Emerging evidence suggests GLP-1 receptor agonists may offer benefits far beyond glycemic control, potentially improving limb preservation outcomes in patients with diabetic foot complications. 

Key Takeaways

• GLP-1 RAs may support limb preservation: New observational studies associate GLP-1 receptor agonists with reduced diabetic foot ulcers, lower-extremity amputations, and all-cause mortality in high-risk patients with diabetes. 
• Benefits extend beyond blood sugar control: These medications may improve vascular function, reduce inflammation, promote weight loss, and support neuropathy management—factors directly tied to diabetic foot health and wound healing. 
• HCPs play an important collaborative role: Even when not prescribing GLP-1 therapies, foot and wound care specialists can help identify appropriate candidates, monitor treatment-related changes, and coordinate multidisciplinary care to improve long-term limb outcomes. 

As a practicing podiatrist, I am encouraged by the new research on glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These medications have moved quickly from being used mainly for blood sugar control to showing benefits for reducing cardiometabolic risk.¹ Now, early evidence suggests they may also help protect limbs and improve outcomes for people with diabetic foot complications.^2-4 Even if podiatrists and wound care clinicians are not prescribing these medications directly, understanding how GLP-1 RAs work, their benefits and limitations, and how they might affect care before and after procedures is increasingly important. This helps ensure that high-risk patients receive the comprehensive support they need.

What are GLP‑1 Medications?

GLP-1 is a natural hormone that helps the body release insulin when needed, slows stomach emptying, and reduces appetite. GLP-1 RAs are medications that mimic these effects but last longer in the body. Today, these medications are available in both injectable and oral forms and are typically used to treat type 2 diabetes and obesity. Examples include semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), and tirzepatide (Mounjaro, Zepbound), which also targets another hormone called glucose-dependent insulinotropic polypeptide (GIP). Newer options, like retatrutide and oral non-peptide GLP-1 receptor agonists such as Orforglipron, are being developed and may offer even more weight loss and simpler dosing in the future.^4,5

Mechanisms Relevant to Foot Health

GLP-1 RAs influence more than just blood sugar. They can also affect several pathways involved in diabetic foot problems. These medications may help blood vessels work better, improve blood flow to the smallest vessels, and protect nerves, which could slow the progression of diabetic neuropathy.⁴ They may also reduce inflammation and support weight loss, which can lower pressure on the feet and improve gait. Taken together, these benefits offer a more comprehensive approach to protecting the feet by addressing metabolic, vascular, nerve, and mechanical risks simultaneously.^2-4

Weight Loss and Mechanical Load

Studies show that people taking GLP-1 RAs such as semaglutide or tirzepatide often lose as much as 15–20% of their body weight.⁵ Weight reduction can lower forefoot pressure, reduce midfoot collapse, and minimize gait changes that cause calluses, skin breakdown, and ulcers—especially for those with neuropathy.⁴ For patients with Charcot foot or severe deformity, weight loss could work alongside offloading, special shoes, and braces; it does not replace these interventions, but may contribute to lowering foot stress between visits.

Glycemic Control, Infection Risk, and Wound Healing

GLP-1 RAs can help keep blood sugar levels in a healthier range and, when used without insulin or sulfonylureas, rarely cause low blood sugar.⁶ More stable blood sugar and less day-to-day fluctuation are linked to a lower risk of infection and better immune cell function, both of which are important for healing ulcers and recovering after surgery. Although dedicated studies evaluating ulcer healing outcomes remain limited, improvements in blood sugar and blood flow are likely to help wounds heal more predictably, especially when combined with good local wound care and offloading.^7,8

Limb Outcomes, Ulcers, and Mortality: Recent Literature

Mounting observational evidence connects GLP‑1 use with improved lower‑extremity outcomes. A large U.S. national cohort matched 180,740 GLP‑1 RA users to 180,740 sodium–glucose cotransporter 2 inhibitor (SGLT2i) users with 3‑year follow‑up. In this study, GLP‑1 RAs were associated with a 23% relative risk reduction in major (above‑ankle) amputations, a 27% reduction in minor amputations, an 8% reduction in incident diabetic foot ulcers, and a 34% reduction in all‑cause mortality compared with SGLT2s. Complementary work in patients with peripheral artery disease indicates GLP‑1 RAs are associated with lower risk of lower‑extremity complications and mortality compared with other second‑line agents, reinforcing a potential limb‑preserving effect in high‑risk vascular subgroups.²

A recent systematic review by Gruzmark et al suggests that GLP‑1 RAs may affect pathways involved in diabetic foot ulcer pathophysiology, including microvascular function, neuropathy, weight, oxidative stress, inflammation, and keratinocyte migration.⁴ Preclinical and human mechanistic data support improved angiogenesis and reduced inflammation, while large clinical trials and database studies indicate possible reductions in foot complications and amputations.⁴ However, human DFU healing data are limited, DFU events are infrequent in trials, and further studies are needed to compare GLP‑1RAs to standard DFU care.

Cardiovascular, Renal, and Systemic Benefits

GLP-1 RAs benefit heart, kidney, and systemic health in those at risk of limb loss. Large trials show reduced heart attack, stroke, cardiovascular death; improved blood pressure; and kidney protection. These benefits are highly relevant for patients with diabetic foot ulcers or amputations, who have high short-term mortality. National data show lower 1-year mortality after a first diabetic foot ulcer in GLP-1 RA users.^2-5

Safety, Side Effects, and Perioperative Considerations

The most common side effects of GLP-1 RAs are stomach-related, like nausea, vomiting, diarrhea, constipation, or feeling full quickly. These symptoms affect many people at first but usually improve within a month or 2 if the dose is increased slowly and patients adjust their diet. Rare but serious risks include pancreatitis, and these medications should not be used in people with a personal or family history of medullary thyroid cancer, type 1 diabetes, pregnancy, or severe gut motility problems.^6,9 For patients having surgery, it is recommended to stop weekly GLP-1 medications about a week before the procedure, since delayed stomach emptying can increase the risk of aspiration under anesthesia. The medication can be restarted once the patient is eating again and their blood sugar plan is back in place.¹⁰

Practical Points for Clinicians

Even if you do not prescribe GLP-1 medications, podiatrists and wound care specialists can make a real difference in how well patients do on these therapies. When taking a history, be sure to note if a patient is using a GLP-1 RA, the dose, and how long they have been on it. This information can guide conversations about rotating injection sites, checking the skin for problems, and avoiding areas with scarring or irritation. If you notice a new ulcer, a rise in skin temperature, or signs of infection, act quickly and work with the diabetes team to keep blood sugar under control, and check if illness or poor eating is affecting how the patient tolerates their medication. For patients who report reduced interest in food or rapid weight loss, encourage them to consume enough protein, and watch for muscle loss or balance changes that could increase their risk of falling.

Advocacy and Referral Opportunities

For podiatrists and wound care providers, these developments may offer a new way to support patients who face the highest risks, those living with repeated diabetic foot ulcers, a history of amputation, severe obesity, or heart disease. By recommending a full metabolic evaluation with an endocrinologist or primary care provider, we can help ensure that each patient's care plan addresses not just wounds, but the underlying factors that threaten limb health. A brief, focused referral that highlights limb risks, weight, and blood sugar control can help make the case for considering GLP-1 therapy as part of a broader limb-preservation strategy rather than viewing it only as a weight-loss option. For those already taking medications like Ozempic, Wegovy, or Mounjaro, it is important to encourage ongoing use, talk about long-term goals, and connect treatment to what matters most—staying mobile, avoiding hospitalizations, and protecting limb health. As new research emerges, we may find even more ways to help patients avoid life-changing amputations and support their overall well-being.

Dr. Rothenberg is a board-certified podiatrist, a Certified Diabetes Care and Education Specialist and Certified Wound Specialist who currently holds a Clinical Associate Professor of Surgery and Internal Medicine dual appointment within the divisions of Vascular Surgery and Endocrinology at the University of Michigan School of Medicine in Ann Arbor, Michigan. He is also the Director of Fellowship Training for the 2-year research-based fellowship at that institution. Additionally, he serves as the Director of Medical Affairs for Podimetrics, a mission-driven company committed to preventing avoidable amputations among people living with diabetes. Dr. Rothenberg is the current President of the American College of Podiatric Medicine.
 
References
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