{
  "abstract": "Introduction This study investigated the incidence of diabetic retinopathy (DR) and sight-threatening DR (STDR) through 2021 in patients diagnosed with type 2 diabetes (T2DM) in 1996–2004. The study also investigated risk factors associated with DR.Research design and methods The cohort comprised patients in the Swedish Skaraborg Diabetes Register in 1996–2004 who were ≤70 years at T2DM diagnosis and without DR at first-eye examination. Clinical data at diagnosis included age, smoking habits, body mass index, blood pressure, HbA1c, high-density lipoprotein cholesterol, triglycerides, c-peptide and antihypertensive drugs as a proxy for hypertension. The level of DR at first eye examination after diagnosis through 31 December 2021 was extracted from medical records at the Department of Ophthalmology, Skaraborg Hospital. The cumulative incidence of DR was estimated by the Kaplan-Meier method, and multivariate Cox regression models were used to estimate the risk of DR.Results The study included 2267 patients; over the course of 24 years of follow-up (mean 12.8±5.8 years), 926 developed DR and 101 developed STDR. The cumulative incidence after 10 and 20 years was 29.0% and 67.6% for DR and 1.4% and 11.4% for STDR. Higher HbA1c (HR 1.02 per 1 mmol/mol, 95% CI 1.01 to 1.02) and antihypertensive treatment at diagnosis (HR 1.26, 95% CI 1.08 to 1.47) were associated with increased risk of DR. Higher age (HR 0.98 per year, 95% CI 0.97 to 0.98) and diagnosis in 1999–2004 versus 1996–1998 (HR 0.58, 95% CI 0.51 to 0.66) were associated with a lower risk of DR.Conclusion During follow-up, 926 patients developed DR, whereas 101 developed STDR. Higher HbA1c and antihypertensive treatment were associated with a higher risk of developing DR and STDR, while higher age at diagnosis and diagnosis in 1999–2004 versus 1996–1998 were associated with lower risk.",
  "authors": [
    {
      "affiliations": [
        "Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden",
        "Department of Ophthalmology, Skaraborg Hospital, Skövde, Sweden",
        "Research, Education, Development and Innovation Department, Skaraborg Hospital, Region Västra Götaland, Skövde, Sweden"
      ],
      "name": "Grete Garberg"
    },
    {
      "affiliations": [
        "General Practice/Family Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden",
        "Regionhälsan R&D Centre, Skaraborg Primary Care, Skövde, Sweden"
      ],
      "name": "Kristina Bengtsson Boström"
    },
    {
      "affiliations": [
        "General Practice/Family Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden",
        "Regionhälsan R&D Centre, Skaraborg Primary Care, Skövde, Sweden"
      ],
      "name": "Per Hjerpe"
    },
    {
      "affiliations": [
        "Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden",
        "Research, Education, Development and Innovation Department, Skaraborg Hospital, Region Västra Götaland, Skövde, Sweden",
        "Department of Ophthalmology, Mölndal Sahlgrenska University Hospital, Mölndal, Sweden"
      ],
      "name": "Marcelo Ayala"
    },
    {
      "affiliations": [
        "Department of Ophthalmology, Lund University Hospital, University of Lund, Lund, Sweden"
      ],
      "name": "Monica Lövestam Adrian"
    },
    {
      "affiliations": [
        "General Practice/Family Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden",
        "Regionhälsan R&D Centre, Skaraborg Primary Care, Skövde, Sweden"
      ],
      "name": "Tobias Andersson"
    }
  ],
  "full_text": "WHAT IS ALREADY KNOWN ON THIS TOPIC Type 2 diabetes mellitus (T2DM) is increasing worldwide and can lead to macrovascular and microvascular complications. Diabetic retinopathy is one of the more important microvascular complications and is associated with diabetes duration and risk factor control.Long-term follow-up studies of diabetic retinopathy in T2DM are scarce.WHAT THIS STUDY ADDS In this cohort study with up to 24 years of follow-up of patients diagnosed with T2DM in 1996–2004, many patients developed diabetic retinopathy.Few patients developed sight-threatening diabetic retinopathy.High HbA1c and the need for antihypertensive treatment were important risk factors for diabetic retinopathy, whereas older age and diagnosis in the latter part of the study were associated with a lower risk of diabetic retinopathy.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY The study underscores the importance of closely monitoring young patients with T2DM to decrease the risk of sight-threatening diabetic retinopathy.Introduction Diabetes mellitus is a common chronic disease worldwide. 1 According to the IDF (International Diabetes Federation) Diabetes Atlas more than 500 million people (about 6% of the world population) are currently living with diabetes.2 In 1999, the WHO changed the diagnostic criteria for diabetes to use lower blood glucose levels,3 which increased the number of people diagnosed with the condition. The prevalence of diabetes varies greatly worldwide. In Sweden, it increased from around 4% in 2005–2006 to 5% in 2012–2013, and 85%–90% have type 2 diabetes mellitus (T2DM).4 T2DM can lead to macrovascular complications (eg, cerebrovascular and coronary heart disease) and microvascular complications (eg, nephropathy, neuropathy and retinopathy),5 but multifactorial control of cardiovascular risk factors reduces the rate of complications.6 7Screening for diabetic retinopathy (DR) is considered cost-effective, as DR can be advanced and even sight-threatening without symptoms.8 T2DM can remain undiagnosed for several years, and DR is, therefore, sometimes present at diagnosis.9 10 In a study in Great Britain, 27% of patients with recently diagnosed diabetes had DR, and as many as 6% had sight-threatening DR (STDR), in that study defined as severe preproliferative retinopathy.10Several studies show an association between DR and risk factors such as hyperglycemia and hypertension.11 12 Furthermore, human experimental studies indicate an association between smoking and retinal blood flow,13 14 and an association between smoking and DR has been seen in type 1 diabetes,15 but the association between smoking and DR in observational studies varies between increased,16 neutral17 and decreased risk of DR in patients with T2DM.12 15DR prevalence in predominantly T2DM varies worldwide from 20% to 30% according to a meta-analysis using 42 studies from seven regions in the International Diabetes Federation Atlas.2 There have been few follow-up studies on the incidence of DR in patients with T2DM and a substantial variation in outcome. For instance, recent studies from primary care in Spain showed that 4.7% were diagnosed with DR during a median of 7-year follow-up,18 while in England, 26.5% were diagnosed with DR after 10 years.19In a previous Swedish study, we investigated the incidence of DR over 10 years of follow-up in patients from the Skaraborg Diabetes Register (SDR) who were diagnosed with T2DM between 1996 and 1998.20 A great proportion of the patients had DR, but very few had STDR, defined as clinically significant maculopathy (CSM) and/or proliferative diabetic retinopathy (PDR).In the present study, we investigated the incidence of DR and STDR through 2021 in patients diagnosed with T2DM in 1996–2004. We also investigated factors associated with development of DR and whether the incidence of DR differed according to the time of diagnosis.Research design and methods The SDR was established in 1991, was active through 2004 and includes clinical data on patients with type 1 and type 2 diabetes. In 1992–1994, it covered 88.4% of patients with prevalent diabetes mellitus in the former Skaraborg County, Sweden. 21 For this study, data were retrieved from the SDR on patients ≤70 years at diagnosis of T2DM from 1 January 1996, through 31 December 2004. This age was chosen for the whole cohort as screening was confined to patients ≤70 years at diabetes diagnosis in the first years of the study. The data included information on sex, date of diagnosis, age at diagnosis, smoking habits, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), HbA1c, triglycerides, high-density lipoprotein (HDL), c-peptide and prescription of antihypertensive treatment. Data were registered in a standardized way for use in SDR.22 Registered nurses, specialized in diabetes care, were sampling data including sex, date of diagnosis and age at diagnosis. Smoking status was self-reported and antihypertensive medication (yes/no) was retrieved from SDR. Blood pressure was measured in the right arm in supine position three times after 5–15 min rest, body height and weight (light clothing).23 Blood samples were retrieved and analyzed by accredited laboratories (Swedac, ISO 17025, Borås, Sweden).According to recommendations based on the Swedish National Board of Health and Welfare patients with diabetes were invited to screening every second or third year depending on blood pressure and HbA1c levels. Otherwise, the intervals were individualized for instance patients with DR were examined more often dependent on severity or progress of DR.From medical records at the Department of Ophthalmology, Skaraborg Hospital, we extracted patients’ data regarding screening for DR by retinal two-field photographs or ophthalmological examination from diagnosis (1996–2004) through 31 December 2021. The eye examinations included two-field colored slides or electronic red-free photos. Some early examinations were purely clinical by bio-microscopy. According to recommendations based on the Swedish National Board of Health and Welfare, patients without DR were screened every second or third year depending on blood pressure and HbA1c levels. Patients with DR were examined more often dependent on severity or progress of DR. All eye examinations were performed at the Department of Ophthalmology, Skaraborg Hospital (except for May–December 2021 when there was an external screening option for some patients). Assessment of the photos was carried out by trained ophthalmologists or nurses in a standardized manner. The level of DR was defined according to the International Clinical Diabetic Retinopathy Disease Severity Scale24 through the whole study period, modified for CSM. A scale score of 0 indicated no DR, 1–3 indicated mild, moderate and severe non-proliferative DR and 4 indicated PDR. PDR was defined as proliferation on the retina or at the optic disc. CSM was classified separately as (para-)foveal edema or hard exudates, according to the ETDRS,25 or central edema ≥400 μm on optical coherence tomography (OCT). PDR and/or CSM are indications for treatment by laser and/or intravitreal injections and are denoted as STDR in this study. Diagnosis of PDR and/or CSM was verified by clinical examination and OCT. The diagnoses PDR, CSM and STDR were maintained throughout the study, even if PDR or CSM regressed after treatment.Ultimately, patients with no DR at the first examination after T2DM diagnosis were included in the study. We registered the date of the first sign of the study outcomes, DR and STDR in the worst eye.The study used register data and involved no direct contact with the patients, who had approved their original registration in the SDR. The study and a later amendment were approved by the Regional Ethics Committee, Gothenburg (registration number 208–06, 17 May 2006) and by the Swedish Ethical Review Authority (registration number 2021–04768, 14 October 2021), respectively.Statistical analyses Statistical analyses were conducted on patients without DR at first examination. Mean±SD was used for descriptive statistics at baseline and last examination. Fisher’s exact test was used to compare categorical variables, and an independent samples t-test was used to compare continuous variables. The cumulative incidences of the study outcomes, DR and STDR, were plotted using the Kaplan-Meier method. Follow-up time during the study was defined as time from the first ophthalmologic examination (retinal photo or clinical examination) to the first of the following events: study outcome, last ophthalmologic examination or end of study (31 December 2021). Cox regression models were fitted to estimate HRs with 95% CIs for the association between exposure variables and the outcome. The exposure variables at diagnosis were calendar year of diagnosis (continuous and dichotomized into the periods 1996–1998 and 1999–2004 corresponding to the change in diagnostic criteria by the WHO in 1999), sex, age, BMI, SBP, DBP, HbA1c, triglycerides, HDL, c-peptide, anti-hypertensive medication and current smoking.In a first Cox regression model, we estimated the bivariate association between the exposure variable and the outcome. In a second model, the estimate was adjusted for age and sex. In a third model, the estimate was additionally adjusted for other baseline variables acting as confounders. Confounder selection followed the modified disjunctive cause criterion, a structured approach that includes all baseline variables that are causes of the exposure, the outcome or both, while avoiding variables that are only instrumental or lie on the causal pathway (mediators).26 This approach reduces bias from inappropriate adjustment, but the analyses remain associational. The covariate selection is presented in online supplemental table S1. In a fourth model, the estimates were mutually adjusted for all other baseline variables. C-peptide was not adjusted for in models 3 or 4 due to a large degree of missing data. Thereafter, Kaplan-Meier curves were stratified and plotted for the significant variables in model 3. Differences between strata were tested using the log-rank test. For CSM, PDR and STDR, we adjusted only for sex and age at diagnosis in the Cox regression model due to the low number of events. All Cox regression models were estimated using complete cases. The statistical analyses were performed using SPSS V.28.0.1.1, and the level of significance was established as p<0.05.SP110.1136/bmjdrc-2025-005356.supp1Supplementary dataResults A total of 3467 patients ≤70 years of age at diagnosis were registered with T2DM in the SDR from 1996 through 2004. Of those, 2539 patients had conclusive data. At their first eye examination, 272 patients had developed DR (of whom 45 (16.5%) had STDR), whereas 2267 were without DR and were included in the study (see flowchart in figure 1).Figure 1Flowchart diagram showing the study’s inclusion of patients in the Skaraborg Diabetes Register (SDR) with type 2 diabetes mellitus, ≤70 years old at diagnosis from 1 January 1996, through 31 December 2004. DR, diabetic retinopathy; T2DM, type 2 diabetes mellitus.Study population characteristics at diagnosis of type 2 diabetes Table 1 presents by sex, age at diagnosis and time periods of diagnosis the baseline data at time of T2DM diagnosis for patients without DR at their first eye examination. In total, 43.4% were women, the mean age at diagnosis was 56.0±9.5 (range 57.0 years) and 35.2% of patients were diagnosed with T2DM in 1996–1998. Compared with men, women had lower HbA1c (54.8±15.5 vs 57.2±18.6 mmol/mol, respectively, p=0.002). Younger patients (age below the mean at diagnosis) had higher HbA1c (57.2±17.8 vs 55.2±16.9 mmol/mol, p=0.01) and were more often on antihypertensive treatment (33.9% vs 28.7%, p=0.01). Compared to those diagnosed in 1999–2004, patients diagnosed in 1996–1998 generally had more cardiovascular risk factors, with numerically higher HbA1c, BMI, SBP, DBP, triglycerides, proportion of antihypertensive treatment and current smoking.Table 1Baseline characteristics of patients in the Skaraborg Diabetes Register with no diabetic retinopathy at their first eye examination, grouped by sex, age below or above mean age at diagnosis of T2DM and period of T2DM diagnosis (1996–1998 vs 1999–2004)Baseline variablesn=number with dataAllSexAge at T2DM diagnosis below or above mean (56.0 years)Time period of T2DM diagnosisWomenMenBelowAbove1996–19981999–2004Number of patients (%)2267984 (43.4)1283 (56.6)1033 (45.6)1234 (54.4)799 (35.2)1468 (64.8)Age at T2DM diagnosis n=226756.0±9.556.3±10.055.9±9.147.8±7.263.0±4.155.6±9.656.1±9.4HbA1c, mmol/moln=2070 (missing 9%)56.1±17.354.8±15.557.2±18.657.2±17.855.2±16.957.4±16.855.4±17.6BMI, kg/m2n=2012 (missing 11%)31.0±5.631.8±6.130.2±5.031.9±6.130.1±4.931.1±5.730.8±5.5SBP, mm Hgn=2066 (missing 9%)140.1±18.4143.0±19.0139.4±17.8136.0±17.1145.1±18.4142.4±8.5140.1±18.3DBP, mm Hgn=2065 (missing 9%)81.1±9.680.3±9.981.6±9.481.6±9.680.7±9.682.1±9.380.4±9.8Triglycerides, mmol/Ln=1753 (missing 23%)2.2±1.72.1±1.32.3±2.02.4±2.02.0±1.42.4±2.22.1±1.4HDL, mmol/Ln=1691 (missing 25%)1.3±1.21.3±0.41.2±0.41.2±0.51.3±0.41.3±0.381.3±0.44c-peptide, nmol/Ln=408 (missing 82%)0.96±0.490.99±0.500.93±0.490.95±0.480.97±0.510.95±0.481.45±0.82a-HTT, yesn=2263 (missing 0.2%)703 (31.1)287 (29.2)416 (32.5)348 (33.9)355 (28.7)280 (31.5)423 (28.9)Current smoking, yesn=1917 (missing 15%)459 (23.9)191 (22.8)268 (24.8)273 (31.0)186 (18.0)178 (26.6)281 (22.5)Data are presented as mean±SD and number (%).a-HTT, antihypertensive treatment; BMI, body mass index; DBP, diastolic blood pressure; HbA1c, glycated haemoglobin A1c; HDL, high density lipoprotein; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus.Development of diabetic retinopathy In patients without DR at the first eye examination, the mean time from diagnosis of T2DM to the first eye examination was 3.7±3.4 years. Diagnosis in 1996–1998 was associated with a longer time to first examination compared with diagnosis in 1999–2004 (4.8±3.5 vs 3.1±3.2 years, respectively, p<0.001). Similarly, older patients (age above mean at diagnosis) had a longer time to first examination than younger patients (3.9±3.5 vs 3.4±3.2 years, respectively, p=0.002) ( online supplemental table S2). The mean follow-up time from first to last eye examination was 12.8±5.8 years. Patients who were younger at diagnosis (age below the mean) had a longer follow-up than older patients (14.5±5.3 vs 11.4±5.9 years, respectively, p<0.001).There was no difference in crude proportions of women and men developing DR, CSM, PDR or STDR (online supplemental table S2). A greater proportion of patients aged below the mean at diagnosis than aged above the mean developed DR (52.6% vs 22.9%, respectively, p<0.001), CSM (5.8% vs 2.4%, respectively, p=0.001), PDR (2.4% vs 0.4%, respectively, p=0.001) and STDR (6.7% vs 2.6%, respectively, p=0.001). Among patients diagnosed with T2DM in 1996–1998 rather than in 1999–2004, the proportion who developed DR was 50.7% vs 35.4% (p<0.001), CSM 5.3% vs 3.2% (p=0.02), PDR 2.5% vs 0.7% (p<0.001) and STDR 6.2% vs 3.5% (p=0.003), respectively (online supplemental table S2).During 29 012 person-years of follow-up, DR was observed in 926 patients, corresponding to an incidence of 31.9 (95% CI 29.9 to 34.0) events per 1000 person-years. According to the Kaplan-Meier method, the cumulative incidences of DR at 10 and 20 years were 29.0% and 67.6%, respectively (figure 2A). CSM was observed in 89 patients (incidence 3.1/1000 person-years (95% CI 2.5 to 3.8)), PDR in 30 patients (incidence 1.0/1000 person-years (95% CI 0.7 to 1.5)) and STDR in 101 patients (incidence 3.5/1000 person-years (95% CI 2.9 to 4.2)). The cumulative incidences of STDR after 10 and 20 years were 1.4% and 11.4%, respectively (figure 2B).Figure 2Kaplan-Meier curves showing the cumulative incidence of diabetic retinopathy (A) and sight-threatening diabetic retinopathy (B) among patients in the Skaraborg Diabetes Register diagnosed with type 2 diabetes in 1996–2004 and with no diabetic retinopathy at their first eye examination.Associations between baseline variables and diabetic retinopathy Table 2 (online supplemental table S3 including p values) presents the results of the Cox regression models to estimate the association between baseline variables and development of DR. In the unadjusted Cox regression model (model 1), we found that higher age at diagnosis of T2DM, diagnosis of T2DM in the later period (1999–2004) and higher HDL were associated with decreased risk of DR. Higher HbA1c, BMI and triglyceride concentration as well as antihypertensive treatment and smoking at diagnosis were associated with increased risk of DR. The HR for development of DR if HbA1c was above rather than below the mean (56.1 mmol/mol) was 1.99 (95% CI 1.74 to 2.28, p<0.001). In model 2, after adjusting for sex and age, BMI, HDL and smoking were no longer associated with the risk of DR. In model 3, which adjusted for multiple confounders according to the modified disjunctive cause criterion, the associations remained significant between development of DR and all variables in model 2 except for triglycerides. In model 4, after mutual adjustment for all other baseline variables (except c-peptide), the directions and magnitudes of significant HRs remained similar (age at diagnosis of T2DM, period of diagnosis, HbA1c and anti-hypertensive treatment) (see online supplemental table S4).Table 2Risk of diabetic retinopathy in relation to baseline variables in patients without retinopathy at T2DM diagnosis registered in the Skaraborg Diabetes Register, 1996–2004 (n=2267)Baseline variables at time of diagnosis of T2DMEventsModel 1Model 2Model 3nHR95% CIHR95% CIConfounding variableHR95% CI1. Sex, malen=22679261.080.94 to 1.231.06*0.93 to 1.212, 3a1.090.96 to 1.242. Age, yearsn=22679260.980.97 to 0.980.98**0.97 to 0.981, 3a0.980.97 to 0.983 a. Year of diagnosisn=22679260.880.86 to 0.910.880.86 to 0.911, 20.880.86 to 0.913 b. Period of diagnosisn=22679260.570.50 to 0.650.580.51 to 0.661, 20.580.51 to 0.664. HbA1c, mmol/moln=2070 (missing 9%)8541.021.01 to 1.021.021.01 to 1.021, 2, 3a, 5, 6, 11, 121.021.01 to 1.025. BMI, kg/m2n=2012 (missing 11%)8371.021.00 to 1.031.011.00 to 1.021, 2, 3a, 121.011.00 to 1.026. SBP, mm Hgn=2066 (missing 9%)8501.000.99 to 1.001.061.00 to 1.011, 2, 3a, 4, 5, 11, 121.001.00 to 1.017. DBP, mm Hgn=2065 (missing 9%)8491.001.00 to 1.011.001.00 to 1.011, 2, 3a, 4, 5, 11, 121.001.00 to 1.018. Triglycerides, mmol/Ln=1653 (missing 23%)7301.071.03 to 1.101.051.02 to 1.091, 2, 3a, 4, 5, 121.020.98 to 1.079. HDL, mmol/Ln=1691 (missing 25%)7000.770.62 to 0.970.870.70 to 1.011, 2, 3a, 4, 5, 120.960.78 to 1.2110. C-peptide, nmol/Ln=408 (missing 82%)2260.950.71 to 1.260.940.71 to 1.25–––11. a-HTT, yesn=2263 (missing 0.2%)9231.531.34 to 1.741.481.30 to 1.691, 2, 3a, 4, 5, 6, 121.261.08 to 1.4712. Smoking, yesn=1917 (missing 15%)7971.201.03 to 1.411.110.94 to 1.301, 2, 3a1.070.91 to 1.25Risk of diabetic retinopathy in relation to baseline variables estimated in Cox regression models.Model 1: univariate.Model 2: adjusted for sex and age at diagnosis of T2DM (*sex adjusted for age, **age at diagnosis adjusted for sex). Model 3: adjusted for variables identified as confounders.Period of diagnosis, diagnosis 1999–2004 versus 1996–1998.a-HTT, anti-hypertensive treatment; BMI, body mass index; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin A1c; HDL, high density lipoprotein; SBP, systolic blood pressure; T2DM, type 2 diabetes.We observed patterns similar to those for DR regarding the association between risk factors and development of CSM, PDR and STDR (online supplemental tables S5–S7). Due to there being fewer individuals with these outcomes, we present only calculations of crude associations and calculations after adjustment for sex and age (models 1 and 2).Figure 3 presents the Kaplan-Meier cumulative incidences of DR in relation to age at diagnosis, period of diagnosis, HbA1c and antihypertensive treatment at time of diagnosis. These baseline variables were found to be statistically significant in models 3 and 4.Figure 3Kaplan-Meier curves showing the cumulative incidence of diabetic retinopathy in patients≤70 years old diagnosed with T2DM registered in the Skaraborg Diabetes Register in 1996–2004. Development of diabetic retinopathy in relation to age below and above the mean age at diagnosis (56.0 years) is shown in (A); diagnosis in 1996–1998 and 1999–2004 in (B); HbA1c (glycated haemoglobin A1c) at diagnosis below and above the mean (56.1 mmol/mol) in (C); and with or without antihypertensive treatment at diagnosis in (D). T2DM, type 2 diabetes.Discussion This cohort study of 2539 patients diagnosed with T2DM in 1996–2004 found that 10.7% of them had DR at diagnosis. Of 2267 patients with T2DM who did not have any DR at their first eye examination, 926 developed DR and 101 developed STDR during up to 24 years of follow-up (mean 12.8 years). High HbA1c and the need for antihypertensive treatment were associated with increased risk of DR, whereas older age and diagnosis in the latter period of the study (1999–2004) were associated with lower risk of DR.Results in relation to other studies The proportion of patients with an eye examination was higher in our study than was recently reported by the Swedish National Diabetes Register (NDR) with data from 2015 to 2019 (73% vs 56%, respectively). 27 The higher proportion in our study may be due to the inclusion of patients who underwent an eye examination for reasons other than diabetes photo screening, whereas the NDR study covered only patients who had been screened for DR. However, the proportion of patients examined in our study is in line with the result in another Swedish study with data from 2016 to 201728 as well as a study from the Danish screening program with data from 2013 to 2018.29We found that 10.7% of patients had DR at their first eye examination after T2DM diagnosis, a result similar to that in another Swedish study.28 The proportion was somewhat larger than in the Danish study (8.8%).29 In contrast, it was smaller than in the NDR study (17.2%), which included older patients and had a greater extent of missing data on DR.27During follow-up, we detected 926 patients who developed DR (an incidence of 32/1000 person-years), among whom 89 (3/1000 person-years) developed CSM, which corresponds to a 29.0% cumulative 10-year incidence of DR. A Spanish prospective study found a similar cumulative incidence at 9 years of follow-up (26.4%).30 Interestingly, the patients in our study were nearly 10 years younger and diagnosed at an earlier period (1996–2004) than those in the Spanish study (2007–2015) but had a similar HbA1c (56.1 vs 57.1 mmol/mol, respectively, converted according to International Federation of Clinical Chemistry and Laboratory Medicine). Despite this, the cumulative incidences of DR are similar in the studies. The Danish study29 also showed similar incidences as ours with 5-year cumulative incidences of DR and PDR of 8.8% and 0.2%, respectively, whereas our corresponding incidences were 9.3% and 0.0% (the first patient with PDR appeared after 8.1 years). The healthcare systems and prevalence of T2DM in Sweden and Denmark31 are similar, and it may be assumed that the patients were comparably monitored.Younger age at T2DM diagnosis was associated with increased risk of DR in our study, and a similar result is seen in studies from NDR,27 Spain30 and Denmark.29 Younger patients in our study’s cohort had higher HbA1c and were more often on antihypertensive treatment. Both these variables were independently associated with risk of DR. Thus, diagnosis of T2DM at a lower age may imply a more serious type of diabetes than diagnosis at an older age, which is in line with earlier studies. In two studies from SDR32 and NDR,33 there was generally a higher risk of any complication of diabetes and a higher mortality in patients with a lower age at diagnosis as was also found in a study including high-income countries.34Higher HbA1c at diagnosis was associated with higher risk of DR compared with those with lower HbA1c, which aligns with several earlier studies, such as the United Kingdom Prospective Diabetes Study (UKPDS 50) from 2001,12 the NDR study27 from 2023 and the studies from Spain30 and Denmark.29 Furthermore, a multicenter study (Action to Control Cardiovascular Risk in Diabetes, ACCORD) from the USA and Canada published in 2014 found a beneficial effect of lowering HbA1c on the progress of DR.35 A long time with high blood glucose levels may result in the production of advanced glycation end products and the upregulation of growth factors,36 resulting in vascular changes and DR. Early normalization of blood glucose levels seems to be important.12 37In our previous study,20 in which prevalent DR was included, we found an association between antihypertensive treatment and lower risk for the development of DR. In our current study, by contrast, antihypertensive treatment was associated with increased risk of developing DR, in line with other studies, such as the Danish study29 and a study from the USA.38 However, we do not interpret our results as that treatment with antihypertensive agents per se increases the risk of DR, but rather that the antihypertensive medication was a proxy for hypertension. We had no information in SDR on which antihypertensive drugs were prescribed in the inclusion period or during follow-up. The levels of SBP and DBP were not associated with a higher risk of developing DR in the present study. The ACCORD study found no benefit of lowering SBP from 140 to 120 mm Hg,35 but the SBP level seemed to be significant in the UKPDS 50 study,12 and the NDR study found an association between risk for DR and an SBP of over 140 mm Hg.27 In our previous study, SBP was associated with the development of DR in patients with HbA1c above 63 mmol/mol.20 This aligns with the UKPDS 30 study,9 in which patients with higher HbA1c than in our current study also showed an association between higher SBP and the development of DR.9 In the present study, patients had a mean SBP of 140 mm Hg, which may explain the lack of association between the development of DR and SBP levels in this population. In addition, the patients had lower HbA1c than in studies in which SBP was associated with the development of DR, suggesting that metabolic status and blood pressure levels may act synergistically on the risk of developing DR.Diagnosis of T2DM in the earlier period (1996–1998) was associated with a higher risk of DR, even after adjustment for confounders. Still, this may partly reflect that patients diagnosed in this period might have been exposed to a greater burden of cardiovascular risk factors over time. It could also be related to the higher glycemic diagnostic threshold that remained in place until the 1999 WHO revision, which lowered the fasting plasma glucose criterion in response to evidence of increased microvascular complications at levels ≥7 mmol/L.3 In addition, monitoring and follow-up of patients with T2DM have continually improved, alongside more ambitious treatment goals for risk factor control. Secular trends of improvement in other outcomes have also been reported in Sweden; for example, a successive decrease in excess mortality among patients diagnosed between 1991 and 2004 has been shown in the SDR,32 and a reduced risk of macrovascular complications between 2001 and 2019 has been observed in nationwide data.39The association between smoking at baseline and time to DR was not significant after adjustment for other factors. Other studies have shown no17 or even a protective12 15 effect of smoking on retinopathy. We had a relatively large amount of missing data on smoking and therefore less power in our analyses. Our data on smoking were self-reported, so the data may be less reliable. Some data indicate a relationship between cigarette smoking and DR and that the effect could be partly reversible.13 It is not known whether patients in our study continued smoking throughout follow-up or ceased smoking shortly after being diagnosed with T2DM.Strengths and limitations Our study has several strengths. It included a relatively large cohort of patients with high coverage and long (up to 24 years) follow-up. Since the 1970s, patients with hypertension in Skaraborg primary healthcare were screened for diabetes at yearly controls. This might contribute to earlier detection of symptomless diabetes and pre-diabetes although no population screening for diabetes was performed. The results on retinopathy are based on a review of medical records and are not the result of extraction of data from registers. Patients with diabetes in Skaraborg County were referred to the Department of Ophthalmology, Skaraborg Hospital for DR screening. There was no alternative screening facility during the study period (except for some patients June–December 2021, which is unlikely to have any significant impact on the results) and all documentation from Skaraborg Hospital was reviewed for correctness and grading by the first author. This results in more complete information on DR than studies based on registers. Skaraborg County is prominently rural and has a relatively stable population, facilitating long follow-up. Most studies on DR among patients with T2DM have either been intervention studies, 40 have investigated the prevalence of DR11 27 or have had relatively short follow-up.28 41 Furthermore, all individuals living in Sweden have a unique identity number, which made it possible to extract clinical data for patients in the SDR from ophthalmological hospital records.The study also has some limitations. We excluded patients >70 years at diagnosis, as they were not included in the screening program in Skaraborg during the early period of inclusion. We do not know whether inclusion of older patients would have changed the results in any direction. Also, we had to address missing data, which inherently reduces statistical power and may bias estimates unless missingness is completely at random. To mitigate this, we excluded C-peptide as a covariate in model 3 due to its high degree of missingness. Furthermore, the risk estimates in models 1 and 2 remained similar after further adjustments in model 3. Unfortunately, we did not have access to longitudinal data on HbA1c, lipids, blood pressure or smoking habits during follow-up. Capturing these measures over time would have provided more detailed insight into their relationship with DR progression. It is reasonable to assume that risk factor control generally improved during the long follow-up period of up to 24 years, given temporal trends towards lower lipid levels, improved blood pressure control, increased smoking cessation and progressively more ambitious treatment targets, including tighter glycemic control in clinical guidelines. Therefore, the baseline measures do not necessarily reflect the cumulative exposure to these risk factors over time, which should be considered when interpreting the associations observed in this study. Neither did we have access to mortality data or to information on whether patients had developed DR at the time of death. This limitation likely resulted in an underestimation of both the total number of patients who developed DR and the overall follow-up time, which in combination may have introduced some bias in the estimated results. Also, we had no data on neuropathy or nephropathy for analyses. Digital patient health records were implemented from 2007 at the ophthalmologic clinic, and paper records from earlier periods may have been stored in archives difficult to access.Conclusions This study with up to 24 years of follow-up found that although 926 of 2267 patients (41%) developed DR, only 101 (4.5%) developed STDR. Younger age at diagnosis, higher HbA1c, need for antihypertensive treatment and diagnosis in 1996–1998 versus 1999–2004 were associated with higher risk of developing DR and STDR.",
  "title": "Progress of diabetic retinopathy up to 24 years in patients with type 2 diabetes in Sweden: a cohort study from the Skaraborgs Diabetes Register",
  "uid": "d6c500a2-be01-591d-9052-077b4e57c672"
}