Case-control study suggests benefit

Metformin may reduce risk of developing age-related macular degeneration (AMD), according to a retrospective case-control study by University of Chicago researchers.

The finding emerged from a case-control study led by Andrea L. Blitzer, MD, Department of Ophthalmology and Visual Science, University of Chicago Medical Center, and published in JAMA Opthalmology.

Blitzer et al wrote that the benefit appears to be dose-dependent and with the greatest benefit observed with low to moderate doses.

But in a commentary accompanying the study, Myra B. McGuinness, MBiostat, PhD, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and colleagues warned that retrospective case-control studies using databases can be associated with a risk of bias.

The Australians pointed out that biostatisticians now recommend that analyses from these studies “be approached with a hypothetical target trial” in mind and suggested that that researchers reflect on the target trial they would wish to emulate to investigate their research question when designing a protocol for any observational study, including those using longitudinal administrative or registry data, and conduct their analyses in accordance with this target trial.”

In addition, McGuinness and her colleagues recommended that “readers interpret results from retrospective case-control studies in light of their limitations.”

AMD is not only the leading cause of irreversible blindness among persons over the age of 50, but its incidence — and the economic burden associated with it — is increasing as the population ages. Currently, there are no effective measures that can prevent the development of AMD, or treatments for the nonexudative form of the condition, which accounts for the vast majority of cases.

On the other hand, epidemiology studies have shown that metformin can be effective against many age-associated diseases, including cardiovascular disease, stroke, cancer, dementia, and primary open-angle glaucoma. It has also been shown to increase lifespans and reduce inflammatory markers in murine models. Thus, in this study Blitzer and her colleagues wanted to assess its effectiveness against AMD.

Blitzer and collegues used a nationwide insurance claims database to identify 312,404 individuals aged 55 years and older with AMD newly diagnosed during a 10-year period January 2008 to December 2017. The cases were then matched against AMD-free controls.

In a multivariable model adjusting for known risk factors and other medications, Blitzer and his colleagues determined that metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]), and that this association was dose dependent. Specifically, the authors found that:

  • Metformin doses of 1 to 270 g over 2 years had reduced odds of AMD (OR, 0.91 [95% CI, 0.89-0.94]).
  • Metformin doses of 271-600 g had the greatest potential benefit with an OR of 0.90 (95% CI, 0.87-0.93).
  • Taking 601 to 1080 g of metformin over 2 years had an OR of 0.95 (95% CI, 0.93-0.98).
  • The highest dose of more than 1080 g over 2 years did not result in reduced odds for AMD (OR, 1.02 [0.99-1.05]).

The authors conducted a subgroup analyses of patients with diabetes (since metformin is most commonly used as an antidiabetic drug) and found that in these patients, like the full cohort, metformin use was associated with reduced odds of developing AMD, and that this association was dose dependent.

While the study suggests that low to moderate doses of metformin are associated with 5% to 10% reduced odds of developing AMD, the association of high doses of metformin with AMD risk was similar to no exposure. “It is possible that high doses of metformin may be more commonly used in patients with poorly controlled diabetes and such patients may benefit less from metformin use,” the authors observed.

Blitzer and his colleagues also found that diabetic retinopathy may be a risk factor for AMD. They determined that metformin use in diabetes patients only reduced the odds of AMD if they did not have diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]), while metformin use increased the odds of AMD in patients with diabetic retinopathy (OR, 1.07 [95% CI, 1.01-1.15]).

“This study highlights metformin as a possible therapeutic intervention to prevent or slow the progression of AMD,” the authors concluded. “If a protective effect of metformin is confirmed in clinical trials, this may lead to a novel therapeutic strategy for this disease, which is the leading cause of blindness in older adults and has no previously established preventive measures.”

  1. Be aware that the finding of a benefit for metformin in reducing risk of AMD is based on a retrospective case-control study, which cannot prove causality.

  2. The analysis found the association between metformin and AMD was observed only at low to moderate metformin doses.

Michael Bassett, Contributing Writer, BreakingMED™

McGuinness reports that the Centre for Eye Research Australia receives operational infrastructure support from the Victorian government.

Cat ID: 240

Topic ID: 92,240,282,494,730,187,192,925,240