Robert E. Ratner, MD

Former Chief Scientific and Medical Officer

American Diabetes Association

Professor of Medicine

Georgetown University School of Medicine

Disclosed no conflict of interest

Newer Therapies

Pathogenesis of Type 2 Diabetes The Ominous Octet

Islet b-cell

Impaired

Insulin Secretion

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

Increased Lipolysis

Increased Glucose

Reabsorption

Increased HGP

Decreased Incretin Effect

DeFronzo RA. DiabCare 2013;36:S127

MET

SGLT2i

GLP1RA

GLP1RA

GLP1RA

GLP1RA

Pathogenesis of Type 2 Diabetes The Ominous Octet

Islet b-cell

Impaired

Insulin Secretion

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

Increased Lipolysis

Increased Glucose

Reabsorption

Increased HGP

Decreased Incretin Effect

DeFronzo RA. DiabCare 2013;36:S127

MET

SGLT2i

DPP IVi

DPP IVi

DPP IVi

Pathogenesis of Type 2 Diabetes The Ominous Octet

Islet b-cell

Impaired

Insulin Secretion

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

Increased Lipolysis

Increased Glucose

Reabsorption

Increased

HGP

Decreased Incretin Effect

Ralph A. DeFronzo et al. Dia Care 2013;36:S127 TZD

TZD

TZD

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

HbA1c≥9%

Me orminintoleranceorcontraindica on

Uncontrolledhyperglycemia

(catabolicfeatures,BG≥300-350mg/dl,HbA1c≥10-12%)

Insulin (basal)

+

or

or

or

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

−0.69

−0.82 −0.82 −0.88

−1.02 −0.932,c

−0.66

-1.5

-1.0

-0.5

0.0

Δ A

1C

, %

Dual Combination Therapy: Efficacy of

Antihyperglycemic Agents Added to METa

a 39 randomized, controlled trials (N = 17,860), subset presented. b Basal insulin efficacy depends upon baseline A1C; range of A1C reduction indicated by dotted line. c Head-to-head, 52-week trials with CANA.

1. Liu SC, et al. Diabetes Obes Metab. 2012;14:810-820. 2. Cefalu W, et al. Lancet. 2013;382:941-950.

3. Ooi CP, et al. Diabet Med. 2014;31:2-14. 4. Kerr JL, et al. Ann Pharmacother. 2010;44:1777-1785.

DPP-4i

TZD

GLP-1 RA

SU

Basal insulin

SGLT-2i

AGI

b

Among the Many Possible Antihyperglycemic Regimens,

Newer AHAs Have Favorable Weight Profiles1,a

a Exenatide was the only GLP-1 RA reported; GLP-1 RAs were only used in combination with other agents. UK General Practice Research Database, 1995-2010. N = 38,408 (1995) to 184,474 (2010); b Data at 6 mo and 12 mo are estimated; c Data from meta-analysis for weight change analyzing DAPA vs PBO; study durations up to 26 weeks and for 48 to 52 weeks.

1. Morgan CL, et al. Diabetes Obes Metab. 2012;14:424-432;

2. Mathieu C, et al. Diabetes Ther. 2013;4:285-308.

3. Clar C, et al. BMJ Open. 2012;2:e001007;

Ab

so

lute

, M

ed

ian

Ch

an

ge

in W

eig

ht

Fro

m B

aselin

e, kg

-10

-8

-6

-4

-2

0

2

4

6

0 6 months 12 months 24 months

MET

SU

TZD

EXN BID

DPP-4i

SGLT-2i (DAPA 10 mg)

Insulin (unspecified)

MET + SU

MET + GLP-1 RA

MET + SU + GLP-1 RA

Solid lines, monotherapies; small dashes, dual therapies; medium dashes, triple therapies

3,c

2,b

Short- vs Long-Acting GLP-1

Receptor Agonists

Category Agent Half-Life (h)

Tmax (h)

Short-acting (<24 h)

Exenatide1 2.4 2.1

Lixisenatide2 2.7-4.3 1.25-2.25

Liraglutide3 13 8-12

Long-acting (≥24 h)

Semaglutide4 155-173 16-20

Dulaglutide5 120 24-72

Albiglutide6 120 72-120

Exenatide ER7

168-336 1008-1176 Investigational

1. Byetta [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; August 2014.

2. Lyxumia Summary of Product Characteristics. March 2013.

3. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk, Inc.; March 2015.

4. Kapitza et al. Diabetologia 2012; 55 (Suppl 1): Abstract 826.

5. Trulicity [package insert. Indianapolis, IN: Eli Lilly and Company; June 2015.

6. Tanzeum [package insert]. Research Triangle Park: GlaxoSmithKline, LLC: March 2015.

7. Fineman et al. Clin Pharmacokinet 2011;50(1):65–74.

Incre

asin

g P

rotr

action

Comparison of Short- and Long-Acting GLP–1 Receptor Agonists

Adapted from: Meier JJ. Nat Rev Endocrinol. 2012;8:728-742.

Parameters Short-acting GLP–1 receptor agonists

Long-acting GLP–1 receptor agonists

Compounds Exenatide Lixisenatide

Albiglutide Dulaglutide Exenatide-LAR Liraglutide

Half-life 2 – 5 h 12 h – several days

Effects

Fasting blood glucose levels Modest reduction Strong reduction

Postprandial hyperglycemia Strong reduction Modest reduction

Fasting insulin secretion Modest stimulation Strong stimulation

Postprandial insulin secretion

Reduction Modest stimulation

Glucagon secretion Reduction Reduction

Gastric emptying rate Deceleration No effect

Body weight reduction (kg) 1 – 5 2 – 5

Induction of nausea 20 – 50%, attenuates over weeks to months

20 – 40%, attenuates over ≈ 4 – 8 weeks

-0.9 -0.8

-1.1

-1.5 -1.5 -1.5

-0.9

-0.6 -0.8

-1.1

-2.0

-1.5

-1.0

-0.5

0.0

0.5Monotherapy

Added toMET

Mean

Δ A

1C

fro

m B

aseli

ne,

%

GLP-1 RAs Improve Glycemic Control

at Early Stages of T2DM Progression

1. Moretto T, et al. Clin Ther. 2008;30:1448-1460; 2. Garber A, et al. Lancet.

2009;373:473-481; 3. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258;

4. Nauck M, et al. ADA 73rd Scientific Sessions. 2013 [abstract 55-LB];

5. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176; 6. DeFronzo R, et al.

Diabetes Care. 2005;28:1092-1100; 7. Pratley R, et al. Lancet. 2010;376:1447-1456;

8. Bergenstal R, et al. Lancet. 2010;376:431-439; 9. Ahren B, et al. Diabetes Care.

2014;37:2141-2148; 10. Nauck M, et al. Diabetes Care. 2014;37:2149-2158.

EXN BID (10 mcg)1,6

LIRA (1.8 mg)2,7

ALBI (50 mg)4,9

EXN QW (2.0 mg)3,8

Duration, wks:

BL A1C, %:

24

7.8

52

8.3

26

8.5

52

8.1

52

7.6

30

8.2

26

8.5

26

8.5

104

8.1

52

8.1

DULA (1.5 mg)5.10

Significantly greater ΔA1C vs ≥ 1 control (P < .05) for alla

a GLP-1 RAs significantly improved A1C vs

PBO1,4,6,9, GLIM2,9, MET5, PIO8, SITA3,7-10.

The role of the kidney in glucose

reabsorption

References:

1. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab.

2012 Jan;14(1):5-14.

2. Clifford J. Bailey. Medscape Education Diabetes & Endocrinology. The Role of the Kidney in Glucose Control.. CME Released: 02/26/2013 ; Valid for credit

through 02/26/2014.

~180L filtered per day by the kidney1

A normal kidney

A kidney in a patient

with type 2 diabetes

Average blood glucose of

~100mg/dL2

Average blood glucose of

~150mg/dL2

~180g of glucose filtered per day2

No increase in SGLT2

cotransporters2

~250g of glucose filtered per day2

glucose reabsorption and

elimination of glucose in the

urine2

Hyperglycaemia

Increase in SGLT2 cotransporters2

Overview of approved SGLT-2 inhibitors by FDA

Diabetes, Obesity and Metabolism, 2013; 15: 372-382

Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and

exercise

Body weight effect of SGLT2

inhibitors

Undesirable side effects

• Genitourinary infections

• Volume related events – orthostasis

• Bone? (mostly long bones, related to falls)

• Bladder cancer?

• Diabetes Ketoacidosis

• Lower extremity amputations?

Other effects

• LDL HDL Triglycerides

• HGP Glucagon

FDA warning – May 2016

• In the ongoing Canagliflozin Cardiovascular Assessment Study (CANVAS) clinical trial, the trial’s independent data monitoring committee (IDMC) identified an increased risk of leg and foot amputations. The amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo, which is an inactive treatment. An interim analysis showed that over a year’s time, the risks of amputation for patients in the trial were equivalent to:

– 7 out of every 1,000 patients treated with 100 mg daily of canagliflozin – 5 out of every 1,000 patients treated with 300 mg daily of canagliflozin – 3 out of every 1,000 patients treated with placebo

• Patients in the CANVAS trial have been followed for an average of 4.5 years to date. The IDMC has recommended, based on an overall assessment, that the CANVAS trial continue.

• The IDMC has also reported that a second, similar trial evaluating canagliflozin, the CANVAS-R trial, has not shown the same risks of increased leg and foot amputations to date. Patients in the CANVAS-R trial have been followed for an average of 9 months.

http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm

SGLT2 Inhibitors + DPP IV Inhibitors

Rosenstock J. DiabCare 2015; 38:376

Emp

a 2

5 +

Lin

a 5

Emp

a 1

0 +

Lin

a 5

Emp

a 2

5

Emp

a 1

0

Lin

a 5

DeFronzo RA. DiabCare 2015; 38:384

SGLT2 Inhibitors + GLP 1 RA Ongoing Studies

Sponsor AZ - DURATION 8 UTHSCSA/Janssen

N 660 90

Key inclusions A1c 8-12% on MET A1c 7-10%, no Rx or MET

Groups • exenatide q wk • dapagliflozin • exenatide + dapagliflozin

• canagliflozin • liraglutide • canagliflozin + liraglutide

Duration 28 wk (108 wk total f/u) 4 months

Primary Outcome

HbA1c HGP

From: www.clinicaltrials.gov

SGLT2i add-on to insulin

Wilding JPH, et al. Diabetic Med 2015 Nov 3. doi: 10.1111/dme.13021.

78-week add-on to basal insulin

Rosenstock J et al. Diab Obes Metab 2015;17:936-48.

Potential Candidates for Concentrated Insulin

1. Cochran E, et al. Diabetes Care. 2005;28:1240-1244.

2. Garg R, et al. Diabetes Metab Res Rev. 2007;23:265-268.

Obese type 2 diabetes with severe

insulin resistance

Multiple daily injections

Continuous subcutaneous insulin

infusion (CSII)

Those with rare forms of

immune-mediated diabetes¹

Anti-insulin receptor antibodies

(type B insulin resistance

syndrome

Those with genetic defects of insulin

action¹

Lipotrophic diabetes

Type A insulin resistance syndrome

Others

Persons with type 2 diabetes

requiring high dose insulin¹,²

Post-operatively or post-

transplant

On high-dose glucocorticoid

therapy

Severe systematic infection

Gestational diabetes mellitus with

severe insulin resistance¹

Pharmacokinetics of U-300 Insulin Glarginea in Healthy Volunteers

a U-300 insulin glargine is not FDA approved for clinical use. Becker R, et al. European Patent EP 2 387 989 A2. 2011.

U-100 0.4 U/kg (n = 24)

U-300 0.4 U/kg (n = 23)

35

30

25

20

15

10

5

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Co

nce

ntr

atio

n (

uIU

/mL)

Time (h)

Comparison of Different Insulin Glargine Concentrations in T2DM

N=811; hypoglycemia defined as needing assistance or confirmed plasma glucose ≤70 mg/dL T2DM=type 2 diabetes; Tx=treatment

Equivalent A1C reduction with U-300 glargine and U-100 glargine

Time, weeks

0

4

6

10

12

0 8 20 28

Cumulative Number of Confirmed or Severe Hypoglycemic

Events/Participant

8

2

4 12 24 16

U-100 GLAR

U-300 GLAR

Yki-Jarvinen H, et al. Diabetes Care. 2014;37:3235-3243.

Weight Change

P = .015

U-100 GLAR

U-300 GLAR

1.0

0.5

0.0

-0.5

Bl Week

2 4 8 12 Month

4 6

Mean

Weig

ht

Ch

an

ge,

kg BL weight, 98.0 kg to 98.7 kg;

mean BMI, 34.8 kg/m²

* p=0.038

*

U-300 Glargine Limitations

● Lower bioavailability with need to up-titrate dose vs U100 glargine (11 to 17% higher dose of U300 glargine vs U100 glargine needed across phase 3 clinical trials)¹

● Hypoglycemia reduction only seen in T2DM trials, not in T1DM trials, and was inconsistent across T2DM trials¹

● U-300 Glargine pen cannot deliver more than 80 units with one injection

● U-300 glargine only contains 450 units of insulin (v 600 units for U200 insulin pens and 1500 units per U500 isulin pen), so prescription (for 3 pens) only gives 1350 units of insulin (vs. 1800 to 2000 units for other concentrated insulin products) per copay

Rosselli JL, et al. J Pharmacy Technol

U200 Degludec Clinical Efficacy Potential Benefits Limitations

• Longest duration of action of all basal insulins (>42 hours)¹

• May need to down-titrate dose from previous basal insulin (prescriber should be aware)

• Pen can inject up to 160 units with a single injection, eliminating the need for 2 daily basal insulin injections for those requiring over 80 to 100 units of basal insulin per day

• Patients need to be aware that it takes 2 t o3 days to build to a steady state

• Bioequivalence of U100 and U200 formulations means no dose titration when changing from one formulation to another

• Cost/formulary restrictions

• Bioequivalence of U100 and U200 formulations suggests therapeutic benefits of U100 would also apply to U200 (i.e., hypoglycemia reduction; flexible dosing of 8-40 hours

• Slightly lower dose requirements (~10% lower basal insulin dose for either U100 or U200) vs other basal insulins²

• Pen contains 600 units vs 1500 units for U100 insulin pens and 1350 units for U300 glargine

1. Rosselli JL, et al. J Pharmacy Technol. DIO:10.1177/8755122515584193 pharmatech.sagepub.com

2. Landstedt-Halkin L. Curr Med Res Opin. 2015;8:1487-1493

a Insulin degludec is not FDA approved for clinical use. Hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition; nocturnal, occurring between 0100 hrs and 0559 hrs.

P = .28

P = .017

P = .106

DEG QD (n = 773; 0.59 U/kg) GLAR QD (n = 257; 0.60 U/kg)

89.4 91.8 BL Wt: ΔA1C −1.19

8.2% 8.2%

Efficacy Weight Change Hypoglycemia

P = .40

P = .038

Zinman B, et al. Diabetes Care. 2012;35:2464-2471.

Degludeca vs Glargine in Insulin-Naïve Patients With

T2DM at 1 Year: BEGIN Once Long

BLA1C:

−1.06

Daily GLP1 RA vs 1 bolus add-on to basal

P=0.0024

P<0.0001

Mattheiu C et al. Diabetes Obes Metab 2014;16:636-644.

Weekly GLP-1RA vs TID bolus add-on to basal insulin

Non-inferior p=<0.0001

Lower risk of hypoglycemia More gastrointestinal events

Rosenstock J al. Diabetes Care 2014;37:2317-2325.

Meta-analysis of GLP-1RA + Basal Insulin vs. Basal-Bolus Insulin¹

1. Eng C, et al. Lancet. 2014;384:2228-2234. 2. Diamant M, et al. Lancet Diabetes Endocrinol. 2014;2:464-473.

3. Rosenstock J, et al; Harmony 6 Study Group. Diabetes Care. 2014;37:2317-2325. 4. Shao N, et al. Diabetes Metab Res Rev. 2014;30:521-529.

Additional benefits of GLP-1RA + basal insulin: weight reduction and reduced incidence of hypoglycemia

-0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4

Author Δ

A1C 95% C.I.

Favors GLP-1+Basal

Favors Basal-bolus

Weight

Diamant M, et al² -0.03 -0.17, 0.11 32.25%

Rosenstock J, et al³

-0.15 -0.33, 0.01 22.50%

Shao N, et al⁴ -0.11 -0.23, 0.01 45.25%

Overall¹ -0.10 -0.17, -

0.02 100.0%

Author Year Background Comparison

Diamant M, et al.² 2014 Glargine

+metformin Exenatide QW vs lispro (with each

meal)

Rosenstock J, et al.³

2014

Glargine ± metformin,

pioglitazone, or both

Albiglutide QW vs lispro (with each meal)

Shao N, et al.⁴ 2014 Glargine Exenatide vs insulin aspart (with

each meal)

• Dual Action of Liraglutide and Insulin Degludec in Type 2

Diabetes: A Trial Comparing the Efficacy and Safety of

Insulin Degludec/Liraglutide, Insulin Degludec and

Liraglutide in Subjects With Type 2 Diabetes

(DUAL™ I) - NCT01336023

• A Trial Comparing the Efficacy and Safety of Insulin

Degludec/Liraglutide and Insulin Degludec in Subjects With

Type 2 Diabetes (DUAL™ II) - NCT01392573

• Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed

Combination Versus Insulin Glargine Alone on Top of

Metformin in Type 2 Diabetic Patients – NCT01476475

http://clinicaltrials.gov/show/NCT01336023; http://clinicaltrials.gov/show/NCT01476475

Co-formulations of Investigational GLP-1 Receptor Agonist

Plus Basal Insulin in Type 2 DM: Ongoing Studies

30

IDegLira*, A Fixed Ratio Combination in Patients with T2DM: Results of a Large, Randomized, Phase 3 Trial

IDegLira vs.

IDeg

Estimate

[95% CI] P-value

IDegLira vs.

Lira

Estimate

[95% CI] P-value

A1C change

(%-points)

−0.47

[−0.58; −0.36] <0.0001

−0.64

[−0.75; −0.53] <0.0001

FPG change

(mg/dL)

−3.1

[−7.4; 1.2] NS

−31.8

[−36.1; −27.5] <0.0001

Weight change

(kg)

−2.22

[−2.64; −1.80] <0.0001

2.44

[2.02; 2.86] <0.0001

31

*Not FDA approved

Buse JB et al ADA 2013, 65-OR

Key Results with IDegLira vs. IDeg or Lira Alone The primary endpoint, A1C, decreased by 1.9% from 8.3% to 6.4% with IDegLira.

This decrease was greater than with IDeg (-1.4% to 6.9%) or Lira (-1.3% to 7.0%).

Technosphere Inhaler: Initial and Gen2 Device

Cavaiola T, Edelman S. Clin Ther 2014;36:1275-1289.

Inhaled Insulin in Type 2 Diabetes (T2DM)

Insulin human inhalation power (48 units)

SC Regular Human Insulin [RHI] (24 units)

5.0

3.0

1.0

GIR

, m

g/

kg

/m

in

0 60 120 180

Time, min

4.0

2.0

0.0 240 300 360 420 480 540

With insulin human inhalation powder:

● Duration of action is much shorter than for RHI1

● Almost complete post-prandial glucose suppression measured in insulin-naive patients with

T2DM using OADs2

1. Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212. 2. Rosenstock J, et al. Diabetes Care. 2015;38:2274-2281.

Technosphere Inhaled Insulin:

Clinical Features of Note

● Compared with Aspart 70/30, inhaled insulin was

associated with reduced risk for

o Hypoglycemia (0.41 vs 0.61 per patient/per month)

o Weight gain (0.9 kg vs 2.5 kg)

● Increased risk for cough (33% vs 6%)

o No change in FEV1

o No difference in URI

Rosenstock J et al. Lancet 2010;375:2244-2253

Dosing of Inhaled Insulin

Afrezza Prescribing information.

Primary outcome

HbA1c >7%, confirmed, on maximally tolerated dose of assigned regimen

Glimepiride +

Metformin

n=1250

Sitagliptin +

Metformin n=1250

Liraglutide +

Metformin n=1250

Glargine +

Metformin n=1250

Observe on assigned therapy

Secondary metabolic outcome

HbA1c >7.5%, confirmed, on maximally tolerated dose of assigned regimen

Add basal insulin (per glargine protocol) Continue

Metformin, continue second agent Tertiary metabolic outcome

HbA1c >7.5%, confirmed, on glargine, assigned agent and metformin

Intensify insulin (add rapid-acting insulin to basal glargine),

continue metformin, and discontinue second agent

Glycemia Reduction Approaches in Diabetes:A Comparative Effectiveness Study

(GRADE Study) Diabetes Care36:2254, 2013

Empa Reg

Primary outcome: 3-point MACE

37 Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio.

* Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

Empa Reg

CV death

38 Cumulative incidence function. HR, hazard ratio

Patients with event/analysed

Empagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

0.25 0.50 1.00 2.00

Empa Reg

CV death, MI and stroke

39

Favours empagliflozin Favours placebo

Cox regression analysis. MACE, Major Adverse Cardiovascular Event;

HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction

*95.02% CI

Empa Reg

Hospitalisation for heart failure

40 Cumulative incidence function. HR, hazard ratio

Empa Reg

All-cause mortality

41

Kaplan-Meier estimate. HR, hazard ratio

Potential mechanisms involved in the reduction of

cardiovascular events observed in the EMPA-REG

OUTCOME trial

Adapted from Sattar N, et al. Diabetologia DOI 10.1007/s00125-016-3956-x

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54

Pa

tie

nts

wit

h a

n E

ve

nt

(%)

Months

Placebo

Liraglutide

0

4

8

12

16

20

0 6 12 18 24 30 36 42 48 54

LEADER Trial: Liraglutide Lowers Major Adverse

Cardiovascular Outcome Rates

Primary Composite Outcome (CV Death, MI, Stroke)*

Hazard ratio, 0.87 (0.78, 0.97)

p < 0.001 for non-inferiority

p = 0.01 for superiority

Marso SP, et al. N Engl J Med. 2016 June 13. [Epub ahead of print]. DOI: 10.1056

Placebo 4668 4593 4496 4400 3280 4172 4072 3982 1562 424

Liraglutide 4672 4588 4473 4352 4237 4123 4010 3914 1543 407

* First occurrence of death from CV causes, nonfatal (including silent MI), or nonfatal stroke

↓ 13%

Secondary Endpoints-as Individual Components

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard

regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months.

CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

↓ 22 % ↓ 12 %

NS

↓ 11 %

NS

CV Death Non-fatal MI Non-fatal Stroke

LEADER Trial: Liraglutide Lowers Major Adverse

Cardiovascular Outcome Rates

Antihyperglycemic Therapy in

Type 2 Diabetes

American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1): SX

CVD Black Box CVA benefit Neutral Mortality benefit Mortality benefit Neutral

Durability of Diabetes Treatment:

GRADE

HbA1c 6.8% - 8.5%

MET monotherapy

Glimepirid

e

(SU)

Sitagliptin

(DPP IV

Inh)

Liraglutide

(GLP-1

RA)

Basal

Insulin

(Glargine)

Primary outcome: time to HbA1c ≥7%

Follow-up 4-7 yrs

www.clinicaltrials.gov/ct2/show/NCT01794143