SGLT2 Inhibitors in Geographic Atrophy

Summary

AMD is a leading cause of blindness in individuals over 50 years old, with dry AMD being the most common form. Geographic atrophy (GA) is an advanced stage of dry AMD characterized by progressive retinal cell degeneration. The primary objectives of the study are to assess the safety, tolerability, and evidence of activity of SGLT2 inhibitors in subjects with Geographic Atrophy associated with AMD.

Timeline

Start

2025-12-02

Primary completion

2027-12

Completion

2028-06

Publications

• Background Yao S, Zheng F, Yu Y, Zhan Y, Xu N, Luo G, Zheng L. Apolipoprotein M promotes cholesterol uptake and efflux from mouse macrophages. FEBS Open Bio. 2021 Jun;11(6):1607-1620. doi: 10.1002/2211-5463.13157. Epub 2021 May 2.
• Background Wolfrum C, Poy MN, Stoffel M. Apolipoprotein M is required for prebeta-HDL formation and cholesterol efflux to HDL and protects against atherosclerosis. Nat Med. 2005 Apr;11(4):418-22. doi: 10.1038/nm1211. Epub 2005 Mar 27.
• Background Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE-TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389. Epub 2018 Nov 10.
• Background Sunness JS, Gonzalez-Baron J, Applegate CA, Bressler NM, Tian Y, Hawkins B, Barron Y, Bergman A. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology. 1999 Sep;106(9):1768-79. doi: 10.1016/S0161-6420(99)90340-8.
• Background Solini A, Giannini L, Seghieri M, Vitolo E, Taddei S, Ghiadoni L, Bruno RM. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017 Oct 23;16(1):138. doi: 10.1186/s12933-017-0621-8.
• Background Schatz H, McDonald HR. Atrophic macular degeneration. Rate of spread of geographic atrophy and visual loss. Ophthalmology. 1989 Oct;96(10):1541-51. doi: 10.1016/s0161-6420(89)32694-7.
• Background Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye (Lond). 1988;2 ( Pt 5):552-77. doi: 10.1038/eye.1988.106.
• Background Ruiz M, Okada H, Dahlback B. HDL-associated ApoM is anti-apoptotic by delivering sphingosine 1-phosphate to S1P1 & S1P3 receptors on vascular endothelium. Lipids Health Dis. 2017 Feb 8;16(1):36. doi: 10.1186/s12944-017-0429-2.
• Background Potter JW, Thallemer JM. Geographic atrophy of the retinal pigment epithelium: diagnosis and vision rehabilitation. J Am Optom Assoc. 1981 Jun;52(6):503-8.
• Background Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14.
• Background McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19.
• Background Maguire P, Vine AK. Geographic atrophy of the retinal pigment epithelium. Am J Ophthalmol. 1986 Nov 15;102(5):621-5. doi: 10.1016/0002-9394(86)90535-0.
• Background Maayah ZH, Ferdaoussi M, Takahara S, Soni S, Dyck JRB. Empagliflozin suppresses inflammation and protects against acute septic renal injury. Inflammopharmacology. 2021 Feb;29(1):269-279. doi: 10.1007/s10787-020-00732-4. Epub 2020 Jun 20.
• Background Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, Nickerson RJ, Pool J, Colton TL, Ganley JP, Loewenstein JI, Dawber TR. The Framingham Eye Study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol. 1980 May-Jun;24(Suppl):335-610.
• Background Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013 Sep;15(9):853-62. doi: 10.1111/dom.12127. Epub 2013 Jun 5.
• Background Kosiborod M, Gause-Nilsson I, Xu J, Sonesson C, Johnsson E. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and concomitant heart failure. J Diabetes Complications. 2017 Jul;31(7):1215-1221. doi: 10.1016/j.jdiacomp.2017.02.001. Epub 2017 Feb 10.
• Background Kohler S, Zeller C, Iliev H, Kaspers S. Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes: Pooled Analysis of Phase I-III Clinical Trials. Adv Ther. 2017 Jul;34(7):1707-1726. doi: 10.1007/s12325-017-0573-0. Epub 2017 Jun 19.
• Background Kim SR, Lee SG, Kim SH, Kim JH, Choi E, Cho W, Rim JH, Hwang I, Lee CJ, Lee M, Oh CM, Jeon JY, Gee HY, Kim JH, Lee BW, Kang ES, Cha BS, Lee MS, Yu JW, Cho JW, Kim JS, Lee YH. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020 May 1;11(1):2127. doi: 10.1038/s41467-020-15983-6.
• Background Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014 May;121(5):1079-91. doi: 10.1016/j.ophtha.2013.11.023. Epub 2014 Jan 14.
• Background Guo Z, Javaheri A. Empagliflozin to Prevent Doxorubicin Cardiotoxicity. JACC CardioOncol. 2025 Feb;7(2):185-187. doi: 10.1016/j.jaccao.2025.01.005.
• Background Guo Z, Valenzuela Ripoll C, Picataggi A, Rawnsley DR, Ozcan M, Chirinos JA, Chendamarai E, Girardi A, Riehl T, Evie H, Diab A, Kovacs A, Hyrc K, Ma X, Asnani A, Shewale SV, Scherrer-Crosbie M, Cowart LA, Parks JS, Zhao L, Gordon D, Ramirez-Valle F, Margulies KB, Cappola TP, Desai AA, Pedersen LN, Bergom C, Stitziel NO, Rettig MP, DiPersio JF, Hajny S, Christoffersen C, Diwan A, Javaheri A. Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury. JACC Basic Transl Sci. 2023 Jan 4;8(3):340-355. doi: 10.1016/j.jacbts.2022.09.010. eCollection 2023 Mar.
• Background Fioretto P, Mansfield TA, Ptaszynska A, Yavin Y, Johnsson E, Parikh S. Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies. Drugs Aging. 2016 Jul;33(7):511-22. doi: 10.1007/s40266-016-0382-1.
• Background Ghanim H, Abuaysheh S, Hejna J, Green K, Batra M, Makdissi A, Chaudhuri A, Dandona P. Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgaa057. doi: 10.1210/clinem/dgaa057.
• Background Feuer WJ, Yehoshua Z, Gregori G, Penha FM, Chew EY, Ferris FL, Clemons TE, Lindblad AS, Rosenfeld PJ. Square root transformation of geographic atrophy area measurements to eliminate dependence of growth rates on baseline lesion measurements: a reanalysis of age-related eye disease study report no. 26. JAMA Ophthalmol. 2013 Jan;131(1):110-1. doi: 10.1001/jamaophthalmol.2013.572. No abstract available.
• Background Elsoe S, Ahnstrom J, Christoffersen C, Hoofnagle AN, Plomgaard P, Heinecke JW, Binder CJ, Bjorkbacka H, Dahlback B, Nielsen LB. Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL. Atherosclerosis. 2012 Mar;221(1):91-7. doi: 10.1016/j.atherosclerosis.2011.11.031. Epub 2011 Nov 27.
• Background Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnstrom J, Sevvana M, Egerer-Sieber C, Muller YA, Hla T, Nielsen LB, Dahlback B. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9613-8. doi: 10.1073/pnas.1103187108. Epub 2011 May 23.
• Background Christoffersen C, Jauhiainen M, Moser M, Porse B, Ehnholm C, Boesl M, Dahlback B, Nielsen LB. Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice. J Biol Chem. 2008 Jan 25;283(4):1839-47. doi: 10.1074/jbc.M704576200. Epub 2007 Nov 15.
• Background Christensen PM, Liu CH, Swendeman SL, Obinata H, Qvortrup K, Nielsen LB, Hla T, Di Lorenzo A, Christoffersen C. Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. FASEB J. 2016 Jun;30(6):2351-9. doi: 10.1096/fj.201500064. Epub 2016 Mar 8.
• Background Bonnet F, Scheen AJ. Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease. Diabetes Metab. 2018 Dec;44(6):457-464. doi: 10.1016/j.diabet.2018.09.005. Epub 2018 Sep 26.
• Background Apte RS. Age-Related Macular Degeneration. N Engl J Med. 2021 Aug 5;385(6):539-547. doi: 10.1056/NEJMcp2102061.
• Background Abidi M, Karrer E, Csaky K, Handa JT. A Clinical and Preclinical Assessment of Clinical Trials for Dry Age-Related Macular Degeneration. Ophthalmol Sci. 2022 Aug 19;2(4):100213. doi: 10.1016/j.xops.2022.100213. eCollection 2022 Dec.

Drugs

Indications