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 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!!!

NephropathyRisk Factors

• Poor blood sugar control

• Smoking

• Family history of high blood pressure or cardiovascular disease

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 dippingearly 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%

Pinhas-Hamiel, Zeitler. Lancet ‘07

Complications in Type 2 Diabetes in Adolescents

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.

Perkins, NEJM, 2005

Cystatin C: Better Estimate of GFR than current equations

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)

0%

5%

10%

15%

20%

25%

30%

TC>200 mg/dL HDL<35 mg/dL Non-HDL>=130mg/dL

T1DM

NHANES

Maahs et al, JPeds, 200518.6% were abnormal for either TC or HDL

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

<10 yrs ≥ 10 yrs

LDL(mg/dl)

T1D T1D T2D

<70 10% 10% 10%

71-100 44% 44% 34%

101-129 35% 32% 33%

130-159 10% 12% 15%

160+ 1% 3% 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 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 activityLDL-C > 160 mg / dL: begin medicationLDL-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 concentrationLDL-C <100 mg/dLHDL-C >35 mg/dL Triglyceride <150 mg/dL

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:

LDL (mg/dl)

Normal Less than 100

Borderline 100-129

Abnormal 130 or higher

Dyslipidemia ManagementIf 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 AgentsMaximum Effect on Serum Lipid Levels

Pharmacologic Class LDL-C Triglycerides HDL-C

Bile acid-binding resins

Decreases 10-30%

Increases3-10%

Unchanged

Fibric acid derivatives Decreases 5-10%*

Decreases 30-60%

Increases5-10%

Niacin Decreases 10-25%

Decreases 5-30%

Increases15-25%

HMG-CoA reductase inhibitors (statins)

Decreases 20-40%

Decreases 10-30%

Increases5-15%

* Fenofibrate may increase LDL-C levels.

Dyslipidemia Management

Silverstein, Klingensmith et al, Diabetes Care, 2005; 28(1): 186-212

• 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

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 BDCCardiovascular 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 studyResearch: 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

ResearchDeterminants of macrovascular disease in

adolescents with T1DM

• For more information:

Contact:Franziska Bishop, MS (303) 724-6764Dr. Paul Wadwa (303) 724-6719Dr. David Maahs (303) 724-6706

Retinopathy

Case Discussion

Web Links

• www.barbaradaviscenter.org

• www.diabetes.org American Diabetes Association

Thank You