- Research article
- Open access
- Published:
Effect of anticoagulant/antiplatelet therapy on the development and progression of diabetic retinopathy
BMC Ophthalmology volume 22, Article number: 127 (2022)
Abstract
Background
We investigated whether antiplatelet/anticoagulant (APAC) therapy can protect patients with type 2 diabetes mellitus (T2DM) from the development or progression of diabetic retinopathy (DR).
Methods
This is a retrospective cohort study using Longitudinal Health Insurance Database in Taiwan. A total of 73,964 type 2 diabetic patients older than 20 years old were included. Hazard ration (HR) of non-proliferative DR (NPDR), proliferative DR (PDR), and diabetic macular edema (DME) were analyzed with APAC usage as a time-dependent covariate. Age, sex, comorbidities, and medicines were further adjusted in a multi-variable model. Contributions of respective APAC was investigated with sensitivity analysis.
Results
Compared with nonusers, APAC users had a lower cumulative incidence of NPDR (P < 0.001), overall incidence of NPDR (10.7 per 1000 person-years), and risk of developing NPDR (adjusted HR = 0.78, 95% CI = 0.73–0.83). However, no significant differences were observed between APAC users and nonusers in the risks of PDR or DME. Hypertension, diabetic nephropathy and diabetic neuropathy were risk factors for NDPR development, while heart disease, cardiovascular disease, peripheral arterial occlusive disease, and statin usage were covariates decreasing NPDR development. Aspirin and Dipyridamole showed significant protection against NPDR development. Clopidogrel, Ticlopidine, and warfarin showed enhanced protection in combination with aspirin usage.
Conclusions
APAC medications have a protective effect against NPDR development. Diabetic patients benefit from single use of aspirin or dipyridamole on prevention of NPDR.
Background
Diabetes mellitus (DM) is characterized by chronic hyperglycemia, which not only causes metabolic disorder but also has profound effects leading to macro- and micro-vasculopathies [1]. Hyperglycemia not only disturbs vascular homeostasis, induces inflammation, endothelial dysfunction, and platelet hyperactivitiy [2], but also causes imbalances of glucose and insulin levels, leading to a procoagulative state [3]. Therefore, patients with DM are at a high risk of thrombosis, which causes diseases such as atherosclerosis [4]. Up to 80% of deaths from type 2 diabetics mellitus (T2DM) are thrombotic [5], and 75% of such deaths result from cardiovascular events [6], with the others resulting from complications of peripheral vascular diseases [7].
Accordingly, antiplatelet/anticoagulant (APAC) therapy with medications, such as low-dose aspirin, is used to target one or multiple pathways responsible for accelerating atherosclerosis and its thrombotic complications in diabetic patients [8]. However, the costs and benefits of primary cardiovascular prevention with aspirin have long been debated. Antithrombotic Trialists’ (ATT) Collaboration reported that aspirin yielded 12% proportional reduction of serious vascular events.[9] The Study of Cardiovascular Events in Diabetes (ASCEND) [10] confirmed the prevention of serious cardiovascular effect from aspirin significantly. However, the benefits accompanied with increase of major bleeding.
A hypercoagulable state with endothelial damage renders patients prone to vascular occlusion, [11] which might relate to microvascular complications of diabetic retinopathy (DR) [12, 13]. Schachat suggested that if a patient had either nonproliferative or mildly proliferative DR, aspirin use appeared safe [14]. Bergerhoff et al. examined randomized controlled clinical trials from the Cochrane Library and Medline in patients with DR comparing aspirin treatment, alone or in combination with dipyridamole, versus placebo. Neither alone nor in combination with dipyridamole did aspirin change the risk of DR [15]. The Early Treatment Diabetic Retinopathy Study (ETDRS) reported that the use of aspirin did not prevent either development of PDR or visual loss [16]. On the other aspect, it did not increase the occurrence of vitreous/preretinal hemorrhages in enrolled patients. They also demonstrated that the severity and duration of these hemorrhages were not significantly affected by the use of aspirin. There were no ocular contraindications to its use (650Â mg/d) in patients with diabetes who require aspirin for treatment of cardiovascular disease or other conditions [17]. Recently, The Singapore Epidemiology of Eye Disease (SEED) study revealed that aspirin use is not significantly associated with DR. Rather, aspirin usage may be an indicator of diabetic complications (cardiovascular disease, chronic kidney disease), which often comorbid with severe DR [18]. Conversely, the MADIABETES study demonstrated an association between aspirin use and DR risk in a well-defined cohort of patients with T2DM at a low risk of cardiovascular events [19]. The DAMAD Study, conducted in two French and two UK centers, concluded that antiplatelet agents, aspirin alone (330Â mg, three times daily) or in combination with dipyridamole (75Â mg, three times daily), significantly slowed the progression of microaneurysm evolution in early DR [20].
Whether using APAC for systemic factors affect DR development or progression is still under debate (supplementary Table 1). In the current study, we revisited this issue and investigated whether the use of APAC therapy affects the development or progression of DR in a Taiwanese longitudinal cohort.
Methods
Data source
The Longitudinal Health Insurance Database (LHID) was used for this retrospective cohort study. The LHID is a subset of the National Health Insurance Research Database (NHIRD) covering 23.74Â million (99%) Taiwan residents [21]. The details of the LHID have been described in previous studies [22, 23]. Diagnoses in the NHIRD are based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The Ethics Review Board of China Medical University and Hospital in Taiwan approved this study (CMUH-104-REC2-115-R3).
Study population
We identified patients aged ≥ 20 years with newly diagnosed T2DM (ICD-9-CM codes 250.x0 and 250.x2) from January 1, 2000, to December 31, 2010. The index date was defined as the date of the first T2DM diagnosis. We excluded patients with a history of non-proliferative DR (NPDR, ICD-9-CM 250.5, 362.01, 362.03–362.06 362.1, 362.81, and 362.82), proliferative DR (PDR, ICD-9-CM 362.02, and 379.23), pan-retinal photocoagulation (PRP) treatment, diabetic macular edema (DME, ICD-9-CM 362.53, 362.83, and 362.07), or intra-vitreous injection (IVI) treatment before T2DM diagnosis. Two groups were created: one comprised APAC users for T2DM patients on APAC therapy (clopidogrel, aspirin, warfarin, dipyridamole, or ticlopidine) for ≥ 28 days, and APAC nonusers for T2DM patients not on APAC therapy.
Outcomes, comorbidities, and medications
All patients were followed from the index date until diagnosis of NPDR, PDR, or DME; withdrawal from the insurance program; or December 31, 2011. Baseline comorbidities including hypertension, dyslipidemia, diabetic nephropathy, diabetic neuropathy, heart disease, cardiovascular disease, and peripheral arteriolar disease were identified. Use of medications such as statins, fibrates, and angiotensin-converting-enzyme inhibitors (ACEIs) was also recorded.
Statistical analysis
Differences in the continuous data of the APAC users and nonusers were tested using Student’s t test. Differences in categorical data were analyzed using the chi-square test. The cumulative incidence of NPDR was estimated and plotted for both groups using the Kaplan–Meier method, and the difference was assessed using the log-rank test. The incidence densities of NPDR, PDR, and DME for each group were calculated as the number of NPDR, PDR, and DME events divided by the total person-years. Because some patients may not have taken APAC regularly during the study period, the effect of the drug might be overestimated. Therefore, we considered APAC use as a time-dependent covariate in a Cox proportional hazards model to estimate the effect as HRs and corresponding 95% CIs. Factors significant in the univariate model were adjusted in a multivariate model, namely, age; sex; comorbidities of hypertension, dyslipidemia, diabetic nephropathy, diabetic neuropathy, heart disease, cardiovascular disease, and peripheral arteriolar disease; and medications such as statins and fibrates. We also examined the 5-year risks of PDR and DME after diagnosis of NPDR. All data management and analyses were performed using SAS 9.4 software (SAS Institute, Cary, NC, USA). The significance level was set at P < 0.05.
Results
Table 1 shows a comparison of the baseline characteristics of APAC users and nonusers. APAC users were older on average than nonusers. The proportions of men among the APAC users and nonusers were approximately 53.2% and 51%, respectively. Higher proportions of APAC users were patients with hypertension, dyslipidemia, diabetic nephropathy, diabetic neuropathy, heart disease, cardiovascular disease, and peripheral arteriolar disease and those on statins, fibrates, or ACEIs.
The cumulative incidence of NPDR was lower in APAC users than in nonusers (log-rank test P < 0.001; Fig. 1). The mean follow-up periods were 7.33 and 5.51 years for APAC users and nonusers, respectively (Table 2). The overall incidence of NPDR was lower in APAC users than in nonusers (10.7 vs. 14.4 per 1000 person-years). APAC users also exhibited a significantly lower risk of NPDR than did nonusers (adjusted HR [aHR] = 0.78, 95% CI = 0.73–0.83).
Table 3 reveals the contributions of various factors to the risk of NPDR as determined by univariate and multivariable Cox proportional hazards models using a time-dependent covariate. The aHR of NPDR increased 1.01-fold (95% CI = 1.01–1.02) for each 1-year age increase. The risk for developing NPDR was higher in patients comorbid with hypertension (aHR = 1.17, 95% CI = 1.09–1.24), diabetic nephropathy (aHR = 1.26, 95% CI = 1.17–1.36), or diabetic neuropathy (adjusted HR = 1.56, 95% CI = 1.34–1.81). The NPDR risk was lower in statin users than in nonusers, with an adjusted HR of 0.74 (95% CI = 0.70–0.78). We also followed up patients for 5 years after they diagnosed with NPDR to observe PDR or DME event occurrences (Table 4). However, PDR and DME risks were not significantly different between APAC users and nonusers. We performed sensitivity analysis to evaluate contributions of each APACs. In monotherapy, only aspirin and Dipyridamole showed significant protection from NDPR development (under Dipyridamole, aHR = 0.85, 95% CI 0.74–0.97, p < 0.05). Clopidogrel, Ticlopidine, Warfarin, and Dipyridamole prevented NDPR development in combination with aspirin (aspirin with Clopidogrel, aHR = 0.57, 95% CI 0.44–0.74, p < 0.001; aspirin with Ticlopidine, aHR = 0.59, 95% CI 0.39–0.90, p < 0.05; aspirin with Warfarin, aHR = 0.59, 95% CI 0.35–0.98, p < 0.05; aspirin with Dipyridamole, aHR = 0.61, 95%CI 0.51–0.73, p < 0.001) (Table 5).
Discussion
In our study, APAC users were older, had more comorbidities, experienced more additional diabetic vascular complications, and were more likely to be statin, fibrate, or ACEI users than were APAC nonusers. This result is in accordance with the ATT and ASCEND studies, which have demonstrated that APACs are prescribed to prevent stroke, acute myocardial infarction, and occlusive vascular diseases [9, 10, 24].
Our APAC users had a lower risk of developing NPDR (aHR = 0.78, 0.73–0.83, p < 0.001). Use of APACs prevented development of NPDR; however, the protective effects of APACs against PDR and DME were insignificant. Aspirin itself showed significant protective effect against NPDR. Protective effects were even more prominent when aspirin was in combination with other anticoagulants. Dipyridamole monotherapy also showed significant protection. Our results are similar to those of the DAMAD study, which prospectively recruited patients with earlier stages of DR. In the DAMAD study, aspirin alone and aspirin plus dipyridamole reduced microaneurysm formation yearly [20]. However, the dosage of aspirin and dipyridamole in the DAMAD study was two to three times higher than regular clinical prescriptions. In a 5-year animal study, aspirin significantly inhibited early stages of DR, including the development of retinal hemorrhages and acellular capillaries, but had limited effects on other pathological changes [25]. Conversely, the prospective MADIABETES study from Spain observed that the risk of DR increased 1.65 times with aspirin use, after adjustments for confounders [19]. The SEED study, after adjusting for covariates, demonstrated that aspirin use was significantly associated with vision-threatening DR; however, the association decreased after adjustments for other diabetic complications, including cardiovascular disease and chronic kidney disease [18]. The ETDRS, which included patients with mild to severe NPDR and PDR, found no significant effects of aspirin on DR development or progression [16]. Moreover, aspirin neither prevented visual loss nor increased hemorrhage rates in DR patients [26]. The dosage of aspirin in the ETDRS was higher than the typically prescribed dose. In study from Italy, aspirin was associated with higher hazard ratio of DR and PDR, but significance disappeared after adjustment with non-fatal major adverse cardiovascular events and diabetic kidney disease [27]. Ticlopidine slowed down microaneurysm progression in insulin-treated diabetic patients in a 3-year follow-up in TIMAD study [28]. In another Belgian study, there was a more favorable trend toward Ticlopidine group however insignificant, which might due to limited study number [29]. In our study, the effects from Clopidogrel, Ticlopidine, and Warfarin were insignificant when prescribed solely. However, the numbers of these APACs were much smaller compared with aspirin and Dipyridamole. Our results also demonstrated that APAC therapy neither increases nor reduces the risk of PDR or DME. However, the event number in our study of PDR or DME were limited and further investigations are needed to explore effects from APAC.
In our cohort, older age, hypertension, and diabetic microvascular angiopathies of nephropathy and neuropathy were associated with higher risks of NPDR; however, patients with cardiovascular disease or peripheral occlusive arteriolar disease had lower risks. The effect of age is inconsistent. Older age was a risk factor for DR in studies in South Korea and Saudi Arabia [30, 31]. In the United Kingdom Prospective Diabetic Study (UKPDS), older age was a risk factor for the progression but not for the incidence of DR [32]. The WESDR, however, reported younger age as a risk factor, [33] and the 10-year incidence of DR, progression of DR, and progression to PDR were the highest in the under-30 age group with diabetes [34]. The ETDRS also reported younger age as a risk factor for PDR and severe visual loss [35].
Associations between DR and diabetic neuropathy and diabetic nephropathy have been identified [35, 36]. Kotlarsky et al. observed that nephropathy preceded retinopathy in their study [37]. Another study indicated that hypertriglyceridemia may be a surrogate marker of DME [38]. The effects of fibrates and statins vary; however, the certainty of relevant evidence appeared low in a systemic review [39]. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) and its subsequent studies (ADVANCE-on), lower-extremity ulceration or amputation increased the risk of vision-threatening DR [40]. Klein et al. found significant associations between DR and coronary heart disease, stroke, and gross proteinuria [41]. Considerable coronary artery calcification in adults with chronic type 1 DM was associated with retinopathy [42]. Our study, however, showed that these macrovascular diseases were inversely related to the risk of DR. Several explanations are possible. First, positive correlations are more frequently reported than negative ones. Second, blood pressure and blood sugar are important controllable factors affecting DR development. Systemic factors may be strictly controlled after macrovascular complications. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), which focused on type 1 diabetes, the progression rate of DR in 25 years was 83%, in which higher glycosylated hemoglobin [HbA(1Â C)] level, and increase diastolic blood pressure were aggravating factors [43]. From UK database, which focused on type 2 DM, increase of HbA(1Â C) and systolic blood pressure increased the odds [44]. In UKPDS, incidence and progression were strongly associated with hyperglycemia [32].
Duration is another nonmodifiable but influential factor. In type 2 diabetes, retinopathy was concomitantly diagnosed with diabetes in about one-fifth of patients [32, 44]. The rate of development of DR increases when duration increases, and prevalence increases amongst patients with diabetes exceeding 10 years [45]. Our cohort comprised newly diagnosed type 2 diabetes from January 1st, 2000, to December 31st, 2010, and the follow-up duration was 12 years. The strength of our cohort in Taiwan has up to 99% of national health insurance coverage, which reflected the panorama. There are several limitations in our study. First, this is a retrospective study, and that data on clinical measurements, such as blood pressure and blood sugar control, could not be retrieved from the database. Second, patients of APAC use with more than 28 days were included. Compared with the long duration of follow-up to 12 years, it was a short period of treatment. Third, the dosage effect from different APACs was not analyzed in this study. Fourth, precise duration of hyperglycemia is hard to track in type 2 diabetes. Hyperglycemia is asymptomatic and lurks before complications develop. In our cohort, the patients were included at diagnosis of type 2 diabetes and tracked until DR development. This is compatible with the real-world clinical situations, and DR development increased when the duration increased as reflected in Fig. 1.
APACs show beneficial effects on NPDR development in diabetics. The effect of APAC on progression from NPDR to DME or PDR was not significant from our study. However, it is prudent to draw conclusion from our study since the number was too small. Further investigation is needed to explore the effect of APAC on development and progression to PDR and DME.
Conclusions
APAC medications have a protective effect against NPDR development. Diabetic patients benefit from single use of aspirin or dipyridamole on prevention of NPDR.
Availability of data and materials
All data and materials analyzed in this study are available at corresponding author.
Abbreviations
- APAC:
-
Antiplatelet/anticoagulant
- CI:
-
Confidence interval
- DM:
-
Diabetes mellitus
- DME:
-
Diabetic macular edema
- DR:
-
Diabetic retinopathy
- HR:
-
Hazard ratio
- LHID:
-
Longitudinal Health Insurance Database
- NHIRD:
-
National Health Insurance Research Database
- NPDR:
-
Non-proliferative diabetic retinopathy
- PDR:
-
Proliferative diabetic retinopathy
- T2DM:
-
Type 2 diabetes mellitus
References
Christensen NJ. Diabetic angiopathy and neuropathy. A review with special reference to circulation in the extremities, the effect of hypophysectomy on capillary resistance and capillary permeability, functional abnormalities in early diabetes. Acta Med Scand Suppl. 1972;541:3–60.
Sena CM, Pereira AM, Seica R. Endothelial dysfunction - a major mediator of diabetic vascular disease. Biochim Biophys Acta. 2013;1832(12):2216–31.
Stegenga ME, van der Crabben SN, Levi M, de Vos AF, Tanck MW, Sauerwein HP, van der Poll T. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes. 2006;55(6):1807–12.
Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K. Mechanisms of diabetic vasculopathy: an overview. Am J Hypertens. 2001;14(5 Pt 1):475–86.
Calles-Escandon J, Garcia-Rubi E, Mirza S, Mortensen A. Type 2 diabetes: one disease, multiple cardiovascular risk factors. Coron Artery Dis. 1999;10(1):23–30.
Mazze RS, Sinnock P, Deeb L, Brimberry JL. An epidemiological model for diabetes mellitus in the United States: five major complications. Diabetes Res Clin Pract. 1985;1(3):185–91.
Sacco RL. Risk factors and outcomes for ischemic stroke. Neurology. 1995;45(2 Suppl 1):10–4.
Rocca B, Patrono C. Aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: A new perspective. Diabetes Res Clin Pract. 2020;160:108008.
Antithrombotic Trialists C, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–60.
Group ASC, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med. 2018;379(16):1529–39.
Lahey JM, Tunc M, Kearney J, Modlinski B, Koo H, Johnson RN, Tanaka S. Laboratory evaluation of hypercoagulable states in patients with central retinal vein occlusion who are less than 56 years of age. Ophthalmology. 2002;109(1):126–31.
Colwell JA, Nair RM, Halushka PV, Rogers C, Whetsell A, Sagel J. Platelet adhesion and aggregation in diabetes mellitus. Metabolism. 1979;28(4 Suppl 1):394–400.
Yamashiro K, Tsujikawa A, Ishida S, Usui T, Kaji Y, Honda Y, Ogura Y, Adamis AP. Platelets accumulate in the diabetic retinal vasculature following endothelial death and suppress blood-retinal barrier breakdown. Am J Pathol. 2003;163(1):253–9.
Schachat AP. Can aspirin be used safely for patients with proliferative diabetic retinopathy? Arch Ophthalmol. 1992;110(2):180.
Bergerhoff K, Clar C, Richter B. Aspirin in diabetic retinopathy. A systematic review. Endocrinol Metab Clin North Am. 2002;31(3):779–93.
Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991, 98(5 Suppl):757–765.
Chew EY, Klein ML, Murphy RP, Remaley NA, Ferris FL 3rd. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report no. 20. Arch Ophthalmol. 1995;113(1):52–5.
Shi Y, Tham YC, Cheung N, Chua J, Tan G, Mitchell P, Wang JJ, Cheung YB, Cheng CY, Wong TY. Is aspirin associated with diabetic retinopathy? The Singapore Epidemiology of Eye Disease (SEED) study. PLoS ONE. 2017;12(4):e0175966.
Salinero-Fort MA, San Andres-Rebollo FJ, de Burgos-Lunar C, Arrieta-Blanco FJ, Gomez-Campelo P, Group M. Four-year incidence of diabetic retinopathy in a Spanish cohort: the MADIABETES study. PLoS ONE. 2013;8(10):e76417.
Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. The DAMAD Study Group. Diabetes 1989, 38(4):491–498.
Wu TY, Majeed A, Kuo KN. An overview of the healthcare system in Taiwan. Lond J Prim Care (Abingdon). 2010;3(2):115–9.
Lin SY, Chen DC, Lin CL, Lee HC, Lin TC, Wang IK, Hsu CY, Kao CH. Risk of acute coronary syndrome in patients with cervical spondylosis. Atherosclerosis. 2018;271:136–41.
Lee YR, Tien NI, Lin CL, Shen HY, Bau DT, Lim YP. Association of antituberculosis treatment and lower risk of hyperlipidemia in Taiwanese patients: a population-based case-control study. In Vivo. 2018;32(1):47–54.
Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71–86.
Kern TS, Engerman RL. Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes. 2001;50(7):1636–42.
Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA 1992, 268(10):1292–1300.
Pafundi PC, Galiero R, Caturano A, Acierno C, de Sio C, Vetrano E, Nevola R, Gelso A, Bono V, Costagliola C, et al. Aspirin in a diabetic retinopathy setting: Insights from NO BLIND study. Nutr Metab Cardiovasc Dis. 2020;30(10):1806–12.
Ticlopidine treatment reduces the progression of nonproliferative diabetic retinopathy. The TIMAD Study Group. Arch Ophthalmol 1990, 108(11):1577–1583.
Clinical study of ticlopidine in diabetic retinopathy. Belgian Ticlopidine Retinopathy Study Group (BTRS). Ophthalmologica 1992, 204(1):4–12.
Magliah SF, Bardisi W, Al Attah M, Khorsheed MM. The prevalence and risk factors of diabetic retinopathy in selected primary care centers during the 3-year screening intervals. J Family Med Prim Care. 2018;7(5):975–81.
Yun JS, Lim TS, Cha SA, Ahn YB, Song KH, Choi JA, Kwon J, Jee D, Cho YK, Park YM, et al. Clinical Course and Risk Factors of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus in Korea. Diabetes Metab J. 2016;40(6):482–93.
Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, Manley SE, Matthews DR. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia. 2001;44(2):156–63.
Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102(4):527–32.
Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol. 1994;112(9):1217–28.
Davis MD, Fisher MR, Gangnon RE, Barton F, Aiello LM, Chew EY, Ferris FL 3rd, Knatterud GL. Riskfactors for high-risk proliferative diabetic retinopathy and severe visualloss: Early Treatment Diabetic Retinopathy Study Report #18. Invest Ophthalmol Vis Sci. 1998;39(2):233–52.
Yin L, Zhang D, Ren Q, Su X, Sun Z. Prevalence and risk factors of diabetic retinopathy in diabetic patients: A community based cross-sectional study. Med (Baltim). 2020;99(9):e19236.
Kotlarsky P, Bolotin A, Dorfman K, Knyazer B, Lifshitz T, Levy J. Link between retinopathy and nephropathy caused by complications of diabetes mellitus type 2. Int Ophthalmol. 2015;35(1):59–66.
Chung YR, Park SW, Choi SY, Kim SW, Moon KY, Kim JH, Lee K. Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovasc Diabetol. 2017;16(1):4.
Mozetic V, Pacheco RL, Latorraca COC, Riera R. Statins and/or fibrates for diabetic retinopathy: a systematic review and meta-analysis. Diabetol Metab Syndr. 2019;11:92.
Mohammedi K, Woodward M, Hirakawa Y, Zoungas S, Colagiuri S, Hamet P, Harrap S, Poulter N, Matthews DR, Marre M, et al. Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study. Cardiovasc Diabetol. 2016;15(1):129.
Klein R, Marino EK, Kuller LH, Polak JF, Tracy RP, Gottdiener JS, Burke GL, Hubbard LD, Boineau R. The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. Br J Ophthalmol. 2002;86(1):84–90.
Lovshin JA, Bjornstad P, Lovblom LE, Bai JW, Lytvyn Y, Boulet G, Farooqi MA, Santiago S, Orszag A, Scarr D, et al. Atherosclerosis and Microvascular Complications: Results From the Canadian Study of Longevity in Type 1 Diabetes. Diabetes Care. 2018;41(12):2570–8.
Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology. 2008;115(11):1859–68.
Kostev K, Rathmann W. Diabetic retinopathy at diagnosis of type 2 diabetes in the UK: a database analysis. Diabetologia. 2013;56(1):109–11.
Voigt M, Schmidt S, Lehmann T, Kohler B, Kloos C, Voigt UA, Meller D, Wolf G, Muller UA, Muller N. 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):570–6.
Tsai FJ, Junod V. Medical research using governments’ health claims databases: with or without patients’ consent? J Public Health (Oxf). 2018;40(4):871–7.
Acknowledgements
Not applicable.
Funding
This study was supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW110-TDU-B-212-124004), China Medical University Hospital (DMR-111-105). The funders had no role in the study design, data collection and analysis, the decision to publish, or preparation of the manuscript. No additional external funding was received for this study.
Author information
Authors and Affiliations
Contributions
CJJ, IJW, YTH, and CLL participated in the study design. CLL performed statistical analysis. YTH interpreted the data. Literature review was performed by CJJ and IJW. All authors are approval of the final version of the manuscript.
Corresponding authors
Ethics declarations
Ethics approval and consent to participate
The study is approved by Ethics Review Board of China Medical University and Hospital in Taiwan (IRB permit number: CMUH-104-REC2-115-R3). The National Health Research Institute de-identified the study participants before NHIRD release for public research. Therefore, the Institutional Review Board waived the requirement for patient written informed consent for this study [46].
Consent for publication
Not applicable since the database has been de-identification and de-linked.
Competing interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Additional file 1: Table S1
. Studies of APAC use.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Jeng, CJ., Hsieh, YT., Lin, CL. et al. Effect of anticoagulant/antiplatelet therapy on the development and progression of diabetic retinopathy. BMC Ophthalmol 22, 127 (2022). https://doi.org/10.1186/s12886-022-02323-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12886-022-02323-z