Anne Katrin Sjølie

Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials

BACKGROUND Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes. METHODS Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1. FINDINGS 1421 participants (aged 18-50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18-55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0.82 (95% CI 0.67-1.00, p=0.0508) for incidence of retinopathy and 1.02 (0.80-1.31, p=0.85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0.65 (0.48-0.87, p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, 0.53-0.95, p=0.046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1.16, 95% CI 1.05-1.30, p=0.0048) and DIRECT-Protect 1 (1.12, 95% CI 1.01-1.25, p=0.0264). Adverse events did not differ between the treatment groups. INTERPRETATION Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.

Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial

BACKGROUND Diabetic retinopathy remains a leading cause of visual loss in people of working age. We examined whether candesartan treatment could slow the progression and, secondly, induce regression of retinopathy in people with type 2 diabetes. METHODS We did a randomised, double-blind, parallel-group, placebo-controlled trial in 309 centres worldwide. We recruited normoalbuminuric, normotensive, or treated hypertensive people with type 2 diabetes with mild to moderately severe retinopathy and assigned them to candesartan 16 mg once a day or placebo. After a month, the dose was doubled to 32 mg once per day. Investigators and patients were unaware of the treatment allocation status. Progression of retinopathy was the primary endpoint, and regression was a secondary endpoint. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00252694. FINDINGS 1905 participants (aged 37-75 years) were randomised to candesartan (n=951) or placebo (n=954). 161 (17%) patients in the candesartan group and 182 (19%) in the placebo group had progression of retinopathy by three steps or more on the Early Treatment Diabetic Retinopathy Study scale. The risk of progression of retinopathy was non-significantly reduced by 13% in patients on candesartan compared with those on placebo (hazard ratio [HR] 0.87, 95% CI 0.70-1.08, p=0.20). Regression on active treatment was increased by 34% (1.34, 1.08-1.68, p=0.009). HRs were not attenuated by adjustment for baseline risk factors or changes in blood pressure during the trial. An overall change towards less severe retinopathy by the end of the trial was observed in the candesartan group (odds 1.17, 95% CI 1.05-1.30, p=0.003). Adverse events did not differ between the treatment groups. INTERPRETATION Treatment with candesartan in type 2 diabetic patients with mild to moderate retinopathy might induce improvement of retinopathy.

The importance of genes and environment for ocular refraction and its determiners: a population based study among 20–45 year old twins

AIMS To estimate the heritability for ocular refraction and its determiners in a population based cohort of 20–45 years old twins. METHODS 114 twin pairs (53 monozygotic and 61 dizygotic) participated. Refraction was determined in cycloplegia and eye dimensions were measured with ultrasound. Educational length was assessed. The heritability was estimated employing aetiological model fitting. Evidence of gene-environment interaction was analysed. Correlations between intrapairwise differences in educational length and in refraction were evaluated. RESULTS The heritability was between 0.89 and 0.94 (95% CI: 0.82, 0.96) for refraction, total refraction, axial length, and radius of corneal curvature. Phenotypic variation was mostly due to additive genetic effects. Refraction revealed evidence of gene-environment interaction (r = −0.29 to −0.32; p <0.05). The heritability for anterior chamber depth and lens thickness was between 0.88 and 0.94 (95% CI: 0.81, 0.96) and dominant genetic effects were the most likely explanation. There was no correlation between age and intrapairwise differences in refraction. The dizygotic twins had significant larger intrapairwise differences in educational length (p <0.05), but the differences were not correlated with differences in refraction. CONCLUSIONS The results indicate a high heritability for ocular refraction and its determiners and thus suggest that environmental impact on refraction is not significant. However, the epidemiological association between educational length (near work) and myopia, the evidence of increasing myopia prevalence within a few generations, and the theory of gene-environment interaction imply that some individuals might be genetically liable to develop myopia if exposed to certain environmental factors.

Effect of Candesartan on Microalbuminuria and Albumin Excretion Rate in Diabetes: Three Randomized Trials

BACKGROUND Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority. OBJECTIVE To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes. DESIGN 3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program. SETTING 309 secondary care centers. PATIENTS 3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 microg/min). INTERVENTION Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up. MEASUREMENTS Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 microg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate >or=20 microg/min). The secondary end point was rate of change in albuminuria. RESULTS Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo. LIMITATIONS Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points. CONCLUSION Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.

The significance of the prepubertal diabetes duration for the development of retinopathy and nephropathy in patients with type 1 diabetes

OBJECTIVE A Danish nationwide prospective cohort of children and adolescents with type 1 diabetes was followed for 8 years to study the effect of the prepubertal duration of diabetes on early retinopathy and elevated albumin excretion rate (AER) (>20 microg/min). RESEARCH DESIGN AND METHODS In 1989, blood glucose control (HbA(1c)) and AER was investigated in approximately 80% of all Danish children and adolescents with type 1 diabetes. A cohort of 339 young patients were restudied in 1995 including physical examination, demographic data, HbA(1c), AER, and fundus photography with central reading. Among the patients, a number of 304 had a prepubertal onset of diabetes defined as an onset age less than 11.7 years in girls and 12.9 years in boys. Microalbuminuria was defined as an AER of 20-150 microg min(-1) and macroalbuminuria as AER >150 microg min(-1) in two out of three timed overnight urine samples. RESULTS At the follow-up in 1995-1996, no patients were younger than 12 years of age. The prevalence of any level of retinopathy was 17.7% in the age group 12-15 years, 45.4% from 16 to 20 years, and increased to 67.6% in patients more than 20 years of age. Diabetic retinopathy was significantly associated to poor long-term metabolic control (HbA(1c)) (P<.0001) and to diabetes duration both in patients with a prepubertal onset of disease as well as patients with a pubertal (P<.001) onset of disease. However, the pubertal diabetes duration contributed two times more than the prepubertal diabetes duration. Mean postpubertal diabetes duration to any retinopathy was significantly shorter (9.4 years) in patients with prepubertal onset of the disease compared to patients with postpubertal onset (11.8 years) (P=.0004). In total, the prevalence of elevated AER (>20 microg/min) increased from 4% in 1989 to 13% in 1995. None of the patients younger than 15 years of age had elevated AER, while the prevalence of elevated AER was about 14% from 15 years of age and onwards. Elevated AER in 1995 was significantly related to long-term metabolic control (P<.001) and elevated AER in the preceding years (P<.001) but was not correlated to diabetes duration neither before nor after the age of 12 years. CONCLUSION The prepubertal diabetes duration is significantly associated with the development of diabetic retinopathy. The period, however, contributes less compared to the years after puberty. In concert with other studies, we found no association between raised AER and diabetes duration. This may be explained by the fact that other factors are more significant and dilute the significance of diabetes duration. Nonetheless, it seems prudent to optimise blood glucose control irrespective of age.

Retinal Vascular Fractals and Microvascular and Macrovascular Complications in Type 1 Diabetes

PURPOSE Fractal analysis is a method to quantify the geometric pattern and complexity of the retinal vessels. This study examined the association of retinal fractal dimension (D(f)) and microvascular and macrovascular complications in a population-based cohort of Danish patients with type 1 diabetes. DESIGN Cross-sectional study. PARTICIPANTS This was a cross-sectional study of 208 long-term surviving type 1 diabetes patients from a population-based Danish cohort identified in 1973. METHODS Retinal photographs were obtained at a clinical examination in 2007 or 2008. D(f) was measured with a semiautomatic computer-based program (International Retinal Imaging Software; National University of Singapore, Republic of Singapore; University of Sydney, Sydney, and University of Melbourne, Melbourne, Australia). D(f) of the retinal vasculature was measured within a predefined circular region of 3.5 optic disc radii centered on the optic disc. Line tracing of the vasculature was provided by the program. Any artifacts were removed by the grader, and the box-counting method then was used by the program to calculate D(f). MAIN OUTCOME MEASURES The association of D(f) with proliferative retinopathy, nephropathy, neuropathy, and macrovascular disease (coronary heart disease, stroke, peripheral artery disease) was examined. RESULTS Retinal fractals were gradable in at least 1 eye in 178 (86.6%) of 208 patients. Median age and duration of diabetes for these patients were 57.8 years and 42 years, respectively. Median D(f) was 1.4610 (range, 1.3774-1.5188). After adjustments for age, gender, duration of diabetes, systolic blood pressure, and smoking, persons with lower D(f) were more likely to have proliferative retinopathy (odds ratio [OR], 1.45 per standard deviation [SD] decrease in D(f); 95% confidence interval [CI], 1.04-2.03) and neuropathy (OR, 1.42 per SD decrease in D(f); 95% CI, 1.01-2.01). There was also a trend of an association between lower D(f) and nephropathy (OR, 1.39 per SD decrease in D(f); 95% CI, 0.97-2.01) but not macrovascular disease. Furthermore, persons with lower D(f) were older. CONCLUSIONS This study adds to the evidence that D(f) may have some role as a global measure of retinal vasculature and its association with systemic disease. Prospective studies clarifying this role are needed. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme.

Diabet. Med. 28, 345–351 (2011)

Blindness in a 25-Year Follow-up of a Population-Based Cohort of Danish Type 1 Diabetic Patients

PURPOSE To assess the long-term incidence of blindness and to evaluate risk factors for blindness in a population-based cohort of type 1 diabetic patients. DESIGN Retrospective cohort study. PARTICIPANTS A population-based cohort of 573 type 1 diabetic patients, all of whom participated in a clinical ophthalmologic examination in 1981 and 1982 and were followed up for 25 years. METHODS At the baseline examination in 1981 and 1982, visual acuity, level of retinopathy, maculopathy, hemoglobin A(1) (HbA(1)), proteinuria, smoking habits, and blood pressure were evaluated and related to the subsequent development of blindness. Blindness was defined as present in patients who were registered as members of the Danish Association of the Blind between baseline and January 2007. The Danish Association of the Blind is a voluntary organization open for all patients with a best-corrected visual acuity in the best eye of <or=6/60 (20/200) or with complications (i.e., visual fields <10 degrees ) subjectively leading to a best-corrected visual acuity in the best eye of <or=6/60 (20/200). MAIN OUTCOME MEASURES Evaluation of 25-year incidence of blindness, predictors for blindness, and gender-specific incidence rates for blindness. RESULTS The 25-year cumulative crude incidence of blindness was 7.5% (men, 8.0%; women, 6.8%; P = 0.61), corresponding to a mortality-adjusted cumulative incidence of blindness of 9.5% (95% confidence interval [CI], 7.1%-12.0%) and an overall incidence rate of blindness of 4.11 per 1000 person-years (95% CI, 3.03-5.59 per 1000 person-years). Blindness was predicted by HbA(1) and maculopathy at baseline. The odds ratio of blindness during follow-up was 1.69 (95% CI, 1.01-2.84) for a 1% increase in baseline HbA(1) and was 6.18 (95% CI, 1.18-32.47) and 8.61 (95% CI, 2.54-29.23) for patients with maculopathy in combination with nonproliferative retinopathy and proliferative retinopathy, respectively. Age and duration at baseline, gender, proteinuria, smoking, systolic and diastolic blood pressure, and visual acuity at baseline were not associated with the development of blindness. Mortality was higher in patients who had become blind (61.0% vs. 42.1%; P = 0.02). CONCLUSIONS Blindness is still a common complication in type 1 diabetes. Glycemic regulation and the presence of maculopathy are important risk factors for the development of blindness.

Prevalence of Age-related Macular Degeneration in Elderly Caucasians: The Tromsø Eye Study

PURPOSE To describe the sex- and age-specific prevalence of drusen, geographic atrophy, and neovascular age-related macular degeneration (AMD). DESIGN Population-based, cross-sectional study. PARTICIPANTS Caucasian adults aged 65 to 87 years from the 6th Tromsø Study, a population-based study conducted in 2007-2008 in the municipality of Tromsø, Norway. METHODS Digital color fundus photographs were graded for predominant phenotype based on drusen size, geographic atrophy, and neovascular AMD. MAIN OUTCOME MEASURES Age-related macular degeneration. RESULTS A total of 3025 subjects participated; 89% of those were invited to the eye examinations. Gradable photographs were available for 2631 persons (mean age 72.3 years). Drusen 63-125 μm as the predominant phenotype were found in 34.9% of participants (95% confidence interval [CI], 33.1-36.8), drusen >125 μm were found in 24.1% (95% CI, 22.5-25.8), geographic atrophy was found in 1.0% of participants (95% CI, 0.6-1.4), and neovascular AMD was found in 2.5% of participants (95% CI, 1.9-3.1). Bilateral involvement of late AMD was present in 1.1% of the sample. Eyes with late AMD had a significantly lower refractive error (spherical equivalent 0.078 vs. 0.99 diopters, P<0.0001), and 42.5% of eyes had Snellen visual acuity ≤ 0.32. CONCLUSIONS The prevalence of AMD among the elderly persons in this study was similar to rates in other Caucasian populations. Late AMD was present in 10.9% of subjects aged 80 years or more. No sex differences in prevalence rates of large drusen or late AMD were observed. Lower refractive error was observed in eyes with late AMD than in eyes without late AMD.

Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration in treatment-naive patients

Purpose:  To report the effects of intravitreal bevacizumab (Avastin®) in treatment‐naive patients with exudative age‐related macular degeneration (ARMD) assessed by visual acuity (VA), optical coherence tomography (OCT) and contrast sensitivity.