Microvascular Complications

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Microvascular Complications

• Flemming Pociot
• Steno Diabetes Center
• STAR Research Course Epidemiology

2
Therapeutic failure in diabetes

• When a patient reaches end stage renal failure
• When a patient becomes blind or severely visually
  impaired
• When a patient has a leg or foot amputated
• When a patient suffers from MI or stroke

3
Screening/detection of late diabetic complications

• Ophthalmoscopy / fundusphotography and visual
  acuity
• Urinary albumin excretion (A/C) and
  s-creatinine
• Blood pressure
• Foot inspection, pulse and vibration threshold

4
Screening/detection of late diabetic complications

• Heart ECG
• Lipids
• Autonomic neuropathy(beat-beat, DBP)
• Erective dysfunction

5
T2DM and complications

• Ratio diagnosed / undiagnosed
• industrialized countries 1 1
• developing countries 1 9
• Complications at diagnosis
• - Retinal 30-40
• - Microalbuminuria 15-30
• - Atherosclerosis 15-25

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INDIA a prediction(all numbers in millions)

• 1994 2010
• Visual impairment 3.5 9.0
• Blind 1.0 2.8
• Renal insufficiency 3.0 8.0
• Amputations ½ - 1 3 - 4

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Retinopathy in Type 1 diabetes

• Background retinopathy
• Present in 90 with 15 years of diabetes
• Maculopathy
• Present in 25 with 25 years of diabetes
• Proliferative retinopathy
• Present in 50 with 25 years of diabetes

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Prevention and treatment of diabetic retinopathy
Primary prevention BG BP Secondary
prevention BG BP Tertiary prevention Laser Vit
rectomi
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DCCT Primary-prevention cohorte
Development of retinopathy
HbA1c 9.1
HbA1c 7.3
NEJM 1993329977
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DCCT Secondary-intervention cohorte
Progression of retinopathy
HbA1c 9.1
HbA1c 7.3
NEJM 1993329977
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DCCT Type 1 diabetes
10 reduction in HbA1c yields 40 reduction in
retinopathy progression
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UKPDS (Type 2 diabetes)

• Intervention Laser treated retinopathy
• ? 1 HbA1c ? 37
• ? 10/5 mm Hg ? 35

13
EUCLID Retinopathy (n354 T1D ptt, 2 years
treatment)
Odds ratio (95 CI) Progression of simplex
retinopathy 0.50 (0.28-0.89) Progression of
proliferative retinopathy 0.18 (0.04-0.82)
Chaturvedi et al. (1998) Lancet 351 28-31
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Laser treatment of diabetic retinopathy
Rate of Severe Visual Loss
Year of Study
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SummaryPrevention and treatment of retinopathy

• Strict metabolic control
• Antihypertensive treatment
• Regular screening
• Laser therapy
• Surgical treatment
• ACE- inhibition ?
• Lipid lowering drugs?
• Prevention of diabetic nephropathy ?

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Cumulative incidence of proliferative retinopathy
in type 1 diabetes
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Diabetic nephropathy

• Diabetic nephropathy is irreversible in humans
• No cases of recovery or cure have been reported
  in the literature
• Once the clinical signs of nephropathy have
  become manifest, the natural course is inexorably
  progressive to death
• The rate of progression is accelerated in the
  later stages

Kussman et al. Jama 1976
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Clinical diagnosis of diabetic nephropathy

• Persistent albuminuria (gt300 mg/24 h)
• Presence of diabetic retinopathy
• No clinical or laboratory evidence of kidney or
  the renal tract disease other than diabetic
  glomerulosclerosis

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Progression of Diabetic Renal Diseasein Patients
with Diabetes
2000
2000
40
? GFR 2-2010
Overt nephropathy
200
200
? GFR 1-3
Albuminuria (µg/min)
Albuminuria (µg/min)
Microalbuminuria
20
20
Normoalbuminuria
? GFR 1
60
2
2
Time (Years)
Time (Years)
20
Diabetic Nephropathy

• 40

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Diabetic nephropathy - costs

• Dialysis 75,000 /year
• Transplantation 15,000 /year

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Prevention and treatment of diabetic nephropathy

• TYPE 1 diabetes
• Primary prevention
• Secondary prevention
• Tertiary prevention

• TYPE 2 diabetes
• ? Progression from normo- to microalbuminuria
• Progression from microalbuminuria to DN
• Progression from DN to ESRD

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Treatment modalities in normo- and hypertensive
patients with incipient and overt diabetic
nephropathy

• Blood pressure reduction
• ? UAE
• T1D ACEi
• T2D A2A
• Improved metabolic control
• Low protein diet ?

24
Treatment of patients with diabetes and
microalbuminuria

• Strict metabolic control
• Antihypertensive treatment
• Blockade of the angiotensin system
• ACE inhibition
• Angiotensin II receptor blocking

25
DCCT Cumulative incidence of micro- and
macroalbuminuria (dashed line)
DCCT (1993) NEJM 329977-986
26
Should all Type 1 diabetic microalbuminuric
patients receive ACE inhibitors ? - a meta
regression analysis (n698)

• 62 reduction in progression to nephropathy
• 3 times ? in regression to normoalbuminuria
• 50 reduction in UAE at 2 years
• Preservation of GFR

Chaturvedi, Ann Intern Med, 2001
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Primary prevention ACEI vs placebo in
normoalbuminuria

• Risk reduction for development
• of MA / progression in UAE
• EUCLID 12.7 ( -2.9 to 26)
• Ravid et al. 12.5 ( 2 to 23)
• MICRO-HOPE 9.0 ( - 4 to 20)

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In summary primary prevention of development of
diabetic nephropathy

• Strict metabolic control
• ACE inhibition
• Lipid lowering drugs?
• Low protein diet?

29
Microalbuminuria

• Higher prevalence of retinopathy, neuropathy and
  foot ulcers
• Enhanced cardiovascular morbidity
• Enhanced all-cause mortality, especially
  cardiovascular
• Predict development of diabetic nephropathy

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The Steno Type 2 study
160 Type 2 diabetic patients with
microalbuminuria
Odds ratio of progression

• Pharmacological Tx
• hyperglycaemia
• hypertension
• dyslipidaemia
• microalbuminuria
• Behavior modification
• exercise
• diet
• smoking

nephropathy
retinopathy
autonomic neuropathy
peripheral neuropathy
0
0,5
1
1,5
2
Favours intensive therapy
Favours standard therapy
Gæde et al, Lancet, 1999
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Effective long-term antihypertensive treatment in
diabetic nephropathy

• Reduces albuminuria
• Reduces the rate of decline in kidney function
• Postpones end stage renal disease
• Improves survival

36
In summary secondary prevention of development
of diabetic nephropathy

• Strict metabolic control
• Antihypertensive treatment
• ACE inhibition
• Angiotensin receptor blockers
• Both ?
• Multifactorial intervention
• Low protein diet ?

37
Start of antihypertensive treatment
38
Effect of ACE inhibition on diabetic nephropathy
in patients with Type 1 diabetes
40
Captopril
Placebo
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Progression to death, dialysis or
transplant ()
p0.006
20
10
0
Follow-up (years)
Lewis EJ et al. N Engl J Med. 1993
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Cumulative incidence of diabetic nephropathy in
type 1 diabetes
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In summary tertiary prevention of progression to
ESRF

• Antihypertensive treatment
• Reduces albuminuria
• Reduces the rate of decline in kidney function
• Postpones end stage renal disease
• Improves survival
• Strict glucose control
• Low protein diet ?
• Lipid lowering drugs ?
• Stop smoking ?

42
Late diabetic complications

• Prevention is better than cure

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