The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients

NCT ID: NCT04068246

Last Updated: 2025-07-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-01
• Study Completion Date: 2021-02-28

Brief Summary

Metformin, a traditional antidiabetic medication, exerts glucose lowering effects by activating AMP-activated protein kinase (AMPK), a critical enzyme involved in the lipid and glucose metabolism. In addition to the antidiabetic effect, metformin has been shown to inhibit Lipopolysaccharide-Induced Inflammation (LPS)-induced inflammation by suppress NF-κB production, which is also regulated by AMPK. These regulatory effects of AMPK on the inflammation, immune and fibroblast-like synovial cells have prompted the investigation on the effects of metformin on rheumatoid arthritis.

Detailed Description

Rheumatoid arthritis (RA) is a chronic, multisystem inflammatory disorder of unknown etiology. It is characterized by polyarthritis and systemic inflammation. The inflammation in the hyperplastic synovium can destruct the structure of affected joints. Although the exact molecular mechanism underlying the pathogenesis of RA remains unknown, it is suggested that T helper cell (Th) 17 plays a central role. Interleukin (IL)-17, mostly secreted by Th17, has synergistic effects with tumor necrosis factor- (TNF-α), IL-1β and IL-6 in cases of RA. Metformin, a traditional antidiabetic medication, exerts glucose lowering effects by activating AMP-activated protein kinase (AMPK), a critical enzyme involved in the lipid and glucose metabolism. In addition to the antidiabetic effect, metformin has been shown to inhibit Lipopolysaccharide-Induced Inflammation (LPS)-induced inflammation by suppress NF-κB production, which is also regulated by AMPK . In addition, metformin activated AMPK may inhibit mammalian target of rapamycin (mTOR), which then regulate the differentiation of T cells in vitro and in vivo. In particular, AMPK has been reported to be associated with the inhibition of TH17 cells through suppressing the phosphorylation of mTOR and its downstream signal transducers, suggesting the therapeutic potential of AMPK agonists. Besides the imbalance between Th17 cells and Treg cells is responsible for the chronic inflammation in RA, synovium hyperplasia also plays a central role in the joint destruction. It has been reported that rapamycin, an inhibitor of mTOR, is able to significantly reduce fibroblastlike synovial cell invasion in RA via suppressing mTOR signaling pathway. These regulatory effects of AMPK on the inflammation, immune and fibroblast-like synovial cells have prompted the investigation on the effects of metformin on rheumatoid arthritis.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Control group

patients will receive the standard therapy (methotrexate) plus placebo tablets

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo tablet plus plus Methotrexate 7.5 mg weekly

Metformin group

patients will receive the standard therapy plus 1 g metformin daily.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

1000 mg of Metformin table taken orally daily plus Methotrexate 7.5 mg weekly

Interventions

Metformin

1000 mg of Metformin table taken orally daily plus Methotrexate 7.5 mg weekly

Intervention Type: DRUG

Placebo

Placebo tablet plus plus Methotrexate 7.5 mg weekly

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients with active rheumatoid arthritis based on DAS28 score. Patients received the standard therapy (i.e. one or more conventional DMARDs) for at least three months.

Exclusion Criteria

• Known hypersensitivity to metformin.
• Patients who have a prior diagnosis with diabetes mellitus.
• Patients receive metformin for any other indications.
• Patients with congestive heart failure.
• Patients with a history of myocardial infarction.
• Patients with severe anemia.
• Patients with active infections or other inflammatory diseases.
• Patients receiving biological therapy.
• Pregnancy or lactation.
• Patients with impaired liver functions.
• Patients with impaired kidney functions (serum creatinine concentrations ≥1.5 and ≥1.4 mg/dL in males and females respectively).
• Patients with malignancies.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sadat City University

OTHER

Sponsor Role: lead

Responsible Party

Mahmoud Samy Abdallah

Lecturer of Clinical Pharmacy, PhD.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Faculty of Pharmacy

Shibīn al Kawm, Menoufia, Egypt

Countries

Egypt

References

Abdallah MS, Alarfaj SJ, Saif DS, El-Naggar ME, Elsokary MA, Elsawah HK, Abdelsattar Zaki S, Wahsh EA, Abo Mansour HE, Mosalam EM. The AMPK modulator metformin as adjunct to methotrexate in patients with rheumatoid arthritis: A proof-of-concept, randomized, double-blind, placebo-controlled trial. Int Immunopharmacol. 2021 Jun;95:107575. doi: 10.1016/j.intimp.2021.107575. Epub 2021 Mar 24.

Reference Type: BACKGROUND

PMID: 33773207 (View on PubMed)

Related Links

https://pubmed.ncbi.nlm.nih.gov/33773207/

Related Info

Other Identifiers

PMRR-8-2019

Identifier Type: -

Identifier Source: org_study_id