Table 1.
Characteristics of the studies included in the meta-analysis.
| Study (year) | Country | Study design | Follow-up period, years | Sample size (% males) | Age, years | Diabetes type | DR identification | Stroke identification | Stroke type | Event (n) | Main findings reported in original studies: OR/RR/HR (95% CIs) | Adjustment factors | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cheung (2006) | Australia | Prospective cohort | Mean ± SD: 7.8 ± 1.9 | 1,546 (47.0) | Range: 45–64 | Both | Fundus photograph and ETDRS adaptation of the modified Airlie House Classification | Medical records | Ischemic stroke | Non-fatal stroke (75) | HR | Any DR: 2.34 (1.13–4.86); severe NPDR: 1.81 (0.57–6.4); retinal hemorrhages or microaneurysms: 1.33 (0.45–2.21); hard exudates: 1.45 (0.61–3.43); cotton wool spots: 2.10 (0.90–4.91) | Age, sex, race, and examination center, 6-year mean arterial blood pressure, use of antihypertensive treatment, fasting glucose, use of insulin, duration of diabetes, high-density lipoprotein and low-density lipoprotein cholesterol, and cigarette smoking status |
| Fuller (2001) | UK | Prospective cohort | 12 | 4,743 (48.9) | Range: 35–53 | Both | Fundus photograph and self-defined classification$ | Self-reported diagnosis history/medical records /death certificate | NR | Fatal or non-fatal stroke (293) | RR | T1DM: 1.4 (0.62–2.18); T2DM: 2.25 (1.61–2.89) | Age |
| Landers (2018) | Australia | Prospective cohort | Median: 8.7 | 1,257 (37.9) | Range: ≥40 | Both | Slit-lamp fundoscopy and ETDRS adaptation of the modified Airlie House Classification | Medical records | NR | Fatal stroke (NR) | HR | 5.81 (1.21–27.88) | Age, sex, and presence of systemic hypertension |
| Drinkwater (2020) | Australia | Prospective cohort | Mean ± SD: 6.6 ± 1.8 | 1,473 (51.9) | NR | T2DM | Fundus photograph and ETDRS adaptation of the modified Airlie House Classification | Medical records/death certificate/autopsy findings | Ischemic/ hemorrhagic/ unspecified stroke |
Fatal or non-fatal stroke (53) | HR | Any stroke: 2.19 (0.79–6.07); ischemic stroke: 1.13 (0.49–2.63); hemorrhagic stroke: 0.36 (0.08–1.68); moderate NPDR or worse vs. mild or no NPDR: 2.55 (1.19–5.47) | Age, sex, duration of diabetes, diabetes treatment, blood pressure, HbA1c, BMI, urinary albumin:creatinine ratio, lipids, smoking status, atrial fibrillation, macroalbuminuria |
| Kawasaki (2013) | Japan | Prospective cohort | 8 | 1,620 (53.7) | Mean ± SD: 58.3 ± 7.0 | T2DM | Ophthalmoscopic examination and slit-lamp biomicroscopic fundus examination/ fundus photography/ fluorescein angiography and international clinical diabetic retinopathy severity scales |
Death certificates/ medical records/ self-reported diagnosis history |
Ischemic/ hemorrhagic/ unspecified stroke/ TIA |
Fatal or non-fatal stroke (76) | HR | Any DR: 1.69 (1.03–2.8); moderate NPDR: 2.15 (0.75–6.21); retinal hemorrhages or microaneurysms: 1.63 (0.97–2.73); hard exudates: 1.76 (0.62–4.97); cotton wool spots: 2.39 (1.35–4.24) | Age, sex, hemoglobin A1c, duration of diabetes, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, log triglycerides, log albumin-to-creatinine ratio, and smoking |
| Klein (2004) | USA | Prospective cohort | 20 | 996 (46.8) | NR | T1DM | Fundus photograph and ETDRS adaptation of the modified Airlie House Classification | Self-reported diagnosis history/medical records | NR | Non-fatal stroke (55) | OR | 1.60 (1.10–2.30) | Age, sex, glycosylated hemoglobin, hypertension, neuropathy, daily aspirin, ocular factors |
| Klein (1999) | USA | Prospective cohort | Median: 16 | 1,370 (46.4) | NR | Both | Fundus photograph and ETDRS adaptation of the modified Airlie House Classification | Death certificate | NR | Fatal stroke (175) | HR | PDR: 1.88 (1.03–3.43) | Age, sex, glycosylated hemoglobin, hypertension, urine protein, history of cardiovascular disease |
| Chou (2016) | China | Retrospective cohort* | 12 | 37,816 (49.0) | NR | Botha | Medical records | Medical records | Ischemic stroke | Non-fatal stroke (4,698) | HR | 1.114 (0.888–1.23) | Age, sex, hypertension, heart failure, previous stroke/TIA, previous vascular diseases, end-stage renal disease, COPD, malignancy, autoimmune disorders, liver cirrhosis, sleep apnea, sulfonylureas, meglitinide, metformin, AGI, insulin, ARB, ACEI, thiazides, calcium channel blockers, statins, beta blocker |
| Petitti (1995) | USA | Retrospective nested case–control | 12 | 2,124 (52.0) | Mean: 67 | Both | Medical records | Medical records | Ischemic stroke (non-embolic) | Non-fatal stroke (52) | RR | 4 (1–14.5) | Age, sex, smoking, insulin, average systolic blood pressure, average random glucose, any other complication |
| Seferovic (2018) | USA | RCT | Range: 0.83–3.91 | 6,068 (69.3) | Mean ± SD: 60.3 ± 9.7 | T2DMb | Self-reported diagnosis history | Clinical diagnosis | Ischemic/ hemorrhagic/ unspecified stroke |
Non-fatal stroke (127) | HR | 1.28 (0.075–2.19) | Age, sex, race, BMI, baseline HbA1c, smoking, history of hypertension, heart rate, total cholesterol, low-density lipoprotein cholesterol, and triglycerides, neuropathy, T2DM duration, and randomized study treatment |
| Gerstein (2013) | Canada | RCT | Mean: 4 | 2,856 (61.8) | NR | T2DM | Fundus photographs and modified version of the ETDRS Final Diabetic Retinopathy Severity Scale | Clinical diagnosis/autopsy | Ischemic/ hemorrhagic stroke |
Fatal or non-fatal stroke (32) | HR | Any DR: 1.34 (0.78–2.3); severe NPDR: 2.05 (0.88–4.8) | The clinical center network, cardiovascular event prior to randomization (i.e., secondary prevention), blood pressure trial, intensive glycemia group, intensive blood pressure group, and fibrate group |
| Hitman (2007) | UK | RCT | Median: 3.9 | 2,778 (69.3) | Range: 40–75 | T2DM | Medical records/ self-reported any retinopathy, maculopathy or previous photocoagulation |
Clinical diagnosis/autopsy | Ischemic/ hemorrhagic/ unspecified stroke |
Fatal or non-fatal stroke (NR) | HR | 1.72 (1.03–2.87) | Unadjusted |
| Hankey (2013) | Australia | RCT | Median: 5 | 9,795 (62.6) | Range: 50–75 | T2DM | Self-reported diagnosis history | clinical diagnosis | Ischemic/ hemorrhagic/ unspecified stroke |
Non-fatal stroke (333) | HR | Small artery ischemic stroke: 1.82 (1.08–3.07); large artery ischemic stroke (negative results not reported) |
Randomized study treatment |
| Hjelmgren (2019) | Sweden | Retros -pective cohort |
Median: 3, IQR: 1–5 | 445 (64.7) | Range: ≥40 | T2DMc | Fundus photograph and medical records (fundus photograph show signs of DR) | Medical records/ death certificate |
Ischemic stroke | Fatal or non-fatal stroke (62) | HR | 0.89 (0.51–1.53) | Age, coronary heart disease, heart failure, periphery artery disease and creatinine |
| Su (2017) | China | Retros -pective cohort* |
Median: 5.21 | 755 (NR) | Range: ≥20 | Both | Medical records | Medical records | Ischemic/ hemorrhagic stroke |
Non-fatal stroke (NR) | HR | 1.69 (1.05–2.72) | Neovascular glaucoma, age, sex, medical comorbidity, ocular comorbidity |
| Protopsaltis (2007) | Greece | Prospective cohort | Median: 10.1, IQR: 8.2–13.4 | 599 (45.7) | Mean ± SD: 60.4 ± 9.6 | T2DM | NR | Medical records/ self-reported disease history |
Ischemic stroke (non-embolic) | Non-fatal stroke (78) | HR | 1.297 (0.816–1.61) | Age, gender, smoking, BMI, HbA1c, lipids, and diabetes duration |
| Bello (2014) | USA | RCT | Mean: 2.4 | 4,038 (42.7) | NR | T2DMd | Self-reported diagnosis history | Clinical diagnosis | Ischemic/ hemorrhagic/ unspecified stroke |
Fatal stroke (NR) | HR | 0.96 (0.7–1.32) | Unadjusted |
| Cohen (2003) | USA | RCT | Mean: 5.3 | 950 (60.9) | Range: 40–74 | T2DM | Fundus photograph and ETDRS adaptation of the modified Airlie House Classification | Clinical diagnosis | NR | Fatal or non-fatal stroke (41) | RRf | 2.16 (1.1–4.28) | Unadjusted |
| Ono (2002) | Japan | Prospective cohort | Mean ± SD: 11.6 ± 4.9 | 223 (77.1) | NR | T2DMe | Ophthalmologic records including ophthalmologic charts, fundus photography, and fluorescein retinal angiography and modification of the Diabetic Retinopathy Study and the ETDRS | Medical records/self-reported diagnosis history | NR | Fatal stroke (9) | RRf | 2.28 (0.63–8.24) | Unadjusted |
USA, the United States of America; UK, the United Kingdom; RCT, randomized controlled trial; NR, no report; SD, standard deviation; T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus; TIA, transient ischemic attack; ETDRS, Early Treatment Diabetic Retinopathy Study; DR, diabetic retinopathy; PDR, proliferative diabetic retinopathy; NPDR, non-proliferative diabetic retinopathy; HR, hazard ratio; RR, risk ratio; OR, odds ratio; HbA1c, hemoglobin A1c; BMI, body mass index; COPD, chronic obstructive pulmonary disease; AGI, alpha-glucosidase inhibitors; ARB, angiotensin II receptor blockers; ACEI, angiotensin-converting enzyme inhibitors.
$
NPDR: one or more microaneurysms or hemorrhages with and without soft or hard exudates; PDR: definite retinal neovascularization, vitreous hemorrhages, or history of photocoagulation treatment; any retinopathy: either NPDR or PDR.
*
Data originated from a national database.
a
Diabetes patients with atrial fibrillation.
b
Diabetes patients with acute coronary syndrome.
c
Diabetes patients all suffered their first stroke or TIA.
d
Diabetes patients with chronic kidney disease and moderate anemia.
e
Diabetes patients with multivessel coronary artery disease following coronary artery bypass graft surgery.
f
Calculated from raw data.