Administration Of Dulaglutide Research Articles

Dulaglutide reduces oxidative DNA damage and hypermethylation in the somatic cells of mice fed a high-energy diet by restoring redox balance, inflammatory responses, and DNA repair gene expressions.

Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide's expediency in treating obesity and its associated complications.

Correlation between intestinal flora and GLP-1 receptor agonist dulaglutide in type 2 diabetes mellitus treatment—A preliminary longitudinal study

GLP-1 receptor agonists (GLP-1 RA) are presently used as the first-line drugs for the clinical treatment of type 2 diabetes mellitus (T2DM). It can regulate blood glucose by stimulating insulin secretion and lowering glucagon levels. We used 16S rRNA amplicon sequencing to detect structural changes in the composition of the intestinal flora of newly diagnosed T2DM after 1 and 48weeks of dulaglutide administration. Our research found no significant changes in the intestinal flora after the administration of dulaglutide for 1week to subjects with newly diagnosed T2DM. Nevertheless, after 48weeks of dulaglutide administration, the composition of the intestinal flora changed significantly, with a significant reduction in the abundance of intestinal flora. Furthermore, we found that fasting glucose levels, fasting c-peptide levels, HbA1c levels, and BMI are also closely associated with intestinal flora. This reveals that intestinal flora may be one of the mechanisms by which dulaglutide treats T2DM.

The effect of subcutaneous dulaglutide on weight loss in patients with Type 2 diabetes mellitus: Systematic review and meta-analysis of randomized controlled trials.

Dulaglutide, a subcutaneously administered glucagon-like peptide 1 receptor agonist, has been hypothesized to lead to weight loss in patients with Type 2 diabetes mellitus (T2DM). However, the consequences of its prescription on body weight (BW) and other anthropometric indices, for example, body mass index (BMI) or waist circumference (WC), have not been completely clarified. Therefore, we aimed to assess the effects of subcutaneous dulaglutide administration on BW, BMI and WC values in T2DM subjects by means of a systematic review and meta-analysis of RCTs. We computed a literature search in five databases (PubMed/Medline, Web of Science, EMBASE, Scopus and Google Scholar) from their inception to February 2023 to identify RCTs that examined the influence of subcutaneous dulaglutide on obesity indices. We calculated effect sizes using the random-effects model (using DerSimonian-Laird method). Results were derived across weighted mean differences (WMD) and 95% confidence intervals (CI). Subgroup analyses were applied to explore possible sources of heterogeneity among the RCTs. The current systematic review and meta-analysis was conducted in compliance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. In total, 18 studies with 33 RCT arms (BW = 33 RCT arms, 14,612 participants, 7869 cases and 6743 controls; BMI = 10 RCT arms, 14,612 subjects, 7869 cases and 6743 controls; WC = 10 RCT arms, 1632 participants, 945 cases and 687 cases) were included in the meta-analysis. BW (WMD: -0.86 kg, 95% CI: -1.22, -0.49, p < 0.001), BMI (WMD: -0.68 kg/m2 , 95% CI: -0.88, -0.49, p < 0.001) and WC (WMD: -1.23 cm, 95% CI: -1.82, -0.63, p < 0.001) values decreased notably following subcutaneous dulaglutide administration versus placebo. BW notably decreased in RCTs lasting >18 weeks (WMD: -1.42 kg, 95% CI: -1.90, -0.94, p < 0.001), whereas notable reductions in WC were seen in RCTs lasting ≤18 weeks (WMD: -1.78 cm, 95% CI: -2.59, -0.98, p < 0.001). Dulaglutide dosages >1 mg/day significantly decreased BW (WMD: -1.94 kg, 95% CI: -2.54, -1.34, p < 0.001), BMI (WMD: -0.80 kg/m2 , 95% CI: -1.07, -0.54, p < 0.001) and WC (WMD: -1.47 cm, 95% CI: -1.80, -1.13, p < 0.001). BW decreased particularly following dulaglutide prescription in individuals with obesity (WMD: -1.05 kg, 95% CI: -1.28, -0.82, p < 0.001) versus overweight. The dose-response meta-analysis revealed that BW decreased significantly when dulaglutide was prescribed in doses ≤3 mg/day versus >3 mg/day. Subcutaneous dulaglutide administration in T2DM reduces BW, BMI and WC. The decrease in BW and WC was influenced by the dose and the duration of dulaglutide administration. The reduction in BMI was only influenced by the dosage of dulaglutide. Moreover, T2DM patients who suffered from obesity experienced a notable decrease in BW versus T2DM subjects without obesity.

Dulaglutide provides protection against sepsis-induced lung injury in mice by inhibiting inflammation and apoptosis

Sepsis is a dangerous condition with a high mortality rate. In addition to promoting insulin secretion in a glucose-dependent manner, glucagon-like peptide-1 (GLP-1) also exhibits anti-inflammatory properties. Dulaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we investigated the effects and mechanism of action of dulaglutide (Dul) in lipopolysaccharide (LPS) induced lung injury in mice with sepsis. In mice with LPS (15 mg/kg, ip, qd)-induced acute lung injury, the administration of dulaglutide (0.6 mg/kg, ip, qd) improved weight loss, reduced lung injury, reversed the increase in IL-1β, TNF-α, IL-6, CXCL1, CCL2 and CXCL2 expression in the lung, and reduced the infiltration of neutrophils and macrophages in the lung tissues. The decline in caspase-3, cleaved caspase-3, caspase-8, and Bcl-2/Bax expression and the increase in the number of TUNEL positive cells in the lung were reversed, suggesting that GLP-1RA could play a protective role in the lung by inhibiting inflammation and apoptosis. In addition, GLP-1RA could reduce the expression of P-STAT3 and NLRP3, suggesting that P-STAT3 and NLRP3 may be potential targets against lung injury in sepsis. Collectively, our data demonstrated that GLP-1RA exerts a protective effect against sepsis-induced lung injury through mechanisms related to the inhibition of inflammation, apoptosis, and STAT3 signaling.

Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice.

Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.

Immediate Glucose-Lowering Effect After the First Administration of Dulaglutide: A Retrospective, Single-Center, Observational Study

IntroductionDulaglutide is a long-acting glucagon-like peptide 1 receptor agonist that is administered once weekly for the treatment of type 2 diabetes. However, the immediate glucose-lowering effect of dulaglutide after the first administration and the factors affecting the efficacy of the drug remain unclear.MethodsThis study was a retrospective and observational study of 80 subjects with type 2 diabetes conducted in a hospitalized setting. The changes (Δ) in the blood glucose (BG) levels at six time points (6-point BG levels) from the baseline (day − 1) to the day after the first administration of 0.75 mg of dulaglutide (day 1) were evaluated. The associations of the Δ 6-point BG levels with the patients’ characteristics and laboratory data were also analyzed.ResultsSignificant reduction of the fasting BG, preprandial BG, postprandial BG, and standard deviation (SD) of the 6-point BG levels was observed on day 1 as compared to day − 1 (P < 0.0001) and the reduced BG levels were maintained throughout the remaining observation period of 5 days. The baseline serum hemoglobin A1c and glycoalbumin levels were positively correlated with the reduction of the fasting BG. The Δ BG levels were not related to the parameters of insulin-secreting capacity. Insulin treatment was positively associated with the reduction of the 6-point BG levels. Patients without cerebrovascular disease and patients without diabetic retinopathy showed greater improvements of the fasting BG and SD of the 6-point BG levels, respectively. Urinary microalbumin level was positively correlated with improvements of the 6-point BG levels. Dulaglutide reduced the BG levels, irrespective of the previously used class of antidiabetic medication(s).ConclusionDulaglutide achieved reduction in glucose level within 24 h of the first injection. The improvement in the BG levels remained stable for a week in the hospitalized clinical setting.

Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandrogenemia and ovarian function in DHEA-induced PCOS rats

ObjectiveThe purpose of this study was to explore the effect of dulaglutide on DHEA induced PCOS rats and its mechanism, to provide new drugs and research directions for clinical treatment of PCOS. MethodsIn this study, the PCOS model was established by giving female SD rats subcutaneous injection of DHEA for 21 consecutive days. After modeling, the treatment group was injected subcutaneously with three doses of dulaglutide for 3 weeks. The model group was injected with sterile ultrapure water, and the normal group did not get any intervention. The body weight changes of rats in each group were recorded from the first day when rats received the administration of dulaglutide. Three weeks later, the rats were fasted the night after the last treatment, determined fasting insulin and fasting glucose the next day. After the rats were anesthetized by chloral hydrate, more blood was collected from the heart of the rat. The serum insulin, testosterone and sex hormone binding globulin (SHBG) levels were detected by the enzyme-linked immunoassay method. After removing the adipose tissue, the obtained rat ovary tissue was used for subsequent experimental detection, using HE staining for morphology and follicular development analysis; qRT-PCR for the detection of 3βHSD, CYP17α1, CYP19α1, and StAR gene expression in ovarian tissue; and western blotting analysis of CYP17α1, CYP19α1, StAR protein expression and insulin level to verify whether dulaglutide has a therapeutic effect on PCOS in rats. ResultsAfter treated with different concentrations of dulaglutide, we found that the body weight of rats in the treatment groups were reduced. Compared with the rats in PCOS group, the serum androgen level of rats in the treatment groups was significantly decreased, and the serum sex hormone binding protein content was significantly increased, and there was statistically significant difference between these groups and PCOS group. In terms of protein expression and gene regulation, the expression of 3βHSD, CYP19α1 and StAR in the ovarian tissue of rats in treatment groups were decreased significantly after received the treatment of dulaglutide, and there was statistically significant difference between these groups and PCOS group. In addition, dulaglutide reduced the insulin content in the ovarian tissue of PCOS rats. ConclusionDulaglutide may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3βHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats. In addition, dulaglutide may reduce the weight of PCOS rats, further reducing the level of high androgen in PCOS rats, and improving the morphology of their polycystic ovaries.

Efficacy of dulaglutide: an evidence-based review of its potential indications

Diabetes mellitus (DM) is the biggest noncontagious epidemic in human history. This review is addressing an urgent challenge of modern healthcare - the treatment of type 2 diabetes mellitus (DM2). Key attention is paid to the prevention of the development and progression of type 2 diabetes complications and the need to manage risk factors for cardiovascular diseases (CVD), which are the leading cause of high mortality rates in people with type 2 diabetes. The clinical trials (CT) of recent decades contributed to the build-up of a solid evidence base on the effect of various antihyperglycemic drugs on the development of diabetic complications and outcomes in patients with T2DM. Also, the emergence of innovative classes of antihyperglycemic drugs have significantly expanded the potential of T2DM therapy. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of glucose-lowering drugs that affect many pathogenetic mechanisms of T2DM and have a high safety profile. Creation of extended-release forms of GLP-1 RAs is an important step in the treatment of T2DM. Dulaglutide (Trulicity) has become the first GLP-1 RA for the treatment of T2DM (2016) authorized in Russia that can be used once weekly without regard to timing of food ingestion, which contributes to high compliance with treatment. The evidence base on the efficacy and safety of dulaglutide is continuously expanding. The authors paid attention to the issues of cardiovascular safety of the administration of dulaglutide, discussed the main results of REWIND study, and brought up a problem about the expediency of an earlier initiation of primary prevention of cardiovascular events in patients with type 2 diabetes. The results of the REWIND study made it possible to recommend the inclusion of GLP-1 RAs into the therapy of patients with type 2 diabetes and cardiovascular risk factors with a view to get additional advantages in terms of life prognosis.

Effects of Switching from Liraglutide or Dulaglutide to Subcutaneous Semaglutide on Glucose Metabolism and Treatment Satisfaction in Patients with Type 2 Diabetes: Protocol for a Multicenter, Prospective, Randomized, Open-Label, Blinded-Endpoint, Parallel-Group Comparison Study (The SWITCH-SEMA 1 Study).

IntroductionGlucagon-like peptide (GLP)-1 receptor agonists exert potent hypoglycemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent manner. Once-weekly subcutaneous administration of the GLP-1 receptor agonist semaglutide has beneficial effects on glycemic and body weight control, but it is currently unclear if semaglutide provides superior glycemic control compared to conventional GLP-1 receptor agonists in the Japanese population. We aim to compare the effects of once-weekly subcutaneous semaglutide with those of liraglutide or dulaglutide administration in Japanese patients with T2D.MethodsThis study is a multicenter, prospective, randomized, open-label, blinded-endpoint, parallel-group trial. In total, 100 participants with T2D who have been treated with liraglutide (0.9–1.8 mg/day in plan A) or dulaglutide (0.75 mg/week in plan B) for more than 12 weeks and have a glycated hemoglobin (HbA1c) level of 6.0–9.9% and a body mass index (BMI) of ≥ 22 kg/m2 will be randomized to either continue using their existing GLP-1 receptor agonist or switch to subcutaneous semaglutide once weekly for 24 weeks. Biochemical analysis, physical assessment, and a quality-of-life questionnaire (DTSQ) will be completed at baseline and at the end of the study. The primary endpoint is the effect of semaglutide on the change in HbA1c. The secondary endpoints are the mean changes in total DTSQ score, body mass, abdominal circumference, systolic and diastolic blood pressure, pulse rate, factors associated with improvement in HbA1c and secondary endpoints, side effects, and other laboratory parameters.Planned OutcomesThe results of the study will provide useful information regarding the effects of switching to semaglutide from other GLP-1 receptor agonists on glycemic control in patients with T2D.Ethics and DisseminationThe Hokkaido University Certified Review Board (CRB no. 1180001) has approved the protocol (no. 018-005). The results will be disseminated in peer-reviewed journals and at scientific conferences.Trial RegistrationUMIN000042369 in the University Hospital Medical Information Network (UMIN); jRCT1011200008 in the Japan Registry of Clinical Trials (jRCT); pre-results.

Patients' preferences for once-daily oral versus once-weekly injectable diabetes medications: The REVISE study.

AimsTo understand patient preferences for once‐daily oral versus once‐weekly injectable type 2 diabetes mellitus (T2DM) medication administration profiles, and reasons for their preferences.Materials and methodsThe REVISE study, a cross‐sectional online survey of 600 participants with T2DM (United Kingdom, n = 300; United States, n = 300), elicited general preferences for once‐daily oral versus once‐weekly injectable diabetes medications, and reasons for the preference. Participants then viewed two videos describing the administration procedures for injectable dulaglutide and oral semaglutide, based on the product instructions for use. Thereafter, participants indicated their preference for a once‐weekly injectable or a once‐daily oral medication based on the video descriptions. Participants who switched preferences were asked to identify the reasons influencing their decision.ResultsThe participants were predominantly male (n = 349; 58.2%), with a mean (SD) age of 64 (11.3) years. Nearly all (n = 557; 92.8%) were taking an oral T2DM medication, and 158 (26.3%) were using an injectable. Initially, 76.5% (n = 459; 95% confidence interval [CI] 73.1–79.9) preferred a once‐daily oral and 23.5% a once‐weekly injectable (n = 141; 95% CI 20.1–26.9; P < 0.0001). After viewing the videos describing the product‐specific administration, the proportions of participants preferring each option were not statistically different (oral semaglutide administration description (n = 315; 52.5%; 95% CI 48.5–56.5; dulaglutide administration description (n = 285; 47.5%; 95% CI 43.5–51.5; NS, P = 0.2207). The most common reason for switching preferences was the timing and steps of administration.ConclusionSeveral treatment‐related characteristics, including route, frequency and complexity of the treatment, play a role in patients' preferences for T2DM treatments and should be considered during treatment selection.

Elderly Diabetic Patients with Effective Add-on Therapy of Dulaglutide as a GLP-1 Receptor Analogue (GLP-1 RA)

Background: For diabetic treatment, Dulaglutide has been used and effective as a glucagon-like peptide-1 receptor analogue (GLP-1 RA). This report is to describe the various responses and to analyze dulaglutide administration in the elderly with DM. Case presentation: Two patients were Type 2 Diabetes Mellitus (T2DM) treated with add-on therapy of Dulaglutide. Case 1 is 81-year-old female is diabetic for 2 years, and on Metformin and Glimepiride as Oral Hypoglycemic Agents (OHAs). Her HbA1c was higher with 10.6% and she was started to given Dulaglutide 0.75mg. Remarkable efficacy was found in 3 months with HbA1c 6.7%. Value of LDL-C increased from 135 mg/dL to 158 mg/dL. Case 2 is 83-year-old male with 27 years of diabetes. He was on medication of Metformin and Glimepiride. His HbA1c persisted around 9.0%-9.4%, then he was provided Dulaglutide as add-on therapy. In 3 months, HbA1c decreased to 8.2% and LDL-C increased from 57 mg/dL to 116 mg/dL. Discussion and conclusion: Dulaglutide is a useful GLP-1 RA with once a week administration. There were some reports concerning LDL changes after dulaglutide therapy, showing that the changes may depend on the basal LDL value before the administration of dulaglutide. Dulaglutide may influence lipid metabolism. This report is expected to become reference in diabetic practice and research in the future.

Long-term treatment with a glucagon-like peptide-1 receptor agonist reduces ethanol intake in male and female rats

Given the limited efficacy of available pharmacotherapies for treatment of alcohol use disorder (AUD), the need for new medications is substantial. Preclinical studies have shown that acute administration of glucagon-like peptide-1 receptor (GLP-1R) agonists inhibits various ethanol-related behaviours, indicating this system as a potential target for AUD. However, the effects of long-term systemic treatment of GLP-1R agonists on ethanol intake in male and female rodents are to date unknown. Therefore, we investigated the effects of 9 or 5 weeks of once weekly administration of dulaglutide, a long-acting GLP-1R agonist, on ethanol intake in male and female rats. The ethanol intake during treatment discontinuation was also monitored. In an initial attempt to identify preliminary underlying mechanisms, the effects of 9 weeks of once weekly dulaglutide treatment on monoaminergic signalling in reward-related areas were explored in both sexes. We found that 9 or 5 weeks of once weekly dulaglutide treatment reduced ethanol intake and preference in male and female rats. Following discontinuation of dulaglutide treatment, the decrease in ethanol consumption was prolonged in males, but not females. We demonstrated that 9 weeks of dulaglutide treatment differentially influenced monoaminergic signalling in reward-related areas of male and female rats. Collectively, these data imply that the GLP-1R attracts interest as a potential molecular target in the medical treatment of AUD in humans: more specifically, dulaglutide should be evaluated as a potential medication for treatment thereof.

Association of glucagon-like peptide-1 receptor-targeted imaging probe with invivo glucagon-like peptide-1 receptor agonist glucose-lowering effects.

Aims/IntroductionGlucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are used for treatment of type 2 diabetes mellitus worldwide. However, some patients do not respond well to the therapy, and caution must be taken for certain patients, including those with reduced insulin secretory capacity. Thus, it is clinically important to predict the efficacy of GLP‐1RA therapy. GLP‐1R‐targeted imaging has recently emerged to visualize and quantify β‐cells. We investigated whether GLP‐1R‐targeted imaging can predict the efficacy of GLP‐1RA treatment.Materials and MethodsWe developed 111Indium‐labeled exendin‐4 derivative (111In‐Ex4) as a GLP‐1R‐targeting probe. Diabetic mice were selected from NONcNZO10/LtJ male mice that were fed for different durations with 11% fat chow. After 3‐week administration of dulaglutide as GLP‐1RA therapy, mice with non‐fasting blood glucose levels <300 mg/dL and >300 mg/dL were defined as responders and non‐responders, respectively. In addition, ex vivo 111In‐Ex4 pancreatic accumulations (111In‐Ex4 pancreatic values) were examined.ResultsThe non‐fasting blood glucose levels after treatment were 172.5 ± 42.4 mg/dL in responders (n = 4) and 330.8 ± 20.7 mg/dL in non‐responders (n = 5), respectively. Ex vivo 111In‐Ex4 pancreatic values showed significant correlations with post‐treatment glycohemoglobin and glucose area under curve during an oral glucose tolerance test (R 2 = 0.76 and 0.80; P < 0.01 and <0.01, respectively). The receiver operating characteristic area under curve for identifying responders by ex vivo 111In‐Ex4 pancreatic values was 1.00 (P < 0.01).Conclusion Ex vivo 111In‐Ex4 pancreatic values reflected dulaglutide efficacy, suggesting clinical possibilities for expanding GLP‐1R‐targeted imaging applications.

Efficacy and Safety of Dulaglutide by Baseline HbA1c in Chinese Patients with Type 2 Diabetes: A Post Hoc Analysis.

IntroductionTo evaluate the efficacy and safety of dulaglutide 0.75 and 1.5 mg in patients with type 2 diabetes mellitus (T2DM) by baseline glycated hemoglobin (HbA1c) < 8.5% or ≥ 8.5% after 26 weeks of treatment.MethodsAssessment of the Weekly AdministRation of dulaglutide in Diabetes (AWARD) China 1 (CHN1) study (NCT01644500, n = 556) included patients on dulaglutide vs. glimepiride who were treatment naïve or on monotherapy but discontinued therapy. AWARD-CHN2 (NCT01648582, n = 591) patients were on dulaglutide vs. insulin glargine and continued on metformin and/or sulfonylurea. Mean daily dose of glimepiride and insulin glargine was 2.51 mg and 21.0 IU, respectively. Post hoc analyses were conducted based on mixed-model repeated measures using a modified intent-to-treat analysis set with only the Chinese population. Change from baseline in HbA1c and body weight was analyzed by individual study.ResultsIn the two studies, 70.1% of patients in AWARD-CHN1 and 59.7% in AWARD-CHN2 had baseline HbA1c < 8.5% (mean HbA1c 7.4% and 7.6%, respectively) and 29.9% in AWARD-CHN1 and 40.3% in AWARD-CHN2 had baseline HbA1c ≥ 8.5% (mean HbA1c 9.2% and 9.4%, respectively). In AWARD-CHN1, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: − 1.1% and − 2.2%; dulaglutide 0.75 mg: − 0.9% and − 2.0%; glimepiride: − 0.7% and − 1.4%. In AWARD-CHN2, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: − 1.2% and − 2.3%; dulaglutide 0.75 mg: − 1.0% and − 1.7%; and insulin glargine: − 0.6% and − 1.7%. Irrespective of baseline HbA1c, body weight decreased with both dulaglutide doses and increased with either glimepiride or insulin glargine at 26 weeks. Dulaglutide demonstrated low incidence of hypoglycemia in both doses in the two trials. Hypoglycemia incidence was generally lower in patients with baseline HbA1c ≥ 8.5%.ConclusionsDulaglutide demonstrated significantly greater HbA1c reduction with weight loss and lower risk of hypoglycemia compared with active comparators in Chinese patients with T2DM irrespective of baseline HbA1c, with much greater HbA1c reductions in patients with a higher baseline HbA1c.Trial registrationClinicalTrials.gov identifier, NCT01644500 and NCT01648582.Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00804-2) contains supplementary material, which is available to authorized users.

1008-P: Efficacy of Dulaglutide on Renal Functions in the Real-World Clinical Practice for Diabetes in Japan

Aims: Efficacy of a GLP-1 receptor agonist, dulaglutide, on renal functions in type 2 diabetic patients under the real-world clinical practice in Japan was retrospectively examined. Subjects: 154 patients with type 2 diabetes treated with dulaglutide (0.75 mg once weekly) in our clinic (mean administration period 540.7 ± 332 days; mean age 58.1 years; mean duration of diabetes 10.5 years). Methods: Dulaglutide was added to the conventional antidiabetes drugs. The dose of sulfonylurea was reduced by 50-67% and all the DPP-4 inhibitors were discontinued. The annual changes in eGFR between 1 year before and 2 years after the administration of dulaglutide were retrospectively analyzed in 2 groups divided by the baseline eGFR; eGFR&amp;lt;90 ml/min/1.73m2 group and eGFR≧90 group. Changes in HbA1c levels and body weight were also evaluated. Results: eGFR in the eGFR&amp;lt;90 group (n = 90) rapidly declined (-5.4 ± 7.8/year) before the administration of dulaglutide (p &amp;lt;0.001). However, the decline was moderate after the administration of dulaglutide (-1.2 ± 7.1/year after 1 year, p = 0.134; -1.1 ± 5.8/year between 1 and 2 years, p = 0.179). In contrast, eGFR in the eGFR≧90 group (n = 57) was not declined before the administration of dulaglutide (+ 1.4 ± 6.6/year, p = 0.318), and significantly decreased after the administration of dulaglutide (-2.9 ± 10.0/year after 1 year, p = 0.036; -2.5 ± 6.8/year between 1 and 2 years, p = 0.048). HbA1c levels were 8.70 ± 1.76% at baseline, -1.32 ± 1.69% at 1 year (p &amp;lt;0.001, n = 86), -1.19 ± 1.56% at 2 years (p &amp;lt;0.001, n = 39). Body weight were 71.3 ± 15.2 kg at baseline, -1.86 ± 3.38 kg at 1 year (p &amp;lt;0.001, n = 86), -2.04±3.33 kg at 2 years (p=0.001, n=39). Conclusions: These observations suggest that dulaglutide may ameliorate renal hyperfiltration and protect renal functions. Disclosure S.T. Sato: None. T. Tosaki: Research Support; Self; Daiichi Sankyo Company, Limited, Sanofi K.K. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. M. Kondo: None. Y. Yamada: None. A. Inagaki: None. S. Tsunekawa: None. T. Himeno: None. Y. Kato: Speaker's Bureau; Self; Merck &amp; Co., Inc. J. Nakamura: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceu. Co. Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. H. Kamiya: Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K.K., MSD K.K., Novartis Pharma K.K., Novo Nordisk Oharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K.

Effect of Once-Weekly Dulaglutide on Glucose Levels in Japanese Patients with Type 2 Diabetes: Findings from a Phase 4, Randomized Controlled Trial.

IntroductionDulaglutide is a recombinant glucagon-like peptide-1 immunoglobulin G4 Fc fusion protein approved for treating patients with type 2 diabetes (T2D). The aim of this study was to assess postprandial data over 4 weeks for dulaglutide (0.75 mg) versus placebo after a standardized test meal in Japanese patients with T2D.MethodsThe pharmacodynamic (PD) effects of once-weekly dulaglutide (0.75 mg) in Japanese patients with T2D on diet and exercise therapy (N = 12) were evaluated by assessing postprandial data up to week 4 in a phase 4, single-center, randomized, cross-over, single-blind, placebo-controlled study. The primary end point was the change in 4-h glucose area under the concentration versus time curve [AUC (0–4 h)] from baseline to week 4. Secondary end points included changes from baseline in other PD parameters (insulin, C-peptide, glucagon, and triglycerides) at weeks 1, 2, and 4 and the safety and tolerability of dulaglutide 0.75 mg. Continuous glucose monitoring (CGM) during the 1st week was performed as an exploratory measure in each treatment period.ResultsThe decrease in AUC (0–4 h) from baseline to week 4 following dulaglutide administration was statistically significant compared with placebo at weeks 1, 2, and 4 (P < 0.0001). Insulin and C-peptide levels were also significantly increased (P < 0.05) with dulaglutide versus placebo at weeks 2 and 4. There were no statistically significant differences between groups in glucagon and triglyceride levels. Daily average glucose concentrations were decreased on the day after the first administration of dulaglutide and remained at similar levels for 4 days. The incidence of treatment-emergent adverse events was slightly higher with dulaglutide versus placebo.ConclusionIn conclusion, dulaglutide decreased postprandial glucose from week 1 in Japanese patients with T2D, indicating that dulaglutide treatment is associated with favorable PD effects soon after treatment begins.Trial RegistrationClinicalTrials.gov identifier: NCT03315780.FundingEli Lilly Japan K.K. (Kobe, Japan).Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0605-7) contains supplementary material, which is available to authorized users.

Dulaglutide Modulates the Development of Tissue-Infiltrating Th1/Th17 Cells and the Pathogenicity of Encephalitogenic Th1 Cells in the Central Nervous System.

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.

Durability of Glucose-Lowering Effect of the First Administration of Dulaglutide: A Retrospective, Single-Center, Single-Arm Study.

IntroductionDulaglutide (Dula) is a once-weekly glucagon-like peptide-1 receptor agonist that efficiently reduces the level of glycated hemoglobin (HbA1c) in patients with type 2 diabetes (T2D). However, the durability of the glucose-lowering effect of the first injection of Dula (1st Dula) remains unclear.MethodsThis study had a retrospective, single-center, and single-arm design in a clinical setting and was conducted between April 2016 and March 2017. We investigated the changes and fluctuations in glucose level in 15 patients with T2D using a continuous glucose monitor, from 1 day before the first administration of Dula to 6 days thereafter.ResultsThe mean glucose levels decreased significantly from 1 day before 1st Dula up to 5 days thereafter, whereas the standard deviation, mean amplitude of glucose excursion, and percentage of the glucose levels > 180 mg/dL were significantly improved only up to 3, 2, and 3 days after the 1st Dula, respectively, compared to those before administration.ConclusionThe effect of blood glucose regulation after the 1st Dula did not continue for a whole week. These effects should be considered when adjusting for other hypoglycemic agents.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0474-5) contains supplementary material, which is available to authorized users.

Improved Glycemic Control due to Reduction in Glucagon Levels by the Administration of Once-Weekly Dulaglutide in a Non-Obese Patient With Type 2 Diabetes

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a cornerstone for the management of obesity and type 2 diabetes. GLP-1RAs improve the glycemic control by suppressing glucagon secretion and stimulating insulin secretion in patients with type 2 diabetes. Here, we report the case of a patient with type 2 diabetes with postprandial hyperglucagonemia who was successfully treated by the administration of once-weekly dulaglutide. A 67-year-old, non-obese woman was admitted to our hospital for preoperative glycemic control. Her glycemic control significantly improved after the administration of dulaglutide. Both fasting and postprandial plasma glucagon levels were effectively suppressed by dulaglutide, which ameliorated hyperglycemia. Thus, to achieve an optimal glycemic control, clinicians should consider suppressing glucagon secretion in addition to improving insulin secretion and sensitivity. J Endocrinol Metab. 2018;8(1):6-9 doi: https://doi.org/10.14740/jem486w

Low body mass index and old age are useful in predicting the hemoglobin A1c-lowering effect of switching from sitagliptin to dulaglutide in Japanese patients with type 2 diabetes mellitus: a single-center, open-label, single-arm, pilot study.

The purpose of this study was to clarify the predictive clinical characteristics of therapy switching from sitagliptin to dulaglutide in patients with type 2 diabetes mellitus. This single-center, open-label, investigator-initiated pilot study was conducted in 40 patients with type 2 diabetes mellitus. The patients, who had been treated with 50mg sitagliptin daily for at least 6months were switched to 0.75mg dulaglutide weekly. A total of 36 patients could be followed for 24weeks of treatment with dulaglutide. They were assessed for several clinical parameters before the start of and 24weeks after the study. Multiple linear regression analysis was used to search for independent predictors of reduction of hemoglobin A1c (HbA1c) levels after 24weeks of treatment switching from sitagliptin to dulaglutide. Dulaglutide administration for 24weeks resulted in significant reductions in fasting plasma glucose (FPG), HbA1c, and low-density lipoprotein cholesterol (LDL-C) levels. In addition, baseline HbA1c, FPG, body mass index (BMI), and age were significantly correlated with the change in HbA1c levels (ΔHbA1c). Furthermore, multiple linear regression analysis revealed that BMI and age significantly correlated with ΔHbA1c. In summary, our prospective 24-week study showed that baseline low BMI and old age are significantly useful in predicting the HbA1c-lowering effect of switching from sitagliptin to dulaglutide. UMIN Clinical Trials Registry (UMIN000023245).