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Oculosystemic Disease Essentials

Steven Ferrucci, OD, FAAO Chief, Sepulveda VA

Professor, MBKU/SCCO

Disclosures

!   Speakers bureau and/or Advisory Board for: !   Alcon ! Autogneomics !   Macula Risk ! MacuLogix ! Nicox !   Science-Based Health ! ThromboGenics

What is diabetes?

•  DM is a chronic disorder characterized by a lack of insulin or increased resistance to insulin

•  Insulin is needed for proper uptake of glucose

•  Clinical result is hyperglycemia –  retinopathy –  nephropathy –  neuropathy

Statistics

•  Approximately 23.6 million Americans with diabetes

•  ≈8.3% of total population •  11.3 % of adults •  25-30% undiagnosed ( 7 million)

•  Another 79 million Americans have pre-diabetes and are likely to develop diabetes if do not change habits –  35% of adults age 20 or older

Statistics, cont.

•  Globally, Type 2 DM affects 5.9% of adult population –  46% ages 40-59

•  Highest percentage in Eastern Mediterranean and Middle East (9.2%) and North America (8.4%)

•  Total Numbers: 246 million Worldwide –  India 40.9 million –  China 39.8 million –  Then USA, Russia, Germany, Japan, Pakistan, Brazil,

Mexico and Egypt

Statistics

!   In 2007, medical expenditures for diabetes $116 billion !   $27 B direct care !   $58 B to treat diabetes related complications !   $31 B in excess general medical costs !   Costs: 2.3 x higher in diabetic vs non-diabetic pt

!  Actual national burden of diabetes likely exceeds $174 B when indirect costs considered

!  Seventh leading cause of death in 2006

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The Diabetes Epidemic

•  Incidence has increased 13.5% from 2005, and over 700% in last 40 years

• WHY??

The Diabetes Epidemic •  Improvements in diabetes care

–  Pts living longer with diabetes

•  Growth in elderly populations: –  10% > 60 vs 16-20% > 80

•  Increasing prevalence of obesity which causes increased insulin resistance

•  Increased number or minority populations in US –  Rates of DM among minority populations are often 2-3

times greater

TYPE 1

•  Formerly IDDM or juvenile onset

•  Prevalence: 0.2%

•  10% of all DM

•  Most common age of onset < 30

•  Destruction of insulin producing B-cells in pancreas (auto-immune? viral?)

•  Total lack of endogenous insulin

•  Need to be on insulin to survive

TYPE 2

•  Formerly NIDDM or adult onset

•  Prevalence: 3.1%

•  90% of all DM

•  Most frequent age of onset > 40

•  Often asymptomatic

•  Characterized by insulin resistance

•  Strong genetic predisposition

Gestational Diabetes

•  Affects 4% of all pregnancies

•  High risk populations: –  Pregnant woman greater than age 25 –  Abnormal body weight –  Have first degree relatives with diabetes –  Hispanic, Asian, Native American , African American

descent

•  Screen in 24th to 28th week of pregnancy

Gestational Diabetes •  Plasma glucose concentration at or above any 2 of

4 values on OGTT –  1. Fasting, 95 mg/dL –  2. 1 hour, 180 mg/dL –  3. 2 hour, 155 mg/dL –  4. 3 hour, 140 mg/dL

•  May be treated with diet changes or insulin if needed

•  At higher risk for developing type 2 later in life –  5 fold increase at 5 yrs, 9 fold after 5 years

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Pre-Diabetes !  Blood sugar levels higher than normal, but not yet

high enough to be diagnosed with DM !   FBS: 100-126 mg/dl !  A1c: 5.7-6.4

!  ADA estimates 79 million Americans have pre-diabetes !  30 minutes of exercise combined with 5-10%

reduction in body weight resulted in 58% reduction in diabetes

Symptoms

•  Often asymptomatic, especially Type 2

•  Classic symptoms –  polydipsia –  polyphagia –  polyurea

•  Others: weight loss, delayed wound healing, dry mouth, dry skin, recurrent infections, refractive changes

Risk Factors •  Family history

•  Specific ethnic backgrounds –  African Americans –  Native Americans –  Hispanic –  Asian American –  Pacific islander

•  Sedentary Lifestyle

•  Pertinent medical history –  obesity –  cardiovascular disease –  HTN –  High cholesterol –  Polycystic ovarian syndrome –  Psychiatric illness –  Gestational DM –  IFG/IGT

Traditional Diagnosis Criteria

•  Fasting blood glucose > 126 mg/dL

•  OGTT > 200 mg/dL (2 hour sample)

•  Any random testing >200 mg/dl should be referred for further testing

•  Random testing > 200 mg/dL with symptoms very suggestive of DM

New Diagnosis Criteria !   Panel of “experts” at ADA annual meeting are

recommending A1C be used for diagnosis of diabetes

! Glycosolated hemoglobin

!   Tells blood sugar control over 3 months !   normal range 4% to 6%

HgbA1c BS Level HgbA1c BS Level 4 60 9 210 5 90 10 240 6 120 11 270 7 150 12 300 8 180 13 330

New Diagnosis Criteria

!   ≥ 6.5 would be indicative of DM !  First major change in 30 years !  In adults and children, not pregnant women !   Advantages: !  Convenience: no fasting !  More accurate: average over 3 months

!   Disadvantage: !  Cost?

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Recommended Criteria for Screening Asymptomatic Individuals for Type 2 DM

•  All pts >45 yrs at 3 yr intervals

•  Younger age or more frequently in pts who: –  are obese –  have a first-degree relative with diabetes –  are members of high-risk ethnic population –  gestational diabetes or delivered a baby > 9 lbs –  are hypertensive –  HDL < 35mg/dl or triglycerides > 250 mg/dl –  have impaired glucose regulation

Treatment of Type 2 DM

!   Goal: to produce desirable blood glucose levels with minimal adverse effects and maximal patient compliance

!   Treatment begins with diet and exercise and ends with insulin

!   Often, adequate control can be achieved with oral agents !   If not, insulin is utilized

Medical Management

!   Sulfonylureas (glyburide, glipizide) !   Often first line

!   Low cost, low side effects

!   Metformin (glucophage) !   First line/Second line to sulfonylureas or in combo

! Glitazones (Avandia, Actos) !   NEJM May, June 2007: Avandia has an increased cardiovascular risk !   FDA Sept 2010: US patients can only take if unable to control blood sugar

with any other drug !   If already on drug, must sign statement that they understand

risks if wish to continue

Medical Management

! Aplha-glucosidase inhibitors ! Acarbose (Precose) and Miglitol (Glyset) !   Used alone or in combo with sulfonylureas

! Meglitinides ! Repaglanide (Prandin) and Nateglinide (Starlix) !   Best used to control mealtime glucose

!   DPP-4 Inhibitors ! Sitagliptin (Januvia) and Saxagliptin (Onglyza) !   Relatively new class of meds !   Only lower BS if levels are elevated

Medical Management

! Exenatide (Byetta) !   Injectable drug used to treat Type 2 DM

! Pramlintide Acetate (Symlin) !   Used as injection in Type 1 or Type 2 DM in conjunction with

mealtime insulin

! Liraglutide (Victoza) !   Once daily injected medication for tx of type 2 DM

!   FDA Approved January 2010

Newest meds

! Alogliptin ( Nesina, Takeda Pharmaceuticals) !   DPP-4 Inhibitor

!   FDA approved January 2013

!   14 clinical trials; 8,500 patients !   Safe and effective

!   Reduced HbA1c at 6 mos by 0.4-0.6 points

! Kazano=alogliptin and metformin

! Oseni=alogliptin and pioglitazone

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Medical Management

!   Insulin !   Replaces natural insulin in body !   Used with type 2 patients who do not respond to oral agents

!   Long acting Insulins ! Glargine (Lantus) and Detemir (Levemir) !   Last 24 hrs with no peak !   More expensive than traditional insulin

!   Inhaled insulin !   FDA approved Jan 2006 (Exubera by Pfizer) !   Removed from market 2010

!   Poor sales? !   Lung CA?

! Afreeza (MannKind)

Current recommendations for Treatment of Type 2 DM

•  Control BS: HgbA1c < 7

•  Control HTN: <120/80

•  Control Cholesterol levels: Total cholesterol < 200

•  No smoking

•  Exercise

•  Normal BMI

•  Yearly foot exams, dental exams, and dilated retinal exams

Diabetic Retinopathy

•  Leading cause of blindness 20-74 year old

•  8-12% of all new cases of legal blindness

•  50,000 Americans legally blind

•  Early diagnosis and treatment can decrease vision loss by 50-60%

•  Factors which influence development of DR –  duration of disease –  control of BS

Diabetic Retinopathy

•  Duration of Disease: Type 2 –  <10 years 1% –  11-13 years 23% –  > 16 years 60%

•  Control of BS (UKPDS) –  for every 1% decrease in HgbA1C there is a 35%

reduction in risk for retinopathy

Diabetic Retinopathy

•  Non-proliferative Diabetic Retinopathy (NPDR) –  mild –  moderate –  severe –  very severe

•  Proliferative Diabetic Retinopathy (PDR) –  Including high-risk

Mild NPDR

! Microaneurysms (ma)

!   Dot/blot hemorrhages

!   Follow Up: 1 year

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Moderate NPDR

!  Marked hemorrhages/ma

!  Cotton wool spots (CWS)

!  Venous beading (VB)

!   Intra-retinal microvascular abnormalities to mild degree (IRMA’s)

!  Follow up: 6 months

Severe/ Very Severe NPDR

!  4-2-1 Rule: !   Marked hemes/ma in all 4 quadrants !   VB in 2 or more quadrants !   Marked IRMA’s in one quadrant

!  Very severe: 2 of the 3 above criteria

!  Follow-up: 3-4 mos or refer to Retinal specialist

Proliferative Diabetic Retinopathy (PDR) •  Hallmark is retinal neovascularization

–  response to ischemia from capillary closure –  new vessels are fragile and easily rupture

•  Neo divided into 2 categories –  NVD: on or within 2 DD of optic disc –  NVE: neovascularization elsewhere

–  Follow-up: Retinal consult within 2 weeks

High Risk PDR

!  NVD >1/4 to 1/3 disc area

!  Any NVD with a PRH or VH

!  Moderate to severe NVE with VH or PRH

!  Poses very high risk of severe VH and vision loss within 2 years

!  Follow-up: Retinal specialist 24-48 hrs

Risk of Progression to PDR

1 year 3 years

Mild NPDR 5% 14%

Moderate NPDR 12-26% 30-48%

Severe NPDR 52% 71%

Pan-Retinal Photocoagulation (PRP)

!   Traditional treatment for proliferative disease

!   Laser applied to retina, destroying parts

!   Eliminates need for oxygen, thereby decreasing vasoproliferative stimulus

!   Elimination of hypoxia causes regression of new vessel growth

!   Not without complications: decreased VF, decreased night vision, CME

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ETDRS and DRS

!   Proved benefit of immediate PRP !   Showed an overall reduction rate of severe vision loss

(ie 5/200) of approximately 50% in treated vs. untreated eyes !   <4% chance of severe vision loss in 5 years w/ tx

!   PRP in 2 to 3 sessions (1200-1600 spots)

!   Treat CSME first, if present

Clinically Significant Macular Edema(CSME)

!  Characteristics !   retinal thickening at or within 500 microns (1/3 DD) of

center of macula !   hard exudates at or within 1/3 DD if associated with

thickening of adjacent retina !   thickening greater than 1 DD in size part of which is

within 1 DD of center of macular

!  May occur at any stage of retinopathy

!  Treatment: retinal consult within 2 weeks

CSME

!   Level of Retinopathy !   mild NPDR 3%

incidence of DME !   moderate to severe

NPDR 40% !   Proliferative 71%

!   Type 2: Duration and Insulin !   no insulin !   10 years 5% !   20 years 15%

!   on insulin !   10 years 10% !   20 years 30-35%

Focal Macular Laser (FML)

!   Standard Treatment for CSME

!   ETDRS: proved benefit of FML in improving vision

!   Reduces the risk of moderate vision loss (doubling of the visual angle) from 30% to less than 15% !   so 50% reduction in MVL after 3 years

!   Real goal is to prevent further loss, not to improve vision

Anti-Vegf

!  RISE/RIDE studies ! Pts with DME received intravitreal Lucentis

0.3 mg or 0.5 mg monthly for 2 years !   33.6% of pts receiving 0.3 mg gained > 15 letters

!   45.7% of pts receiving 0.5 mg gained > 15 letters

!   Only 12.3% in placebo group gained > 15 letters

!  3-4 fold increases in treated patients

What is Hypertension?

!   Systolic BP > 140 or

!   Diastolic BP > 90

!   Affects ≈ 70 million Americans

!   Essential HTN

!   Malignant HTN

!   Secondary HTN

SYSTOLIC DIASTOLIC Normal <120 <80 Pre-hypertension

120-139 80-89

Stage 1 hypertension

140-159 90-99

Stage 2 hypertension

>160 >100

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Essential HTN: >140/90

!   Most common type of HTN !   90-95%

!   Family History common

!   Risk Factors include: !   Sedentary lifestyle, smoking , stress, alcohol intake, obesity,

high sodium intake, vitamin D deficiency, aging

!   Usually controlled with 1 or 2 oral meds

Secondary HTN

!   By definition results from an identifiable cause ! Cushings Syndrome

!   Hypo/hyperthyroidism

!   Kidney disease

!   Pregnancy (pre-eclampsia)

! Coarctation of the aorta !   Certain prescription and illegal dugs

Malignant HTN: BP>210/130

!   Ocular findings ! Papillidema

!   Exudates

!   CWS

!   FSH

!   AV changes

!   Systemic Findings !   None

!   HA’s

!   Vomiting

!   Coma

Malignant HTN

! Immediate referral for BP lowering !   ER or PCP

!   MRI to r/o space occupying lesion

!   MRA to r/o “venous sinus thrombus’

!   LP if needed

Malignant HTN

!   80% of patients with malignant HTN die within 1 year

!   95% mortality within 3 years

Hypertension

!   Other Complications !   Retinopathy !   Left ventricular Hypertrophy !   Angina !   Myocardial infarction !   Heart Failure !   Stroke !   Peripheral vascular disease !   Chronic kidney disease

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Hypertension

!   Risk !   Each increase of 20 mmHg systolic or 10 mmHg

diastolic doubles risk of complications

!   Risk reduction with treatment !   35-40% reduction in stroke !   20-25% reduction in myocardial infarction !   >50% reduction in heart failure

Hypertension Treatment

!   Lifestyle !   Weight reduction

!   BMI goal 18.5-25

!   Diet !   Sodium restriction !   DASH diet

! Dietary Approaches to Stop Hypertension

!   Physical activity !   Moderation of alcohol consumption

DASH Diet

! Dietary Approaches to Stop Hypertension !   Proven to lower BP in as little as 14 days

!   Best with moderate or less or pre-hypertension

!   Includes whole grains, poultry, fish, and nuts and has reduced amounts of fats, red meats, sweets, and sugared beverages.

! www.dashdiet.org

Hypertension Treatment !  Medical management !   Thiazide diuretics (hydrochlorothiazide)

!   Work by helping body reduce sodium and water thereby decreasing blood volume

!   Beta blockers (atenolol) !   Reduce workload on heart, causing decreased heart rate

!   Angiotensin-converting enzyme (ACE) inhibitors (lisinopril, captopril) !   Help relax blood vessels by blocking the formation of enzymes

which narrow blood vessels

Hypertension Treatment !  Medical management, cont !   Angiotensin II receptor blockers (losartan)

!   Relax blood vessels by blocking action of the enzymes which narrow blood vessels

!   Calcium Channel Blockers (verapamil, diltiazem) !   Help relax the smooth muscles of the arteries and heart, thereby

decreasing blood pressure

!   Renin inhibitors (aliskiren) !   Newer drug which works on renin, an enzyme produced in the

kidneys which starts hypertensive cascade

Hypertensive Retinopathy

! Pts with HTN retinopathy suffer (obviously) from systemic HTN

!   However, at times, this may be first clue to pts underlying disease

! Pts are almost always asymptomatic, unless they have rare finding of edema or papilladema, which would cause decreased acuity

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Hypertensive Retinopathy

!   Typically pts with HTN retinopathy are middle aged or older !   HTN more common in middle aged men than

women !   But more common in elderly woman than elderly

men

!   Much more prevalent in African-Americans than Caucasians

Hypertensive Retinopathy

!   Clinical findings include !   Retinal artery narrowing and attenuation !   Retinal artery nicking and crossing changes !   Flame shaped hemes !   Cotton wool spots !   Rarely retinal or macula edema !   May have macular star

!   Disc edema

Hypertensive Retinopathy !  Keith Wagner Baker

Classification System !   Grade 1 Hypertensive

Retinopathy !   Retinal arterial narrowing

and straightening

!   Grade 2 !   AV Nicking

Hypertensive Retinopathy !  Keith Wagner Baker

Classification System !   Grade 3

!   Retinal hemorrhages !   Cotton wool spots !   Hard exudates

!   Macular star

!   Grade 4 !   Grade 3 with ONH

edema

Hypertensive Retinopathy

!   Rare to have either macula edema or optic disc edema unless there is malignant HTN, where BP is elevated in 250/130 range !   However presentation of macular star and disc

edema is almost pathognomonic for HTN crisis

!   CWS typically do not appear until diastolic BP is > 110

Hypertensive Retinopathy

!   Monitor fundus q 12 months !   Sooner if severe

! Pt education

!   Management involves appropriate tx of underlying HTN, with referral to primary care physician or internist

!   If papilledema from HTN, consider medical emergency!! !   Immediate referral and/or trip to ER!!

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Retinal Plaques

!   Several different types of plaques can often be visualized in the retinal vasculature

!   Pt is typically elderly, has HTN, CAD, hypercholesterolemia/hyperlipidemia, and/or atherosclerotic disease

!   Often totally asymptomatic and found on routine exam

Retinal Plaques !   May present with amarosis fugax, transient episodes of

monocular blindness

!   Rarely, may report transient ischemic attack (TIA) , which is above with hemiparesis, parasthesia or aphasia

!   Three different types of plaques, but all share strong association to significant cardiovascular disease

Retinal Plaques

!   Cholesterol (Hollenhorst) plaque !   shiny yellow-orange in appearance !   typically from the ipsilateral carotid artery !   Rarely causes occlusion, unless multiple !   Typically occurs at bifurcations !   Mobile in nature

Retinal Plaques

!   Calcific !   Appears more whitish than HH !   Classically within arteriole, not at bifurcation !   Typically immobile !   Often causes BRAO !   Often from cardiac arethromas of heart valves

Retinal Plaques

!   Fibrino-platelet !   Appear as dull white to gray, long plugs !   Typically within arterioles, not at bifurcations !   May break-up and dissolve with time !   May lead to BRAO or CRAO !   Often associated with carotid disease or mitral valve

insufficiency

Retinal plaques

!   No direct management of plaques is needed

!   Management is aimed at discovering source of embolus to decrease risk of other emboli, occlusion, or stroke

!   Pts need referral to internist for complete physical

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Retinal Plaques

!   Examination should include !   Complete physical, including cardiac risk factors and BP

evaluation !   Carotid ultrasound !   Stress echocardiogram !   Fasting BS !   Lipid profiles !   Cardiac enzymes

Retinal Plaques

!   After ruling out underlying etiology, see patient regularly, q 6 -12 mos, to evaluate for additional plaques or other disease associated with vascular disease !   BRVO/CRVO !   BRAO/CRAO !   NTG

Retinal Plaques

!   If carotid stenosis or coronary artery disease is found treatment may include !   Carotid endarterectomy !   Angioplasty !   Aspirin therapy !   Other anti-coagulation therapy, such as coumadin

!  Pts with cholesterol HH emboli have 15% mortality at 1 yr, 29% by year 3, and 54% by 7 years !   Mostly from cardiac disease

Hyperlipidemia !  Elevation of lipids in the bloodstream !   Cholesterol and triglycerides are most commonly

affected !   High lipids causes accelerated atherosclerosis

(hardening of the arteries) !   Increased risk of plaque formation, heart disease, stroke, and

other vascular disease

!   Can be genetic, but most often affected by lifestyle !   Obesity, sedentary lifestyle, smoking !   Also associated with diabetes, kidney disease, pregnancy, and

hypo-thyroidism

Hyperlipidemia

!   Diagnosis !   Fasting Lipid Profile

!   Total Cholesterol !   LDL (low-density lipoproteins)

!   high levels associated with increased heart attack !   HDL (high-density lipoproteins)

!   protective against heart attack !   Triglycerides !   Total Chol/HDL ratio

Hyperlipidemia

!   Total cholesterol !   < 200 desirable !   200-239 borderline high !   > 240 high

!   HDL (“good” cholesterol) !   < 40 for men and < 50 for women is low !   > 60 considered protective for heart disease

!   LDL (“bad” cholesterol) !   <100 desirable !   100-129 borderline !   130-159 borderline high !   >160 high

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Hyperlipidemia

!   Triglycerides !   < 150 is desirable !   150-199 borderline high !   > 200 is high

!   Total chol/HDL !   3.5:1 is optimal !   Below 5:1 is acceptable !   Above 5:1 unhealthy

Hyperlipidemia

!   National Cholesterol Education Program (NCEO) recommends cholesterol screenings for: !   Males and females > 20 every 5 yrs !   More often if risk factors

!   Diabetes !   Obesity !   Family history !   > 65 years of age

Hyperlipidemia

!   Treatment !   Exercise !   Weight loss !   Elimination of trans-fats !   Increase omega-3’s !   Identify and treat other risk factors

!   Hypertension !   Diabetes

!   Smoking cessation

What is Obesity?

!   Increased body weight caused by excessive accumulation of fat

!   BMI defined as patient’s weight (kg) divided by height (m2) !   BMI categories of obesity

!   Normal 20-24.9 !   Overweight 25-29.9 !   Obesity 30-34.9 !   Moderate obesity 35-39.9 !   Extreme obesity over 40

BMI 25 - 29.9 = Overweight

BMI > 30 Obese

BMI > 40 Morbidly Obese

BMI > 50 Super Morbidly Obese

What is Obesity?

BMI = Weight in Kg

(Height in Meters)2

Body Mass Index

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BMI Table Statistics

!   1/3 of US adults are obese

!   1 in 6 US children is overweight

!   #2 modifiable risk factor for death (tobacco)

!   May result in reduced life expectancy for the 1st time in 200 years! !   Obese patients have 6.7 years less life expectancy than

non-obese patients !   New England Journal of Medicine

!   300,000 Deaths Each Year (Directly Related)

Obesity: Ocular Complications

!  AMD

!  Diabetic retinopathy

!  Cataract

! Pseudotumor cerebri (papilledema)

!  Floppy lid syndrome

!  Ocular hypertension

!  Exophthalmos/proptosis

Obesity: Systemic Complications

!   HTN

!   Dyslipidemia

!   Type 2 DM

!   CAD

!   Stroke

!   Gall bladder disease

!   Osteoarthritis

!   Malignancies

Other Scary Stuff

!   165 Million Americans will be obese by 2030 !   ½ of all American men will be obese by 2030 !   US healthcare spending expected to increase $66

Billion per year by 2030 if this trend continues !   165 million obese Americans would correlate to an

additional 8 million cases of DM, 6.8 million cases of heart disease and stroke, and 0.5 million cases of cancer

!   A 1% reduction in BMI would prevent as many as 2.4 million cases of DM and 1.7 million cases of heart disease and stroke