Tirzepatide

[Glucagon-like peptide-1 agonists and heart failure].

Nisha Soborun, Lucie Favre, Henri Lu +1 more

Developed to treat type 2 diabetes, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been associated with a reduced risk of cardiovascular events in high-risk patients with diabetes, and later in obese patients with cardiovascular disease without diabetes. More recently, semaglutide and tirzepatide have demonstrated benefits in obese patients with heart failure (HF) with preserved or mildly reduced ejection fraction, including fewer HF hospitalisations and improvements in symptoms and functional capacity. Data remain limited in heart failure with reduced ejection fraction. This article summarises current evidence on these therapies, particularly in HF, and provides practical guidance for their prescription and follow-up.

The Paradox and Future of GLP-1/GIP Combination Therapies: Efficacy and Mechanisms.

Iona Davies, Jens J Holst, Mette M Rosenkilde +1 more

Glucagon-like peptide-1 (GLP-1)-based obesity pharmacotherapies have revolutionized obesity treatment. In this review, we discuss the discovery of GLP-1 and evaluate the efficacy of marketed and investigational GLP-1 receptor (GLP-1R) agonists (GLP-1RAs), most notably semaglutide, as well as their potential central mechanism of action. We highlight the GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist tirzepatide and the GLP-1RA/GIPR antagonist maridebart cafraglutide, discussing how both methods of GIPR targeting can produce beneficial metabolic effects. The lack of evidence for the anorectic effects of GIPR agonism or antagonism alone in humans is noted, and the review concludes with an evaluation of other reasons for the greater efficacy of GIPR/GLP-1R dual targeting compounds over semaglutide.

[Obesity and type 2 diabetes mellitus (Update 2026)].

Johanna M Brix, Martin Clodi, Jürgen Harreiter +9 more

Obesity is a chronic disease with a variety of metabolic, mechanical and psychosocial complications, including a high risk of developing prediabetes and subsequently type 2 diabetes mellitus. The choice of antidiabetic treatment as well as concomitant treatment, increasingly takes this into account. Modern glucagon-like peptide 1 (GLP-1) analogues and the combined gastric inhibitory polypeptide (GIP)/GLP‑1 agonist tirzepatide play an important role in the combined treatment of obesity and type 2 diabetes mellitus. Metabolic surgery is currently indicated for people with type 2 diabetes mellitus and a body mass index (BMI) > 30 kg/m2 and can contribute, at least in part, to diabetes remission but it must be integrated into an appropriate lifelong care plan. Every obesity therapy is always based on lifestyle modifications. Due to the large number of new drugs and the many new studies in which an attempt was made to cite the most relevant ones, major changes were made to this chapter compared to 2023. The indications for metabolic treatment were also adjusted.

Causes and consequences of discontinuation of GLP1RAs or tirzepatide.

Antonio Ceriello, Francesco Prattichizzo, Abdul Raouf Mastan Sheik Abdullah +7 more

Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists and tirzepatide, a dual GLP1R and glucose-dependent insulinotropic polypeptide receptor agonist, have become fundamental in managing type 2 diabetes mellitus (T2DM) and obesity due to their potent glycaemia-lowering and weight-lowering effects as well as their cardiovascular and renal benefits. However, data from the past 2 years suggest that real-world persistence on these drug classes is often suboptimal, with many people discontinuing these medications, even within their first year of therapy. Reasons for treatment discontinuation include, but are not limited to, gastrointestinal adverse effects, less-than-desired efficacy, high cost, and fear about uncommon or rare adverse effects. When treatment is discontinued, weight regain and the deterioration of multiple cardiometabolic risk factors are common. Repeated cycles of initiation, interruption and re-initiation of these drugs might induce body weight and HbA1c fluctuations - two risk factors for cardiovascular and microvascular events. These phenomena, coupled with the re-development of overweight or obesity and poor glycaemic control when not on therapy, might increase the long-term risk of complications. The lack of anti-atherosclerotic and plaque-stabilizing effects of incretin-based medications might contribute to elevated cardiovascular risk, especially acutely following their discontinuation. However, at present, few data are available regarding the incidence of hard outcomes in people discontinuing such drugs. In this Review, we discuss common reasons for GLP1R agonist and tirzepatide discontinuation and examine available evidence related to potential cardiometabolic consequences. We also discuss long-term implications for T2DM care, weight management and, ultimately, cardiorenal disease prevention in patients with T2DM and/or overweight or obesity.

Comment on Sattar et al. Weight Reduction With Tirzepatide Varied Meaningfully by Baseline HbA1c Category in Adults With Overweight or Obesity and Type 2 Diabetes in SURMOUNT-2. Diabetes Care 2025;48:e136-e137.

Salvatore Corrao

DUAL GIP/GLP-1Ra reduces residual proteinuria in non-diabetic fabry disease.

Eleonora Riccio, Alessandra Cuomo, Ivana Capuano +4 more

Residual proteinuria remains a major determinant of renal disease progression in Fabry disease (FD) despite optimized enzyme replacement or chaperone therapy and maximal renin-angiotensin system (RAS) blockade. Dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonists exert anti-inflammatory, natriuretic, and antifibrotic effects beyond metabolic control. We evaluated the impact of add-on tirzepatide on residual proteinuria in overweight, non-diabetic Fabry patients receiving optimized background therapy.

Tirzepatide attenuates neurotoxicity by suppressing inflammation, apoptosis and restoring neurotrophin expression in an Alzheimer's disease-like rat model.

Mohamed S M Attia, Sheikh F Ahmad, Ahmed Nadeem +7 more

Despite numerous milestones in Alzheimer's disease (AD) research, the disease remains incurable, with a high prevalence and significant financial burdens. As a result, researchers are keen to look for new medications that can help manage or prevent the disease.

Cost-effectiveness and budget-impact analysis of tirzepatide in heart failure with preserved ejection fraction and obesity in the German health-care system.

Bent Estler, Hanna Fröhlich, Tobias Täger +3 more

Heart failure with preserved ejection fraction is common, obesity-related, and associated with high symptom burden and healthcare use. Tirzepatide, a dual GIP/GLP-1 receptor agonist, improved symptoms and outcomes in SUMMIT, but its acquisition cost raises concerns about value and affordability.

Effects of Tirzepatide on Body Composition, Metabolic Parameters, and Sleep Outcomes: A Real-World One-Year Prospective Study.

Nikos Adamidis, Theodora Margariti, Vasiliki E Georgakopoulou +7 more

Background Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial efficacy in reducing body weight and improving glycemic control in randomized trials; however, real-world data on its long-term effects remain limited. Our objective was to evaluate the one-year effects of tirzepatide on body composition, metabolic parameters, inflammation, and sleep-related outcomes in a real-world setting. Methods In this prospective study, 164 consecutive adult participants receiving tirzepatide in routine clinical practice were followed longitudinally. Anthropometric measurements, bioelectrical impedance-derived body composition indices, glycemic markers, inflammatory and biochemical parameters, and sleep-related indices were assessed at baseline and follow-up. Changes (D variables) were calculated as follow-up minus baseline values. Statistical analyses included descriptive statistics, paired comparisons, and correlation analyses. Results Tirzepatide treatment was associated with significant weight reduction (change in body weight (DWeight) -8.66 ± 8.02 kg), primarily driven by decreases in fat mass (change in fat mass (DFM) -11.34 ± 10.86 kg) and waist circumference (change in waist circumference (DWC) -10.11 ± 10.10), with relative preservation of lean mass (change in fat-free mass (DFFM) 0.87 ± 14.56 kg). Improvements were observed in glycemic control (change in glycated hemoglobin (DHbA1c) -0.59 ± 0.56%) and insulin resistance (change in homeostasis model assessment of insulin resistance (DHOMA-IR) -0.52 ± 0.29), along with reductions in inflammatory markers (change in C-reactive protein (DCRP) -1.48 ± 2.39 mg/L) and liver enzymes (change in aspartate aminotransferase (DAST) and alanine aminotransferase (DALT)). Sleep-disordered breathing improved, with a reduction in apnea-hypopnea index (change in apnea-hypopnea index (DAHI) -6.64 ± 6.63 events/h). Sex-specific differences were observed, with greater FM reduction in females and greater improvement in IR and sleep apnea indices in males. Conclusions In a real-world setting, tirzepatide demonstrates sustained benefits across adiposity, metabolic function, inflammation, and sleep outcomes over one year, with preservation of lean mass. These findings support its role as a comprehensive metabolic therapy.

Impact of Tirzepatide Therapy on Thyroid Disease: Understanding Risks and Emerging Insights.

Emiliano G Manueli Laos, Bianca Serafica, Andres Fontaine-Nicola +6 more

The dual GLP-1/GIP agonist tirzepatide is a highly effective anti-obesity therapy. While promising, it is associated with potential adverse effects, including thyroid disease reported in animal models. Due to limited human data, this study seeks to identify and characterise risk factors for thyroid disease development in patients undergoing 1 year of tirzepatide treatment. This study retrospectively analysed medical records of patients completing a 12-month course of tirzepatide (2.5-15 mg weekly) between September 2023 and September 2024. The primary endpoint is the development or worsening of any thyroid disease including DIT, Hashimoto thyroiditis, Graves' disease, benign neoplasms, goitre, and thyroid cancer. In 527 patients on tirzepatide, 28 (5.3%) developed or had progression of thyroid disease. The most frequent diagnoses were Nodular/Goitre Disease and Drug-Induced Thyroiditis. Multivariate analysis showed that a history of End-Stage Renal Disease (OR = 2.94) and baseline thyroid disease (OR = 3.78) were significant risk factors. Baseline thyroid disease and end-stage renal disease are significantly associated with an increased risk of new or recurrent thyroid disorders during tirzepatide treatment. These conditions should be classified as high risk, warranting periodic thyroid testing and further large-scale prospective validation.

Discovery of a High-Potency Balanced GLP-1/GIP Dual Agonist by Molecular Dynamics Evolution.

Nan Zhang, Li Teng, Xiang Yu +4 more

HDM1005 (poterepatide), a novel highly potent GLP-1/GIP dual agonist, was engineered via computational alanine scanning and rational acylation design. Nonacylated HDM1005 (P001) showed stable receptor binding and higher affinity than nonacylated Tirzepatide in molecular dynamics simulations and MMGBSA calculation. Alanine scanning and steric clash analysis (radius of gyration) guided proper K24/28 acylation sites on P001. Optimized linker and acyl chain design at K24 precisely tuned bioactivity and extended long-acting performance (T1/2 ∼ 20.3-23.1 h vs Tirzepatide's 9.21 h in mice). HDM1005 exerted 3-fold more potent HbAlc reduction in db/db mice and superior weight loss in DIO mice (39.97% vs 34.47%) versus Tirzepatide, yielding enhanced metabolic benefits, plus preferential fat loss with lean mass preservation in obese mice. It exhibited a favorable safety profile with a NOAEL of 5 mg/kg. With enhanced receptor binding, extended pharmacodynamic activity, and superior efficacy, HDM1005 represents a potential best-in-class therapeutic agent for metabolic disorders.

Tirzepatide-induced Weight Loss in Overweight or Obese Midlife Adults with and without Type 2 Diabetes: A Real-world Comparative Cohort Study.

Prabhat Kumar Agrawal, Shambo Samrat Samajdar, Ruchika Garg +5 more

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, has demonstrated robust weight loss and glycemic benefits in randomized controlled trials. However, real-world data comparing its effectiveness and tolerability in obese adults with and without type 2 diabetes (T2D) are limited. The present study aimed to evaluate the real-world short-term effectiveness and safety of tirzepatide in promoting weight loss among obese or overweight adults with and without T2D.

Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial.

Louis J Aronne, Deborah B Horn, Carel W le Roux +11 more

Incretins have improved the management of obesity and its related complications, but maintaining these health benefits requires ongoing administration, which can be challenging. Orforglipron, a once-daily oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated weight loss efficacy, improvements in cardiometabolic risk factors, and safety generally similar to injectable GLP-1 receptor agonists. Here this double-blind, placebo-controlled trial randomized participants previously treated with tirzepatide (cohort 1: N = 205) or semaglutide (cohort 2: N = 171) during the SURMOUNT-5 study to orforglipron once daily or placebo. Cohort 1 participants who achieved body weight plateau maintained a model-based estimate (MBE) of 74.7% (s.e.m. 4.05) of body weight reduction with orforglipron compared with an MBE of 49.2% (s.e.m. 3.92) with placebo, resulting in an estimated treatment difference of MBE 25.5% (95% confidence interval 14.5 to 36.5); P < 0.001; treatment-regimen estimand) at week 52. Cohort 2 participants who achieved body weight plateau maintained an MBE of 79.3% (s.e.m. 4.42) of body weight reduction with orforglipron compared with an MBE of 37.6% (s.e.m. 7.46) with placebo, resulting in an estimated treatment difference of MBE 41.7 (95% confidence interval 24.4 to 59.0); P < 0.001; treatment-regimen estimand) at week 52. All key secondary endpoints were met. The most common adverse events were gastrointestinal effects, which were mostly mild to moderate in severity. These data demonstrate orforglipron's potential as a globally scalable option for minimizing weight changes after injectable therapy. Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial's 1-year duration. ClinicalTrials.gov registration: NCT06584916 .

Tirzepatide for maintenance of bodyweight reduction in people with obesity in the USA (SURMOUNT-MAINTAIN): a multicentre, double-blind, randomised, placebo-controlled trial.

Deborah B Horn, Louis J Aronne, Sean Wharton +10 more

Obesity treatment improves long-term health and quality of life outcomes. Weight reduction and its maintenance play an important role in achieving these goals. We evaluated the efficacy and safety of continuing tirzepatide at the maximum tolerated dose (MTD) or lowering the dose to 5 mg compared with switching to placebo on the maintenance of bodyweight reduction obtained with tirzepatide MTD in adults with obesity.

Tirzepatide attenuates lipopolysaccharide-induced acute lung injury via AMPK/NF-κB signaling pathway.

Yan Zhang, Ling Li

Sepsis-associated acute lung injury (ALI) is characterized by unregulated systemic inflammation, disruption of the redox balance, and impaired pulmonary function. Tirzepatide, a synthetic dual GLP-1 and GIP receptor agonist possessing anti-inflammatory and metabolic-regulating properties, was investigated for its protective effects in lipopolysaccharide (LPS)-induced ALI and the underlying mechanisms.

Tirzepatide ameliorates cisplatin-induced acute kidney injury by restoring NAMPT/NAD + homeostasis and enhancing Pink1-Parkin-mediated mitophagy.

Chongyang Han, Zhicheng Tan, Yu Wang +8 more

Mitochondrial dysfunction and insufficient mitophagy are central to cisplatin-induced acute kidney injury (AKI). Tirzepatide, a dual GLP‑1/GIP receptor agonist, exhibits reno-protective effects, but its mechanism related to mitochondrial homeostasis remains unclear. Here, we used metabolomics, in vivo mouse AKI model, and in vitro cisplatin-injured HK‑2 cells to explore the protective effects and underlying mechanisms. Tirzepatide pretreatment significantly alleviated renal dysfunction, tubular injury, and mitochondrial damage caused by cisplatin. Metabolomic analysis revealed that tirzepatide strongly regulated energy metabolism and autophagy , particularly NAD + homeostasis. Mechanistically, tirzepatide boosted NAD+ levels by nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting enzyme for NAD + synthesis , which in turn activating the Pink1-Parkin mitophagy pathway. Inhibition of autophagy or NAMPT abolished the mitochondrial and reno-protective effects of tirzepatide. Taken together, our findings demonstrate that tirzepatide protects against cisplatin‑induced AKI by enhancing NAMPT‑dependent NAD + restoration and promoting mitophagy, highlighting a promising therapeutic strategy for chemotherapy‑related nephrotoxicity.

Effect of Tirzepatide on Health-Related Quality of Life in Japanese Patients With Obesity Disease: Patient-Reported Outcomes From the SURMOUNT-J Study.

Hiroaki Masuzaki, Hirotaka Nagashima, Tomotaka Shingaki +2 more

We evaluated the impact of tirzepatide on health-related quality of life (HR-QoL) in Japanese individuals with obesity disease from the phase 3 SURMOUNT-J trial.

Use of Semaglutide and Tirzepatide in Rheumatic and Musculoskeletal Diseases: Insights on Initiation Patterns and Weight Loss From the Rheumatology Informatics System for Effectiveness Registry.

Nicholas P McCormick, Cristiano S Moura, Jingyi Zhang +5 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide (SEM) and tirzepatide (TZP) were initially approved for type 2 diabetes management but are increasingly used for weight loss. Limited data exist on real-world use among patients with rheumatic and musculoskeletal diseases (RMDs). This study aimed to describe characteristics and trends in SEM and TZP initiation among individuals with RMDs and to identify factors associated with weight loss.

Tirzepatide vs. semaglutide for obesity, glycemic control, and cardiovascular outcomes: a narrative review of clinical trials.

Maan H Harbi, Ahmad M Ashour, Nasser M Alorfi +3 more

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an effective therapy for obesity and type 2 diabetes mellitus (T2DM). Its dual-incretin mechanism may offer enhanced metabolic benefits compared with selective GLP-1 receptor agonists such as semaglutide.

Pharmacological therapy in the obese patient: is it only a matter of fat loss?

Claudio Borghi, Alessio Bragagni

Obesity is a chronic, multifactorial condition strongly associated with increased cardiovascular and metabolic risk, as well as the development of systemic complications. Recent evidence from randomized controlled trials-including SELECT, STEP-HFpEF, STEP-HFpEF DM, SUMMIT, and SURMOUNT-5-has demonstrated the effectiveness of glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonists in the treatment of obesity, with clinical benefits that appear to extend beyond weight reduction alone. In addition to substantial reductions in fat mass, these agents improve cardiovascular parameters (including reductions in major adverse cardiovascular events), functional capacity, and quality of life. Additional benefits have been observed at the metabolic level, with reductions in glycated haemoglobin, blood pressure, triglycerides, and systemic inflammatory markers such as high-sensitivity C-reactive protein. These results confirm that pharmacological modulation of the incretin axis should not be viewed merely as an adjunctive strategy for weight loss, but rather as an integrated therapeutic intervention capable of modifying overall cardiovascular risk and improving the inflammatory and metabolic profile of the obese patient. In light of these findings, a re-evaluation of the role of pharmacological therapy in the clinical management paradigm of obesity is warranted.

Treatment of the disease of obesity in patients with type 1 diabetes with tirzepatide: a protocol for a randomised controlled trial in a single-centre setting.

Ebaa Al Ozairi, Ameenah Al Awadhi, Etab Taghadom +5 more

Medication for the disease of obesity has improved, and clinical trials based on natural gut hormones such as tirzepatide, showed only mild side effects and ~22% weight loss maintenance. However, patients with type 2 diabetes only lose 15% bodyweight with tirzepatide while tolerating the medications very well, but little is known in patients with the disease of obesity who also have type 1 diabetes, especially regarding safety of the medications. Tirzepatide's licence in the Gulf countries and Europe for obesity does not exclude patients with obesity and type 1 diabetes, unlike the USA. In Kuwait, more than a quarter of patients with type 1 diabetes also have the disease of obesity. Tirzepatide is not approved for glycaemic control in patients with type 1 diabetes, because it is unlikely to make a difference. Because tirzepatide is approved for the treatment of obesity in patients who also have type 1 diabetes we can now test how effective treatments for obesity such as tirzepatide are for patients with obesity and type 1 diabetes. Concerns regarding the safety of the medication in type 1 diabetes can also be addressed thus addressing an important knowledge gap.

Should Incretin Agonist-Based Brugs be Considered for First Line Antihypertensive Therapy?

Dominik Kylies, Leonie Dreher, Ulrich O Wenzel

This review evaluates the antihypertensive potential of next-generation incretin-based therapies, including GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists. It examines their effects on blood pressure reduction, underlying mechanisms, clinical benefits, and implications for future guidelines.

Dercum Disease: Exploratory Therapeutic Approaches in the Absence of Standardized Medical Treatment-A Single Center Case Series.

Alessandro Magnatta, Alice Verdelli, Virginia Corti +14 more

Dercum's disease (DD) is a rare chronic disorder characterized by painful subcutaneous lipomas, mostly affecting overweight or obese middle-aged women. The etiology remains unclear, and evidence for medical treatments is limited. Surgical approaches may reduce pain but are associated with frequent relapses and are difficult to implement in extensive clinical pictures. We investigated the outcomes of multiple medical and surgical therapeutic strategies. Particularly, we explored immunomodulators (methotrexate and infliximab), used alone or combined with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide, as well as the dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 RAs tirzepatide. Five patients with DD were included in this retrospective single-center case series. Baseline clinical data, medical history, and longitudinal information on Dermatology Life Quality Index (DLQI), Visual Analogue Scale (VAS) for pain, and body mass index (BMI) were collected from existing medical records and scheduled follow-up visits conducted since 2021. Clinical trajectories differed across patients and regimens. Methotrexate and infliximab coincided with variable and often transient improvements in pain and quality of life. Combination regimens including GLP-1 RAs were accompanied by weight reduction and, in selected patients, by sustained improvements in pain and DLQI. In other cases, the benefit was limited or absent. Adverse events were manageable and consistent with the known safety profiles of these drugs. In this small real-world case series, therapeutic responses in DD were highly individualized, underscoring the absence of standardized medical treatment and the need for patient-tailored strategies. The observed patterns suggest that immunomodulatory and incretin-based therapies may represent exploratory options in selected patients, especially when surgery is not feasible. However, controlled studies are needed to clarify their role.

Shifts in waist-to-height ratio categories within tirzepatide groups: a post-hoc analysis of SURMOUNT-1.

Naveed Sattar, Beverly G Tchang, Royce P Vincent +5 more

To evaluate shifts in waist-to-height ratio (WHtR) categories among adults with obesity or overweight, with or without prediabetes, treated with tirzepatide in the SURMOUNT-1 study.

Weight loss maintenance after tirzepatide cessation in people with overweight/obesity: a real-world follow-up of the phase 3 SURMOUNT-CN trial.

Congling Chen, Zhen Ying, Qi Tang +11 more

Tirzepatide, a dual GIP/GLP-1 receptor agonist, has shown unprecedented efficacy in weight loss and improving metabolic parameters in clinical trials. However, the durability of these benefits after treatment cessation remains poorly understood. This study aimed to investigate the effect of tirzepatide cessation on body weight change in people with obesity or overweight. This real-world, observational 26-week follow-up study included participants who completed 52 weeks' study treatment during SURMOUNT-CN (NCT05024032). The analysis excluded participants who received anti-obesity medications or bariatric procedures during the 26-week follow-up. Key outcomes were the changes in body weight and waist circumference after 26 weeks, from treatment cessation (Week 52) and trial baseline (Week 0), by the SURMOUNT-CN treatment groups (tirzepatide 10 or 15 mg, or placebo). Overall, 152 participants were included (tirzepatide 10 mg: n = 57; tirzepatide 15 mg: n = 51; placebo: n = 44). Following treatment cessation (Week 52), the mean (SD) percentage changes in body weight at Week 78 were 9.1% (7.4), 12.3% (9.9), and 1.8% (5.2), and the absolute changes in waist circumference were 2.9 cm (7.5), 5.5 cm (6.5) and -0.5 cm (5.6), in tirzepatide 10 and 15 mg, and placebo groups, respectively. From trial baseline to Week 78, the mean (SD) net percentage weight changes were -8.7% (6.9), -10.6% (10.2), and -2.5% (7.0), and the changes in waist circumference were -10.5 cm (8.1), -10.6 cm (9.3) and -4.0 cm (7.2), in the tirzepatide 10 and 15 mg, and placebo groups, respectively. At Week 78, residual improvements in multiple cardiometabolic indicators were evident in the tirzepatide groups. Despite weight gain following tirzepatide cessation, participants achieved a large net weight loss and reduction in waist circumference from trial baseline to Week 78, with residual improvements in several cardiometabolic indicators.

Data-driven prioritization of high-risk individuals for weight loss interventions.

Kamil Demircan, Julia Carrasco-Zanini, Alice Williamson +13 more

New obesity medications have demonstrated efficacy in trials, but their real-world deployment is partly limited by the absence of approaches that identify individuals for treatment based on risks for obesity-related complications. Here we present a risk prediction model to guide prioritization of high-risk individuals. In a population-based sample of ~200,000 individuals with a body mass index (BMI) exceeding 27 kg m-2, our machine learning framework identified the 20 most informative features, from among thousands tested, that predict future onset of 18 complications of obesity, providing information beyond BMI. An integrated model (OBSCORE) successfully stratified individuals into risk groups based on incidence over 10 years: for example, 5.7%, 1.8%, 0.9%, 0.4% and 0.1% for cardiovascular mortality. We demonstrate generalizability of the model in independent populations of European and non-European ancestry and, in SURMOUNT-1 trial participants, show that weight loss was similar across baseline OBSCORE risk groups and that predicted risks decreased following treatment with tirzepatide. In summary, OBSCORE provides a framework for prioritizing high-risk individuals with overweight or obesity based on their risk of obesity-related complications, complementing BMI-based frameworks.

Indirect Comparative Efficacy and Safety of Tirzepatide Versus Oral Semaglutide for the Treatment of Overweight and Obesity.

Andreea Ciudin, Erin Johansson, Sarah Zimner-Rapuch +5 more

Tirzepatide, an injectable glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA), is approved for weight management in several regions. Oral GLP-1 RAs, such as semaglutide, are under investigation to improve convenience, acceptance and adherence versus injectable formulations. Currently, no studies have compared the efficacy and safety of tirzepatide with oral semaglutide for weight management. This study aimed to indirectly compare the efficacy and safety of weekly injectable tirzepatide 5, 10 and 15 mg for weight management in obesity and overweight versus daily oral semaglutide 50 mg.

Impact of Tirzepatide on FIB-4 in Patients with Type 2 Diabetes: A Comparison between GLP-1RA-naïve and GLP-1RA Switch Initiation in a Retrospective Cohort.

Hiroyuki Ito, Chiaki I, Mizuki Matsushita +6 more

Objective Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to improve hepatic inflammation and steatosis in patients with type 2 diabetes. However, whether its effects on Fibrosis-4 (FIB-4), a surrogate marker of liver fibrosis, differ between patients naїve to GLP-1 receptor agonists (GLP-1RAs) and those who have switched from a GLP-1RA remains unclear. Methods In this single-center retrospective study, 65 Japanese patients with type 2 diabetes received tirzepatide for ≥6 months (GLP-1RA-naïve: n=15; GLP-1RA-treated: n=50). The primary outcome was change in the FIB-4. The secondary endpoints included changes in glycated hemoglobin (HbA1c), body weight, urinary protein, and estimated glomerular filtration rate (eGFR). Multivariable analyses were performed to identify the predictors of FIB-4 improvement. Results FIB-4 significantly decreased in the GLP-1RA-naïve group (from 1.55±1.01 to 1.25±0.74, Δ-0.26±0.32, p<0.01) but not in the GLP-1RA-treated group (Δ-0.02±0.23), with a significant between-group difference (p<0.05). HbA1c decreased in both groups, with a greater reduction in GLP-1RA-naïve patients (Δ-2.0±1.3% vs. -1.0±1.3%, p<0.01). Body weight decreased significantly in both groups (-3.5±5.5 kg vs. -2.2±3.5 kg), with no between-group difference. A multivariable analysis identified age, baseline FIB-4, and GLP-1RA-naïve status as independent predictors of FIB-4 reduction. Conclusion Tirzepatide significantly reduced FIB-4, particularly in patients who were GLP-1RA-naïve, and produced substantial reductions in HbA1c and body weight. As an exploratory and hypothesis-generating analysis, these findings suggest that initiating tirzepatide in GLP-1RA-naïve patients may be associated with favorable changes in fibrosis-related risk markers in patients with type 2 diabetes at a high risk of liver fibrosis.

Blamed but not at fault: Anti-obesity medication adverse effects misidentified as perioperative complications - a comprehensive review and medicolegal warning for anesthesiologists.

Hyun Jeong Kwak, Jung Ju Choi, Dongchul Lee +1 more

The rapid proliferation of anti-obesity medications (AOMs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonist tirzepatide, and non-incretin agents, including orlistat, phentermine, and bupropion/naltrexone, has created an underappreciated perioperative patient safety hazard. Existing guidelines have focused narrowly on GLP-1 RAs and aspiration risk, leaving some critical gaps unaddressed: (1) the misidentification trap, whereby drug-induced adverse effects, including acute pancreatitis, bowel obstruction, sudden visual loss, and neuropsychiatric dysfunction, are clinically and radiographically indistinguishable from surgical or anesthetic complications, exposing clinicians to unwarranted blame, and (2) the full perioperative risk profile of non-GLP-1 AOM classes. This narrative review synthesizes the current pharmacovigilance evidence, consensus guidelines, and clinical case data to address these gaps. Non-arteritic anterior ischemic optic neuropathy (NAION) from semaglutide (HR 7.64; World Health Organization safety alert 2025) may be attributed to anesthetic corneal injury, emotional lability may be misinterpreted as emergence delirium, drug-induced pancreatitis from GLP-1 RAs (adjusted HR 9.09 vs. comparator) may be misattributed to the operating surgeon, and bowel obstruction from premature postoperative GLP-1 RA resumption has prompted unnecessary re-laparotomy. Structured preoperative AOM documentation, explicit postoperative hold orders, and the inclusion of drug etiology in postoperative differentials constitute the defensible standard of care in the era of pharmacological obesity management.

Dietary Strategies and Nutritional Management in Patients Receiving GLP-1 and Dual GIP/GLP-1 Receptor Agonists as Adjuncts to Lifestyle Interventions: A Systematic Review of Randomised Clinical Trials.

Rayanne Santos de Paulo, Dandara Baia Bonifácio, Matheus Henrique Lana de Carvalho +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 RAs are widely used to manage obesity, prediabetes and type 2 diabetes, typically in combination with lifestyle interventions. Their nutritional implications, however, remain unclear. This systematic review summarised evidence from randomised clinical trials investigating dietary strategies and nutritional management in individuals treated with these medications.

Medical Nutrition in the Glucagon-Like Peptide-1 (GLP-1) Era: Protein Strategies, Micronutrient Monitoring, and Lean Mass Preservation.

Sedat Arslan

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agents produce substantial, sustained weight loss primarily by suppressing appetite and lowering ad libitum energy intake. While fat mass loss predominates, randomized trials with body-composition substudies indicate a clinically relevant reduction in absolute lean mass. Concurrently, baseline micronutrient inadequacies are common in people with obesity and may be exacerbated by reduced intake, nausea, or vomiting during therapy. This narrative review synthesizes evidence on energy/macronutrient dynamics, body-composition outcomes, and guideline-informed protein targets to present a practical, dietitian-led framework for care. We propose pragmatic energy floors to preserve micronutrient adequacy; daily protein intakes of ≥1.2 g/kg (up to 1.6 g/kg in appropriate adults without chronic kidney disease (CKD)) with meal-wise targets of ∼0.3-0.4 g/kg and ∼2.5-3 g leucine; a structured laboratory panel (vitamin D, B12, iron studies, folate, zinc, and thiamine in high-risk patients); and integration of progressive resistance training. We also outline monitoring schedules using dual-energy X-ray absorptiometry (DXA)/bioelectrical impedance analysis (BIA) and adaptations for special populations (older adults, type 2 diabetes, CKD, vegetarian/vegan, sarcopenic obesity). The goal is to preserve lean mass, prevent deficiencies, and optimize outcomes of GLP-1-based obesity pharmacotherapy.

Real-World Comparison of Short-Term Adverse Events, Treatment Persistence, and Efficacy of Semaglutide and Tirzepatide: A Nationwide Multicenter Study.

Sema Hepşen, Cem Haymana, Gizem Ertepe Küçükgöde +78 more

Real-world data directly comparing the safety, tolerability, and effectiveness of semaglutide and tirzepatide in patients with obesity remain limited. This nationwide multicenter observational study compared short-term adverse events, treatment discontinuation, body weight loss (BWL), and metabolic outcomes between the two treatments.

Persistence-Dependent Effectiveness of Tirzepatide on the Cardio-Metabolic-Kidney Syndrome Outcomes in Obesity: Real-World Evidence from the United Arab Emirates.

Imran Rashid Rangraze, Mohamed El-Tanani, Andrej Janez +9 more

Tirzepatide has been associated with significant reductions in body weight in randomized clinical trials. However, real-world evidence evaluating the multisystemic effects of tirzepatide across the cardio-metabolic-kidney (CKM) continuum remains limited. The aim of this study was to assess the real-world persistence-driven cumulative benefits of tirzepatide beyond weight reduction in adults with obesity but without type 2 diabetes mellitus (T2DM).

Enhancing economic modelling in obesity: integrating novel type 2 diabetes progression & obstructive sleep apnea remission - a UK case study.

Lieven Annemans, Erin Johansson, Erik Spaepen +4 more

This study presents an updated health economic model for evaluating the long-term cost-effectiveness of interventions in overweight and obesity, integrating new clinical evidence from the SURMOUNT clinical trial programme and methodological advancements in type-2 diabetes and obstructive sleep apnea (OSA) modelling.

LEAN mass Preservation with Resistance Exercise and Protein during semaglutide and tirzepatide therapy (LEAN-PREP study): a protocol for a randomised controlled trial.

Ameenah A Alawadhi, Dherar Alroudhan, Dalal J Alsaeed +6 more

Obesity is a global public health issue, with its effects a particular issue in Kuwait. Advances in pharmaceutical treatment (eg, glucagon-like peptide-1s) offer an effective solution, with the magnitude of weight lost something to celebrate. However, this level of weight loss also results in dramatic reductions in lean mass, reflecting loss of muscle mass and muscle strength which can predispose people to sarcopenia. This is a particular issue in people with type 2 diabetes in Kuwait, where the prevalence of muscle weakness is extremely high. Solutions to mitigate this loss of muscle mass and strength are needed, with a pragmatic resistance exercise intervention and increasing dietary protein intake having potential. This trial aims to determine whether resistance exercise and/or protein intake can preserve muscle mass and improve physical function in people with obesity initiating semaglutide/tirzepatide therapy.

Cost-effectiveness of tirzepatide versus semaglutide for patients with obesity or overweight in the US: evidence from the SURMOUNT-5 head-to-head phase-3 trial.

Erin Johansson, John P H Wilding, Navneet Upadhyay +6 more

This study evaluated the cost-effectiveness (from the United States [US] societal perspective) of tirzepatide at its maximum-tolerated-dose (MTD) compared to semaglutide (MTD), both administered adjunct to a reduced-calorie diet and increased physical activity. The analysis focused on individuals with obesity (body mass index [BMI] ≥ 30 kg/m2), or overweight (BMI ≥27 to <30 kg/m2 + ≥1 obesity-related complication), using data from the head-to-head Phase-3 SURMOUNT-5 trial (patients without type 2 diabetes [T2D]).

Cost-Effectiveness of Incretin Therapies: A Canadian Lens on Diabetes, Obesity, and Emerging Indications.

Luke Awadalla, Siena Iskander, Cherry Chu +1 more

Incretin therapies have emerged as key interventions for glycemic control and weight reduction, and are now among Canada's costliest outpatient drug classes. This review synthesizes current clinical and economic evidence on the cost-effectiveness of incretin-based therapies, specifically glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual agonists (e.g., semaglutide, tirzepatide) in patients with type 2 diabetes mellitus (T2DM) or for weight loss. We review data from clinical trials and recent Canadian and international economic models, identify emerging indications, and discuss limitations in current health-technology assessment (HTA) frameworks. Implications for Canadian reimbursement are highlighted, with attention to price, patient selection, and outcome considerations.

Tirzepatide as Adjunct to Insulin in Adults With Type 1 Diabetes and Overweight or Obesity: A Systematic Review of Randomized and Real-World Evidence.

Giuseppina Alessia Acucella, Danilo Caponio

Overweight and obesity are increasingly common in adults with type 1 diabetes (T1D), contributing to insulin resistance, higher insulin requirements, and greater cardiometabolic burden. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, has shown major metabolic benefits in type 2 diabetes and obesity, but its role in T1D remains unclear. This systematic review evaluated tirzepatide as adjunctive therapy to insulin in adults with T1D and overweight or obesity.

Shifts in body mass index category with tirzepatide and associated changes in cardiometabolic risk factors in people with obesity: a post hoc analysis from the SURMOUNT-1 and SURMOUNT-4 trials.

Naveed Sattar, Clare J Lee, Reshmi Srinath +6 more

Obesity is a chronic disease that results in increased morbidity and mortality if left untreated. Tirzepatide is a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist approved in the United States for the treatment of type 2 diabetes, obesity, and obstructive sleep apnea. These post hoc analyses assessed the cardiometabolic risk factors of participants with obesity or overweight treated with tirzepatide who shifted to a lower body mass index (BMI) category.

Metabolic advances in 2025: from clinical breakthroughs to molecular reprogramming.

Maria Dalamaga, Junli Liu

The year 2025 represented a turning point in metabolic research, marked by advances that combined unprecedented clinical efficacy with deep mechanistic insight. Landmark obesity trials redefined therapeutic expectations, with head-to-head and combination studies showing that the depth and distribution of weight loss are critical determinants of metabolic benefit across obesity and type 2 diabetes. In parallel, gene-editing studies crossed a translational threshold, showing that durable modification of metabolic pathways in humans is feasible, from bespoke correction of inborn errors to population-scale lipid lowering. Mechanistic investigations challenged long-standing assumptions about metabolic regulation. Experimental work revealed that mitochondrial electron transport functions as a dynamic redox regulator rather than a passive energy conduit, linking coenzyme Q imbalance and reverse electron transport to hepatic steatosis and metabolic dysfunction. Other studies reframed nutrient exposure and endogenous metabolites, demonstrating that non-nutritive sweeteners and cyanide exert context-dependent metabolic effects through regulated endocrine and redox pathways. At the systems level, multi-omics analyses defined reproducible microbiome-metabolome signatures associated with impaired glucose regulation, while artificial intelligence and continuous glucose monitoring exposed dynamic glycemic phenotypes invisible to conventional biomarkers. Precision-nutrition studies further showed that selective manipulation of sulfur amino acid availability can program thermogenic and metabolic responses. Collectively, these studies illustrate how metabolism in 2025 was approached as a modifiable, programmable system, shaped by clinical intervention, molecular control, and data-driven phenotyping, and point toward an era of increasingly precise and integrated metabolic medicine.

Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5.

Rodolfo J Galindo, Louis J Aronne, Deborah B Horn +8 more

Tirzepatide therapy reduces subclinical leaflet thrombosis and paravalvular leak after transcatheter aortic valve replacement in obese patients: The TAVR-MET trial.

A M Thirugnanam, Chandrakanth, Pruthvi

Obesity is increasingly recognized as a critical modifier of outcomes following transcatheter aortic valve replacement (TAVR), predisposing patients to subclinical leaflet thrombosis (SLT), hypo-attenuated leaflet thickening (HALT), and paravalvular leak (PVL). Metabolic inflammation, endothelial dysfunction, and pro-thrombotic states associated with obesity contribute to impaired bioprosthetic valve healing. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated robust metabolic, anti-inflammatory, and vascular protective effects. However, its impact on post-TAVR valve performance has not been previously evaluated.

Effects of tirzepatide, a dual GIP and GLP-1 receptor agonist, on blood pressure, cardiac function, and sympathetic nervous system in stroke-prone spontaneously hypertensive rats.

Yoshiyasu Ono, Keisuke Shinohara, Hiroka Nakashima +13 more

Tirzepatide, a dual agonist for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown robust efficacy in treating diabetes and obesity, and in obese patients with heart failure with preserved ejection fraction (HFpEF), it reduced weight, lowered blood pressure, and improved outcomes. However, its cardiovascular effects in non-obese, non-diabetic hypertension remain unclear. We investigated the impact of tirzepatide on blood pressure, cardiac function, and sympathetic nervous system activity in stroke-prone spontaneously hypertensive rats. Starting at 8 weeks of age, rats received tirzepatide (TZP, 25 nmol/kg, every two days), vehicle (VEH), or pair-fed vehicle (VEH-PF) to control for differences in food intake for 4 weeks. Tirzepatide significantly reduced food intake and body weight. Contrary to prior clinical observations, tirzepatide elevated mean blood pressure (197.4 ± 16.6 vs. 153.7 ± 5.4 mmHg at Day 28; TZP vs. VEH-PF, n = 9 vs. 8; p < 0.05) and increased heart rate, accompanied by left ventricular hypertrophy, myocardial fibrosis, and impaired diastolic function. Sympathetic activation was evident, with higher plasma norepinephrine levels and increased ΔFosB expression-a marker of sustained neuronal excitation-in the parvocellular paraventricular nucleus and the rostral ventrolateral medulla. Moreover, ΔFosB expression was increased in anorexigenic proopiomelanocortin neurons within the hypothalamic arcuate nucleus, which reduce feeding and have been implicated in promoting sympathetic excitation. These findings point to a central mechanism underlying increased sympathetic outflow. In conclusion, tirzepatide increased blood pressure and sympathetic activity in hypertensive rats without cardiac protection, highlighting context-dependent cardiovascular actions. Tirzepatide increased blood pressure, impaired LV diastolic function, and induced cardiac hypertrophy and fibrosis, as well as sympathetic overactivation in SHRSP.

Glucagon-Like Peptide-1 Receptor Agonists: Their Therapeutic Potential in Cystic Fibrosis.

Theodoros Panou, Evanthia Gouveri, Djordje S Popovic +1 more

Cystic fibrosis (CF) is a monogenic disorder leading to pulmonary disease, pancreatic insufficiency and cystic fibrosis-related diabetes (CFRD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now being investigated in people with cystic fibrosis (pwCF) and CFRD. To date, their therapeutic potential has been almost exclusively studied in case reports or case series. These agents improved glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) parameters. Benefits were also observed in weight reduction, particularly for subjects on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). However, discordant results have also been reported. Moreover, GLP-1RAs have improved pulmonary function, even following lung transplantation. Importantly, the dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has also yielded favourable outcomes. Finally, preliminary evidence suggests potential inhibition of bone resorption, pointing to a therapeutic perspective in cystic fibrosis-related bone disease (CFBD). However, potential adverse events should not be ignored. These include risk of acute pancreatitis, nausea/vomiting, nutritional depletion, bowel dysmotility and distal intestinal obstruction syndrome, as well as others. Adverse events should be addressed with caution, and dose adjustments may be useful. Large prospective multicentre studies are now required to validate these outcomes and to suggest implications for clinical practice.

Comparative Efficacy and Safety of Tirzepatide Versus Dulaglutide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Sadia Qazi, Mohammad Dawar Zahid, Eshal Atif +8 more

Background: Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrates substantial glycemic and weight benefits versus GLP-1 receptor agonists in indirect comparisons, but direct comparative safety evidence versus dulaglutide remains limited. We evaluated comparative safety (primary outcome: overall adverse events) and efficacy. Methods: Following PRISMA 2020 (prospectively registered: PROSPERO CRD420251276594), we searched MEDLINE, Embase, Scopus, and CENTRAL (inception-31 December 2025) for randomized controlled trials (≥26 weeks) comparing once-weekly tirzepatide with dulaglutide in adults with type 2 diabetes. Three trials (N = 13,590 participants) were included. Dichotomous outcomes were pooled using random-effects models (risk ratios [RRs], 95% confidence intervals [CIs]). GRADE assessed certainty of evidence. Results: Overall adverse event incidence did not differ significantly (RR 1.04 [0.98-1.10]; I2 = 36%; moderate-certainty evidence). Discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32 [1.20-1.45]; I2 = 0%; high-certainty evidence), representing a 32% increased risk across all populations. Categorical HbA1c target achievement was analyzed in two trials; the third trial reported HbA1c as a continuous outcome only. At the primary threshold (HbA1c < 7.0%), tirzepatide was consistently superior with no heterogeneity (RR 1.48 [1.33-1.64]; I2 = 0%; p < 0.00001). Across all thresholds combined, heterogeneity was extreme (I2 = 92%), limiting confidence in any pooled summary estimate; the greatest instability occurred at the strictest threshold (HbA1c < 5.7%; I2 = 98%; p = 0.40). Tirzepatide showed greater HbA1c target attainment in treatment-naive patients receiving dulaglutide 0.75 mg, whereas the glycemic advantage was smaller in patients with established cardiovascular disease receiving dulaglutide 1.5 mg. Categorical weight-loss outcomes were analyzed in two trials; tirzepatide was associated with greater weight-loss threshold achievement (RR 8.80 [4.04-19.17]; very low-certainty evidence), although interpretation is limited by substantial heterogeneity and restricted generalizability. Serious adverse events were not significantly different (RR 0.82 [0.47-1.43]; I2 = 42%). Conclusions: Overall adverse events were similar between treatments, but tirzepatide consistently increased discontinuation risk, indicating a clinically important tolerability-persistence trade-off. Glycemic efficacy was highly population-dependent: benefits were consistent at the primary HbA1c target (<7.0%; I2 = 0%) in early-stage disease, whereas the advantage was smaller in long-standing disease with established cardiovascular disease. Tirzepatide may be favored when glycemic or weight efficacy is prioritized in earlier-stage disease, provided tolerability is proactively managed. Dulaglutide remains appropriate when persistence is threatened by tolerability concerns or cardiovascular risk reduction is the primary goal.

Novel evidence for tirzepatide, a dual GLP-1/GIP receptor agonist, to reduce the motivation for cocaine in rodents.

Lori A Knackstedt

Clinical Potential of GIP in Type 2 Diabetes and Obesity.

Michael Nauck, Fiona Gribble, Frank Reimann +2 more

Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). While the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established, the potency of this agent has reignited interest in the clinical potential of GIPR agonism. Here, we discuss incretin biology as it relates to metabolic pharmacology and contextualize the mechanisms by which GIPR activity could contribute to the development of new and effective drugs. We explore current and future applications of GIPR agonists and antagonists, to underscore the potential that this signaling system could add to treatment of type 2 diabetes and obesity.

Pharmacologic Treatment of Obesity in the Context of Type 2 Diabetes.

Caterina Conte, Anastassia Amaro

To examine the role of pharmacologic obesity treatment in people with type 2 diabetes (T2D), with a focus on efficacy, safety, and clinical positioning in the context of T2D-specific metabolic and therapeutic challenges.

Real-world prescribing patterns and early weight and blood pressure outcomes of GLP-1-based therapies: a retrospective observational study in the United Arab Emirates.

Salma Almemari, Nour Almulla, Yasmin Alsarraf +2 more

Real-world weight impact upon tirzepatide discontinuation at a single-center endocrinology clinic in patients with overweight or obesity.

Lily Huang, Angla Lee, Dahye Kim +3 more

Overweight and obesity are major contributors to cardiovascular-kidney-metabolic (CKM) disease. Tirzepatide (TZP-MJ), originally approved for type 2 diabetes (T2D), has demonstrated significant weight loss beyond glycemic improvement. Despite these benefits, real-world medication access barriers may lead to abrupt therapy discontinuation. Currently, there is a lack of real-world data of TZP-MJ discontinuation in outpatient settings.

Cardiovascular adverse event reporting profile of tirzepatide: a real-world pharmacovigilance analysis of heart failure, arrhythmias, and ischemic events.

Daqiu Chen, Zixun Wang, Zhanxiong Xie +3 more

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is highly effective for glycaemic control and weight reduction. However, its real-world cardiovascular adverse event reporting profile remains incompletely characterised.

Acute onset of neovascular age-related macular degeneration after initiation of tirzepatide.

Kohzo Takebayashi, Yurina Iemura, Mototaka Yamauchi +4 more

Recent retrospective cohort studies showed that use of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) increased the incident risk of diabetic retinopathy and nonarteritic anterior ischemic optic neuropathy (NAION). Furthermore, it was recently reported that use of GLP-1RAs for more than 6 months increased the risk of neovascular age-related macular degeneration (nAMD) by about twofold, although the association between a gastric inhibitory polypeptide (GIP)/GLP-1 receptor dual agonist (GIP/GLP-1RA) and nAMD is not clearly established. We describe the case of a middle-aged male patient with type 2 diabetes without apparent diabetic retinopathy. Due to poor glycemic control, tirzepatide (a GIP/GLP-1RA) was started instead of sitagliptin (a dipeptidyl peptidase-4 inhibitor). After switching from sitagliptin to tirzepatide, glycemic control rapidly improved, but the patient felt haziness with distortion of the central part of the left eye. A diagnosis of neovascular age-related degeneration (nAMD) was made by ophthalmologists in our hospital. The basis for the possible association of tirzepatide administration with onset of nAMD is unknown. However, clinicians should pay attention to potential visual impairments after achieving acute glycemic control with incretin-related drugs, including tirzepatide.

Early intervention with tirzepatide or semaglutide influences anti-atherosclerotic effects in ApoE knockout mice.

Kazunori Dan, Junpei Sanada, Tomohiko Kimura +10 more

This study aimed to investigate the anti-atherosclerotic properties of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, in comparison with semaglutide, a selective GLP-1 receptor agonist. ApoE knockout mice were divided into early diabetes (dosed from 10 to 22 weeks of age), late diabetes (dosed from 18 to 30 weeks of age), and non-diabetic groups after streptozotocin treatment, and each group received semaglutide, tirzepatide, or saline for 12 weeks. In the early diabetes group, both agents significantly suppressed aortic plaque formation compared with control, while modestly improving glycemia and lipid levels. No significant vascular effects were observed in late diabetes or non-diabetic groups. Tirzepatide markedly reduced inflammatory mediators, including Mcp-1, Il-6, I-cam, and Cd68, whereas semaglutide showed partial overlap. Notably, these anti-inflammatory effects were also detected in non-diabetic mice, suggesting vascular protection may involve arterial actions independently of metabolic control. Taken together, our findings demonstrate that tirzepatide exerts anti-atherosclerotic effects comparable to semaglutide, supporting the concept that GIP and GLP-1 signaling can confer vascular benefits. These results highlight the potential clinical relevance of dual incretin receptor agonism for cardiovascular risk reduction, although further studies are required to clarify the specific role of GIP signaling.

Real-World Clinical Evidence of Tirzepatide for Metabolic Abnormalities in Subjects With Type 2 Diabetes: The Multicenter Retrospective Observational Hokkaido-TZP Study.

Fumika Maruyama, Hiroya Kitsunai, Naoyuki Kitao +12 more

Tirzepatide has demonstrated potent glucose-lowering efficacy and metabolic benefits in subjects with type 2 diabetes (T2D) in Phase III clinical trials. However, its efficacy in real-world clinical practice, particularly among patients receiving various antidiabetic therapies, remains to be elucidated.

Tirzepatide attenuates mesolimbic cocaine-evoked dopamine levels and reduces cocaine taking, motivation and seeking behaviours in male rodents.

Christian E Edvardsson, Xinming Zhang, Thaynnam A Emous +5 more

Cocaine use disorder (CUD) remains among the most treatment-resistant addictions, characterised by high relapse rates even following extended abstinence periods. Dopamine signalling in mesocorticolimbic circuits contributes to cocaine's reinforcing effects and remains an important target for therapeutic intervention. Growing evidence suggests appetite-regulating peptides may influence central dopamine transmission. Whether recently approved incretin polyagonists can modulate cocaine-related behaviours through their capacity to simultaneously engage multiple appetite-regulating peptide receptor pathways remains unexplored.

Vitreous hemorrhage in a patient on tirzepatide: Coincidence or drug induced?

Sitara Azeem, Lujain Al Bulushi, Buthaina Isa Sabt

Tirzepatide is a synthetic polypeptide classified as glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist. It stimulates insulin secretion from the pancreas and helps lower blood sugar levels in patients with type 2 diabetes mellitus. It also reduces appetite and helps in weight reduction management. We report a case of unilateral vitreous hemorrhage in a middle-aged woman on tirzepatide for weight loss. A 55-year-old female, nondiabetic, on tirzepatide for weight loss presented with sudden visual loss in the right eye while being on tirzepatide. Her ocular history is known for angle-closure glaucoma status postsurgical peripheral iridectomy in both eyes many years back. Her medical history is notable for palpitations and is currently managed with beta blockers. At presentation, the best-corrected visual acuity in the right eye was 0.16 and 1.0 in the left eye. Fundus examination revealed vitreous hemorrhage in the right eye. Vitreous hemorrhage spontaneously resolved and uncorrected visual acuity improved to 1.0 over a period of four months. The key point to be conveyed from this case is the need for more studies into whether there is a causal relationship between tirzepatide and vitreous hemorrhage in nondiabetic patients and to promote caution when administering tirzepatide.

Dose-response analysis of tirzepatide and acute pancreatitis: An international systematic review and quantitative meta-analysis of randomised trials.

Olivia Benny, Anurag Agarwal, Harvey Alecock +47 more

Tirzepatide, a dual GIP/GLP-1 receptor agonist for type 2 diabetes and obesity, carries a theoretical risk of pancreatitis. Whether risk varies by dose is uncertain.

Tirzepatide in Metabolic Diseases: Clinical Efficacy and Safety Beyond Diabetes and Obesity.

Shixuan Dong, Ying Xu, Ran Gan +3 more

Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has attracted substantial attention for its exceptional efficacy in managing type 2 diabetes and obesity. Emerging evidence suggests that tirzepatide may also exert broad therapeutic benefits in cardiovascular diseases, metabolic dysfunction-associated steatotic liver disease, and chronic kidney disease. However, its potential clinical risks are increasingly being recognized. This review begins by outlining the structural and pharmacological advantages of tirzepatide. We then comprehensively evaluate recent clinical evidence, including randomized controlled trials and real-world studies, based on a comprehensive literature search, to analyze its efficacy and safety for metabolic disorders. Tirzepatide exhibits considerable promise in treating multiple metabolic diseases; however, its therapeutic benefits must be carefully weighed against potential risks. Conclusions on cardiorenal benefits are supported by high-level outcome trials, while the evidence for hepatic, renal and musculoskeletal effects is exploratory or preliminary. Further large-scale, long-term studies remain essential to fully elucidate its mechanisms of action and overall clinical impact, given the current safety signals and other evidence are largely based on case reports, post hoc analyses, and non-prespecified endpoints. Continued pharmacovigilance is also crucial to identify and mitigate potential adverse drug reactions in diverse patient populations, especially for rare but serious events identified through spontaneous reporting systems.

Efficacy of tirzepatide, lanifibranor, and resmetirom in metabolic dysfunction-associated steatotic liver disease: a meta-analysis of high-quality randomized controlled trials.

Shuai Zhao, Fei Tian, Lan Yu +6 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition and a leading cause of chronic liver disease worldwide. Several pharmacological agents are currently used in its clinical management. This meta-analysis assesses the comparative efficacy and safety profiles of three novel therapeutic agents-tirzepatide (a dual GIP/GLP-1 receptor agonist), lanifibranor (a pan-PPAR agonist), and resmetirom (a thyroid hormone receptor-β agonist)-in patients with MASLD/MASH.We systematically searched PubMed, Scopus, Web of Science, the Cochrane Library, and Embase from inception to December 31, 2024. Eligible randomized controlled trials (RCTs) were those that enrolled adults with MASLD/MASH and compared tirzepatide, lanifibranor, or resmetirom with placebo. Non-randomized trials, animal studies, trials using only imaging or biomarkers for diagnosis, studies without a placebo arm, and those including subjects aged < 18 years were excluded. Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool. Data synthesis was performed using RevMan 5.3. The protocol was registered with PROSPERO (CRD 42025637054). Five placebo-controlled trials met the inclusion criteria: one for tirzepatide (NCT04166773), one for lanifibranor (NCT04849728), and three for resmetirom (NCT03900429, NCT04197479, NCT04951219). The analysis included 2497 individuals (1112 [45%] male, mean age 55.6 years [SD 11.6], mean BMI 35.3 kg/m2 [SD 6.3], and 1385 [55%] with diabetes). All agents led to MASH resolution without worsening of fibrosis in a proportion of patients, with significant effects observed for tirzepatide and resmetirom. Tirzepatide (mean difference [MD] - 34.90% [95% CI: - 53.31 to - 16.49]) and resmetirom (MD - 31.45% [95% CI: - 35.93 to - 26.97]) significantly reduced hepatic steatosis as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Tirzepatide significantly reduced serum aminotransferase levels (ALT: MD - 30.90%, p < 0.00001; AST: MD - 20.71%, p < 0.00001). Although lanifibranor demonstrated improvements in lipid profiles (HDL-C + 9.87%, triglycerides - 26.90%), it did not achieve a statistically significant improvement in fibrosis (OR 1.26, p = 0.08). Gastrointestinal adverse events were frequently reported across all treatment arms. Tirzepatide and resmetirom significantly improved MASH resolution without worsening of fibrosis and reduced hepatic steatosis. All three agents lowered serum aminotransferase levels, while lanifibranor and resmetirom improved lipid profiles. Gastrointestinal adverse events were common, which may affect tolerability. Due to the limited number of trials for tirzepatide and lanifibranor, further large-scale studies are warranted to confirm their role in MASLD/MASH management.

Cardiorenal Outcomes With Tirzepatide Compared With Dulaglutide in Patients With Diabetes and Cardiovascular Disease: A Post Hoc Analysis of the SURPASS-CVOT Randomized Clinical Trial.

Steven E Nissen, Kathy Wolski, David D'Alessio +6 more

The dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide was noninferior to a GLP-1 agonist, dulaglutide, for effects on the composite outcome of cardiovascular death, myocardial infarction (MI), or stroke. However, comparison for a comprehensive range of major adverse cardiovascular and kidney outcomes has not been reported.

Safety and efficacy of switching from dulaglutide to tirzepatide across clinically relevant baseline characteristics in participants with T2D: subgroup analysis of SURPASS-SWITCH.

Rafael Violante-Ortiz, Ludger Rose, Palash Sharma +3 more

In SURPASS-SWITCH, switching from dulaglutide to tirzepatide resulted in greater improvements in glycemic control and body weight in adults with type 2 diabetes (T2D). This study aimed to investigate the efficacy and safety of switching from weekly dulaglutide to weekly tirzepatide in adults with T2D in prespecified baseline subgroups from SURPASS-SWITCH.

A Rare Case of Tirzepatide-Associated Immune Thrombocytopenia.

Kelvin Rojas, Arshia Ahmed, Salman J Khan +1 more

Tirzepatide, a novel dual glucagon inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the management of type 2 diabetes mellitus (T2DM) and chronic weight management. There are no current case reports on tirzepatide causing drug-induced thrombocytopenia (DIT) despite its metabolic benefits and common gastrointestinal side effects being well documented. This case report details a 47-year-old male with a history of obesity and T2DM who presented with an ecchymotic, petechial rash within a week of increasing the dose of tirzepatide to 12.5 mg. Pertinent labs showed isolated thrombocytopenia (6000/µL), and other secondary causes of thrombocytopenia were ruled out. The patient was started on intravenous immunoglobulin (IVIG) and steroids. Platelet counts ultimately increased to baseline in response to the treatment with tirzepatide cessation, IVIG, and corticosteroids. Overall, these findings suggest an immune-mediated, drug-induced mechanism of severe thrombocytopenia. Our case intends to raise clinical awareness regarding this potential rare side effect of tirzepatide-induced thrombocytopenia. Prompt discontinuation of the drug and early initiation of steroids/IVIG can prevent life-threatening bleeding and promote recovery.

GLP-1 and dual GIP/GLP-1 agonists in obese patients with HFpEF: a systematic review and meta-analysis of RCTs.

Elhaitham Yasir Awad Musa, Amar Yasir Awad Musa

Tirzepatide mitigates atherosclerosis progression and modulates oxLDL-mediated proatherogenic effects in macrophages: evidence for M1/M2 homeostasis restoration.

Mengjie Kang, HaoLin Ren, Yanru Zhen +10 more

Tirzepatide (TZP), a novel dual agonist of glucagon-like peptide (GLP)-1/glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R/GIPR), has been shown to reduce cardiovascular (CV) risk in patients with diabetes or obesity. This study investigated anti-atherosclerotic effects of TZP and the underlying mechanisms using apo E-/- mice and cultured macrophages. In the present study, apo E-/- mice were fed a high fat/high cholesterol (HF) diet with or without TZP treatment for 12 weeks. Atherosclerotic lesions, metabolic parameters, and M1/M2 macrophage homeostasis were assessed. In vitro, RAW264.7 and THP-1 macrophages were treated with oxLDL and TZP to evaluate foam cell formation, inflammation, and signaling pathways. The results showed that TZP significantly lowered body weight, plasma lipids, and atherosclerotic burden in vivo, and favorably modulated the expression of M1/M2 macrophage markers. ANCOVA suggested that the anti-atherosclerotic effect may be partially independent of metabolic improvements, although further studies are needed for confirmation. While these data support macrophage modulation as a key mechanism, other vascular cell types and plaque components likely contribute to the observed plaque-stabilizing effects. In vitro, TZP inhibited oxidized Low-density Lipoprotein (oxLDL)-induced cholesterol accumulation and foam cell formation, cluster of differentiation (CD) 36 expression and M1 inflammatory markers while promoting M2 markers. These effects were blocked by combined GLP-1R/GIPR antagonism and further confirmed in human THP-1 macrophages. Mechanistically, the anti-inflammatory effects and modulation of M1/M2 macrophage homeostasis by TZP were mediated via activating kruppel-like factor 4/the peroxisome proliferator-activated receptor γ pathway. Collectively, these findings indicate that TZP confers CV protection and anti-atherosclerotic benefits through both lipid-lowering dependent and independent mechanisms, highlighting its therapeutic potential for diabetic and obese patients who are at high risk of atherosclerotic CV diseases.

Real-World Weight-Loss Outcomes in Weight-Reduced Patients Treated With Tirzepatide.

Sarah R Barenbaum, Ariel Gonzalez, Zoe Verzani +2 more

This study compared weight-loss outcomes in patients prescribed tirzepatide by weight-loss status and assessed results among patients transitioning from semaglutide.

Gastrointestinal adverse events associated with tirzepatide: A bibliometric and pharmacovigilance analysis.

Peng Shen, Meng-Si Peng, Sun Jo Kim +2 more

This study examines gastrointestinal adverse events (GIAEs) associated with tirzepatide using bibliometric and pharmacovigilance analyses.

Incretin polyagonists as an alternative to bariatric surgery to manage obesity.

Rohit Jacob Manoj, Cornelius J Fernandez, Sunil Nair +1 more

Incretins are gut hormones involved in maintaining metabolic homeostasis in the human body, and disorders of the incretin system are recognized as contributing to the pathobiology of metabolic dysfunction and obesity. Incretin polyagonists are transforming the landscape of obesity treatment by offering potent, non-surgical alternatives to bariatric procedures. Acting on multiple incretin and related receptors, these novel pharmacological agents harness the synergistic effects of gut hormones such as glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon to achieve unprecedented weight loss and metabolic improvements. Recent clinical trials demonstrate that dual and triple agonists can produce weight reductions comparable to, or in some cases approaching, those seen with bariatric surgery, while simultaneously improving glycemic control, lipid profiles, liver fat, and cardiovascular risk factors. Unlike conventional monotherapies, these polyagonists address the complexity of energy homeostasis and metabolic dysfunction in obesity, with some agents displaying a favorable side effect profile and thereby enhancing patient tolerability. Practical considerations, such as ease of administration, cost, long-term safety, and accessibility, remain evolving challenges; yet, incretin polyagonists have rapidly gained prominence in clinical guidelines for the management of obesity and type 2 diabetes mellitus. As evidence mounts regarding their efficacy, safety, and potential to modify cardiometabolic disease risk, incretin polyagonists emerge as promising alternatives, especially for patients unable or unwilling to undergo bariatric surgery. Ongoing research will further define their long-term role, comparative effectiveness, and optimal integration into multidisciplinary obesity care. This review discusses the current evidence-base for optimal use of incretin polyagonists as an alternative to bariatric surgery.

Tirzepatide as adjunct therapy in patients with type 1 diabetes: a systematic review and meta-analysis.

Ahmed Soliman, Bishoy Hamour, Abdelwahab Hammad +7 more

Tirzepatide, a dual agonist of the glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1R) receptors, has demonstrated efficacy in glycemic control and weight loss in patients with Type 2 diabetes mellitus (T2DM). Its role as adjunctive therapy in individuals with Type 1 diabetes mellitus (T1DM), particularly those who are overweight or obese, remains underexplored. This review aims to evaluate the efficacy of tirzepatide as an adjunct to insulin therapy in adults with Type 1 diabetes mellitus (T1DM) and overweight or obesity, focusing on changes in glycemic control, body weight, body mass index (BMI), and insulin dose requirements.

Lean Mass Changes With Incretin Therapy Versus Lifestyle Intervention: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Naseem Eisa, Omar Barood

To compare lean mass changes between incretin-based therapies (GLP-1 receptor agonists and dual GLP-1/GIP agonists) and intensive lifestyle interventions in adults with overweight or obesity, and to determine whether the proportion of total weight lost as lean mass differs between these treatment modalities.

Bispecific GLP-1/GLP-2 agonism in advanced type 2 diabetes: preclinical characterization and a randomized, double-blind, placebo-controlled phase I trial.

Sang-In Yang, Sae Won Kim, Kyung-Hwa Son +4 more

PG-102 is a potency-optimized bispecific Fc fusion protein targeting GLP-1 and GLP-2 receptors. In db/db mouse models of advanced diabetes characterized by uncontrolled hyperglycemia and catabolic weight loss, PG-102 achieved superior and sustained glycemic control compared with semaglutide or tirzepatide while preserving body weight, uncoupling glycemic control from catabolic weight loss. Mechanistic studies indicated that these effects were not driven by acute insulinotropic activity, but by β-cell preservation and enhanced glucose uptake. These benefits required dual GLP-1R/GLP-2R engagement, as PG-102 outperformed monospecific Fc fusion agonists or their combination and promoted coordinated receptor trafficking with delayed internalization. We conducted a randomized, double-blind, placebo-controlled multiple ascending dose phase 1 study at a single center in the Republic of Korea in adults with overweight (BMI 25-30 kg/m²). Twenty-four participants were randomized within three weekly dose cohorts (15 mg, 30 mg, and 30/60 mg; n = 6 per cohort) in a 6:2 ratio to receive PG-102 (n = 18) or placebo (n = 6). All randomized participants (PG-102 n = 18; placebo n = 6) received at least one dose and were included in the safety analysis. Safety and tolerability were predefined as the primary endpoint and assessed by treatment-emergent adverse events (TEAEs). TEAEs occurred in 5/6 (83.3%) participants in each PG-102 cohort and 4/6 (66.7%) in placebo; treatment-related AEs occurred in 5/6 (83.3%) and 3/6 (50.0%), respectively. No serious adverse events or discontinuations due to adverse events occurred. Gastrointestinal events were mild to moderate. These findings support bispecific GLP-1/GLP-2 agonism as a mechanistically distinct incretin strategy in advanced T2D. ClinicalTrials.gov identifier: NCT06309667.