Age-related macular degeneration (AMD) is a leading cause of blindness and is becoming a global crisis as its incidence is increasing; it has been estimated that 288 million people will be affected by 2040.1 A characteristic feature of AMD is the permanent loss of light-sensitive retinal neurons known as photoreceptors, or their support cells, the retinal pigmented epithelium (RPE). The mechanism underlying photoreceptor and RPE degeneration is believed to be metabolic dysfunction, including inflammation and oxidative stress.2 Since the retina is one of the highest oxygen consuming tissues in the human body, it generates significant reactive oxygen species (ROS) and free radicals, which makes it vulnerable to oxidative injury over time.3 Inflammation and oxidative stress are also known to increase production of vascular endothelial growth factor,4,5 a key component underlying AMD pathology, and to play a role in the formation of drusen,6 yellow deposits of lipid and protein that are the hallmark of AMD.
Inflammation and oxidative stress are also known to be important in the development and progression of diabetes.7,8 Metformin is a glucose-lowering agent that has been the mainstay of diabetes treatment for over 50 years, though its mechanism of action has not been fully established.9 Recent preclinical and clinical studies have suggested that, in addition to its glucose-lowering action, metformin also has a direct anti-inflammatory action involving the inhibition of nuclear factor κB via adenosine monophosphate-activated protein kinase (AMPK)–dependent and independent pathways.10 Metformin also has antioxidant effects,11 which have been explained by various hypotheses, including lowering ROS, up-regulation of uncoupled protein 2 in the fat cells, as well as the AMPK system activation.12
These facts led a research team from Taiwan to form the hypothesis that if metformin can inhibit inflammation and oxidative stress, it may also reduce the risk of AMD. Their findings were presented at the 122nd Annual Meeting of the American Academy of Ophthalmology, which was held on October 27–30, 2018, in Chicago, IL, US.13 The investigators collected data from the Taiwan National Health Insurance Research Database on 73,118 patients with a new diagnosis of type 2 diabetes from January 2001 to December 2013. After excluding patients with type 1 diabetes and a diagnosis of AMD at enrolment, 68,205 patients remained. These were then split into two groups: those who took metformin (45,524 patients) and those who did not (22,681 patients). After following both groups for up to 13 years, investigators found that 3.4% of metformin users and 5.6% of non-users had new diagnoses of AMD (p<0.0001). Each AMD diagnosis was confirmed by fundoscopy, fluoroangioscopy, optical coherence tomography, or another accepted test. At baseline, the patients in the metformin treatment group had a higher incidence of systemic comorbidities (hypertension 70.3% vs 64.0%, p<0.0001, hyperlipidemia 69.4% vs 59.5%, p<0.0001, and coronary heart disease 31.8% vs 28.0%, p<0.0001). After adjustment for age, gender, and these comorbidities, Cox regression showed an almost 50% lower risk of AMD development in the metformin group than in the comparator group (hazard ratio [HR] 0.53; 95% confidence interval 0.49–0.58, p<0.0001). The only other significant predictive factor for AMD was increasing age (HR 2.57 to HR 6.44 for each increasing decade, p<0.0001).13
The risk of developing AMD was strongly associated with the time for which the patient had been taking metformin. Patients who had been taking metformin for less than 1.5 years had no increased risk for AMD, while the risk was increased by 50% among patients treated with metformin for 1.5 to 4.0 years and to 85% for patients treated for more than four years. The cumulative dose of metformin also affected the risk: compared with patients who received a total metformin dose <400 g, those who received a total dose of 400–1,400 g had a 50% reduction in the risk of developing AMD, increasing to 72% for patients who had received total doses higher than 1,400 g.13
Principal Investigator Yu-Yen Chan of Taichung Veterans General Hospital in Taipei, commented: “Our study is the first to reveal the protective effect of metformin on the development of AMD. While more study is required to determine just how metformin protects against the development of AMD, this is an exciting development for patients at risk.”13
These findings are consistent with a recent study in which metformin was investigated in three different mouse models of retinal degeneration. Treatment protected photoreceptors from light damage and delayed degeneration of the rod and cone cells in the retina. It also made the supporting cells that nourish retinal visual cells more resistant to damage. After eight weeks, metformin-treated mice retained more than 50% of cone cell activity, whereas untreated mice did not respond to light flashes used as visual cues.2
The potential implications of this finding are far-reaching. Metformin is a well-tolerated medication that is widely used and its anti-inflammatory effects are known to be exerted irrespective of diabetes status.14 However, it is important to remember that this was a retrospective study and further prospective studies will be needed to confirm a relationship between metformin and AMD before metformin can be considered as a treatment for AMD. This study did not did not measure the extent or severity of AMD, which would be useful to clarify the association between metformin use and AMD risk. Nevertheless, this is an exciting development for a growing patient population.
Published: 6 February 2019
References
1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106–16.
2. Xu L, Kong L, Wang J, et al. Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2018;115:10475–80.
3. Yu DY, Cringle SJ. Retinal degeneration and local oxygen metabolism. Exp Eye Res. 2005;80:745–51.
4. Kim YW, Byzova TV. Oxidative stress in angiogenesis and vascular disease. Blood. 2014;123:625–31.
5. Simão S, Bitoque D, Calado S, et al. Oxidative stress modulates the expression of VEGF isoforms in the diabetic retina. New Front Ophthalmol. 2016;2. doi: 10.15761/NFO.1000119.
6. Anderson DH, Mullins RF, Hageman GS, et al. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134:411–31.
7. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–70.
8. Lontchi-Yimagou E, Sobngwi E, Matsha TE, et al. Diabetes mellitus and inflammation. Curr Diab Rep. 2013;13:435–44.
9. Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–56.
10. Saisho Y. Metformin and inflammation: Its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets. 2015;15:196–205.
11. Araujo AA, Pereira A, Medeiros C, et al. Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS One. 2017;12:e0183506.
12. Faure P, Rossini E, Wiernsperger N, et al. An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes. 1999;48:353–7.
13. New study is first to show metformin can reduce the risk of age-related macular degeneration. 2018. Available at: www.aao.org/newsroom/news-releases/detail/diabetes-medication-may-protect-against-common-cau (January 30, 2019).
14. Cameron AR, Morrison VL, Levin D, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119:652–65.
