Complications of Diabetes

1
Complications of Diabetes

• Sunder Mudaliar, M.D.
• Staff Physician
• VA Medical Center, San Diego
• Associate Clinical Professor of Medicine
• University of California, San Diego
• Co-Investigator, Diabetes Prevention Program

2
Overview of the Different Types of Complications

• Microvascular Complications
• Retinopathy, Nephropathy and Neuropathy
• Macrovasular Complications
• Coronary Heart Disease, Stroke and PVD
• Other Complications
• Gastrointestinal, Dermatologic, and
  Rheumatologic
• Emotional Complications
• Fear, Guilt, Anxiety, Depression, Denial, etc

3
Diabetic Retinopathy

• 1 cause of new blindness in working-age adults
  in US1
• 12,00024,000 lose sight because of diabetes each
  year1
• NEI 90 of lost vision is preventable2

1. CDC. Available at www.cdc.gov/diabetes/pubs/es
timates.htm2. National Eye Institute. Facts
About Diabetic Retinopathy. Available at
www.nei.nih.gov/health/diabetic/retinopathy.htm
4
Diabetic Nephropathy

• 1 cause of ESRD in US43 of all new cases1
• 38,160 patients developed ESRD in 1999 104 each
  day1
• 100 more develop diabetic nephropathy each day1
• Over 130,000 with diabetes undergo dialysis or
  kidney transplantation each year
• NIDDK most future ESRD is probably preventable2

1. Statistics for Diabetes and Nephropathy
(Kidney Complications). Available at
www.diabetes.org/main/info/facts/facts_nephropath
y.jsp 2. National Kidney Disease Education
Program. Available at www.nkdep.nih.gov/pdf/fina
lstrategicplan.pdf
5
Diabetic Neuropathy

• 60 to 70 of people with diabetes have mild to
  severe forms of nervous system damage
• Major factor leading to lower extremity
  amputations

CDC. Available at www.cdc.gov/diabetes/pubs/estim
ates.htm
6
Diabetic Amputations

• Diabetes is 1 cause of nontraumatic lower
  extremity amputations in US60 of all
  amputations1
• 15- to 40-fold increase risk vs nondiabetic
  population1
• 82,000 limbs lost/yrnearly 225/day1
• ADA and CDC gt85 of limb loss is preventable2

1. CDC. Available at www.cdc.gov/diabetes/pubs/es
timates.htm) 2. Skyler JS. Am Fam Physician.
1998581290
7
Cellular and Molecular Mechanisms of Vascular
Disease in Diabetes
Glucose
Diacylglycerol
Flux thru hexosamine pathway
Advanced glycation end products
Polyol pathway flux
Protein kinase C activation ? And ? isoforms
Aldose Reductase
Glucose Sorbitol
eNOS Endothelin-1 Vascular
endothelial growth factor (VEGF) Tumor growth
factor ? NADPH Oxidases PAI-1 Nuclear factor
? B
Arachidonate Prostaglandin E2
Altered Protein function Gene
expression Signal Induction
NADPH
Regeneration of reduced glutathione
Na/K ATPase
Altered Redox state
Abnormal blood flow Prthrombotic
state Angiogenesis Altered gene expression
Vascular Dysfunction
8
Evidence For Treatment of Diabetic Complications
9
DCCT Study Design

• Prospective study in type 1 diabetes
• Random treatment assignment
• 2 cohorts
• Primary prevention (no retinopathy at baseline)
• Secondary intervention (mild retinopathy at
  baseline)
• 2 interventions
• Intensive
• Conventional
• 1441 patientsfollowed up to 9 yr

DCCT. N Engl J Med. 1993329977
10
Effect of Intensive Glycemic Control in the DCCT
HbA1c Levels
Conventional therapy
HbA1c ()
Intensive therapy
6.05
Normal
Study year
Diabetes Control and Complications Trial Research
Group. N Engl J Med. 1993329977-986.
11
Intensive Therapy ReducesRisk of Retinopathy and
Nephropathy DCCT
Retinopathy Primary Prevention
Nephropathy (albuminuria) Primary Prevention
-76 Plt0.001
-34 Plt0.04
Cumulative percent progressing
Secondary Intervention
Secondary Intervention
-54 Plt0.001
-43 Plt0.001
Time (years)
Time (years)
DCCT Research Group. N Engl J Med.
1993329977-986.
12
DCCT Diabetic ComplicationEvent Rates
76 Risk Reduction
59 Risk Reduction
39 Risk Reduction
54 Risk Reduction
64 Risk Reduction
60

• 55.0

50
40
Cumulative Incidence ()
30
29.8

• 23.9

20
16.4

• 13.4

10
13.0
7.9

• 5.1

5.0
2.5
0
Retinopathy
Laser Rx1
Micro-
Albuminuria2
Clinical
Progression1
albuminuria2
Neuropathy3
1. DCCT Research Group. Ophthalmology.
1995102647 2. DCCT Research Group.Kidney Int.
1995471703 3. DCCT Research Group. Ann Intern
Med. 1995122561
13
DCCT Lifetime Benefits of Intensive Therapy
Gain inComplications-Free Living
15.3
Gain in Length of Life
5.1
0
5
10
15
20
Years
Significant microvascular or neurologic
complication
DCCT. JAMA. 19962761409
14
Relative Risk of Progression of Diabetic
Complications as a Function of Mean A1C
19
Diabetic retinopathy
17
Nephropathy
15
Severe nonproliferative or proliferative
retinopathy
13
Neuropathy
11
Microalbuminuria
Relative Risk
9
7
5
3
1
6
7
8
9
10
11
12
A1C
Based on DCCT data
Reprinted with permission from Skyler J.
Endocrinol Metab Clin North Am. 199625243
15
Insulin Reduces Long-term Risk ofMacrovascular
ComplicationsDCCT-EDIC
Nonfatal Myocardial Infarction, Stroke, or Death
From CVD
Any CV Outcome
42 risk reductionP0.02
57 risk reductionP0.02
Cumulative incidence
Conventional
Conventional
Intensive
Intensive
Years since entry
Years since entry
721 694 637 96 705 686 640 118
No. at Risk Conventional 714 688 618 92 Intensive
705 683 629 113
CVcardiovascular CVDcardiovascular disease
DCCT/EDIC Study Research Group. N Engl J Med.
20053532643-2653
16
UKPDSMain Randomization
Eligible
4209
Overweight
342
Metformin
Overweight and Nonoverweight
3867
Conventional Policy
Intensive Policy
1138 (30)
2729 (70)
Aim FPG lt15.0 mmol/L (lt270 mg/dL)
Aim FPG lt6.0 mmol/L (lt108 mg/dL)
Sulfonylurea
Insulin
Hyperglycemia
1573
1156
702
Metformin
Chlorpropamide
Insulin
Sulfonylurea
Glibenclamide
Glipizide
73 (Overweight)
788
259
370
615
170
Adapted from UK Prospective Diabetes Study
(UKPDS) Group. Lancet. 1998352837-853.
3-8
17
UKPDSIntensive Treatment Policy and Risk
Reduction
P
.0099
Microvascular
25
21
Retinopathy
P
.015
Albuminuria
33
P
.000054
Myocardial
P
.052
16
infarction
Diabetes-related
P
.029
12
end points
0
5
10
15
20
25
30
35
Risk Reduction ()
UK Prospective Diabetes Study (UKPDS) Group.
Lancet. 1998352837-853.
3-11
18
A1C and Risk of Complications in Type 2 Diabetes
UKPDS Epidemiologic Data
Microvascular Complications
Macrovascular Complications
10
Plt0.0001
0
1
1
7
8
9
0
1
0
Plt0.0001
0
5
0
7
8
9
1
0
1
1
Stratton IM et al. BMJ. 2000321405-412
19
UKPDS - Conclusions

• Intensive glucose control reduces microvascular
  complications.
• Intensive glucose control has marginal effects on
  macrovascular (atherosclerotic) disease.
• Sulfonylurea and insulin did not increase
  macrovascular disease.
• Both sulfonylurea and insulin increased weight
  gain and the occurrence of hypoglycemia.
• Chlorpropamide group did not do as well as other
  sulfonylurea group or insulin group.

Lancet 1998352837-53
20
Key Messages

• Microvascular complications seen in type 1 and
  type 2 diabetes have the same pathophysiology
• The severity and duration of glucose control is
  the main determinate of the development and
  progression of microvascular complications
• It has been proven that we can prevent the
  development and delay the progression of
  microvascular complications

21
Algorithm for Managing Retinopathy Complications
of Type 2 Diabetes
Screening-PreventionTreatment
Retinopathy Complications

• Annual Exam
• Dilated exam
• Retinal vessels
• Cataract
• Intraocular pressure

Treatment Priorities
Glucose control Hypertension Photocoagulation
Adapted with permission from Bergenstal R et al.
In DeGroot LJ, Jameson JL, eds. Endocrinology.
4th ed. Philadelphia WB Saunders 2001821
22
(No Transcript)
23
Eye Photograph
24
(No Transcript)
25
Photocoagulation Laser Therapy
26
WHY DO DIABETICS GET KIDNEY DISEASE?

• 1. Years of chronically elevated blood
  glucose levels
• 2. Inadequate screening for the early signs of
  kidney disease, delaying treatment
• 3. Poorly controlled blood pressure

27
EARLY SCREENING FOR DIABETIC KIDNEY DISEASE

• 1. Yearly 24 hour urine collection for
  microalbumin
• 2. Frequent and accurate blood pressure
  measurements (know the normal range)

28
Tight Blood Pressure ControlReduces
Complications in Diabetes UKPDS Hypertension Sub
study
Diabetes-Related Deaths
Mortality
40
Tight controlwith captopril or atenolol mean
144/82 mm Hg
32 Risk Reduction
30
P0.02
20
Less tight controlmean 154/87 mm Hg
10
0
0
1
2
3
4
5
6
7
8
9
Stroke
Microvascular Endpoints
with events
with events
20
20
44 Risk Reduction
37 Risk Reduction
P0.01
P0.001
10
10
0
0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Time (years)
Time (years)
UK Prospective Study Group. BMJ. 1998317703-13.
29
Effect of ACE Inhibition on Diabetic Nephropathy
in Patients with Type 1 Diabetes
Captopril
Placebo
Progressing to death, dialysis or
transplant ()

Follow-up (y)
Collaborative Study Group p 0.006 vs
placebo. n 409
Adapted from Lewis EJ et al. N Engl J Med.
19933291456-1462.
30
Algorithm for Managing Nephropathy Complications
of Type 2 Diabetes
Screening-PreventionTreatment
Nephropathy Complications

• Annual Microalbumin
• Screen albumincreatinine ratio
• Repeat to confirm
• Timed specimen
• Interval creatinine clearance if indicated

Treatment Priorities
Glucose control ACE inhibitor or ARB BP
Control Dietary Protein restriction
Adapted with permission from Bergenstal R et al.
In DeGroot LJ, Jameson JL, eds. Endocrinology.
4th ed. Philadelphia WB Saunders 2001821
31
Neuropathy

• Distal,symmetrical polyneuropathy
• Stocking-Glove distribution
• Sensory, Motor and Autonomic fibers
• MAJOR CAUSE OF FOOT PROBLEMS

32
SENSORY NEUROPATHY

• Pain
• Pressure
• Temperature
• Fine Touch
• Vibration

33
Sensory neuropathy

• 52 y/o type 2 Diabetic with peripheral neuropathy
• Furniture shopping
• Importance of Daily Foot Check!

34
Motor neuropathy affecting the intrinsic muscles
of the foot
35
Plantar calluses
36
Etiology of Foot Ulcers

• The majority of foot ulcers appear to result
  from minor trauma in the presence of sensory
  neuropathy
• Mc Neely,MJ,et al. Diabetes Care 182,Feb 1995

37
VASCULAR DISEASE
38
BASIC FOOT EXAM

• Check Pedal pulses!
• Dorsalis pedis (DP) on top of foot
• Posterior Tibial (PT) behind medial malleolus
• Check for protective sensation !

39
PROTECTIVE SENSATION

• Semmes-Weinstein
• Monofilament(5.07)
• 10 gm Pressure
• Check foot while patient closes eyes!

40
Algorithm for Managing Neuropathy Complications
of Type 2 Diabetes
Screening-PreventionTreatment
Neuropathy Complications

• Comprehensive Foot Exam
• Inspection
• Vascular (pulses/ankle-brachial index)
• Vibratory perception (128 Hz)
• Monofilament sensation (10 g)

Treatment Priorities
Glucose control Foot care/foot wear
Adapted with permission from Bergenstal R et al.
In DeGroot LJ, Jameson JL, eds. Endocrinology.
4th ed. Philadelphia WB Saunders 2001821
41
Microvascular Complications Conclusions

• Acute and chronic hyperglycemia lead to
  microvascular complications of the eyes, kidneys
  and nerves.
• Good glycemic control prevents the onset and
  reduces the progression of complications
• Optimal management of microvascular required not
  only glycemic control but also blood pressure
  control, ace inhibition and a long term
  individualized team approach to the patient.

42
What is the common cause of death in people with
diabetes?

• It is not diabetic retinopathy
• It is not diabetic kidney disease
• It is not from amputations
• It is not from hypoglycemia

43
Cardiovascular Disease Leading Cause of Death in
the U.S. 1998
800
700
600
500
Deaths (in thousands)
400
300
200
100
0
Heart disease
Cancer
Stroke
COPD
Morbidity Mortality 2000 Chart Book on
Cardiovascular, Lung, and Blood Diseases. NHLBI.
May 2000.
44
Causes of Death in People With Diabetes
50
40
of Deaths
30
20
10
0
Ischemic Heart Disease
Other Heart Disease
Diabetes
Cancer
Stroke
Infection
Other
Geiss LS, et al. In Diabetes in America, 2nd ed.
1995. Bethesda, MD National Institutes of
Health 1995Chapter 11.
45
CAD Mortality in Type 2 Diabetes
Men
Women
60
60
50
50
Diabetes(Joslin)
Diabetes(Joslin)
40
40
Mortality Rate Per 1000
30
30
No Diabetes(Framingham)
20
20
No Diabetes(Framingham)
10
10
0
0
03
47
811
1215
1619
2023
03
47
811
1215
1619
2023
Duration of Follow-Up (yr)
Duration of Follow-Up (yr)
Krolewski AS et al. Am J Med. 199190(suppl
2A)56s61s.
46
Type 2 Diabetes and CHD 7-yr Incidence of
Fatal/Nonfatal MI
Diabetic Patients
Nondiabetic Patients
45.0
7-Year Incidence of MI
20.2
18.8
3.5
n1304
n69
n890
n169
Haffner SM et al. N Engl J Med. 1998339229
47
Alternative Definition of Diabetes
Diabetes .. Is a state of premature
cardiovascular death which is associated with
chronic hyperglycemia, and may also be associated
with blindness and renal failure.
BM Fisher
Diabet Med 15275, 1998
48
Insulin Resistance SyndromeCardioMetabolic
Syndrome
EnvironmentalInfluences
GeneticInfluences
InsulinResistance
Hyperinsulinemia
GlucoseIntolerance
IncreasedTriglyceride
DecreasedHDL-Cholesterol
Small DenseLDL
Increased Blood Pressure
??PAI-1
Coronary HeartDisease
49
Multiple Assaults on the Vascular SystemDeadly
H Quartet
Insulin Resistance Hyperinsulinemia
Hyperglycemia
Hyperlipidemia
HbA1C lt 7 FPG 90-130 mg/dl PPPG lt 180 mg/dl
LDL goal lt 100 mg/dl (lt 70 mg/dl) HDL goal gt 40
in men and 50 in women Triglycerides lt 150 mg/dl
Low dose Aspirin daily
Hypercoagulable/ Inflammatory State
Hypertension
lt 130/80 mm Hg
50
4S Effect of Simvastatin on Coronary Events6 yr
Nondiabetic Patients
Diabetic Patients
50
45
40
55 Risk Reduction
30
Patients With Major Coronary Event ()
32 Risk Reduction
27
23
20
19
10
0
Placebo
Simvastatin
Placebo
Simvastatin
n4242
n202
CHD death or nonfatal MI
Pyörälä et al. Diabetes Care. 199720614
51
UKPDS BP Control Absolute Risk Reductions
Deaths Related to Diabetes
Any Diabetes-Related End Point
n1148
Less Tight BP control BP lt180/105 mm Hg Tight
BP control BP lt150/85 mm Hg
UKPDS. BMJ. 1998317703
52
HOPE MICRO-HOPE
Primary Endpoints and Total Mortality With ACE
Inhibitors
25
Total Mortality
16
33
Stroke
32
22
MI
20
37
CV Death
26
0
5
10
15
20
25
30
35
40
Percent reduction in RR
Diabetic Overall
The Heart Outcomes Prevention Evaluation (HOPE)
Study Investigators. Lancet. 2000355253-259.
53
ADA Recommendations Aspirinin Adults With
Diabetes

• Use aspirin therapy (75325 mg/day) for
• Diabetic patients with macrovascular disease
• Diabetic patients gt30 yr old with ?1 other CV
  risk factor
• Not recommended aspirin allergy, bleeding
  tendency, anticoagulant therapy, recent GI
  bleeding, and clinically active hepatic disease

ADA. Diabetes Care. 200326(suppl 1)S33
54
UKPDS Glucose Control Risk Reductions
n3867
UKPDS. Lancet. 1998352837
55
Does Intensive Anti-Hyperglycemic Therapy
Increase or Decrease Cardiovascular Risk ??
56
ACCORD Study Interim Results
Standard Therapy Intensive Therapy
HbA1C 7.5 6.4
Mortality 203 257
Mortality Rate 14 per 1000 17 per 1000
NHLBI Press Release Feb 6, 2008
57
ACCORD Study Interim Results

• Discontinued Intensive Therapy Arm
• A thorough review of the data shows that the
  medical treatment strategy of intensively
  reducing blood sugar below current clinical
  guidelines causes harm in these especially high
  risk patients with type 2 diabetes Elizabeth
  Nabel NHLBI Director

NHLBI Press Release Feb 6, 2008
58
What Do We Do in the Light of Current Data ??
59
ACCORD/ADVANCE Study ADA Position

• ACCORD suggests that very intensive glucose
  lowering treatment aimed at normalizing blood
  glucose (A1Clt6) may be detrimental, at least in
  middle-aged and older adults with vascular
  disease or multiple risk factors for vascular
  disease
• Information from ADVANCE is very important and
  further magnifies the uncertainty over whether
  intensive glucose control may harm some people
  with diabetes

60
ACCORD/ADVANCE Study ADA Position

• The ADA awaits the esults of a third trial, the
  VA Diabetes Trial examining the relationship
  between intensive glycemic control and
  cardiovascular outcomes in type 2 diabetes which
  is due out soon
• In the meantime, the ADA continues to advise
  most people with diabetes to strive for an A1C of
  lt 7, but as always stresses individualization of
  treatment goals. People with type 2 diabetes who
  have existing CVD or multiple CVD risk factors
  should consult with their healthcare team about
  their treatment goals

61
Reducing The Burden of CVDin Diabetes

• Near normal diabetes control
• Aggressive treatment of dyslipidemia and
  hypertension
• One aspirin a day
• ACE inhibition
• Exercise and eat well
• Stop smoking

62
Dermatologic ComplicationsDry Skin Fungus
InfectionsYeast InfectionsAcanthosis
NigricansNecrobiosis LipoidicaEruptive Xanthomas
63
Dry skin mainly from decreased Sweating due to
autonomic neuropathy
64
Fungus nails associated with immunoconprimised
state such as diabetes
65
Tinea or fungus infection on the skin
66
Acanthosis Nigricans associated with insulin
resistance and type 2 diabetes
67
NLD Necrobiosis Lipoidica Diabeticorum Immunologi
c Etiology Type 1 DM
68
Eruptive Exanthomas secondary to
hypertriglyceridemia seen in type 2 diabetes
69
Rheumatologic ComplicationsStiff Hands Trigger
FingersCarpel Tunnel SyndromeAdhesive
CapsulitisDupuytrens ContractureCharcots Joint
70
How Does Diabetes Affect the Musculoskeletal
System?

• It is thought that the increased glucose levels
  cause changes in collagen, an important component
  of musculoskeletal tissue
• Microvascular complications of diabetes are also
  thought to play a role (endothelial cell
  dysfunction)

71
Diabetic Stiff Hand Syndrome or Limited Mobility
Syndrome

• Prayer sign

72
Trigger Finger

• Flexor tenosynovitis
• Swelling where flexor tendon passes through its
  sheath

73
Charcots JointDiabetic Osteoarthropathy

• Charcot or neuropathic joint
• A severe destructive arthritis
• Caused by underlying diabetic peripheral
  neuropathy gt repeated inadvertent microtrauma to
  the joint (unnoticed)
• Feet most commonly affected

74
Gastrointestinal Manifestations

• Gastroparesis
• Bacteria Overgrowth Syndrome
• Constipation
• Diarrhea (exocrine deficiency)

75
Periodontal Disease

• Tooth and gum disease is common in diabetes
• Brush twice a day
• Floss once a day
• At least 1 week before and after the dentist
  visit!

76
Emotional Complications Obstacles to Good
Self-Care

1. Stress and depression
2. Poor social support
3. Paralyzing beliefs
4. Discouraging results
5. An unclear plan for action

77
Prevalence of Tough Feelings

• Worrying about complications 82
• Hopeless about complications 69
• Diabetes takes too much energy 66
• Feel angry, scared or depressed 58
• Diabetes controls my life 60
• indicating at least a minor problem (gt2)

78
Towards A Clear Plan for Action

• Make your action steps CLEAR
• Make your action steps MEANINGFUL
• Make your action steps ACHIEVABLE
• PRIORITIZE your action steps

79
Inaccurate Beliefs AboutPoor Adherence Strong
Endorsements by Physicians
Poor self-discipline 53.2 Poor will
power 50.0 Not scared enough 36.9 Not
intelligent enough 16.3
Polanski WR, Boswell SL, Edelman SV. J Diabetes.
199645(suppl 2)14A. Abstract.
80
Overview of the Different Types of Complications

• Microvascular Complications
• Retinopathy, Nephropathy and Neuropathy
• Macrovasular Complications
• Coronary Heart Disease, Stroke and PVD
• Other Complications
• Gastrointestinal, Dermatologic, and
  Rheumatologic
• Emotional Complications
• Fear, Guilt, Anxiety, Depression, Denial, etc