotropic effects of GLP1-a beyond BMI reduction, this treatment modality may serve as a game changer in challenging cases.

Glucagon-like peptide-1 therapy in people with obesity restores natural killer cell metabolism and effector function.

People with obesity (PWO) have functionally defective natural killer (NK) cells, with a decreased capacity to produce cytokines and kill target cells, underpinned by defective cellular metabolism. It is plausible that the changes in peripheral NK cell activity are contributing to the multimorbidity in PWO, which includes an increased risk of cancer. This study investigated whether therapy with long-acting glucagon-like peptide-1 (GLP-1) analogues, which are an effective treatment for obesity, could restore NK cell functionality in PWO. In a cohort of 20 PWO, this study investigated whether 6 months of once weekly GLP-1 therapy (semaglutide) could restore human NK cell function and metabolism using multicolor flow cytometry, enzyme-linked immunosorbent assays, and cytotoxicity assays. These data demonstrate that PWO who received GLP-1 therapy have improved NK cell function, as measured by cytotoxicity and interferon-γ/granzyme B production. In addition, the study demonstrates increases in a CD98-mTOR-glycolysis metabolic axis, which is critical for NK cell cytokine production. Finally, it shows that the reported improvements in NK cell function appear to be independent of weight loss. The restoration, by GLP-1 therapy, of NK cell functionality in PWO may be contributing to the overall benefits being seen with this class of medication.

Effects of Glucagon-Like Peptide-1 Analogs on Sexual Desire: A randomized, double-blind, placebo-controlled crossover trial

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Study design and baseline profile for adults with type 2 diabetes in the once-weekly subcutaneous SEmaglutide randomized PRAgmatic (SEPRA) trial

IntroductionOnce-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve...

Stroke Prevention and Treatment in People With Type 2 Diabetes: Is There a Role for GLP-1 (Glucagon-Like Peptide-1) Analogues?

Stroke is a leading cause of disability and death, and people with type 2 diabetes (T2D) have a greater risk of stroke and death or disability from stroke. The underlying pathophysiology associating stroke and T2D is complicated by the association of risk factors for stroke frequently seen in people with T2D. Treatments to reduce the excess risk of new-onset stroke or to improve outcomes in people with T2D following stroke would be of major clinical interest. In practice, the focus of care in people with T2D remains treating risk factors for stroke, such as lifestyle and pharmacological interventions for hypertension, dyslipidemia, obesity, and glycemic control. More recently, cardiovascular outcome trials primarily designed to assess the cardiovascular safety of GLP-1RAs (glucagon-like peptide-1 receptor analogues) have consistently observed a reduced stroke risk in people with T2D. This is supported by several meta-analyses of cardiovascular outcome trials observing clinically important risk reductions in stroke. Moreover, phase II trials have described reductions in poststroke hyperglycemia in people with acute ischemic stroke suggestive of improved outcomes following admission to hospital with acute stroke. In this review, we discuss the increased risk of stroke in people with T2D and outline the key associated mechanisms responsible. We discuss the evidence from cardiovascular outcome trials exploring GLP-1RA use and highlight areas of potential interest for future work in this rapidly developing area of clinical research.

Liraglutide, a glucagon-like peptide-1 analog, in individuals with obesity in clinical practice

Obesity is a disease requiring treatment. The prevalence of obesity is steadily increasing both in Korea and worldwide. Individuals with obesity are at elevated risks of diabetes, cerebrovascular disease, and solid cancer; therefore, obesity is now considered to be a disease requiring treatment, rather than merely a cosmetic problem. Nutrition and exercise are the basic forms of obesity management, but it is not easy to lose weight through only one’s own willpower. Accordingly, policies for establishing a cultural environment that encourages desirable behaviors are proposed through multifaceted efforts involving the media and local organizations. However, the pharmacological and surgical treatments selected as medical interventions should be individualized based on an understanding of each individual’s cause of obesity and characteristics. It is important to understand how to enhance and maintain the effectiveness of treatment not only for the prescribing medical staff, but also for the individual with obesity who is being treated.

Evaluating the Long-Term Cost-Effectiveness of Once-Weekly Semaglutide 1mg Versus Liraglutide 1.8 mg: A Health Economic Analysis in the UK.

Glucagon-like peptide-1 (GLP-1) receptor agonists represent highly efficacious treatment options for type 2 diabetes. Liraglutide was amongst the first authorised for use in 2010, but once-weekly semaglutide represents the most efficacious GLP-1 analogue currently available for type 2 diabetes. The aim of the present analysis was therefore to evaluate the long-term cost-effectiveness of once-weekly semaglutide 1mg versus liraglutide 1.8mg with a lowered acquisition cost in the UK, as potentially lower cost liraglutide formulations may soon be developed. Outcomes were projected over patients' lifetimes using the IQVIA Core Diabetes Model (v9.0). Baseline cohort characteristics were sourced from SUSTAIN 2, with changes in HbA1c, blood pressure and body mass index applied from a network meta-analysis, in which SUSTAIN 2 was used to inform the semaglutide arm. Modelled patients received semaglutide or liraglutide for 3years, after which treatment was intensified to basal insulin. Costs were accounted from a healthcare payer perspective and expressed in 2021 pounds sterling (GBP). The acquisition cost of liraglutide was reduced by 33% compared with the currently marketed formulation. Life expectancy and quality-adjusted life expectancy were projected to improve with once-weekly semaglutide 1mg, by 0.05years and 0.06 quality-adjusted life years, respectively, versus liraglutide 1.8mg. Clinical benefits were due to a reduced incidence of diabetes-related complications with semaglutide. Direct costs were estimated to be GBP280 lower with semaglutide, entirely because of avoidance of diabetes-related complications versus liraglutide. Semaglutide 1mg was therefore considered dominant versus liraglutide 1.8mg, even with the liraglutide price reduced by 33%. Once-weekly semaglutide 1mg is likely to represent a dominant treatment option versus liraglutide 1.8mg for the treatment of type 2 diabetes in the UK, even with the liraglutide price reduced by 33%.

Glucagon-like peptide-1 analogues: a new way to quit smoking? (SKIP)—a structured summary of a study protocol for a randomized controlled study

BackgroundCigarette smoking is the leading preventable cause of premature death. Despite dedicated programmes, quit rates remain low due to barriers such as nicotine withdrawal syndrome or post-cessation weight gain. Glucagon-like peptide-1 (GLP-1) analogues reduce energy intake and body weight and seem to modulate addictive behaviour. These GLP-1 properties are of major interest in the context of smoking cessation. The aim of this study is to evaluate the GLP-1 analogue dulaglutide as a new therapy for smoking cessation.MethodsThis is a placebo-controlled, double-blind, parallel group, superiority, single-centre randomized study including 255 patients. The intervention consists of a 12-week dulaglutide treatment phase with 1.5 mg once weekly or placebo subcutaneously, in addition to standard of care (behavioural counselling and pharmacotherapy with varenicline). A 40-week non-treatment phase follows. The primary outcome is the point prevalence abstinence rate at week 12. Smoking status is self-reported and biochemically confirmed by end-expiratory exhaled carbon monoxide measurement. Further endpoints include post-cessational weight gain, nicotine craving analysis, glucose homeostasis and long-term nicotine abstinence.Two separate substudies assess behavioural, functional and structural changes by functional magnetic resonance imaging and measures of energy metabolism (i.e. resting energy expenditure, body composition).DiscussionCombining behavioural counselling and medical therapy, e.g. with varenicline, improves abstinence rates and is considered the standard of care. We expect a further increase in quit rates by adding a second component of medical therapy and assume a dual effect of dulaglutide treatment (blunting nicotine withdrawal symptoms and reducing post-cessational weight gain). This project is of high relevance as it explores novel treatment options aimed at preventing the disastrous consequences of nicotine consumption and obesity.Trial registrationClinicalTrials.gov NCT03204396. Registered on June 26, 2017.

Design, synthesis, and biological evaluation of a potential long-acting glucagon-like peptide-1 (GLP-1) analog

By binding to its receptor, glucagon-like peptide-1 (GLP-1) plays various physiological roles, including activating glucose-dependent insulin secretion, inhibiting gastric emptying, and reducing appetite. This suite of activities makes GLP-1 and its analogs an attractive choice for treating type 2 diabetes mellitus in the context of overweight or obesity. This study used different types and lengths of fatty acids to design dual fatty acid side chains for GLP-1 receptor agonists including decanoic, dodecanoic, tetradecanoic, hexadecanoic, dodecanedioic, tetradecanedioic, hexadecanedioic, and octadecanedioic acids. Sixteen GLP-1 receptor agonists (conjugates 13–28) with dual fatty acid side chains were obtained by liquid-phase synthesis. After structural confirmation using high-resolution mass spectrometry, peptide mapping, and circular dichroism, the biological activities of the conjugates were screened. First, the conjugates were screened for albumin binding and activity in GLP-1R-CRE-bla CHO-K1 cells. Albumin binding results suggested a synergistic effect between the two fatty acids in the conjugates. Next, conjugates 18, 19, and 21 selected after primary screening were assessed for receptor affinity, activity in INS-1 cells, plasma stability across different species, and efficacy and pharmacokinetics in normal and db/db mice. One candidate (conjugate 19) was found to have albumin binding of >99 %, good receptor affinity, activities of INS-1 cells, and plasma stability. We found that cellular activities in GLP-1R-CRE-bla CHO-K1 cells and pharmacodynamics and pharmacokinetics in normal and db/db mice for conjugate 19 were superior to those of semaglutide.

Exploring the Complex Relationship between Diabetes and Cardiovascular Complications: Understanding Diabetic Cardiomyopathy and Promising Therapies

Diabetes mellitus (DM) and cardiovascular complications are two unmet medical emergencies that can occur together. The rising incidence of heart failure in diabetic populations, in addition to apparent coronary heart disease, ischemia, and hypertension-related complications, has created a more challenging situation. Diabetes, as a predominant cardio-renal metabolic syndrome, is related to severe vascular risk factors, and it underlies various complex pathophysiological pathways at the metabolic and molecular level that progress and converge toward the development of diabetic cardiomyopathy (DCM). DCM involves several downstream cascades that cause structural and functional alterations of the diabetic heart, such as diastolic dysfunction progressing into systolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis, and subsequent heart failure over time. The effects of glucagon-like peptide-1 (GLP-1) analogues and sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular (CV) outcomes in diabetes have shown promising results, including improved contractile bioenergetics and significant cardiovascular benefits. The purpose of this article is to highlight the various pathophysiological, metabolic, and molecular pathways that contribute to the development of DCM and its significant effects on cardiac morphology and functioning. Additionally, this article will discuss the potential therapies that may be available in the future.

Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment.

Diabetes mellitus (DM) increases the destruction of periodontal tissue and impairs osteogenesis differentiation. Exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analogue, can be used for treating DM and promotes bone regeneration. The aim of this study was to explore the effect and mechanism of Ex-4 on improving the osteogenesis of periodontal ligament stem cells (PDLSCs) in a high glucose environment. Alkaline phosphatase staining and alizarin red staining were used to detect the osteogenic differentiation of PDLSCs. The results showed that 10 nM Ex-4 could reduce the osteogenesis inhibition of PDLSCs induced by high glucose. RT-PCR and western blot results showed that Ex-4 increased the osteogenesis-related gene expression of ALP, Runx2, and Osx, and upregulated the phosphorylation of P38, JNK, and ERK1/2; the peak effect was observed in the range 0.5-1.0 h. Mitogen-activated protein kinase (MAPK) inhibitors PD98059, SB203580, and SP600125 blocked the effects of Ex-4 on MAPK activation and decreased the expression of ALP, Runx2, and Osx in PDLSCs. Moreover, after Ex-4 treatment, the total β-catenin, p-GSK3β, LEF, and Runx2 protein levels increased under normal or high glucose environments. In conclusion, our results indicated that Ex-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of PDLSCs in a high glucose environment.

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

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

α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both invitro and invivo.

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its invivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t 1/2>14 days) compared to t 1/2 (<1 day) of GLP-1 in the blood plasma and invivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

Impact of GLP-1 receptor agonist versus omega-3 fatty acids supplement on obesity-induced alterations of mitochondrial respiration.

To compare administration of the glucagon-like peptide-1 (GLP-1) analogue, exenatide, versus dietary supplementation with the omega-3 fatty acid-rich Calanus oil on obesity-induced alterations in mitochondrial respiration. Six-week-old female C57BL/6JOlaHSD mice were given high fat diet (HFD, 45% energy from fat) for 12 weeks to induce obesity. Thereafter, they were divided in three groups where one received exenatide (10 μg/kg/day) via subcutaneously implanted mini-osmotic pumps, a second group received 2% Calanus oil as dietary supplement, while the third group received HFD without any treatment. Animals were sacrificed after 8 weeks of treatment and tissues (skeletal muscle, liver, and white adipose tissue) were collected for measurement of mitochondrial respiratory activity by high-resolution respirometry, using an Oroboros Oxygraph-2k (Oroboros instruments, Innsbruck, Austria). It was found that high-fat feeding led to a marked reduction of mitochondrial respiration in adipose tissue during all three states investigated - LEAK, OXPHOS and ETS. This response was to some extent attenuated by exenatide treatment, but not with Calanus oil treatment. High-fat feeding had no major effect on hepatic mitochondrial respiration, but exenatide treatment resulted in a significant increase in the various respiratory states in liver. Mitochondrial respiration in skeletal muscle was not significantly influenced by high-fat diet or any of the treatments. The precise evaluation of mitochondrial respiration considering absolute oxygen flux and ratios to assess flux control efficiency avoided misinterpretation of the results. Exenatide increased hepatic mitochondrial respiration in high-fat fed mice, but no clear beneficial effect was observed in skeletal muscle or fat tissue. Calanus oil did not negatively affect respiratory activity in these tissues, which maintains its potential as a dietary supplement, due to its previously reported benefits on cardiac function.

Proteomic analysis reveals semaglutide impacts lipogenic protein expression in epididymal adipose tissue of obese mice.

Obesity is a global health problem with few pharmacologic options. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that induces weight loss. Yet, the role of semaglutide in adipose tissue has not yet been examined. The following study investigated the mechanism of semaglutide on lipid metabolism by analyzing proteomics of epididymal white adipose tissue (eWAT) in obese mice. A total of 36 C57BL/6JC mice were randomly divided into a normal-chow diet group (NCD, n = 12), high-fat diet (HFD, n = 12), and HFD+semaglutide group (Sema, n = 12). Mice in the Sema group were intraperitoneally administered semaglutide, and the HFD group and the NCD group were intraperitoneally administered an equal volume of normal saline. Serum samples were collected to detect fasting blood glucose and blood lipids. The Intraperitoneal glucose tolerance test (IPGTT) was used to measure the blood glucose value at each time point and calculate the area under the glucose curve. Tandem Mass Tag (TMT) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to study the expression of eWAT, while cellular processes, biological processes, corresponding molecular functions, and related network molecular mechanisms were analyzed by bioinformatics. Compared with the model group, the semaglutide-treated mice presented 640 differentially expressed proteins (DEPs), including 292 up-regulated and 348 down-regulated proteins. Bioinformatics analysis showed a reduction of CD36, FABP5, ACSL, ACOX3, PLIN2, ANGPTL4, LPL, MGLL, AQP7, and PDK4 involved in the lipid metabolism in the Sema group accompanied by a decrease in visceral fat accumulation, blood lipids, and improvement in glucose intolerance. Semaglutide can effectively reduce visceral fat and blood lipids and improve glucose metabolism in obese mice. Semaglutide treatment might have beneficial effects on adipose tissues through the regulation of lipid uptake, lipid storage, and lipolysis in white adipose tissue.

Pharmacokinetics and brain distribution of the therapeutic peptide liraglutide by a novel LC–MS/MS analysis

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog that has been utilized for the treatment of type 2 diabetes mellitus. Liraglutide at a higher dose also shows beneficial effects in weight loss, which prompted its widespread use as an anti-obesity drug. The potential of liraglutide to treat Alzheimer’s disease and cognitive impairment has also been suggested. Nevertheless, the pharmacokinetics of liraglutide, including its distribution to the brain, has not been fully characterized. Therefore, this study aimed to develop a simple and sensitive bioanalytical method using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and determine the pharmacokinetics and brain distribution of liraglutide in rats. Liraglutide in the rat plasma and brain tissue homogenates was extracted by protein precipitation using methanol. A gradient elution profile was used for chromatographic separation with mobile phases comprising 0.3% formic acid in water and 0.3% formic acid in acetonitrile. The mass spectrometry was operated in the positive electrospray ionization with multiple reaction monitoring mode. The lower limit of quantification of the present LC–MS/MS was 1 ng/mL in the plasma and 2 ng/mL in the brain tissue. Following intravenous injection (0.05 mg/kg, n = 5), plasma concentrations of liraglutide decreased monoexponentially with an average half-life of 3.67 h. The estimated absolute bioavailability of liraglutide after subcutaneous injection was 13.16%. Brain distribution of liraglutide was not significant, with the tissue-to-plasma partition coefficient (Kp) of liraglutide less than 0.00031. However, the concentrations of liraglutide were significantly different in the different brain regions following IV injection. In the brain, liraglutide concentrations were the highest in the hypothalamus, followed by the cerebellum and cerebrum. The present LC–MS/MS assay and the pharmacokinetic results may be helpful to understand better the effect of liraglutide in the brain for further preclinical and clinical studies of liraglutide.

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial

Patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis are at high risk of liver-related and all-cause morbidity and mortality. We investigated the efficacy and safety of the glucagon-like peptide-1 analogue semaglutide in patients with NASH and compensated cirrhosis. This double-blind, placebo-controlled phase 2 trial enrolled patients from 38 centres in Europe and the USA. Adults with biopsy-confirmed NASH-related cirrhosis and body-mass index (BMI) of 27 kg/m2 or more were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2·4 mg or visually matching placebo. Patients were randomly allocated via an interactive web response system, stratified by presence or absence of type 2 diabetes. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH after 48 weeks, assessed by biopsy in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is closed and completed, and registered with ClinicalTrials.gov, number NCT03987451. 71 patients were enrolled between June 18, 2019, and April 22, 2021; 49 (69%) patients were female and 22 (31%) were male. Patients had a mean age of 59·5 years (SD 8·0) and mean BMI of 34·9 kg/m2 (SD 5·9); 53 (75%) patients had diabetes. 47 patients were randomly assigned to the semaglutide group and 24 to the placebo group. After 48 weeks, there was no statistically significant difference between the two groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06-1·24; p=0·087). There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (p=0·29). Similar proportions of patients in each group reported adverse events (42 [89%] patients in the semaglutide group vs 19 [79%] in the placebo group) and serious adverse events (six [13%] vs two [8%]). The most common adverse events were nausea (21 [45%] vs four [17%]), diarrhoea (nine [19%] vs two [8%]), and vomiting (eight [17%] vs none). Hepatic and renal function remained stable. There were no decompensating events or deaths. In patients with NASH and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo. No new safety concerns were raised. Novo Nordisk A/S.