Glucagon-like peptide-1 receptor agonists and diabetic retinopathy: nationwide cohort and Mendelian randomization studies
Tóm tắt
The ability of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to decrease certain microvascular events has called for the investigation of GLP-1 RAs against diabetic retinopathy (DR), but the evidence is limited. By combining data from observational and Mendelian randomization (MR) studies, we aimed to investigate whether GLP-1 RAs decrease the risk of DR. We combined data from several Swedish Registers and identified patients with incident type 2 diabetes being treated with GLP-1 RAs between 2006 and 2015, and matched them to diabetic patients who did not use GLP-1 RAs as the comparisons. The Cox proportional hazards models were applied to assess the risk of DR. We further performed the summary-data-based MR (SMR) analyses based on the Genotype-Tissue Expression databases and the Genome-Wide Association Study of DR from the FinnGen consortium. A total of 2390 diabetic patients were treated with GLP-1 RAs and the incidence of DR was 5.97 per 1000 person-years. Compared with diabetic patients who did not use GLP-1 RAs having an incidence of 12.85 per 1000 person-years, the adjusted hazard ratio (HR) of DR was 0.42 [95% confidence interval (CI), 0.29–0.61]. Genetically-predicted GLP1R expression (the target of GLP-1 RAs) showed an inverse association with background [odds ratio (OR)=0.83, 95% CI, 0.71–0.97] and severe nonproliferative DR (OR=0.72, 95% CI, 0.53–0.98), and a non-significant association with overall (OR=0.97, 95% CI, 0.92–1.03) and proliferative DR (OR=0.98, 95% CI, 0.91–1.05). Both observational and mendelian randomization analyses showed a significantly lower risk of DR for patients treated with GLP-1 RAs, which calls for further studies to validate these findings.
Tài liệu tham khảo
Shah AR, Gardner TW. Diabetic retinopathy: research to clinical practice. Clin Diabetes Endocrinol. 2017;3:9.
Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, et al. Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis. Ophthalmology. 2021;128(11):1580–91.
Flaxel CJ, Adelman RA, Bailey ST, Fawzi A, Lim JI, Vemulakonda GA, et al. Diabetic Retinopathy Preferred Practice Pattern®. Ophthalmology. 2020;127(1):P66–p145.
Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018;20(Suppl 1):5–21.
Ma X, Liu Z, Ilyas I, Little PJ, Kamato D, Sahebka A, et al. GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential. Int J Biol Sci. 2021;17(8):2050–68.
Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125–s43.
Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323.
Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834–44.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311–22.
Abcouwer SF, Gardner TW. Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann N Y Acad Sci. 2014;1311:174–90.
Hölscher C. Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. CNS Drugs. 2012;26(10):871–82.
Hernández C, Bogdanov P, Corraliza L, García-Ramírez M, Solà-Adell C, Arranz JA, et al. Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes. Diabetes. 2016;65(1):172–87.
Wang T, Lu W, Tang H, Buse JB, Stürmer T, Gower EW. Assessing the Association Between GLP-1 Receptor Agonist Use and Diabetic Retinopathy Through the FDA Adverse Event Reporting System. Diabetes Care. 2019;42(2):e21–e3.
Ueda P, Pasternak B, Eliasson B, Svensson AM, Franzén S, Gudbjörnsdottir S, et al. Glucagon-Like Peptide 1 Receptor Agonists and Risk of Diabetic Retinopathy Complications: Cohort Study in Nationwide Registers From Two Countries. Diabetes Care. 2019;42(6):e92–e4.
Douros A, Filion KB, Yin H, Yu OH, Etminan M, Udell JA, et al. Glucagon-Like Peptide 1 Receptor Agonists and the Risk of Incident Diabetic Retinopathy. Diabetes Care. 2018;41(11):2330–8.
Gaborit B, Julla JB, Besbes S, Proust M, Vincentelli C, Alos B, et al. Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study. J Clin Endocrinol Metab. 2020;105(4):dgz069.
Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin Pract. 2014;103(3):e37–9.
Zhu Z, Zhang F, Hu H, Bakshi A, Robinson MR, Powell JE, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016;48(5):481–7.
Pingault JB, O'Reilly PF, Schoeler T, Ploubidis GB, Rijsdijk F, Dudbridge F. Using genetic data to strengthen causal inference in observational research. Nat Rev Genet. 2018;19(9):566–80.
Ji J, Sundquist K, Sundquist J, Hemminki K. Comparability of cancer identification among Death Registry, Cancer Registry and Hospital Discharge Registry. Int J Cancer. 2012;131(9):2085–93.
Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad Olausson P, Bergman U, et al. The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf. 2007;16(7):726–35.
GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45(6):580–5.
Consortium GTEx. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318–30.
Consortium GTEx. GTEx version 8. https://yanglab.westlake.edu.cn/data/SMR/GTEx_V8_cis_eqtl_summary.html. Accessed 11 Sept 2020.
FinnGen. GWAS summary results: diabetic retinopathy. https://r6.finngen.fi/pheno/DM_RETINOPATHY_EXMORE. Accessed 24 Jan 2022.
FinnGen. GWAS summary results: background diabetic retinopathy. https://r6.finngen.fi/pheno/DM_BCKGRND_RETINA. Accessed 24 Jan 2022.
FinnGen. GWAS summary results: severe nonproliferative diabetic retinopathy. https://r6.finngen.fi/pheno/DM_BCKGRND_RETINA_NONPROLIF. Accessed 24 Jan 2022.
FinnGen. GWAS summary results: proliferative diabetic retinopathy. https://r6.finngen.fi/pheno/DM_RETINA_PROLIF. Accessed 24 Jan 2022.
VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med. 2017;167(4):268–74.
Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(13):1228–39.
Gaspari T, Liu H, Welungoda I, Hu Y, Widdop RE, Knudsen LB, et al. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model. Diab Vasc Dis Res. 2011;8(2):117–24.
Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail ISB. Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets. BioMed Research International. 2014;2014:801269.
Cai X, Li J, Wang M, She M, Tang Y, Li J, et al. GLP-1 Treatment Improves Diabetic Retinopathy by Alleviating Autophagy through GLP-1R-ERK1/2-HDAC6 Signaling Pathway. Int J Med Sci. 2017;14(12):1203–12.
Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017;2(14):e93751.
Sterling JK, Adetunji MO, Guttha S, Bargoud AR, Uyhazi KE, Ross AG, et al. GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension. Cell Rep. 2020;33(5):108271.
Simó R, Hernández C. Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab. 2014;25(1):23–33.
Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012;366(13):1227–39.
Simó R, Hernández C. GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe? Diabetes. 2017;66(6):1453–60.
Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.