Influencing factors on clinical response to conbercept for diabetic macular edema_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhu Tingting , Wang Quan , Zhao Rong , Liu Yong , Chen Wei , Zhao Yanyan , Luo Ling , Jie Chuanhong , Tian Tian ,  Jiang Caihui

Air Force Clinical College, Anhui Medical University, Beijing 100142, China (Zhu Tingting, Jiang Caihui); Department of Ophtalmology, Air Force General Hospital, Beijing 100142, China (Wang Quan, Zhao Rong, Liu Yong, Chen Wei, Zhao Yanyan, Jiang Caihui); The 306th Hospital of PLA, Beijing 100142, China (Luo Ling);Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100142, China (Jie Chuanhong, Tian Tian);

Corresponding author：

Jiang Caihui, Email: jiangcaihui.afg@qq.com

Keywords：

Diabetic retinopathy/complications; Macular edema/drug therapy; Angiogenesis inhibitors/therapeutic use; Antibodies, monoclonal/therapeutic use

DOI：

10.3760/cma.j.issn.1005-1015.2018.05.005

Video：

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ObjectiveTo analyze the influencing factors on clinical response to conbercept for diabetic macular edema (DME).MethodsA total of 51 patients (51 eyes) with DME who underwent intravitreal injection of conbercept were included in this retrospective study. The general information (age, sex, body mass index, smoking history, drinking history), blood glucose indicators (duration of diabetes, fasting blood glucose, HbA1c), blood pressure indicators (history of hypertension, systolic blood pressure, diastolic blood pressure), lipid indicators [total cholesterol (TC), high-density lipoprotein (HDL), apolipoprotein A (APOA)], biochemical indicators [neutrophil concentration, hemoglobin (HB), serum creatinine (Scr)] were collected. The best corrected visual acuity (BCVA) and macular central macular thickness (CMT) before and after treatment were comparatively analyzed. CMT reduced not less than 20% and BCVA increased by 2 lines as effective standards. Univariate analysis and multivariate logistic regression analysis were used to determine the factors affecting the efficacy of intravitreal injection of conbercept in patients with DME.ResultsUnivariate analysis showed that diastolic blood pressure, HDL, serum neutrophil concentration, baseline CMT and baseline BCVA were associated with edema regression (P＜0.05); HbA1c was associated with vision improvement (P＜0.05). Multivariate logistic regression analysis showed that there was a history of smoking (OR=0.122, 95% CI 0.017 − 0.887), low diastolic blood pressure (OR=0.850, 95%CI0.748 − 0.966), low HDL (OR=0.007, 95%CI 0.000 1 − 0.440), thin baseline CMT (OR=0.986, 95%CI0.977 − 0.995) were independent risk factors for failure outcome of edema regression (P＜0.05); long duration of diabetes (OR=1.191, 95%CI 1.011 − 1.404), high APOA (OR=1.007, 95% CI 1.000 − 1.013) were independent risk factors for failure outcome of vision improvement. Age, fasting blood glucose, systolic blood pressure, TC, HB, Scr and other indicators had no effect on the efficacy of edema regression and vision improvement after treatment (P＞0.05).ConclusionsSmoking history, long duration of diabetes, low diastolic blood pressure, low HDL level, high APOA level and thin baseline CMT are independent risk factors for the treatment of DME with intravitreal injection of conbercept.

Citation： Zhu Tingting, Wang Quan, Zhao Rong, Liu Yong, Chen Wei, Zhao Yanyan, Luo Ling, Jie Chuanhong, Tian Tian, Jiang Caihui. Influencing factors on clinical response to conbercept for diabetic macular edema. Chinese Journal of Ocular Fundus Diseases, 2018, 34(5): 436-442. doi: 10.3760/cma.j.issn.1005-1015.2018.05.005 Copy

1.	Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9[J]. Ophthalmology, 1991, 98(Suppl 5):S766-785.
2.	Chen E, Looman M, Laouri M, et al. Burden of illness of diabetic macular edema: literature review[J]. Curr Med Res Opin J, 2010, 26(7): 1587-1597. DOI: 10.1185/03007995.2010.482503.
3.	Gabbay KH, Hasty K, Breslow JL, et al. Glycosylated hemoglobins and long-term blood glucose control in diabetes mellitus[J]. J Clin Endocrinol Metab, 1977, 44(5): 859-864. DOI: 10.1210/jcem-44-5-859.
4.	Roy MS, Affouf M. Six-year progression of retinopathy and associated risk factors in African American patients with type 1 diabetes mellitus:The New Jersey 725[J]. Arch Ophthalmol, 2006, 124(9): 1297-1306. DOI: 10.1001/archopht.124.9.1297.
5.	Leske MC, Wu SY, Hennis A, et al. Nine-year incidence of diabetic retinopathy in the Barbados Eye Studies[J]. Arch Ophthalmol, 2006, 124(2): 250-255. DOI: 10.1001/archopht.124.2.250.
6.	Bhagat N, Grigorian RA, Tutela A, et al. Diabetic macular edema: pathogenesis and treatment[J]. Surv Ophthalmol, 2009, 54(1): 1-32. DOI: 10.1016/j.survophthal.2008.10.001.
7.	Klein R, Knudtson MD, Lee KE, et al. The Wisconsin epidemiologic study of diabetic retinopathy ⅩⅩⅢ: the twenty-five-year incidence of macular edema in persons with type 1 diabetes[J]. Ophthalmology, 2009, 116(3): 497-503. DOI: 10.1016/j.ophtha.2008.10.016.
8.	Lammert A, Hasenberg T, Imhof I, et al. High prevalence of retinal endothelial dysfunction in obesity WHO class Ⅲ[J]. Microvasc Res, 2012, 84(3): 362-366. DOI: 10.1016/j.mvr.2012.09.004.
9.	Leveziel N, Ragot S, Gand E, et al. Association between diabetic macular edema and cardiovascular events in type 2 diabetes patients: a multicenter observational study[J]. Medicine (Baltimore), 2015, 94(33): 1220. DOI: 10.1097/MD.0000000000001220.
10.	Raman R, Rani PK, Kulothungan V, et al. Influence of serum lipids on clinically significant versus nonclinicallysignificant macular edema:SN-DREAMS Report number 13[J]. Ophthalmology, 2010, 117(4): 766-772. DOI: 10.1016/j.ophtha.2009.09.005.
11.	Aroca PR, Salvat M, Fernandez J, et al. Risk factors for diffuse and focal macular edema[J]. J Diabetes Complitions, 2004, 18(4): 211-215. DOI: 10.1016/S1056-8727(03)00038-2.
12.	Ajoy Mohan VK, Nithyanandam S, Idiculla J. Microalbuminuria and low hemoglobin as risk fators for the occurrence and increasing severity of diabetic retinopathy[J]. Indian J Ophthalmol, 2011, 59(3): 207-210. DOI: 10.4103/0301-4738.81029.
13.	Li W, Sinclair SH, Xu GT. Effects of intravitreal erythropoietin therapy for patients with chronic and progressive diabetic macular edema[J]. Ophthalmic Surg Lasers Imaging, 2010, 41(1): 18-25. DOI: 10.3928/15428877-20091230-03.
14.	Kocabora MS, Telli ME, Fazil K, et al. Serum and aqueous concentrations of inflammatory markers in diabetic macular edema[J]. Ocul Immunol Inflamm, 2016, 24(5): 549-554. DOI: 10.3109/09273948.2015.1034804.
15.	Idris I, Warren G, Donnellv R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes[J]. Arch Intem Med, 2012, 172(13): 1005-1011. DOI: 10.1001/archinternmed.2012.1938.
16.	Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase Ⅲ randomized trials: RISE and RIDE[J]. Ophthalmology, 2012, 119(4): 789-801. DOI: 10.1016/j.ophtha.2011.12.039.
17.	Warid Al-Laftah FA, Elshafie M, Alhashimi M, et al. Pretreatment clinical variables associated with the response to intravitreal bevacizumab (Avastin) injection in patients with persistent diabetic macular edema[J]. Saudi J Ophthalmol, 2010, 24(4): 133-138. DOI: 10.1016/j.sjopt.2010.05.001.
18.	Diabetic Retinopathy Clinical Research Network. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab[J]. Arch Ophthalmol, 2012, 130(9): 1153-1161. DOI: 10.1001/archophthalmol.2012.1107.
19.	Matsuda S, Tam T, Singh RP, et al. The impact of metabolic parameters on clinical response to VEGF inhibitors for diabetic macular edema[J]. J Diabetes Complications, 2014, 28(2): 166-170. DOI: 10.1016/j.jdiacomp.2013.11.009.
20.	Singh RP, Habbu K, Ehlers JP, et al. The impact of systemic factors on clinical response to ranibizumab for diabetic macular edema[J]. Ophthalmology, 2016, 123(7): 1581-1587. DOI: 10.1016/j.ophtha.2016.03.038.
21.	Li X, Zarbin MA, Bhagat N. Anti-vascular endothelial growth factor injections: the new standard of care in proliferative diabetic retinopathy?[J]. Dev Ophthalmol, 2017, 60: 131-142. DOI: 10.1159/000459699.
22.	Diabetic Retinopathy Clinical Research Network.Retinal thickness on Stratus optical coherence tomography in people with diabetes and minimal or no diabetic retinopathy[J].Am J Ophthalmol, 2008, 145(5): 894-901.DOI: 10.1016/j.ajo.2007.12.025.
23.	Sheu SJ, Lee YY. Early response to ranibizumab is associated with 12-month outcome in diabetic macular edema after prior macular laser therapy[J].Ophthalmologica, 2017, 238(3): 139-146. DOI: 10.1159/000477627.
24.	中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2013年版)[J]. 中华糖尿病杂志, 2014, 6(7): 4447-4498. DOI: 10.3760/cma.j.issn.1674-5809.2014.07.004.Chinese Diabetes Society of Chinese Medical Association. The prevention guidelines for type 2 diabetes mellitus in China[J]. Chin J Diabetes Mellitus, 2014, 6(7): 4447-4498. DOI: 10.3760/cma.j.issn.1674-5809.2014.07.004.
25.	Shimura M, Yasuda K, Yasuda M, et al. Visual outcome after intravitreal bevacizumab depends on the optical coherence tomagraphic patterns of patients with diffuse diabetic macular edema[J]. Retina, 2013, 33(4): 740-747. DOI: 10.1097/IAE.0b013e31826b6763.
26.	Bressler NM, Varma R, Suñer IJ, et al. Vision-related function after ranibizumab treatment for diabetic macular edema: results from RIDE and RISE[J]. Ophthalmology, 2014, 121(12): 2461-2472. DOI: 10.1016/j.ophtha.2014.07.008.
27.	Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase Ⅲ trials: RISE and RIDE[J].Ophthalmology, 2013, 120(10): 2013-2022. DOI: 10.1016/j.ophtha.2013.02.034.
28.	Cai X, Chen Y, Yang W, et al. The association of smoking and risk of diabetic retinopathy in patients with type 1 and type 2 diabetes: a meta-analysis[J/OL]. Endocrine, 2018, 2018:E30128962[2018-08-20] . https://www.ncbi.nlm.nih.gov/pubmed/30128962. DOI: 10.1007/s12020-018-1697-y.[published online ahead of print].
29.	Morgado PB, Chen HC, Patel V, et al. The acute effect of smoking on retinal blood flow in subjects with and without diabetes[J]. Ophthalmology, 1994, 101(7): 1220-1226.
30.	Wautier JL, Guillausseau PJ. Advanced glycation end products, their receptors and diabetic angiopathy[J]. Diabetes Metab, 2001, 27(5 Pt 1): 535-542.
31.	Bansal AS, Khurana RN, Wieland MR, et al. Influence of glycosylated hemoglobin on the efficacy of ranibizumab for diabetic macular edema: a post hoc analysis of the RIDE/RISE trials[J]. Ophthalmology, 2015, 122(8): 1573-1579. DOI: 10.1016/j.ophtha.2015.04.029.
32.	Barter PJ, Nicholls S, Rye KA, et al. Antiinflammatory properties of HDL[J]. Circ Res, 2004, 95(8): 764-772. DOI: 10.1161/01.RES.0000146094.59640.13.
33.	Simó R1, García-Ramírez M, Higuera M, et al. Apolipoprotein A1 is overexpressed in the retina of diabetic patients[J]. Am J Ophthalmol, 2009, 147(2): 319-325. DOI: 10.1016/j.ajo.2008.08.009.
34.	Hrarat L, Fajnkuchen F, Boubay M, et al. Outcomes after a 1-Year treatment with ranibizumab for diabetic macular edema in a clinical setting[J]. Ophthalmologica, 2016, 236(4): 207-214. DOI: 10.1159/000453006.
35.	Cheng CK, Cheng CK, Peng CH. The incidence and risk factors for the development of vitreomacular interface abnormality in diabetic macular edema treated with intravitreal injection of anti-VEGF[J]. Eye (Lond), 2017, 31(5): 762-770. DOI: 10.1038/eye.2016.317.

1. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9[J]. Ophthalmology, 1991, 98(Suppl 5):S766-785.
2. Chen E, Looman M, Laouri M, et al. Burden of illness of diabetic macular edema: literature review[J]. Curr Med Res Opin J, 2010, 26(7): 1587-1597. DOI: 10.1185/03007995.2010.482503.
3. Gabbay KH, Hasty K, Breslow JL, et al. Glycosylated hemoglobins and long-term blood glucose control in diabetes mellitus[J]. J Clin Endocrinol Metab, 1977, 44(5): 859-864. DOI: 10.1210/jcem-44-5-859.
4. Roy MS, Affouf M. Six-year progression of retinopathy and associated risk factors in African American patients with type 1 diabetes mellitus:The New Jersey 725[J]. Arch Ophthalmol, 2006, 124(9): 1297-1306. DOI: 10.1001/archopht.124.9.1297.
5. Leske MC, Wu SY, Hennis A, et al. Nine-year incidence of diabetic retinopathy in the Barbados Eye Studies[J]. Arch Ophthalmol, 2006, 124(2): 250-255. DOI: 10.1001/archopht.124.2.250.
6. Bhagat N, Grigorian RA, Tutela A, et al. Diabetic macular edema: pathogenesis and treatment[J]. Surv Ophthalmol, 2009, 54(1): 1-32. DOI: 10.1016/j.survophthal.2008.10.001.
7. Klein R, Knudtson MD, Lee KE, et al. The Wisconsin epidemiologic study of diabetic retinopathy ⅩⅩⅢ: the twenty-five-year incidence of macular edema in persons with type 1 diabetes[J]. Ophthalmology, 2009, 116(3): 497-503. DOI: 10.1016/j.ophtha.2008.10.016.
8. Lammert A, Hasenberg T, Imhof I, et al. High prevalence of retinal endothelial dysfunction in obesity WHO class Ⅲ[J]. Microvasc Res, 2012, 84(3): 362-366. DOI: 10.1016/j.mvr.2012.09.004.
9. Leveziel N, Ragot S, Gand E, et al. Association between diabetic macular edema and cardiovascular events in type 2 diabetes patients: a multicenter observational study[J]. Medicine (Baltimore), 2015, 94(33): 1220. DOI: 10.1097/MD.0000000000001220.
10. Raman R, Rani PK, Kulothungan V, et al. Influence of serum lipids on clinically significant versus nonclinicallysignificant macular edema:SN-DREAMS Report number 13[J]. Ophthalmology, 2010, 117(4): 766-772. DOI: 10.1016/j.ophtha.2009.09.005.
11. Aroca PR, Salvat M, Fernandez J, et al. Risk factors for diffuse and focal macular edema[J]. J Diabetes Complitions, 2004, 18(4): 211-215. DOI: 10.1016/S1056-8727(03)00038-2.
12. Ajoy Mohan VK, Nithyanandam S, Idiculla J. Microalbuminuria and low hemoglobin as risk fators for the occurrence and increasing severity of diabetic retinopathy[J]. Indian J Ophthalmol, 2011, 59(3): 207-210. DOI: 10.4103/0301-4738.81029.
13. Li W, Sinclair SH, Xu GT. Effects of intravitreal erythropoietin therapy for patients with chronic and progressive diabetic macular edema[J]. Ophthalmic Surg Lasers Imaging, 2010, 41(1): 18-25. DOI: 10.3928/15428877-20091230-03.
14. Kocabora MS, Telli ME, Fazil K, et al. Serum and aqueous concentrations of inflammatory markers in diabetic macular edema[J]. Ocul Immunol Inflamm, 2016, 24(5): 549-554. DOI: 10.3109/09273948.2015.1034804.
15. Idris I, Warren G, Donnellv R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes[J]. Arch Intem Med, 2012, 172(13): 1005-1011. DOI: 10.1001/archinternmed.2012.1938.
16. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase Ⅲ randomized trials: RISE and RIDE[J]. Ophthalmology, 2012, 119(4): 789-801. DOI: 10.1016/j.ophtha.2011.12.039.
17. Warid Al-Laftah FA, Elshafie M, Alhashimi M, et al. Pretreatment clinical variables associated with the response to intravitreal bevacizumab (Avastin) injection in patients with persistent diabetic macular edema[J]. Saudi J Ophthalmol, 2010, 24(4): 133-138. DOI: 10.1016/j.sjopt.2010.05.001.
18. Diabetic Retinopathy Clinical Research Network. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab[J]. Arch Ophthalmol, 2012, 130(9): 1153-1161. DOI: 10.1001/archophthalmol.2012.1107.
19. Matsuda S, Tam T, Singh RP, et al. The impact of metabolic parameters on clinical response to VEGF inhibitors for diabetic macular edema[J]. J Diabetes Complications, 2014, 28(2): 166-170. DOI: 10.1016/j.jdiacomp.2013.11.009.
20. Singh RP, Habbu K, Ehlers JP, et al. The impact of systemic factors on clinical response to ranibizumab for diabetic macular edema[J]. Ophthalmology, 2016, 123(7): 1581-1587. DOI: 10.1016/j.ophtha.2016.03.038.
21. Li X, Zarbin MA, Bhagat N. Anti-vascular endothelial growth factor injections: the new standard of care in proliferative diabetic retinopathy?[J]. Dev Ophthalmol, 2017, 60: 131-142. DOI: 10.1159/000459699.
22. Diabetic Retinopathy Clinical Research Network.Retinal thickness on Stratus optical coherence tomography in people with diabetes and minimal or no diabetic retinopathy[J].Am J Ophthalmol, 2008, 145(5): 894-901.DOI: 10.1016/j.ajo.2007.12.025.
23. Sheu SJ, Lee YY. Early response to ranibizumab is associated with 12-month outcome in diabetic macular edema after prior macular laser therapy[J].Ophthalmologica, 2017, 238(3): 139-146. DOI: 10.1159/000477627.
24. 中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2013年版)[J]. 中华糖尿病杂志, 2014, 6(7): 4447-4498. DOI: 10.3760/cma.j.issn.1674-5809.2014.07.004.Chinese Diabetes Society of Chinese Medical Association. The prevention guidelines for type 2 diabetes mellitus in China[J]. Chin J Diabetes Mellitus, 2014, 6(7): 4447-4498. DOI: 10.3760/cma.j.issn.1674-5809.2014.07.004.
25. Shimura M, Yasuda K, Yasuda M, et al. Visual outcome after intravitreal bevacizumab depends on the optical coherence tomagraphic patterns of patients with diffuse diabetic macular edema[J]. Retina, 2013, 33(4): 740-747. DOI: 10.1097/IAE.0b013e31826b6763.
26. Bressler NM, Varma R, Suñer IJ, et al. Vision-related function after ranibizumab treatment for diabetic macular edema: results from RIDE and RISE[J]. Ophthalmology, 2014, 121(12): 2461-2472. DOI: 10.1016/j.ophtha.2014.07.008.
27. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase Ⅲ trials: RISE and RIDE[J].Ophthalmology, 2013, 120(10): 2013-2022. DOI: 10.1016/j.ophtha.2013.02.034.
28. Cai X, Chen Y, Yang W, et al. The association of smoking and risk of diabetic retinopathy in patients with type 1 and type 2 diabetes: a meta-analysis[J/OL]. Endocrine, 2018, 2018:E30128962[2018-08-20] . https://www.ncbi.nlm.nih.gov/pubmed/30128962. DOI: 10.1007/s12020-018-1697-y.[published online ahead of print].
29. Morgado PB, Chen HC, Patel V, et al. The acute effect of smoking on retinal blood flow in subjects with and without diabetes[J]. Ophthalmology, 1994, 101(7): 1220-1226.
30. Wautier JL, Guillausseau PJ. Advanced glycation end products, their receptors and diabetic angiopathy[J]. Diabetes Metab, 2001, 27(5 Pt 1): 535-542.
31. Bansal AS, Khurana RN, Wieland MR, et al. Influence of glycosylated hemoglobin on the efficacy of ranibizumab for diabetic macular edema: a post hoc analysis of the RIDE/RISE trials[J]. Ophthalmology, 2015, 122(8): 1573-1579. DOI: 10.1016/j.ophtha.2015.04.029.
32. Barter PJ, Nicholls S, Rye KA, et al. Antiinflammatory properties of HDL[J]. Circ Res, 2004, 95(8): 764-772. DOI: 10.1161/01.RES.0000146094.59640.13.
33. Simó R1, García-Ramírez M, Higuera M, et al. Apolipoprotein A1 is overexpressed in the retina of diabetic patients[J]. Am J Ophthalmol, 2009, 147(2): 319-325. DOI: 10.1016/j.ajo.2008.08.009.
34. Hrarat L, Fajnkuchen F, Boubay M, et al. Outcomes after a 1-Year treatment with ranibizumab for diabetic macular edema in a clinical setting[J]. Ophthalmologica, 2016, 236(4): 207-214. DOI: 10.1159/000453006.
35. Cheng CK, Cheng CK, Peng CH. The incidence and risk factors for the development of vitreomacular interface abnormality in diabetic macular edema treated with intravitreal injection of anti-VEGF[J]. Eye (Lond), 2017, 31(5): 762-770. DOI: 10.1038/eye.2016.317.

Chinese Journal of Ocular Fundus Diseases

Influencing factors on clinical response to conbercept for diabetic macular edema

Abstract Full text Figures/Tables Video References Cited by

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