1. Screening for Eye and Kidney Complications and Dyslipidemia
Brian Bucca, OD, FAAO
David Maahs, MD
R. Paul Wadwa, MD

2. Disclosures Dr. David Maahs Dr. Paul Wadwa Dr. Brian Bucca
Merck: clinical trial support
Dr. Paul Wadwa
Dr. Brian Bucca

3. 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.

4. Outline
Nephropathy
Dyslipidemia
Retinopathy
Case Discussion

5. 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

6. 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

7. Albuminuria Definitions
Spot samples:
ACR (albumin-to-creatinine ratio)
Microalbuminuria: mg/g
Macroalbuminuria: ≥300 mg/g
Timed overnight or 24 hour samples:
AER (albumin excretion rate)
Microalbuminuria: μg/min
Macroalbuminuria: ≥200 μg/min

8. Why Screen?
Opportunity to detect microalbuminuria during the reversible phase of diabetic nephropathy.
start ACE/ARB
intensify glycemic control

9. Treatment Angiotensin-converting enzyme inhibitors (ACE)
Glycemic control
Smoking cessation
Treat Hypertension if it exists
LDL treatment may be of benefit
Consider Nephrology referral

10. Why is it Important?
Diabetic Nephropathy (DN) occurs in 20-40% 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!!!

11. Nephropathy Risk Factors Poor blood sugar control Smoking
Family history of high blood pressure or cardiovascular disease

12. ISPAD guidelines 2007 Differences
Screen: annually once 11y with 2y duration and 9y once 5y duration
Treatment: also include ARB
Definitions: mg/mmol or mg/g in a spot sample but with 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

13. 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+

14. 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%

15. Complications in Type 2 Diabetes in Adolescents
Pinhas-Hamiel, Zeitler. Lancet ‘07

16. 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)

17. 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.

18. than current equations
Cystatin C:
Better Estimate of GFR
than current equations
Perkins, NEJM, 2005

19. Perkins, JASN, 2005

20. Dyslipidemia

21. 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):
Clinical report just published this month
Getting some media attention
Nice overview of landmark studies on CV risk factors in childhood (including Bogalusa, Muscatine, PDAY, NHANES, others)
Recommendations for lipids screening, management in all children with mention of diabetes, but not emphasized
Good discussion of metabolic syndrome
Excellent reference regarding lipids in pediatrics (but diabetes not a focus)

22. 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

23. 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)

24. 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

25. 18.6% were abnormal for either TC or HDL
Total Cholesterol, HDL, and non-HDL Cholesterol Abnormalities in T1DM subjects (n=682) compared to NHANES (n=3,798)
18.6% were abnormal for either TC or HDL
Maahs et al, JPeds, 2005

26. Maahs, Wadwa et al, J Pediatr 2007
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
Maahs, Wadwa et al, J Pediatr 2007

27. LDL by age and diabetes type in SEARCH
<10 yrs
≥ 10 yrs
LDL
(mg/dl)
T1D
T2D
<70
10%
71-100
44%
34%
35%
32%
33%
12%
15%
160+ 1% 3% 9%
Kershnar, JPediatr 2006

28. Recommendations of the ADA on Lipid Screening and Management in Children and Adolescents with Diabetes
ADA, Diabetes Care 2003, Kershnar, JPediatr 2006
Type 1
Type 2
Initial screening
> 2 years old at diagnosis if other CVD risk factors; otherwise at 12 years old (puberty)
At diagnosis regardless of age
Re-screening if lipid profile is normal
5 years
2 years
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

29. 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

30. Dyslipidemia Management
Lowering LDL has proven benefit in adults
Primary goal of therapy is to lower LDL to target:
LDL (mg/dl)
Normal Less than 100
Borderline
Abnormal 130 or higher

31. 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

32. Dyslipidemia Management
Pharmacologic therapy
Age > 10 years old
LDL > 160 mg/dl
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)
Resins = bile acid sequestrants
Statins = hmg-coA reductase inhibitors- inhibits cholesterol synthesis from liver, decreases LDL; Risks: liver damage, muscle aches, GI side effects;
Fibric acid – lowers TG- gemfibrozil, fenofibrate
Ezetimibe (Zetia) – acts at brush border of small intestine to decrease absorption of cholesterol

33. Lipid-Lowering Agents Maximum Effect on Serum Lipid Levels
Pharmacologic Class
LDL-C
Triglycerides
HDL-C
Bile acid-binding resins
Decreases 10-30%
Increases
3-10%
Unchanged
Fibric acid derivatives
Decreases 5-10%*
Decreases 30-60%
5-10%
Niacin
Decreases 10-25%
Decreases
5-30%
15-25%
HMG-CoA reductase inhibitors (statins)
Decreases 20-40%
5-15%
* Fenofibrate may increase LDL-C levels.

34. 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):

35. 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

36. 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

37. 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

38. Research: Cardiovascular assessment study
Determinants of macrovascular disease in adolescents with T1DM
Now enrolling!
Adolescents age years with T1DM for 5 yrs or longer
also recruiting control subjects (age yrs) without diabetes or other significant medical issues
Fasting blood draw, urine collection
Arterial stiffness measures

39. Research
Determinants of macrovascular disease in adolescents with T1DM
For more information:
Contact:
Franziska Bishop, MS (303)
Dr. Paul Wadwa (303)
Dr. David Maahs (303)

40. Retinopathy
Dr. Brian Bucca – start his slides

41. Case Discussion

42. Web Links www.barbaradaviscenter.org www.diabetes.org
American Diabetes Association

43. Thank You