Tirzepatide

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.