GLP-1s Could Replace the Need for Knee Replacement Surgery

Among patients living with knee osteoarthritis (OA), glucagon-like peptide-1 (GLP-1) receptor agonist medication was associated with long-term reductions in the risk of total knee arthroplasty (TKA), otherwise known as knee replacement surgery, according to Regional Anesthesia & Pain Medicine.¹

“Basic movements such as walking and bending put pressure on the bones and joints in our lower extremities,” wrote the STOP Obesity Alliance.² “The largest joint in the human body, the knee joint, bears the brunt of force during locomotion and is especially prone to injury. The force exerted on the knee joint is directly proportional to body weight.”

For a 200-pound adult, a mere 10-pound weight gain translates to an additional 15 pounds of force on the knee during walking and up to 50 pounds when squatting. This mechanical stress is compounded by the fact that adipose tissue is metabolically active, secreting proinflammatory cytokines that accelerate joint degeneration.

Providers have termed this synergistic downward spiral “osteobesity,” where joint pain leads to a sedentary lifestyle, which in turn increases BMI and further exacerbates the underlying OA. Despite TKA often being the definitive treatment for end-stage disease, it is essentially a “resurfacing” procedure where damaged bone is replaced with metal and plastic implants.^3,4

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Despite its success, TKA carries risks such as joint infection and life-threatening blood clots, and it is often contraindicated in patients with severe obesity due to high complication rates.

Recent Data on GLP-1 Use for TKA Risk Reduction

The groundbreaking TriNetX Global Research Network study published in Regional Anesthesia & Pain Medicine suggests that GLP-1s may break this cycle by offering more than just weight loss. The retrospective analysis revealed that GLP-1 use was associated with a significantly lower cumulative incidence of TKA across all exposure classes and follow-up intervals.¹

The most substantial benefits were seen with “new generation” agents—specifically semaglutide and tirzepatide—when used long-term for at least 3 years. For these patients, the absolute risk difference for surgery reached -4.71 percentage points at the 8-year mark.

Pharmacists should note that these effects likely stem from metabolic reprogramming within cartilage tissue and the suppression of proinflammatory signaling, suggesting a direct disease-modifying activity.¹

The pharmacological toolkit for delaying TKA is not limited to GLP-1s, as other common medications managed by pharmacists may play a role. Research indicates that non-selective beta-blockers, such as propranolol, are associated with a 54% reduction in TKA risk by potentially downregulating the adrenergic signals that contribute to cartilage degradation.⁵

“Current OA management focuses on symptomatic relief and reducing disability progression, via a combination of lifestyle, nonpharmacological, pharmacological, and surgical approaches tailored to the needs of the individual,” wrote the authors of a study in Health Expectations.⁶ “To further facilitate lifestyle and nonpharmacological approaches, established guidelines encourage engagement in self‐care activities.”

Furthermore, a comprehensive clinical approach that combines medication with aggressive lifestyle modification has shown transformative results. A case study from the Cleveland Clinic highlighted a patient with a BMI of 53.4 who avoided surgery entirely by losing 148 pounds through a “periodized” approach, alternating semaglutide with the more affordable phentermine alongside a rigorous exercise prescription.³

Looking Ahead at TKA and GLP-1 Capabilities

As health care shifts toward integrating metabolic health into musculoskeletal care, the dissemination of this data remains paramount. Professionals often rely on secure digital infrastructures to ensure critical radiology and orthopedic research is available to the global medical community.^1,5

For the 700,000 Americans undergoing TKA annually, these findings suggest that sustained pharmacological intervention could soon offer a viable path toward joint preservation. By identifying eligible patients with concurrent metabolic disease, pharmacists can help move the treatment paradigm away from reactive surgery and toward proactive, metabolic management of OA.^1,4

“In this large, multicenter, real world cohort study, GLP-1 RA use was associated with a significantly reduced long term risk of TKA in patients with knee OA, with effects that were greater with longer treatment duration and newer generation agents,” concluded authors of the current study.¹ “These duration and agent dependent associations are consistent with potential disease modifying activity beyond weight loss alone, although prospective trials are needed to establish causality and define optimal treatment targets.”

READ MORE: Obesity Management Resource Center

REFERENCES

1. Carter V, Desverreaux E, Amin I, et al. Glucagon-like peptide 1 receptor agonist use and risk of arthroplasty for knee osteoarthritis: retrospective database analysis. Reg Anesth Pain Med. June 2, 2026. https://doi.org/10.1136/rapm-2026-107658

2. Osteoarthritis and obesity. STOP Obesity Alliance. August 1, 2019. Accessed June 3, 2026. https://stop.publichealth.gwu.edu/LFD-july19

3. Exercise medicine helps patient with “osteobesity” avoid knee replacement. Cleveland Clinic. October 11, 2024. Accessed June 3, 2026. https://consultqd.clevelandclinic.org/exercise-medicine-helps-patient-with-osteobesity-avoid-knee-replacement

4. Total knee replacement. OrthoInfo. Accessed June 3, 2026. https://orthoinfo.aaos.org/en/treatment/total-knee-replacement/

5. Common blood pressure medications linked to lower risk of total knee replacement. Wolters Kluwer. September 13, 2023. Accessed June 3, 2026. https://www.wolterskluwer.com/en/news/common-blood-pressure-medications-linked-to-lower-risk-of-total-knee-replacement

6. McLachlan AJ, Carroll PR, Hunter DJ, et al. Osteoarthritis management: Does the pharmacist play a role in bridging the gap between what patients actually know and what they ought to know? insights from a national online survey. Health Expect. 2022 Jun;25(3):936-946. doi: 10.1111/hex.13429.