METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial
NCT02684578 | METforMIN | Shen et al. (2024)
Shen, L. L., Keenan, J. D., Chahal, N., Taha, A. T., Saroya, J., Ma, C. J., Sun, M., Yang, D., Psaras, C., Callander, J., Flaxel, C., Fawzi, A. A., Schlesinger, T. K., Wong, R. W., Leung, L. S. B., Eaton, A. M., Steinle, N. C., Telander, D. G., Afshar, A. R., Neuwelt, M. D., Lim, J. I., Yiu, G. C., Stewart, J. M. METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial. Ophthalmology Science, 2024; 4:100440.
Locations
12 clinical centers in the United States
Study Period
October 2016 to August 2021
Study Design
Phase 2, randomized, multicenter, parallel-group trial
Study Population
Experimental Group
Control Group
Follow-up Time: The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively.
Outcomes
Durability
N/A
Vision
Best-Corrected Visual Acuity (BCVA)
The decline from baseline to 18 months:
• Metformin: -3.4 ± 1.1 letters/year
• Observation: -4.8 ± 1.7 letters/year
• Difference = 1.2 letters/year (95% CI: -5.1 to 2.7, p = 0.56).
Low Luminance Visual Acuity (LLVA)
The decline from baseline to 18 months:
• Metformin: -0.8 ± 2.2 letters/year
• Observation: -7.3 ± 2.5 letters/year
• Difference = 6.5 letters/year (95% CI: -0.1 to 13.2, p = 0.06).
Other
Efficacy: Progression
Annualized Growth Rate of Square Root-Transformed GA Area The change from baseline to 18 months (Primary Outcome):
• Metformin: 0.42 ± 0.04 mm/year
• Observation: 0.35 ± 0.04 mm/year
• Difference = 0.07 mm/year (95% CI: -0.05 to 0.18, p = 0.26).
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Not reported
Safety
Treatment-emergent AEs (TEAEs)
14 participants in the metformin group experienced adverse events.
Most Common AEs
• Gastrointestinal side effects (diarrhea): 6 cases
• GI discomfort: 4 cases
• Nausea: 2 cases
• Vomiting: 1 case
• Constipation: 1 case
• Abdominal swelling: 1 case
• Lethargy: 4 cases
• Dizziness: 2 cases.
Serious Adverse Events Three participants (ascending thoracic aortic aneurysm, acute kidney injury, hepatic fibrosis), none attributed to metformin.
Conclusion
The trial did not support a significant effect of metformin in reducing GA progression. Further placebo-controlled trials may be needed to assess its potential role in AMD treatment.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “We randomly assigned participants in a 1:1 ratio to observation or 18 months of 1000 mg oral metformin hydrochloride twice daily. A research coordinator generated the random allocation sequence stratified by clinical site but without other restrictions.” In addition, “Baseline demographics, medical conditions, and ocular characteristics were generally comparable between the observation and metformin groups.”
Missing Outcome Data
Some Concerns
Note: The withdrawal of both groups was very high (>30%) without information of the reasons. However, there is evidence that the result was not biased by missing outcome data (appropriate analysis models were applied to correct for bias).
Selection of the Reported Results
Low risk Note: registration with the protocol.
Deviations from Intended Observations
Some concerns Note: Patients were aware of the treatment and there is no information on if there were deviations that arose because of the trial context. However, the deviations are balanced between the groups (Figure 1). ITT principle was applied for the data analysis.
Measurement of the Outcome
Low risk Note: “Each FAF image was graded by 2 independent graders masked to treatment allocation using the Heidelberg Eye Explorer software…”
Overall
Some concerns
Categories: Dry AMD Geographic Atrophy