Screening for Eye and Kidney
Complications and
Dyslipidemia
Brian Bucca, OD, FAAO
David Maahs, MD
R. Paul Wadwa, MD
Disclosures
• Dr. David Maahs
– Merck: clinical trial support
• Dr. Paul Wadwa
– Merck: clinical trial support
• Dr. Brian Bucca
Objectives
• The practitioner will be able to understand
and apply current ADA guidelines for
screening evaluation and management of
nephropathy and dyslipidemia in youth with
diabetes.
• The practitioner will be able to identify risk
factors, which will be useful in screening
patients who are at risk for retinopathy
progression.
Outline
• Nephropathy
• Dyslipidemia
• Retinopathy
• Case Discussion
Kidneys
Nephropathy: persistent
macroalbuminuria associated
with changes in the kidney
leading to abnormal ability to
filter and HTN
• Treatable with medications
• Earliest sign is microalbuminuria
• Failure to detect/treat can lead to
macroalbuminuria, renal failure
ADA Guidelines for T1D Youth
• Annual screening >10y + T1D >5y
– More frequent if values increasing
• Methods
– Spot, timed, 24 hour
• Repeat if abnormal, 2/3 required for
diagnosis of persistent abnormal
microalbumin excretion (exercise,
smoking, menstruation all effect results)
Silverstein, Klingensmith et al, Diabetes Care, January 2005
Albuminuria Definitions
• Spot samples:
– ACR (albumin-to-creatinine ratio)
• Microalbuminuria: 30-299 mg/g
• Macroalbuminuria: ≥300 mg/g
• Timed overnight or 24 hour samples:
– AER (albumin excretion rate)
• Microalbuminuria: 20-199 μg/min
• Macroalbuminuria: ≥200 μg/min
Why Screen?
• Opportunity to detect microalbuminuria
during the reversible phase of diabetic
nephropathy.
– start ACE/ARB
– intensify glycemic control
Treatment
• Angiotensin-converting enzyme inhibitors
(ACE)
• Glycemic control
• Smoking cessation
• Treat Hypertension if it exists
• LDL treatment may be of benefit
• Consider Nephrology referral
Why is it Important?
• Diabetic Nephropathy (DN) occurs in 2040% of patients
• Single leading cause of ESRD
• Persistent MA is earliest stage of DN, also
an established CVD risk factor
• Patients with MA who progress to
macroalbuminuria are likely to progress to
ESRD
• It is TREATABLE!!!
Nephropathy
Risk Factors
• Poor blood sugar control
• Smoking
• Family history of high blood pressure or
cardiovascular disease
ISPAD guidelines 2007
Differences
• Screen: annually once 11y with 2y
duration and 9y once 5y duration
• Treatment: also include ARB
• Definitions: 2.5-25 mg/mmol or 30-300
mg/g in a spot sample but with 3.5-25
mg/mmol in females because of lower
creatinine excretion
• Loss of nocturnal dippingearly marker of
diabetic renal disease preceeding MA
Donaghue etal, Pediatric Diabetes, 2007
ADA 2008 Practice Guidelines
• Type 2 Diabetes
– Screen at diagnosis and annually
• Adults: check serum creatinine annually to
estimate GFR
• With ACE/ARB/diuretic treatment monitor
serum creatinine and K+
Rates of MA in Youth with DM
• SEARCH (Maahs, Diabetes Care ’07):
– T1D: 9.2%
– T2D: 22.2%
• Australia (Eppens, Diabetes Care ’06):
– T1D: 6%
– T2D: 28%
Complications in Type 2 Diabetes in Adolescents
Pinhas-Hamiel, Zeitler. Lancet ‘07
Cystatin C
• Emerging as a marker of GFR associated
with outcomes
• Appears independent of age, sex, and
muscle mass
• Described as HbA1c for renal function
(Perkins, Curr Diab Rep, ‘05)
• Cystatin C is a stronger predictor of death
and CV events in elderly persons than
creatinine (Shlipak, NEJM, ‘06)
Cystatin C
• Why does Cystatin C reflect GFR?
– stably produced by nucleated cells
– freely filtered at the glomerulus due to a
small molecular mass = increases as
GFR decreases
– not reabsorbed or secreted, metabolized
in the proximal tubules.
Cystatin C:
Better Estimate of GFR
than current equations
Perkins, NEJM, 2005
Perkins, JASN, 2005
Dyslipidemia
Breaking News!
“Lipid screening and cardiovascular health in
childhood”
Clinical report from American Academy of Pediatrics
• Just published in July 2008 Pediatrics
• Overview of lipids screening in all children
• Recommendations for screening and management in
context of available evidence
• Mention of youth with diabetes mellitus as a high risk
group, cutpoint for LDL level
• Discussion of metabolic syndrome
SR Daniels, FR Greer, Committee on Nutrition, Pediatrics July 2008; 122(1): 198-208
Dyslipidemia Background
• Atherosclerosis starts in childhood
• In adults, the risk for heart disease in
patients with diabetes is equivalent to risk
in patients with known coronary disease
• Early detection of abnormal cholesterol
level and/ or high blood pressure can
decrease risk for heart disease later in
life
Dyslipidemia Background
• Studies on lipid levels in childhood show an
association with lipid levels in adults
• Data on treating diabetic youth with lipid
lowering medication are limited
• No studies document lipid levels in childhood
associated with CVD events in adulthood
(studies do show association with cIMT)
Dyslipidemia Background
• In BDC data, lipid levels are elevated in 18 %
of T1DM patients
• But only 23 of 360 patients in latest data are
on medication to treat dyslipidemia
Maahs et al, J Pediatr 2005
Maahs, Wadwa et al, J Pediatr 2007
Total Cholesterol, HDL, and non-HDL Cholesterol
Abnormalities in T1DM subjects (n=682) compared
to 2001-02 NHANES (n=3,798)
30%
25%
20%
15%
T1DM
10%
NHANES
5%
0%
TC>200 m g/dL
HDL<35 m g/dL
Non-HDL>=130
m g/dL
18.6% were abnormal for either TC or HDL
Maahs et al, JPeds, 2005
Sustained Lipid Abnormalities in
T1DM Youth, n=360 subjects with
1,095 lipid measurements
TC ≥ 200 mg/dl
16.9%
HDL <35 mg/dl
3.3%
Non-HDL ≥ 130 mg/dl
27.8%
Non-HDL ≥ 160 mg/dl
10.6%
Non-HDL ≥ 190 mg/dl
3.3%
Maahs, Wadwa et al, J Pediatr 2007
LDL by age and diabetes type in
SEARCH
LDL
<10 yrs
T1D
≥ 10 yrs
T1D
T2D
(mg/dl)
<70
71-100
101-129
130-159
160+
10%
44%
35%
10%
1%
10%
44%
32%
12%
3%
10%
34%
33%
15%
9%
Kershnar, JPediatr 2006
Recommendations of the ADA on Lipid Screening and
Management in Children and Adolescents with Diabetes
ADA, Diabetes Care 2003, Kershnar, JPediatr 2006
Type 1
Initial screening
> 2 years old at diagnosis if other CVD risk
factors; otherwise at 12 years old (puberty)
Re-screening if lipid profile
5 years
is normal
Initial management of
dyslipidemia LDL-C
concentration for
pharmacologic treatment if
initial management fails
(10+ years)
Glycemic control, diet, physical activity
LDL-C > 160 mg / dL: begin medication
LDL-C 130–159 mg/dL: “consider” medication based on
other adult risk factors:
• smoking
• hypertension
• obesity (>= 95th percentile for age and sex)
• parental TC >= 240 mg / dL or family history of
cardiovascular event in a parent before 55 years of age
• HDL-C <35 mg/dL
Optimal concentration
LDL-C <100 mg/dL
HDL-C >35 mg/dL
Triglyceride <150 mg/dL
Type 2
At
diagnosis
regardless
of age
2 years
Dyslipidemia Evaluation
Lipids screening for T1DM youth
• If positive family history or unknown history
– Lipids screening (fasting) after 2 yrs of age and
glucose control obtained after diagnosis
• If negative family history
– Lipids screening after 12 yrs of age and glucose
control obtained after diagnosis
• Repeat every 5 years if normal (LDL< 100)
ADA, Diabetes Care 2003
Silverstein, Klingensmith et al, Diabetes Care, January 2005
Dyslipidemia Management
• Lowering LDL has proven benefit in adults
• Primary goal of therapy is to lower LDL to
target:
Normal
Borderline
Abnormal
LDL (mg/dl)
Less than 100
100-129
130 or higher
Dyslipidemia Management
If fasting lipids abnormal:
• Optimize blood sugar control
• Decrease fat in diet
– Limit saturated fat to <7% of calories
– Minimize intake of trans fat
– Limit dietary cholesterol to <200 mg/day
• Increase exercise; weight loss as necessary
• Smoking cessation
ADA, Diabetes Care 2003
Silverstein, Klingensmith et al, Diabetes Care, January 2005
Dyslipidemia Management
Pharmacologic therapy
– Age > 10 years old
– LDL
> 160 mg/dl
130-159 mg/dl: consider based on profile or
once lifestyle modification
attempted
–
–
–
–
Statins (first line?)
Resins (approved for use in Pediatrics)
Fibric acid derivatives if TG > 1000 mg/dl*
ezetimibe (Zetia)
Lipid-Lowering Agents
Maximum Effect on Serum Lipid Levels
Pharmacologic Class
LDL-C
Bile acid-binding
Decreases
resins
10-30%
Fibric acid derivatives Decreases
5-10%*
Niacin
Decreases
10-25%
HMG-CoA reductase Decreases
inhibitors (statins)
20-40%
Triglycerides
HDL-C
Increases
3-10%
Decreases
30-60%
Decreases
5-30%
Decreases
10-30%
Unchanged
* Fenofibrate may increase LDL-C levels.
Increases
5-10%
Increases
15-25%
Increases
5-15%
Dyslipidemia Management
• Pharmacologic therapy
• Goal is LDL < 100 mg/dl
** Counsel youth ‘at risk’ for pregnancy
regarding lipid lowering agents and stop
drug immediately if pregnancy suspected
Silverstein, Klingensmith et al, Diabetes Care, 2005; 28(1): 186-212
Dyslipidemia Summary
Current ADA guidelines recommend:
• Screening of lipids beginning after 2 or 12 years of
age depending on family history
• Repeat at least every 5 years (every 2 yrs in T2DM)
(more often if screening is abnormal)
• Treatment options include:
• Lifestyle modification (glycemic control, diet, exercise)
• After 10 years old, consideration of oral medications
depending on type and degree of lipid abnormality
Research
• Evidence in youth with diabetes is
needed to support ADA guidelines
• More research is needed in this area to
start to prevent CVD early in youth with
diabetes
Cardiovascular Research at the BDC
•
CACTI (Coronary Artery Calcification in Type 1 Diabetes)
– Study of coronary artery calcification progression in T1DM and non-DM
young adults, now in year 9 of data collection
– PI: Marian Rewers, MD, PhD
• SEARCH for Diabetes in Youth
– Multi-center epidemiologic study of diabetes in youth
– Ancillary examined CVD risk in adolescents with T1DM and T2DM
• Determinants of macrovascular disease in adolescents with T1DM
– Assessment of CVD risk factors/ arterial stiffness measures in BDC cohort
of T1DM and non-DM adolescents
– PI: Paul Wadwa, MD
• VAST (Vytorin And Simvastatin Trial)
– Clinical trial of lipid lowering medications in youth with T1DM
– PI: David Maahs, MD
– *funding/ medications provided by Merck
Research: Cardiovascular assessment study
Determinants of macrovascular disease
in adolescents with T1DM
• Now enrolling!
– Adolescents age 12- 19 years with T1DM for
5 yrs or longer
– also recruiting control subjects (age 12-19
yrs) without diabetes or other significant
medical issues
• Fasting blood draw, urine collection
• Arterial stiffness measures
Research
Determinants of macrovascular disease in
adolescents with T1DM
• For more information:
Contact:
Franziska Bishop, MS
Dr. Paul Wadwa
Dr. David Maahs
(303) 724-6764
(303) 724-6719
(303) 724-6706
Retinopathy
Case Discussion
Web Links
• www.barbaradaviscenter.org
• www.diabetes.org
American Diabetes Association
Thank You