Acoustic and Clinical Outcomes of Next-Generation Pharmacological Weight Loss Therapies on Obesity-Related Osteoarthritis of the Knee

This is an application for a Career Development Award (CDA-2) to Dr. David Ewart, MD, a staff rheumatologist at the Minneapolis VA Medical Center and Assistant Professor at the University of Minnesota. Dr. Ewart’s research area of interest is in osteoarthritis of the knee. His current VA-funded project is using acoustics measured from the human knee to diagnose early knee OA. His published data suggest that knee acoustics, when measured during scripted maneuvers, are highly accurate at identifying symptomatic pre-radiographic evaluate whether next-generation weight loss therapies improve knee pain in a real-world cohort of participants with obesity and symptoms of knee OA regardless of their radiographic severity as well as determine if knee acoustics are sensitive to knee health status or symptoms of knee OA in this cohort knee OA. This CDA-2 award will provide Dr. Ewart support to . It will provide the training, experience, and mentorship he requires to establish an independent research program developing and testing technologies for the evaluation and treatment of knee OA and to compete for a VA Merit award. To achieve these goals, Dr. Ewart has established a mentorship team of experts in clinical research, knee OA, and advanced analytic methods. Knee OA is a prevalent and disabling disease. Pharmacologic and surgical treatments for knee OA symptoms are insufficient for many patients and there are no therapies that halt or even delay the structural progression of disease. Research into disease-modifying therapies for knee OA is hindered by a lack of an established benchmark for successful treatment of knee structure that is also associated with improvement in patient- reported outcomes. Obesity is associated with progression of knee OA and significant weight loss improves knee OA symptoms, but it is not known if it reduces or stops progression because weight loss is very difficult to sustain long term. There are new next-generation weight loss drugs that represent a revolution in the pharmacologic management of obesity, being not only highly effective but also highly durable. It is likely that individuals who lose weight with these drugs will have an improvement in their knee pain and function and possible that these drugs will provide disease-modifying benefits in obesity-related knee OA. This offers an opportunity to measure and compare knee acoustics in the context of obesity, where their sensitivity for knee health is unknown, as well as dynamic changes in symptoms and a potentially structure-modifying therapy. By bridging knee structure and symptoms, acoustics could potentially address major difficulties in developing effective therapies for knee OA, such as identification of individuals with a high likelihood of rapid progression and non-invasive monitoring of knee health and function. This CDA-2 proposal is a prospective cohort study of participants with obesity and persistent knee pain who are initiating next-generation weight loss therapy Aim 1 is an evaluation of whether initiation of semaglutide is associated with an improvement in knee pain in obese individuals with symptoms of knee OA regardless of their disease severity on x-ray. Aim 2 and Aim 3 are studies of the accuracy of knee acoustics for radiographic, biomechanical, and clinical knee health status in individuals with obesity. (semaglutide). Participants will be followed for a year after starting semaglutide and their longitudinal symptoms, acoustics, and biomechanics will be measured pre- and post-semaglutide. The overall objective of the proposed project is to develop a framework for the rigorous evaluation of whether semaglutide improves the natural history of obesity-related knee OA and to develop knee acoustics as a non- invasive measure of knee health and function. This work will form the basis for a larger, longitudinal follow-up study of next-generation weight loss therapies to delay the progression of knee OA and of using acoustics as an outcome Project Number: 1IK2RX004802-01A2 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: David Ewart | Institution: MINNEAPOLIS VA MEDICAL CENTER, MINNEAPOLIS, MN | Activity Code: IK2 | Study Section: Career Development Program - Panel II[RRD9] View on NIH RePORTER: https://reporter.nih.gov/project-details/11112910