Observational study of patients with diabetes and KOA
Dr. Zhu and colleagues recently published results of the first clinical investigation of long-term effects of GLP-1 receptor agonists on KOA in patients with comorbid type 2 diabetes.
They analyzed data from a subset of patients with KOA and type 2 diabetes from the Shanghai Osteoarthritis Cohort, including 233 patients who received a GLP-1 receptor agonist (semaglutide, liraglutide, or dulaglutide [Trulicity]) for at least 2 years and 1,574 patients who did not receive this therapy.
The patients had a mean weight of 66 kg (145 pounds), a mean body mass index of 27 kg/m2, and a mean A1c of 7.3%.
“According to conventional wisdom, a weight change greater than 5% is considered clinically relevant for KOA,” the researchers wrote. They found that patients had substantial weight loss after GLP-1 receptor agonist therapy.
The primary outcome, the incidence of knee surgery, was lower in the patients who received a GLP-1 receptor agonist than in the other patients (1.7% vs. 5.9%; adjusted P = .014).
Patients who received a GLP-1 receptor agonist also had greater improvements in secondary outcomes than did other patients, including pain subscale scores and cartilage-loss velocity of the medial femorotibial joint in patients with predominantly lateral OA.
“The effects of GLP-1 receptor agonists on arthritic knees were largely mediated by weight loss instead of glycemic control,” Dr. Zhu and colleagues reported.
They concluded that with long-enough treatment, “GLP-1 receptor agonist therapies might be disease-modifying for KOA patients with comorbid [type 2 diabetes mellitus].”
They called for further research to elucidate the effects of GLP-1 receptor agonists on the disease process, joint structure, and patient-reported outcomes of OA.
Dr. Garvey noted that “whether your BMI is 30 or 40, if there are complications, that tells you that degree of adiposity is sufficient to impair health.” So, if a patient in southeast China has a BMI of 27 kg/m2 and has osteoarthritis, he or she could still benefit from weight loss, he said.
Liraglutide and pain-related behavior in mouse models of OA
Dr. Berenbaum and colleagues reported that liraglutide alleviated pain-related behavior in sodium monoiodoacetate mouse models of KOA.
In addition, liraglutide had anti-inflammatory and anticatabolic effects in synovial fluid from the knees of six patients with OA of varying severity.
The researchers analyzed generic liraglutide (from Hybio Pharmaceuticals, Shenzhen, China) and nongeneric liraglutide (from Novo Nordisk, Bagsværd, Denmark).
They found that “when injected intra-articularly, liraglutide blunts the inflammatory process that is present in OA synovial tissue, explaining the acute analgesic effect,” Dr. Berenbaum said.
“Liraglutide could be a game-changer,” he said, “by demonstrating not only an effect on joint structures like synovial tissue and cartilage, but also on symptoms in a short-term period.”
Dr. Garvey said the symptom improvements after intrasynovial infusion of liraglutide in this trial were “impressive.” This study “adds credence to the hypothesis that these GLP-1 receptor agonists could have effects above and beyond weight loss,” he said.
Two trials near completion, one is upcoming
Phase 1 and 2 trials of 4P-004
“We are now in a phase 1 clinical trial [of 4P-004/liraglutide] in patients suffering from knee OA and should start a large phase 2 trial next year,” said Dr. Berenbaum.
The phase 1 LASARE trial, sponsored by 4Moving Biotech, planned to enroll 32 patients with KOA.
The primary outcome is safety and tolerability of single IA administration of 4P-004 at escalating doses in patients with KOA. Secondary outcomes include plasma concentration of liraglutide when administered this way.
Phase 3 trial of semaglutide for KOA
Novo Nordisk is performing a phase 3 study, “Effect of Subcutaneous Semaglutide 2.4 mg Once-weekly Compared to Placebo in Subjects With Obesity and Knee Osteoarthritis,” with an expected enrollment of 407 patients with KOA and estimated trial completion in September.
Eligible patients were aged 18 and older, with BMI > 30 kg/m2 and KOA with Kellgren-Lawrence grades 2 or 3. The co-primary outcomes are change in body weight and change in WOMAC pain score, from baseline to 68 weeks.
The LOSEIT trial was supported by Novo Nordisk and the Cambridge Weight Plan. The observational study in China was supported by the Shanghai Shenkang Hospital Development Centre, the Clinical Research Plan of SHDC, and the National Natural Science Foundation of China. The preclinical trial was supported by 4P Pharma/4Moving Biotech.
Dr. Berenbaum is CEO of 4Moving Biotech and chair of the scientific advisory board of 4P Pharma. He has received personal fees from 4P Pharma as well as numerous other pharmaceutical companies. Dr. Garvey has reported being a consultant to Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Merck, Fractyl Health, and Alnylam Pharmaceuticals, and reported being an investigator for studies sponsored by Novo Nordisk, Eli Lilly, Pfizer, and Epitomee. Dr. Gudbergsen, Dr. King, and Dr. Zhu report no relevant financial relationships.
A version of this article appeared on Medscape.com.