Semaglutide Use Shows Bonus Benefit Of Osteoarthritis Risk Reduction
Overview
Osteoarthritis (OA) is a widespread degenerative joint condition. While the influence of obesity on OA is well-established, the effect of semaglutide on OA remains less understood.
The objective was to evaluate the effect of semaglutide on the risk of OA among patients with obesity in the United States.
A retrospective cohort study utilized Kythera Medicare closed claims data from November 1, 2020, to October 31, 2023. Patients continuously enrolled with obesity diagnoses during the baseline period (November 1, 2020–October 31, 2021) were selected. These patients were categorized based on their use of semaglutide during the identification period (November 1, 2021–October 31, 2022) and were monitored for the occurrence of OA during the follow-up period. Multivariate analysis was applied to adjust for demographic factors and comorbidities.
Introduction
Osteoarthritis (OA) is a common degenerative joint disease characterized by excessive joint loading, altered biomechanical patterns, and disruptions in cytokine and hormonal balance. It affects various body parts, such as knees, hips, and hands, significantly diminishing the quality of life, particularly among older adults. OA is the most prevalent form of arthritis, affecting 32.5 million adults in the United States, and its incidence is expected to rise by 50% in the next two decades. The majority of arthritis patients are aged 55 years or older, reflecting an age-related increase in OA prevalence.
The substantial prevalence of OA imposes a considerable financial burden on both the healthcare system and patients. The annual direct per-patient costs for OA in the US range from $1,442 to $21,335. Studies show that individuals with knee OA have significantly more annual physician and non-physician visits compared to those without OA.
Risk factors for OA include female sex, advanced age, mental illness, and cardiovascular disease, with obesity being one of the most significant. Obesity places additional stress on weight-bearing joints like the knees, hips, and spine, and fat tissue releases inflammatory chemicals that contribute to joint damage. Overweight individuals have a 1.9 times higher risk of developing hand OA compared to those with normal weight. Additionally, obesity limits physical activity, leading to muscle weakness and joint stiffness, and increases the risks associated with OA treatments such as total joint arthroplasty. Therefore, weight management is crucial for both preventing and managing OA.
Semaglutide, a medication recently approved by the US Food and Drug Administration (FDA) for obesity treatment, reduces appetite, increases feelings of fullness, and modifies fat storage and utilization. Marketed as Ozempic for diabetes treatment since 2017, semaglutide showed weight loss effects that led to the development and FDA approval of Wegovy for obesity treatment in 2021. Ozempic had been used off-label for obesity treatment before Wegovy’s approval.
Semaglutide is often used in conjunction with comprehensive weight management strategies, including dietary changes, physical activity, and behavioral counseling, leading to an average weight loss of up to 10% of initial body weight. Recent clinical trials also demonstrated that semaglutide reduces the risk of major adverse cardiovascular events in people with type 2 diabetes.
Also read Obesity Treatment With Tirzepatide And Semaglutide
Despite its efficacy in weight loss and cardiovascular benefits, the impact of semaglutide on OA, another prevalent condition, has not been previously studied. This retrospective cohort study aims to assess the effect of semaglutide (Ozempic and Wegovy) on the risk of developing OA, utilizing real-world data to provide updated insights.
Methods
A retrospective cohort study was conducted using Kythera Medicare closed claims data from November 1, 2020, to October 31, 2023. This dataset, covering 79% of the US patient population, encompasses approximately 310 million patients, 6.1 million practitioners, 1.6 million organizations, and 1.4 million facilities, generating around 40 billion healthcare claims. This study focused on the Medicare portion, including a random sample of 61% of total Medicare enrollees, with data on demographics, diagnoses, and medication usage, allowing for comprehensive longitudinal analysis.
Two cohorts were identified: patients with obesity using semaglutide (Ozempic and Wegovy) and a randomly selected 10% sample of obese patients who did not use semaglutide. The semaglutide group consisted of patients with at least one pharmacy claim for Ozempic or Wegovy between November 1, 2021, and October 31, 2022, who also had a prior obesity diagnosis and continuous medical and pharmacy benefits for 12 months pre-index date. The non-semaglutide group included patients with a similar obesity diagnosis and continuous benefits within the same period. Exclusion criteria for both groups included prior obesity medication use, OA diagnosis, diabetes, or age over 99 years during the baseline period.
Obesity medications considered in the baseline exclusion included orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, and any obesity-related surgical procedures. ICD-10 codes were used to define diabetes and OA diagnoses. Baseline demographic and clinical factors were examined, including gender, age, socioeconomic status (SES), and the Chronic Disease Score (CDS) as a comorbidity index. OA-specific comorbidities were also identified using appropriate ICD-10 codes.
Descriptive analyses compared demographic and clinical variables at baseline between the cohorts. Subgroup analyses were performed based on medication type (Ozempic or Wegovy). Statistical tests, including Student’s t-tests and Pearson chi-square tests, assessed differences between cohorts, and standardized differences were computed.
During the follow-up period, the incidence and risk of OA between cohorts were determined using the Cox regression model and Aalen’s additive regression model. The Cox model, which assumes proportional hazards, was complemented by Aalen’s model to assess additive effects over time. Likelihood ratio tests and Wald tests were used to compare differences between groups. Analyses were conducted using Pyspark, SparkR on Databricks, and the R software package.
Results
After applying inclusion and exclusion criteria, 1360 obese patients in the semaglutide cohort and 39,891 obese patients in the non-semaglutide cohort were identified. Within the semaglutide cohort, 1125 patients used Ozempic, and 235 used Wegovy. The average patient age was 71.22 years in the semaglutide group and 74.02 years in the non-semaglutide group (p < 0.0001). Both cohorts had a higher proportion of female patients (68.90% vs. 55.79%, p < 0.0001). High-comorbidity patients were defined as those with a comorbidity score of two or above. Individuals in the semaglutide cohort had a significantly higher proportion of patients with a high CDS (78.31% vs. 36.67%, p < 0.0001). Both the semaglutide and the non-semaglutide cohorts tended to live in high-SES score areas (not significant).
The most prevalent baseline OA-related comorbidity in both the semaglutide and non-semaglutide groups was COPD (15.96% vs. 15.64%, p = 0.7504). The following comorbidities were found in greater proportions in patients receiving semaglutide than in those not on semaglutide: depression (14.49% vs. 11.22%, p = 0.0002), anxiety (12.65% vs. 10.41%, p = 0.0080), metabolic disorders (3.75% vs. 0.87%, p < 0.0001), gout (2.50% vs. 1.53%, p = 0.0044), and fibromyalgia (1.62% vs. 1.03%, p = 0.0346). Nonetheless, PVD (9.74% vs. 6.91%, p = 0.0005) and CVD (2.94% vs. 1.99%, p = 0.0393) were found in greater proportion in patients in the non-semaglutide cohort than in the semaglutide cohort. Comparison of the Ozempic and Wegovy cohorts indicated no age difference between the groups. Female patients were predominant in both cohorts, with a greater proportion in the Wegovy cohort than in the Ozempic cohort (74.89% vs. 67.64%, p = 0.0290). Patients in the Ozempic cohort had a higher CDS than those in the Wegovy cohort (80.89% vs. 65.96%, p < 0.0001). More patients living in high-SES score areas were in the Wegovy cohort than in the Ozempic cohort (40.69% vs. 32.43%, p = 0.0158).
The most common comorbidity was COPD for the Ozempic cohort (not significant) and depression for the Wegovy cohort (21.28% vs. 13.07%, p = 0.0011). The Wegovy cohort had anxiety (20.00% vs. 11.11%, p = 0.0002) and migraine (4.26% vs. 1.69%, p = 0.0133) in higher proportions than the Ozempic cohort. Consistent with Cox regression, semaglutide treatment is associated with a reduced likelihood of OA. The treatment plot shows an initial reduction in the likelihood of OA during the first 100–200 days after initiation of treatment. After that period, the effect of treatment on the likelihood of OA is insignificant. The likelihood of OA increased for female patients, patients aged 71–80 years, and patients with high CDS initially, but the effect disappeared after 600–700 days.
Discussion
To date, no studies have specifically investigated the association between semaglutide use and osteoarthritis (OA). Existing research highlights a strong, positive correlation between high levels of obesity and OA. Generally, obesity increases the risk of inflammatory and degenerative health conditions.
Extensive evidence demonstrates that higher body weight elevates the risk of OA, with studies finding that weight loss is an effective preventive measure. Weight loss has been shown to alleviate pain from OA and can significantly delay the progression of joint structural damage. Due to the high prevalence of obesity and its complications, medications like orlistat, semaglutide, and phentermine/topiramate are used for treatment. Literature suggests semaglutide is an effective weight loss method when combined with diet and exercise, and is beneficial for individuals struggling with weight loss due to metabolic issues.
OA is rapidly increasing in prevalence and is a leading cause of disability, behind only diabetes and dementia. The CDC projects that by 2040, 78.4 million US adults will have arthritis, with OA currently affecting 32.5 million adults in the US. The economic burden of OA is substantial, with annual costs in the US estimated at nearly $200 billion, of which excess OA-specific expenses account for almost 25%. The yearly healthcare costs for OA per person are estimated at $7585. Consequently, weight loss strategies are critical in reducing the economic and clinical burden of this prevalent and costly disease.
In our study, semaglutide cohort patients were slightly younger (average age 71.22 years) compared to the non-semaglutide group (average age 74.02 years). The semaglutide cohort had a higher proportion of female patients (68.90%) and more patients with a higher comorbidity score (CDS ≥ 2) compared to the non-semaglutide group. Additionally, the semaglutide group had higher rates of depression, anxiety, gout, and fibromyalgia. Previous research has shown that weight loss can improve symptoms in individuals with depression and obesity. Anxiety and depression are also prevalent among patients with OA. Obese patients with depression might benefit from semaglutide for overall health and mental outcomes improvement.
Gout and OA share risk factors like older age, obesity, and prior joint injury, which may explain the higher prevalence of gout in the semaglutide cohort. Fibromyalgia, often linked with OA, is also prevalent in obese patients. Our results support the association between obesity, gout, and OA, as well as the link between obesity, fibromyalgia, and OA. Additionally, our findings align with previous research indicating that female patients are more prone to OA and obesity.
Patients using Ozempic were typically older, male, and sicker, evidenced by a higher CDS score, compared to those using Wegovy. Ozempic is often part of the treatment for complex conditions like diabetes and heart failure, while Wegovy is more associated with mental health treatment, having a higher proportion of patients with depression, anxiety, and migraine. Wegovy users were also more likely to live in high SES areas, possibly due to its higher cost compared to Ozempic.
After adjusting for clinical and sociodemographic factors, semaglutide treatment was associated with a 16% reduction in OA risk. However, this association should not be interpreted as causation due to the non-randomized nature of the study. The weight reduction effect of semaglutide likely contributed to the decreased OA risk. Further research is needed to explore this association.
The study also found that being female increased the risk of OA by 35%, having a CDS score ≥ 2 by 20%, depression by 8%, migraine by 18%, gout by 53%, and fibromyalgia by 47%. These results also support the association between migraine and OA, especially among women aged 65 and older.
There were no significant differences in OA risk between Ozempic and Wegovy users, likely due to both being semaglutide formulations.
Limitations
The study used only Medicare data, lacking information on ethnicity, which may introduce bias due to unaccounted racial disparities in musculoskeletal health. Administrative data sets used may have inaccuracies in patient diagnosis and procedure coding, and the analysis was limited to conditions and treatments defined by ICD-10-CM codes. Claims data may miss some health information, and a diagnosis code on a medical claim may not confirm disease presence. Future studies should consider additional methods for patient identification, such as the use of biologics and other OA treatments.
Variables not included in claims databases, such as clinical and disease-specific parameters, may affect study outcomes. The data may not be generalizable to the entire population due to potential processing or reimbursement omissions. Additionally, not all health data are captured in the claims.
Conclusion
Osteoarthritis (OA) is rapidly emerging as a leading cause of disability, incurring substantial societal and individual costs. Obesity exacerbates the risk of inflammatory and degenerative conditions, including OA. Recently approved semaglutide medications, such as Ozempic and Wegovy, have shown potential in addressing these health issues, warranting further investigation. Our study revealed that semaglutide use in obese patients was linked to a 16% reduction in OA risk compared to those not on semaglutide. Therefore, semaglutide could be an effective strategy for preventing and managing OA in obese patients, potentially decreasing the clinical and economic burden associated with the disease.
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