Anti-Diabetic Drug, Exercise and Healthy Diet for Knee Osteoarthritis With Overweight/Obesity, a Randomized Controlled Trial

Unhealthy diet (high fat, sugar) and physical inactivity result in overweight/obesity, which is the major cause of knee osteoarthritis (KOA). KOA further leads to increased intake of comfort food (unhealthy diet) and reduced exercise due to knee pain, forming a vicious cycle. Overweight and obesity are the main risk factors for the major non-communicable diseases (NCDs) like diabetes, etc. which are additional exacerbating factors for KOA. Compared to other NCDs, KOA is more painful and disabling and therefore it commonly leads to early medical consultation for an obese individual. This provides a unique therapeutic opportunity to conduct weight control intervention and lifestyle modification when they are referred for management and waiting for total knee replacement (TKR). Achieving weight control can reduce their subsequent risk of development of other NCDs which lead to increased mortality, and potentially improve their osteoarthritic symptoms, and potentially avoid TKR.

Overweight and Obesity is defined as body mass index (BMI) exceeding 23 and 25 kg/m2 in Hong Kong respectively. Principal applicant (PA) reviewed the BMI of all KOA patients that subsequently had TKR in our hospitals and found the average BMI were 27.72 (2005-2009), 27.78 (2010-2015), and 28.07 (2016-2021) with the number of obese patients increased more than 6 times in 2016-2021 compared to 2005-2009. 73.74% of them were in obese class I and II in 2016- 2021, compared to just 33% of the whole Hong Kong population (same age group) were in these two classes (Based on Department of Health Population Health Survey). Obesity is disproportionally prevalent among KOA patients in Hong Kong with a worsening trend.

Studies and our pilot have found obese KOA patients have more medical comorbidities, with higher prevalence of metabolic syndrome, with more hypertension, dyslipidemia and impaired fasting glucose/diabetes. They are also associated with higher risks of cardiovascular disease, myocardial infarction, and stroke. Obesity is associated with greater pain while waiting for surgery but also with higher chances of developing various perioperative problems, such as surgical site infections, acute kidney injury, increased narcotics consumption, etc. compared to non-obese patients. Therefore, weight loss interventions for KOA are being explored recently to reduce the requirement of TKR, improve the health of KOA subjects, and improve the outcome if TKRs are eventually performed.

Diet modification to achieve weight loss with exercise therapy have been reported reducing KOA pain and improving physical function like walking distance and stair-climb time, compared to control in RCT (ADAPT trial). And it has been showed combining dietary weight loss and exercise can achieve better pain relief and joint loading than either dietary weight loss or exercise alone (Intensive Diet and Exercise for Arthritis (IDEA) trial). Despite these encouraging results, follow-up study at 3.5 years after initial intervention found participants experienced weight regain and reduced pain relief, suggesting difficulty in maintaining long-term weight loss. This matched our published Mendelian Randomization Study which found high BMI contributes to KOA more than effect of dietary intake.

Metformin, an oral anti-diabetic medication, is considered safe, affordable, and well-tolerated. It has been shown to promote weight loss and is a cost-effective option for long-term use on a large scale. Combining metformin with exercise and a balanced diet has been found to be more effective than using metformin alone. Metformin acts on pathways that are also involved in exercise, helping to reduce feelings of hunger and combat obesity. Additionally, metformin has anti-inflammatory and pain-relieving effects that can benefit individuals with osteoarthritis. Moreover, metformin has been shown to enhance muscle quality and reduce the process of muscle aging.