This randomized controlled trial aims to investigate if metformin has osteoarthritis protective effects among overweighted knee osteoarthritis patients. The co-primary outcomes are changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Arthritis Index (WOMAC) from baseline to month 24. The secondary outcomes are changes in visual analog scale (VAS)-assessed knee pain, tibiofemoral cartilage defect, effusion-synovitis volume, and tibiofemoral bone marrow lesion maximum size from baseline to month 24.

Inclusion Criteria:

1. Meet the American College of Rheumatology (ACR) criteria for symptomatic knee osteoarthritis assessed by a rheumatologist;
2. Age 50 to 75 years;
3. Body mass index ≥ 24 kg/m2;
4. Knee pain ≥ 20 on a 100 mm visual analogue scale (VAS);
5. Able to listen, speak, read and understand Chinese; capable of understanding the study requirements and willing to cooperate with the study instructions; able to provide written, informed consent.

Exclusion Criteria:

1. Severe radiographic knee OA as grade 3 joint space narrowing according to the Osteoarthritis Research Society International (OARSI) atlas;
2. Severe knee pain as knee pain ≥ 80 on a 100 mm VAS;
3. Planned knee or hip surgery (including arthroscopy, joint replacement, and joint open operation) within 2 years;
4. Severe knee trauma history (including arthroscopy, severe injury of knee ligament or meniscus);
5. Contraindication to MRI scanning (e.g. implanted pacemaker, artificial metal valve or cornea, aneurysm clipping surgery, arterial dissection, metal foreign bodies in the eyeball, claustrophobia);
6. Other forms of inflammatory arthritis (e.g. rheumatoid arthritis, psoriatic arthritis);
7. Active malignant cancer or other life-threatening diseases;
8. Type 1 or type 2 diabetes mellitus;
9. Clinical manifestation of liver dysfunction or alanine aminotransferase/aspartate aminotransferase exceeding 2 times the upper limit of normal value;
10. Estimated glomerular filtration rate less than 60 ml/min/1.73 m2;
11. Hypoxic state (e.g. chronic heart insufficiency, acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, cor pulmonale, peripheral vascular disease);
12. Alcoholism;
13. Pregnancy or lactation;
14. Allergic to metformin hydrochloride;
15. Conditions affecting the absorption of oral drugs (e.g. postgastrectomy and malabsorption syndrome);
16. Use of metformin in recent 30 days or plan to use metformin in the next 2 years;
17. Use of investigational drug in recent 30 days.