Slide 1

Lecture:
Screening, Treatment and Evaluation of
Complications

Husaini Umar
 Slide 2

Screening, Treatment and Evaluation of Complications

Lecture

Main Learning Points

• Understand the screening, diagnose

and treatment options / refer for
diabetes associated complications:
• Nephropathy
• Retinopathy
• Neuropathy
• Erectile Dysfunction
• CVD
• CAD
 Slide 3

Recap: The goal of diabetes management is to secure

optimal glycemic control to avoid complications

Microvascular Macrovascular
Stroke
Diabetic
retinopathy 1.2- to 1.8-fold
increase in stroke3
Leading cause
of blindness
in working-age
adults1 Cardiovascular
disease
75% diabetic patients
Diabetic die from CV events4
nephropathy

Diabetic
Leading cause of neuropathy
end-stage renal disease2 Leading cause of
non-traumatic lower
Erectile Dysfunction extremity amputations5
The most secretive
Complication of DM
Diabetic Foot

1Fong DS, et al. Diabetes Care 2003;e 26 (Suppl.1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl.1):S94–S98. 3Kannel WB, et al. Am
Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. Textbook of Diabetes 1997. 5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl.1):S78–S79.
 Slide 4

Recap: Risk of Complications increases as Hb1Ac

increases

80
Incidence per 1.000

60
patient-years

Microvascular disease

40 Myocardial infarction

20

0
5 6 7 8 9 10 11
Updated Mean HbA1c (%)

Adjusted for age, sex, and ethnic group

Stratton IM et al. BMJ 2000;321:405–12

 Slide 5

Recap: It’s the diabetes-related complications – not

the diabetes medicine - that carries the biggest cost
to the society

Cost increases with a factor of 22.5 if patients develop complications (ASKES Data)

US$
900
900
800
700
600
500 22.5X
400
300
200
100 40
0
Without Complications With Complications

Approximate Annual Cost / Diabetes Patient

ASKES 2010 Unpublished data

 Slide 6

Positive legacy effect of earlier glucose control

Provides long-term reductions in both microvascular and

macrovascular complications
RRR* at end of UKPDS
RRR* at end F/U (median 8.5 years)

16% 15% 25% 24% 6% 13% 12% 9%

p=0.052 p=0.01 p=0.0099 p=0.001 p=0.44 p=0.007 p=0.03 p=0.04

Myocardial Death Any

infarction (any diabetes
cause) endpoint
Microvascular
disease

RRR: relative risk reduction of intensive therapy over

conventional therapy

UKPDS 80. Holman et al. NEJM 2008; 359:1577-89.

 Slide 7

Classification of Micro- and Macrovascular

Complications

Chronic complications of diabetes

• Microvascular complications
• Kidney – nephropathy » kidney failure
• Eyes – retinopathy » blindness
• Nerves – neuropathy » disability
• Peripheral Arterial Diseases » disability
• Erectile Dysfunction

• Macrovascular complications
• Heart – myocardial infarction
• Brain – stroke
• Atherosclerosis – myocardial infarction
 Slide 8

Microvascular Complications – an overview

Retinopathy and blindness

Nephropathy

Erectile Dysfunction

Neuropathy

International Diabetes Federation. Diabetes Atlas 2006;111–2

 Slide 9

Diabetes Nephropathy
Characteristics

• Persistent albuminuria
• Diabetic retinopathy
• Hypertension
• Decline in kidney function (about 12 ml/min/year)
 Slide 10

Diabetes Nephropathy
Prevention and Treatment

• Maintain tight glycaemic and

blood pressure control

• Multifactorial disease
0.8
management:
• antihypertensive agents
microalbuminuria

0.6
• good blood glucose control
Probability of

0.4 • control of dyslipidaemia

0.2 • monitoring renal function
• lifestyle changes, including
0.0
smoking cessation and
5 6 7 8 9 10 11 12
low-protein diet
Glycated haemoglobin (%)

DCCT. Diabetes 1996;45:1289–98

 Slide 11

Micro / Macro-albuminuria

In 2 of 3 measurements

Micro Macro
24h: 30 - 299 mg/24h >300 mg/24h

Random spot: 30 - 299 mcg/mg >300 mcg/mg

Morning spot: 30 – 299 mcg/mg >300 mcg/mg

Dipstick/overnight albumin: low sensitivity

Slide and
no 11 •specificity
•
Natural history of diabetic nephropathy

GFR Urinary protein excretion

Pre Incipient diabetic Overt diabetic End-stage

Urinary protein excretion (mg/d)

nephropathy nephropathy renal disease
Glomerular filtration rate (GFR)

1 2 3 4 5
5000
150
(mL/min)

100 1000

200
50

20
0
5 10 15 20 25
Years
GFR Microalbuminuria, Proteinuria, nephrotic
Functional
(90-95%) hypertension syndrome, GFR ¯

Vora JP, et al. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. New York: Mosby; 2000
 Slide 13

Treating Albuminuria

• Use ACE-I or ARB in nonpregnant patiens with micro- or

macroalbuminuria
• Reduce protein intake to 0.8-1.0 g/kgBW/day in DM &
early CKD; 0.8 g/kgBW/day in later CKD
• If ACE-Is /ARBs/diuretics are given, monitor serum
creatinine and potassium
• When eGFR <60 ml/min/1.73m2, evaluate for CKD
complications
• Consider referral to experienced physician in kidney
disease care

Diabetes Care. 2012

 Slide 14

Diabetes Retinopathy

Non-
Diabetic
Retina

Diabetic Proliferative
Maculopathy Diabetic
Retinopathy
 Slide 15

Diabetes Retinopathy
Risk Factors and Classification

35 • Poor glycaemic and

Retinopathy incidence (odds ratio)

30
blood pressure control
increase the risk of
25
retinopathy
20
• Five categories:
15 • Mild Nonproliferative
10 • Moderate
Nonproliferative
5
• Severe
0
Nonproliferative
4 5 6 7 8 9 10
London HbA1c (%) • proliferative
5.7 6.7 7.7 8.8 9.8 10.8 11.9 • advanced diabetic
DCCT HbA1c (%) eye disease
• maculopathy

Chaturvedi et al. Diabetes Care 2001;24:284–9

 Slide 16

Diabetes Retinopathy
Prevention and Treatment

• Maintain tight glycaemic and blood pressure control

• Regular eye examinations
• Treat with laser photocoagulation and vitreoretinal
surgery

Klein et al. Ann Intern Med 1996;124:90–6

 Slide 17

Diabetes Neuropathy
Risk Factors and Common Types

Symmetrical
diffuse
Femoral
neuropathy
Other acute
Pressure palsies • Hyperglycaemia
sensorimotor mononeuropathies
neuropathy
(amyotrophy)
is the leading
III VI
cause of diabetic
Truncal neuropathy
Ulnar
• Alcohol makes
neuropathy worse
Median
Lateral • A number of
popliteal
clinical
Sensory loss 0 → +++ Sensory loss 0 → + Sensory loss 0 → + Sensory loss + → +++
syndromes are
Pain + → +++
Tendon reflexes N → ↓
Pain + → +++
Tendon reflexes ↓ → 0
Pain + → +++
Tendon reflexes N
Pain + → ++
Tendon reflexes N
recognisable
Motor deficit 0 → + Motor deficit + → +++ Motor deficit + → +++ Motor deficit + → +++

Pickup & Williams. In: Slide Atlas of Diabetes 2004

Watkins et al. In: Diabetes and Its Management 2003. Pickup & Williams. In: Slide Atlas of
Diabetes 2004
 Slide 18

Diabetes Neuropathy
The Most Frequent Diabetes related Complication in
Indonesia (and in the World…)

A1Chieve Indonesia IDMPS Indonesia

(2.240 patients) (715 patients)
100% 100%
90% 90%
80% 80%
70% 70%
60% 60% 54.0%
50% 50%
41.9%
40% 40% 33.4%
30% 30% 26.5%
21.7% 19.1%
20% 16.1% 20%
6.7% 8.7%
10% 10%
0% 0%
Neuropathy CV Eye Renal Foot Neuropathy Eye Renal Foot
Ulcer Ulcer
Frequency of complications Frequency of complications

Note: One patient can have more than one complication

 Slide 19

Diabetes Neuropathy
Prevention and Treatment

• Maintain tight glycaemic

16 control to reduce the
risk or progression of
Percentage of cases affected

Conventional therapy

12
neuropathy
p<0.001 • Exclude or treat
contributory factors:
8 • alcohol excess
• vitamin B12
4
deficiency
Intensified therapy • uraemia
• Offer pain relief based
0 on the dominant
0 1 2 3 4 5 symptoms
Time (years)

DCCT. NEJM 1993;329:977–86

 Slide 20

Diabetic Foot Complications

 Slide 21

Erectile Dysfunction
Definition

ED is the inability to achieve and maintain an erection

adequate for intercourse to the mutual satisfaction of
the man and his partner.

Remember, both partners in a relationship are affected

 Slide 22

Erectile Dysfunction
Background

• 35%-75% of men with diabetes will experience at least

some degree of ED

• Men with diabetes tend to develop erectile dysfunction 10

to 15 years earlier than men without diabetes.

• Men with diabetes will have ED

• 50%-60% in > 50 years old
• 95% in >70 years old
 Slide 23

Erectile Dysfunction
Risk Factors

 Risk Factors

 Neuropathy

 Peripheral vascular disease

 Poor glycemic control

 Diabetes duration and complications

 Age and high BMI

 Smoking doubles the risk

 Slide 24

Erectile Dysfunction
Screening

Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the
International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999
Dec;11(6):319-26
 Slide 25

Erectile Dysfunction
Treatment Options

• Oral medications: Sildenafil (Viagra), Vardenafil (Levitra),

Tadalafil (Cialis)

• Urethral suppositories (MUSE)

• Injection therapy: Caverject, Trimix, Bimix

• Vacuum constriction device

• Surgery

• Sex therapy
 Slide 26

MACRO VASCULAR
COMPLICATION
 Slide 27

Macrovascular Complications – an overview

Stroke

Cardiovascular/heart disease

Peripheral vascular disease

 Slide 28

Cardiovascular Diseases
Patients with Type 2 Diabetes at a increased risk of CVD

Incidence of myocardial • Risk of cardiovascular

infarction over 7 years
disease is greater in
patients with diabetes
than in those without
• Having diabetes results in
Patients (%)

a similar risk of heart

attack as a prior heart
attack

With diabetes n=1059

Without diabetes n=1373

Haffner et al. N Engl J Med 1998;339:229–34

 Slide 29

Cardiovascular Diseases
Risk for Myocardial infaction and stroke increases with
progression to Type 2 Diabetes

Relative risk for MI and stroke in women

Relative risk

No diabetes Prior to After Diabetic at

during study diagnosis diagnosis baseline

*Nurses’ Health Study (NHS) cohort comprised women only

Adapted from Hu et al. Diabetes Care 2002; 25:1129-34

 Slide 30

Prevention of Cardiovascular Diseases

140 Non-diabetic
• Reduce risk factors for
Number of deaths per 10,000 patient-years

subjects

120 Subjects with cardiovascular disease:

type 2 diabetes
• stop smoking
100
• treat hypertension
80 • treat hyperlipidaemia
• improve glycaemic
60
control
40 • reduce weight in the
obese
20
• take regular exercise
0
0 1 2 3
Number of risk factors

Adapted from Stamler et al. Diabetes Care 1993;16:434–44

 Slide 31

Poor Control of CV Risk Factors in Diabetes (NHANES)

CV risk factors target Frequency

• S-Cholesterol < 200 mg/dl (5.2 mmol/l) 52 %
• BP < 130/80 mmHg 36 %
• HbA1c < 7.0% 37 %
• All three risk factors controlled 7%

• Unchanged CV risk factors from 1991 to 2000

Saydak SH et al. JAMA 2004

 Slide 33

Treatment of Cardiovascular Diseases Risk factors

Hypertension SBP 130-139 or DPB 80-89 mmHg: lifestyle modification

(DASH) for 3 months, if fails  pharmacological agents

SBP ≥140 or DBP ≥90 mmHg:

Lifestyle modification +pharmacological therapy

Dyslipidemia Lifestyle modification + statins

Antiplatelet agents* Aspirin and/or clopidogrel

Smoking cessation Stop smoking, counseling

CHD screening and treatment ACE-I and aspirin and statin (if not contraindicated)

*Depends on risk factors (???)

Diabetes Care 2012

 Slide 37

STENO-2 STUDY
 Slide 38

The STENO2 Study – “a multifactorial approach to Type

2 Diabetes”

• 160 patients
• Type 2 diabetes and
microalbuminuria
• Mean age 55 yrs, BMI 30 kg/m2;
HbA1c 8.4 %
New Engl J Med 2003; 383-93
• Randomized to
• conventional therapy assigned to
their GPs
• or intensive care at Steno
Diabetes Center

New Engl J Med 2008; 358: 580-91

 Slide 39

The STENO2 Study – Study Design

Conventional treatment
80
Micro-vascular Macro-vascular

n=160 Endpoint examinations

4 years 8 years
80
Intensive treatment
 Slide 40

Advice to the Intensive Group

• Food Advice
• Cut down on animal fat
• Have some kind of seafood every day
• 5-6 vegetables and fruits every day
• Exercise Advice
• Enjoy physical performance
> 150 min/week
• Smoking cessation
• Intensification of OHA and insulin
• Treatment with ACE/ARB, Statin and
baby aspirin
 Slide 41

Patients in the Intensive Group had obtained better

outcomes than patients in the Conventional Group…

Intervention Standard
n=55 n=38

Haemoglobin A1c (%) 7.7 8.0

F-s-total-cholesterol (mg/dl) 147 155

F-s-LDL-cholesterol (mg/dl) 71 77

F-s-triglycerides (mg/dl) 99 148

Systolic BP (mm Hg) 140 146

Diastolic BP (mm Hg) 74 73

Albumin excretion rate (mg/24h)* 69 75

Values are mean

* median
 Slide 42

…and Mortality Rate was lower in the Intensive Group…

100
90
80
70
60
50
40
30
20
10
0

30% of patients (n=24) died in the intensive group compared to

50% of patients (n=40) in the conventional group

Absolute risk reduction = 20%

 Slide 43

The STENO2 Study

Risk Reduction in Intensive Group

Relative risk reduction after 8 years

• Cardiovascular disease 53%
• Diabetic Nephropathy 61%
• Diabetic Retinopathy 58%
• Autonomic Neuropathy 63%
 Slide 44

Screening, Treatment and Evaluation of Complications

Lecture

Summary Main Learning Points

• Complications should be screened for • Understand the treatment options for

and treated according to guidelines diabetes associated complications:
• Routine follow up on treatment of • Nephropathy
complications should be performed
• Retinopathy
• CVD complications are the mail cause
of death among patients with diabetes • Neuropathy
• Risk of end-stage renal disease and • Erectile Dysfunction
blindness is significantly reduced by
treatment of hyperglycemia and • CVD
hypertension
• CAD