Metformin Use Linked to Lower Odds of AMD Development

Results of a case-control study show metformin use may protect against the development of age-related macular degeneration (AMD) in adults 55 years and older, and the association is dose-dependent, with the greatest benefit at low to moderate doses. Findings were published in JAMA Ophthalmology.

Specifically, investigators found that metformin use over 2 years was associated with a 5% to 10% reduced odds ratio (OR) of developing AMD.

In American adults over the age of 50, AMD is the leading cause of irreversible blindness. There are no efficacious preventive measures against the disease, and no treatments exist for the nonexudative form, which accounts for the majority of cases.

Metformin is the most commonly prescribed oral antihyperglycemic drug for patients with diabetes, the researchers wrote, and it has been shown to have antiaging and protective effects against age-associated diseases. The drug has been previously shown to lower the risk of primary-open angle glaucoma, along with stroke, cancer, and dementia.

“Metformin acts directly and indirectly on several targets,” the authors explained, “including 5′ adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and sirtuin-1 (SIRT1) to affect important cell functions, such as survival, stress defense, autophagy, oxidative stress, protein synthesis, and inflammatory response.”

To determine the effects of metformin on risk of developing AMD, the researchers conducted a case-control study using deidentified data from the IBM MarketScan Commercial and Medicare Supplemental Databases. Combined, the databases “represent the annual health services of approximately 30 to 50 million employees, dependents, and retirees annually in the United States with primary or Medicare supplemental coverage through privately insured health plans.”

Enrollment records and inpatient and outpatient prescription drug claims recorded between January 2006 and December 2017 were included in the analysis. All participants (n = 312,404) were 55 years or older, had newly diagnosed AMD, and had at least 2 eye examinations during the previous 12 months.

A control group (n = 312,376) from the general population in the MarketScan data was matched 1:1 to a cohort of patients based on age, anemia, hypertension, region, and Charlson Comorbidity Index (CCI) score. “Patients with exposures [to metformin] had to have at least 1 outpatient prescription drug claim for a medication within 2 years preceding the index date,” the authors wrote.

Compared with the total control pool (n = 31,343,467), patients with AMD tended to be older and live in the US Northeast and US North Central regions, and were more likely to have hypertension, anemia, and a higher CCI score.

Analyses revealed:

• The case group had a slightly higher percentage of participants with diabetes (81,262 participants [26.0%]) compared with the control group (79,497 participants [25.5%]).
• Metformin use was associated with reduced odds of developing AMD (OR, 0.94 [95% CI, 0.92-0.96]).
• Low to moderate doses of metformin showed the greatest potential benefit (dosages over 2 years: 1-270 g: OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g: OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g: OR, 0.95 [95% CI, 0.92-0.98]).
• Doses of more than 1080 g of metformin over 2 years did not reduce odds of developing AMD.
• Both the reduction in OR and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes.

When it comes to incidence of diabetic retinopathy, investigators found that “Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI, 1.01-1.15]).”

Future studies ought to be carried out to better determine the molecular pathways involved in the potential protective outcome seen in this study. Due to the current study’s design, researchers were unable to determine the probability of developing AMD, marking a limitation. In addition, some patient characteristics including demographic information and medical information were not taken into account, leaving open the possibility of ethnic differences among patients taking metformin vs those who are not.

“If a protective effect of metformin is confirmed in clinical trials, this may lead to a novel therapeutic strategy for this disease,” authors concluded.

Reference

Blitzer AL, Ham SA, Colby KA, Skondra D. Association of metformin use with age-related macular degeneration: a case-control study. JAMA Ophthalmol. Published online January 21, 2021. doi:10.1001/jamaophthalmol.2020.6331