Background/Purpose: Tirzepatide is a dual GIP/GLP-1 receptor co-agonist approved for weight loss in patients with obesity or body mass index (BMI) > 27 kg/m2 with comorbidities. GLP-1-based therapies may ease osteoarthritis symptoms indirectly via weight loss and directly through anti-inflammatory effects [1-3]. The STEP 9 trial demonstrated improvement in knee pain and function as well as reduced NSAID use in patients with obesity and knee osteoarthritis treated with semaglutide [4]. Tirzepatide differs from semaglutide in its dual agonism and greater weight loss [5]. No studies have examined musculoskeletal pain or analgesic use with tirzepatide. This study evaluated whether patients treated with tirzepatide had reduced joint pain and analgesic use than those receiving phentermine, the most prescribed anti-obesity medication in the U.S.

Methods: We conducted a cohort study using the TriNetX Research network, a large network of U.S. electronic health records and claims data. ICD-10 codes identified non-diabetic patients with BMI > 27 kg/m2. Using an intention-to-treat approach, we analyzed the overall rate of musculoskeletal pain encounters and risky analgesic use, as well as cardiovascular endpoints following initiation of tirzepatide or phentermine, excluding patients with prior history of the outcomes of interest. Outcomes were defined as > 1 encounter with applicable ICD-10 code occurring one day or more after treatment initiation. Nausea served as a positive control outcome. Propensity score matching adjusted for > 400 factors including demographics, comorbidities, medications, and baseline BMI; key covariates are included in Table 1. Kaplan-Meier and Cox models estimated the risk of the outcomes of interest.

Results: A total of 62,722 patients started on tirzepatide and 119,020 patients started on phentermine were included. After 1:1 matching, 27,930 patients per group had balanced baseline characteristics (Table 1). Mean follow-up was 276 days among patients on tirzepatide and 318 days among patients on phentermine. Tirzepatide users were more likely to achieve normal BMI (HR 3.02; 95% CI: 2.61, 3.49) with lower risk of joint pain (HR 0.91; 95% CI: 0.84, 0.99), especially knee pain (HR 0.84; 95% CI: 0.76, 0.93), and lower risk of NSAID (HR 0.88; 95% CI: 0.81, 0.95) and opioid prescriptions (HR 0.86; 95% CI: 0.79, 0.93) (Table 2). Risk of nausea was increased among tirzepatide users (HR 1.22; 95% CI: 1.10, 1.35), while risks of mortality and overall major adverse cardiac events (acute myocardial infarction, cerebral infarction, and/or mortality) were reduced (respectively, HR 0.48 with 95% CI of 0.28, 0.80; and HR 0.77 with 95% CI of 0.61, 0.99).

Conclusion: This large population-based study of non-diabetic patients with overweight or obesity demonstrates improvement in musculoskeletal pain requiring clinical care, reduced risky analgesic use, and better cardiovascular outcomes, among those receiving tirzepatide compared to phentermine. These findings support tirzepatide’s role in reducing musculoskeletal pain and the need for NSAID and opioid medications in this population.References1. PMID: 350915842. PMID: 394763453. PMID: 352809314. PMID: 394763395. PMID: 38976257

Table 1. Baseline Characteristics 0f Patients Receiving Tirzepatide versus Phentermine, after 1:1 Propensity-Score Matching

Table 2. Outcomes Among Patients Receiving Tirzepatide versus Phentermine

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impact-of-tirzepatide-on-musculoskeletal-pain-and-high-risk-analgesic-use-among-non-diabetic-patients-with-overweight-or-obesity-a-propensity-score-matched-active-comparator-new-user-study/