Metformin for Osteoarthritis After ACL Surgery (PIKASO Trial)
Recruiting in Palo Alto (17 mi)
+8 other locations
Age: 18 - 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Brigham and Women's Hospital
Prior Safety Data
Trial Summary
What is the purpose of this trial?This study is being done to find out if metformin is effective at reducing pain by delaying the onset of post-traumatic osteoarthritis (PTOA) after anterior cruciate ligament (ACL) reconstruction. This research study will compare metformin to placebo. The placebo tablet looks exactly like metformin, but contains no metformin. Placebos are used in research studies to see if the results are due to the study drug or due to other reasons.
Metformin is approved by the U.S. Food and Drug Administration (FDA) to treat type II diabetes. Notably, it also has anti-inflammatory effects, suggesting it could benefit people who have an ACL injury and are undergoing ACL reconstruction.
What safety data exists for Metformin treatment?Metformin is considered safe with a low risk of serious adverse events when contraindications, especially regarding renal function, are observed. Common side effects are mild gastrointestinal symptoms, which can be minimized by careful dose titration and taking the medication with meals. Lactic acidosis is rare and can be avoided by following prescribing precautions. Metformin does not cause hypoglycemia or weight gain, making it a preferred combination drug with other oral agents.12345
Do I have to stop taking my current medications for this trial?The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using metformin or topiramate.
Is Metformin a promising drug for osteoarthritis after ACL surgery?Metformin shows promise as a drug for osteoarthritis because it may reduce knee pain, protect against joint damage, and lower the risk of needing knee surgery, especially in people with obesity or diabetes.78101113
What data supports the idea that Metformin for Osteoarthritis After ACL Surgery is an effective drug?The available research shows that Metformin may help with osteoarthritis by reducing knee pain and inflammation, especially in people who are overweight or obese. One study suggests that Metformin can protect knee cartilage and reduce the need for knee replacement surgery. Another study highlights its anti-inflammatory effects, which can lessen cartilage damage and improve joint health. These findings suggest that Metformin could be a beneficial option for managing osteoarthritis symptoms.69111213
Eligibility Criteria
This trial is for adults aged 25-45, or those 18-24 with significant preoperative knee pain, who have an ACL tear confirmed by MRI and plan to undergo reconstruction. It's not for individuals with inflammatory arthritis, kidney issues, heavy alcohol use, hepatic disease, pregnancy plans within a year, current metformin users or those with certain other knee injuries.Inclusion Criteria
I am planning to have ACL reconstruction surgery.
Exclusion Criteria
I have inflammatory arthritis.
I cannot take metformin due to health reasons.
I am currently taking metformin or topiramate.
I have had ACL reconstruction surgery on one of my knees.
My knee X-ray shows cartilage loss and bone spurs.
I have a broken upper part of my shinbone in my knee.
I am scheduled for a transplant from a donor.
I need surgery for a knee ligament injury besides the ACL.
I am able to understand and give consent for my treatment.
My surgery is scheduled in less than 14 days from now.
I have Type 1 diabetes or have experienced diabetic ketoacidosis.
I drink heavily or have a liver disease.
I have a knee fracture that requires surgery.
I have kidney problems.
Participant Groups
The study tests if metformin can reduce pain and delay post-traumatic osteoarthritis after ACL surgery compared to a placebo (a pill without the drug). Metformin is known as a diabetes medication but may help due to its anti-inflammatory properties.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: MetforminExperimental Treatment1 Intervention
3x500mg metformin hydrochloride (HCl) extended-release (ER) tablets taken orally once a day for 1 year
Group II: PlaceboPlacebo Group1 Intervention
3x metformin placebo tablets matching metformin extended-release taken orally once a day for 1 year
Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:
🇪🇺 Approved in European Union as Glucophage for:
- Type 2 diabetes
🇺🇸 Approved in United States as Glucophage for:
- Type 2 diabetes
🇨🇦 Approved in Canada as Glucophage for:
- Type 2 diabetes
🇯🇵 Approved in Japan as Glucophage for:
- Type 2 diabetes
🇨🇳 Approved in China as Glucophage for:
- Type 2 diabetes
🇨🇭 Approved in Switzerland as Glucophage for:
- Type 2 diabetes
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Emory UniversityAtlanta, GA
Brigham and Women's HospitalBoston, MA
University of Iowa Hospitals and ClinicsIowa City, IA
The Ohio State UniversityColumbus, OH
More Trial Locations
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Who is running the clinical trial?
Brigham and Women's HospitalLead Sponsor
Arthritis FoundationCollaborator
References
Metformin: a biguanide. [2013]Metformin is an effective agent in the oral treatment of non-insulin-dependent diabetes mellitus and does not cause hypoglycemia like the sulfonylureas. This drug is safe provided the cautions and contraindications are followed and the patient is monitored for hepatic and renal function. Metformin is used extensively outside the United States in the treatment of type II diabetes and recently was approved by the FDA for marketing under the brand name of Glucophage.
Metformin: a review. [2019]Metformin is a well-established ingredient of diabetes management, both as a monotherapy in early stages of type 2 diabetes and as adjunct therapy to virtually every other antihyperglycemic medicine available today. Despite low potency and a long list of contraindications, metformin has remained successful and even expanded experimental use due to its well-established effects on glucose metabolism and, as more recently demonstrated, its benefits on other cardiovascular risk factors. Unlike insulin and secretagogues, metformin does not increase body weight and when used as monotherapy does not likely cause hypoglycemia. The most common adverse effects associated with metformin are mild, transient gastrointestinal symptoms, which are usually self-limiting. These side effects can be minimized by initiating metformin therapy at a low dose and gradually titrating upward, and by taking metformin with meals. Lactic acidosis caused by metformin is rare, and the risk of this complication may be diminished by the observance of prescribing precautions and contraindications that avoid accumulation of metformin or lactate in the body. The many clinical benefits and the lack of safety risks when used with other antihyperglycemic agents have made metformin a preferred combination drug with other oral agents.
Metformin therapy and clinical uses. [2022]Metformin is now established as a first-line antidiabetic therapy for the management of type 2 diabetes. Its early use in treatment algorithms is supported by lack of weight gain, low risk of hypoglycaemia and its mode of action to counter insulin resistance. The drug's anti-atherosclerotic and cardioprotective effects have recently been confirmed in prospective and retrospective studies, and appear to reflect a collection of glucose-independent effects on the vascular endothelium, suppressant effects on glycation, oxidative stress and formation of adhesion molecules, stimulation of fibrinolysis and favourable effects on the lipid profile. Although avoidance of troublesome gastrointestinal tolerability issues requires careful dose titration, the risk of serious adverse events is considered low provided that contra-indications (especially with respect to renal function) are observed. As many of its actions go beyond glucose lowering, emerging evidence indicates potential benefits in other insulin-resistant states and possibly tumour suppression.
Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. [2023]The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy.
Cardiovascular safety of combination therapies with incretin-based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus--a retrospective nationwide study. [2022]Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment of type 2 diabetes; however, data on long-term safety compared with conventional combination therapies are limited.
Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative-a prospective cohort study. [2020]To examine whether metformin use was associated with knee cartilage volume loss over 4 years and risk of total knee replacement over 6 years in obese individuals with knee osteoarthritis.
Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. [2022]Osteoarthritis causes significant pain and disability with no approved disease-modifying drugs. We systematically reviewed the evidence from both pre-clinical and human studies for the potential disease-modifying effect of metformin in osteoarthritis.
Metformin use and the risk of total knee replacement among diabetic patients: a propensity-score-matched retrospective cohort study. [2022]Metformin has been shown to modulate meta-inflammation, an important pathogenesis in knee osteoarthritis (OA). The study aimed to test the association between regular metformin use with total knee replacement (TKR) in patients with diabetes. This is a retrospective study with electronic records retrieved in Hong Kong public primary care. Patients with diabetes aged ≥ 45 who visited during 2007 to 2010, were followed up for a four-year period from 2011 to 2014 to determine the incidence of TKR. Propensity score matching based on age, sex, co-medications and chronic conditions was conducted to adjust for confounding. Cox regression was implemented to examine the association between metformin use and TKR. In total, 196,930 patients were eligible and 93,330 regular metformin users (defined as ≥ 4 prescriptions over the previous year) and non-users were matched. Among 46,665 regular users, 184 TKRs were conducted, 17.1% fewer than that among non-users. Cox regression showed that regular metformin users had a 19%-lower hazard of TKR [hazard ratio (HR) = 0.81, 95% confidence interval: 0.67 to 0.98, P = 0.033], with a dose-response relationship. Findings suggest a potential protective effect of metformin on knee OA progression and later TKR incidence among diabetic patients.
Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes. [2023]To investigate the therapeutic effect and mechanism of metformin on knee OA in normal diet (ND) mice or high-fat diet (HFD)-induced obese mice.
Association between Metformin Use and Risk of Total Knee Arthroplasty and Degree of Knee Pain in Knee Osteoarthritis Patients with Diabetes and/or Obesity: A Retrospective Study. [2023]Objectives: We aimed to examine whether metformin (MET) use is associated with a reduced risk of total knee arthroplasty (TKA) and low severity of knee pain in patients with knee osteoarthritis (OA) and diabetes and/or obesity. Methods: Participants diagnosed with knee OA and diabetes and/or obesity from June 2000 to July 2019 were selected from the information system of a local hospital. Regular MET users were defined as those with recorded prescriptions of MET or self-reported regular MET use for at least 6 months. TKA information was extracted from patients’ surgical records. Knee pain was assessed using the numeric rating scale. Log-binomial regression, linear regression, and propensity score weighting (PSW) were performed for statistical analyses. Results: A total of 862 participants were included in the analyses. After excluding missing data, there were 346 MET non-users and 362 MET users. MET use was significantly associated with a reduced risk of TKA (prevalence ratio: 0.26, 95% CI: 0.15 to 0.45, p
Development of Osteoarthritis in Adults With Type 2 Diabetes Treated With Metformin vs a Sulfonylurea. [2023]Metformin may have a protective association against developing osteoarthritis (OA), but robust epidemiological data are lacking.
Metformin Attenuates the Inflammatory Response via the Regulation of Synovial M1 Macrophage in Osteoarthritis. [2023]Osteoarthritis (OA), the most common chronic inflammatory joint disease, is characterized by progressive cartilage degeneration, subchondral bone sclerosis, synovitis, and osteophyte formation. Metformin, a hypoglycemic agent used in the treatment of type 2 diabetes, has been evidenced to have anti-inflammatory properties to treat OA. It hampers the M1 polarization of synovial sublining macrophages, which promotes synovitis and exacerbates OA, thus lessening cartilage loss. In this study, metformin prevented the pro-inflammatory cytokines secreted by M1 macrophages, suppressed the inflammatory response of chondrocytes cultured with conditional medium (CM) from M1 macrophages, and mitigated the migration of M1 macrophages induced by interleukin-1ß (IL-1ß)-treated chondrocytes in vitro. In the meantime, metformin reduced the invasion of M1 macrophages in synovial regions brought about by the destabilization of medial meniscus (DMM) surgery in mice, and alleviated cartilage degeneration. Mechanistically, metformin regulated PI3K/AKT and downstream pathways in M1 macrophages. Overall, we demonstrated the therapeutic potential of metformin targeting synovial M1 macrophages in OA.
Metformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial. [2023]Over half of the populations with knee osteoarthritis (OA) have obesity. These individuals have many other shared metabolic risk factors. Metformin is a safe, inexpensive, well-tolerated drug that has pleiotropic effects, including structural protection, anti-inflammatory and analgesic effects in OA, specifically the knee. The aim of this randomised, double-blind, placebo-controlled trial is to determine whether metformin reduces knee pain over 6 months in individuals with symptomatic knee OA who are overweight or obese.