Tight Blood Glucose and Blood
Pressure (BP) Control
for Prevention and Management of
Diabetic Retinopathy (DR)
Thomas Ciulla, MD, PC
Attending Physician and Surgeon,
Methodist Hospital, Indianapolis
Co-Director, Retina Service
Midwest Eye Institute
Indiana University
Indianapolis, Indiana
1
Presentation Outline
• DR Overview
– Risk factors
– Characteristics
– Complications
• Prevention
– Primary care provider role
– Risk factor management
– Referral and screening recommendations
• Supporting evidence for tight BP and diabetes
control
• Intervention
– Laser photocoagulation
– Vitrectomy
• Roundtable Discussion
2
DR Overview
• Leading cause of blindness in the working-age
population
– Vision to 20/200 or worse in 50% of patients
within 5 yrs of proliferative diabetic retinopathy
(PDR) onset
– Complications can have sudden and severe
effects on visual acuity
• Affects retinal vessels
3
American Diabetes Association (ADA). Available at: http://www.diabetes.org/diabetes-statistics/complications.jsp.
Ferris F. Tr Am Ophth Soc. 1996;94:505-537.
Ciulla TA, Amador AG, Zinman B. Diabetes Care. 2003;26:2653-2664.
DR Overview
• Two categories
– PDR
– Nonproliferative (NPDR)
• Asymptomatic unless
–
–
–
–
4
Macular edema/ischemia
Vitreous hemorrhage
Retinal detachment
Neovascular glaucoma
ADA. Available at: http://www.diabetes.org/type-1-diabetes/eye-complications.jsp.
American Academy of Ophthalmology (AAO). Available at:
http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZL4RFEH4C&sub_cat=112.
DR Risk Factors
•
•
•
•
•
•
•
•
5
Diabetes duration
Hyperglycemia
Hypertension
Hyperlipidemia
Nephropathy (microalbuminuria)
Pregnancy
Smoking
Cataract surgery
ADA. Diabetes Care. 2005;28(suppl 1):S4-S87.
Chew EY, et al. Arch Ophthalmol. 1999;117:1600-1606.
Fong DS, et al. Diabetes Care. 2004;27:2540-2553.
Haire-Joshu D, Glasgow RE, Tibbs TL. Diabetes Care. 1999;2:1887-1898.
International Clinical DR Disease
Severity Scale
Proposed Disease Severity
6
Dilated Ophthalmoscopy Findings
No apparent retinopathy
No abnormalities
Mild NPDR
Microaneurysms (MAs) only
Moderate NPDR
More than just MAs, but less than severe
NPDR
Severe NPDR
No signs of PDR + any of the following:
• >20 intraretinal hemorrhages in each of 4
quadrants
• Venous beading in ≥2 quadrants
• Intraretinal microvascular anomalies in ≥1
quadrant
PDR
≥1 of the following:
• Neovascularization
• Vitreous or preretinal hemorrhage
Ciulla TA, Amador AG, Zinman B. Diabetes Care. 2003;26:2653-2664.
NPDR
• Levels of severity: mild, moderate, severe
• Severity correlates with probability of
progression to PDR
• Early physiologic changes
– Increased capillary permeability
– Leakage of fluid into the retina
– Macular thickening
– Closure of retinal capillaries
– Macular ischemia
– Vision loss
7
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
Mild NPDR
• Clinical features:
– Dot and blot
hemorrhages (Hs)
– Microaneurysms
(MAs)
• Little threat to vision
• Follow-up every 6-12
months
8
Image courtesy of National Eye Institute (NEI),
National Institutes of Health (NIH). Available at:
http://www.nei.nih.gov/photo/search/keyword.a
sp?keyword=diabetic.
Aiello LP, et al. Diabetes Care. 1998;21:143-156.
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
Moderate NPDR
• Clinical features
– Increased Hs/MAs
– Intraretinal
microvascular
abnormalities (IRMAs)
– Venous beading (VB)
and looping
– Cotton-wool spots
(CWS)
Cotton-wool spot
• Follow-up every 4-6
months
9
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
Image: Custom Medical Stock Photo (CMSP). Available at:
http://www.cmsp.com/cmsp/vlbd231/imagepreview?stockno=Z031-Z-97.
Severe NPDR
• Clinical features
– Hs/MAs in all 4
quadrants
Or
– VB in 2 quadrants
Or
– IRMAs in 1 quadrant
• High risk of PDR
• Follow-up every 2-4
months
10
AAO. 2003; Available at:
http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
Image: Custom Medical Stock Photo (CMSP). Available at:
http://www.cmsp.com/cmsp/vlbab23/imagepreview?stockno=Z031-Z-103.
PDR
• Proliferation of fragile
new vessels
• Neovascularization of
the disk (NVD) or
elsewhere (NVE)
• Attempt to supply
oxygenated blood to
ischemic retina
• Activated endothelial
cells migrate, grow
on posterior surface
of vitreous gel
11
Image courtesy of National Eye Institute (NEI),
National Institutes of Health (NIH). Available at:
http://www.nei.nih.gov/photo/search/keyword.a
sp?keyword=diabetic.
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
High-risk PDR
• Increased risk of
severe vision loss
• Clinical features
– NVD >1/3 disc diameter
– NVD with vitreous or
preretinal H
– NVE >1 disc area with
vitreous or preretinal H
12
Aiello LP, et al. Diabetes Care. 1998;21:143-156.
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
Image: CMSP. Available at: http://www.cmsp.com/cmsp/vlb9a6a/imagepreview?stockno=Z500-Z-5162.
DME
• Consequence of DR at any
stage
• Physiologic changes
– Blood–retinal barrier breakdown
– Extracellular fluid accumulation
and/or hard exudate deposition
Image courtesy of National Eye Institute (NEI),
National Institutes of Health (NIH). Available at:
http://www.nei.nih.gov/photo/search/keyword.a
sp?keyword=diabetic.
13
• Focal, diffuse, or ischemic
• Visual acuity loss, impaired
color vision, metamorphopsia
• Clinically significant ME
(CSME)
– Involves or threatens fovea
– Endangers central vision
– Macular laser treatment
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
Aiello LP, et al. Diabetes Care. 1998;21:143-156.
Porta M, Bandello F. Diabetologia. 2002;45:1617-1634.
Complications of Severe PDR
• Tractional retinal detachment
1
– Fibrotic NV and posterior gel
surface pull on retina and cause
detachment
– Leads to severe vision loss
2
• Vitreous hemorrhage
– Fragile NV tears and bleeds
• Neovascular glaucoma
3
– NV on iris and trabecular meshwork
– Causes elevated pressure, pain,
blindness
14
AAO. Available at: http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZL4RFEH4C&sub_cat=112.
Images: 1CMSP. Available at: Available at:http://www.cmsp.com/cmsp/vlb5d03/imagepreview?stockno=Z031-Z-157.
2
CMSP. http://www.cmsp.com/cmsp/vlb7bb4/imagepreview?stockno=Z031-Z-130.
3
Courtesy of Thomas Ciulla, MD, PC.
DR Prevention:
Role of the Primary Care Physician
• Identify patients at risk for DR
• Educate patients about DR consequences
• Coordinate risk factor management
– Hyperglycemia
– Hypertension
– Hyperlipidemia
• Refer for screening and treatment
• Be aware of the role of laser
photocoagulation and surgical intervention
15
O’Shea JG, Infeld DA. Available at: http://medweb.bham.ac.uk/easdec/screening_review.html.
Colucciello M. Postgrad Med. 2004;116:57-64.
DR Prevention and Early Treatment:
Screening and Exam Recommendations
Diabetes Type
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First Exam
Follow-up
Type 1
5 yrs after onset
Annually
Type 2
At diagnosis
Annually
Prior to pregnancy
(type 1 or type 2)
Prior to conception or • No DR to moderate
early in the first
NPDR: every 3-12
trimester
months
• Severe NPDR or
worse: every 1-3
months
ADA. Diabetes Care. 2005;28(suppl 1):S4-S87.
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
Evidence: Benefits of Glycemic Control
• United Kingdom Prospective Diabetes
Study (UKPDS)
– Type 2 diabetes
– Tight control (oral agents or insulin) vs
conventional treatment
– Tight control reduced the risk of diabetic
retinopathy progression by 21%
– Tight control reduced the risk of retinal
photocoagulation by 29%
17
UKPDS Group. Lancet. 1998;352:837-853.
Evidence: Benefits of Glycemic Control
• Diabetes Control and Complications Trial
(DCCT)
– Type 1 diabetes
– Tight (intensive insulin) vs conventional
treatment
– 76% risk reduction (RR) in DR development
– 54% RR in DR progression
• Tight glycemic control is an effective
medical treatment to slow onset and
progression of DR
18
DCCT Research Group. N Engl J Med. 1993;329:977-986.
Evidence: Benefits of BP Control
• UKPDS (Report No. 38)
– Tight (T) vs less tight (LT) BP control
– 37% reduction in DR progression
– 47% RR in visual acuity deterioration
• Eurodiab Controlled Trial of Lisinopril in
Insulin Dependent Diabetes (EUCLID)
– Normotensive type 1 diabetes patients
– Trend (not significant) toward reduced
retinopathy progression
19
Reviewed in Fong D, et al. Diabetes Care. 2004;27:2540-2553.
Evidence: Benefits of BP Control
• Appropriate Blood Pressure Control in
Diabetes (ABCD)
– Type 2 diabetes patients with hypertension,
intensive vs moderate BP control
– Also, normotensive type 2 diabetes patients,
antihypertensive agents (AHA) vs placebo
– 5 yrs
– Hypertensive group: no difference in DR
progression
– Normotensive group: DR progression less
frequent among AHA-treated
20
Fong D, et al. Diabetes Care. 2004;27:2540-2553.
UKPDS 69:
Hypertension in Diabetes Study (HDS)
• Primary objective: Determine the
relationship between tight BP control and
DR in type 2 diabetes patients
– DR considered apart from nephropathy and
neuropathy
– Endpoints: photocoagulation, vitreous
hemorrhage, specific lesions, retinopathy
progression, vision loss
21
UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
UKPDS Group. Diabetologia. 1991;34:877-890.
UKPDS 69: Study Demographics
• HDS participants comprised of a subset of UKPDS
participants
– Newly diagnosed type 2 diabetes patients
– Exclusion criteria (for UKPDS):
•
•
•
•
•
•
•
•
•
•
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Retinopathy requiring photocoagulation
Malignant hypertension
Ketonuria
MI in the previous year
Current angina or heart failure
>1 vascular episode
Elevated serum creatinine
Uncorrected endocrine abnormality
Occupation prohibiting insulin therapy
Life-threatening or systemic illness
UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
UKPDS 69: Study Demographics
• N = 1,148
• 54% male
• 56.4 ± 8.1 yrs of age
• Enrollment based on mean of 3 BPs at
consecutive clinic visits
– 160/90 mm Hg if not on antihypertensive
therapy
– 200/85 mm Hg if treated for hypertension
23
UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
UKPDS 69:
Study Design–Treatment Protocol
• Tight BP control (T group; n = 758)
– Goal BP <150/85 mm Hg
– ACE inhibitor (captopril; n = 400) OR
– β blocker (atenolol; n = 358)
– Additional agents considered if goal BP was not
attained on maximum allocated therapy drug
• Less tight BP control (LT group; n = 390)
– Goal BP <200/105 mm Hg
– Avoiding therapy with ACE inhibitors or β blockers
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UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
UKPDS 69 Study Design:
DR Assessment
• Retinal color photography, ophthalmoscopy, and
visual acuity at UKPDS enrollment and every 3
yrs thereafter
– 1.5, 4.5, and 7.5 yrs after randomization
• Annual direct ophthalmoscopy
• Lesions (MA, hard exudates, CWS) assessed
• Progression graded using modified ETDRS
scale
• Ocular endpoints: photocoagulation, vitreous
hemorrhage, cataract extraction, vision loss
(acuity and blindness)
25
UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
UKPDS 69: Safety and BP Endpoints
• No reported adverse events
• Among patients with 9-year follow-up data:
– Significantly better BP control in T group
• P <0.001
• T group mean = 144/82 mm Hg
• LT group mean = 154/87 mm Hg
26
UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
UKPDS 69: Outcomes (T vs LT)
• Fewer DR lesions*
– MAs, hard exudates, CWSs
– Significantly lower in T group at 4.5 and 7.5 yrs
– P <0.05 for each
• Slower DR progression*
– Fewer in T group deteriorated 2 steps or more
on ETDRS scale
– P <0.002 and P <0.001 at 4.5 and 7.5 yrs,
respectively
*No difference between captopril and atenolol.
27
UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
UKPDS 69: Outcomes (T vs LT)
• Lower photocoagulation rate*
– Most due to maculopathy
– 37% RR in T group (P = 0.03)
• Vision loss
– Lower risk of blindness in 1 eye in T group
(P = 0.046)
– 47% lower risk of acuity deterioration in
T group (P = 0.004)
*No difference between captopril and atenolol.
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UKPDS Group. Arch Ophthalmol. 2004;122:1631-1640.
Intervention
• If DR progresses despite glycemic and
BP control…
– Intervention
• Laser photocoagulation
• Vitrectomy
• Potential future interventions?
– Intraocular injections
– Oral agents
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Laser Photocoagulation
• Delivered through a slit-lamp
via a corneal contact lens
• PDR
–
–
–
–
Panretinal (PRP; scatter)
Palliative
Destroys ischemic retinal tissue
Seals, shrinks, and prevents
growth of abnormal vessels
– AEs: ↓night, color, peripheral vision;
exacerbate existing DME
Image courtesy of NEI, NIH
• DME
–
–
–
–
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Focal for focal DME
Grid for diffuse or ischemic DME
Cauterizes leaking MAs
Allows absorption of fluid, hard exudates
AAO. 2003; Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf.
AAO. 2003. Available at: http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZL4RFEH4C&sub_cat=112.
Image: NEI, NIH. Available at: http://www.nei.nih.gov/photo/search/keyword.asp?keyword=diabetic.
Vitrectomy
• To remove vitreous
hemorrhage
• To treat or prevent
retinal detachment
• Outpatient procedure
• Usually combined with
PRP
31
AAO. 2003. Available at: http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZL4RFEH4C&sub_cat=112.
Image: EyeMDLink.com. Available at: http://www.eyemdlink.com/EyeProcedure.asp?EyeProcedureID=58.
Summary
• DR is progressive and a leading cause of
blindness
• DR risk factors include hyperglycemia and
hypertension
• Tight glycemic and BP control decrease
risks of DR development and progression
• If all else fails, surgical intervention may
prevent further vision loss
32