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

The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Placebo; Drug: Metformin

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Egypt
  • Menoufia
    • Shibīn Al Kawm, Menoufia, Egypt, 13829
      • Faculty of pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control group; patients will receive the standard therapy (methotrexate) plus placebo tablets	Drug: Placebo; Placebo tablet plus plus Methotrexate 7.5 mg weekly
Experimental: Metformin group; patients will receive the standard therapy plus 1 g metformin daily.	Drug: Metformin; 1000 mg of Metformin table taken orally daily plus Methotrexate 7.5 mg weekly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ACR 20% improvement criteria (ACR20) response rate	based on tender and swollen joint counts, patient's assessment of pain, patient and physician global assessment of arthritis, Health Assessment Questionnaire Disability Index (HAQ DI), and CRP level	week 12
ACR50 & ACR70 response rate	based on tender and swollen joint counts, patient's assessment of pain, patient and physician global assessment of arthritis, Health Assessment Questionnaire Disability Index (HAQ DI), and CRP level	week 12
Disease activity scale in 28 joints (DAS-28)	Scale assessing severity of rheumatoid arthritis based on number of tender, swollen joints, erythrocyte sedimentation rate (ESR) levels, and patient self-assessment of his condition (global health assessment). Whereas "28" describes the number of different joints including in the measurement: proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2), knees (2).	week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TNF-α	Serum level Tumor necrosis factor- alpha (TNF-α)	at baseline and at week 12
CRP	Serum level of C-reactive protein (CRP)	at baseline and at week 12
the Short Form 36 (SF-36) Health Survey	both the physical component score [PCS] and the mental component score [MCS])	week 12
HAQ-DI (Health Assessment Score- Disability index)	HAQ-DI (Health Assessment Score- Disability index), in which patients are asked to rate their capacity to perform 20 activities of daily living (ADL). Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section the score given to that section is the worst score within the section	week 12
AMPK expression	AMPK expression in synovium or serum	at baseline and at week 12
IGF-IR expression	IGF-IR expression in Blood	at baseline and at week 12
TGF-Beta1	Serum level tissue growth factor beta 1	at baseline and at week 12
Inteleukins	Serum levels of Interleukins (IL) IL-17, IL-1β , IL-6 & IL-10	at baseline and at week 12
Drug Adverse effects	Adverse effect incidence: adverse effect will be reported by patients or their caregivers and recorded by investigator.	3 months

Collaborators and Investigators

• Sponsor: Sadat City University

Publications and helpful links

General Publications

• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2019
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): February 28, 2021

Study Registration Dates

• First Submitted: August 21, 2019
• First Submitted That Met QC Criteria: August 22, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Actual): July 14, 2025
• Last Update Submitted That Met QC Criteria: July 9, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Joint Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: PMRR-8-2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes