Metformin for Osteoarthritis After ACL Surgery

(PIKASO Trial)

Recruiting at 8 trial locations

Overseen By Lily M Waddell, BA

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Brigham and Women's Hospital

Must not be taking: Metformin, Topiramate

Disqualifiers: Inflammatory arthritis, Pregnancy, Type I diabetes, others

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.

Will I have to stop taking my current medications?

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.

What data supports the effectiveness of the drug Metformin for osteoarthritis after ACL surgery?

Research suggests that Metformin, commonly used for type 2 diabetes, may help reduce inflammation and protect joint cartilage in people with knee osteoarthritis, especially those who are obese. It has shown potential in reducing knee pain and slowing disease progression by targeting inflammatory cells and pathways. ^{1 2 3 4 5}

Is metformin generally safe for humans?

Metformin is generally considered safe for humans when used as directed, with the most common side effects being mild stomach issues that usually go away on their own. Serious side effects are rare, especially if precautions are taken to avoid problems with kidney function. ^{6 7 8 9 10}

How is the drug metformin unique for treating osteoarthritis after ACL surgery?

Metformin is unique for treating osteoarthritis after ACL surgery because it is primarily known as a diabetes medication but has shown potential benefits in reducing knee pain and delaying the need for knee replacement surgery due to its anti-inflammatory and protective effects on joint structures. ^{1 2 11 12 13}

Research Team

Morgan H Jones, MD, MPH

Principal Investigator

Brigham and Women's Hospital

Cale A Jacobs, PhD

Principal Investigator

Brigham and Women's Hospital

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 between 25-45 years old, or 18-24 with significant knee pain after an ACL injury.

An MRI scan within the last 6 months has confirmed that you have a tear in your ACL.

I am planning to have ACL reconstruction surgery.

Exclusion Criteria

Applying for or receiving Workers' Compensation for their knee injury

Pregnancy and/or lactation, or plans to become pregnant in the next 12 months

I have inflammatory arthritis.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either metformin or placebo for 1 year post-ACL reconstruction

52 weeks

Regular visits for assessments at baseline, 3, 6, 9, 12, 18, and 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including KOOS and MRI scores

12 months

Assessments at 12 and 24 months

Treatment Details

Interventions

• Metformin (Anti-diabetic agent)
• Placebo (Placebo)

Trial Overview 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.

Participant Groups

Group I: Metformin Experimental Treatment 1 Intervention

3x500mg metformin hydrochloride (HCl) extended-release (ER) tablets taken orally once a day for 1 year

Group II: Placebo Placebo Group 1 Intervention

3x metformin placebo tablets matching metformin extended-release taken orally once a day for 1 year

Metformin is already approved in Canada, Japan, China, Switzerland for the following indications:

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

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Arthritis Foundation

Collaborator

Trials

36

Recruited

46,500+

Findings from Research

In a study of over 41,000 individuals with type 2 diabetes, metformin treatment was associated with a 24% reduced risk of developing osteoarthritis (OA) compared to those treated with sulfonylureas.

While metformin showed a significant reduction in OA risk, there was no significant difference in the risk of joint replacement between the two treatment groups, suggesting that while metformin may help prevent OA, it does not necessarily affect the need for joint replacement surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Osteoarthritis in Adults With Type 2 Diabetes Treated With Metformin vs a Sulfonylurea. Baker, MC., Sheth, K., Liu, Y., et al.[2023]

This study will evaluate the efficacy of metformin in reducing knee pain over 6 months in 102 overweight or obese participants with symptomatic knee osteoarthritis, using a randomized, double-blind, placebo-controlled design.

The primary outcome is the reduction of knee pain measured by a Visual Analogue Scale, with secondary outcomes including overall function and quality of life, ensuring a comprehensive assessment of metformin's effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial. Lim, YZ., Wang, Y., Urquhart, DM., et al.[2023]

Metformin demonstrated protective effects against knee osteoarthritis (OA) in both normal diet and high-fat diet mice, with more significant improvements observed in the high-fat diet group after 10 weeks of treatment, as indicated by reduced OARSI and synovitis scores.

The mechanism of action for metformin includes decreasing apoptosis and matrix-degrading enzyme expression in chondrocytes, as well as reducing the infiltration and pro-inflammatory polarization of synovial macrophages, particularly in obese mice where it also lowers leptin secretion from adipose tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes. Li, D., Ruan, G., Zhang, Y., et al.[2023]

In a study of 818 obese individuals with knee osteoarthritis, metformin users experienced significantly less medial cartilage volume loss over 4 years compared to non-users, suggesting a protective effect on knee joint health.

Metformin use was also associated with a trend towards a reduced risk of total knee replacement over 6 years, indicating potential long-term benefits for obese patients with knee osteoarthritis, although further randomized controlled trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative-a prospective cohort study. Wang, Y., Hussain, SM., Wluka, AE., et al.[2020]

Metformin, a diabetes medication, shows promise in treating osteoarthritis (OA) by reducing inflammation caused by M1 macrophages, which are linked to cartilage degeneration.

In laboratory and mouse studies, metformin not only prevented the secretion of harmful cytokines from M1 macrophages but also mitigated cartilage loss and inflammation, suggesting it could be a beneficial therapy for OA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Attenuates the Inflammatory Response via the Regulation of Synovial M1 Macrophage in Osteoarthritis. Zheng, M., Zhu, Y., Wei, K., et al.[2023]

Metformin is a first-line treatment for type 2 diabetes due to its effectiveness in reducing insulin resistance without causing weight gain or hypoglycemia, making it a safe option for patients.

Recent studies have shown that metformin also has cardiovascular benefits and may help in conditions beyond diabetes, such as insulin resistance and potentially tumor suppression, highlighting its broader therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin therapy and clinical uses. Scarpello, JH., Howlett, HC.[2022]

In a 26-week study involving 1,091 participants with type 2 diabetes, liraglutide significantly reduced A1C levels compared to placebo, with reductions of up to 1.0% for higher doses, while also promoting weight loss of 1.8-2.8 kg.

Liraglutide had a similar incidence of minor hypoglycemia (around 3%) compared to placebo, which was much lower than the 17% incidence seen with glimepiride, indicating a safer profile for liraglutide in combination with metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Nauck, M., Frid, A., Hermansen, K., et al.[2023]

In a study of 40,028 Danish patients with type 2 diabetes, DPP-4 inhibitors combined with metformin showed a significantly lower risk of all-cause mortality (RR 0.65) and cardiovascular mortality (RR 0.57) compared to metformin with sulphonylurea, indicating a safer profile for this combination.

GLP-1 agonists also demonstrated a favorable safety profile, although their risk reductions were less pronounced, suggesting that incretin-based therapies may be beneficial for cardiovascular risk management in type 2 diabetes patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Mogensen, UM., Andersson, C., Fosbøl, EL., et al.[2022]

Metformin is an effective oral medication for treating non-insulin-dependent diabetes mellitus (type II diabetes) and does not cause hypoglycemia, which is a common side effect of other diabetes medications like sulfonylureas.

The drug is considered safe when proper precautions are taken, including monitoring liver and kidney function, and it has gained widespread use internationally, recently receiving FDA approval under the brand name Glucophage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin: a biguanide. Tanja, JJ., Langlass, TM.[2013]

Metformin is a key medication for managing type 2 diabetes, effective both alone and in combination with other diabetes drugs, and it does not cause weight gain or hypoglycemia, making it a safer option for patients.

While mild gastrointestinal side effects are common, they can be managed by starting with a low dose and taking the medication with food; serious complications like lactic acidosis are rare when prescribing guidelines are followed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin: a review. Strack, T.[2019]

A systematic review of 15 studies (10 pre-clinical and 5 human) found that metformin may have beneficial effects in treating knee osteoarthritis, showing chondroprotective, immunomodulatory, and pain-reducing properties, primarily through the activation of AMPK (adenosine monophosphate-activated protein kinase).

While pre-clinical studies consistently demonstrated these effects, human studies also supported the findings, although more high-quality clinical trials are needed to confirm metformin's potential as a disease-modifying treatment for osteoarthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. Lim, YZ., Wang, Y., Estee, M., et al.[2022]

In a study of 862 participants with knee osteoarthritis, diabetes, and/or obesity, regular use of metformin was associated with a significantly reduced risk of total knee arthroplasty (TKA), with a prevalence ratio of 0.26, indicating a strong protective effect.

Metformin use also correlated with a reduction in knee pain severity, showing a decrease of 0.48 on the numeric rating scale, suggesting it may help manage symptoms in patients with metabolic-associated osteoarthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Chen, S., Ruan, G., Zeng, M., et al.[2023]

In a study of 196,930 diabetic patients aged 45 and older, regular metformin users (93,330 patients) had a 19% lower risk of needing total knee replacement (TKR) compared to non-users, suggesting a protective effect against knee osteoarthritis progression.

The study found a dose-response relationship, indicating that higher usage of metformin correlates with a greater reduction in TKR incidence, highlighting its potential role in managing knee OA in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin use and the risk of total knee replacement among diabetic patients: a propensity-score-matched retrospective cohort study. Lai, FTT., Yip, BHK., Hunter, DJ., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Development of Osteoarthritis in Adults With Type 2 Diabetes Treated With Metformin vs a Sulfonylurea. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Metformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative-a prospective cohort study. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Metformin Attenuates the Inflammatory Response via the Regulation of Synovial M1 Macrophage in Osteoarthritis. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Metformin therapy and clinical uses. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

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]

8. England pubmed.ncbi.nlm.nih.gov

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]

9. United States pubmed.ncbi.nlm.nih.gov

Metformin: a biguanide. [2013]

10. Spain pubmed.ncbi.nlm.nih.gov

Metformin: a review. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

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]

13. England pubmed.ncbi.nlm.nih.gov

Metformin use and the risk of total knee replacement among diabetic patients: a propensity-score-matched retrospective cohort study. [2022]