diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM10372diaendo-10372Research ArticleОбзорыReviewДиабетическая ретинопатия: средство для стратификации сердечно-сосудистого рискаDiabetic retinopathy: a tool for cardiovascular risk stratificationhttps://orcid.org/0000-0002-1177-0516AvogaroAngelo

Professor of Endocrinology & Metabolic Diseases Department Medicine, Section of Diabetes and Metabolic Diseases

angelo.avogaro@unipd.itFadiniGian Paolo

MD, associate professor Department Medicine, Section of Diabetes and Metabolic Diseases

gianpaolofadini@hotmail.comUniversity of PadovaItaly201917012020225455460Copyright © Avogaro A., Fadini G., 20192019Avogaro A., Fadini G.Avogaro A., Fadini G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/10372

Рандомизированные одномоментные и проспективные исследования показали, что микрососудистые осложнения у пациентов с сахарным диабетом не только вызывают слепоту, почечную недостаточность и нетравматические ампутации, но также служат мощным прогностическим фактором развития сердечно-сосудистых осложнений. Патофизиология микрососудистых осложнений сахарного диабета обусловлена несколькими факторами, включающими эпигенетические изменения и сниженный выход клеток-предшественниц из костного мозга в периферическую кровь. Выявление микрососудистых осложнений, особенно ретинопатии, повышает возможность стратифицировать пациентов относительно сердечно-сосудистого риска. Рассматривать микроангиопатию и макроангиопатию необходимо, скорее, не как отдельные нозологические формы, а как части непрерывного спектра генерализованного сосудистого поражения, обусловленного сахарным диабетом.

Randomized, cross-sectional, and prospective studies have demonstrated that microvascular complications in patients with diabetes are not only the cause of blindness, renal failure and non-traumatic amputations, but also powerful predictors of cardiovascular complications. The pathophysiology of diabetic microvascular complications is determined by several factors including epigenetic modifications, and reduced release of circulating progenitor cells by the bone marrow. Identifying microvascular complications, in particular retinopathy, increases the ability to stratify patients in terms of cardiovascular risk. There may no longer be a rational to consider microangiopathy and macroangiopathy as entirely separate entities, but they should most likely be viewed as a continuum of the widespread vascular damage determined by diabetes mellitus.

сахарный диабетдиабетическая ретинопатияишемическая болезнь сердцасердечная недостаточностьdiabetes mellitusdiabetic retinopathycoronary heart diseaseheart failureПубликация этой статьи поддержана Novartis Pharma AG, Базель, Швейцария.The publication of this article was supported by Novartis Pharma AG, Basel, Switzerland.ReferencesSolini A, Penno G, Bonora E, et al. Diverging association of reduced glomerular filtration rate and albuminuria with coronary and noncoronary events in patients with type 2 diabetes: the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study. Diabetes Care. 2012;35(1):143−149. doi: https://orcid.org/10.2337/dc11-1380Solini A, Penno G, Bonora E, et al. Diverging association of reduced glomerular filtration rate and albuminuria with coronary and noncoronary events in patients with type 2 diabetes: the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study. Diabetes Care. 2012;35(1):143−149. doi: https://orcid.org/10.2337/dc11-1380Voigt M, Schmidt S, Lehmann T, et al. Prevalence and progression rate of diabetic retinopathy in type 2 diabetes patients in correlation with the duration of diabetes. Exp Clin Endocrinol Diabetes. 2018;126(9):570−576. doi: https://orcid.org/10.1055/s-0043-120570Voigt M, Schmidt S, Lehmann T, et al. Prevalence and progression rate of diabetic retinopathy in type 2 diabetes patients in correlation with the duration of diabetes. Exp Clin Endocrinol Diabetes. 2018;126(9):570−576. doi: https://orcid.org/10.1055/s-0043-120570Salvotelli L, Stoico V, Perrone F, et al. Prevalence of neuropathy in type 2 diabetic patients and its association with other diabetes complications: The Verona Diabetic Foot Screening Program. J Diabetes Complications. 2015;29(8):1066−1070. doi: https://orcid.org/10.1016/j.jdiacomp.2015.06.014Salvotelli L, Stoico V, Perrone F, et al. Prevalence of neuropathy in type 2 diabetic patients and its association with other diabetes complications: The Verona Diabetic Foot Screening Program. J Diabetes Complications. 2015;29(8):1066−1070. doi: https://orcid.org/10.1016/j.jdiacomp.2015.06.014Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383−393. doi: https://orcid.org/10.1056/NEJMoa021778Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383−393. doi: https://orcid.org/10.1056/NEJMoa021778Sandholm N, Groop PH. Genetic basis of diabetic kidney disease and other diabetic complications. Curr Opin Genet Dev. 2018;50:17−24. doi: https://orcid.org/10.1016/j.gde.2018.01.002Sandholm N, Groop PH. Genetic basis of diabetic kidney disease and other diabetic complications. Curr Opin Genet Dev. 2018;50:17−24. doi: https://orcid.org/10.1016/j.gde.2018.01.002Quinn M, Angelico MC, Warram JH, Krolewski AS. Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia. 1996;39(8):940−945. doi: https://orcid.org/10.1007/bf00403913Quinn M, Angelico MC, Warram JH, Krolewski AS. Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia. 1996;39(8):940−945. doi: https://orcid.org/10.1007/bf00403913Avogaro A, Giorda C, Maggini M, et al. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care. 2007;30(5):1241−1247. doi: https://orcid.org/10.2337/dc06-2558Avogaro A, Giorda C, Maggini M, et al. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care. 2007;30(5):1241−1247. doi: https://orcid.org/10.2337/dc06-2558Gordin D, Harjutsalo V, Tinsley L, et al. Differential association of microvascular attributions with cardiovascular disease in patients with long duration of type 1 diabetes. Diabetes Care. 2018;41(4):815−822. doi: https://orcid.org/10.2337/dc17-2250Gordin D, Harjutsalo V, Tinsley L, et al. Differential association of microvascular attributions with cardiovascular disease in patients with long duration of type 1 diabetes. Diabetes Care. 2018;41(4):815−822. doi: https://orcid.org/10.2337/dc17-2250Li YH, Sheu WH, Lee IT. Effects of retinopathy and chronic kidney disease on long-term mortality in type 2 diabetic inpatients with normal urinary albumin or protein: a retrospective cohort study. BMJ Open. 2018;8(7):e021655. doi: https://orcid.org/10.1136/bmjopen-2018-021655Li YH, Sheu WH, Lee IT. Effects of retinopathy and chronic kidney disease on long-term mortality in type 2 diabetic inpatients with normal urinary albumin or protein: a retrospective cohort study. BMJ Open. 2018;8(7):e021655. doi: https://orcid.org/10.1136/bmjopen-2018-021655Avogaro A, Fadini GP. Microvascular complications in diabetes: a growing concern for cardiologists. Int J Cardiol. 2019;291:29−35. doi: https://orcid.org/10.1016/j.ijcard.2019.02.030Avogaro A, Fadini GP. Microvascular complications in diabetes: a growing concern for cardiologists. Int J Cardiol. 2019;291:29−35. doi: https://orcid.org/10.1016/j.ijcard.2019.02.030Xie J, Ikram MK, Cotch MF, et al. Association of diabetic macular edema and proliferative diabetic retinopathy with cardiovascular disease: a systematic review and meta-analysis. JAMA Ophthalmol. 2017;135(6):586−593. doi: https://orcid.org/10.1001/jamaophthalmol.2017.0988Xie J, Ikram MK, Cotch MF, et al. Association of diabetic macular edema and proliferative diabetic retinopathy with cardiovascular disease: a systematic review and meta-analysis. JAMA Ophthalmol. 2017;135(6):586−593. doi: https://orcid.org/10.1001/jamaophthalmol.2017.0988Brownrigg JR, Hughes CO, Burleigh D, et al. Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. Lancet Diabetes Endocrinol. 2016;4(7):588−597. doi: https://orcid.org/10.1016/S2213-8587(16)30057-2Brownrigg JR, Hughes CO, Burleigh D, et al. Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. Lancet Diabetes Endocrinol. 2016;4(7):588−597. doi: https://orcid.org/10.1016/S2213-8587(16)30057-2Tromp J, Lim SL, Tay WT, et al. Microvascular disease in patients with diabetes with heart failure and reduced ejection versus preserved ejection fraction. Diabetes Care. 2019;42(9):1792−1799. doi: https://orcid.org/10.2337/dc18-2515Tromp J, Lim SL, Tay WT, et al. Microvascular disease in patients with diabetes with heart failure and reduced ejection versus preserved ejection fraction. Diabetes Care. 2019;42(9):1792−1799. doi: https://orcid.org/10.2337/dc18-2515de Kreutzenberg SV, Coracina A, Volpi A, et al. Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes. Nutr Metab Cardiovasc Dis. 2011;21(4):286−293. doi: https://orcid.org/10.1016/j.numecd.2009.10.003de Kreutzenberg SV, Coracina A, Volpi A, et al. Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes. Nutr Metab Cardiovasc Dis. 2011;21(4):286−293. doi: https://orcid.org/10.1016/j.numecd.2009.10.003Carbonell M, Castelblanco E, Valldeperas X, et al. Diabetic retinopathy is associated with the presence and burden of subclinical carotid atherosclerosis in type 1 diabetes. Cardiovasc Diabetol. 2018;17(1):66. doi: https://orcid.org/10.1186/s12933-018-0706-zCarbonell M, Castelblanco E, Valldeperas X, et al. Diabetic retinopathy is associated with the presence and burden of subclinical carotid atherosclerosis in type 1 diabetes. Cardiovasc Diabetol. 2018;17(1):66. doi: https://orcid.org/10.1186/s12933-018-0706-zForce M, Ryden L, Grant PJ, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34(39):3035−3087. doi: https://orcid.org/10.1093/eurheartj/eht108Force M, Ryden L, Grant PJ, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34(39):3035−3087. doi: https://orcid.org/10.1093/eurheartj/eht108Wilson PW, Polonsky TS, Miedema MD, et al. Systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3210−3227. doi: https://orcid.org/10.1016/j.jacc.2018.11.004Wilson PW, Polonsky TS, Miedema MD, et al. Systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3210−3227. doi: https://orcid.org/10.1016/j.jacc.2018.11.004Seidelmann SB, Claggett B, Bravo PE, et al. Retinal Vessel calibers in predicting long-term cardiovascular outcomes: the atherosclerosis risk in communities study. Circulation. 2016;134(18):1328−1338. doi: https://orcid.org/10.1161/CIRCULATIONAHA.116.023425Seidelmann SB, Claggett B, Bravo PE, et al. Retinal Vessel calibers in predicting long-term cardiovascular outcomes: the atherosclerosis risk in communities study. Circulation. 2016;134(18):1328−1338. doi: https://orcid.org/10.1161/CIRCULATIONAHA.116.023425Barthelmes J, Nagele MP, Cantatore S, et al. Retinal microvascular dysfunction in patients with coronary artery disease with and without heart failure: a continuum? Eur J Heart Fail. 2019;21(8):988−997. doi: https://orcid.org/10.1002/ejhf.1537Barthelmes J, Nagele MP, Cantatore S, et al. Retinal microvascular dysfunction in patients with coronary artery disease with and without heart failure: a continuum? Eur J Heart Fail. 2019;21(8):988−997. doi: https://orcid.org/10.1002/ejhf.1537Taqueti VR, Di Carli MF. Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(21):2625−2641. doi: https://orcid.org/10.1016/j.jacc.2018.09.042Taqueti VR, Di Carli MF. Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(21):2625−2641. doi: https://orcid.org/10.1016/j.jacc.2018.09.042Taqueti VR, Solomon SD, Shah AM, et al. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. Eur Heart J. 2018;39(10):840−849. doi: https://orcid.org/10.1093/eurheartj/ehx721Taqueti VR, Solomon SD, Shah AM, et al. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. Eur Heart J. 2018;39(10):840−849. doi: https://orcid.org/10.1093/eurheartj/ehx721Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes. 1999;48(10):1899−1906. doi: https://orcid.org/10.2337/diabetes.48.10.1899Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes. 1999;48(10):1899−1906. doi: https://orcid.org/10.2337/diabetes.48.10.1899Orasanu G, Plutzky J. The pathologic continuum of diabetic vascular disease. J Am Coll Cardiol. 2009;53(5 Suppl):S35−42. doi: https://orcid.org/10.1016/j.jacc.2008.09.055Orasanu G, Plutzky J. The pathologic continuum of diabetic vascular disease. J Am Coll Cardiol. 2009;53(5 Suppl):S35−42. doi: https://orcid.org/10.1016/j.jacc.2008.09.055Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation. 2003;108(12):1527−1532. doi: https://orcid.org/10.1161/01.CIR.0000091257.27563.32Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation. 2003;108(12):1527−1532. doi: https://orcid.org/10.1161/01.CIR.0000091257.27563.32Avogaro A, Albiero M, Menegazzo L, et al. Endothelial dysfunction in diabetes: the role of reparatory mechanisms. Diabetes Care. 2011;34 Suppl 2:S285−290. doi: https://orcid.org/10.2337/dc11-s239Avogaro A, Albiero M, Menegazzo L, et al. Endothelial dysfunction in diabetes: the role of reparatory mechanisms. Diabetes Care. 2011;34 Suppl 2:S285−290. doi: https://orcid.org/10.2337/dc11-s239Rodrigues M, Xin X, Jee K, et al. VEGF secreted by hypoxic Muller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. Diabetes. 2013;62(11):3863−3873. doi: https://orcid.org/10.2337/db13-0014Rodrigues M, Xin X, Jee K, et al. VEGF secreted by hypoxic Muller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. Diabetes. 2013;62(11):3863−3873. doi: https://orcid.org/10.2337/db13-0014Tremolada G, Del Turco C, Lattanzio R, et al. The role of angiogenesis in the development of proliferative diabetic retinopathy: impact of intravitreal anti-VEGF treatment. Exp Diabetes Res. 2012;2012:728325. doi: https://orcid.org/10.1155/2012/728325Tremolada G, Del Turco C, Lattanzio R, et al. The role of angiogenesis in the development of proliferative diabetic retinopathy: impact of intravitreal anti-VEGF treatment. Exp Diabetes Res. 2012;2012:728325. doi: https://orcid.org/10.1155/2012/728325Gerstein HC, Nair V, Chaube R, et al. Dysglycemia and the density of the coronary vasa vasorum. Diabetes Care. 2019;42(5):980−982. doi: https://orcid.org/10.2337/dc18-2483Gerstein HC, Nair V, Chaube R, et al. Dysglycemia and the density of the coronary vasa vasorum. Diabetes Care. 2019;42(5):980−982. doi: https://orcid.org/10.2337/dc18-2483Sluimer JC, Gasc JM, van Wanroij JL, et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol. 2008;51(13):1258−1265. doi: https://orcid.org/10.1016/j.jacc.2007.12.025Sluimer JC, Gasc JM, van Wanroij JL, et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol. 2008;51(13):1258−1265. doi: https://orcid.org/10.1016/j.jacc.2007.12.025Sluimer JC, Daemen MJ. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol. 2009;218(1):7−29. doi: https://orcid.org/10.1002/path.2518Sluimer JC, Daemen MJ. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol. 2009;218(1):7−29. doi: https://orcid.org/10.1002/path.2518Kockx MM, Cromheeke KM, Knaapen MW, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(3):440−446. doi: https://orcid.org/10.1161/01.ATV.0000057807.28754.7FKockx MM, Cromheeke KM, Knaapen MW, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(3):440−446. doi: https://orcid.org/10.1161/01.ATV.0000057807.28754.7FSluimer JC, Kolodgie FD, Bijnens AP, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage. J Am Coll Cardiol. 2009;53(17):1517−1527. doi: https://orcid.org/10.1016/j.jacc.2008.12.056Sluimer JC, Kolodgie FD, Bijnens AP, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage. J Am Coll Cardiol. 2009;53(17):1517−1527. doi: https://orcid.org/10.1016/j.jacc.2008.12.056Fadini GP, Rattazzi M, Matsumoto T, et al. Emerging role of circulating calcifying cells in the bone-vascular axis. Circulation. 2012;125(22):2772−2781. doi: https://orcid.org/10.1161/CIRCULATIONAHA.112.090860Fadini GP, Rattazzi M, Matsumoto T, et al. Emerging role of circulating calcifying cells in the bone-vascular axis. Circulation. 2012;125(22):2772−2781. doi: https://orcid.org/10.1161/CIRCULATIONAHA.112.090860Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res. 2012;110(4):624−637. doi: https://orcid.org/10.1161/CIRCRESAHA.111.243386Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res. 2012;110(4):624−637. doi: https://orcid.org/10.1161/CIRCRESAHA.111.243386Rigato M, Bittante C, Albiero M, et al. Circulating progenitor cell count predicts microvascular outcomes in type 2 diabetic patients. J Clin Endocrinol Metab. 2015;100(7):2666−2672. doi: https://orcid.org/10.1210/jc.2015-1687Rigato M, Bittante C, Albiero M, et al. Circulating progenitor cell count predicts microvascular outcomes in type 2 diabetic patients. J Clin Endocrinol Metab. 2015;100(7):2666−2672. doi: https://orcid.org/10.1210/jc.2015-1687Albiero M, Poncina N, Ciciliot S, et al. Bone marrow macrophages contribute to diabetic stem cell mobilopathy by producing Oncostatin M. Diabetes. 2015;64(8):2957−2968. doi: https://orcid.org/10.2337/db14-1473Albiero M, Poncina N, Ciciliot S, et al. Bone marrow macrophages contribute to diabetic stem cell mobilopathy by producing Oncostatin M. Diabetes. 2015;64(8):2957−2968. doi: https://orcid.org/10.2337/db14-1473Oikawa A, Siragusa M, Quaini F, et al. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol. 2010;30(3):498−508. doi: https://orcid.org/10.1161/ATVBAHA.109.200154Oikawa A, Siragusa M, Quaini F, et al. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol. 2010;30(3):498−508. doi: https://orcid.org/10.1161/ATVBAHA.109.200154Fadini GP, Ferraro F, Quaini F, et al. Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med. 2014;3(8):949−957. doi: https://orcid.org/10.5966/sctm.2014-0052Fadini GP, Ferraro F, Quaini F, et al. Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med. 2014;3(8):949−957. doi: https://orcid.org/10.5966/sctm.2014-0052Fadini GP, Sartore S, Baesso I, et al. Endothelial progenitor cells and the diabetic paradox. Diabetes Care. 2006;29(3):714−716. doi: https://orcid.org/10.2337/diacare.29.03.06.dc05-1834Fadini GP, Sartore S, Baesso I, et al. Endothelial progenitor cells and the diabetic paradox. Diabetes Care. 2006;29(3):714−716. doi: https://orcid.org/10.2337/diacare.29.03.06.dc05-1834Busik JV, Tikhonenko M, Bhatwadekar A, et al. Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J Exp Med. 2009;206(13):2897−2906. doi: https://orcid.org/10.1084/jem.20090889Busik JV, Tikhonenko M, Bhatwadekar A, et al. Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J Exp Med. 2009;206(13):2897−2906. doi: https://orcid.org/10.1084/jem.20090889George J, Afek A, Abashidze A, et al. Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2005;25(12):2636−2641. doi: https://orcid.org/10.1161/01.ATV.0000188554.49745.9eGeorge J, Afek A, Abashidze A, et al. Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2005;25(12):2636−2641. doi: https://orcid.org/10.1161/01.ATV.0000188554.49745.9eDavies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669−2701. doi: https://orcid.org/10.2337/dci18-0033Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669−2701. doi: https://orcid.org/10.2337/dci18-0033American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S124−S138. doi: https://orcid.org/10.2337/dc19-S011American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S124−S138. doi: https://orcid.org/10.2337/dc19-S011Muskiet MH, Wheeler DC, Heerspink HJ. New pharmacological strategies for protecting kidney function in type 2 diabetes. Lancet Diabetes Endocrinol. 2019;7(5):397−412. doi: https://orcid.org/10.1016/S2213-8587(18)30263-8Muskiet MH, Wheeler DC, Heerspink HJ. New pharmacological strategies for protecting kidney function in type 2 diabetes. Lancet Diabetes Endocrinol. 2019;7(5):397−412. doi: https://orcid.org/10.1016/S2213-8587(18)30263-8Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834−1844. doi: https://orcid.org/10.1056/NEJMoa1607141Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834−1844. doi: https://orcid.org/10.1056/NEJMoa1607141Douros A, Filion KB, Yin H, et al. Glucagon-like peptide 1 receptor agonists and the risk of incident diabetic retinopathy. Diabetes Care. 2018;41(11):2330−2338. doi: https://orcid.org/10.2337/dc17-2280Douros A, Filion KB, Yin H, et al. Glucagon-like peptide 1 receptor agonists and the risk of incident diabetic retinopathy. Diabetes Care. 2018;41(11):2330−2338. doi: https://orcid.org/10.2337/dc17-2280Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2015;132(15):e198. doi: https://orcid.org/10.1161/CIR.0000000000000330Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2015;132(15):e198. doi: https://orcid.org/10.1161/CIR.0000000000000330Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316(5):500−508. doi: https://orcid.org/10.1001/jama.2016.10260Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316(5):500−508. doi: https://orcid.org/10.1001/jama.2016.10260Fadini GP, Sarangdhar M, Avogaro A. Glucagon-like peptide-1 receptor agonists are not associated with retinal adverse events in the FDA Adverse Event Reporting System. BMJ Open Diabetes Res Care. 2018;6(1):e000475. doi: https://orcid.org/10.1136/bmjdrc-2017-000475Fadini GP, Sarangdhar M, Avogaro A. Glucagon-like peptide-1 receptor agonists are not associated with retinal adverse events in the FDA Adverse Event Reporting System. BMJ Open Diabetes Res Care. 2018;6(1):e000475. doi: https://orcid.org/10.1136/bmjdrc-2017-000475

The authors declare that there are no conflicts of interest present.