Screening for Eye and Kidney Complications and Dyslipidemia

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Screening for Eye and Kidney Complications and
Dyslipidemia

• Brian Bucca, OD, FAAO
• David Maahs, MD
• R. Paul Wadwa, MD

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Disclosures

• Dr. David Maahs
• Merck clinical trial support
• Dr. Paul Wadwa
• Merck clinical trial support
• Dr. Brian Bucca

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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.

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Outline

• Nephropathy
• Dyslipidemia
• Retinopathy
• Case Discussion

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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

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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
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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

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Why Screen?

• Opportunity to detect microalbuminuria during the
  reversible phase of diabetic nephropathy.
• start ACE/ARB
• intensify glycemic control

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Treatment

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

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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!!!

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Nephropathy

• Risk Factors
• Poor blood sugar control
• Smoking
• Family history of high blood pressure or
  cardiovascular disease

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ISPAD guidelines 2007Differences

• 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
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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

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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

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

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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.

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Cystatin C Better Estimate of GFR than current
equations
Perkins, NEJM, 2005
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Perkins, JASN, 2005
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Dyslipidemia
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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

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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

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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)

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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

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Total Cholesterol, HDL, and non-HDL Cholesterol
Abnormalities in T1DM subjects (n682) compared
to 2001-02 NHANES (n3,798)
18.6 were abnormal for either TC or HDL
Maahs et al, JPeds, 2005
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Sustained Lipid Abnormalities in T1DM Youth,
n360 subjects with 1,095 lipid measurements
Maahs, Wadwa et al, J Pediatr 2007
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LDL by age and diabetes type in SEARCH
Kershnar, JPediatr 2006
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Recommendations of the ADA on Lipid Screening and
Management in Children and Adolescents with
Diabetes ADA, Diabetes Care 2003, Kershnar,
JPediatr 2006
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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

ADA, Diabetes Care 2003 Silverstein, Klingensmith
et al, Diabetes Care, January 2005
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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 100-129
• Abnormal 130 or higher

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Dyslipidemia Management

• If fasting lipids abnormal
• Optimize blood sugar control
• Decrease fat in diet
• Limit saturated fat to
• Minimize intake of trans fat
• Limit dietary cholesterol to
• Increase exercise weight loss as necessary
• Smoking cessation

ADA, Diabetes Care 2003 Silverstein,
Klingensmith et al, Diabetes Care, January 2005
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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)

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Lipid-Lowering AgentsMaximum Effect on Serum
Lipid Levels
Fenofibrate may increase LDL-C levels.
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Dyslipidemia Management

• Pharmacologic therapy
• Goal is LDL
• 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
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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

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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

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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

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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

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Research

• Determinants of macrovascular disease in
  adolescents with T1DM
• For more information
• Contact
• Franziska Bishop, MS [phone]
• Dr. Paul Wadwa [phone]
• Dr. David Maahs [phone]

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Retinopathy
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Case Discussion
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Web Links

• www.barbaradaviscenter.org
• www.diabetes.org
• American Diabetes Association

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Thank You