The prognosis of diabetic retinopathy in patients with type 2 diabetes since

1996-1998.

The Skaraborg Diabetes Register

Grete Garberg1, Monica Löwestam2, Salmir Nasic1, Kristina Bengtsson Boström3

1Department of Ophthalmology, Skaraborg Hospital, Skövde, 2Department of Ophthalmology, Lund University Hospital, University of Lund, 3R&D Centre Skaraborg Primary Care

Reprint requests and correspondence toGrete Garberg, MDDepartment of Ophthalmology, Skaraborg Hospital, Skövde S-541 xx Skövde, Sweden.E-mail grete.garberg@vgregion.se

This research was funded by the Skaraborg research and development council, Skaraborg SkaS fonder??

Manus 20091022

Total word count: Skall vara xxxx max. Vilken tidskrift skall vi sända till? Acta

Opthalmologica

Key points

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Keywords diabetes mellitus type 2, retinopathy, ophthalmological investigation, database

Abstract

Purpose: To investigate the prognosis of eye complications in diabetic patients during 10 year

follow up and the extent of screening.

Methods: Data from the Diabetes Screening Program of 1258 diabetic patients (104 of type 1,

1138 of type 2 and 14 with clinically indeterminate type) with clinical debut 1996-1998 from

the Skaraborg Diabetes Register (SDR) were retrieved. Their ophthalmological records were

examined, and the consecutive data from all visits during the period comprised occurrence of

retinopathy and other complications, laser treatment and visual outcome.

Results: Seven hundred and seventy three were type 2 diabetes and ≤ 70 years at diagnosis,

and 81% of them have been examined some time. Visual result was noticed from 548 patients

(of 659 still alive at the last registration), and 527 (96%) had visual acuity above limit for

driving license (0.5 Snellen). Laser treatment was performed on 19 patients; of these 1 were

treated for other vascular diseases. Among the 9 with severe visual impairment (Snellen <0.3),

at least 6 had other diagnoses than diabetic complications. Mean glycosylated haemoglobin

(Hba1c) at diagnosis was 6.7, five years later it was 6.6. Retinopathy appears about 1 year

earlier if HbA1c ≥ 7 at diagnosis, anti hypertensive treatment seems to protect from

retinopathy, but BMI (Body Mass Index) at diagnosis does not affect retinopathy

development.

Conclusions: Most diabetic patients do well during the first 10 years after diagnosis. The

older patients often have ophthalmological co-morbidity contributing to visual impairment.

Key words: Diabetes mellitus type 2, Diabetic retinopathy, retinal photo screening,

longitudinal study

Word count: 248

Introduction

Screening for retinopathy is regarded to be beneficial and cost effective in preventing visual

loss in diabetic patients (Squirrel & Talbot 2003) and was introduced in Skaraborg in the

nineteen eighties. Local guidelines for screening were based on the national Swedish ones,

and have been modified during the follow up period of 10 years (table 1).

Skaraborg, a rural area of Västra Götaland in the southwest of Sweden, has a population of

approximately 250 000 inhabitants. The population is stable, especially among adults.

Diabetic patients are mostly been cared for by public primary care (about 84%). Those with

severe complications are cared for by specialized clinics (type1 and type 2 diabetics). Very

few patients are cared for by private practitioners.

Skaraborg Diabetes Register (SDR) was established in 1991, and after a few years comprised

most prevalent patients and incorporated consecutively all newly diagnosed diabetic patients,

type 1 and type 2, mainly from primarily care. SDR was closed in 2004 and the patients were

thereafter registered in the Swedish National Diabetes Register (NDR). The capture rate of

SDR in 1996 was 88%; 97% of patients receiving pharmaceutical treatment and 80% of those

with diet only (Berger & al. 1999).

Diabetes retinopathy is the main reason for visual impairment among people of working ages.

Appropriate treatment of retinopathy at time reduces the risk of severe visual loss by more

than 50 % (ETDRS report no 9 1991). Severe retinopathy was seen at diagnosis by 8% of

male and 4% female patients at fist visit in Early Treatment Diabetic Retinopathy Study

(ETDRS) 30 (Kohner et al. 1998). Diabetic patients are often asymptomatic even at quite

advanced levels of retinopathy and type 2 diabetes patients should therefore be examined at

diagnosis (Kohner et al. 1998).

The Wisconsin Epidemiologic Study of Diabetic Retinopathy XV indicates an association

between maculopathy and higher levels of glycosylated haemoglobin during 10 years follow

up of type 1 diabetes patients (Klein & al. 1995). In the United Kingdom Prospective

Diabetes Study (UKPDS) patients with better blood glucose (BG) and blood-pressure (BP)

control have reduced eye complication rate in type 2 diabetes. Tight BG-control does not

seem to reduce total mortality though (UKPDS 33 1998, UKPDS 38 1998). Not only present,

but even previous metabolic control seems to affect the progression of retinopathy after ten

years in type1 diabetes, more pronounced for adults than adolescents (White & al. 2010).

Aggressive control of known risk factors like blood glucose and blood pressure affects the

risk of background, but not for proliferative retinopathy (PDR) (Brown & al. 2003). In the

UKPDS 50 it seems to be an association between retinopathy, baseline glycaemia and

glycaemic exposure (Stratton & al. 2001). The ACCORD trial (Chew et al. 2011) showed

lower progression of retinopathy with tight blood sugar control (HbA1c<6%) and blood lipid

medication, but no effect of tighter blood pressure (BP) control.

The aim of this study was to investigate the screening frequency and occurrence of

retinopathy during 10 years follow up in a population based cohort of patients that were

diagnosed with diabetes in 1996-1998. Over-weight is associated with diabetes type 2 and

hypertension, and might be related to HbA1c. Therefore we also wanted to investigate the

relationship between HbA1c, BP or BMI at diagnosis and later complications.

Material and methods

Patients from the SDR diagnosed with diabetes from 1 January 1996 until 31 December 1998

were specifically registered, and those 65 years and younger were investigated for

development of islet antibodies (Berger & al. 1998). Patients ≤ 70 years at diagnosis were

supposed to participate in the screening program, and are the basis of this study.

Retinal photo screening took place in four clinics in Skaraborg. Standard photos included two

fields (60 degrees) of each eye, one with macula and one with optic papilla in centre. Visual

acuity, when available, is measured by Snellen charts.

The extent of the screening has been relatively constant during the follow-up period, but there

have been a few modifications in the criteria for screening (table 1). Grading was made

mainly by 3 persons using a modified grading from AAO’s Focal Points (AAO focal points

1993) (table2).

Data from ophthalmological and screening records for all available patients as close to debut

of diabetes as possible, after about 5 years duration and the last available (ca 10 years

duration) were registered. The degree of retinopathy, presence of significant maculopathy,

laser treatment (focal/grid or pan retinal photocoagulation (PRP)), visual acuity and reasons

for visual impairment, other than diabetic retinopathy, were noticed. Retinopathy from the

worse and visual acuity of the better eye was used. Patients treated for maculopathy with no

residual oedema or exudate, were noted as no maculopathy in the screening, but registered as

treated for maculopathy on subsequent visits and are included among patients with

maculopathy, but some might be missing. Patients treated by PRP even in a pre proliferative

(PPDR) state were noted as PDR.

From the referrals information was retrieved on date of diabetes diagnosis, HbA1c level,

systolic and diastolic BP (SBP and DBP), anti hypertension treatment, nephropathy (micro

albuminuria >200µmol/l, diagnosis of uraemia, or kidney transplantation), neuropathy

(impaired vibration sense, tendon reflex or autonomous neuropathy (ortostatism, gastro

paresis or erectile dysfunction)). The BP and HbA1c were incomplete from referral so BP and

HbA1c, as well as BMI are from SDR.

Statistics: SBSS is used for statistic analyses. Cox regression analysis is used for survival

function. HbA1c=7 was chosen as statistic breakpoint because that level was the therapeutic

aim during the investigation period.

Results

The material comprises 1,258 people with a registered debut of diabetes between 1996 and

1998 (fig1). In total we recalled records of 488 patients within 2-3 years of debut, and 949

patients have been examined at some time (table 3 and 4). Patients >70 years at debut were

not regularly part of the screening, but some were included, and others had ophthalmic

records from other reasons.

Patients ≤70 years at debut (n= 877) should be part of the screening program from the

beginning; 113 were type 1, 9 type 0 (not defined by the referral), and 764 type 2 (patients

<65 without islet-antibodies). Patients typed as 0 are most likely type 2 and are here

considered as type 2. This study is based on the 773 patients with type 2 and ≤ 70 years at

diagnosis.

We have results from 639 (83%) at some time during follow up (table 6); at first visit 288,

second visit 540 and 559 at last visit. The mortality before September 2009 was 114; which

means that we have results from 85% of the 659 still alive at examination 3. Visual acuity was

above level of demands for driving licence in 527 of 548 (96%). Among 9 patients with

severe visual impairment (<0.3) at least 6 have ocular co morbidity; only 4 of them had

significant maculopathy and was treated by laser. One patient was legally blind (visus<0.1

Snellen) because of diabetes complications.

Mean HbA1c at diagnosis (HbA1c96) is 6.7, and at 5 years duration (HbA1c01) 6.6 (fig 5).

HbA1c96 seems to be relevant for development of retinopathy. The mean HbA1c96 was

7.4(±0.16)% among those who developed retinopathy, and 6.5(±0,07)% in the group who did

not (p<0,001). The first sign of retinopathy appears about 1 year later if HbA1c96≤7.0 than if it

is >7.0 (p<0.001 chi square) (table6, fig4).

There is no statistical relation between HbA1c96<7 and development of maculopathy. If we

look at HbA1c96 >8, or >10 there is a tendency, but there are too few individuals for statistical

significance. However there is a higher risk for maculopathy with higher HbA1c96 if systolic

blood pressure at diagnosis (SBP96)<140 (fig7, table 8). HbA1c01>7(at the second assessment

point) (table5) however, seems to relate to development of maculopathy (p<0.001). The

difference in maculopathy related to HbA1c96 seems to increase with time (fig6).

The relation between SBP and retinopathy is more complicated. SBP96 (SBP at diagnosis) is

not significant for the development of retinopathy or maculopathy, but there is a lower

incidence of retinopathy (but not of maculopathy) among patients treated for hypertension.

Patients treated for hypertension have a lower HbA1c at diagnosis, though. High HbA1c96 is a

higher risk factor for maculopathy if SBP96<140 (fig 8). The BMI at debut (BMI96) does not

seem to influence the development of neither maculopathy nor retinopathy.

Conclusion and discussion

The primary care in Skaraborg has been well established and has a good work up for diabetic

and hypertensive patients. It is mostly publically run, and attending the SDR (and later NDR)

and screening program has been encouraged. The cooperation between public primary care

and the eye clinic has worked well, and attendance rate of screening was relatively good at the

last occasion The grading of retinopathy was made for clinical use and not for research, and is

maybe too coarse for statistical analyses, but endpoints like laser treatment and visual acuity

gives some information on complication rate. We might have missed some patients with

maculopathy because of the registration during screening (see “Methods”), but the visual

results, although we did not use ETDRS charts, should be relatively correct.

Patients treated for hypertension have been more intensively screened for diabetes. Diabetic

patients with anti hypertensive treatment were therefore probably detected earlier, which may

explain why anti hypertensive treatment seems to protect from retinopathy. In DIRECT-

Protect 2 (Sjølie et al. 2008) they found that ACE-inhibitors may reduce existing retinopathy.

We do not have any information of what kind of anti hypertensive treatment our patients had

at diagnosis, but ACE-inhibitors were not frequently used in late 90-ties.

Hypertension and diabetes is more frequent among obese people, and we expected that people

with higher BMI96 would have higher HbA1c at diagnosis and develop more retinopathy, but

we could not see any relationship between BMI at diagnosis and retinopathy, nether could we

see a relationship between SBP96 per se and retinopathy. In the UKPDS 38 there was a benefit

of reduction of BP (aim SBP < 150mmHg). The ACCORD (Chew et al. 2010) could not see

any benefit of reducing BP, but their patients were relatively well controlled with mean SBP

(systolic blood pressure) 137mmHg. That is consistent with our results; with initial SBP <

140mmHg, the HbA1c level is more important for development of maculopathy, and with

SBP > 140, maculopathy is more related to blood pressure level.

Debut often precedes discovery for several years in type 2 diabetes. At first examination

26/357 (7%) of our patients had any retinopathy, and 4 (0.1%) had more severe, similar to the

Beaver Dam Eye Study (Klein & al. 1992), It is therefore desirable to have a first examination

as close to diagnosis as possible. The increased rate of retinopathy among patients with

HbA1c>7 at diagnosis, might be due to a longer duration at diagnosis at higher HbA1c, but

also to the “memory”-effect described in DCCT/EDIC (White & al. 2010). Long duration

and/or high levels of HbA1c may result in more end-glycation of proteins, as well as more

oxidative stress and more harm to the retina.

Diabetic patients often express their fear of visual impairment, but the risk seems to be low at

least the fist ten years. Totally we had 9/548 (0.02%) visually impaired (Snellen acuity<0.3)

among patients type 2 ≤70 years at diagnosis, and 1 legally blind (<0.1 Snellen). Of the 22

blind right eyes and 16 left eyes only one right and one left eye did not have any other known

reason than diabetes for their blindness. Totally 38 blind eyes at about 10 years duration is in

same magnitude as total 30 legally blind eyes from 1148 patients after 7.5 years in the

UKPDS 69 (Matthews & al. 2004).

Many older patients have other complicating eye diseases like glaucoma, retinal vascular

diseases and age related macular degeneration (AMD), contributing to their visual

impairment. Theoretically there might be an association through oxidative stress and

inflammation between diabetes and those diagnoses. Diabetes is considered as a risk factor in

retinal vein occlusion, and often implies more complications (more ischemia) whenever it

occurs in diabetics. The Oxford Record Linkage Study could see a relation between diabetes

and AMD, glaucoma (neovascular glaucoma included), retinal vein and artery occlusion as

well as cataract (Goldacre & al. 2012). The Beaver Dam Eye Study (Klein & al. 1992) didn’t

find any relationship between AMD and diabetes. For glaucoma there is no consensus on

whether diabetes is a risk factor (Primus & al. 2011).

Complication rate for type1 diabetics, and probably for type 2, has decreased with debut

1996-1998, related to populations with debut 20-30 years earlier due to better follow up and

treatment in well developed countries (Klein & Klein 2010). Ten years of follow up is

relatively short. Many diabetics with high age at debut, and restricted expected remaining life

time, do not have time to develop significant retinopathy. But we can not conclude that there

is an upper age limit for including diabetics in a screening program. There was no difference

in development of retinopathy in different age groups. As we see an abrupt increase of

retinopathy after 10 yeas, it would be interesting to make a new follow up at 15 years.

We conclude that most diabetic patients do well during 10 years follow up. Patients with

severe visual impairment often have ocular co morbidity, and that the extent of screening is

reasonable.

Ref

1. D M Squirrel, J F Talbot. Screening for diabetic retinopathy. J R Soc Med 2003; 96:273-

276

2. E M Kohner, S J Aldington, I M Stratton, S E Manley, R R Holman, D R Matthews, R C

Turner. Diabetes Retinopathy at Diagnosis of Non-Insulin-Dependent Diabetes Mellitus and

Associated Risk Factors. UKPDS 30. Arch Ophtalmol 1998; 116 (3): 297-303

3. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation

treatment for diabetic retinopathy, ETDRS report number 9 Ophthalmology 1991; 98:766-85

4. R Klein, B E Klein, S E Moss, K J Cruickshanks. The Wisconsin Epidemiologic Study of

Diabetic Retinopathy XV. Ophthalmology 1995; 102 (1):7-16

5. UKPDS 33. Intensive blood-glucose control with sulphonylureas or insulin compared with

conventional treatment and risk of complications in patients with type 2 diabetes. The Lancet

1998; 352: 837-852

6. UKPDS 38. Tight blood pressure control and risk of macrovascular and microvascular

complications in type 2 diabetes. BMJ 1998; 317: 703-713

7. N H White, W Sun P A Cleary, W V Tamborlane, R P Danis, D P Hainsworth, M D Davis.

Effect of Prior Intensive Therapy in Type I Diabetes on 10-Year Progression of Retinopathy

in the DCCT/EDIC: Comparison of Adults and Adolescents. Diabetes 2010; 59 (5):1244-

1253

8. J B Brown, K L Pedula K H Summers. Diabetic Retinopathy. Contemporary prevalence in

a well controlled population. Diabetes Care 2003; 26: (9) 2637-2642

9: I M Stratton, E M Kohner, S J Aldington, R C Turner, R R Holman, S E Manley, D R

Matthews. Risk factors for incidence and progression of retinopathy in Type II diabetes over

6 years from diagnosis. UKPDS 50 Diabetologia 2001; 44: 156-163.

10. B Berger, G Stenström, Y-F Chang, G Sundkvist. The Prevalence of Diabetes in a

Swedish population of 280411 Inhabitants. Diabetes Care 1998; 21 (4): 546-548.

11.B Berger, G Stenström, G Sundkvist. Incidence, Prevalence, and Mortality of diabetes in a

Large Population. A report from the Skaraborg Diabetes Register. Diabetes Care 1999; 22

(5):773-778

12. American Association of Ophthalmology (AAO) Focal Points, September 1993

13. D R Matthews, I M Stratton, S J Aldington. Risk of progression of retinopathy and vision

loss related to tight blood pressure control in type 2 diabetes, UKDPS 69.Arch

Ophthalmology 2004; 122 (11): 1631-40

14. R Klein, B E K Klein, S E Scot, K L P Linton. Retinopathy in Adults with Newly

Diagnosed Diabetes Mellitus. The Beaver Dam Eye Study. Ophtalmology 1992; 99 (1): 58-62

14 B Diabetes, hyperglycemia and age related maculopathy

15. R Klein, B E K Klein. Are Individuals With Diabetes Seeing Better? Diabetes 2010; 59

(8): 1853-1860.

16. S Primus, A Harris, B Siesky, G Guidiboni. Diabetes: a risk factor for glaucoma? Br.

Journal of Ophtalmology 2011; 95: 1621-1622.

17. M J Goldacre, C J Wotton, T D L Keenan. Risk of selected eye diseases in people

admitted to hospital for hypertension or diabetes mellitus: record linkage studies. Br J

Ophthalmol 2012;96(6):872-876

18 E Y Chew, W T Ambrosius, M D Davis, ACCORD

19 Sjöllie et al. DIRECT-Protect 2 Effect of condesartan on progression and regression of

retinopathy Lancet 2008 vol 372 Oct 2008.

Table 1

Criteria of inclusion Age at debut Type* Duration at first screening episode

Screening interval (no retinopathy)

Before 2000

<70 years 2 5 years 2 years “

<40 years 1 5 years 1-2 years”

>40 years 1 0 years 1-2 years”

Dietary treated 5 and 10 years **”

>70 years 1 and 2 Excluded –

After 2000No limit 1 and 2 0 years 2-3 years

Dietary treated 0 years ***Type* 1 Insulin dependent

2 Non-insulin dependent** Excluded after 10 years*** Excluded until medically treated“ Excluded if >72 years old

Table2

Table I Grading of retinopathy in patients from the Skaraborg Diabetes Registry 1996-1998

Retinopathy grade

Description

0 No retinopathy

I (mild) At least one MA, few retinal H and/or HE, nerve fiber infarcts, SE

II (moderate) More MA, H, HE and/or SE

III (pre-proliferative) PPR (several MA, H, SE and/or venous beading and/or IRMA)

IV (proliferative) PR in periphery of retina or in papilla or treated with pan-retinal photocoagulation

Significant maculopathy HE, retinal thickening < 500µ from foeva or ≥1 disc area within 1 disc diameter from foeva

Treated macular oedema/no maculopathy No residual oedema or exudate

MA, microaneuysm, H, hemorrages, HE, hard exudates,IRMA, intraretinal microangio-pathies; PPR, pre-proliferative retinopathy; PR proliferatibve retinopathy; SE, soft exudates

Number in register Examination* Number

examined Dead Any retinopathy Maculopathy Proliferative Visus Other

reasonLaser treatment

Examined

>0,5 < 0,3 Mac Panret

Type1106

ABC

759795

114

51124

036

024

709795

689691

112

111

024

014

Type 21138 (1 secondary)

ABC

421607663

79190289

3186

157

41829

139

392650661

367612601

172726

797

41018

2(1”)4(2””)

10(5”””)

Type 014

ABC

542

91112

100

000

000

533

432

000

100

000

000

Total1258

ABC

502768763

89206305

37100165

62135

16

13

465748759

438709684

172628

9108

41122

2(1”)7(2””)

14(5”””)

Results Cohort A (n= 1258)

Table 3* A = first examination 1996-2000 B = second examination 2001-2003

C = third examination, latest“ 1 patient with branch vein occlusion (BRVO)“” 2 patients with BRVO“”” 1 patient with central vein occlusion (CRVO), 2 with arterial occlusion, 2 with BRVO

Table 4

Patients ≤ 70 at diagnosis with diabetes mellitus type 2

Number of patients Examination 1

1996-1998

Examination 2

2000-2002

Examination 3

2003- August

2009§

Number examined 288 540 559

Any retinopathy 21 76 144 (25.6%)

Maculopathy 3 15 40 (5.7%)

Proliferative

retinopathy

0 2 7(1.4%)

Laser treatment

A maculopathy

B scatter

3

3

0

7

7

1

19 (3.4%)

18

6 (1BRVO)

Visual acuity

Number examined

≥0.5

≤0.3

264

259

3

541

514

5

548

527

9

Other reason for

visus< 0.3

3 5 6

Mortality 20* 53** 114***

*Before 01/01/99, ** Before 01/01/03, *** Before 10/08/09, § last examination

17

Table 5

Test Statisticsa

HbA1c_1 HbA1c_2 HbA1c_3

Mann-Whitney U 1780,000 3033,000 4742,000

Wilcoxon W 22486,000 99174,000 122597,000

Z -1,562 -3,754 -1,839

Asymp. Sig. (2-tailed) ,118 ,000 ,066

a. Grouping Variable: maculopati at any examination

Table 6

Means and Medians for Survival Time

HBA1C96_7

Meana Median

Estimate

Std.

Error

95% Confidence Interval

Estimate

Std.

Error

95% Confidence Interval

Lower

Bound

Upper

Bound

Lower

Bound

Upper

Bound

<7 11,318 ,205 10,916 11,720 11,937 ,067 11,807 12,068

>=7 10,257 ,195 9,875 10,638 11,346 ,115 11,120 11,571

Overall 10,943 ,154 10,641 11,246 11,639 ,148 11,348 11,929

a. Estimation is limited to the largest survival time if it is censored.

Table7

BP96_reg * ret_status Crosstabulation

ret_status

TotalNo retionopathy Any retinopathy

BTB96_reg No treatment Count 322 140 462

% within BTB96_reg 69,7% 30,3% 100,0%

Hypertension

treatment

Count 172 50 222

% within BTB96_reg 77,5% 22,5% 100,0%

Total Count 494 190 684

18

% within BTB96_reg 72,2% 27,8% 100,0%

Table 8

Variables in the Equation

B SE Wald df Sig. Exp(B) 95,0% CI for

Exp(B)

Lower Upper

SBP96_reg ,105 ,038 7,784 1 ,005 1,111 1,032 1,196

HBA1C96_reg 2,253 ,699 10,399 1 ,001 9,518 2,420 37,436

HBA1C96_reg*SBP96_reg -,014 ,005 7,688 1 ,006 ,986 ,976 ,996

19

Figure1: Illustration of the cohort

20

1258 (cohort A)deb 1996-1998

(305 dead)

381 deb > 70 years(cohort C)(187 dead)

877 debut< 70 years(cohort B)(118 dead)

6 type 0

2type 1

403type 2

8type 0

104type 1

765type 2

Population distribution

Fig 2 Retinopathy related to BMI at diagnosis

Fig 3 relation between systolic blood pressure at diagnosis (SBP96) and retinopathy

21

Fig 4 Retinopathy related to HbA1c 96 and duration in years

22

Fig 5 Distribution of HbA1c96 and HbA1c01

23

Fig 6 Maculopathy related to HbA1c96 and duration in years.

24

Fig 7 Relation BP96/ Hba1c96 and development of maculopathy

25