Why carry out this systematic review?
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The aim is to review the epidemiology of early worsening of diabetic retinopathy (EWDR) after substantial improvements in glycaemic control. |
What was learned from this systematic review?
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The occurrence of EWDR and progression of retinopathy were found to have an association with the amplitude of HbA1c reduction. |
Introduction
Methods
Search Strategy
Diabetes or IT-related terms | EWDR-related terms |
---|---|
‘Diabetes mellitus type 1’ | ‘Diabetic retinopathy’ |
‘Diabetes mellitus type 2’ | ‘Pre-proliferative diabetic retinopathy’ |
‘Intensive insulin treatment’ | ‘Proliferative diabetic retinopathy’ |
‘Intensive insulin infusion treatment’ | ‘Worsening of diabetic retinopathy’ |
‘Insulin pump therapy’ | ‘Paradoxical phenomenon’ |
‘Rapid improvement of blood glucose’ | ‘Early worsening diabetic retinopathy’ |
‘Rapid blood glucose control’ | ‘Retinopathy progression’ |
‘Large HbA1c reductions’ | ‘Early retinal damage’ |
‘GLP-1 agonist therapy’ | ‘Paradoxical early aggravation of diabetic retinopathy’ |
‘Insulin pump therapy’ | ‘Incidence’ |
‘Uncontrolled diabetes’ | |
‘Hyperglycemia’ |
Inclusion criteria | Exclusion criteria |
---|---|
Not an original research manuscript | |
Cohorts and observational studies displaying the retinopathy outcomes in patient with diabetes and who receive intensive therapy | Not a human study |
Full-text publications | Not conducted in adults (at least 18 years of age) |
Did not have a diabetes mellitus group who receive intensive therapy | |
Did not report diabetic retinopathy | |
Not written in English |
Data Extraction
Critical Appraisal
Primary Outcome
Data Analysis
Compliance with Ethics Guidelines
Results
Author | Country/study type | Sample size | Study group | Group size | Mean age (years ± SD or range) | Sex (female/male) | Follow-up/baseline HbA1c | Retinopathy evaluation how/when | Factors associated with EWDR | Incidence of EWDR (%) |
---|---|---|---|---|---|---|---|---|---|---|
Steno study [26] | Denmark/prospective randomized study | 30 | CSII | 15 | Med age 36 (21–51) | 8/7 | 1 year/10% | Colour fundus photographs and fluorescein angiogram/retinal function: oscillatory potential, macular recovery time, and posterior vitreous fluorophotometry/ Every 6 months | No association between progression to PDR and HbA1c decrease in first 2 months or in mean blood glucose during follow-up | 11% CSII EWDR described as further cotton-wool exudates, haemorrhages, and “red spots” on fundus photographs and appearance of further microaneurysms, haemorrhages, and capillary-free areas on fluorescein angiograms and an PDR findings |
CT | 15 | Med age 32 (24–26) | 6/9 | |||||||
Steno study [28] | Denmark/prospective randomized study | 30 | CSII | 15 | Med age 36 (21–51) | 8/7 | 2 years | 6% CSII PDR in 4 CSII, 5 CT DR improvement in 47% CSII vs 14% CT | ||
CT | 15 | Med age 32 (24–26) | 6/9 | |||||||
Oslo study [29] | Norway/prospective randomized study | 45 | CII | 15 | 26 (18–38) | 7/8 | 1 year/8.5% | 2 months before treatment, at the beginning of treatment, and after 3, 6 and 12 months with indirect ophthalmoscopy, colour photos, FA | Previous DR, long-term T1D, female gender Larger HbA1c decreases | Cotton-wool spots in half of IT 3.3% (CII, n = 7; MI, n = 8) vs none in CT at 3 months Regression at 6–12 months in all except 4 1.3% |
MI | 15 | 26 (19–42) | 7/8 | |||||||
CT | 15 | 26 (18–36) | 7/8 | |||||||
Oslo study [30] | Norway/prospective randomized study | 45 | CII | 10 | After 41 months the treatment protocol was changed | 7 years | 15 patients who developed cotton-wool spots did not have a different retinopathy outcome at year 7 | |||
MI | 29 | |||||||||
CT | 6 | |||||||||
Kroc study [31] | USA/observational study | 70 | CSII | 36 | 31.9 ± 1.7 | 16/19 | 8 months/10% | 30° stereoscopic photographs/ At baseline, 4 and 8 months | Baseline DR level, No age and blood pressure association | 47% CSII vs 27% CT More frequent cotton-wool spots and intraretinal microvascular abnormalities in CSII vs CT (P < 0.025) |
CT | 34 | |||||||||
Kroc study [32] | USA/observational study | 47 | CSII | 24 | 34. ± 1.6 | 19/16 | 2 years | At 2 years the degree of retinopathy in two treatment groups was indistinguishable, with some trend to lesser overall deterioration with CSII | ||
CT | 23 | |||||||||
DCCT study [33] | USA/prospective randomized study | 1441 | PP-IT | 348 | 27 ± 7 | 178/170 | 6.5 years/9% | Seven field fundus photographs/Baseline, at 3 months, in subgroup | Higher baseline HbA1c, greater magnitude of HbA1creduction in first 6 months, longer duration of diabetes, greater severity of DR | 3 months: EWDR in 11% IT vs 3.6% CT Regression at 6 months in half 13% of IT vs 7.6% in CT Regression in 51% and 55%, respectively (P = 0.39) At 6 months, clinically significant EWDR in 9 IT vs 6 CT |
PP-CT | 378 | 26 ± 8 | 174/208 | |||||||
SP-IT | 363 | 27 ± 7 | 171/192 | |||||||
SP-CT | 352 | 27 ± 7 | 162/190 | |||||||
Klefter et al. [34] | Denmark/observational study | 51 | CSII | 31 | 37 (19–63) | 20/11 | 1 year/9% | Retinopathy level, dark adaptation kinetics, retinal and subfoveal choroidal thickness, macular perfusion velocities, retinal vessel diameters at baseline and after 1, 4, 16, 32 and 52 weeks | 1 year CSII reduced HbA1c by 1.6% vs 0.3% with CT | Central retinal thickness increased by 1.5% in CSII without macular oedema. No EWDR reported |
CT | 20 | 42 (26–63) | 8/12 |
Author | Country/study type | Sample size | Study group | Group size | Mean age (years ± SD or range) | Sex (female/male) | Follow up/baseline HbA1c | Retinopathy evaluation how/when | Factors associated with EWDR | Incidence of EWDR (%) |
---|---|---|---|---|---|---|---|---|---|---|
UK/prospective randomized study | 3867 | IT | 2729 | 53.2 ± 8.6 | 444/649 | 9 years/ 7% | Retina morphology/retinal function with oscillatory potential, macular recovery time, and posterior vitreous fluorophotometry/ Baseline, 3, 6, 9 years | DR incidence associated with baseline plasma glucose, glucose exposure over 6 years, high blood pressure | No EWDR reported | |
CT | 1138 | 53.4 ± 8.6 | 433/705 | |||||||
Adrem (ADVANCE) study [20] | Europe/prospective randomized study | 1241 (from 1602 patients) | IT | 791 | 65.6 ± 6.0 | 300/491 | 4 years/7.5% | Standard retinal photography (ETDRS Classification)/Baseline, 2 and 4 years | Intensive or conventional treatment not associated with decreased incidence or progression of DR | No EWDR reported |
CT | 811 | 65.6 ± 5.7 | 347/464 | |||||||
USA/prospective randomized study | 2856 | IT | 1429 | 61.6 ± 6.4 | 538/891 | 4 years/8.2% | Fundus photography of seven standard stereoscopic fields, at baseline and year 4 of follow-up | Intensive glycaemic control: reduced risk of DR progression especially in cases with non-proliferative DR at inclusion | No EWDR reported | |
CT | 1427 | 61.5 ± 6.3 | 552/875 | |||||||
VADT study [44] | USA/prospective randomized study | 858 (from 1791) | IT | 433 | 60 ± 8 | 16/417 | 5 years/9.5% | Seven-field stereoscopic colour photographs of the retina/Baseline and 5 years | DR incidence reduced in patients aged < 55 years with IT | No EWDR reported |
CT | 425 | 60 ± 8 | 13/412 | |||||||
Henricsson et al. [46] | USA/prospective non-randomized clinical study | 1378 | IT | 333 | 3 years/10% | Fundus photographs/ Annually | HbA1c level, previous DR | DR progression (≥ 3 stages): × 2 in those initiating insulin therapy vs others | ||
CT | 1045 (174 of whom to insulin) | |||||||||
Henricsson et al. [47] | USA/observational study | 45 | IT | 45 patients with type 2 diabetes | 2 years/9.7% | Fundus photographs baseline and 11, 3, 6, 12 and 24 months | HbA1c level, IGF-1, and hemostatic variables | DR progression 23/45 patients (51%) progressed in the retinopathy scale | ||
Shurter et al. [48] | USA/retrospective case control study | 68 | IT | 34 | 52 | 14/20 | 2 years/10.7% IT vs 7.8% CT | 45° retinal photographs/ Annually | Higher baseline HbA1c, larger decrease with IT | At least one step progression IT group 25/64 eyes (39%), CT group only 10 /65 eyes (15%) (p = 0.0025). Sight-threatening retinopathy 8 eyes IT versus 0 eyes CT, p = 0.003 |
CT | 34 | 52 | 17/17 | |||||||
Arun et al. [49] | UK/observational clinical study | 294 | IT | 284 | 62 ± 9.6 | 152/132 | 5 years/10% | Retinal photography/Annually | Higher baseline HbA1c (P = 0.002), smaller decrease in HbA1c (P = 0.007), longer duration of diabetes, higher HbA1c at follow-up | 13% of patients had EWDR within the first 3 years of insulin treatment |
CT | 70 | 59.4 ± 12.1 | 38/32 | |||||||
SUSTAIN 6 study [45] | Europe-US-CN/prospective randomized study | 3297 | GLP-1 agonist | 826 | 64.7 ± 7.2 | 635/1013 | 2 years/8.7% | Fundus photographs/Baseline, 2 years | Pre-existing DR, duration of diabetes, higher HbA1c at baseline; insulin treatment at trial entry | DR progression 3% GLP-1 agonist vs 1.8% placebo |
Placebo | 1649 | 64.6 ± 7.5 | 660/989 |