New treatments for an old disease Ahdy Wadie Helmy, MD, FACP

Associate Professor of Medicine IU School of Medicine

Type 2 Diabetes Mellitus that is hitting back

with

vengeance

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

2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% > 26.0%

No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0%

United States Surveillance System available at http://www.cdc.gov/diabetes/data

2014

2014

USA . A new Diabetic case Dx

every 20 secs(1.7 million/yr)

Diabetes kills 1 Amer ican

every 3 minutes

180 diabetics loose a limb

every 24 hrs

55 Diabetics end on dialysis

every 24 hrs

Globally, same mess, only Bigger! Estimated global prevalence of diabetes

International Diabetes Federation. IDF Diabetes Atlas. 7th ed.accessed April 2016.

2000 2011 2040

151 million 366 million 642 million

NA 19.7 33.9 72%

EU 17.8 25.1 41%

A+NZ 1.2 2.0 65%

LAC 13.3 33.0

248%

SSA 7.1 18.6 261%

MEC 20.1 52.8 263%

China 20.8 42.3 204%

India 31.7 79.4 251%

it takes years of preparation

Liver

Cardiac Muscle Pancreas

Visceral Adiposity

More Insulin to suppress lipolysis

Feeding

-­Cell mass in Type 2 diabetes

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

ND IFG T2DM ND T2DM

-Cel

l vol

ume

(%)

Obese Lean

-50%

-63%

Butler et al. Diabetes. 2003 ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus

÷IR

2-Hour Plasma Glucose (mg/dL)

Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT

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

30

20

10

0

40

NGT

Lean

Obese

IGT T2DM IR IS

Getting Back up on

TZDs,Metformin

Pathogenesis of Type 2 Diabetes

HGP=hepatic glucose production.

Islet -cell

Impaired Insulin Secretion

Increased HGP Decreased Glucose

Uptake

Time (minutes)

1st Phase 2nd Phase

i.v. Glucose

Diabetes

Normal glucose tolerance

-5

-10

0 5 10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

100

95

Insu

lin S

ecre

tion

Time (minutes)

1st Phase (AIR ) 2nd Phase

i.v. Glucose

Diabetes

Normal glucose tolerance

-5 -10 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 100 95

Insu

lin S

ecre

tion

Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.

-18

-32

-8

-40

-30

-20

-10

0

Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGT

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

Latino/Hispanic Pima Indian White

AIR

(%)

Insulin resistance

Decrease in AIR Necessary to Convert From NGT to IGT

10

Hormones in Sequence

Meal (min)

0

5

10

15

20

-30 0 30 60 90 120 150 180

Meal

Without diabetes; n = 27 Late-stage type 2; n = 12 Type 1; n = 190 Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398

Amylin

0

20

40

60

80

Insu

lin (m

U/L

)

0 30 60 90 120 150 180

* * * * * * *

insulin secretion 2nd wave

insulin secretion AIR

Beta Cells

GLP-1: Secreted upon the

ingestion of food

The Incretins Gut-­derived factors that increase glucose-­ ( Intestine Secretion of Insulin )

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

Stomach: Helps regulate

gastric emptying

Promotes satiety and reduces appetite

Liver: Glucagon reduces

hepatic glucose output Beta cells: Enhances glucose-dependent

insulin secretion

Alpha cells: Postprandial

glucagon secretion

GLP-1: Secreted upon the ingestion of food

The Incretin Effect is Reduced in Subjects with Type 2 Diabetes

Nauck MA, et al. Diabetologia 1986;29:46 52. *P

Time (min) Intravenous Glucose Oral Glucose

0

20

40

60

80

Insu

lin (m

U/L

)

0 30 60 90 120 150 180

* * * * * * *

Control subjects

0

20

40

60

80

0 30 60 90 120 150 180 Time (min)

* *

*

Subjects with type 2 diabetes

Insu

lin (m

U/L

)

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

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 -­cells (in vitro)2

Resistant to DPP-­IV inactivation3

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.

Following injection, exenathours4

Site of DPP-IV Inactivation2,3 A SYL GQ AKE A H G F V E A T T S D S S Y L E G Q A A K E F I A GLP-1

Human

Liraglutide has

97 % AA sequence

identity with human GLP-1

liraglutide OD T½ 13 h

exenatide T½ 2.4 h

Chemical Structures of GLP-­1 RAs

BYETTA (Exenatide)

53% Homology Gila monster

saliva

VICTOZA (Liraglutide)

97% Homology C-­16 Fatty Acid

Chain

Weekly BYDUREON

(Exenatide ER)

53% Homology Microsphere technology Weekly

TANZEUM (Albiglutide)

97% Homology

Dimer fused to Albumin Weekly

TRULICITY (Dulaglutide)

90% Homology Linked to

modified IgG

Drug Initial Titrate Max Dose Adjustments

Exenatide IR (Byetta®)

5 mcg BID within 60 mins of a meal (> 6H between doses)

to 10 mcg after 1 month 10 mcg Renal impairment: CrCl 30-­50 mL/min: use

caution;; CrCl < 30 mL/min not recommended Hepatic impairment: not studied

Exenatide ER (Bydureon®)

2 mg once weekly N/A 2 mg once

weekly

Liraglutide (Victoza®)

0.6 mg once daily

1.2 mg once daily per week

1.8 mg once daily

Renal & hepatic impairment: use caution limited experience

Albiglutide (Tanzeum®)

30 mg once weekly

to 50 mg once weekly if inadequate response

50 mg once daily

Renal impairment: use caution when initiating or escalating doses Hepatic impairment: not studied, unlikely required

Dulaglutide (Trulicity®)

0.75 mg once weekly

to 1.5 mg once weekly if inadequate response

1.5 mg once weekly

Renal impairment: use caution when initiating or escalating doses 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 insulin glargine as first injectable therapy

3-­year endpoint Exenatide QW

(n=233)

Insulin glargine (n=223)

P Value

Change in A1C -­1.01% -­0.81% 0.03

Change in body weight -­5.5 lbs +4.4 lbs <0.001

Hypoglycemia (exposure-­adjusted events)

0.3 events per patient-­year

0.9 events per patient-­year

NR

Diamant M et al. Lancet. 2014:2:464-­473. NR = not reported.

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 Microspheres consist of a biodegradable polymer that dissipates into CO2 and water1 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

Further degradation and metabolism of microsphere polymer provide sustained level

of exenatide1

Microsphere degradation and continued release of

exenatide1

Individual microspheres

aggregate and initial release of exenatide1

Subcutaneous injection of microsphere suspension 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

Improves first- phase insulin response

Suppresses glucagon secretion, decreasing glucose output

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 of Dipeptidyl Peptidase 4 (DPP-­4) Inhibitors

Sitagliptin ( januvia)

Linagliptin ( Tradjenta)

Saxagliptin (onglyza )

Alogliptin (Nesina )

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

QD

Half-­life (t1/2), h 12.4 12.5 21.1 2.2 3.8 21 hrs DPP-­4 inhibition at 24 h

~80% ~80% (25 mg) ~55% (5 mg)

Elimination Kidney (mostly unchanged)

Bile but not kidney (mostly unchanged)

Liver and kidney Active metabolite

Renal dose adjustments required

Yes

No Yes Yes

Selectivity for DPP-­4

>2600-­fold vs DPP-­8 >10,000-­fold vs DPP-­

9

>10,000-­fold vs DPP-­8/9 >400-­fold vs DPP-­8 >100-­fold vs DPP-­9

Potential for drugdrug interaction

Low Low Strong CYP3A4/5 inhibitors

Food effect No No No

Bile

The Kidneys Play an Important Role in the Handling of Glucose

Wright EM, et al. J Intern Med. 2007.

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

Urinary glucose 0 g

SGLT2 receptors High Capcity/Low

affinity @ Prox Renal Tubules

Filtered glucose load 180 g/day

SGLT1

SGLT2

~ 10%

~ 90%

Gerich JE. Diabet Med. 2010;;27:136 142.

Renal glucose re-­absorption in healthy individuals

23

Gerich JE. Diabet Med. 2010;;27:136 142.

Renal glucose re-­absorption in patients with hyperglycaemia

SGLT1

SGLT2

~ 10%

~ 90%

When blood glucose increases

above the renal threshold

(~ 10 mmol/l or 180 mg/dL), the

capacity of the transporters is

exceeded, resulting in urinary glucose excretion

Filtered glucose load > 180 g/day

*Loss of ~ 80 g of glucose/day (~ 240 cal/day). Gerich JE. Diabet Med. 2010;;27:136 142.

Urinary glucose excretion via SGLT2 inhibition

SGLT2 SGLT2 inhibitor

SGLT1

SGLT2 inhibitors reduce glucose re-absorption

in the proximal tubule, leading to urinary glucose excretion* and

osmotic diuresis

Filtered glucose load > 180 g/day

Renal Glucose Handling After SGLT-2 Inhibition

Farber SJ, 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.

Urin

ary

Glu

cose

Exc

retio

n (g

/day

) 150

100

50

100 300 400

Plasma Glucose (mg/dL)

Normal Threshold

0 0

Diabetes Threshold SGLT-2 Inhibition

200

SGLT2 receptors up-regulated in diabetes,

increasing glucose reabsorption

(CANAGLIFLOZIN) (DAPAGLIFLOZIN) (EMPAGLIFLOZIN)

Dosing Frequency Dosage 100 & 300 mg 5 & 10 mg 10 & 25 mg

Half-life (hours) 10.6 13.1 ~ 12.9 ~ 12.4

Metabolism UGT1A9, UGT2BA UGT1A9

UGT2B7, UGT1A3 UGT1A8, UGT1A9

Elimination Fecal / Renal Renal / Fecal Renal / Fecal

Renal Dosing (eGFR): Not Recommended

< 45 mL/min < 60 mL/min

< 45 mL/min

Ipragliflozin Luseogliflozin Tofogliflozin Ertugliflozin

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-­i saxagliptin alogliptin sitagliptin linagliptin linagliptin

Comparator placebo placebo placebo sulfonylurea 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 lixisenatide semaglutide 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 7300 4300 22,200 3900

Results 2015 2017 2019 2020

Large CV Outcomes Trials in Diabetes

Reported EASD 2015

Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk

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

Simvastatin

for 5.4 years

1994 2000 2015

Pre-statin era

Ramipril for 5 years

Pre-ACEi/ARB era

<29% statin

Empagliflozin for 3 years

>80% ACEi/ARB

>75% statin

Insulin degludec injected

Long multi-­hexamers assemble

Phenol Zn2+

Insulin degludec from solution to subcutaneous depot

(Multi-­hexamer formation key to protraction mechanism..Tresiba ®)

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

Insulin degludec: slow release following injection

Insulin degludec multi-­hexamers

Zinc diffuses slowly causing individual hexamers to disassemble, releasing

monomers

Subcutaneous depot Zn2+

Monomers are absorbed from the depot into the circulation

Capillary membrane

Subcutaneous tissue

Insulin degludec in blood Albumin binding

Monomers

Insulin degludec: Mechanism of protraction

Cell Membrane

Capillary blood

Insulin Receptors

Multi-­hexamers Half-life is ~24 hours, duration >42 hours, days

Comes in 2 different degrees of green pens (Forest G/Garden G) U200& U100

Timing of flexible insulin degludec administration

morning

Mon Tue Wed Thu Fri Sat Sun

morning morning

evening evening evening evening

40h 40h 40h

8h 8h

24h

8-­12 AND 36-­40 hours between insulin administration

Similar reduction in A1c compared to U-100 glargine

Less nocturnal

hypoglycemia with U-300 glargine

For patients maintained on insulin glargine (U-100), expect a higher daily dose

requirement of (U-300) to maintain the same level of glycemic control

Insulin detemir (Levemir®) Insulin glargine (Lantus®) Insulin glargine U300 (Toujeo®) Insulin glargine (BasaglarTM)

ONSET 90 min 90 min

Up to 6 h 90 min

Up to 24 h (detemir 16-24 h)

Up to 24 h (glargine 24 h) Up to 30 h

Up to 24 h (glargine 24 h)

Combination of Basal Insulin with a GLP-­1 Agonist has a Scientific Logic

Basal insulin analogs Simple to initiate Control nocturnal and FPG Lower hypoglycaemia risk vs NPH Modest weight increase (1 3 kg) Achieve A1C targets in ~50 60%

GLP-­1 agonists Simple to initiate Pronounced PPG control No increase in hypoglycaemia Weight lowering/neutral effects Achieve A1C targets in ~40 60%

Complementary actions

Additive effects

Insulin Degludec/Liraglutide ( Xultophy ) P

Insulin Lantus/Lixisenitide ( iGlarlixi ) OK

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

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

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®

pH < 6 as

pH > 6 in the lungs

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.

10 U SC Ins

Peak Effect: SQ( RAA): ~1 hrs Inhaled: 53 min

Duration: Inhaled: 160-­180 min SQ(RAA): 2-­4 hrs

Cough ~30% No clinically meaningful changes in

-term)

More Changes to Insulin Formulations

BioD-­090(VIAject) recombinant insulin + (EDTA);; loosely packed insulin multimers with rapid dissociation into monomers & dimers.

Ultra-­fast-­acting insulin aspart(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

39

Hyaluronidase Mechanism of Action

Hyaluronidases increase the dispersion of SC Insulin

Produces earlier and greater peak insulin concentrations,

leading to improved postprandial glycemic control

Using Nanotechnology;; Oral Insulin Delivery by PH Sensitive Microspheres

PH 2 PH 7

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

The insulin canister hold 400 units and delivers 10 units per puff in a precisely metered dose. The formulated insulin is called Oral-lyn ,had a 10% absorption. University of Toronto Researchers enhanced the Oral-lynformulation, 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-lynnoted 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 narrow 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

Buccal Insulin Delivery using RapidMist Technology

G2

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

Older Therapies revisited ( teaching old dogs new tricks)

IR XR

DR

Intramuscular Fat

Intrahepatic Fat

Intraabdominal Fat

Subcutaneous Fat

Effect of TZD ( Pioglitazone ) & 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 Hi FFA

TG FFA TZD

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

4% more

20 % less

Any questions

?