Once-weekly Glucagon-like Peptide-1 Receptor Agonist Research Articles

Efficacy and safety of albiglutide, a once-weekly glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes: A systematic review and meta-analysis.

No meta-analysis has holistically analyzed and summarized the therapeutic efficacy and safety of albiglutide in type 2 diabetes (T2D). This meta-analysis addresses this knowledge gap. Randomized controlled trials involving patients with T2D receiving albiglutide in the intervention arm and either a placebo or an active comparator in the control arm were searched through electronic databases. The primary outcome was the change from baseline (CFB) in glycated hemoglobin (HbA1c); secondary outcomes included CFB in fasting plasma glucose, body weight, and adverse events (AE). From 443 initially screened articles, data from 12 randomized controlled trials involving 6423 subjects were analyzed. Albiglutide, at both doses, outperformed placebo in terms of HbA1c reductions (for albiglutide 30 mg: mean differences -1.04%, 95% confidence interval [CI] [-1.37--0.72], P < .00001, I2 = 89%; and for albiglutide 50 mg: mean differences -1.10%, 95% CI [-1.45--0.75], P < .00001, I2 = 90%). Higher proportions of subjects achieved HbA1c < 7% in the albiglutide arm than in placebo (for albiglutide 30 mg: odds ratio 6.26, 95% CI [2.50-15.70], P < .0001, I2 = 82%; and for albiglutide 50 mg: odds ratio 5.57, 95% CI [2.25-13.80], P = .0002, I2 = 84%). Albiglutide had glycemic efficacy comparable to other glucose-lowering drugs. CFB in body weight was similar with albiglutide and placebo. AE profile, including gastrointestinal AE, was identical with albiglutide and placebo, except for higher drug-related AE and injection-site reaction with albiglutide. Albiglutide provides reassuring data on good glycemic efficacy, tolerability, and safety over an extended period of clinical use in patients with T2D. Albiglutide 30 mg has comparable efficacy and safety profiles to albiglutide 50 mg.

EE139 Intensification with Insulin Glargine 300 U/Ml (Gla-300) or First- Generation Basal Insulins (BIs) in People with Type 2 Diabetes (T2D) on Once-Weekly Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs): Deliver New-G

EE139 Intensification with Insulin Glargine 300 U/Ml (Gla-300) or First- Generation Basal Insulins (BIs) in People with Type 2 Diabetes (T2D) on Once-Weekly Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs): Deliver New-G

Efficacy and safety of semaglutide in patients with heart failure with preserved ejection fraction and obesity.

Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, has shown promise in weight management and cardiovascular outcomes in other populations. This study aimed to evaluate the efficacy of semaglutide in heart failure with preserved ejection fraction(HFpEF) patients with obesity. A retrospective study analyzed 318 patients with HFpEF, of which 104 received semaglutide and 214 received placebo. Primary endpoints included evaluating changes in exercise capacity and weight management. Semaglutide treatment led to significant improvements in the primary endpoints. Patients in the semaglutide group demonstrated substantial enhancements in exercise capacity, as measured by the 6-min walk distance, compared to the placebo group (mean difference 15.1 meters, 95% CI 5.8 to 24.4, p = 0.002). Additionally, semaglutide resulted in substantial weight loss compared to placebo (mean difference -2.9%, 95% CI -4.1--1.7, p = 0.001). Several secondary endpoints, including reductions in C-reactive protein levels and improvements in other clinical parameters, further supported the efficacy of semaglutide. Adverse events were generally well-tolerated, with no unexpected safety concerns. Semaglutide demonstrated significant clinical benefits in HFpEF patients with obesity, as evidenced by improved symptoms, physical function, and weight reduction.

Real-world effectiveness of GLP-1 receptor agonist-based treatment strategies on "time in range" in patients with type 2 diabetes.

Background: Diabetes affects millions of people worldwide annually, and several methods, including medications, are used for its management; glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of medications. The efficacy and safety of GLP-1RAs in treating type 2 diabetes mellitus (T2DM) have been assessed and have been shown to significantly improve time in range (TIR) in several clinical trials. However, presently, there is a lack of real-world evidence on the efficacy of GLP-1RAs in improving TIR. To address this, we investigated the effect of GLP-1RA-based treatment strategies on TIR among patients with T2DM in real-world clinical practice. Methods: This multicenter, retrospective, real-world study included patients with T2DM who had previously used a continuous glucose monitoring (CGM) system and received treatment with GLP-1RAs or oral antidiabetic drugs (OADs). Patients who received OADs served as controls and were matched in a 1:1 ratio to their GLP-1RA counterparts by propensity score matching. The primary endpoint was the TIR after 3-6 months of treatment. Results: According to propensity score matching, 202 patients were equally divided between the GLP-1RA and OAD groups. After 3-6 months of treatment, the TIR values for the GLP-1RA and OAD groups were 76.0% and 65.7%, respectively (p < 0.001). The GLP-1RA group displayed significantly lower time above range (TAR) and mean glucose values than the OAD group (p < 0.001). Subgroup analysis revealed that, compared with the administration of liraglutide, the administration of semaglutide and polyethylene glycol loxenatide (PEG-Loxe) significantly improved TIR over 3-6 months of treatment (p < 0.05). Conclusion: These real-world findings indicate that GLP-1RA-based treatment strategies could be superior to oral treatment strategies for improving TIR among patients with T2DM and that once-weekly GLP-1RA may be more effective than a once-daily GLP-1RA. Clinical trial registration: http://www.chinadrugtrials.org.cn/index.html, identifier number ChiCTR2300073697.

Comparing Machine Learning and Advanced Methods with Traditional Methods to Generate Weights in Inverse Probability of Treatment Weighting: The INFORM Study.

Observational research provides valuable insights into treatments used in patient populations in real-world settings. However, confounding is likely to occur if there are differences in patient characteristics associated with both the exposure and outcome between the groups being evaluated. One approach to reduce confounding and facilitate unbiased comparisons is inverse probability of treatment weighting (IPTW) using propensity scores. Machine learning (ML) and entropy balancing can potentially be used in generating propensity scores for IPTW, but there is limited literature on this application. We aimed to assess the feasibility of applying these methods for reducing confounding in observational studies. These methods were assessed in a study comparing cardiovascular outcomes in adults with type 2 diabetes and established atherosclerotic cardiovascular disease taking once-weekly glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors. We applied advanced methods to generate the propensity scores compared to the original logistic regression method in terms of covariate balance. After calculating weights, a weighted Cox proportional hazards model was used to calculate the sample average treatment effect. Support Vector Classification, Support Vector Regression, XGBoost, and LightGBM were the ML models used. Entropy balancing was also performed on features identified in the original cardiovascular outcomes study. Accuracy (range: 0.71 to 0.73), area under the curve (0.77 to 0.79), precision (0.53 to 0.60), recall (0.66 to 0.68), and F1 score (0.60 to 0.64) were similar between all of the advanced propensity score methods and traditional logistic regression. Among ML models, only XGBoost achieved balance in all measured baseline characteristics between the two treatment groups, closely approximating the performance of the original logistic regression. Entropy balancing weights provided the best performance among all models in balancing baseline characteristics, achieving near perfect balancing. Among the advanced methods examined, entropy balancing weights performed the best for optimizing balancing and can produce similar results compared to traditional logistic regression.

PEGylated exenatide injection (PB-119) improves beta-cell function and insulin resistance in treatment-naïve type 2 diabetes mellitus patients.

Objective: PB-119, a PEGylated exenatide injection, is a once-weekly glucagon-like peptide-1 receptor agonist. In the present study, we aimed to evaluate the effects of PB-119 on insulin resistance and beta-cell function in Chinese patients with type 2 diabetes mellitus (T2DM) to uncover its antidiabetic characteristics. Methods: A total of 36 Chinese T2DM patients were randomized to receive 25μg and 50μg PB-119 once weekly and exenatide (5-10μg injected under the skin 2 times a day adjusted by the doctor) for 12weeks. Oral mixed meal tolerance tests were conducted before the study and on Day 79. The data were fitted to estimate beta-cell function and insulin sensitivity parameters using the SAAM II package integrating the oral minimal model (OMM), which was compared with Homeostatic Model Assessment (HOMA) analysis results. Results: Exenatide or PB-119 treatment, compared with their baseline, was associated with higher beta-cell function parameters (φb, φs and φtot), disposition index, insulin secretion rates, and a lower glucose area under the curve. High-dose PB-119 also has a higher insulin resistance parameter (SI) than the baseline, but HOMA-IR did not. For the homeostatic model assessment parameters, HOMA-IR showed no statistically significant changes within or between treatments. Only high-dose PB-119 improved HOMA-β after 12weeks of treatment. Conclusion: After 12weeks of treatment, PB-119 decreased glycemic levels by improving beta-cell function and insulin resistance.

Comparison of clinical efficacy and safety of weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in Japanese patients with type 2 diabetes: Randomized, parallel-group, multicentre, open-label trial (COMING study).

To compare the clinical usefulness of once-weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes. In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24-week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks. HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%-6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%-7.4 ± 0.8%) (p < .0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p < .05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p < .0001). The parameters such as low-density lipoprotein cholesterol, alanine aminotransferase and γ-glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p < .01). The Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group. This prospective trial showed that semaglutide has more pronounced glucose- and body mass index-lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms.

Effects of once-weekly glucagon-like peptide-1 receptor agonists on type 2 diabetes mellitus complicated with coronary artery disease: Potential role of the renin-angiotensin system.

To investigate the potential mechanism of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the treatment of type 2 diabetes mellitus (T2DM) complicated with coronary artery disease (CAD). We searched both Chinese and English databases for randomized controlled trials related to once-weekly GLP-1 RA for T2DM complicated with CAD to verify the safety and efficacy of GLP-1 RA. The underlying mechanism was analysed by network pharmacology. In total, 13 studies with 35 563 participants were included in the analysis. The pooled analysis found that dulaglutide, exenatide and semaglutide outperformed placebo in cardiovascular outcomes in patients with T2DM, with a significant reduction in the incidence of non-fatal stroke (p < .00). Levels of cardiovascular risk factors were significantly reduced in the once-weekly GLP-1 RA group compared with the conventional treatment group (glycated haemoglobin: p < .00; fasting blood glucose: p < .00; weight: p < .00; systolic blood pressure: p < .00; total cholesterol: p < .00; low-density lipoprotein cholesterol: p < .00). Network pharmacology results were enriched to the renin-angiotensin system, and matrix metalloproteinase 2 and renin (REN) may be the key targets. In addition, four key targets of dulaglutide, five key targets of exenatide and two key targets of semaglutide were enriched. Our study suggests that once-weekly GLP-1 RA may have a potential protective effect on cardiovascular events in patients with T2DM combined with CAD, possibly through the renin-angiotensin system. However, further research is needed to confirm these findings and determine cause and effect.

78-LB: PK Studies in Rats and Minipigs of GB-7001, a Novel Monthly Microsphere Formulation Containing High Drug Content of Semaglutide

Semaglutide, a once-weekly GLP-1 receptor agonist, has been developed as a treatment for type 2 diabetes and obesity. Currently, the longest-acting GLP-1 product (including dulaglutide, semaglutide, and tirzepatide) is a weekly injection, and there are no approved once-monthly long-acting injectables. There is a need for a product that lasts up to 1 month to improve patient convenience. GB-7001 is a monthly injectable with high content of semaglutide under development with an improvement that reduces the side effect of existing microspheres. The goal of this study is to investigate the pharmacokinetics (PK) of GB-7001 in rats and minipigs. Pharmacokinetic evaluation in rats and minipigs was performed by a single subcutaneous injection, and semaglutide concentration in serum was analyzed by liquid chromatography-tandem mass spectrometry. GB-7001 had a spherical shape with a D50 value of 34.4 µm. The drug content of semaglutide was determined to be 18.0%. Regardless of the high drug content, the sustained release of GB-7001 was shown for up to 28 days without an initial burst and without a lag phase. Although the release rate of GB-7001 slows after 28 days, semaglutide was detected within the quantifiable range for up to 56 days. In conclusion, GB-7001 is an improved 1-month semaglutide injectable that has shown promising results in PK studies in rats and minipigs. Further preclinical studies of the final formulation are scheduled, and GB-7001 is planned to apply for IND once the final formulation is selected. Disclosure E. Seol: None. Y. Kim: None. Funding Ministry of Health &amp; Welfare, Republic of Korea (HI21C1732)

791-P: Comparing the Real-World Effects of Once-Weekly GLP-1 RAs and DPP-4 Inhibitors on Ischemic Stroke and Myocardial Infarction in Individuals with T2D and ASCVD

Despite guidelines advocating for their use, there is limited real-world evidence comparing the effects of once-weekly (OW) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 inhibitors (DPP-4is) on the risk of cardiovascular events in individuals with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). This retrospective cohort study compared the time to incidence of ischemic stroke, myocardial infarction (MI), and 2-point major adverse cardiovascular events (MACE; ischemic stroke or MI) while on treatment in new adult users of OW GLP-1 RAs and DPP-4is who had T2D and ASCVD using data from the Optum Clinformatics® Data Mart (2017-2021). Patients were followed until drug discontinuation, enrollment end, or an event. Inverse probability of treatment weighting was used to balance baseline characteristics, and survival analyses were conducted to compare risks during exposure, defined as continuous use of either drug. We found that users of OW GLP-1 RAs (weighted N=25,287) had significantly lower risks of ischemic stroke (HR=0.74 [95% CI, 0.63, 0.87]), MI (0.78 [0.67, 0.92]), and 2-point MACE (0.76 [0.68, 0.86]) compared with users of DPP-4is (weighted N=39,684; all P&amp;lt;0.01). This study suggests that OW GLP-1 RAs reduce the risk of MI and stroke relative to DPP-4is in individuals with T2D and ASCVD. Disclosure X. Tan: Employee; Merck &amp; Co., Inc. Stock/Shareholder; Merck &amp; Co., Inc. Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Y. Liang: Employee; Novo Nordisk. J.R. Rajpura: Employee; Novo Nordisk. L. Yedigarova: Employee; Novo Nordisk. Stock/Shareholder; AbbVie Inc. J. Noone: Employee; Novo Nordisk. L. Xie: Employee; Pfizer Inc., Novo Nordisk A/S. A. de Havenon: Consultant; Novo Nordisk, Integra Lifesciences Holdings Corp. Other Relationship; UpToDate. Stock/Shareholder; TitinKM, Certus.

Impact of polyethylene glycol loxenatide on cardiovascular outcomes in patients with type 2 diabetes: study protocol for a multicentre, randomised, double-blind, placebo-controlled trial (BALANCE-3)

IntroductionRecent cardiovascular outcomes trials have demonstrated that glucagon-like peptide 1 receptor agonist (GLP-1RA) decreases the incidence of major adverse cardiovascular events (MACEs) in individuals with type 2 diabetes mellitus (T2DM)....

Antidiabetic Therapy in Patients Related to CKD (Chronic Kidney Disease)

Patients with type 2 diabetes mellitus (T2DM) are more likely to have chronic kidney disease (CKD) in stages 3-5 (glomerular filtration rate [GFR] 60 mL/min) by roughly 25–30%. Despite the limits of most oral anti-diabetic medications in people with CKD, incretin-based treatments are being utilized more frequently to treat type 2 diabetes. This study examines the impact of CKD on the pharmacokinetics of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, as well as the efficacy/safety profile of these medications when used in patients with T2DM and CKD. Sitagliptin, Vildagliptin, Saxagliptin, and Alogliptin are the most common DPP-4 inhibitors that are primarily excreted by the kidneys. This led to recommendations for appropriate dose reductions based on the severity of CKD after pharmacokinetic studies revealed that total exposure to the medication is increased in proportion to the fall in GFR. Clinical investigations found that patients with CKD had a high effectiveness and safety profile under these circumstances. Lintagliptin, on the other hand, is primarily excreted through the hepatobiliary system. No dose adjustment of lintagliptin is necessary in the setting of CKD because a pharmacokinetic investigation revealed that lower GFR had a negligible impact on total exposure. Patients with CKD have less experience using GLP-1 receptor agonists. Exenatide should not be administered to patients with severe CKD because it is excreted through renal processes. Due to the limited experience with CKD patients, ligarglutide should be administered with caution even if the kidneys do not remove it from the body. For lixisenatide, exenatide long-acting release (LAR), and other once-weekly GLP-1 receptor agonists now under development, only scant pharmacokinetic data are also available. GLP-1 receptor agonists have been implicated in several case reports of acute renal failure, which was most likely brought on by dehydration brought on by gastrointestinal side effects. Nevertheless, improving GLP-1 may also have advantageous renal effects that could help lower the incidence of diabetic nephropathy. In conclusion, the physician has new chances due to the DPP-4 inhibitors' broad and encouraging experience in CKD patients, whereas the limited experience with GLP-1 receptor agonists in this population calls for greater caution.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist

Ashley.H.Shoemaker@VUMC.org International Journal of Obesity 2022, Epub 2022 Jan 3. doi: 10.1038/s41366-021-01043-6. https://pubmed.ncbi.nlm.nih.gov/34975146/

An exploratory clinical trial on the efficacy and safety of glucagon-like peptide-1 receptor agonist dulaglutide in patients with type 2 diabetes on maintenance hemodialysis

BackgroundDulaglutide is a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). However, the efficacy and safety of dulaglutide remain unclear in insulin-treated patients with T2DM on maintenance hemodialysis (HD).MethodsDulaglutide treatment was initiated, and the insulin dose was adjusted according to the needs of individual participants. Primary outcomes were changes in the mean and standard deviation (SD) of blood glucose (BG) levels and mean amplitude of glycemic excursions (MAGE) evaluated by continuous glucose monitoring (CGM) for six days, glycated albumin (GA), glycated hemoglobin (HbA1c), pre-dialysis blood glucose levels, and daily total insulin dose from the baseline over 24 weeks. Secondary outcomes were changes in treatment satisfaction and QOL levels from the baseline, measured by using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Diabetes Therapy-Related Quality of Life questionnaire (DTR-QOL) scores.ResultsThe analysis was performed on the 12 participants who completed the study. The GA level (median − 1.8 [interquartile range − 6.6, − 0.3] %; p = 0.026) and daily total insulin dose (− 15.0 [− 24.5, − 9.4] U/day; p = 0.002) significantly decreased without increasing hypoglycemia (area over the glucose curve < 70 mg/dL: 0.0 [− 0.2, 0.0] mg·24 h/dl; p = 0.917). Four patients successfully withdrew from insulin therapy. The levels of HbA1c, SD of BG, and MAGE showed a decreasing tendency, but no significant improvement. Regarding treatment satisfaction and QOL, the total scores of DTSQ (8.0 [0.3, 12.5]; p = 0.041) and DTR-QOL (15.5 [− 1.8, 42.0]; p = 0.023) significantly improved.ConclusionDulaglutide may help improve glycemic control, treatment satisfaction, and QOL without increasing hypoglycemia in insulin-treated patients with T2DM on maintenance HD.Trial registration This study was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on October 11, 2016 (registration ID, UMIN000024283).

5-LB: Dulaglutide in Youth with Type 2 Diabetes (T2D) —Results of the AWARD-PEDS Randomized, Placebo-Controlled Trial

AWARD-PEDS was a Phase 3 trial to assess the efficacy and safety of dulaglutide (DU) , a once-weekly GLP-1 receptor agonist, in youth (10 to &amp;lt;18 years old) with T2D treated with lifestyle alone or on stable metformin with or without basal insulin. Participants (mean age, 14.5 yrs; mean BMI, 34.1 kg/m2) were randomized to placebo (N=51) , DU 0.75 mg (N=51) , or DU 1.5 mg (N=52) . The primary aim was to demonstrate superiority of DU (pooled doses) vs. placebo for change in HbA1c at 26 weeks. Analyses included all patients with ≥1 dose of study drug, excluding data after initiation of rescue therapy. DU was superior to placebo (figure) in improving glycemic control measured by change in HbA1c, percent of patients with HbA1c &amp;lt;7%, and change in fasting glucose at Week 26. No effect of DU was observed on BMI change (p=0.776) . Fewer patients assigned to DU compared to placebo required rescue therapy (2.9% vs. 17.6% respectively, p=0.003) . Incidence of common GI adverse events was higher in DU group vs. placebo [nausea (14.6% vs. 7.8%) , vomiting (15.5% vs. 3.9%) , diarrhea (18.4% vs. 13.7%) ] but comparable to that observed in adults. In conclusion, in youth with inadequately controlled T2D treated with or without metformin and/or basal insulin, once weekly DU 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control without an effect on BMI through 26 weeks, with a safety profile consistent with that established in adults. Disclosure S. A. Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk. Research Support; Eli Lilly and Company, Novo Nordisk. Other Relationship; AstraZeneca. J. Cho: None. T. S. Hannon: Advisory Panel; Eli Lilly and Company. P. Zeitler: Consultant; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited. L. Chao: None. M. Barrientos: Research Support; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Research &amp; Development, LLC, Novo Nordisk. C. C. Boucher-Berry: None. E. Bismuth: None. S. A. Dib: None. D. Cox: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

719-P: Tirzepatide Induces Weight Loss in Patients with Type 2 Diabetes Regardless of Baseline BMI: A Post Hoc Analysis of SURPASS-1 through -5 Studies

Tirzepatide (TZP) is a novel once-weekly dual GIP and GLP-1 receptor agonist evaluated in patients with type 2 diabetes (T2D) . Five Phase 3 SURPASS (S) trials have demonstrated safety and shown robust efficacy of TZP in improvement of glycaemic control and body weight (BW) in adults with T2D. To understand whether the weight-lowering effects of TZP are dependent on baseline BMI, we conducted subgroup analyses of S-1 through -5. BW change in the BMI subgroups (Subgroup 1 [&amp;lt;27 or ≥27 kg/m2] and Subgroup 2 [&amp;lt;30; ≥30 to &amp;lt;35; ≥35 kg/m2]) at primary endpoint was assessed in patients while on treatment without rescue medication (efficacy estimand) in the modified intention-to-treat (mITT) population, defined as all randomized patients who received at least one dose of study drug. All TZP doses (5, 10, 15 mg) lowered BW in patients with T2D irrespective of baseline BMI in both subgroups (p&amp;lt;0.001) . The weight reductions were generally dose-dependent and absolute weight change was generally greater in higher BMI categories. TZP-treated patients with T2D experienced weight loss across a spectrum of mean baseline BMI values in S-1 through -5 studies. The most frequent adverse events were GI-related events that were mild to moderate in severity and occurred during the dose-escalation period. Disclosure A.Kwan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Maldonado: Employee; Eli Lilly and Company. H.Wang: None. N.Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. J.Wilding: Advisory Panel; Alnylam Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Mundipharma, Novo Nordisk A/S, Rhythm Pharmaceuticals, Inc., Sanofi, Research Support; AstraZeneca, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. Funding Eli Lilly and Company

Abstract #1184056: Tirzepatide Improves Glucose Levels from Baseline Irrespective of Gender: A Post Hoc Analysis of the SURPASS-1 to -5 Studies

Tirzepatide is a once-weekly dual GIP and GLP-1 receptor agonist developed as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes (T2D). The SURPASS (S) program spanning the T2D disease progression from no background therapy to multiple background combinations and comparators led to robust improvements in glycaemic control by tirzepatide as shown by a reduction in HbA1c and fasting serum glucose (FSG) at 40 and/or 52 weeks. This post-hoc analysis from the 5 SURPASS studies (S-1 to S-5) assessed the effect of tirzepatide on glycaemic control and safety, according to patient gender.

The Efficacy of Treatment Intensification by Quadruple Oral Therapy Compared to GLP-1RA Therapy in Poorly Controlled Type 2 Diabetes Mellitus Patients: A Real-world Data Study.

We compared the glycemic efficacy of treatment intensification between quadruple oral antidiabetic drug therapy and once-weekly glucagon-like peptide-1 receptor agonist (GLP-1RA)-based triple therapy in patients with poorly controlled type 2 diabetes mellitus refractory to triple oral therapy. For 24 weeks, changes in glycosylated hemoglobin (HbA1c) from baseline were compared between the two treatment groups. Of all 96 patients, 50 patients were treated with quadruple therapy, and 46 were treated with GLP-1RA therapy. Reductions in HbA1c for 24 weeks were comparable (in both, 1.1% reduction from baseline; P=0.59). Meanwhile, lower C-peptide level was associated with a lower glucose-lowering response of GLP-1RA therapy (R=0.3, P=0.04) but not with quadruple therapy (R=-0.13, P=0.40). HbA1c reduction by GLP-1RA therapy was inferior to that by quadruple therapy in the low C-peptide subgroup (mean, -0.1% vs. -1.3%; P=0.04). Treatment intensification by switching to quadruple oral therapy showed similar glucose-lowering efficacy to weekly GLP-1RA-based triple therapy. Meanwhile, the therapeutic response was affected by C-peptide levels in the GLP-1RA therapy group but not in the quadruple therapy group.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist.

Background/Objectives:Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure.Subjects/Methods:Forty-two patients aged 10–26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n=23) or placebo (n=19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference.Results:As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (−1 800 kJ (−430 kcal), 95% CI −3 184 to −418 kJ, p= 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (−695 kJ/day (−166 kcal/day), 95% CI −1 130 to −264 kJ/day, p< 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (−372 kJ/day (−89 kcal/day), 95% CI −699 to −42 kJ/day, p= 0.04) or change in leptin (−695 kJ/day (−166 kcal/day), 95% CI −1 130 to −264 kJ/day, p< 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p= 0.88 and 1.5 vs. 4.6 kg fat mass, p= 0.04, ExQW vs. placebo).Conclusions:Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

Tirzepatide: A Novel, Once-weekly Dual GIP and GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes.

Gastrointestinal hormones are currently used to treat type 2 diabetes mellitus (T2D). Incretin preparations with gastric inhibitory polypeptide (GIP) activity or glucagon-like peptide-1 (GLP-1) provide new means for controlling blood glucose levels, body weight, and lipid metabolism. GIP, an incretin, has not been used due to lack of promising action against diabetes. However, recent studies have shown that GIP has an important effect on glucagon and insulin secretion under normoglycaemic conditions. Co-existence of GIP with GLP-1 and glucagon signalling leads to a stronger effect than that of GLP-1 stimulation alone. The development of a GIP/GLP-1R unimolecular dual agonist with affinity for both GIP and GLP-1 receptors is under investigation, and the drug is expected to be clinically available in the near future. Tirzepatide, a GIP/GLP-1R unimolecular dual agonist, regulates metabolism via both peripheral organs and the central nervous system. The SURPASS phase III clinical trials conducted for tirzepatide comprise 10 clinical trials, including five global trials and the global SURPASS-CVOT trial, with >13,000 patients with T2D (ClinicalTrials.gov Identifier: NCT04255433). The clinical application of tirzepatide as a therapy for T2D may provide new insights into diabetic conditions and help clarify the role of GIP in its pathogenesis.