Diagnosing Diabetes In Adults– Type 1, LADA, or Type 2? Stanley Schwartz MD, FACE, FACP Affiliate Main Line Health Emeritus, Clinical Assoc. Prof. of Medicine Perlman School of Medicine, University of Pennsylvania Part 4 of 4 Struan F.A. Grant, Ph.D Vanessa Guy Children’s Hospital of Philadelphia Children’s Hospital of Philadelphia Associate Professor, University of Pennsylvania Senior Clinical Research Coordinator Co-Investigators NIH RO-1, Genes in LADA

Egregious Eleven Defect Intervention / Therapy β-Cell (Islet Cell) Classification Model- Implications for Therapy: (Not Core Defects)-Targets for Therapies Direct Effect on β-Cells On #1-4 of ‘Egregious Eleven’ Egregious Eleven Defect Intervention / Therapy 1 β-CELL Incretin , Ranolazine 2 α-Cell Glucagon Incretin, Pramlintide 3 ↓INCRETIN EFFECT Incretin 4 Inflammation Incretin, ? Anti-inflammatory Hierarchy of Medication Choice (a la AACE Guideline)(this and next slide) , not just reduction in HgA1c, but Efficacy Number of Targets of Therapy each drug addresses Weight loss Proven Reduction in CV outcomes

β-Cell (Islet Cell) Classification Model- Implications for Therapy: (Not Core Defects)-Targets for Therapies In-Direct Effect on β-Cells On #5-11 of ‘Egregious Eleven’ Egregious Eleven Target: Intervention / Therapy 5,6,7 Liver, Muscle, Fat Insulin Resistance: MET, TZD, Bromocriptine-QR (wt. reduction agents– GLP-1 RA, SGLT-2 Inhibitors) 8 Kidney Renal Threshold for Glucosuria: SGLT-2 Inhibitors 9 Brain Appetite: Incretin Centrally Controlled Peripheral IR: Bromocriptine-QR Sympathetic Tone: Bromocriptine-QR 10 Stomach/Intestine Rate of Appearance of Glucose in the blood: AGI, GLP-1 RA, Pramlintide 11 Colon/Biome Gut Biome: ? Probiotic (may improve IR, β-cell function, inflam.) 5-11 ALL Decrease Glucose/ Lipotoxicity

FOR ALL DM – potential CV benefit (ANTI-INFLAMMATORY) Hedge your Bets: All get Incretins  DPP_4 Inh, GLP-1 RAs, [ or agents that increase GLP-1 e.g.: Metformin, Colesevalam, (TGR-5)] Type 1- minimize brittle, dawn, unpredictable, variability, ? CV benefits, Treat those ‘Type 2’ Genes’, ANTI-INFLAMMATORY LADA = SPIDDM/ Autoimmune T2DM Same- Slow , stabilize disease process, ANTI-INFLAMMATORY Type 2- treats 7 MOA’s of DeFronzo’s Octet, or 9/11 EE  Decreases oxidative stress, β-cell inflam., decreases lipo- and gluco-toxicity, ?preserve mass, decreases appetite, treats IR via wt. loss MODY 3- recent report FOR ALL DM – potential CV benefit (ANTI-INFLAMMATORY)

Reference list for last slide  LADA Zhao Y,et al . Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study.,J Clin Endocrinol Metab. 2014 Jan 16:jc20133633. TYPE 1 Ellis et al, Effect of Sitagliptin on glucose control in Adult patients with Type 1 DM, Diabetic Medicine DOI: 10.1111/j.1464-5491.2011.03331 Kielgast U., et al Treatment of Type ! Diabetic Patients with GLP-1 and GLP-1 Agonists, Current Diabetes Reviews,2009, 5:266-275 TYPE 2 Ju-Young Kim,Exendin-4 Protects Against Sulfonylurea-Induced β-Cell Apoptosis, J Pharmacol Sci 118, 65 – 74 (2012) Drucker DJ, Rosen CF. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia 2011;54:2741–2744 Chaudhuri A, Ghanim H, Vora M, et al. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab 2012;97:198–207 Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab 2012;97:3333–3341 Drucker, D., Incretin Action in the Pancreas: Potential Promise, Possible Perils, and Pathological PitfallsDiabetes 62:3316–3323, 2013 Shimoda M, Kanda Y, Hamamoto S, Tawaramoto K, Hashiramoto M, Matsuki M, Kaku K.The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia. 2011 May;54(5):1098-108. doi: 10.1007/s00125-011-2069-9. Epub 2011 Feb 22. Kim JY, Lim DM, Moon CI, Jo KJ, Lee SK, Baik HW, Lee KH, Lee KW, Park KY, Kim BJ.Exendin-4 protects oxidative stress-induced β-cell apoptosis through reduced JNK and GSK3β activity. J Korean Med Sci. 2010 Nov;25(11):1626-32. doi: 10.3346/jkms.2010.25.11.1626. Epub 2010 Oct 26. Liu Z, Stanojevic V, Brindamour LJ, Habener GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic β-cells from glucolipotoxicity. J Endocrinol. 2012 May;213(2):143-54. doi: 10.1530/JOE-11-0328. Epub 2012 Mar 13. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus Diabetologia - Clinical and Experimental Diabetes and Metabolism, 03/04/2014  Hogan AE,

Follow current AACE GUIDELINE PRINCIPLES Treat as many of the Egregious 11 Targets as needed, with least # of agents, to get lowest sugars/HgA1c as possible without undue weight gain or hypoglycemia Early Combination Therapy First Tier- Efficacy, (my add- CV event reduction, Weight Loss) Treat with agents that address FBS AND PPG Ideally agents will stabilize, preserve β-cells, the CORE DEFECT ( NO SU/GLINIDES) Ideally agents will have potential to synergistically decrease in CV risk factors / outcomes

Summary: What do we do for Treatment Which therapies to use will be based on: New research as available New guidelines to be developed Each physicians assessment / comfort with modalities at hand in an… Evidence-Based PRACTICE approach eg: I give incretins to (nearly) all (my) patients with diabetes now (whenever possible), even ‘off-label’ ‘Patient-centric approach’ PICK RIGHT DRUG FOR THE RIGHT PATIENT, AND VICE-VERSA Eg: no hesitation to use , for example TZD, SGLT-2, Incretins in ‘usual’ T1DM

Patient-Centric Diagnosis and Care/Therapy Traditional Labs/Testing FBS, RBS, HgA1c Specific Therapy At Risk Individuals Genes Etiologic Diagnostic Markers: β-Cell, IR, Inflam, Environment, Genes Pre-Diabetes Rx B = β-cell- (Incretin) Br= Brain- (Bromo-QR) I = Inflam- (Incretin, new) R = Resistance- MET, Pio- E = Environment- diet, exercise Biome- (? Effects on IR, β-cell, Inflam) (? Multiple- a la DeFronzo pilot) Diabetes Rx B = β-cell- Incretin, suppressing glucagon agents, SGLT-2 Br = Brain- Bromo-QR, stomach, R I = Inflam- Incretin, (New) R = Resistance- MET, Pio, (New) E = Environment- diet, exercise Biome-(? Effects on IR, β-cell, Inflam) Tempered by DATA- focus for future Research  ( ) = Not proven

Based on ‘New’ Classification: Recommended Process For Prevention, Diagnosis and Therapy, 2014 Convene ADA/EASD/WHO/AACE Committee : Revising Classification of Diabetes Mellitus Set Processes in Place Increase current repositories- JAEB, JDRI to include LADA patients, (but all ‘kinds of hyperglycemic patient types), HDLI, Large Health Systems ( K-P) Research- into these ideas/ approaches EDUCATE MDs re :issues Allan D. Sniderman et al The Necessity for Clinical Reasoning in the Era of Evidence-Based Medicine,Mayo Clin Proc. 2013;88(10):1108-1114 THEN, use Evidence-Based Practice Approaches to DX & provide Therapy Where evidence incomplete, But logic exists to help patients, apply appropriate Clinical Reasoning,= Evidence Based Practice

So For Now, with Current Terminology, Cost- Driven Diagnosis of Diabetes in Adults ‡ FH + (-) Ketosis prone Younger BMI >30 Type 2 FH - ( +) ketosis prone Younger Type 1 ‘LADA’ SPIDDM Autoimmune Type2 Antibody /HLA to Verify BMI >30 Older (-) Ketosis prone FH+ BMI >30 Type 2 Genome to Clarify <30 BMI MODY ‘LADA’ SPIDDM Autoimmune Type2 BMI <30 Antibody /HLA to Verify ‡ BASED ON FAMILY HX (GENES) AGE, ?KETOSIS PRONE BMI, ANTIBODIES If cost ‘less of an Issue’- antibodies in all Stanford Antibody Chip- fraction of cost of RAI At some point ,NOW- genotype all 

So For Now, with Current Terminology, Cost- Driven Diagnosis of Diabetes in Adults ‡ FH + (-) Ketosis prone Younger BMI >30 Type 2 Older (-) Ketosis prone FH+ BMI >30 Type 2 Genome to Clarify <30 BMI MODY ‘LADA’ SPIDDM Autoimmune Type2 BMI <30 Antibody /HLA to Verify ‡ BASED ON FAMILY HX (GENES) AGE, ?KETOSIS PRONE BMI, ANTIBODIES If cost ‘less of an Issue’- antibodies in all Stanford Antibody Chip- fraction of cost of RAI At some point, NOW-genotype all 

So For Now, with Current Terminology, Cost- Driven Diagnosis of Diabetes in Adults ‡ FH - ( +) ketosis prone Younger Type 1 ‘LADA’ SPIDDM Autoimmune Type2 Antibody /HLA to Verify BMI >30 ‡ BASED ON FAMILY HX (GENES) AGE, ?KETOSIS PRONE BMI, ANTIBODIES If cost ‘less of an Issue’- antibodies in all Stanford Antibody Chip- fraction of cost of RAI At some point, NOW- genotype all 

So For Now, with Current Terminology, Cost- Driven Diagnosis of Diabetes in Adults ‡ FH + (-) Ketosis prone Younger BMI >30 Type 2 FH - ( +) ketosis prone Younger Type 1 ‘LADA’ SPIDDM Autoimmune Type2 Antibody /HLA to Verify BMI >30 Older (-) Ketosis prone FH+ BMI >30 Type 2 Genome to Clarify <30 BMI MODY ‘LADA’ SPIDDM Autoimmune Type2 BMI <30 Antibody /HLA to Verify If cost ‘less of an Issue’- antibodies in all Stanford Antibody Chip- fraction of cost of RAI At some point, NOW- genotype all  VOILA et MERCI ‡ BASED ON FAMILY HX (GENES) AGE, ?KETOSIS PRONE BMI, ANTIBODIES

In Summary Current Classification of Diabetes Types are unable to differentiate patients; inhibit appropriate use of all therapies that are available to us now , and in near future New Classification that recognizes the Beta-cell as THE CORE DEFECT in ALL Diabetes, and describes the multiple causes for their dysfunction offers wonderful opportunities for Prevention, Therapy, Research and Education In particular we must recognize that multiple types of therapy are, and will be available, to be used in any patient with diabetes, based on the causes of their dysfunction- genes, inflammation, insulin resistance, gut biome, central (brain) mechanisms; defining markers, and processes of care in using them, will then allow appropriate patient-centric approaches- whether we choose to use old ie: current nomenclature or develop a new nomenclature. Eg : even at present it allows us to use, for example, incretins, insulin sensitivity agents, SGLT-2 inhibitors in T1DM, LADA patients etc. More research always needed, but, in an evidence-based PRACTICE approach to care, we can START NOW

With Great Thanks!! Dr. Richard Aguilar- Clinician, Educator, Collaborator, A Best Friend!! Our Mentors • Arthur Rubenstein, David Rabin, Jesse Roth, Al Weingrad, Oscar Crawford, John Williamson , Barabara Corkey, Lester Baker, Charles Stanley • Hakon Hankerson

Acknowledgements: Our NIH Grant Collaborators Action LADA Consortium T1D Exchange Institut de Biologie de Lille David Leslie Carla Greenbaum Philippe Froguel Mohammed Hawa Asa Davis Véronique Dhennin Bernhard Boehm Kristen Kuhns Marianne Deweirder Knud Yderstræde T1D Exchange Biobank Operations Center Didac Mauricio Puente Alberto Deleiva Geisinger Clinic Mayo Clinic Charles Thivolet Ronald Harris Adrian Vella Werner Scherbaum John Kennedy Paula Giesler Nanette Schloot Rosemarie Delucca Jeanette Laugen Mary Ann Ngoc Dang National Disease Research Interchange University of Leicester Adventist Health System/Sunbelt John Lonsdale Kamlesh Khunti Richard Pratley Lee Ducat Melanie Davies Julie Clyatt Stephanie Goldby University of Alabama at Birmingham Sian Hill University of Pennsylvania Fernando Ovalle Michael Rickels Kentress Davison Nora Rosenfeld University of Washington Weill Cornell Medical College Health Diagnostic Laboratory, Inc. Santica Marcovina David Brillon Steven Varvel Jessica Harting Karen Hyams Joe McConnell