1 Glycemic Management in Type 2 Diabetes Efficacy and Safety of Modern Antihyperglycemic Therapies.

1

Glycemic Management inType 2 Diabetes

Efficacy and Safety of Modern Antihyperglycemic Therapies

2

DPP-4 INHIBITORS

Glycemic Management in Type 2 Diabetes: Efficacy and Safety of Modern Antihyperglycemic Therapies

3

DPP-4 Inhibitors

FDA-Approved Agents

• Alogliptin• Linagliptin• Saxagliptin• Sitagliptin

Key Features

• Oral administration• Increase endogenous

GLP-1 and GIP levels• Increase glucose-

dependent insulin secretion

• Suppress glucagon production

DPP-4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

4

Monotherapy Add-on to Metformin Add-on to SU

Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†

Baseline A1C (%) 7.9 8.0 8.0 7.5 8.1 8.2 8.6 8.4 7.8 7.9 8.5 8.3

Glucose Controlwith DPP-4 Inhibitors

-0.9-0.8-0.7-0.6-0.5-0.4-0.3-0.2-0.1

0

-0.57-0.5 -0.53

-0.69-0.64 -0.62-0.65

-0.83-0.72

-0.67 -0.65-0.74

Placebo-Adjusted Change from Baseline(Not Head-to-Head Trials)

*SU + metformin. †With or without metformin. ‡Absolute change from baseline (active-controlled trial).

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.3. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 4. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 5. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 6. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 7. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 8. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 9. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 10. Owens DR, et al. Diabet Med. 2011;28:1352-61. 11. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.

Pla

cebo

-adj

uste

d

A1C

(%

)

‡

5



Weight Changewith DPP-4 Inhibitors

-2

-1.5

-1

-0.5

0

0.5

1

-0.22 -0.3

0.68

-0.1

-0.87

0.8

-1.5

0.8

-0.4

0.27

Absolute Change from Baseline(Not Head-to-Head Trials)

NR, value not reported.

*SU + metformin. †With or without metformin.


W

eigh

t (kg

) NR NR

6



Hypoglycemia with DPP-4 Inhibitors

0

5

10

15

20

25

1.50

9.6

0.3 0.6

22.7

5.2 5.2

14.6

4.9

1.3

12.2

Percentage of Patients Reporting Hypoglycemia(Not Head-to-Head Trials)

NR, value not reported.

*SU + metformin. †With or without metformin.


Pat

ient

s (%

)

7

Safety Considerationswith DPP-4 Inhibitors

GI adverse events

• Minimal

Pancreatitis

• Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established

• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents

• Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected

Pancreatic cancer


• Further assessments required from long duration-controlled studies or epidemiological databases

Renal impairment

• Kidney function monitoring and dose reduction required for alogliptin, saxagliptin, and sitagliptin when used in patients with moderate-to-severe renal impairment

• Linagliptin does not require dose adjustment or periodic monitoring of drug-related kidney function

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013. http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html.

8

Monotherapy26 Weeks1

Initial Combo w/ Pioglitazone

26 Weeks2

Add-on to Metformin26 Weeks3

Add-on to Glyburide26 Weeks4

Add-on toMet + Pio52 Weeks5

Add-on to Insulin +/- Met

26 Weeks6

N 329 655 527 500 803 390

Treatment PBO Alo Pio Alo Alo + Pio

Met Alo +Met

Gly Alo + Gly

Met+ Pio

Alo+ Met+ Pio

Ins+/- Met

Alo+ Ins+/- Met

Baseline A1C (%)

7.9 7.9 8.8 8.8 8.8 8.0 7.9 8.1 8.1 8.1 8.3 9.3 9.3

P<0.001 vs comparator(s).

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Rosenstock J, et al. Diabetes Care. 2010;33:2406–2408.3. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55.4. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176.5. Bosi E, et al. Diabetes Obes Metab. 2011;13:1088-1096. 6. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.

Glucose Control With Alogliptin

-2

-1.5

-1

-0.5

0

0.5

-0.02

-1.15

-0.1

0.01

-0.29-0.13

-0.59

-0.96

-0.6 -0.53-0.7 -0.71

-1.71

A

1C (

%)

* * * *

*

*

9

P<0.01 vs comparator.

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Rosenstock J, et al. Diabetes Care. 2010;33:2406–2408.3. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55.4. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176.5. Bosi E, et al. Diabetes Obes Metab. 2011;13:1088-1096. 6. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.

Weight Change With Alogliptin

-0.50

0.51

1.52

2.53

3.5

0.18

2.19

0

-0.2

1.6

0.6

-0.22 -0.29 -0.3

0.681.1

0.6

3.14


Initial Combo w/ Pioglitazone

26 Weeks2




Add-on to Insulin +/- Met

26 Weeks6

N 329 655 527 500 803 390

Treatment PBO Alo Pio Alo Alo + Pio

Met Alo +Met

Gly Alo + Gly

Met+ Pio

Alo+ Met+ Pio

Ins+/- Met

Alo+ Ins+/- Met

W

eigh

t (kg

)

*

10

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Nesina (alogliptin) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2013. 3. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55.4. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 5. Bosi E, et al. Diabetes Obes Metab. 2011;13:1088-1096.6. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.

Hypoglycemia With Alogliptin

0

5

10

15

20

25

30

1.63

11.1

1.5

24

1.50

9.6

4.5

27.1

Monotherapy26 Weeks1,2




Add-on toInsulin +/- Met

26 Weeks6

N 329 527 500 803 390

Treatment PBO Alo Met Alo +Met

Gly Alo +Gly

Met+Pio

Alo+Met+Pio

Ins+/-Met

Alo+Ins+/-Met

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (

%)

11

Alogliptin: Adverse Events

Nesina (alogliptin) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2013.

Adverse Events* Patients (%)

Alogliptin 25 mg(n=5902)

Placebo(n=2926)

Active comparator

(n=2257)

Nasopharyngitis 4.4 3.0 5.0

Headache 4.2 2.5 5.4

Upper respiratory tract infection 4.2 2.1 5.0

*Occurring in ≥4% of patients receiving alogliptin 25 mg and more commonly than in placebo-treated patients.

12


Initial Combo w/ Metformin

24 Weeks2

Initial Combow/ Pioglitazone

24 Weeks3


Add-on to Metformin2 Years5

Add-on to Metformin +

SU24 Weeks6

N 503 791 389 700 1552 1055

Treatment PBO Lin Lin Met HD

Lin + Met LD

Lin + Met HD

Pio Lin +Pio

Met Lin +Met

Glim + Met

Lin + Met

Met + SU

Lin +Met +

SU

Baseline A1C (%)

8.0 8.0 8.7 8.5 8.7 8.7 8.6 8.6 8.0 8.1 7.7 7.7 8.1 8.2

* P<0.0001 vs comparator. † P<0.0001 vs placebo and vs metformin 1000 mg twice daily.

HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily).

1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267. 2. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 3. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661. 4. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74.5. Gallwitz B, et al. Lancet. 2012;380:475-483. 6. Owens DR, et al. Diabet Med. 2011;28:1352-61.

Glucose Control With Linagliptin

-2

-1.5

-1

-0.5

0

0.5 0.25

-1.1

-0.56

0.15

-0.41

-0.1

-0.44

-1.2-1.06

-0.49-0.21

-0.72-0.5

-1.6

A

1C (

%)

*

**

*

†

13

Initial Combo w/ Metformin24 Weeks1


24 Weeks2

Add-on toMetformin24 Weeks3

Add-on toMetformin2 Years4

N 791 389 700 1552

Treatment Lin Met HD

Lin + Met LD

Lin + Met HD

Pio Lin +Pio

Met Lin +Met

Glim + Met

Lin + Met

Weight Changes With Linagliptin

-2

-1

0

1

2

3

0.2

-0.5

1.2

-0.5

1.3

-0.1

2.3

-0.4

-1.4

-0.8 W

eigh

t (kg

)

* P<0.0001 vs comparator.


1. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 2. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661.3. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 4. Gallwitz B, et al. Lancet. 2012;380:475-483.

*

14


Initial Combo w/ Metformin

24 Weeks2


24 Weeks3


Add-on to Metformin2 Years5

Add-on to Metformin +

SU24 Weeks6

N 503 791 389 700 1552 1055

Treatment PBO Lin Lin Met HD

Lin + Met LD

Lin + Met HD

Pio Lin +Pio

Met Lin +Met

Glim + Met

Lin + Met

Met + SU

Lin +Met +

SU

Hypoglycemia With Linagliptin

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (

%)

0

5

10

15

20

25

30

35

40

0.63.4

02.8

36

14.8

0.33.5

1.2 0.6

7

22.7

0 0


1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267. 2. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 3. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661. 4. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74.5. Gallwitz B, et al. Lancet. 2012;380:475-483. 6. Owens DR, et al. Diabet Med. 2011;28:1352-61.

15

Linagliptin: Adverse Events

Tradjenta (linagliptin) prescribing information. Ridgefield, CT: Boehringer Ingelheim, Inc.; 2014.

Adverse Events*

Patients (%)

Linagliptin 5 mg(n=3625)

Placebo(n=2176)

Nasopharyngitis 7.0 6.1

Diarrhea 3.3 3.0

Cough 2.1 1.4

*Occurring in ≥2% of patients receiving linagliptin 5 mg and more commonly than in placebo-treated patients.

16


Initial Combow/ Metformin

24 Weeks2



Add-on to Glyburide vs Uptitration24 Weeks5

Add-on toTZD

24 Weeks6

N 401 1306 743 801 768 565

Treatment PBO Sax Met Sax +Met

Met Sax +Met

Sit +Met

Sax +Met

Gly Sax +Gly

TZD Sax +TZD

Baseline A1C (%) 7.9 8.0 9.4 9.4 8.1 8.1 7.7 7.7 8.4 8.5 8.2 8.4

P<0.0001 vs comparator.

1. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622. 3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26:540-549. 5. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.

Glucose Control With Saxagliptin

Series1

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5 0.19

-2

0.13

-0.62

0.08

-0.3-0.46

-2.5

-0.69-0.52 -0.64

-0.94*

A

1C (

%)

*

*

**

17



24 Weeks2




Add-on toTZD

24 Weeks6

N 401 1306 743 801 768 565


Met Sax +Met

Sit +Met

Sax +Met

Gly Sax +Gly

TZD Sax +TZD

*P=0.01 vs glyburide uptitration.

1. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622.3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26:540-549.5. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.

Wei

ght (

kg)

Weight Changes With Saxagliptin

Series1

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

-1.4-1.6

-0.92

-0.4

0.3

0.9

-0.1

-1.8

-0.87

-0.4

0.8

1.4*

18



24 Weeks2




Add-on toTZD

24 Weeks6

N 401 1306 743 801 768 565


Met Sax +Met

Sit +Met

Sax +Met

Gly Sax +Gly

TZD Sax +TZD

1. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622.3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26:540-549.5. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.

Hypoglycemia With Saxagliptin

Series102468

10121416

6.3

45

2.8

10.1

3.85.2

3.4

5.2

3.2

14.6

2.7

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (

%)

19

Saxagliptin: Adverse Events

Adverse Events* Patients (%)

Saxagliptin 5 mg Placebo

Headache 6.5 5.9

Upper respiratory tract infection

7.7 7.6

Urinary tract infection 6.8 6.1

*Occurring in ≥5% of patients receiving saxagliptin 5 mg and more commonly than in placebo-treated patients.

Onglyza (saxagliptin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb. 2013.

20

*P<0.001 vs active comparator monotherapy. †P<0.001 vs active comparator dual therapy.

1. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 2. Goldstein BJ, et al. Diabetes Care. 2007;30:1979-1987.3. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 4. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177.5. Derosa G, et al. Metab Clin Exp. 2010;59:887-895. 6. Dobs AS, et al. J Diabetes. 2013;5:68-79.

Glucose Control With SitagliptinMonotherapyvs Glipizide52 Weeks1


24 Weeks2


Add-on toInsulin

24 Weeks4

Add-on toPioglitazone vs

Met + Pio12 Months5

Add-on to Rosiglitazone +

Metformin54 Weeks6

N 1172 1091 701 641 151 278

Treatment Glip Sit Met Sit Sit+Met

Met Sit+Met

Ins Sit+Ins

Met +Pio

Sit +Pio

Rosi + Met

Sit +Rosi +

Met

Baseline A1C (%)

7.5 7.5 8.7 8.9 8.8 8.0 8.0 8.6 8.7 8.4 8.5 8.7 8.8

A

1C (

%)

-2

-1.5

-1

-0.5

0

-0.7 -0.7

-0.02

0.0

-1.4

-0.3

-0.7

-1.9

-0.7 -0.6

-1.4

-1.1-1.13

*

* *†

21

*P<0.001 vs glipizide; †P<0.05 vs sitagliptin.

1. Aschner P, et al. Diabetes Care. 2006;29:2632-2637. 2. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205.3. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 4. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 5. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 6. Derosa G, et al. Metab Clin Exp. 2010;59:887-895.

W

eigh

t (kg

)

Weight Changes With Sitagliptin

Series1

-4

-3

-2

-1

0

1

2

3

-1.1

1.11.5

-0.4

0.1

-2.8

-0.2

-1.5

1.8

0.8

0.1

-1.6



Add-on to Pioglitazone24 Weeks3

Add-on to Glimepiride24 Weeks4

Add-on toInsulin

24 Weeks5

Add-on to Pio vs Met + Pio12 Months6

N 741 793 353 441 641 151

Treatment PBO Sit Glip Sit Pio Sit +Pio

Glim Sit + Glim

Ins Sit +Ins

Met + Pio

Sit +Pio

†

*

22

1. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 2. Goldstein BJ, et al. Diabetes Care. 2007;30:1979-1987.3. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 4. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568.5 . Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 6. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177.

Hypoglycemia With SitagliptinSitagliptin vs

Glipizide52 weeks1


24 Weeks2


Add-on to Pioglitazone24 Weeks4

Add-on to Glimepiride24 Weeks5

Add-on toInsulin

24 Weeks6

N 793 1091 701 353 441 641

Treatment Glip Sit PBO Met Sit +Met

Met Sit +Met

Pio Sit +Pio

Glim Sit +Glim

Sit +Glim +

Met

Ins Sit +Ins

0

5

10

15

20

25

30

35 32

1.1 2.10

7.5 8.04.9

2.2 1.3 1.1

16.4 16.0

0.62.8P

atie

nts

Rep

ortin

g H

ypog

lyce

mia

(%

)

23

Selected Adverse Events With Sitagliptin: Pooled Data

Adverse Event

Incidence per 100 patient-years

Difference (95% CI)Sitagliptin 100 mg Nonexposed

Constipation 2.6 1.9 0.8 (0.1, 1.4)

Diarrhea 6.9 9.6 -2.3 (-3.6, -1.0)

Headache 5.8 5.6 0.4 (-0.7, 1.4)

Nasopharyngitis 7.7 7.0 0.9 (-0.3, 2.1)

Pancreatitis 0.08 0.10 -0.02 (-0.20, 0.14)

Rash 1.3 0.9 0.4 (-0.1, 0.8)

Upper respiratory tract infection 8.6 9.0 -0.3 (-1.6, 1.0)

Williams-Herman D, et al. BMC Endocr Disord. 2010;10(7) . http://www.biomedcentral.com/1472-6823/10/7.Engel SS, et al. Int J Clin Pract. 2010;64:984-990.

24

GLP-1 RECEPTOR AGONISTS


25

GLP-1 Receptor Agonists

FDA-Approved Agents

• Albiglutide• Dulaglutide• Exenatide• Exenatide ER• Liraglutide

Key Features

• Injectable administration• Mimic action of native

GLP-1• Increase glucose-

dependent insulin secretion

• Suppress glucagon production

• Slow gastric emptying

ER, extended release; GLP-1, glucagon-like peptide 1.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

26


Alb1 Dul2 Exe3 Exe ER4

Lir5 Alb6 Dul7 Exe8 Exe ER9

Lir10 Alb11,* Exe12 Exe ER13,†

Lir14

Baseline A1C (%) 8.1 7.6 7.8 8.5 8.3 8.1 8.1 8.2 8.6 8.4 8.2 8.6 8.3 8.5

Glucose Controlwith GLP-1 Receptor Agonists

-1.8-1.6-1.4-1.2

-1-0.8-0.6-0.4-0.2

0

-1.0-0.9

-0.8-0.8

-1.4

-1.0

-0.7-0.9

-1.5-1.5 -1.5-1.4

-1.1

-1.5


*Metformin with or without SU or TZD. †Metformin with or without SU. ‡Absolute change from baseline (active-controlled trial).

1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 7. Dungan KM, et al. Lancet. 2014;384:1349-1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 9. Bergenstal RM, et al. Lancet. 2010;376:431-439. 10. Pratley RE, et al. Lancet. 2010;375:1447-1456. 11. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 12. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 13. Diamant M, et al. Lancet. 2010;375:2234-2243. 14. Marre M, et al. Diabet Med. 2009;26:268-278.

Pla

cebo

-adj

uste

d

A1C

(%

)

‡

‡

‡ ‡

‡

‡

‡

‡

27





Lir14

Weight Change with GLP-1 Receptor Agonists

-4

-3

-2

-1

0

-0.9-1.2

-0.6

-2.3-2.6

-1.6

-3.1-2.8 -2.6

-2-2.3

-0.2

-2.5

-3.4

*Metformin with or without SU or TZD. †Metformin with or without SU.

1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 7. Dungan KM, et al. Lancet. 2014;384:1349-1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 9. Bergenstal RM, et al. Lancet. 2010;376:431-439. 10. Pratley RE, et al. Lancet. 2010;375:1447-1456. 11. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 12. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 13. Diamant M, et al. Lancet. 2010;375:2234-2243. 14. Marre M, et al. Diabet Med. 2009;26:268-278.

W

eigh

t (kg

)


28





Lir14

Hypoglycemia with GLP-1 Receptor Agonists

05

10152025303540

03

10.412.39

36

4.0 5.0

13.0

5.21

8.183

*Metformin with or without SU or TZD. †Metformin with or without SU.

1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 7. Dungan KM, et al. Lancet. 2014;384:1349-1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 9. Bergenstal RM, et al. Lancet. 2010;376:431-439. 10. Pratley RE, et al. Lancet. 2010;375:1447-1456. 11. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 12. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 13. Diamant M, et al. Lancet. 2010;375:2234-2243. 14. Marre M, et al. Diabet Med. 2009;26:268-278.


Pat

ient

s (%

)

29

Safety Considerationswith GLP1 Receptor Agonists

GI adverse events

• Common • Usually dose dependent and transient• Usually reduced with dose titration

Pancreatitis

• Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established


• Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected• Labeling for GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of

pancreatitis

Pancreatic cancer


• Further assessments required from long duration-controlled studies or epidemiological databases

Medullary thyroid cancer

• Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking

• Labeling for liraglutide and exenatide ER:• Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid

tumors• Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia

syndrome type 2

Renal impairment

• Renal Impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide is contraindicated in patients with severe renal insufficiency or ESRD

ER, extended release.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013. http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html.

30

Monotherapy vsPlacebo

52 Weeks1

Add-on to Metformin

104 Weeks2

Add on to Pio +/- Met

52 Weeks3

Add-on toMet +/- SU +/- TZD

32 Weeks4

Add-on toMet +/- SU52 Weeks5

Add-on toBasal Insulin

26 Weeks6

N 296 1049 310 841 779 586

Treatment† PBO Alb 50 mg

Met Glim+

Met

Sit+Met

Alb 50

mg+ Met

Pio+/-Met

Alb 30 mg+

Pio+/- Met

Lir Alb 50 mg

Glar Alb 30 mg

Lispro Alb 50 mg

Baseline A1C (%)

8.0 8.1 8.2 8.1 8.1 8.1 8.1 8.1 8.2 8.2 8.4 8.3 8.4 8.5

*P<0.0001 vs placebo. **P<0.001 vs active comparators.

1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 3. Reusch J, et al. Diabetes Obes Metab. 2014;16:1257-1264. 4. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 5. Weissman PN, et al. Diabetologia. 2014;57:2475-2484. 6. Rosenstock J, et al. Diabetes Care. 2014;37:2317-2325.

Glucose Control With Albiglutide

A

1C (

%)

-1.2-1

-0.8-0.6-0.4-0.2

00.20.4

0.2

-0.36

-0.1

-0.98

-0.79-0.66

-0.90

-0.28

-0.80 -0.79-0.67

-0.82

0.27

-0.63

**** *

31

Weight Change With Albiglutide


52 Weeks1

Add-on to Metformin

104 Weeks2


52 Weeks3


32 Weeks4



26 Weeks6

N 296 1049 310 841 779 586

Treatment‡ PBO Alb 50 mg

Met Glim+

Met

Sit+Met

Alb 50

mg+ Met

Pio+/-Met

Alb 30 mg+

Pio+/- Met

Lir Alb 50 mg

Glar Alb 30 mg

Lispro Alb 50 mg

-3

-2

-1

0

1

2

-0.7

1.2

-2.2

1.6

0.8

-0.9 -0.9

-0.2-0.6

-1.1-0.7

-1 -1.21 W

eigh

t (kg

)

***

**

*P<0.0001 vs glimepiride or insulin. **P<0.0001 vs albiglutide.†Between-group difference shown; absolute changes not reported.

1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 3. Reusch J, et al. Diabetes Obes Metab. 2014;16:1257-1264. 4. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 5. Weissman PN, et al. Diabetologia. 2014;57:2475-2484. 6. Rosenstock J, et al. Diabetes Care. 2014;37:2317-2325.

†

32



32 Weeks2

Add-on to Met +/- SU52 Weeks3

N 1049 841 779

Treatment Met Glim +Met

Sit +Met

Alb50 mg+

Met

Lira+ Met+/-

SU

Alb50 mg+ Met+/-

SU

Glar Alb30 mg

1. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 2. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297.3. Weissman PN, et al. Diabetologia. 2014;57:2475-2484.

Blood Pressure Change With Albiglutide

S

ysto

lic B

P (

mm

Hg)

-2-1.5

-1-0.5

00.5

11.5

22.5 2.2

1.5

0.30.20

-1.40-1

Decrease of <1 mmHg in both groups

33

Hypoglycemia With Albiglutide

Pat

ient

s w

ith d

ocum

ente

d sy

mpt

omat

ic h

ypog

lyce

mia

(%

)

0

5

10

15

20

25

30

35

2.0

17.9

1.3

13.0

27.429.9

0.01.7

3.3

10.4

17.515.8

4 3

1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 3. Reusch J, et al. Diabetes Obes Metab. 2014;16:1257-1264. 4. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 5. Weissman PN, et al. Diabetologia. 2014;57:2475-2484. 6. Rosenstock J, et al. Diabetes Care. 2014;37:2317-2325.


52 Weeks1

Add-on to Metformin

104 Weeks2


52 Weeks3


32 Weeks4



26 Weeks6

N 296 1049 310 841 779 586

Treatment‡ PBO Alb 50 mg

Met Glim+

Met

Sit+Met

Alb 50

mg+ Met

Pio+/-Met

Alb 30 mg+

Pio+/- Met

Lir Alb 50 mg

Glar Alb 30 mg

Lispro Alb 50 mg

34

Albiglutide: Adverse Events

Adverse Events*

Patients (%)

Albiglutide(n=923)

Placebo(n=468)

Upper respiratory tract infection 14.2 13.0

Diarrhea 13.1 10.5

Nausea 11.1 9.6

Injection site reaction 10.5 2.1

Cough 6.9 6.2

Back pain 6.7 5.8

Arthralgia 6.6 6.4

Sinusitis 6.2 5.8

Influenza 5.2 3.2

*Adverse events of interest occurring in ≥5% of patients receiving albiglutide.

Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.

35

Glucose Control With Dulaglutide

*P<0.02 vs glargine. **P<0.01 vs metformin. ***P<0.001 vs comparator.†All dulaglutide dosages shown are 1.5 mg once weekly.

1. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 2. Nauck M, et al. Diabetes Care. 2014;37:2149-2158. 3. Dungan KM, et al. Lancet. 2014;384:1349-1357. 4. Wysham C, et al. Diabetes Care. 2014;37:2159-2167. 5. Giorgino F, et al. Diabetes. 2014;63(suppl 1):A87. Abstr. 330-OR. 6. Jendle J, et al. Diabetes. 2014;63(suppl 1):A246. Abstr. 962-P.




Add-on toPio + Met52 Weeks4

Add-on toMet + SU

52 Weeks5

Add-on to Lispro

26 Weeks6

N 807 1098 599 976 807 884

Treatment† Met Dul Sit Dul Lir Dul Exe Dul Glar Dul Glar Dul

Baseline A1C (%) 7.6 7.6 8.1 8.1 8.1 8.1 8.1 8.1 8.1 8.5

A

1C (

%)

-1.8-1.6-1.4-1.2

-1-0.8-0.6-0.4-0.2

0

-0.56-0.39

-1.36

-0.8-0.63

-1.41

-0.78

-1.1

-1.42 -1.36

-1.08

-1.64

*****

****

***

36

Weight Reduction With Dulaglutide

*P<0.05 vs glargine. **P<0.001 vs sitagliptin.†All dulaglutide dosages shown are 1.5 mg once weekly.






Add-on toMet + SU

52 Weeks5

Add-on to Lispro

26 Weeks6

N 807 1098 599 976 807 884

Treatment† Met Dul Sit Dul Lir Dul Exe Dul Glar Dul Glar Dul

W

eigh

t (kg

)

-4

-3

-2

-1

0

1

2

3

-2.22-1.53

-2.43

-1.07

1.44

2.33

-2.29-3.03

-2.56

-1.3-1.87

-0.87

**

**

37

Blood Pressure Change With Dulaglutide

†All dulaglutide dosages shown are 1.5 mg once weekly.





Add-on to Pio + Met52 Weeks4

N 807 1098 599 976

Treatment† Met Dul Sit Dul Lir Dul Exe Dul

S

ysto

lic B

P (

mm

Hg)

-4

-3

-2

-1

0

1

2

-1-0.5

-2.8

0.02

-0.1

-0.8

-3.26

0.83

38

Hypoglycemia With Dulaglutide

†All dulaglutide dosages shown are 1.5 mg once weekly.






N 807 1098 599 976

Treatment† Met Dul Sit Dul Lir Dul Exe Dul

Pat

ient

s re

port

ing

hypo

glyc

emia

(%

)

02468

1012141618

12.7

4.86

15.9

12.3

10.29

10.4

Add-on toMet + SU

52 Weeks5

Add-on to Lispro

26 Weeks6

807 884

Glar Dul Glar Dul

Hyp

ogly

cem

ia

even

ts/p

atie

nt p

er y

ear

05

1015202530354045

3

39.9

1.7

31

39

Dulaglutide: Adverse Events

Adverse Events*

Patients (%)

Dulaglutide 1.5 mg(n=834)

Dulaglutide 0.75 mg(n=836)

Placebo(n=568)

Nausea 21.1 12.4 5.3

Diarrhea 12.6 8.9 6.7

Vomiting 12.7 6.0 2.3

Abdominal pain 9.4 6.5 4.9

Decreased appetite 8.6 4.9 1.6

Dyspepsia 5.8 4.1 2.3

Fatigue 5.6 4.2 2.6

*Adverse events occurring in ≥5% of patients receiving dulaglutide.

Trulicity (dulaglutide) injection prescribing information. Indianapolis, IN: Eli Lilly and Company; 2014.

40

Glucose Control With Exenatide

*P<0.001 vs comparator.†All exenatide dosages shown are 10 μg BID.

1. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460 . 2. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 4. Zinman B, et al. Ann Intern Med. 2007;146:477-485. 5. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. 6. Heine RJ, et al. Ann Intern Med. 2005;143:559-569.



Add-on to Sulfonylurea

30 Weeks3

Add-on to TZD16 Weeks4

Add-on to Metformin + SU

30 Weeks5

Add-on to Met + SU vs Glargine

26 Weeks6

N 233 336 377 233 733 551

Treatment† PBO Exe Met Exe +Met

SU Exe +SU

TZD Exe +TZD

Met +SU

Exe + Met +

SU

Glar + Met +

SU

Exe +Met +

SU

Baseline A1C (%) 7.8 7.8 8.2 8.2 8.7 8.6 7.9 7.9 8.5 8.5 8.3 8.2

A

1C (

%)

-1.2-1

-0.8-0.6-0.4-0.2

00.20.4

-0.2

0.1 0.12 0.090.2

-1.1

-0.9-0.8 -0.86 -0.89 -0.9

-1.1* * ***

41

Weight Reduction With Exenatide

*P<0.05 vs comparator. **P<0.0001 vs glargine.†All exenatide dosages shown are 10 μg BID.

1. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460 . 2. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 4. Zinman B, et al. Ann Intern Med. 2007;146:477-485. 5. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. 6. Heine RJ, et al. Ann Intern Med. 2005;143:559-569.




30 Weeks3


Add-on to Metformin + SU

30 Weeks5

Add-on to Met + SU vs Glargine

26 Weeks6

N 233 336 377 233 733 551


SU Exe +SU

TZD Exe +TZD

Met +SU

Exe + Met +

SU

Glar + Met +

SU

Exe +Met +

SU

W

eigh

t (kg

)

-4

-3

-2

-1

0

1

2

3

-1.4

-0.3-0.6

-0.24-0.9

1.8

-3.1-2.8

-1.6 -1.75 -1.6

-2.3

** **

***

42*P<0.05 vs placebo.

Moretto TJ, et al. Clin Ther. 2008;30:1448-1460.

S

ysto

lic B

P

(mm

Hg)

Blood Pressure Changes With Exenatide

Series1

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

-0.3

-3.7

Monotherapy24 Weeks

N 233

Treatment PBO Exe 10 μg BID

*

43




30 Weeks3


N 233 336 377 233


SU Exe +SU

TZD Exe +TZD

†All exenatide dosages shown are 10 μg BID.

1. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460 . 2. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 4. Zinman B, et al. Ann Intern Med. 2007;146:477-485.

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (

%)

Hypoglycemia With Exenatide

Series10

5

10

15

20

25

30

35

40

1

53

7.14 5

36

10.7

44

Exenatide: Adverse Events

Adverse Events*

Patients (%)

Monotherapy + Met and/or SU + TZD +/- Met

Exe(n=155)

PBO(n=77)

Exe(n=963)

PBO(n=483)

Exe(n=121)

PBO(n=112)

Nausea 8 0 44 18 40 15

Vomiting 4 0 13 4 13 1

Diarrhea 13 6 6 3

Feeling Jittery 9 4

Dizziness 9 6

Headache 9 6

Dyspepsia 3 0 6 3 7 1

Asthenia 4 2

GERD 3 1 3 0

Hyperhidrosis 3 1

*Occurring in ≥2% of patients receiving exenatide

Byetta (exenatide) injection prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2013 .

45

*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents.†Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.

1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243. 5. Buse JB, et al. Lancet. 2013;381:117-124.

Glucose Control With Exenatide ERAdd-on to

OAs*30 Weeks1

Monotherapy vs OAs

26 Weeks2



Add-on toOAs†

26 Weeks5

N 258 820 514 456 911

Treatment Exe BID

Exe ER

Sit Pio Met Exe ER

Sit+ Met

Pio+ Met

Exe ER+ Met

Glar+

OAs

Exe ER +OAs

Lira+

OAs

Exe ER +

OAs

Baseline A1C (%)

8.3 8.3 8.5 8.5 8.6 8.5 8.5 8.5 8.6 8.3 8.3 8.4 8.5

A

1C (

%)

-2

-1.5

-1

-0.5

0

-1.5-1.63

-0.9

-1.3-1.48

-1.90

-1.48

-1.20

-1.50-1.28

-1.15

-1.53 -1.5

P<0.001 P<0.0001P<0.01P=0.017 P=0.02

46


1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258.3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243.5. Buse JB, et al. Lancet. 2013;381:117-124.

Add-on toOAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2



Add-on toOAs†

26 Weeks5

N 258 820 514 456 911

Treatment (mg/day)

Exe BID

Exe ER

Sit Pio Met Exe ER

Sit+ Met

Pio+ Met

Exe ER+ Met

Glar +

OAs

Exe ER + OAs

Lira +

OAs

Exe ER + OAs

Weight Reduction With Exenatide ER

-5-4-3-2-101234

-3.6

1.5

-0.8

1.4

-3.6-3.7

-2.0

2.8

-2.6 -2.7

-0.8

-2.0 -2.3

P<0.0001

W

eigh

t (kg

)

P<0.001P<0.001

47


1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258.3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243.5. Buse JB, et al. Lancet. 2013;381:117-124.

Add-on toOAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2



Add-on toOAs†

26 Weeks5

N 258 820 514 456 911

Treatment Exe BID

Exe ER

Sit Pio Met Exe ER

Sit+ Met

Pio+ Met

Exe ER+ Met

Glar +

OAs

Exe ER + OAs

Lira +

OAs

Exe ER + OAs

Hypoglycemia With Exenatide ER

0

5

10

15

20

25

30

35

6.1 3.7 3.0

31.0

8.95.4 4.1

1.0

13.011.0

3.1 5.21.0P

atie

nts

repo

rtin

g hy

pogl

ycem

ia (

%)

48

Exenatide Extended Release: Adverse Events

Adverse Events*

Patients (%)

Monotherapy + Met + Met +/- SU

Exe ER(n=248)

Sit(n=163)

Pio(n=163)

Met(n=246)

Exe ER(n=160)

Sit(n=166)

Pio (n=165)

Exe ER(n=233)

Glar(n=233)

Nausea 11.3 3.7 4.3 6.9 24.4 9.6 4.8 12.9 1.3

Diarrhea 10.9 5.5 3.7 12.6 20.0 9.6 7.3 9.4 4.0

Injection site reaction 10.5 6.7 3.7 10.2 5.0 4.8 1.2 6.0 0

Constipation 8.5 2.5 1.8 3.3 6.3 3.6 1.2

Headache 8.1 9.2 8.0 12.2 9.4 9.0 5.5 9.9 7.6

Dyspepsia 7.3 1.8 4.9 3.3 5.0 3.6 2.4

Vomiting 11.3 2.4 3.0

Fatigue 5.6 0.6 3.0

*Adverse events of interest occurring in ≥5% of patients receiving exenatide extended release.

Bydureon (exenatide extended release) injection prescribing information.Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2014.

49

*P<0.0001 vs monotherapy. **P<0.0001 vs dual therapy. ***P=0.0015 vs glargine.†All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456.4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

Glucose Control With LiraglutideMonotherapy vs

Glimepiride52 Weeks1




26 Weeks4

Add-on toMet + TZD26 Weeks5

Add-on toMet + SU

26 Weeks6

N 746 1091 665 1041 821 581

Treatment† Glim Lir Met Glim +

Met

Lir+Met

Sit+Met

Lir+Met

SU Rosi +

SU

Lir+SU

Rosi +

Met

Lir+Rosi+ Met

Met+SU

Glar+Met+ SU

Lir+Met+ SU

Baseline A1C (%)

8.4 8.3 8.4 8.4 8.4 8.5 8.4 8.4 8.4 8.5 8.4 8.6 8.3 8.2 8.3

A

1C (

%)

-2

-1.5

-1

-0.5

0

0.5

-0.51

-0.98 -0.9

-0.44 -0.5

-1.09-1.14-1.00

-1.50

-1.13

-1.50-1.33

0.090.23

-0.24

*** ***

*******

*

50

Monotherapy vs Glimepiride52 Weeks1




26 Weeks4


Add-on toMet + SU

26 Weeks6

N 746 1091 665 1041 821 581


Met

Lir+Met

Sit+Met

Lir+Met

SU Rosi +

SU

Lir+SU

Rosi +

Met

Lir+Rosi+ Met

Met+SU

Glar+Met+ SU

Lir+Met+ SU

*P<0.0001 vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU.†All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

-4

-3

-2

-1

0

1

2

3

1.10 1.00

-0.96

2.10

0.60

1.60

-2.50 -2.80-3.38

-0.20

-2.00 -1.80-1.50

-0.10 -0.42

W

eigh

t (kg

)

Weight Reduction With Liraglutide

* ****

*

*

***

*

51

Blood Pressure Changes With Liraglutide

Monotherapy vs Glimepiride52 Weeks1



Add-on to Sulfonylurea26 Weeks4,5


Add-on toMet + SU

26 Weeks7

N 746 1091 665 1041 821 581


Met

Lir+Met

Sit+Met

Lir+Met

SU Rosi +

SU

Lir+SU

Rosi +

Met

Lir+Rosi+ Met

Met+SU

Glar+Met+ SU

Lir+Met+ SU

*P<0.05 vs comparator.†All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90.3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278.5. Colagiuri S, et al. Diabetes. 2008;57(suppl 2): Abstr. 554-P. 6. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 7. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055

-6

-5

-4

-3

-2

-1

0

1

-0.7

0.4

-0.9 -0.9 -1.1

0.5

-3.6

-2.3

-0.7

-2.8

-5.6

-4.0

-1.8-2.3

S

ysto

lic B

P

(mm

Hg)

**

**

52

*P<0.01 vs active comparator.†All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278.

Hypoglycemia With Liraglutide

Series10

5

10

15

20

25

30

24

3 2.6

8

35

8.1

17

5 4.3




Add-on to Sulfonylurea26 Weeks4

N 746 1091 665 1041

Treatment† Glim Lir Met Glim+Met

Lir+Met

Sit+Met

Lir+Met

SU Rosi+SU

Lir+SU

*

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (

%)

**

53

Liraglutide: Adverse Events

Adverse Events*

Patients (%)

Monotherapy + Met + Glim + Met + TZD

Lir(n=497)

Glim(n=248)

Lir(n=724)

PBO(n=121

)Lir

(n=695)PBO

(n=114)Lir

(n=355)PBO

(n=175)

Nausea 28.4 8.5 15.2 4.1 7.5 1.8 34.6 8.6

Diarrhea 17.1 8.9 10.9 4.1 7.2 1.8 14.1 6.3

Vomiting 10.9 3.6 6.5 0.8 12.4 2.9

Constipation 9.9 4.8 5.3 0.9 5.1 1.1

Headache 9.1 9.3 9.0 6.6 8.2 4.6

Dyspepsia 5.2 0.9

*Adverse events of interest occurring in ≥5% of patients receiving liraglutide.

Victoza (liraglutide) injection prescribing information. Princeton, NJ: Novo Nordisk Inc. 2013.

54

SGLT2 INHIBITORS


55

SGLT2 Inhibitors

FDA-Approved Agents

• Canagliflozin• Dapagliflozin• Empagliflozin

Key Features

• Oral administration• Inhibit reabsorption of

glucose into the bloodstream from renal fluid

SGLT2, sodium-glucose cotransporter 2.

DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14.

56

Glucose Controlwith SGLT2 Inhibitors


*Absolute change from baseline (active-controlled trial).

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6. Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9

Baseline A1C (%)

8.1 7.8 7.9 8.1 8.2 7.9 8.2 8.6 8.3

Pla

ceb

o-a

dju

sted

A

1C (

%)

*

*

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-1.2

-0.9

-0.4

-0.66-0.52 -0.57

-0.86

-0.64-0.46

57

Weight Changewith SGLT2 Inhibitors


W

eig

ht

(kg

)



-4.5-4

-3.5-3

-2.5-2

-1.5-1

-0.50

-3.4

-4.0

-1.4

-3.2 -3.2

-1.6

-2.48 -2.46-2.04


58

Hypoglycemia with SGLT2 Inhibitors





0

10

20

30

40

50

60

70

3.0 5.0

51.2

2.9 3.4

53.6

1.4

58.2

Pat

ien

ts (

%)

<1

59

Safety Considerationswith SGLT2 Inhibitors

Genitourinary infection

• Increased incidence; patients should be monitored and treated if necessary

Increased LDL-C • Small increases in LDL-C have been observed in clinical trials

Bladder cancer

• Increased incidence of bladder cancers in patients receiving dapagliflozin

• Dapagliflozin labeling recommends not using in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer

Renal impairment

• Monitor kidney function during therapy, especially in patients with GFR <60 mL/min/1.73 m2

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company. 2014.Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2014.

60




Add-on toMetformin + SU

52 Weeks4

Add-on toOAs +/- Insulin

in CKD†

26 Weeks5

N 584 451 1452 755 269

Treatment* (mg/day)

PBO Can Met Sit + Met

Can + Met

Glim + Met

Can + Met

Sit+ Met+ SU

Can+ Met+ SU

Ins + OAs

Can + Ins + OAs

Baseline A1C (%)

8.0 8.0 7.8 7.6 7.7 7.8 7.8 8.1 8.1 8.0 8.0

*All canagliflozin dosages shown are canaglifozin 300 mg.†Estimated glomerular filtration rate 30-50 mL/min/1.73 m2.

**P<0.001 vs placebo.‡Met criteria for noninferiority and superiority (upper limit of confidence interval <0.0%).

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238. 3. Cefalu WT, et al. Lancet. 2013;382:941-950. 4. Schernthaner G, et al. Diabetes Care. 2013;36:2508-2515. 5. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473.

Glucose Control With Canagliflozin

A1C

(%

)

-1.2-1

-0.8-0.6-0.4-0.2

00.20.4

0.14

-0.74 -0.81-0.66

-0.03

-1.03-0.92 -0.93

-1.03

-0.44

-0.22

****

**‡

**

61


**P<0.001 vs comparator.

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238. 3. Cefalu WT, et al. Lancet. 2013;382:941-950. 4. Schernthaner G, et al. Diabetes Care. 2013;36:2508-2515. 5. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473.

Weight Change With Canagliflozin





52 Weeks4


in CKD†

26 Weeks5

N 584 451 1452 755 269

Treatment* (mg/day)


Can + Met

Glim + Met

Can + Met

Sit+ Met+ SU

Can+ Met+ SU

Ins + OAs

Can + Ins + OAs

-5

-4

-3

-2

-1

0

1

-0.5 -0.5

0.70.1 0.2

-3.4-3.0

-4.0

-2.3

-1.4-0.9

****

**

****

Wei

ght (

kg)

62


**P<0.001 vs comparator.

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.3. Cefalu WT, et al. Lancet. 2013;382:941-950. 4. Schernthaner G, et al. Diabetes Care. 2013;36:2508-2515.5. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473.

Blood Pressure Change With Canagliflozin





52 Weeks4


in CKD†

26 Weeks5

N 584 451 1452 755 269

Treatment* (mg/day)


Can + Met

Glim + Met

Can + Met

Sit+ Met+ SU

Can+ Met+ SU

Ins + OAs

Can + Ins + OAs

-8

-6

-4

-2

0

20.4

-0.8

0.20.9

-0.3

-5.0

-3.6-4.6

-5.1

-6.4

-1.3

** **

S

ysto

lic B

P

(mm

Hg)

63


1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.3. Cefalu WT, et al. Lancet. 2013;382:941-950. 4. Schernthaner G, et al. Diabetes Care. 2013;36:2508-2515.5. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473.

Hypoglycemia With Canagliflozin





52 Weeks4


in CKD†

26 Weeks5

N 584 451 1452 755 269

Treatment* (mg/day)


Can + Met

Glim + Met

Can + Met

Sit+ Met+ SU

Can+ Met+ SU

Ins + OAs

Can + Ins + OAs

0

10

20

30

40

50

60

2.65.0

34.040.7

36.4

3.00.0

5.0

43.2

51.2

2.0Pat

ient

s re

port

ing

hypo

glyc

emia

(%

)

64

Canagliflozin: Adverse Events

Adverse Events*

Patients (%)

Canagliflozin 100 mg(n=833)

Canagliflozin 300 mg(n=834)

Placebo(n=646)

Female genital mycotic infections 10.4 11.4 3.2

Urinary tract infections 5.9 4.3 4.0

Increased urination 5.3 4.6 0.8

Male genital mycotic infections 4.2 3.7 0.6

Vulvovaginal pruritis 1.6 3.0 0

Thirst 2.8 2.3 0.2

Constipation 1.8 2.3 0.9

Nausea 2.2 2.3 1.5

*Adverse events of interest occurring in ≥2% of patients receiving canagliflozin.

Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2014.

65


Initial Combo with

Metformin24 Weeks2


Add-on toPioglitazone24 Weeks4

Add-on toSitagliptin +/-

Metformin24 Weeks5

Add-on toinsulin + OAs

24 Weeks6

N 485 603 814 480 451 808

Treatment* (mg/day)

PBO Dap Met Dap Dap + Met

Glip+ Met

Dap + Met

Pio Dap + Pio

Sit+/- Met

Dap+ Sit+/- Met

Ins+/- OAs

Dap+ Ins+/- OAs

Baseline A1C (%)

7.8 8.0 9.1 9.1 9.1 8.1 7.9 8.3 8.4 8.7 8.7 8.5 8.6

*All dapagliflozin dosages shown are dapagliflozin 10 mg.

**P<0.001 vs placebo. ***P<0.0001 vs comparator.

1. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 2. Henry RR, et al. Int J Clin Pract. 2012;66:446-456.3. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 4. Rosenstock J, et al. Diabetes Care. 2012;35:1473-1478.5. Jabbour SA, et al. Diabetes Care. 2014;37:740-750. 6. Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.

Glucose Control With Dapagliflozin

A1C

(%

)

-2.5

-2

-1.5

-1

-0.5

0

0.5

-0.23

-1.45

-0.52 -0.42

0

-0.39

-0.89

-1.98

-0.52

-0.97

-0.50

-0.96

-1.44 *****

***

***

***

66


Initial Combo with

Metformin24 Weeks2




Metformin24 Weeks5


24 Weeks6

N 485 603 814 480 451 808

Treatment* (mg/day)


Glip+ Met

Dap + Met

Pio Dap + Pio

Sit+/- Met

Dap+ Sit+/- Met

Ins+/- OAs

Dap+ Ins+/- OAs


**P<0.001 vs placebo. ***P<0.0001 vs comparator.


Weight Change With Dapagliflozin

Wei

ght (

kg)

-4

-3

-2

-1

0

1

2

-2.2-2.7

1.4 1.6

-0.3

0.4

-3.2 -3.3 -3.2

-0.1

-2.1-1.6-1.4

*****

***

*** ***

67


Initial Combo with

Metformin24 Weeks2




Metformin24 Weeks5


24 Weeks6

N 485 603 814 480 451 808

Treatment* (mg/day)


Glip+ Met

Dap + Met

Pio Dap + Pio

Sit+/- Met

Dap+ Sit+/- Met

Ins+/- OAs

Dap+ Ins+/- OAs



Blood Pressure Change With Dapagliflozin

S

ysto

lic B

P

(mm

Hg)

-8

-6

-4

-2

0

2

-0.9

-4.0

0.81.3

-5.1

-3.6-3.6 -3.3-4.3

-3.4

-6.0-6.7

-1.2

68


Initial Combo with

Metformin24 Weeks2



Add-on toSitagliptin+/-

Metformin24 Weeks5


24 Weeks6

N 485 603 814 480 451 808

Treatment* (mg/day)


Glip+ Met

Dap + Met

Pio Dap + Pio

Sit+/- Met

Dap+ Sit+/- Met

Ins+/- OAs

Dap+ Ins+/- OAs



Hypoglycemia With Dapagliflozin

Pat

ient

s re

port

ing

hypo

glyc

emia

(%

)

0

10

20

30

40

50

60

2.7 0.9

39.7

0.7 1.8

51.8

2.9 3.3 3.40.0 2.7

53.6

2.9

69

Dapagliflozin: Adverse Events

Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company. 2014.

Adverse Events*

Patients (%)

Dapagliflozin 5 mg(n=1145)

Dapagliflozin 10 mg(n=1193)

Placebo(n=1393)

Female genital mycotic infections 8.4 6.9 1.5

Nasopharyngitis 6.6 6.3 6.2


Back pain 3.1 4.2 3.2



Nausea 2.8 2.5 2.4

Influenza 2.7 2.3 2.3

Dyslipidemia 2.1 2.5 1.5

Constipation 2.2 1.9 1.5

Discomfort with urination 1.6 2.1 0.7

*Adverse events occurring in ≥2% of patients receiving dapagliflozin.

70



Add-on toMetformin

104 Weeks3

Add-on toMet + SU

24 Weeks4

Add-on toPio +/- Met24 Weeks5

Add-on toMDI insulin52 Weeks6

N 899 638 1549 669 499 563

Treatment* (mg/day)

PBO Sit Emp Met Emp + Met

Glim+ Met

Emp + Met

Met+SU

Emp+ Met+SU

Pio+/-Met

Emp+ Pio+/- Met

Ins Emp+ Ins

Baseline A1C (%)

7.9 7.9 7.9 7.9 7.9 7.9 7.9 8.2 8.1 8.2 8.1 8.3 8.3

*All empagliflozin dosages shown are empagliflozin 25 mg.

**P<0.001 vs placebo. ***P<0.05 vs active comparator.

1. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208-219. 2. Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 3. Ridderstrale M, et al. Lancet Diabetes Endocrinol. 2014;2:691-700. 4. Haring HU, et al. Diabetes Care. 2013;36:3396-3404. 5. Kovacs CS, et al. Diabetes Obes Metab. 2014;16:147-158. 6. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.

Glucose Control With Empagliflozin

A1C

(%

)

-1.5

-1

-0.5

0

0.5

0.08

-0.66

-0.13

-0.55

-0.17 -0.11

-0.81-0.78 -0.77-0.66

-0.77 -0.72

-1.27

**

******** ***

71



Add-on toMetformin

104 Weeks3

Add-on toMet + SU

24 Weeks4



N 899 638 1549 669 499 563

Treatment* (mg/day)


Glim+ Met

Emp + Met

Met+SU

Emp+ Met+SU

Pio+/-Met

Emp+ Pio+/- Met

Ins Emp+ Ins




Weight Change With Empagliflozin

Wei

ght (

kg)

-4

-3

-2

-1

0

1

2

-0.33

0.18

-0.45

1.6

-0.39

0.34 0.44

-2.48 -2.46

-3.10

-2.39

-1.47-2.04

**

********

******

72



Add-on toMetformin

104 Weeks3

Add-on toMet + SU

24 Weeks4



N 899 638 1549 669 499 563

Treatment* (mg/day)


Glim+ Met

Emp + Met

Met+SU

Emp+ Met+SU

Pio+/-Met

Emp+ Pio+/- Met

Ins Emp+ Ins




Blood Pressure ChangeWith Empagliflozin

S

ysto

lic B

P (

mm

Hg)

-6-5-4-3-2-10123

0.7 0.4

-0.4

2.5

-1.4

0.72

-2.9

-5.00 -5.20

-3.10 -3.50-4.00 -3.80

******

***

*****

73



Add-on toMetformin

104 Weeks3

Add-on toMet + SU

24 Weeks4



N 899 638 1549 669 499 563

Treatment* (mg/day)


Glim+ Met

Emp + Met

Met+SU

Emp+ Met+SU

Pio+/-Met

Emp+ Pio+/- Met

Ins Emp+ Ins


1. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208-219. 2. Haring HU, et al. Diabetes Care. 2014;37:1650-1659.3. Ridderstrale M, et al. Lancet Diabetes Endocrinol. 2014;2:691-700.4. Haring HU, et al. Diabetes Care. 2013;36:3396-3404. 5. Kovacs CS, et al. Diabetes Obes Metab. 2014;16:147-158.6. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.

Hypoglycemia With Empagliflozin

Pat

ient

s re

port

ing

hypo

glyc

emia

(%

)

0

10

20

30

40

50

60

70

0.5

25.0

8.41.8

59.0

1.4 4.0

11.5

2.4

58.2

<1 <1 <1

74

Empagliflozin: Adverse Events

Jardiance (empagliflozin) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2014.

Adverse Events*

Patients (%)

Empagliflozin 10 mg(n=999)

Empagliflozin 25 mg(n=977)

Placebo(n=995)


Female genital mycotic infections

5.4 6.4 1.5

Upper respiratory tract infection 3.1 4.0 3.8


Dyslipidemia 3.9 2.9 3.4

Arthralgia 2.4 2.3 2.2


Nausea 2.3 1.1 1.4

*Adverse events occurring in ≥2% of patients receiving empagliflozin at rates greater than placebo.

75

NONINSULIN AGENTS: CLASS COMPARISONS


76

DPP-4 Inhibitors GLP-1 Receptor Agonists SGLT2 Inhibitors

Alo1 Lin2 Sax3 Sit4 Alb5 Dul6 Exe7 Exe ER8 Lir9 Can10 Dap11 Emp12

Baseline A1C (%) 7.9 8.1 8.1 8.0 8.1 8.1 8.2 8.6 8.4 7.8 7.9 7.9

Glucose ReductionDPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin

(Absolute Changes from Baseline; Not Head-to-Head Trials)

1. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 2. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 5. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148.6. Dungan KM, et al. Lancet. 2014;384:1349-1357. 7. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 8. Bergenstal RM, et al. Lancet. 2010;376:431-439. 9. Pratley RE, et al. Lancet. 2010;375:1447-1456. 10. Cefalu WT, et al. Lancet. 2013;382:941-950. 11. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 12. Haring HU, et al. Diabetes Care. 2014;37:1650-1659.

A

1C (

%)

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-0.6-0.5

-0.7 -0.7 -0.63

-1.42

-0.8

-1.5 -1.5

-0.93

-0.52

-0.77

77

Weight ReductionDPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin

(Separate Studies; Not Head-to-Head Trials)

NR, not reported.

1. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 2. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 5. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148.6. Dungan KM, et al. Lancet. 2014;384:1349-1357. 7. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 8. Bergenstal RM, et al. Lancet. 2010;376:431-439. 9. Pratley RE, et al. Lancet. 2010;375:1447-1456. 10. Cefalu WT, et al. Lancet. 2013;382:941-950. 11. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 12. Haring HU, et al. Diabetes Care. 2014;37:1650-1659.

NR

DPP-4 Inhibitors GLP-1 Receptor Agonists SGLT2 Inhibitors

Alo1 Lin2 Sax3 Sit4 Alb5 Dul6 Exe7 Exe ER8 Lir9 Can10 Dap11 Emp12

-5

-4

-3

-2

-1

0

-0.3 -0.4-0.9

-1.2

-2.6 -2.8

-2.0

-2.8

-4.0

-3.2

-2.5

W

eigh

t (kg

)

78

Effects of Antihyperglycemic Therapies on Blood Pressure

Class∆ Systolic BP, mmHg

(95% CI)∆ Diastolic BP, mmHg

(95% CI)

Newer therapies

GLP-1 receptor agonists1 -3.57 (-5.49 to -1.66)

-1.38 (-2.02 to -0.73)

DPP-4 inhibitors2 -0.1 (-1.2 to 0.8) —

SGLT2 inhibitors3 -3.77(-4.65 to -2.90)

-1.75(-2.27 to -1.23)

Older therapies

Metformin4 -1.09 (-3.01 to 0.82)

-0.97 (-2.15 to 0.21)

TZDs5 -4.70 (-6.13 to -3.27)

-3.79 (-5.82 to -1.77)

1. Vilsbøll T, et al. BMJ. 2012 Jan 10;344:d7771. doi: 10.1136/bmj.d7771.2. Monami M, et al. Diabetes Obes Metab. 2013;15:112-120.3. Vasilakou D, et al. Ann Intern Med. 2013;159:262-274.4. Wulffelé M, et al. J Intern Med. 2004;256:1-14.5. Qayyum R, Adomaityte J. J Clin Hypertens (Greenwich). 2006;8:19-28.

Meta-analyses

79

INHALED INSULIN


80

Inhaled Insulin

• Inhaled administration• Rapid-acting insulin

– Peak levels achieved in ~15 minutes

Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.

81

Glucose Control withInhaled Insulin

*Difference from placebo (95% CI): -0.40% (-0.57% to -0.23%).

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Add-on to Metformin and/or Other OAs24 Weeks

Placebo Inhaled insulin

N 353

Baseline A1C (%) 8.3 8.3

A

1C (

%)

*

*-1

-0.8

-0.6

-0.4

-0.2

0

-0.42

-0.82

82

Weight Change withInhaled Insulin


Placebo Inhaled insulin

N 353

*

-1.5

-1

-0.5

0

0.5

1

-1.13

0.49

W

eigh

t (kg

)


83

Hypoglycemia withInhaled Insulin


N 353

Nonsevere Severe

PBO II PBO II

01020304050607080

30

1.7

67

5.1Pat

ient

s W

ith

Hyp

ogly

cem

ia

(%)

II, inhaled insulin.


84

Safety Considerationswith Inhaled Insulin

Lung disease

• Contraindicated in asthma, COPD, and other chronic lung diseases• Perform spirometry to assess lung function before initiating inhaled

insulin, after 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms

• Do not use in patients with active lung cancer and use with caution in patients with a history of lung cancer or those at risk for lung cancer

Heart failure• Observe for signs and symptoms of fluid retention or heart failure,

especially when used with TZDs

Hypoglycemia • Increase frequency of glucose monitoring


85

Inhaled Insulin:Adverse Events

Adverse Events*

Patients (%)

Inhaled insulin(n=1991)

Placebo(n=290)

Active comparators(n=1363)

Cough 25.6 19.7 5.4

Throat pain or irritation 4.4 3.8 0.9

Headache 3.1 2.8 1.8

Diarrhea 2.7 1.4 2.2

Productive cough 2.2 1.0 0.9

Fatigue 2.0 0.7 0.6

Nausea 2.0 0.3 1.0

*Adverse events of interest occurring in ≥2% of patients receiving inhaled insulin.


86

GLARGINE U-300


871. Bolli GB, et al. Diabetes Obes Metab. 2015;17:386-394. 2. Yki-Järvinen H, et al. Diabetes Care. 2014;37:3235-3243.3. Riddle MC, et al. Diabetes Care. 2014;37:2755-2762.

Glucose Control WithGlargine U-300

A

1C (

%)

Add-on to OA, Insulin-Naive

6 Months1

Add-on to OA,Basal Insulin Users

6 Months2

Basal-BolusInsulin Regimen

6 Months3

N 878 811 807

Treatment Gla 100 Gla 300 Gla 100 Gla 300 Gla 100 Gla 300

Baseline A1C (%) 8.6 8.5 8.2 8.3 8.2 8.2

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-1.46

-0.56

-0.83

-1.42

-0.57

-0.83


Weight Change WithGlargine U-300


6 Months1


6 Months2


6 Months3

N 878 811 807


00.10.20.30.40.50.60.70.80.9

1

0.710.66

0.9

0.49

0.08

0.9

W

eigh

t (kg

)


Hypoglycemia WithGlargine U-300


6 Months1


6 Months2


6 Months3

N 878 811 807


0102030405060708090

100

52.5

79.388.6

46.2

71.5

83.4

Pat

ient

s re

port

ing

hypo

glyc

emia

(%

)

90

Risk of Hypoglycemia WithGlargine U-300

Pooled Analysis of Phase III Trials(N=2496)

Ritzel R, et al. Diabetes Obes Metab. 2015 Apr 30. doi: 10.1111/dom.12485. [Epub ahead of print].

Favors Glargine 300 Favors Glargine 100

Hypoglycemia any time of day Relative risk (95% CI)

Confirmed (≤70 mg/dL) or severe 0.91 (0.87-0.96)

Documented symptomatic (≤70 mg/dL) 0.88 (0.82-0.94)

Nocturnal hypoglycemia

Confirmed (≤70 mg/dL) or severe 0.75 (0.68-0.83)

Documented symptomatic (≤70 mg/dL) 0.75 (0.66-0.85)

0.50 0.70 0.90 1.10 1.30 1.50


Insulin Dose WithGlargine U-300


6 Months1


6 Months2


6 Months3

N 878 811 807


Baseline dose (U/kg/day) 0 0 0.66 0.64 0.67 0.67

0

0.2

0.4

0.6

0.8

1

1.2

0.53

0.84 0.88

0.62

0.92 0.97

In

sulin

dos

e (U

/kg/

day)

92

Safety Considerationswith Glargine U-300

Hypoglycemia • Increase frequency of glucose monitoring

Hypokalemia• Monitor potassium levels in at-risk patients and treat as

necessary

Heart failure• Observe for signs and symptoms of fluid retention or heart

failure, especially when used with thiazolidinediones

Toujeo (glargine U-300) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC.

93

Glargine U-300: Adverse Events

Adverse Events*

Patients (%)

Type 1 diabetes(n=304)

Type 2 diabetes(n=1242)

Nasopharyngitis 12.8 7.1

Upper respiratory infection 9.5 5.7

*Adverse events of interest occurring in ≥5% of patients receiving glargine 300 Units/mL.

Toujeo (glargine U-300) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC.

1 Glycemic Management in Type 2 Diabetes Efficacy and Safety of Modern Antihyperglycemic Therapies.

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