Metformin for Achilles Tendinopathy

Overseen By James H Wang, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: James Wang

Must not be taking: Diabetic medications, Carbonic anhydrase inhibitors

Disqualifiers: Diabetes, BMI > 30, others

Compensation: Varies

Number of Visits: 4

Duration: 16 weeks

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as diabetic medications like sitagliptin and carbonic anhydrase inhibitors like topiramate. If you are currently taking metformin or have taken it in the last 6 months, you cannot participate.

What data supports the effectiveness of the drug Metformin for Achilles Tendinopathy?

Research suggests that Metformin may have anti-inflammatory effects, as seen in its use for rheumatoid arthritis and knee osteoarthritis, which could potentially help with conditions like Achilles Tendinopathy. ^{1 2 3 4 5}

How does the drug Metformin differ from other treatments for Achilles tendinopathy?

Metformin is unique for Achilles tendinopathy because it is primarily a diabetes medication that may influence tendon health by affecting blood sugar levels, unlike traditional treatments like corticosteroid injections or exercise therapy, which directly target inflammation or physical rehabilitation. ^{6 7 8 9 10}

What is the purpose of this trial?

The purpose of the current exploratory clinical trial is to determine the effect of oral ingestion of metformin (OIM) in non-diabetic patients with chronic Achilles tendon pain. The trial has two aims; 1) to assess the effects of OIM treatment on tendon pain, and 2) to determine the effects of OIM capsules on tendon healing and repair. Twenty participants will be treated with metformin capsules for 16 weeks combined with a home exercise program. A comparison group of 20 participants will be treated with placebo tablets along with home exercise program.

Research Team

James H Wang, PhD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for non-diabetic individuals with chronic Achilles tendon pain who can consent to participate, have a specific level of disability due to the pain, and show signs of tendon damage on an ultrasound. They must not have had recent treatments or surgery on the tendon, be pregnant or breastfeeding, suffer from systemic inflammatory diseases or severe liver problems, take certain medications like metformin recently, or have a BMI over 30.

Inclusion Criteria

Willing and able to provide informed consent for participation

Ability to read, speak, and understand English

I have been diagnosed with Achilles tendinopathy.

Exclusion Criteria

Subjects must not be pregnant or breastfeeding, or planning to become pregnant or breastfeed during the course of the trial

You have a history of lactic acidosis or high levels of lactate in your body.

I have severe liver problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive metformin or placebo capsules combined with a home exercise program for 16 weeks

16 weeks

3 visits (in-person) at baseline, week 4, and week 16

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin
• Placebo

Trial Overview The study is testing if taking metformin pills helps reduce tendon pain and aids in healing compared to placebo (dummy pills). Both groups will also follow a home exercise program. There are two groups: one receiving metformin capsules for 16 weeks and another receiving placebo tablets for the same duration.

Participant Groups

Group I: Treatment Group, Metformin Capsules Experimental Treatment 1 Intervention

Treatment Group (n=20) Week 1: One metformin ER capsule (500 mg) daily Week 2: Two metformin (ER) capsules (1,000 mg) daily Week 3: Three metformin (ER) capsules (1,500 mg) daily Week 4-16: Four metformin (ER) capsules (2,000 mg) daily

Group II: Placebo Group, Placebo Capsules Placebo Group 1 Intervention

Placebo Group (n=20) Week 1: One placebo capsule (500 mg) daily Week 2: Two placebo capsules (1,000 mg) daily Week 3: Three placebo capsules (1,500 mg) daily Week 4-16: Four placebo capsules (2,000 mg) daily

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

Who Is Running the Clinical Trial?

James Wang

Lead Sponsor

Trials

1

Recruited

40+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

A review of 10 studies involving over 1.4 million patients found that dipeptidyl peptidase-4 inhibitors (Dpp-4i) do not significantly increase the risk of developing rheumatoid arthritis, with a relative risk of 0.96.

The analysis suggests that Dpp-4 inhibitors are safe in terms of rheumatoid arthritis risk, but long-term monitoring of patients is still recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis: dipeptidyl peptidase-4 inhibitors and rheumatoid arthritis risk. Wang, M., Li, M., Xie, Y.[2021]

In a study of 1986 adults with type 2 diabetes, gliclazide modified release (MR) was found to be more effective than sitagliptin in achieving target HbA1c levels, with higher rates of reaching HbA1c <7.0% and HbA1c ≤6.5%.

Both treatments showed similar durability and persistence, and hypoglycaemic events were rare, indicating that gliclazide MR is a safe and effective second-line option for patients already on metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of gliclazide modified release versus sitagliptin as second-line treatment after metformin monotherapy in patients with uncontrolled type 2 diabetes. Zaccardi, F., Jacquot, E., Cortese, V., 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 120 adults with active rheumatoid arthritis, metformin (1000 mg daily) significantly improved treatment response rates compared to placebo, with 80.8% of patients achieving ACR20 response after 12 weeks versus 54.7% in the placebo group.

Metformin was well-tolerated with no serious adverse effects reported, and it enhanced the efficacy of methotrexate, suggesting it could be a beneficial addition to standard RA treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The AMPK modulator metformin as adjunct to methotrexate in patients with rheumatoid arthritis: A proof-of-concept, randomized, double-blind, placebo-controlled trial. Abdallah, MS., Alarfaj, SJ., Saif, DS., et al.[2021]

A 104-week study showed that initial combination therapy with sitagliptin and metformin significantly improved blood sugar control in patients with type 2 diabetes, with 60% of those on the higher dose combination achieving HbA1c levels below 7%.

Both sitagliptin and metformin were well tolerated, with low rates of hypoglycemia and fewer gastrointestinal side effects reported in the sitagliptin group, indicating a safe treatment option for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. Williams-Herman, D., Johnson, J., Teng, R., et al.[2022]

In a randomized clinical trial involving 100 patients with Achilles tendinopathy, those receiving corticosteroid injections combined with exercise therapy showed a significant improvement in their VISA-A scores (17.7 points higher) compared to those receiving placebo injections at 6 months.

The study found no severe adverse events in either treatment group, indicating that the combination of corticosteroid injections and exercise therapy is a safe and effective option for managing chronic Achilles tendinopathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Ultrasonography-Guided Corticosteroid Injection vs Placebo Added to Exercise Therapy for Achilles Tendinopathy: A Randomized Clinical Trial. Johannsen, F., Olesen, JL., Øhlenschläger, TF., et al.[2023]

A 63-year-old man developed bilateral Achilles enthesopathy after starting sitagliptin, a medication for type II diabetes, indicating a potential side effect of this drug.

The symptoms of Achilles enthesopathy completely resolved after discontinuing sitagliptin, suggesting that gliptins may be linked to musculoskeletal disorders, which are not commonly reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sitagliptin-induced Achilles enthesopathy: Case report and literature review. Rızvanoğlu, IH., Kısacık, B.[2023]

A systematic review of 31 studies found that individuals with diabetes are significantly more likely to develop tendinopathy, with an odds ratio of 3.67, indicating a strong association between the two conditions.

People with diabetes not only have a higher prevalence of tendinopathy but also tend to have thicker tendons and a longer duration of diabetes compared to those without tendinopathy, which may impact their ability to engage in exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there an association between tendinopathy and diabetes mellitus? A systematic review with meta-analysis. Ranger, TA., Wong, AM., Cook, JL., et al.[2022]

The trial will evaluate the long-term efficacy of high-volume injections (HVI) with and without corticosteroids compared to a sham injection in 192 participants with Achilles tendinopathy over a 12-month period.

The primary outcome will be measured using the Victorian Institute of Sport Assessment - Achilles (VISA-A), which assesses pain and function, providing a reliable way to determine the effectiveness of the treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of high-volume injections with and without corticosteroid compared with sham for Achilles tendinopathy: a protocol for a randomised controlled trial. Malliaras, P., Connell, D., Boesen, AP., et al.[2022]

In a study involving 80 adults with chronic midportion Achilles tendinopathy, a high volume injection without corticosteroids did not lead to significant improvements in pain or function compared to a placebo after 24 weeks of treatment.

Both groups showed similar improvements in their VISA-A scores, indicating that the high volume injection did not provide any additional benefit over usual care alone, leading to the conclusion that this treatment should not be recommended for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of a high volume injection as treatment for chronic Achilles tendinopathy: randomised controlled trial. van der Vlist, AC., van Oosterom, RF., van Veldhoven, PLJ., et al.[2020]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis: dipeptidyl peptidase-4 inhibitors and rheumatoid arthritis risk. [2021]

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

Comparative effectiveness of gliclazide modified release versus sitagliptin as second-line treatment after metformin monotherapy in patients with uncontrolled type 2 diabetes. [2022]

3. 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]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The AMPK modulator metformin as adjunct to methotrexate in patients with rheumatoid arthritis: A proof-of-concept, randomized, double-blind, placebo-controlled trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. [2022]

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

Effect of Ultrasonography-Guided Corticosteroid Injection vs Placebo Added to Exercise Therapy for Achilles Tendinopathy: A Randomized Clinical Trial. [2023]

7. Turkey pubmed.ncbi.nlm.nih.gov

Sitagliptin-induced Achilles enthesopathy: Case report and literature review. [2023]

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

Is there an association between tendinopathy and diabetes mellitus? A systematic review with meta-analysis. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Efficacy of high-volume injections with and without corticosteroid compared with sham for Achilles tendinopathy: a protocol for a randomised controlled trial. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Effectiveness of a high volume injection as treatment for chronic Achilles tendinopathy: randomised controlled trial. [2020]