Potent incretin-based therapy for obesity: A systematic review and meta-analysis of the efficacy of semaglutide and tirzepatide on body weight and waist circumference, and safety.

Potent incretin-based therapy shows promise for the treatment of obesity along with reduced incidence of cardiovascular events in patients with preexisting cardiovascular disease and obesity. This study assessed the efficacy and safety of the incretin-based obesity treatments, once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg, in people with obesity without diabetes. Of the 744 records identified, seven randomized controlled trials (n = 5140) were included. Five studies (n = 3288) investigated semaglutide and two studies (n = 1852) investigated tirzepatide. The treatment effect, shown as placebo-subtracted difference, on body weight was -15.0% (95% CI, -17.8 to -12.2) with -12.9% (95% CI, -14.7 to -11.1) for semaglutide and -19.2% (95% CI, -22.2 to -16.2) for tirzepatide. The treatment effect on waist circumference was -11.4 cm (95% CI, -13.7 to -9.2) with -9.7 cm (95% CI, -10.8 to -8.5) for semaglutide and -14.6 cm (95% CI, -15.8 to -13.4) for tirzepatide. The adverse events related to semaglutide and tirzepatide were primarily of mild-to-moderate severity and mostly gastrointestinal, which was more frequent during the dose-titration period and leveled off during the treatment period. This emphasizes that once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg induce large reductions in body weight and waist circumference and are generally well-tolerated.

White analytical insight for sensitive fluorescent determination of semaglutide and tirzepatide in pharmaceuticals and biological matrices.

The present study is focused on the sensitive determination of newly FDA-approved glucagon-like-peptide agonists semaglutide (SEM) and tirzepatide (TIR). Direct, selective and label-free spectrofluorometric method was proposed and validated (according to ICH guidelines) for determination SEM and TIR in their pure form, newly approved pharmaceuticals and spiked human plasma. The developed method was based on measuring the native fluorescence of SEM and TIR in ethanol at 294.8 and 303 nm after being excited at 216 and 225 nm for SEM and TIR in order. The method sensibility allowed the quantification of both drugs in nano-scale up to 10 ng/mL. Several experimental variables including solvent type, surfactant, and pH were optimized after several attempts to get the best sensitivity for both drugs. The mean recovery percentage of SEM was compared and found in agreement with the reported method using student's t-test and the variance ratio F-test. Additionally, the greenness and whiteness profiles for this approach were evaluated using the GAPI, AGREE, and RGB algorithm; the positive results supported its use as great candidates for successful implementation in quality control labs and the pharmaceutical analysis companies.

Evidence that tirzepatide protects against diabetes-related cardiac damages.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. METHODS: A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. RESULTS: Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40-0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. CONCLUSION: Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.

The effect of subcutaneous Lixisenatide on weight loss in patients with type 2 Diabetes Mellitus: Systematic review and Meta-Analysis of randomized controlled trials.

BACKGROUND: The impacts of subcutaneous Lixisenatide on body weight in patients with type 2 DM, remain inadequately understood; consequently, this systematic review and meta-regression analysis of randomized controlled trials (RCTs) was conducted to evaluate the influence of subcutaneous Lixisenatide administration on BW and BMI values in individuals with Type 2 diabetes. METHODS: A comprehensive literature search was conducted across four databases, spanning from their inception to February 2023. We computed effect sizes employing the random-effects model and reported results in terms of weighted mean differences (WMD) along with their corresponding 95% confidence intervals (CI). RESULTS: 23 articles with 26 RCT arms were included in the meta-analysis. The combined findings from a random-effects model demonstrated a significant reduction in body weight (WMD: -0.97 kg, 95 % CI: -1.10, -0.83, p < 0.001) and BMI (WMD: -0.48 kg/m2, 95 % CI: -0.67, -0.29, P < 0.001) after subcutaneous administration of Lixisenatide. Furthermore, a more pronounced reduction in body weight was discovered in RCTs lasting less than 24 weeks (WMD: -1.56 kg, 95 % CI: -2.91, -0.20, p < 0.001), employing a daily dosage of subcutaneous Lixisenatide lower than 19 Âµg per day (WMD: -1.94 kg, 95 % CI: -2.54, -1.34, p < 0.001) and with a mean participant age of 60 years or more (WMD: -1.86 kg, 95 % CI: -3.16, -0.57, p = 0.005). CONCLUSIONS: Lixisenatide was found to significantly decrease BW and BMI in patients with type 2 DM and could be considered as a therapeutic option for those suffering from weight gain caused by other anti-diabetic agents. However, while prescribing Lixisenatide, careful consideration of patient-specific factors is recommended.

Semaglutide and Tirzepatide for the Management of Weight Recurrence After Sleeve Gastrectomy: A Retrospective Cohort Study.

BACKGROUND: Metabolic and bariatric surgery (MBS) is the most effective treatment for obesity and improvement of obesity-associated comorbidities. However, a proportion of these patients may suffer from weight recurrence and recurrence of obesity-associated comorbidities. METHOD: A retrospective cohort study of patients who underwent SG between January 2008 and August 2022 and sought treatment for weight recurrence with semaglutide or tirzepetide from January 2022 onwards. RESULT: A total of 115 patients were included, of which 70 had SG and treated for weight recurrence with semaglutide and 45 had SG and treated with tirzepatide. The mean age of patients was 38.8 (10.4) and 80.9% of patients were female. The mean pre-treatment weight and BMI was 94.0 (23.8) kg and 35.1 (6.0) kg/m2. Following treatment with semaglutide and tirzepatide, the mean post-treatment weight at 6 months was 81.0 (19.0) kg from 90.1 (19.6) kg and 87.6 (28.3) kg from 100.2 (28.5) kg respectively, corresponding to a clinically significant mean weight loss from baseline to 6 months of 10.3 (5.9)% (p < 0.05) and 15.5 (6.3)% (p < 0.05). Weight loss in tirzepatide patients was significantly greater than the semaglutide patients at 6 months (p < 0.02). There were no reported severe adverse events to the treatment. CONCLUSION: Short-term outcomes show that semaglutide and tirzepatide can be an effective treatment for managing weight recurrence after SG. Studies with longer follow-up are needed to determine the durability, as weight regain after discontinuation of the medication is highly likely, and the high cost of these medications can limit their use.

Reduction of prevalence of patients meeting the criteria for metabolic syndrome with tirzepatide: a post hoc analysis from the SURPASS Clinical Trial Program.

BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.

Use of Dulaglutide, Semaglutide, and Tirzepatide in Diabetes and Weight Management.

PURPOSE: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are effective therapies in lowering glycosylated hemoglobin (HbA1c), providing cardioprotective benefits, and lowering weight. The use of GLP1-RA solely for weight-loss has become commonplace in many practices, which in turn has made it difficult in some areas for those with type 2 diabetes (T2DM) to obtain these much-needed medications. METHODS: Using recent published literature, along with clinical experience, it has become apparent that many GLP1-RAs have become difficult to obtain for patients with diabetes. FINDINGS: Many clinicians started to prescribe the brand Ozempic® (semaglutide*) and dulaglutide for weight loss despite neither of them being Food and Drug Administration (FDA) approved for this indication. Ozempic, having outperformed dulaglutide in in both HbA1c reduction and weight loss, along with FDA approval of semaglutide for weight loss, has quickly become widely used off-label for weight loss. This off-label use may have increased, despite the approval of semaglutide,† because many insurances will not cover semaglutide solely for weight management. Most recently, Eli Lilly was able to develop tirzepatide,‡ which was FDA approved in May of 2022, and they are seeking fast-track FDA approval for weight loss and are projected to gain this approval within 2023. IMPLICATIONS: Insurance coverage for weight management remains sparse, and obtaining these therapies for diabetes has now become more burdensome, with insurance companies requiring a prior authorization proving FDA-approved diagnosis of T2DM. Hopefully, should more GLP1-Ras receive approval for weight loss, along with an increase in insurance coverage, the burden on patients with diabetes will be lessened as they are able to quickly obtain this highly effective therapy.

Tirzepatide: A novel cardiovascular protective agent in type 2 diabetes mellitus and obesity.

Cardiovascular disease (CVD) remains a major global health concern, and obesity and diabetes mellitus have been found to be important risk factors. Tirzepatide a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1) receptor agonist has been shown to have cardioprotective effects. Noteworthy benefits of Tirzepatide include decreased cardiovascular risk factors in people with Type 2 diabetes mellitus (T2DM). In the SURPASS-4 trial, tirzepatide significant decreased blood pressure, body weight, and HbA1c. Furthermore, the SURMOUNT-1 trial demonstrated the effectiveness of tirzepatide in reducing cardiometabolic risk factors in people with obesity without T2DM. Together, the dual receptor agonism improves lipid profiles, increases insulin secretion, reduces inflammation, and promotes endothelial integrity. Tirzepatide shows promise as a comprehensive therapeutic option for managing cardiovascular risk factors in patients with T2DM and obesity. While further studies are needed to assess the long-term cardiovascular benefits, current evidence supports tirzepatide's potential impact on cardiovascular health beyond its antidiabetic properties.

Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide.

Tirzepatide is a first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population-based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well-described by a two-compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half-life of tirzepatide was ~5 days and enabled sustained exposure with once-weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations.

Tirzepatide 10 and 15 mg vs semaglutide 2.0 mg: A long-term cost-effectiveness analysis in patients with type 2 diabetes in the United States.

BACKGROUND: Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes (T2D) treatment. OBJECTIVE: To compare the long-term cost-effectiveness of tirzepatide 10 mg and 15 mg vs semaglutide 2.0 mg, an injectable glucagon-like peptide-1 receptor agonist, in patients with T2D from a US health care payer perspective. METHODS: The PRIME T2D Model was used to project clinical and cost outcomes over a 50-year time horizon. Baseline cohort characteristics and treatment effects were sourced from a published adjusted indirect treatment comparison that used data from the SURPASS-2 and SUSTAIN FORTE trials. Patients were assumed to intensify to insulin therapy at a hemoglobin A1c of greater than 7.5%. Costs and health state utilities were derived from published sources. Future costs and clinical benefits were discounted at 3% annually. RESULTS: Tirzepatide 10 mg and 15 mg were associated with improved quality-adjusted life-expectancy (10 mg: 0.085 quality-adjusted life-years [QALYs], 15 mg: 0.121 QALYs), higher direct costs (10 mg: USD 5,990, 15 mg: USD 6,617), and incremental cost-effectiveness ratios of USD 70,147 and 54,699 per QALY gained, respectively, vs semaglutide 2.0 mg. Both doses of tirzepatide remained cost-effective vs semaglutide 2.0 mg over a range of sensitivity analyses. CONCLUSIONS: Long-term projections using the PRIME T2D model and based on treatment effects from an adjusted indirect treatment comparison indicate that tirzepatide 10 mg and 15 mg are likely to be cost-effective vs semaglutide 2.0 mg for the treatment of T2D in the United States.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

AIMS: To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). MATERIALS AND METHODS: Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. RESULTS: Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. CONCLUSIONS: In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

Tirzepatide as a novel effective and safe strategy for treating obesity: a systematic review and meta-analysis of randomized controlled trials.

Objective: To systematically evaluate the efficacy and safety of a new hypoglycemic drug, tirzepatide, for treating obesity based on indicators such as BMI, waist circumference, and body weight. Methods: A search formula was written using search terms such as "tirzepatide," "overweight," and "obesity." A comprehensive search was conducted on databases such as PubMed, Cochrane Library, Embase, and Web of Science using a computer. Random controlled trial (RCT) literature was selected based on inclusion and exclusion criteria. After extracting the data, literature bias risk assessment and meta-analysis were conducted using RevMan 5.4 software. The search deadline is from the establishment of each database to May 2023. Results: A total of 12 randomized controlled trials were included, with a total of 11,758 patients. Meta analysis results showed that compared with the glucagon like peptide-1 receptor agonist (GLP-1 RAs), placebo and insulin groups, tirzepatide could significantly reduce the BMI (body mass index) of patients [MD = -1.71, 95% CI (-2.46, -0.95), p < 0.00001], [MD = -3.99, 95% CI (-3.69, -2.45), p < 0.00001], [MD = -4.02, 95% CI (-4.72, -3.31), p < 00.00001]. In terms of decreasing waist circumference, tirzepatide has a more significant advantage [MD = -4.08, 95% CI (-5.77, -2.39), p < 0.00001], [MD = -7.71, 95% CI (-10.17, -5.25), p < 0.00001], [MD = -9.15, 95% CI (-10.02, -8.29), p < 0.00001]. In the analysis of body weight, tirzepatide showed a more significant reduction effect compared to the control group [MD = -5.65, 95% CI (-7.47, -3.82), p < 0.001], [MD = -10.06, 95% CI (-12.86, -7.25), p < 0.001], [MD = -10.63, 95% CI (-12.42, -8.84), p < 0.001]. In comparison with placebo, tirzepatide had a prominent advantage in weight loss ≥20% and ≥25% [RR = 30.43, 95% CI (19.56, 47.33), p < 0.00001], [RR = 37.25, 95% CI (26.03, 53.30), p < 0.00001]. Subgroup analysis showed a dose-dependent therapeutic effect. In terms of safety, compared with the placebo and insulin groups, the incidence of gastrointestinal adverse reactions was markedly higher in the tirzepatide group, slightly higher to the GLP-1 RAs group. The hypoglycemic (<70 mg/dL) risk of tirzepatide was slightly higher to that of placebo and GLP-1 RAs, but significantly lower than that of the insulin group [RR = 0.46, 95% CI (0.36, 0.58), p < 0.001]. The incidence of other adverse events, including pancreatitis, cholecystitis, major adverse cardiovascular events-4, hypersensitivity reactions, and neoplasms did not show significant statistical differences compared to the control group (p > 0.05). Conclusion: Tirzepatide, as a weight loss drug, significantly reduces BMI, waist circumference and body weight while gastrointestinal adverse reactions need to be vigilant. Overall, its efficacy is significant and its safety is high.

Model-based simulation of glycaemic effect and body weight loss when switching from semaglutide or dulaglutide to once weekly tirzepatide.

OBJECTIVE: To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. METHODS: Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. RESULTS: Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. CONCLUSION: In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions.

Type 2 diabetes is a disease of elevated blood sugar levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type of medication used to treat type 2 diabetes that work on GLP-1 receptors in the body. Semaglutide and dulaglutide are examples of GLP-1 RAs, which lower blood sugar and body weight. Tirzepatide is a newer medication, which works on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. It reduces blood sugar and body weight in people living with type 2 diabetes. Healthcare professionals and patients are interested in how switching medication from semaglutide or dulaglutide to tirzepatide might change blood glucose levels and body weight. However, because tirzepatide is a newer medication, there is not much information available on this aspect. Data from clinical trials of these medications were used to predict the effects of switching from semaglutide or dulaglutide to tirzepatide. These model-based simulations showed that switching to tirzepatide may further reduce HbA1c (a measure of blood sugar) and body weight. This may provide useful information to healthcare professionals and patients when making decisions about treatment with these medications.

Tirzepatide: A Review in Type 2 Diabetes.

Tirzepatide (Mounjaro®), a first-in-class dual incretin agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, is approved for use as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM) in the USA, EU, Japan and other countries. It comes as single-dose prefilled pens and single-dose vials. In phase III SURPASS trials, once-weekly subcutaneous tirzepatide, as monotherapy or add-on-therapy to oral glucose-lowering medications and insulin, was superior to the GLP-1 receptor agonists (RAs) dulaglutide 0.75 mg and semaglutide 1 mg as well as basal and prandial insulin for glycaemic control and weight loss in adults with inadequately controlled T2DM. Tirzepatide was generally well tolerated, with a safety profile consistent with that of GLP-1 RAs. Tirzepatide was associated with a low risk of clinically significant or severe hypoglycaemia and no increased risk of major adverse cardiovascular events. Adverse events were mostly mild to moderate in severity, with the most common being gastrointestinal events including nausea, diarrhoea, decreased appetite and vomiting. In conclusion, tirzepatide is a valuable addition to the treatment options for T2DM.

Many people with type 2 diabetes mellitus (T2DM) do not achieve and maintain glycaemic and weight management goals using currently available treatments. Tirzepatide (Mounjaro^®) is the first incretin-based glucose-lowering medication to be approved as an add-on to diet and exercise in adults with T2DM that targets both the glucose-dependent insulinotropic polypeptide receptor (GIP) and the glucagon-like peptide-1 (GLP-1) receptor. In patients with inadequately controlled T2DM, tirzepatide improved glycaemic control and body weight more so than dulaglutide 0.75 mg, semaglutide 1 mg and insulin when used on its own or in combination with other medications. Tirzepatide was generally well tolerated and had a low risk of hypoglycaemia. The most common adverse events were usually short-lived gastrointestinal-related events, which were generally mild to moderate in nature, including nausea, diarrhoea, decreased appetite and vomiting. Tirzepatide is a valuable addition to the treatment options for people with inadequately controlled T2DM.

Psychiatric adverse events associated with semaglutide, liraglutide and tirzepatide: a pharmacovigilance analysis of individual case safety reports submitted to the EudraVigilance database.

BACKGROUND: Semaglutide, liraglutide and tirzepatide are glucagon-like peptide-1 (GLP-1) receptor agonists that are effective for weight reduction. Recent reports of patients experiencing suicidal thoughts and other psychiatric adverse events while using GLP-1 agonists have raised concerns about the potential risk of self-harm and led the European Medicines Agency to investigate these medications. AIM: To identify and analyse the psychiatric adverse events associated with semaglutide, liraglutide and tirzepatide. METHOD: All individual case safety reports for semaglutide, liraglutide, and tirzepatide reported to the EudraVigilance database from 01/01/2021 to 30/05/2023 were analysed. Descriptive statistics were used to explore study population characteristics. RESULTS: During the study period, 31,444 adverse event reports were identified: semaglutide (n = 13,956; 44.4%), liraglutide (n = 16,748; 53.2%), and tirzepatide (n = 740; 2.3%). There were 372 reports with psychiatric adverse event reports (n = 372; 1.18%) with a total of 481 adverse events. Women accounted for 65% (n = 242) of these reports. Depression was the most commonly reported adverse event (n = 187; 50.3%), followed by anxiety (n = 144; 38.7%) and suicidal ideation (n = 73; 19.6%). Nine deaths (8 with liraglutide and 1 with semaglutide) and 11 life-threatening outcomes (4 associated with liraglutide and 7 with semaglutide) were reported. The fatal outcomes occurred primarily among men (8 out of 9) resulting from completed suicidal attempts and depression. CONCLUSION: Psychiatric adverse events comprised only 1.2% of the total reports for semaglutide, liraglutide, and tirzepatide. However, the severity and fatal outcomes of some of these reports warrant further investigation.

Tirzepatide prevents neurodegeneration through multiple molecular pathways.

BACKGROUND: Several 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. METHODS: We 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. RESULTS: For 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. CONCLUSIONS: We 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.