Prevalence of Diabetes Mellitus Affects 9.3% of the US populaxon (29.1 million people) 1 Seventh leading cause of death in the US 1

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1 Disclosures THE ORS Presents: Diabetes Update 2016 Steven Ferrucci, OD, FAAO Jeff Gerson, OD, FAAO FERRUCCI Alcon AutoGenomics B&L Centervue Heidelberg Macula Risk MacuLogix Science Based Health ThromboGenics GERSON Allergan B&L Centervue Kemin Macula Risk Maculogix Optos Optovue VSP Zeavision 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 Leads to microvascular damage retinopathy nephropathy neuropathy Prevalence of Diabetes Mellitus Affects 9.3% of the US populaxon (29.1 million people) 1 Seventh leading cause of death in the US 1 Age-adjusted Prevalence 2000: 6.0% : 9.3% 1 Diabetes Incidence (cases/1000) Obesity Prevalence (%) Centers for Disease Control and PrevenXon. h[p:// diabetes- report- web.pdf. Accessed June 30, Centers for Disease Control and PrevenXon. h[p:// Accessed July 25, Centers for Disease Control and PrevenXon. h[p:// Accessed February 28, Centers for Disease Control and PrevenXon. h[p:// Accessed February 28, Centers for Disease Control and PrevenXon. h[p://apps.nccd.cdc.gov/brfss/list.asp?cat=ob&yr=2000&qkey=4409&state=all. Accessed February 28, Centers for Disease Control and PrevenXon. h[p://apps.nccd.cdc.gov/brfss/list.asp?cat=ob&yr=2012&qkey=8261&state=all. Accessed February 28, Cost of Care ñ from $172 Billion in 2007 to $245 Billion in ñ 41% $ 176 B direct costs $ 69 B indirect In CA alone, $24.5 Billion (July 2015) Medical cost 2.3X higher in pts with DM Care of people with DM accounts for 1 out 5 healthcare dollars in US Traditional Diagnosis: FBS 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 1

2 Newer Diagnosis: HgbA1c Panel of experts at ADA annual meeting now recommend A1C be used for diagnosis of diabetes Glycosolated hemoglobin Used for control for years Tells blood sugar control over 3 months normal range 4% to 6% HgbA1c BS Level HgbA1c BS Level Newer Diagnosis: HgbA1c 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? Risk Factors Symptoms 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 Often asymptomatic, especially Type 2 Classic symptoms polydipsia polyphagia polyurea Others: weight loss, delayed wound healing, dry mouth, dry skin, recurrent infections, refractive changes TYPE 1 TYPE 2 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 Formerly NIDDM or adult onset Prevalence: 8.0% 90% of all DM Most frequent age of onset > 40 Often asymptomatic Characterized by insulin resistance Strong genetic predisposition One parent, 50% likelihood Both parents, 80% 2

3 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 STUDIES SHOW NO ADDITIONAL RETINAL SCREENING NEEDED Gestational Diabetes Plasma glucose concentration at or above any 2 of 4 values on OGTT Fasting, 95 mg/dl 1 hour, 180 mg/dl 2 hour, 155 mg/dl 3 hour, 140 mg/dl Traditionally, treated with diet changes or insulin New studies looking at oral meds At higher risk for developing type 2 later in life 5 fold increase at 5 yrs, 9 fold after 10 years Pre-Diabetes Blood sugar levels higher than normal, but not yet high enough to be diagnosed with DM FBS A1c ADA estimates 35% of adults over age 40 (79 million Americans) have pre-diabetes 30 minutes of exercise combined with 5-10% reduction in body weight resulted in 58% reduction in diabetes DRUG CLASS Medical Management of DM EXAMPLES Generic (Trade) Biguanide Mejormin (Glucophage ) α- Glucosidase Inhibitors Acarbose (Precose ), miglitol (Glyset ) Sulfonylureas Glipizide (Glucotrol ), glyburide (Micronase ), glimepiride (Amaryl ) MegliXnides Repaglinide (Prandin ), nateglinide (Starlix ) TZDs (glitazones) Pioglitazone (Actos), rosiglitazone (Avandia ) DPP- 4 Inhibitors (dipepxdyl pepxdase- 4 inhibitors) SGLT2 Inhibitors (sodium- glucose cotransporter 2 inhibitors) Oral Agents 1 SitaglipXn (Januvia ), saxaglipxn (Onglyza ), linaglipxn (Tradjenta ), aloglipxn (Nesina) Canagliflozin (Invokana ), dapagliflozin (Farxiga ), empagliflozin (Jardiance ) 1. Garber AJ, et al. American AssociaXon of Clinical Endocrinologists comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(3): Medical Management of DM Medical Management of DM DRUG CLASS GLP- 1 Agonists (increxn mimexcs) Injectable Non- Insulin Agents 1 EXAMPLES Generic (Trade) Amylin Analogs PramlinXde (Symlin ) LiragluXde (Victoza ), exenaxde (Bye[a ), exenaxde ER (Bydureon ), dulagluxde (Trulicity ), albigluxde (Tanzeum ) DRUG CLASS EXAMPLES Generic (Trade) Basal Insulin Glargine (Lantus ), detemir (Levemir ), glargine U- 300 (Toujeo ) Rapid- AcXng Insulin Analogs Insulin Therapy 1,2 Aspart (NovoLog ), lispro (Humalog ), glulisine (Apidra ), lispro U- 200 (Humalog U- 200) Premixed Insulin 70:30, 75:25, 50:50 (Humulin, Novolin ) Regular Insulin U- 500 (Humulin R) Inhaled Insulin Afrezza 1. Garber AJ, et al. American AssociaXon of Clinical Endocrinologists comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(3): Garber AJ, et al. American AssociaXon of Clinical Endocrinologists comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(3): American Diabetes AssociaXon. Insulin basics. h[p:// with- diabetes/treatment- and- care/medicaxon/insulin/insulin- basics.html. Accessed October 14,

4 Medical Management of DM CombinaXons INSULIN PUMP THERAPY COMPANY Medtronic EXAMPLES Tandem t:slim, t:flex Insulet OmniPod MiniMed 530G, Paradigm Revel Animas Vibe, OneTouch Ping Accu- chek Insulin Delivery Devices Combo Pioglitazone/mejormin: Actoplus Met Glyburide/mejormin: Glucovance SitaglipXn (Januvia)/mejormin: Janumet SaxiglipXn (Onglyza)/mejormin: Kombiglyze Repaglinide(Prandin)/mejormin: Prandimet Pioglitazone/Glimepiride: Duetact AloglipXn/ mejormin: Kazano AloglipXn/ pioglitazone:oseni Sleep Many studies show quality and quanxty of sleep are related to glycemic control in Type 2 DM Short (<6hrs) and long sleep duraxon( >9 hrs) associated with increased A1c Poor sleep quality also associated with increased HgA1c Goal; 7-8 qulaity hrs of sllep Current recommendations for Treatment of DM Control BS levels HgbA1c < 7 Control HTN <120/80 Control Cholesterol levels Total cholesterol < 200 No smoking Exercise Yearly foot exams, dental exams, and dilated retinal exams Here is my summaxon (at the beginning) and then I will prove my points DiabeXc ReXnopathy What s new and what do we need to know? Systemic control ma[ers! Know your Xpping point ReXnopathy is not just located centrally Oral supplements / treatments can be beneficial Treatments for CSME are evolving no clear winner (besides pharmaceuxcal companies!) When all else fails 4

5 What does A1c mean to your paxents? Likely not much When did they have it done last? What was it? What is it supposed to be? Diabetes Control and ComplicaXons Trial & UK ProspecXve Diabetes Study n Pts randomized to convenxonal or intense control n Showed slower progression for intense control group n For those with no NPDR at start, if intense, then 76% less devel. of rexnopathy n If A1c down by 2%, PDR would decrease by 50% n Decrease in A1C by 1 %: n 14% decrease in MI n 12% decrease in stroke n 37% decrease in microvascular dz n 21% decrease in any DM endpoint n DCCT reported relaxonship of A1C and avg. Glucose %HbA1C* Avg Glucose (mg/dl) Control group in DCCT: 9-10% Strict control group: 7% Sources: NEJM 329: UKPDS: Lancet 352: ,1998 Later updates. Further analysis shows. 10 years later, prevalence of DR progression or PDR less in intensive group azer 10 yrs (24 vs 41% & 6.5 vs 19%) Other studies have confirmed rexnopathy linked to inixal BS control 2 Similar effect seen in neuroathy and albuminiria Metabolic memory appears to last 10 years, but may wane at some Xme 18 yrs later: The HbA 1c ma[ers today, tomorrow, and for many, many years to come. It ma[ers. DCCT/EDIC biostaxsxcian John M. Lachin, ScD Remaining differences: ReXnopathy: 46% Cataract: 48% RD or Vitrectomy: 44% CV: 33% Fatal cardio event 31% (2013 ADA meexng) For every 10% decrease in A1c, you decrease risk of DR progression by 43%! Holds true for A1c between 5 and 8% Example: from 8.0 to 7.2 equals a 43 decrease in risk 1. Prolonged Effect of Intensive Therapy with T1DM. DCCT group. Arch Ophth 12/ Reichard P. Glycemic thresholds for complicaxons. J Diab Complic. 199:9(1); DiabeXc ReXnopathy n Virtually 100% of people with diabetes have at least NPDR within 20yrs of diagnosis n Up to 20% of newly diagnosed T2DM have NPDR at diagnosis n Major cause of vision loss is CSME n Today s treatment based on ETDRS n Should the standard shiz to more modern treatment? DR some real numbers n Pooled analysis from almost 23k w DM 34.6% prevalence for any DR 6.96% for PDR 6.81% for DME 10.2% for VTDR All DR end points increased with DM duration, A 1c & BP n Higher in people with T1DM compared w T2DM n Worldwide: 93M w DR, 17M PDR, 21M DME, 28M VTDR Yao et al. Prevalence of DR. Diabetes Care. March

6 DiabeXc rexnopathy Prevalence DR in USA NaXonal Health and NuriXonal ExaminaXon Survey (NHANES) Published JAMA 8/2010 Looked at 1006 individuals with DM (A1c >6.5%) DR vs VTDR vs PDR vs CSME Extrapolate: 3.8% of US has DR and.6% VTDR!!! Prevalence DR in US. Zhang et al. JAMA 8/ % DR 4.4% VTDR 1.5% PDR and 2.7% CSME Higher in Hispanic and AA VTDR > if >65yo DR more if on insulin >DR if >A1c, HTN, duraxon and insulin use 21% of those in NHANES with DM were undiagnosed Why talk about CSME n Is it a rare complicapon? 1 n 955 subjects dx before 30yo n 25yr cumulapve incidence was: n 29% for ME n 17% for CSME** n Higher incidence in males, more severe DR, higher A1c, proteinuria, Higher BP n Risk seemed to slightly decrease at end of study WHY? n By the way, sxll treated with tradixonal laser no be[er vision with micro- pulse laser 2 1WESDR of DR XXIII: 25yr Incidnce of ME in T1DM. Klein et al. Ophth. 3/09 2. Figueira et al. Micropulse vs standard laser for CSME. BJO Risk Factors For Diabetic Retinopathy Established Disease duration HbA1c Disease sub-type Gender HTN Microalbuminuria Race Invest Ophthalmol Vis Sci Jun 22;52(7): Diabet Med Apr;27(4): Emerging Obesity Sleep apnea Vitamin D insufficiency Vit B12 deficiency Carotenoid imbalance (low serum xanthophylls i.e. lutein/zeaxanthin) Endocr Pract Mar-Apr;18(2): PLoS One. 2011;6(11):e26747 NPDR n Mild n At least 1 ma n Moderate n Hemorhages &/or ma s (2A), CWS, or VB(< 6B) or IRMA (<8A) n Severe n 4/2/1 (Heme, Beading, IRMA) n 15% to PDR in 1yr 1* n Very Severe n 2 or severe findings without neo. n 45% to PDR in 1 yr 1 1. As reported by ETDRS Macular Edema n 3 classic criteria* n Thickening <1/3DD from center of macula n Heme/exudate with thickening of adjacent rexna <1/3dd from center of macula n Thickening >1dd size within 1dd center n Current treatment: AnX- VEGF InvesXgaXonal treatments n Failed treatments (steroid) DiabeXc ReXnopathy/Maculopathy and OCT n Tissue thickening n CysXc changes n DisrupXon of NFL n Monitor efficacy of Tx. Pre Treatment 4 days s/p injecxon 6

7 DR in the periphery Can periphery predict worsening? To properly grade DR, you need to see the periphery Up to 10% of pts will have more severe DR when periphery considered vs standard 7- field photography Temporal was most important field Peripheral DR Silva et al. Peripheral DR and Severity. Ophth. No DR in macula Outcome: 2 step progression or to PDR Primary peripheral lesions (PPLs) = 3.2x risk of progression 4.7x risk to go to PDR(25%! Of PPL to PDR!!) Independent of duraxon, A1c, age, gender, type or baseline severity More areas of PPL = more likely to progress Silva et al. PLs on UWF and progression. Ophth. 3/15 Is DME a macular disease? Or is it a macular manifestaxon of peripheral non- perfusion/pathology? Chronic vs acute The same thing is potenxally happening in periphery as as posterior pole Could UWF FA help determine tx needed? Does UWF FA offer value Proof of concept study shows can do less PRP and adjuncxve anx- VEGF as Tx for poor perfusion to decrease need for injecxons Could less do more?? DiabePc RePnopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultra widefield Angiography The presence of peripheral lesions is associated with increased non- perfusion area and nonperfusion index These findings were not correlated with macular edema or visual acuity and remained significant azer adjusxng for DR severity and diabetes duraxon. The data from our current study provide UWF angiographic evidence to support this hypothesis further and the long- held observaxon that nonperfusion in DR begins in the midperipheral repna and ischemia, thus accounxng for the increased risk of progression. This approach [color ETDRS photos] generally remains the current standard of care in the management of DR. However, substanxal advances in eye and medical care have improved visual and anatomic outcomes for many paxents with diabetes and have shized the focus from intervening only at advanced stages of disease to diagnosing and managing earlier stages of DR to potenxally slow progression or prevent DR development. Bo[om line of periphery and DR..AccumulaXng evidence suggests that UWF imaging idenxfies findings in the rexnal periphery that may substanxally improve rates of DR detecxon, be[er characterize DR severity and more accurately define risk of DR progression.. may support a need to redefine our current DR severitly classificaxon systems to inforporate the new findings and thus improve the ability to predict natural history of DR and guide therapeuxc intervenxons Sun JK and Aiello LP in JAMA Ophthalmology 12/2015 Reference: Aiello et al. DiabeXc ReXnopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography Ophthalmology,

8 Macular Pigment in Diabetes Significantly lower in DM subjects than age matched normals IOVS 2010 Nov;51(11): Inversely associated with A1c & DR severity Br J Nutr 2009 Jan;101(2): IOVS 2010 Nov;51(11): Vitamin D and Retinopathy in T2DM Mean Serum 25-OH vitamin D (ng/ml) DM (n=123) 22.9 No DM (n=98) 30.3 DM without DR 23.2 DM with NPDR 21.5 DM with PDR % of pts taking a multivitamin were vit D insufficient 83% of pts not taking a multivitamin were insufficient American Academy of Ophthalmol: Abstract PO223. Presented October 17, Lutein Zeaxanthin Lycopene Non- provitamin A Carotenoids Highest serum raxo of non- PVA: PVA carotenoids associated with a 66% lower risk of DR in pts with T2DM Br J Nutr 2009 Jan;101(2): Diabetes & DR Affect Visual FuncPon Snellen visual acuity is a 150+ yr old test that does not always reflect real world visual funcxon DM/DR also impair: color percepxon, contrast sensixvity, visual field sensixvity Graefes Arch Clin Exp Ophthalmol Dec;250(12): Diabet Med Jul;28(7): Acta Opthalmol 2005; 82(5): Graefes Arch Clin Exp Ophthalmol Sep;239(9):643-8 BJO 1996;80: IOVS 1997; 38(9): Diabetes Care 1992; 15(5): Graefes Arch Clin Exp Ophthalmol.1996 May;234(5):300-5 Brit J Ophthalmol E- published June 18, 2015 Diabetes Visual FuncPon Supplement Study (DiVFuSS) n 6 month placebo-controlled RCCT of adults with T1DM or T2DM > 5 years n No DR (2:1) and mild-moderate NPDR (1:1) n Daily use of a multi-component nutritional supplement including zeaxanthin & lutein n Pre- and post- analysis of CSF, MPOD, color vis., macular perimetry, OCT, A1c, lipids, 25(OH) vit. D, TNF-a, hscrp Chous AP, Richer SP, Gerson JG, Kowluru RA. The Diabetes Visual FuncXon Supplement Study. Br J Ophthalmol June 18,

9 Mean Change/SD in visual function measures, serum lipids, hscrp, TNF-α, glycohemoglobin, foveal thickness and symptoms of diabetic peripheral neuropathy with 95% p-values Δ from baseline Suppl v. Plac p-value Contrast Sens (%) < Color Error Score < MD (db) < MPOD (du) < LDL-C (mg/dl) HDL-C (mg/dl) TGs (mg/dl) hscrp (mg/l) HbA1c (%) Foveal Thickness µm µm 0.35 DPNSS -30.7% +10.7% Fisher s Exact Test What about oral Tx for DR Fenofibrate (Tricor) 1 As part of ACCORD- EYE and FIELD, looked at 11,400 Dm ½ fenofibrate +/- staxn Presence of Fenofibrate reduced progression to need laser by 31% (PRP or focal) Stronger results in those w exisxng DR than w/out NNT w rexnopathy: FIELD: 9 ACCORD: 14 (s ret: 333/500) Minocyline 2012 ARVO paper 2 reporxng improvement in DME w 100mg BID +5.8 le[ers and 7% decrease OCT in 6mos (n=5) Previous studies in animals and some human showing efficacy 1. Fenofibrate for DR. Wong et al. AJO 7/ Minocycline for DME. Cukras et al. ARVO What If My PaXent Needs Treatment? PRP reduces the risk of severe vision loss from PDR by 50-75% DRS/ETDRS AnX- VEGF (LucenXs) is non- inferior to PRP for proliferaxve DR at 2 years Less DME Be[er visual field DRCR.net Protocol S JAMA 2015 ; 314(20): Protocol T Published Results n Aflibercept yielded 5-7 additional ETDRS letters compared to bevacizumab & ranibizumab when baseline VA was 20/50 or worse n Fewer pts needed rescue laser n 1 fewer injection n Few adverse events in all 3 groups n No difference for serious events, hospitalization or death n Still only 1-year data N Engl J Med 2015; 372: Protocol T 2 year Basically no difference between drugs Protocol 2 Years T No significant difference between Eylea and LucenXs at 2 yrs irrespecxve of baseline VA (+2 ETDRS le[ers with aflibercept) Eylea was superior to AvasXn (+ 5 le[ers) Eylea paxents were 20% less likely to need rescue laser LucenXs paxents were 2X more likely to have an APTC event Ophthalmology Feb 27,

10 Time to Switch It Up? DME paxents unresponsive to AvasXn and/or LucenXs were switched to Eylea RetrospecXve analysis Mean of 90/120 micron decrease in CFT at 1 and 5 months follow- up (p < 0.001) VA improved 2.5 ETDRS le[ers on average (p =0.04) n = 19 subjects/21 eyes Clin Ophthalmol Sep 16;9: OrCam A way to bring reading to those that are not able to read A[aches to a standard pair of glasses Ba[ery operated and lasts for hours Can read books, magazines, newspapers, product labels, indenxfy money, facial recognixon and other programmable features Resources n n n n n DiabeXc Eye Disease by A. Paul Chous, O.D. n n Endocrinologist Who is more likely to get DR? Anybody that has diabetes long enough. Worse overall control (A1c) More fluctuaxons / spikes Certain medicaxons (blood pressure in parxcular) Nutrient deficient (Vitamin D, Lutein/ Zeaxanthin) 10