Dual Glucose-dependent Insulinotropic Polypeptide Research Articles

Compounded GLP 1 and Dual GIP/GLP 1 Receptor Agonists: A Statement from the American Diabetes Association

The use of glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA (GIP/GLP-1 RA) classes has increased substantially over the past several years for treating type 2 diabetes and obesity. Increased demand for these pharmacotherapies has resulted in temporary product shortages for both GLP-1 RA and dual GIP/GLP-1 RA medications. These shortages, in part, have led to entities producing and marketing compounded formulations that bypass regulatory measures, raising safety, quality, and efficacy concerns. Even as shortages resolve, compounded GLP-1 RA and GIP/GLP-1 RA products continue to be heavily marketed to people with diabetes and obesity. The purpose of this statement by the American Diabetes Association is to guide health care professionals and people with diabetes and/or obesity in these circumstances of medication unavailability to promote optimal care and medication use safety.

Comparison of cardiovascular outcomes in patients with diabetes treated with tirzepatide versus semaglutide: a multi-institutional analysis

Abstract Introduction Glucagon-like-peptide-1 (GLP-1) receptor agonists have been demonstrated to have cardiovascular benefits in patients with diabetes. Two of the most prescribed medications in this class are tirzepatide and semaglutide. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, while semaglutide is a selective GLP-1 receptor agonist. Tirzepatide and semaglutide have previously been directly compared to assess efficacy in glycemic control as the primary endpoint. However, there is limited data directly comparing cardiovascular outcomes between the two medications in patients with diabetes. This retrospective cohort study compares the incidence of major adverse cardiovascular events (MACE) in patients with diabetes treated with tirzepatide or semaglutide. Purpose The purpose of this study is to identify differences in cardiovascular outcomes between patients with diabetes treated with tirzepatide as compared to semaglutide. Materials and Methods The TriNetX research network was used for this study. Two patient cohorts were generated using International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX system. Both cohorts of patients had a history of diabetes (E08-E13) and no prior history of cerebral vascular accident (I63) or myocardial infarction (I21). One cohort received semaglutide and the other tirzepatide. Each cohort was prohibited from receiving the other agent. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm resulting in 36,212 patients in each arm. They were then evaluated for the 3-year outcomes of major adverse cardiovascular events (myocardial infarction, cerebral vascular accident, and death). Results Tirzepatide was associated with statistically significantly fewer MACE outcomes compared to semaglutide for each of the individual endpoints as well as the overall composite endpoint over the 3 year follow up period. Table 1. MACE events for semaglutide and tirzepatide. Table 2. Relative risks for semaglutide MACE endpoints compared to tirzepatide. Conclusions In this retrospective cohort study, tirzepatide was associated with a lower incidence of major adverse cardiovascular events compared to semaglutide in patients with diabetes. These findings suggest that tirzepatide offers superior cardiovascular protection for primary prevention compared to semaglutide and warrant further investigation in future studies and clinical trials.Table 1Table 2

Exploring cutting-edge approaches in diabetes care: from nanotechnology to personalized therapeutics.

Diabetes mellitus (DM) is a persistent condition characterized by high levels of glucose in the blood due to irregularities in the secretion of insulin, its action, or both. The disease was believed to be incurable until insulin was extracted, refined, and produced for sale. In DM, insulin delivery devices and insulin analogs have improved glycemic management even further. Sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones are examples of newer-generation medications having high efficacy in decreasing hyperglycemia as a result of scientific and technological advancements. Incretin mimetics, dual glucose-dependent insulinotropic polypeptide, GLP-1 agonists, PPARs, dipeptidyl peptidase-4 inhibitors, anti-CD3 mAbs, glucokinase activators, and glimins as targets have all performed well in recent clinical studies. Considerable focus was placed on free FA receptor 1 agonist, protein tyrosine phosphatase-1B inhibitors, and Sparc-related modular calcium-binding protein 1 which are still being studied. Theranostics, stem cell therapy, gene therapy, siRNA, and nanotechnology are some of the new therapeutic techniques. Traditional Chinese medicinal plants will also be discussed. This study seeks to present a comprehensive analysis of the latest research advancements, the emerging trends in medication therapy, and the utilization of delivery systems in treating DM. The objective is to provide valuable insights into the application of different pharmaceuticals in the field of diabetes mellitus treatment. Also, the therapeutic approach for diabetic patients infected with COVID-19 will be highlighted. Recent clinical and experimental studies evidence the Egyptian experience. Finally, as per the knowledge of the state of the art, our conclusion and future perspective will be declared.

Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future.

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or overweight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2% and weight loss exceeding 15% from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease.

Does glucose-dependent insulinotropic polypeptide receptor blockade as well as agonism have a role to play in management of obesity and diabetes?

Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.

Evaluating the Efficacy and Safety of Tirzepatide on Glycaemic and Non-glycaemic Outcomes in Diabetes: A Systematic Review of Meta-Analyses.

Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, recently approved for type 2 diabetes mellitus (T2DM) and obesity. A systematic review of the literature published in multiple meta-analyses on Tirzepatide with emphasis on its effect on glycaemic and non-glycaemic parameters was conducted. We systematically searched the electronic databases PubMed and Google Scholar up to August 2023 for meta-analyses that compared Tirzepatide with placebo or active antihyperglycaemic drugs in subjects with T2DM. Various parameters for efficacy and safety, with their point estimates and confidence intervals, such as glycated haemoglobin (HbA1c), fasting serum glucose (FSG), body weight, lipid, and cardiovascular outcomes were assessed. Six meta-analyses fulfilled the pre-specified criteria and were included in the study. In all the studies, Tirzepatide treatment at different doses resulted in a significant reduction in HbA1c and FSG levels along with a significant reduction in weight compared with active control and placebo groups. Tirzepatide significantly reduced levels of triglycerides and increased high-density lipoprotein (HDL) cholesterol, whether used as monotherapy or add-on therapy. The studies suggested the cardiovascular safety ofTirzepatide as there was no increase in major adverse cardiovascular events(MACE). The drug shows lesser hypoglycemia but predominant gastrointestinal adverse effects such as nausea, vomiting, and diarrhoea. In conclusion, Tirzepatide shows superior glycaemic control and weight loss in patients with T2DM with beneficial effects on lipids, without an increased risk of hypoglycemia and cardiovascular events.

Practical guide: Glucagon-like peptide-1 and dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus.

In 2005, exenatide became the first approved glucagon-like peptide-1 receptor agonist (GLP-1 RA) for type 2 diabetes mellitus (T2DM). Since then, numerous GLP-1 RAs have been approved, including tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, which was approved in 2022. This class of drugs is considered safe with no hypoglycemia risk, making it a common second-line choice after metformin for treating T2DM. Various considerations can make selecting and switching between different GLP-1 RAs challenging. Our study aims to provide a comprehensive guide for the usage of GLP-1 RAs and dual GIP and GLP-1 RAs for the management of T2DM.

Tirzepatide prevents neurodegeneration through multiple molecular pathways

BackgroundSeveral evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders.MethodsWe investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures.ResultsFor the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level.ConclusionsWe demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy.Graphical

Tirzepatide Prescribing Practices and Efficacy in Patients with Diabetes and Chronic Kidney Disease at a Large Tertiary Care Center in the United States.

Chronic kidney disease is a frequent complication of diabetes mellitus. Tirzepatide is the first dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for glycemic control in patients with type 2 diabetes. We present the efficacy and prescribing practices of tirzepatide in a cohort with diabetes and chronic kidney disease in a large tertiary care setting. We retrospectively identified new outpatient tirzepatide prescriptions in adults ≥18 years with diabetes and chronic kidney disease stages 1-5 from 2022 to 2023 across the Barnes Jewish Hospital system (St Louis, Missouri). We identified 102 subjects with chronic kidney disease and diabetes who started tirzepatide between 2022 and 2023, and used for ≥6 months. Mean duration of tirzepatide use in our cohort was 13.89 ± 2.51 months. Among subjects who stopped, 57% (n=4) were due to limited medication availability or lack of insurance coverage. Tirzepatide use led to a significant reduction in hemoglobin A1c by 1.15%, weight by nearly 10%, systolic and diastolic blood pressure, and total cholesterol (p<0.05 for all). We found that tirzepatide was an effective therapy with significant benefits on glycemic control, blood pressure, cholesterol, and weight in subjects with diabetes and chronic kidney disease treated at a tertiary care facility.

In brief: GI effects of GLP-1 receptor agonists.

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide (Mounjaro) are widely prescribed for treatment of type 2 diabetes and weight management (see Table 1), but they delay gastric emptying and commonly cause nausea and vomiting. Gastroparesis and bowel obstruction (ileus) have also been reported with their use.

THU255 Tirzepatide-induced Weight Loss In A Type 2 Diabetic Taking Oral Contraceptives

Abstract Disclosure: A. Arunachalam: None. A. Nguyen: None. N.L. Shah: None. Obesity is a global health challenge which can lead to type 2 diabetes, hypertension, cardiovascular disease, and decreased life expectancy. In addition to lifestyle intervention, pharmacotherapy to sustain weight loss has remained limited due to effectiveness, cost, and adverse effects. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like-peptide-1 receptor agonist currently approved for type 2 diabetes treatment. Tirzepatide-induced weight loss may provide new options for treatment of obesity. We report a 32-year-old female with a history of T2DM and PCOS originally on metformin who was started on semaglutide 0.25 mg, which was uptitrated to 0.5mg weekly for 6 months. She lost 25 lbs with no side effects. Semaglutide and OCPs were discontinued due to fertility with her weight and hemoglobin A1C rebounding off medication. She was started on tirzepatide 2.5mg weekly. At that time, she weighed 223 lbs with a hemoglobin A1C 8.2%. She was counseled to resume OCPs and improve glucose control and weight reduction prior to attempting to conceive. Once increased tirzepatide dosing to 5mg weekly, she endorsed severe nausea and intermittent epigastric abdominal pain on day of injection. She attempted to increase dose to 7.5mg weekly, but dose was reduced due to complaints of constipation and worsened abdominal pain requiring bowel regimen. She remained on tirzepatide for a total of 4 months prior to becoming pregnant while on oral contraceptives. Her weight decreased from 223 to 212 lbs with reduction in hemoglobin A1C from 8.2% to 6.1%. While initially studied for use in type 2 diabetes, tirzepatide was found to induce clinically significant weight reduction. The recent SURMOUNT-1 trial, which studied the effects of tirzepatide in non-diabetics, demonstrated that once-weekly tirzepatide at three different doses demonstrated substantial and sustained weight reduction in patients with obesity. In trials involving patients with once-weekly injectable semaglutide, the mean reduction in hemoglobin A1C was 1.8 percentage points and reduction in mean body weight was 6.5 kg. In the SURPASS-2 trial, reductions in body weight were greater with tirzepatide when compared to semaglutide with mean estimated treatment difference −1.9kg, -3.6kg, and -5.5 kg respectively based on dosing of 5mg, 10mg, and 15mg. The adverse events most commonly reported in patients on tirzepatide include nausea, vomiting, and diarrhea, which occurred most commonly during dose-escalation. Mounjaro is known to reduce the efficacy of oral contraceptive pills due to delayed gastric emptying. This delay is largest after the first dose so recommended to switch from oral to non-oral contraceptives for the first four weeks when tirzepatide is initiated. It is important to counsel patients on the decreased efficacy of oral contraceptives while on tirzepatide. &amp;lt;!--EndFragment--&amp;gt; Presentation: Thursday, June 15, 2023

Comparing Efficacy and Safety of Different Doses of Tirzepatide for the Treatment of Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials.

Our study assessedthe efficacyand safety of the three primary tirzepatide (TZP) doses, 5 mg, 10 mg, and 15 mg using network meta-analysis to assess their relative impact on type 2 diabetes mellitus (T2DM) treatment.This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Two authors independently screened online databases, including PubMed, Cochrane Library, and Embase. We employed the keywords "Type 2 diabetes OR T2DM or diabetes" AND "Tirzepatide OR LY3298176 OR twincretin OR dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist" AND "randomized controlled trial". The outcomes evaluated in this study comprised changes in hemoglobin (Hb)A1c levels from baseline (%), changes in weight from baseline (Kg), changes in fasting serum glucose from baseline (mg/dL), and occurrences of serious adverse events (SAE), adverse events (AE) and major adverse cardiovascular events (MACE). A total of eight studies met the inclusion criteria and were included in this meta-analysis. Our findings suggest that among the evaluated doses, TZP at 15 mg demonstrated superior effectiveness in reducing HbA1c, weight, and fasting serum glucose compared to doses of 10 mg and 5 mg. Notably, the reduction in HbA1c and weight showed a dose-dependent trend, with the 15 mg dose achieving the most substantial benefits. The safety analysis indicated that while serious adverse events and major adverse cardiovascular events (MACE) did not significantly differ among the three doses, the risk of overall adverse events was notably higher in the 10 mg and 15 mg TZP groups compared to the 5 mg group.

Tirzepatide for type 2 diabetes.

One in ten adults worldwide is living with diabetes, with 95% having type 2 diabetes (T2D). Sustained glycaemic control in people with T2D is difficult to achieve despite recent advances in T2D management with the advent of glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Tirzepatide represents a first-in-class agent as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP1RA to be approved in the USA and Europe for the treatment of T2D. This narrative review intends to list and discuss the glycaemic efficacy, key safety and weight loss outcomes related to the treatment of T2D with tirzepatide. Tirzepatide has been evaluated in five published clinical trials (n=6278) within the SURPASS clinical trial programme, with a focus on glycaemic control and weight loss. These trials have demonstrated significant improvements in glycosylated haemoglobin (-1.24% to -2.11% versus placebo and -0.6% to -1.14% versus active comparator) and weight (up to 15.5 kg versus placebo or active comparator) in patients with T2D. Notably, tirzepatide exhibited superior glycaemic control and weight loss when compared directly with a GLP1RA. Adverse events with the use of tirzepatide are similar to other approved GLP1RA and are predominantly gastrointestinal (nausea, vomiting). The tirzepatide cardiovascular outcomes trial (SURPASS-CVOT) is in progress and is expected to be completed in the fall of 2024. Tirzepatide represents an attractive new option and first-in-class agent for the treatment of T2D in people unable to achieve their glycaemic or weight management goals.

Obesity wars: hypothalamic sEVs a new hope.

There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application.

The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease.

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA1c and body weight in people with type 2 diabetes. This has led to increasing scientific interest in incretin hormones and incretin interactions, and several compounds based on dual- and multi-agonists are now being investigated for the treatment of metabolic diseases. Herein, we highlight the key scientific advances in utilising incretins for the treatment of obesity and, potentially, non-alcoholic fatty liver disease (NAFLD). The development of multi-agonists with multi-organ targets may alter the natural history of these diseases.

Efficacy and safety of the dual GIP and GLP-1 receptor agonist tirzepatide for weight loss: a meta-analysis of randomized controlled trials.

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes. We performed a meta-analysis to assess tirzepatide's weight reduction efficacy and safety. We searched PubMed, Embase, and Cochrane for randomized controlled trials published from inception to July 2022, comparing tirzepatide with placebo for the co-primary endpoints of absolute and percent change in weight. Mean difference (MD) and odds ratio (OR) were calculated for continuous and binary outcomes, respectively. Review Manager 5.4.1 and RStudio were used for the statistical analysis, and RoB-2 (Cochrane) to assess the risk of bias. Of 397 search results, 6 studies (4036 participants) ranging from 12 to 72 weeks were included. Pooled analysis showed that tirzepatide 5 mg, 10 mg, and 15 mg were more effective than placebo, with MD in body weight of -7.7 kg (95% CI -11.0, -4.4; p < 0.001), -11.6 kg (95% CI -18.8, -4.3; p = 0.002), and -11.8 kg (95% CI -17.4, -6.2; p < 0.001), respectively, and MD in percent change in weight of -8.1% (95% CI -11.0, -5.2; p < 0.001), -11.9% (95% CI -18.1, -5.6; p < 0.001), and -12.4% (95% CI -17.2, -7.5; p < 0.001), respectively. Tirzepatide also reduced BMI and waist circumference. Adverse events were more common with tirzepatide with respect to nausea (OR 4.2; 95% CI 2.4, 7.5; p < 0.001), vomiting (OR 7.0; 95% CI 4.3, 11.4; p < 0.001), and diarrhea (OR 2.8; 95% CI 1.6, 4.9; p < 0.001) (15 mg dose), when compared with placebo. The results support that tirzepatide leads to substantial weight reduction and constitutes a valuable therapeutic option for weight management, despite an increase in gastrointestinal symptoms. CRD42022348576.

Semaglutide versus tirzepatide for people with type 2 diabetes: cost of glycemic control in Austria, the Netherlands, Lithuania, and the United Arab Emirates

Objectives The glucagon-like peptide-1 agonist semaglutide and the dual glucose-dependent insulinotropic polypeptide tirzepatide have proven to significantly reduce glucose levels in people with type 2 diabetes. However, the costs needed to achieve a sustained decrease in HbA1c level and disease control with semaglutide and tirzepatide, respectively, are unclear. Therefore, this study aimed to compare the cost of treatment with semaglutide with the cost of treatment with tirzepatide for type 2 diabetes in Austria, the Netherlands, Lithuania, and the United Arab Emirates in order to determine their respective value for money. Methods The primary outcome of this analysis was the cost in euros needed to achieve disease control in one person with type 2 diabetes based on the composite endpoint of HbA1c <7%, ≥5% weight loss, and no hypoglycemic events. In addition, analyses regarding the cost needed to reach relevant HbA1c endpoints were performed. Clinical data were obtained from the SURPASS 2 trial, registered at clinicaltrials.gov (NCT03987919), and drug cost was based on wholesale acquisition cost or pharmacy purchase prices from public domains obtained in Q1 of 2023. Results The cost needed to achieve disease control in one person with type 2 diabetes (HbA1c <7%, ≥5% weight loss, and no hypoglycemic events) was up to three times lower using semaglutide compared with all three doses of tirzepatide in most markets. In the HbA1c analyses, semaglutide was also found to be the least expensive treatment option. Conclusion Semaglutide provides better value for money than tirzepatide for HbA1c-lowering endpoints.

1704-P: Efficacy and Safety of Tirzepatide for Weight Loss—A Meta-analysis of Randomized Controlled Trials

Tirzepatide (TZP) is a new dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes and shown to have substantial efficacy on weight loss. We performed a meta-analysis to assess the efficacy and safety of TZP for weight loss. We searched PubMed, Cochrane and Embase up until July 2022 for RCTs comparing TZP with placebo for the co-primary endpoints of absolute and percent change in weight. Mean difference (MD) and odds ratios (OR) were utilized, respectively, for continuous and binary outcomes. Of 397 search results, 6 studies were included, with 4036 participants. Pooled analysis showed that TZP 5 mg, 10 mg, and 15 mg were more effective than placebo, with MD in body weight change ranging from -7.7 kg (95% CI -11.0, -4.4; p &amp;lt; 0.001) to -11.8 kg (95% CI -17.4, -6.2; p &amp;lt; 0.001) - Figure 1A. The MD in percent change in weight ranged from -8.1% (95% CI -11.0, -5.2; p &amp;lt; 0.001) to -12.4% (95% CI -17.2, -7.5; p &amp;lt; 0.001) - Figure 1B. Adverse events were more frequent with TZP compared with placebo, especially with the 15 mg dose, with respect to nausea (OR 4.2; 95% CI 2.4, 7.5; p &amp;lt; 0.001), vomiting (OR 7.0; 95% CI 4.3, 11.4; p &amp;lt; 0.001), and diarrhea (OR 2.8; 95% CI 1.6, 4.9; p &amp;lt; 0.001). The results support that TZP leads to a significant reduction in body weight and may be a valuable therapeutic option for weight management, despite an increase in gastrointestinal side effects. Disclosure Y.L.L.Mesquita: None. I.P.Calvi: None. I.R.Marques: None. S.A.Cruz: None. E.M.H.Padrao: None. R.Cardoso: None. F.Moura: None. V.V.Rafalskiy: None.

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

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

New insights into the treatment of obesity.

Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long-term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight-related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight-loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long-term obesity management and position them in a framework according to their weight loss effects.