Tirzepatide: Safety Profile & Research Summary

Animal Studies

• Metabolic/Energy (Mice, Bossi 2025): 10 nmol/kg SC daily × 4 weeks — 15.6 g weight loss (vs. 8.3 g semaglutide, +2.7 g vehicle). Temporarily increased energy expenditure and fat oxidation. [16]
• Food Preference (Mice/Rats, Geisler 2022): Selectively reduced palatable high-fat/sugar food intake while preserving chow intake. Effect abolished in GLP-1R knockout mice. [28]
• Carcinogenicity (Rats, 2-year): Dose-dependent increase in thyroid C-cell tumors at clinically relevant exposures (Boxed Warning). Not tumorigenic in 6-month transgenic mouse study. [29]
• Sepsis-Induced Cardiomyopathy (Mice, Liu 2023): Attenuated inflammatory response, inhibited TLR4/NF-κB/NLRP3 pathway, reduced cardiac injury markers (CK-MB, LDH, AST). [12]
• Alzheimer’s Disease (APP/PS1 Mice, Yang 2024): 10 nmol/kg IP weekly × 8 weeks — reduced amyloid-β plaques, astrocytic activation, and neuronal ROS production. [26]
• Neuroprotection In Vitro (Fontanella 2024): 0.2 µM in SHSY5Y cells prevented HG-induced GLUT3/GLUT4 downregulation and DNA methylation changes in CREB/BDNF promoters. [13]

Human Clinical Trials

• SURPASS-1 (T2DM, n=478): HbA1c −1.87% to −2.07% vs. +0.04% placebo; weight loss −7.0 to −9.5 kg. [19]
• SURPASS-2 (T2DM, n=1,879): Superior to semaglutide 1 mg in HbA1c (−2.01–−2.30% vs. −1.86%) and weight (−7.6–−11.2 kg vs. −5.7 kg). [7]
• SURPASS-CVOT (T2DM+CVD, n=13,299): MACE HR 0.92 vs. dulaglutide (non-inferiority confirmed). All-cause death HR 0.84. [20]
• SURMOUNT-1 (Obesity, n=2,539): Weight loss −15.0% to −20.9% at 72 weeks; 3-year follow-up: 94% T2D risk reduction. [21] [22]
• SURMOUNT-5 (Obesity, n=751): −20.2% tirzepatide vs. −13.7% semaglutide 2.4 mg — superiority confirmed. [23]
• SUMMIT (HFpEF+Obesity, n=731): 38% reduction in CV death/worsening HF (HR 0.62); KCCQ-CSS improved 6.9 pts. [24]
• SURMOUNT-OSA (OSA+Obesity, n=469): AHI reduced 55–63% (−25–29 events/hr vs. −5 placebo). [25]
• SYNERGY-NASH (MASH, n=190): Resolution in 44–62% vs. 10% placebo; fibrosis improved in ~51–55% vs. 30%. [17]

Regulatory Status

FDA: Approved — Mounjaro® (T2DM, May 2022), Zepbound® (obesity, Nov 2023; OSA, Dec 2024). [4]

EMA: Approved (Mounjaro) for T2DM and weight management.

WADA: Prohibited in competition and out-of-competition (S2 — Peptide Hormones).

reported tolerability profile: Most common AEs are GI (nausea 12–33%, diarrhea 12–23%, vomiting 2–13%, constipation). Boxed Warning for thyroid C-cell tumors based on rat data. Pancreatitis and gallbladder events reported at low rates. Hypoglycemia risk low as monotherapy. [29]