Patients presenting for orthopedic, podiatric, or wound-related surgery are increasingly likely to be taking a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a dual GLP-1/GIP receptor agonist such as tirzepatide. For wound care physicians, podiatrists, orthopedic surgeons, and wound center coordinators, the practical question is how these medications affect surgical risk, wound biology, and recovery.
Direct evidence linking GLP-1RAs to orthopedic surgical outcomes is still evolving. The references below do not establish a definitive causal effect on infection, non-union, or flap failure. Instead, they illuminate the mechanisms that should shape how surgical teams evaluate and prepare patients already on these medications.
What GLP-1 Receptor Agonists Actually Do
GLP-1RAs activate the GLP-1 receptor to produce glucose-dependent insulin secretion, suppression of glucagon release, delayed gastric emptying, and appetite reduction. These effects underlie the glycemic and weight benefits observed in diabetes and obesity.
Tirzepatide simultaneously activates the GIP receptor. Willard et al. showed that tirzepatide is an imbalanced dual agonist: it engages the GIP receptor to a greater degree than the GLP-1 receptor, and at the GLP-1 receptor it favors cAMP generation over beta-arrestin recruitment. This biased signaling is associated with reduced GLP-1 receptor internalization compared with native GLP-1, suggesting a pharmacologic profile distinct from selective GLP-1RAs.
Regmi et al. extended this picture to adipose tissue. In human adipocytes and mouse models, long-acting GIP receptor agonism enhanced insulin signaling, augmented glucose uptake, and increased glucose-to-glycerol conversion when insulin was present. In the absence of insulin, it increased lipolysis. In obese mice, this translated into lower circulating triglycerides during an oral lipid challenge and greater uptake of lipoprotein-derived fatty acids into adipose tissue. These findings improve nutrient partitioning, but do not automatically translate into better wound healing or lower infection risk.
Why This Matters in Orthopedic and Wound Care Practice
Perioperative implications fall into three categories: metabolic, nutritional, and anesthetic.
Metabolic. Better glycemic control and weight reduction can lower systemic inflammation and improve baseline healing biology. However, benefits are not guaranteed and must be balanced against the catabolic effects of rapid weight loss.
Nutritional. Reduced appetite and delayed gastric emptying can lead to inadequate protein, micronutrient, and caloric intake. Poor preoperative nutrition is a known risk factor for delayed wound healing, infection, and soft-tissue complications. Screen patients for recent weight trajectory, oral intake, and protein adequacy before elective surgery.
Anesthetic. Delayed gastric emptying raises aspiration risk and may affect preoperative fasting and medication absorption. Liu et al. identify perioperative management as a novel and evolving domain for GLP-1RAs and dual agonists. Coordinate with anesthesia and follow institutional protocols rather than relying on a universal rule.
Tirzepatide and Dual Agonism: A Different Signaling Profile
Tirzepatide should not be treated as merely a stronger GLP-1RA. Its greater GIP receptor engagement and biased GLP-1 receptor signaling produce a distinct metabolic footprint. The GIP component contributes to adipose insulin sensitization and dynamic lipid handling, while the GLP-1 component suppresses glucagon, slows gastric emptying, and reduces appetite.
Patients may arrive at surgery with improved metabolic markers but also reduced oral intake, possible dehydration, and altered gastrointestinal function. Each case requires individualized assessment rather than a simple stop-or-continue directive.
Perioperative Considerations for Surgical Teams
Practical checklist for patients on GLP-1RAs or dual agonists:
- Document the agent, indication, dose, and date of last administration at the first surgical visit.
- Coordinate with anesthesia regarding gastric emptying, aspiration risk, and fasting instructions.
- Assess recent weight change, oral intake, and protein status; involve nutrition support when needed.
- Optimize glycemic control without overcorrecting; hypoglycemia risk rises when oral intake is poor.
- For reproductive-age patients, confirm pregnancy status and discuss plans. Ozbek et al. found that periconceptional or early-pregnancy exposure to GLP-1-based therapies was not consistently associated with increased maternal, fetal, or neonatal risk in adjusted analyses, though data on continued use throughout gestation remain limited.
- Plan postoperative wound care early, including advanced wound biologics for high-risk closures.
A Practical Comparison
| Feature | GLP-1 Receptor Agonist | GLP-1/GIP Dual Agonist (Tirzepatide) |
|---|---|---|
| Primary receptor target | GLP-1 receptor | GLP-1 and GIP receptors |
| Key metabolic effects | Glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, appetite reduction | Adds GIP receptor-mediated insulin sensitization in adipose tissue and dynamic lipid handling |
| Perioperative concern | Aspiration risk from delayed gastric emptying; reduced oral intake | Same concerns, potentially amplified by broader metabolic and appetite effects |
| Wound care relevance | Metabolic optimization may help, but nutrition must be monitored | May improve metabolic substrate handling; still requires individualized nutritional and wound planning |
Key Takeaways
- GLP-1RAs and dual GLP-1/GIP agonists are increasingly common in orthopedic and wound care patients.
- Mechanisms include glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, appetite reduction, and GIP-mediated adipose insulin sensitization.
- Direct evidence tying these agents to orthopedic surgical outcomes is limited; manage metabolic, nutritional, and anesthetic implications proactively.
- Do not treat these drugs as a binary reason to cancel surgery, and do not ignore their perioperative effects.
- Coordinate across anesthesia, endocrinology, and nutrition; document medication use clearly and plan wound care accordingly.
Ready to optimize your high-risk wound closures?
Request samples of AmnioAMP or Rampart at nextgenbiologicsusa.com/request-samples.
References
- Willard FS, Douros JD, Gabe MBJ, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532. PMID: 32730231. https://pubmed.ncbi.nlm.nih.gov/32730231/
- Regmi A, Aihara E, Christe ME, et al. Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor. Cell Metab. 2024;36(7):1542-1558. PMID: 38878772. https://pubmed.ncbi.nlm.nih.gov/38878772/
- Liu Z, Yu S, Jin X, Sheng L, et al. The Clinical Application of GLP-1RAs and GLP-1/GIP Dual Receptor Agonists Based on Pharmacological Mechanisms: A Review. Drug Des Devel Ther. 2025;19:10383-10405. PMID: 41312047. https://pubmed.ncbi.nlm.nih.gov/41312047/
- Ozbek L, et al. Safety of GLP-1 and Dual GLP-1/GIP Receptor Agonists in Preconception, Pregnancy, and Lactation: A Systematic Review of Maternal, Fetal, and Neonatal Outcomes. Diabetes Obes Metab. 2026;28(4):1342-1362. PMID: 41885132. https://pubmed.ncbi.nlm.nih.gov/41885132/