New treatments for an old disease Ahdy Wadie Helmy, MD, FACP Associate Professor of Medicine IU School of Medicine

Type 2 Mellitus that is hitting back with

vengeance Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults

2EHVLW\ %0,•NJP2) 1994 2000 2014 USA. A new Diabetic case Dx every 20 secs(1.7 million/yr) No Data <14.0% 14.0%±17.9% 18.0%±21.9% 22.0%±25.9% > 26.0% Diabetes kills 1 American Diabetes every 3 minutes 1994 2000 2014 180 diabetics loose a limb every 24 hrs 55 Diabetics end on dialysis

No Data e v 9.0%

&'&¶V'LYLVLRQRI'LDEHWHV7UDQVODWLRQUnited States Surveillance System available at http://www.cdc.gov/diabetes/data Globally, same mess, only Bigger! Estimated global prevalence of diabetes

EU NA 17.8 19.7 25.1 33.9 41% China 72% 20.8 42.3 MEC 204% 20.1 52.8 263% SSA 7.1 India 18.6 31.7 79.4 LAC 261% 251% 13.3 33.0 248% A+NZ 151 million 1.2 366 million 642 million2.0 65% 2000 2011 2040

International Diabetes Federation. IDF Diabetes Atlas. 7th ed.accessed April 2016. 'LDEHWHVGRHVQ¶WGHYHORSRYHUQLJKW it takes years of preparation

Feeding

More to suppress lipolysis

Liver Visceral Adiposity

Pancreas Cardiac Muscle ǃ-Cell mass in

3.5

3.0 -50% 2.5

2.0 -63% 1.5

-Cell -Cell volume (%) 1.0 E 0.5

0.0 ND IFG T2DM ND T2DM Obese Lean ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus Butler et al. Diabetes. 2003 Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT

Getting Back up on WKH&XUYH¶ 40

Lean 30

¨,¨* 20 ÷IR

10 Obese TZDs, 0

IS NGT IGT T2DM IR 2-Hour Plasma Glucose (mg/dL)

G=glucose; I=insulin; IR=insulin resistance. Gastaldelli A, et al. Diabetologia. 2004;47:31-39. Pathogenesis of Type 2 Diabetes

Islet E-cell

Diabetes Diabetes Normal glucose tolerance Normal glucose tolerance

Impaired

Insulin Insulin Secretion Insulin Secretion

1st Phase 2nd Phase

- - 0 5 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 1 1 5 0 5 0 5 0 5 0 5 0 5 0 5 0 5 0 5 0 5 0 Time (minutes) 0 i.v. Glucose 0 Insulin Secretion Insulin

1st Phase (AIR ) 2nd Phase

-10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Increased Decreased Glucose HGP i.v. Glucose Time (minutes) Uptake

HGP=hepaticAdapted from glucoseWeyer C, production. et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502. Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGT

Decrease in AIR Necessary to Convert From NGT to IGT

Pima Indian Latino/Hispanic White 0

-10 -8 -20 -18 AIR AIR (%) -30 ǻ -32 -40

Insulin resistance ĹĹĹ ĹĹ Ĺ

AIR=acute insulin response to glucose. Abdul-Ghani MA, et al. Diabetes Care. 2006;29:1130-1139. Hormones in Sequence

insulin secretion insulin secretion Meal 2nd wave AIR 80 20

Beta Cells 60 15

40 10 Insulin (mU/L) Insulin * * 5 20 * * * * *

0 0 -30 0 30 60 90 120 150 180 0 30 60 90 120 150 180 GLP-1: Secreted Meal (min) upon the ingestion of food

Without diabetes; n = 27 Late-stage type 2; n = 12 Type 101; n = 190 Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398 The Incretins ³Gut-derived factors that increase glucose-VWLPXODWHGLQVXOLQVHFUHWLRQ´ ( Intestine Secretion of Insulin )

GLP-1: Secreted upon the ingestion of food Promotes satiety and reduces appetite

Alpha cells: p Postprandial glucagon secretion

Liver: p Glucagon reduces Beta cells: hepatic glucose output Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying

Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169 The Incretin Effect is Reduced in Subjects with Type 2 Diabetes

The Incretin Effect accounts for ~ 60% of total Insulin release following a meal

Control subjects Subjects with type 2 diabetes

80 80

60 60

40 40 * Insulin (mU/L) Insulin Insulin (mU/L) Insulin * * * * 20 * * * 20 * *

0 0 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Time (min) Time (min) Oral Glucose Intravenous Glucose

Nauck MA, et al. Diabetologia 1986;29:46±52. *P ”FRPSDUHGZLWKUHVSHFWLYHYDOXHDIWHURUDOORDG GLP-1 Is Cleaved and Inactivated by DPP-4

T1/2= 1 to 2 min Development of more incretin mimetics

50% overlap with human GLP-11 ± Binds GLP-1 receptors on ȕ-cells (in vitro)2 ± Resistant to DPP-IV inactivation3

OD T½ 13 h Liraglutide GLP-1 Human H AAE G T F T S D V S SSYL Y L E GGQ Q A AAKE K E F I AA has Site of DPP-IV Inactivation2,3 97 % AA sequence Ŷ FollowingT½ 2.4 injection, h exenathours4 identity with human GLP-1

1Eng J, et al. J Biol Chem 1992;267:7402±7405; Adapted from 2Nielsen LL, et al. Regul Pept 2004;117:77±88; 3Drucker DJ. Diabetes Care 2003;26:2929±2940; 4Calara F, et al. Clin Ther 2005;27:210±215. Chemical Structures of GLP-1 RAs

BYETTADrug Initial Titrate Max Dose Adjustments (Exenatide)

53% Homology 5 mcg BID within Weekly Gila monster Exenatide IR 60 mins of a meal Ĺ to 10 mcg BYDUREON saliva 10 mcg (Byetta®) (> 6H between after 1 month (ExenatideRenal ER) impairment: CrCl 30-50 mL/min: use

doses) 53%caution; CrCl < 30 mL/min not Homologyrecommended MicrosphereHepatic impairment: not studied Exenatide ER 2 mg once 2 mg oncetechnology WeeklyN/A (Bydureon®) weekly weekly TANZEUM () VICTOZA 0.6 mg once Liraglutide 1.2 mg once 1.8 mg once Renal & hepatic impairment: use caution (Liraglutide) daily 97% (Victoza®) daily per week daily ± limited experience Homology

97% Homology Dimer fused C-16 Fatty Acid to AlbuminĹ to 50 mg Renal impairment:Weekly use caution when AlbiglutideChain 30 mg once once weekly if 50 mg once initiatingTRULICITY or escalating doses (Tanzeum®) weekly inadequate daily Hepatic() impairment: not studied, unlikely

response required90% Homology Linked to modified IgG Ĺ to 1.5 mg Renal impairment: use caution when Dulaglutide 0.75 mg once once weekly if 1.5 mg once initiating or escalating doses (Trulicity®) weekly inadequate weekly response Hepatic impairment: use with caution Deciding about First Injectable Drug for Patients Not Controlled by Oral Agents

‡ DURATION-3 trial of once-weekly exenatide vs as first injectable therapy

Exenatide Insulin 3-year endpoint QW glargine P Value (n=233) (n=223)

Change in A1C -1.01% -0.81% 0.03

Change in body -5.5 lbs +4.4 lbs <0.001 weight Hypoglycemia 0.3 events 0.9 events (exposure-adjusted per patient- per patient- NR events) year year

NR = not reported. Diamant M et al. Lancet. 2014:2:464-473. ITKA 650 osmotic pump for continuous Exenetide infusion implanted yearly

60 Mcg daily was found to be the most tolerable dose . Diab Care. Vol 36 : 2013, lancet 04/2016 Exenetide QMS once-monthly suspension dosing ( Phase II study data ) ‡ Microsphere technology provides a continuous level of exenatide1 1 Microspheres consist of a biodegradable polymer that dissipates into CO2 and water Using a non-aqueous suspending medium of Medium Chain Trigs Miglyol 812 that keeps the microspheres suspended & preserved eliminating the need for reconstitution immediately before injection. ( 5, 8, 11 MG dosing ) with efficacy & tolerability c/w Exenetide QW

Subcutaneous injection Individual Microsphere Further degradation of microsphere microspheres degradation and and metabolism of suspension of aggregate and initial continued release of microsphere polymer exenatide1 release of exenatide1 exenatide1 provide sustained level of exenatide1

Wysham et al.Efficacy & Safety of multiple doses of exenetide once-monthly suspension in patients with Type 2 DM: a phase II RCT. Diabetes Care 2016;39:1768-1776. DPP-4 Inhibitors Prevent the Inactivation of GLP-1 GLP-1 Modulates Numerous Functions in Humans

GLP-1 Receptor Agonism DPP-4 Inhibition

Decreases food intake

Slows gastric Emptying

Suppresses glucagon secretion, decreasing Improves first- glucose output phase insulin response Stimulates glucose- dependent insulin secretion

1. Stonehouse A, et al. Curr Diabetes Rev 2008;4:101-109; 2. Nielsen LL, et al. Regul Pept 2004;117:77-88 3. Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089; 4. Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991-5997 Comparison( januvia of) Dipeptidyl( Tradjenta Peptidase) (onglyza±4 ) (DPP(Nesina-4) )

Dose frequency 100 mg QD Inhibitors5 mg QD 5 mg QD 6.25mg, 12.5,25 QD

Half-life (t ), h 12.4 12.5±21.1 2.2±3.8 1/2 21 hrs

DPP-4 inhibition at ~80% ~80% (25 mg) ~55% (5 mg) 24 h

Elimination Kidney Bile but not kidney Liver and kidney (mostly unchanged) (mostly unchanged) Active metabolite

Renal dose Yes Yes Yes adjustments required NoBile

Selectivity for DPP- >2600-fold vs DPP-8 >10,000-fold vs DPP-8/9 >400-fold vs DPP-8 4 >10,000-fold vs DPP- >100-fold vs DPP-9 9

Potential for drug± Low Low Strong CYP3A4/5 drug interaction inhibitors

Food effect No No No The Kidneys Play an Important Role in the Handling of Glucose

Total glucose stored in body ~450 g ‡ ‡ Glucose utilization ~250 g/day ‡ Brain ~125 g/day ‡ Rest of body ~125 g/day ‡ Glucose in Western diet ~180 g/day ‡ Renal glucose production (gluconeogenesis + ~70 g/day glycogenolysis) ‡ Renal glucose filtration & reabsorption ~180 g/day SGLT2 receptors ‡ Urinary glucose High Capcity/Low 0 g affinity @ Prox Renal Tubules Wright EM, et al. J Intern Med. 2007. Renal glucose re-absorption in healthy individuals Filtered glucose load 180 g/day

SGLT2

~ 90%

SGLT1

~ 10%

Gerich JE. Diabet Med. 2010;27:136±142. 23 Renal glucose re-absorption in patients with hyperglycaemia Filtered glucose load > 180 g/day

SGLT2 When blood glucose increases ~ 90% above the renal threshold (~ 10 mmol/l or 180 mg/dL), the capacity of the SGLT1 transporters is exceeded, ~ 10% resulting in urinary glucose excretion

Gerich JE. Diabet Med. 2010;27:136±142. Urinary glucose excretion via SGLT2 inhibition Filtered glucose load > 180 g/day

SGLT2SGLT2 inhibitor SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to SGLT1 urinary glucose excretion* and osmotic diuresis

*Loss of ~ 80 g of glucose/day (~ 240 cal/day). Gerich JE. Diabet Med. 2010;27:136±142. Renal() Glucose Handling() After () SGLT-2 Inhibition 150

Dosing Frequency Diabetes Threshold SGLT-2 Inhibition 100 Dosage 100 & 300 mg 5 & 10 mg 10 & 25 mg

Half-life (hours) 10.6 ± 13.1 Normal ~ 12.9 SGLT2 receptors~ 12.4 up- (g/day) Threshold 50 regulated in diabetes, Metabolism UGT1A9, UGT2BA UGT1A9 increasingUGT2B7, glucose UGT1A3 reabsorptionUGT1A8, UGT1A9 Urinary Excretion Glucose Urinary Elimination 0 Fecal / Renal Renal / Fecal Renal / Fecal 0 100 200 300 400 Renal Dosing < 45 mL/minPlasma Glucose< 60 (mg/dL) mL/min < 45 mL/min (eGFR): FarberNot SJ, Recommended et al. J Clin Invest. 1951;30: 125-129. Mogensen CE. Scand J Clin Lab Invest. 1971;28:101-109. Silverman M, Turner RJ. Handbook of Physiology. In: Windhager EE, ed. Oxford University Press. 1992: 2017-2038. Cersosimo E, et al. Diabetes. 2000;49:1186-1193. DeFronzo RA, et al. Endocr Pract. 2008;14: 782-790. Large CV Outcomes Trials in Diabetes

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA DPP4-i saxagliptin alogliptin✓ sitagliptin✓ linagliptin linagliptin Comparator placebo placebo placebo placebo

n 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017 Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND GLP1-RA liraglutide exenatide LR dulaglutide Comparator placebo placebo placebo placebo placebo n 16,500 14,000 6,000 5,400 8,300 Results 6/2016 2015 10/2016 2018 2019

Study EMPA-REG CANVAS DECLARE NCT01986881 SGLT-2-i empagliflozin canagliflozin dapagliflozin ertugliflozin Comparator placebo placebo placebo placebo n Reported7300 4300 22,200 3900 EASD 2015 Results 2015 2017 2019 2020 Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk

Simvastatin Ramipril Empagliflozin for 5 years for 5.4 years for 3 years

Pre-ACEi/ARB era >80% ACEi/ARB

Pre-statin era <29% statin >75% statin

1994 2000 2015

28 1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm; 2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm from solution to subcutaneous depot (Multi-hexamer formation key to protraction mechanism..Tresiba ®)

Phenol Zn2+

Insulin degludec injected

As phenol from the vehicle diffuses degludec hexamers link up via single side-chain contacts

Long multi-hexamers assemble Insulin degludec: slow release following injection

Subcutaneous depot Zn2+

Insulin degludec multi-hexamers

Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers

Monomers are absorbed from the depot into the circulation Insulin degludec: Mechanism of protraction

Multi-hexamers Subcutaneous tissue Half-life is ~24 hours, duration Monomers>42 hours, VWHDG\VWDWHídays Comes in 2 different degrees of green pens (Forest G/Garden G) U200& U100

Capillary membrane Insulin degludec in blood Albumin binding Capillary blood

Cell Membrane Insulin Receptors Timing of flexible insulin degludec administration

Mon Tue Wed Thu Fri Sat Sun

8h 8h

8-morning12 AND 36-40 hoursmorning between insulinmorning administration

40h 40h 40h 24h

evening evening evening evening ONSET

90 min UpSimilar to 24 h (detemir reduction 16-24 h) in ‡ (Levemir®) 90 min Up to 24 h (glargine 24 h) ‡ Insulin glargine (Lantus®) Up to 6 h A1cUp compared to 30 h to ‡ Insulin glargine U300 (Toujeo®) 90 min Up to 24 h (glargine 24 h) ‡ Insulin glargine (BasaglarTM) U-100 glargine

For patients maintained on insulinLess glargine (U-100), expect a higher dailynocturnal dose requirement of (U-300) to maintainhypoglycemia the same level of glycemic control with U-300 glargine Combination of Basal Insulin with a GLP-1 Agonist has a Scientific Logic

Complementary Insulin Degludec/actionsLiraglutide ( Xultophy ) P Basal insulin analogs GLP-1 agonists ‡ Simple to initiate ‡ Simple to initiate ‡ Control nocturnal and FPG ‡ Pronounced( iGlarlixi PPG control ) OK ‡ LowerInsulin hypoglycaemia Lantus/ risk vs NPHLixisenitide ‡ No increase in hypoglycaemia ‡ Modest weight increase (1±3 kg) ‡ Weight lowering/neutral effects

‡ Achieve A1C targets in ~50±60% ‡ Achieve A1C targets in ~40±60%

Additive effects Once-daily prandial lixisenatide versus once-daily rapid- acting insulin in patients with type 2 diabetes mellitus insufficiently controlled with basal insulin: analysis of data from five randomized, controlled trials.. GETGOAL DUO -2

Triple Composite Outcome

Journal of Diabetes and Its Complications 2014 28, 40-44DOI: (10.1016/j.jdiacomp.2013.10.003) Copyright © 2014 Terms and Conditions Ultra rapid Acting Inhaled Insulin

‡ Pulling Zinc ions out will destabilize the hexamer structure allowing for quicker absorption.

‡ Max Blood concentrations within 15 mins, rapid hypoglycemic effect with 2-3 hrs total duration of action.

Technosphere® ,QVXOLQ $)5(==$Œ Technosphere insulin particles made up of diketopiperazine derivatives and insulin, which self-organize into a lattice array, and form particles of 2±4 µm diameter.

pH Peak< 6 Effect: ‡ SQ( RAA): ~1 hrs as ‡ Inhaled: 53 min ‡ $)5(==$ŒCoughDuration: ~30% ‡ Inhaled: 160-180 min ‡ No clinically meaningful10 U SC changes Ins in ‡ SQ(RAA): 2-4 hrs 3)7¶V VKRUW-term) pH > 6 in the lungs More Changes to Insulin Formulations

‡ BioD-090(VIAject) recombinant insulin + (EDTA); loosely packed insulin multimers with rapid dissociation into monomers & dimers. ‡ Ultra-fast-acting (FIAsp) recombinant insulin + nicotinamide & arginine causing increased local blood flow & so accelerated pharmacokinetics. ‡ Hyaluronidase + analogue insulin ( uPH20/Hylenex) accelerated insulin action, time to peak, PP glycemic excursions reduced by 82 %, and statistically significant reduction in hypoglycemic events. ‡ Injectable nano-network ( smart insulin ); where Dextran nanoparticles loaded with insulin & glucose-specific enzymes, causing glucose-dependent insulin release

Hyaluronidase Mechanism of Action

Hyaluronidases increase the dispersion of SC Insulin

Produces earlier and greater peak insulin concentrations, leading to improved postprandial glycemic control

39 Using Nanotechnology; Oral Insulin Delivery by PH Sensitive Microspheres Gel/Microsphere system with polymethacrylic acid + PEG In stomach (pH 2) pores in the polymer shrink & block protein release In neutral pH ( small intestine) the pores swell & release protein

PH 2 PH 7

Buccal Insulin Delivery using RapidMist Technology

G2

The insulin canister hold 400 units and delivers 10 units per puff in a precisely metered dose. The formulated insulin is called Oral-lynŒLQLWLDOO\,had a 10% absorption. University of Toronto Researchers enhanced the Oral-lynŒ formulation, a 9-fold increase in serum insulin at 15 minutes and nearly 500 percent higher absorption of insulin over the 2-hour test period was verified in comparison to dogs that received the original formulation; a 33 percent decrease in serum glucose around minute 30 for the enhanced Generex Oral-lynŒIRUPXODWLRQZDV noted in comparison to a 12 percent increase in serum glucose in those that received the original formulation. It may be taken just before the first bite and just after the last. This flexibility offers both Type 1 and Type 2 patients a unique opportunity to aggressively treat diabetes with a minimal risk of hypoglycemia. The formulated insulin is stable at room temperature (North America) for 6 months or more. The micelles that are formed, containing the insulin, are > 7 microns and cannot enter the deep lungs regardless of effort. It is important to remember that only 20 ± 40% of subcutaneous injection is absorbed. As will be mentioned below, insulin appears in the blood within 5 min, peaks at 30 min and is back to baseline at 2 hr«7KLVnarrow window is unique to buccal insulin. It is possible because of the rich vascularity below the buccal epithelium. As with nitroglycerin, the insulin PK-PD is very fast, thus affording flexibility. The ODFNRIDµWDLO¶RILQVXOLQDFWLYLW\ZRXOGIDYRUOHVVK\SRJO\FHPLD Older Therapies revisited ( teaching old dogs new tricks)

IR XR DR

Published in: André J. Scheen; Expert Opinion on Pharmacotherapy 2016, 17, 627-630. DOI: 10.1517/14656566.2016.1149166 Copyright © 2016 Informa UK Limited, trading as Taylor & Francis Group Effect of TZD ( ) & on Fat Topography Recent Data from IRIS trial ( Insulin Resistance Intervention after Stroke ) (Pio reduced DM risk by 52 % in Stroke Pts, Reduced MACE by 24 % over 5 yrs)

Hi TG TG Hi FFA TZD FFA

Intramuscular 4% Fat Subcutaneous Fat more

Intrahepatic Fat Intraabdominal 20 % Fat less

DeFronzo RA, JCEM 89:463-478, 2004 Inzucchi et al. Pioglitazone prevents Diabetes in patients with IR & CVA. Diabetes Care 2016;39:1684-1692. Any questions ?