T2D S5 New Antidiabetic Therapies 020218

Glycemic Management in
Type 2 Diabetes
Efficacy and Safety of Modern
Antihyperglycemic Therapies
1
Glycemic Management in Type 2 Diabetes: Efficacy
and Safety of Modern Antihyperglycemic Therapies
DPP4 INHIBITORS
2
DPP4 Inhibitors
FDA-Approved Agents Key Features

• Alogliptin • Oral administration
• Linagliptin • Increase endogenous
• Saxagliptin GLP1 and GIP levels
• Sitagliptin • Increase glucose-
dependent insulin
secretion
• Suppress glucagon
production
DPP4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP1, glucagon-like peptide 1.
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
3
Glucose Control
with DPP4 Inhibitors
Placebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)
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
0
Placebo-adjusted
-0.2
 A1C (%)
-0.4
-0.6 -0.5 -0.53

-0.57
-0.62
-0.8 -0.69 -0.65 -0.67‡ -0.64 -0.65
-0.72 -0.74
-0.83
-1
*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. 4
Weight Change
Absolute Change from Baseline
1 0.68 0.8 0.8

0.5 0.27
 Weight (kg)
NR NR
0
-0.22 -0.1
-0.5 -0.3 -0.4
-1 -0.87
-1.5
-1.5
-2
NR, value not reported.

*SU + metformin. †With or without metformin.
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. 5
Hypoglycemia with DPP4 Inhibitors
Percentage of Patients Reporting Hypoglycemia
25 22.7
20
Patients (%)
14.6
15 12.2
9.6
10
5.2 4.9 5.2
5
1.5 0.6 1.3
0.3 0
0
NR, value not reported.

*SU + metformin. †With or without metformin.
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. 6
Safety Considerations
GI adverse
• Minimal
events
• 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
Pancreatitis 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
• Extensive review by FDA of studies involving >80,000 patients has not uncovered
Pancreatic reliable evidence of increased pancreatic risk with incretins vs other agents
cancer • Further assessments required from long duration-controlled studies or
epidemiological databases
• Kidney function monitoring and dose reduction required for alogliptin, saxagliptin,
Renal and sitagliptin when used in patients with moderate-to-severe renal impairment
impairment • Linagliptin does not require dose adjustment or periodic monitoring of drug-related
kidney function
• Potentially increased risk of congestive heart failure hospitalization with alogliptin

CHF and saxagliptin
Garber AJ, et al. Endocr Pract. 2016;22:84-113. White W, et al. N Engl J Med. 2013;369:1327-1335. Scirica BM, et al. Circulation. 2014;130:1579-
1588. 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. 7
Glucose Control With Alogliptin
Monotherapy Initial Combo Add-on to Add-on to Add-on to Add-on to
26 Weeks1 w/ Pioglitazone Metformin Glyburide Met + Pio Insulin +/- Met
26 Weeks2 26 Weeks3 26 Weeks4 52 Weeks5 26 Weeks6
N 329 655 527 500 803 390
Treatment PBO Alo Pio Alo Alo + Met Alo + Gly Alo + Met+ Alo+ Ins+/- Alo+
Pio Met Gly Pio Met+ Met Ins+/-
Pio 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
(%)
0.5
0.01
0
 A1C (%)
-0.02 -0.1 -0.13

-0.5 -0.29
-0.59 -0.6 -0.53
-0.7 -0.71
-1
* -0.96 * * * *
-1.15
-1.5
-2 -1.71
*
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. 8
Weight Change With Alogliptin
26 Weeks1 w/ Pioglitazone Metformin Glyburide Met + Pio Insulin +/- Met
N 329 655 527 500 803 390
Treatment PBO Alo Pio Alo Alo + Met Alo + Gly Alo + Met+ Alo+ Ins+/- Alo+
Pio Met Gly Pio Met+ Met Ins+/-
Pio Met
3.5 3.14
3
 Weight (kg)
2.5 2.19
2 1.6
1.5
1
*
0.68
1.1
0.6 0.6
0.5 0.18
0
0
-0.5 -0.22 -0.29 -0.3 -0.2
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. 9
Hypoglycemia With Alogliptin
Monotherapy Add-on to Add-on to Add-on to Add-on to
26 Weeks1,2 Metformin Glyburide Met + Pio Insulin +/- Met
26 Weeks3 26 Weeks4 52 Weeks5 26 Weeks6
N 329 527 500 803 390
Treatment PBO Alo Met Alo + Gly Alo + Met+ Alo+ Ins+/- Alo+
Met Gly Pio Met+ Met Ins+/-
Pio Met
30 27.1
Patients Reporting
Hypoglycemia (%)
24
25
20
15
11.1
9.6
10
4.5
5 3
1.6 1.5 1.5
0
0
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. 10
Alogliptin: Adverse Events
Adverse Events* Patients (%)
Active
Alogliptin 25 mg Placebo comparator
(n=5902) (n=2926) (n=2257)
Nasopharyngitis 4.4 3.0 5.0
Headache 4.2 2.5 5.4
Upper respiratory
4.2 2.1 5.0
tract infection
*Occurring in ≥4% of patients receiving alogliptin 25 mg and more commonly than in
placebo-treated patients.
Nesina (alogliptin) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2013. 11
Glucose Control With Linagliptin
Monotherapy Initial Combo Initial Combo Add-on to Add-on to Add-on to
24 Weeks1 w/ Metformin w/ Pioglitazone Metformin Metformin Metformin +
24 Weeks2 24 Weeks3 24 Weeks4 2 Years5 SU
24 Weeks6
N 503 791 389 700 1552 1055
Treatment PBO Lin Lin Met Lin + Lin + Pio Lin + Met Lin + Glim + Lin + Met + Lin +
HD Met Met Pio Met Met Met SU Met +
LD HD 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
(%)
0.5 0.25 0.15
0
 A1C (%)
-0.1
-0.5 -0.21
-0.44 -0.5 -0.49 -0.41
-0.56
-0.72
-1 * *
-1.5
-1.1 -1.2 -1.06
*
-1.6
*
-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.
12
Weight Changes With Linagliptin
Initial Combo w/ Initial Combo Add-on to Add-on to
Metformin w/ Pioglitazone Metformin Metformin
24 Weeks1 24 Weeks2 24 Weeks3 2 Years4
N 791 389 700 1552
Treatment Lin Met Lin + Lin + Pio Lin + Met Lin + Glim Lin +
HD Met Met Pio Met + Met Met
LD HD
2.5 2.3
2
1.5 1.2 1.3
 Weight (kg)
1
0.5 0.2
0
-0.5 -0.1
-0.5 -0.5 -0.4
-1 -0.8
-1.5
-1.4
-2
*
* 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. 13
Hypoglycemia With Linagliptin
Monotherapy Initial Combo Initial Combo Add-on to Add-on to Add-on to
24 Weeks1 w/ Metformin w/ Pioglitazone Metformin Metformin Metformin +
24 Weeks2 24 Weeks3 24 Weeks4 2 Years5 SU
24 Weeks6
N 503 791 389 700 1552 1055
Treatment PBO Lin Lin Met Lin + Lin + Pio Lin + Met Lin + Glim + Lin + Met + Lin +
HD Met Met Pio Met Met Met SU Met +
LD HD SU
40 36
Patients Reporting
Hypoglycemia (%)
35
30
25 22.7
20
14.8
15
10 7
5 3.4 3.5 2.8
0.6 0.3 0 0 0 1.2 0.6
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. 14
Linagliptin: Adverse Events
Patients (%)
Linagliptin 5 mg Placebo
Adverse Events* (n=3625) (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.
Tradjenta (linagliptin) prescribing information. Ridgefield, CT: Boehringer Ingelheim, Inc.; 2014. 15
Glucose Control With Saxagliptin
24 Weeks1 w/ Metformin Metformin Metformin Glyburide vs TZD
24 Weeks2 24 Weeks3 18 Weeks4 Uptitration 24 Weeks6
24 Weeks5
N 401 1306 743 801 768 565
Treatment PBO Sax Met Sax + Met Sax + Sit + Sax + Gly Sax + TZD Sax +
Met Met Met Met Gly 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
0.5 0.19 0.13 0.08

0
-0.5
 A1C (%)
-0.3
-0.46
-1 -0.69 -0.62 -0.52 -0.64
-1.5 * * *
-0.94
-2
*
-2
-2.5
-2.5
-3
*
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
16
al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.
Weight Changes With Saxagliptin
24 Weeks5
N 401 1306 743 801 768 565
2
1.4
1.5
1
*
0.8 0.9
Weight (kg)
0.5 0.3
0
-0.5 -0.1
-0.4 -0.4
-1
-0.92 -0.87
-1.5
-1.4
-2 -1.6
-1.8
*P=0.01 vs glyburide uptitration.

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. 17
Hypoglycemia With Saxagliptin
24 Weeks5
N 401 1306 743 801 768 565
16 14.6
Patients Reporting
Hypoglycemia (%)
14
12
10.1
10
8 6.3
6 5.2 5 5.2
4 3.4 3.8
4 2.8 3.2 2.7
2
0
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. 18
Saxagliptin: Adverse Events
Adverse Events* Patients (%)

Saxagliptin 5 mg Placebo
Headache 6.5 5.9
Upper respiratory 7.7 7.6
tract infection
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. 19

Glucose Control With Sitagliptin
vs Glipizide w/ Metformin Metformin Insulin Pioglitazone vs Rosiglitazone +
52 Weeks1 24 Weeks2 24 Weeks3 24 Weeks4 Met + Pio Metformin
12 Months5 54 Weeks6
N 1172 1091 701 641 151 278
Treatment Glip Sit Met Sit Sit+ Met Sit+ Ins Sit+ Met + Sit + Rosi + Sit +
Met Met Ins Pio Pio Met 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
(%)
0.0
0
-0.02
-0.5 -0.3
 A1C (%)
-0.7 -0.7 -0.7 -0.7 -0.6

-1
* *
-1.13 -1.1
-1.5 -1.4 -1.4 †
-2 -1.9
†P<0.001
*
*P<0.001 vs active comparator monotherapy. 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. 20
Weight Changes With Sitagliptin
Monotherapy Monotherapy Add-on to Add-on to Add-on to Add-on to Pio
24 Weeks1 52 Weeks2 Pioglitazone Glimepiride Insulin vs Met + Pio
24 Weeks3 24 Weeks4 24 Weeks5 12 Months6
N 741 793 353 441 641 151

Treatment PBO Sit Glip Sit Pio Sit + Glim Sit + Ins Sit + Met + Sit +
Pio Glim Ins Pio Pio
3
1.8
2 1.5
 Weight (kg)
1.1
0.8
1
0.1 0.1
0
-0.2 -0.4
-1
-1.1
-2 -1.5 -1.6
-3 * -2.8
-4 †
*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. 21
Hypoglycemia With Sitagliptin
Sitagliptin vs Initial Combo Add-on to Add-on to Add-on to Add-on to
Glipizide w/ Metformin Metformin Pioglitazone Glimepiride Insulin
52 weeks1 24 Weeks2 24 Weeks3 24 Weeks4 24 Weeks5 24 Weeks6
N 793 1091 701 353 441 641
Treatment Glip Sit PBO Met Sit + Met Sit + Pio Sit + Glim Sit + Sit + Ins Sit +
Met Met Pio Glim Glim + Ins
Met
35 32
30
Patients Reporting
Hypoglycemia (%)
25
20 16.4 16.0
15
10 7.5 8.0
4.9
5 2.2 2.1 1.3 2.8
0.6 1.1 0 1.1
0
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. 22
Selected Adverse Events With
Sitagliptin: Pooled Data
Incidence per 100 patient-years

Adverse Event Sitagliptin 100 mg Nonexposed Difference (95% CI)
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
8.6 9.0 -0.3 (-1.6, 1.0)
tract infection
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. 23
GLP1 RECEPTOR AGONISTS
24
GLP1 Receptor Agonists

• Albiglutide • Injectable administration
• Dulaglutide • Mimic action of native
• Exenatide GLP1
• Exenatide ER • Increase glucose-
• Liraglutide dependent insulin
secretion
• Lixisenatide
• Suppress glucagon
production
• Slow gastric emptying
ER, extended release; GLP1, glucagon-like peptide 1.

Garber AJ, et al. Endocr Pract. 2016;22:84-113. 25
Glucose Control
with GLP1 Receptor Agonists

Alb1 Dul2 Exe3 Exe Lir5 Lix6 Alb7 Dul8 Exe9 Exe Lir11 Lix12 Alb13, Exe14 Exe Lir16
ER4 ER10 * ER15,†
Baseline A1C (%) 8.1 7.6 7.8 8.5 8.3 8.0 8.1 8.1 8.2 8.6 8.4 8.0 8.2 8.6 8.3 8.5
0
Placebo-adjusted
-0.5 -0.4
 A1C (%)
-0.54
-1 -0.8‡ -0.7 -0.8‡
-0.9 -0.9 -1.0
-1.0
-1.1‡
-1.5 -1.4 ‡ -1.4
-1.5‡ -1.5‡ -1.5‡ -1.5‡
-2
*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. Fonseca VA, et al. Diabetes Care. 2012;35:1225-1231. 7. Ahrén B, et al.
Diabetes Care. 2014;37:2141-2148. 8. Dungan KM, et al. Lancet. 2014;384:1349-1357. 9. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100.
10. Bergenstal RM, et al. Lancet. 2010;376:431-439. 11. Pratley RE, et al. Lancet. 2010;375:1447-1456. 12. Rosenstock J, et al. Diabetes Care.
2013;36:2945-2951. 13. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 14. Buse JB, et al. Diabetes Care. 2004;27:2628-2635.
15. Diamant M, et al. Lancet. 2010;375:2234-2243. 16. Marre M, et al. Diabet Med. 2009;26:268-278. 26
Weight Change with GLP1
Receptor Agonists

Alb1 Dul2 Exe3 Exe Lir5 Lix6 Alb7 Dul8 Exe9 Exe Lir11 Lix12 Alb13,* Exe14 Exe Lir16
ER4 ER10 ER15,†
0
-0.2
-0.6
 Weight (kg)
-1
-0.9
-1.2
-2 -1.6
-2 -2
-2.3 -2.3
-3 -2.5 -2.6 -2.6
-2.8 -2.96
-3.1
-3.4
-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. Fonseca VA, et al. Diabetes Care. 2012;35:1225-1231. 7. Ahrén B, et
al. Diabetes Care. 2014;37:2141-2148. 8. Dungan KM, et al. Lancet. 2014;384:1349-1357. 9. DeFronzo RA et al. Diabetes Care. 2005;28:1092-
1100. 10. Bergenstal RM, et al. Lancet. 2010;376:431-439. 11. Pratley RE, et al. Lancet. 2010;375:1447-1456. 12. Rosenstock J, et al. Diabetes
Care. 2013;36:2945-2951. 13. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 14. Buse JB, et al. Diabetes Care. 2004;27:2628-
2635. 15. Diamant M, et al. Lancet. 2010;375:2234-2243. 16. Marre M, et al. Diabet Med. 2009;26:268-278. 27
Hypoglycemia with GLP1
Receptor Agonists
Alb1 Dul2 Exe3 Exe Lir5 Lix6 Alb7 Dul8 Exe9 Exe Lir11 Lix12 Alb13,* Exe14 Exe Lir16
ER4 ER10 ER15,†
40 36
35
Patients (%)
30
25
20
15 12.3 13.0
9 10.4
10 8 8.1
4.0 5.2 2.5 3
5.0
3 2.5
5 0 1
0
*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. Fonseca
VA, et al. Diabetes Care. 2012;35:1225-1231. 7. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 8. Dungan KM, et al. Lancet. 2014;384:1349-
1357. 9. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 10. Bergenstal RM, et al. Lancet. 2010;376:431-439. 11. Pratley RE, et al. Lancet.
2010;375:1447-1456. 12. Rosenstock J, et al. Diabetes Care. 2013;36:2945-2951. 13. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-
297. 14. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 15. Diamant M, et al. Lancet. 2010;375:2234-2243. 16. Marre M, et al. Diabet Med.
2009;26:268-278. 28
A1C Reductions With GLP1 RAs
Head-to-Head Trials
Exenatide BID
Exenatide BID Exenatide BID vs Liraglutide vs Liraglutide vs Liraglutide vs
vs lixisenatide vs liraglutide exenatide OW albiglutide4
1 2 3 dulaglutide5 exenatide OW6
634 464 295 841 599 912
Exe Lix Exe BID Lir Exe BID Exe OW Lir Alb Lir Dul Lir Exe OW
Baseline A1C 8.0 8.0 8.1 8.2 8.3 8.3 8.2 8.2 8.1 8.1 8.4 8.5
(%)
0
-0.5
 A1C (%)
-1 -0.8 -0.79 -0.79

-0.95 -0.98 Not
NI -1.12
-1.5 P<0.0001
NI -1.36 -1.28
-1.5 -1.42 -1.48
NI P=0.02
-2 -1.9
P=0.002
BID, twice daily; OW, once weekly (extended release); NI, noninferior; Not NI, not noninferior.
1. Rosenstock J, et al. Diabetes Care. 2013;36:2945-2951. 2. Buse JB, et al. Lancet. 2009;374:39-47. 3. Drucker DJ, et al. Lancet. 2008; 372:1240-
1250. 4. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 5. Dungan KM, et al. Lancet. 2014;384:1349-1357. 6. Buse JB, et al.
Lancet. 2013;381:117-124. 29
Weight Reductions With GLP1 RAs
Head-to-Head Trials
Exenatide BID
634 464 295 841 599 912
0
 Weight (kg)
-1 -0.64
-2
-3 -2.19
-2.96 -2.87 P<0.0001 -2.9 -3.03
-4 -3.24
-3.6 -3.7 -3.61
-3.98 -3.94
-5 P=0.011
BID, twice daily; OW, once weekly (extended release)

Lancet. 2013;381:117-124. 30
Systolic BP Reductions With GLP1
Receptor Agonists
Head-to-Head Trials
Exenatide BID
634 464 295 841 599 912
 Systolic BP (mmHg)
0
<1 <1
-1
-2
-2
-3 -2.5 -2.51 -2.48
-2.9 -2.82
-4 -3.4 -3.36 -3.45
-5 -4.7
BID, twice daily; BP, blood pressure; OW, once weekly (extended release).
Lancet. 2013;381:117-124. 31
Nausea Rates With GLP1 Receptor
Agonists
Percentage of Patients Reporting Nausea in Head-to-Head Trials
Exenatide BID
40 35.1 34.5
35 P<0.05
P<0.05 29.2
30 28 26.4
25.5
Patients (%)
24.5
25 20 21
20 18
P<0.0001
15
9.9 9
10
5
0
BID, twice daily; OW, once weekly (extended release).

Lancet. 2013;381:117-124. 32
with GLP1 Receptor Agonists
• Common
GI adverse
• Usually dose dependent and transient
events • Usually reduced with dose titration
• 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
Pancreatitis increased pancreatic risk with incretins vs other agents
• Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected
• Labeling for GLP1 receptor agonists suggests consideration of other therapies for patients with a history of
pancreatitis
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of
Pancreatic
increased pancreatic risk with incretins vs other agents
cancer • Further assessments required from long duration-controlled studies or epidemiological databases
• Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but
confirmatory population studies are lacking
Medullary • Labeling for albiglutide, dulaglutide, exenatide ER, and liraglutide:
thyroid • Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid
cancer tumors
• Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia
syndrome type 2
• Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea,
Renal or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide
impairment should not be used in patients with severe renal insufficiency or ESRD. Liraglutide was found to be safe in
patients with moderate renal impairment and may confer a beneficial effect.
ER, extended release.
Garber AJ, et al. Endocr Pract. 2016;22:84-113. 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. Davies MJ, et al. Diabetes Care. 2016;39:222-230.
33
Marso SP, et al. N Engl J Med. 2016;375:311-322.
Glucose Control With Albiglutide
Monotherapy vs Add-on to Add on to Pio +/- Add-on to Add-on to Add-on to
Placebo Metformin Met Met +/- SU +/- TZD Met +/- SU Basal Insulin
52 Weeks1 104 Weeks2 52 Weeks 3 32 Weeks4 52 Weeks5 26 Weeks6
N 296 1049 310 841 779 586
Treatment† PBO Alb Met Glim Sit+ Alb Pio+/- Alb 30 Lir Alb Glar Alb Lispro Alb 50
50 + Met 50 Met mg+ 50 30 mg
mg Met mg+ Pio+/- mg mg
Met Met
Baseline 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
A1C (%)
0.4 0.27
0.2
0.2
0
 A1C (%)
-0.2 -0.1
-0.4 -0.28
-0.36
-0.6
-0.8 -0.63 -0.67 -0.66
-0.80 -0.79 -0.79
-1 -0.90 * -0.82
-1.2 ** * -0.98
*
*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.
34
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.
Weight Change With Albiglutide
52 Weeks1 104 Weeks2 52 Weeks3 32 Weeks4 52 Weeks5 26 Weeks6
N 296 1049 310 841 779 586
Treatment‡ PBO Alb Met Glim Sit+ Alb Pio+/- Alb 30 Lir Alb Glar Alb Lispro Alb 50
50 + Met 50 Met mg+ 50 30 mg
2 Met Met
1.6
1.2
 Weight (kg)
1 0.8
0
-0.2
-1 -0.7
† -0.6 -0.7
-0.9 -1 -0.9
-1.21 -1.1
-2
* *
* -2.2
-3
**
*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.
35
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.
Blood Pressure Change With
Albiglutide
Add-on to Metformin Add-on to Add-on to Met +/- SU
104 Weeks1 Met +/- SU +/- TZD 52 Weeks3
32 Weeks2
N 1049 841 779
Treatment Met Glim + Sit + Alb Lira+ Alb Glar Alb
Met Met 50 mg+ Met+/- 50 mg+ 30 mg
Met SU Met+/-
SU
2.5 2.2
2
1.5
1.5
1
0.5 0.20 0.3
0
-0.5
Decrease of
-1
-1 <1 mmHg in
-1.5
both groups -1.40
-2
1. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 2. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297.
36
3. Weissman PN, et al. Diabetologia. 2014;57:2475-2484.
Hypoglycemia With Albiglutide
N 296 1049 310 841 779 586

Treatment‡ PBO Alb Met Glim Sit+ Alb Pio+/- Alb 30 Lir Alb Glar Alb Lispro Alb 50
50 + Met 50 Met mg+ 50 30 mg
symptomatic hypoglycemia (%)
Met Met
Patients with documented
35
29.9
30 27.4
25
20 17.9 17.5
15.8
15 13.0
10.4
10
4 3.3
5 2.0 1.7 3 1.3
0.0
0
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.
37
2014;57:2475-2484. 6. Rosenstock J, et al. Diabetes Care. 2014;37:2317-2325.
Albiglutide: Adverse Events
Patients (%)
Albiglutide Placebo
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. 38
Glucose Control With Dulaglutide
Monotherapy Monotherapy Add-on to Add-on to Add-on to Add-on to
52 Weeks1 52 Weeks2 Metformin Pio + Met Met + SU Lispro
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
-0.5 -0.39
 A1C (%)
-0.56 -0.63
-1 -0.78 -0.8
** -1.1 -1.08
-1.5
*** -1.36 -1.42 -1.36
*** -1.41
-2
*** -1.64
*
*P<0.02 vs glargine. **P<0.01 vs metformin. ***P<0.001 vs comparator.
†Alldulaglutide 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 Care. 2015;38:2241-2249.
6. Blonde L, et al. Lancet. 2015:385:2057-2066. 39
Weight Reduction With
Dulaglutide
N 807 1098 599 976 807 884
3 2.33
2
 Weight (kg)
1.44
1
0
-1
-1.07 -0.87
-2 -1.53 -1.3
-3 -2.22 -2.29 -2.43 -2.56

-1.87 *
-4
-3.03 *
**
*P<0.05 vs glargine. **P<0.001 vs sitagliptin.
Dulaglutide
Monotherapy Monotherapy Add-on to Metformin Add-on to Pio + Met
N 807 1098 599 976
Treatment† Met Dul Sit Dul Lir Dul Exe Dul
2
0.83
1
0.02
0
-0.1
-1 -0.5
-0.8
-1
-2
-3 -2.8
-3.26
-4

2014;384:1349-1357. 4. Wysham C, et al. Diabetes Care. 2014;37:2159-2167. 41
Hypoglycemia With Dulaglutide

N 807 1098 599 976 807 884
events/patient per year

20 50
hypoglycemia (%)
Patients reporting
15.9 39.9
Hypoglycemia
15
40
*
12.7 12.3
10.2
*
10.4 30
31
10 9
6 20
4.8
5
10 7.9
5.2
*
0 0
*P<0.01 vs comparator. †All dulaglutide dosages shown are 1.5 mg once weekly.
Dulaglutide: Adverse Events
Patients (%)
Dulaglutide 1.5 mg Dulaglutide 0.75 mg Placebo
Adverse Events* (n=834) (n=836) (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. 43
Glucose Control With Exenatide
Monotherapy Add-on to Add-on to Add-on to TZD Add-on to Add-on to Met +
24 Weeks1 Metformin Sulfonylurea 16 Weeks4 Metformin + SU SU vs Glargine
N 233 336 377 233 733 551
Treatment† PBO Exe Met Exe + SU Exe + TZD Exe + Met + Exe + Glar + Exe +
Met SU TZD SU Met + Met + Met +
SU SU 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
0.5
0.2
0.1 0.12 0.09
0
 A1C (%)
-0.2
-0.5
-1 -0.8 -0.86
-0.9 -0.89 -0.9
* * * * * -1.1 -1.1
-1.5
*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. 44
Weight Reduction With Exenatide
Monotherapy Add-on to Add-on to Add-on to TZD Add-on to Add-on to Met +
24 Weeks1 Metformin Sulfonylurea 16 Weeks4 Metformin + SU SU vs Glargine
N 233 336 377 233 733 551
Treatment† PBO Exe Met Exe + SU Exe + TZD Exe + Met + Exe + Glar + Exe +
Met SU TZD SU Met + Met + Met +
SU SU SU
3
1.8
2
 Weight (kg)
1
0
-0.3 -0.24
-1 -0.6
-0.9
-2 -1.4 -1.6 -1.6
-1.75
-3
-3.1
-2.8 * * *
-2.3
-4
* **
*
*P<0.05 vs comparator. **P<0.0001 vs glargine.
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. 45
Blood Pressure Changes With
Exenatide
Monotherapy
24 Weeks
N 233
Treatment PBO Exe 10 μg BID
0
-0.5 -0.3
-1
 Systolic BP
-1.5
(mmHg)
-2
-2.5
-3
-3.5
-4 -3.7
*
*P<0.05 vs placebo.
Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 46
Hypoglycemia With Exenatide
Monotherapy Add-on to Metformin Add-on to Add-on to TZD
24 Weeks1 30 Weeks2 Sulfonylurea 16 Weeks4
30 Weeks3
N 233 336 377 233
Treatment† PBO Exe Met Exe + SU Exe + TZD Exe +
Met SU TZD
40 36
35
Patients Reporting
Hypoglycemia (%)
30
25
20
15
10.7
10 7.1
4 5 5
5 3
1
0

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. 47
Exenatide: Adverse Events
Patients (%)
Monotherapy + Met and/or SU + TZD +/- Met
Exe PBO Exe PBO Exe PBO
Adverse Events* (n=155) (n=77) (n=963) (n=483) (n=121) (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 . 48
Glucose Control With Exenatide ER
Add-on to Monotherapy vs Add-on to Add-on to Add-on to
OAs* OAs Metformin Met +/- SU OAs†
N 258 820 514 456 911
Treatment Exe Exe Sit Pio Met Exe Sit+ Pio+ Exe Glar Exe Lira Exe ER
BID ER ER Met Met ER+ + ER + + +
Met OAs OAs OAs OAs
Baseline 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
A1C (%)
0
-0.5
 A1C (%)
-1 -0.9
-1.15 -1.20
-1.5 -1.3 -1.28
-1.5 -1.48-1.53 -1.5 -1.50 -1.48
-1.63
P=0.02
-2 -1.90 P<0.0001
P=0.017
P<0.01 P<0.001
*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. 49
Weight Reduction With Exenatide ER
N 258 820 514 456 911
Treatment Exe Exe Sit Pio Met Exe Sit+ Pio+ Exe Glar Exe Lira Exe
(mg/day) BID ER ER Met Met ER+ + ER + + ER +
Met OAs OAs OAs OAs
4
2.8
3
1.5
 Weight (kg)
2 1.4
1
0
-1
-0.8 -0.8
-2
-3 -2.0 -2.0 -2.3 -2.6 -2.7
-4 -3.6 -3.7 -3.6
-5 P<0.0001
P<0.001 P<0.001

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.
50
Hypoglycemia With Exenatide ER

N 258 820 514 456 911
Treatment Exe Exe Sit Pio Met Exe Sit+ Pio+ Exe Glar Exe Lira Exe
BID ER ER Met Met ER+ + ER + + ER +
Met OAs OAs OAs OAs
35 31.0
hypoglycemia (%)
Patients reporting
30
25
20
15 13.0
11.0
8.9
10 6.1 5.4 5.2
5 3.1 3.7 4.1 3.0
1.0 1.0
0

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. 51
Exenatide Extended Release:
Adverse Events
Patients (%)
Adverse Monotherapy + Met + Met +/- SU
Events*
Exe ER Sit Pio Met Exe ER Sit Pio Exe ER Glar
(n=248) (n=163) (n=163) (n=246) (n=160) (n=166) (n=165) (n=233) (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
10.5 6.7 3.7 10.2 5.0 4.8 1.2 6.0 0
reaction
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. 52
Glucose Control With Liraglutide
Monotherapy vs Add-on to Add-on to Add-on to Add-on to Add-on to
Glimepiride Metformin Metformin Sulfonylurea Met + TZD Met + SU
N 746 1091 665 1041 821 581
Treatment† Glim Lir Met Glim Lir+ Sit+ Lir+ SU Rosi Lir+ Rosi Lir+ Met+ Glar+ Lir+
+ Met Met Met + SU + Rosi+ SU Met+ Met+
Met SU Met Met SU SU
Baseline 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
A1C (%)
0.5 0.23
0.09
0
 A1C (%)
-0.5 -0.24
-0.51 -0.44 -0.5
-1 -0.9
-0.98 -1.00 -1.09
-1.14 -1.13
-1.5
* * -1.50 * -1.50
-1.33
** **
-2
** ** ***
*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. 53
Weight Reduction With Liraglutide
N 746 1091 665 1041 821 581
3 ***
2.10
2 1.60
 Weight (kg)
1.10 1.00
1 0.60
0
-1 -0.10 -0.20 -0.42
-0.96
-2 -1.50 * -1.80
-2.00
-3 -2.50
-4
-2.80
-3.38 * *
* *
** *
*P<0.0001 vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU.
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. 54
Blood Pressure Changes
With Liraglutide
52 Weeks1 26 Weeks2 26 Weeks3 26 Weeks4,5 26 Weeks6 26 Weeks7
N 746 1091 665 1041 821 581

1 0.4 0.5
0
 Systolic BP
-1 -0.7 -0.9 -0.7

(mmHg)
-0.9 -1.1
-2 -1.8
-3 -2.3 -2.3
-2.8
-4 -3.6 * -4.0
-5
-6
* *
-5.6
*P<0.05 vs comparator.
*
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 55
Hypoglycemia With Liraglutide
Monotherapy Add-on to Metformin Add-on to Metformin Add-on to Sulfonylurea
N 746 1091 665 1041
Treatment† Glim Lir Met Glim+ Lir+ Sit+ Lir+ SU Rosi+ Lir+
Met Met Met Met SU SU
30
Patients Reporting
Hypoglycemia (%)
24
25
20 17
15
10
*8 *
8.1
5 3
*3 5 5
2.6
4.3
*P<0.01 vs active comparator.

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. 56
Liraglutide: Adverse Events
Patients (%)
Monotherapy + Met + Glim + Met + TZD
Adverse Lir Glim Lir PBO Lir PBO Lir PBO
Events* (n=497) (n=248) (n=724) (n=121) (n=695) (n=114) (n=355) (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. 57
Glucose Control With
Lixisenatide
Add-on to
Titrated
Add-on to Glargine+OAs
Add-on to Add-on to Add-on to Stable (Insulin-Naïve
Monotherapy Metformin Metformin Pioglitazone Glargine±Met Patients)
N 361 484 639 484 495 446
Treatment† PBO Lix Met Lix+ Exe BID Lix+ Pio Lix+ Glar Lix+ Glar Lix+
Met + Met Met Pio Glar Glar
Baseline 8.1 8.0 8.0 8.1 8.0 8.0 8.1 8.1 8.4 8.4 7.6 7.6
A1C (%)
0
-0.2
 A1C (%)
-0.4 -0.27
-0.34
-0.4 -0.4 -0.4
-0.6
-0.8 -0.73 -0.7 -0.7
-0.8 -0.79
-1 P<0.0001 -0.9 P=0.0002 P<0.0001
-1.2
P<0.0001 -0.96
* P<0.0001
*Noninferiority criteria met.

†All lixisenatide dosages shown are 20 g QD, administered in a 2-step dose increase regimen.
1. Fonseca VA, et al. Diabetes Care. 2012;35:1225-1231. 2. Bolli GB, et al. Diabet Med. 2014;31:176-184. 3. Rosenstock J, et al. Diabetes Care.
2013;36:2945-2951. 4. Pinget M, et al. Diabetes Obes Metab. 2013;15:1000-1007. 5. Riddle MC, et al. Diabetes Care. 2013;36:2489-2496.
6. Riddle MC, et al. Diabetes Care. 2013;36:2497-2503. 58
Weight Reduction With Lixisenatide
Add-on to
Titrated
N 361 484 639 484 495 446
2 1.2 P=0.0012
1 0.3
 Weight (kg)
0.2
0
-1 -0.2 -0.5
-2 -1.6
-2 -2 -1.8
-3 -2.7 P<0.0001
-2.96
-4 P<0.01 -3.98
-5
Hypoglycemia With Lixisenatide
Add-on to
Titrated
N 361 484 639 484 495 446
Patients Reporting
Hypoglycemia (%)
30 26.5
25 21 20.2
20
15 11.7
10 7.9
P<0.05
5 2.5 2.5 2.5 3.4
1.6 0.6 1.2
0
Lixisenatide: Adverse Events
Patients (%)
Placebo Lixisenatide
Nausea 6 25
Vomiting 2 10
Headache 6 9
Diarrhea 6 8
Dizziness 4 7
*Occurring in ≥5% of patients receiving lixisenatide.
Adlyxin (lixisenatide) injection prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC. 2016. 61
SGLT2 INHIBITORS
62
SGLT2 Inhibitors

• Canagliflozin • Oral administration
• Dapagliflozin • Inhibit reabsorption of
• Empagliflozin glucose into the
bloodstream from renal
fluid
SGLT2, sodium-glucose cotransporter 2.

DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14. 63
Glucose Control
with SGLT2 Inhibitors
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
(%)
0
-0.2
Placebo-adjusted
-0.4
 A1C (%)
-0.4 -0.46
-0.6 -0.52* -0.57
-0.8 -0.66 -0.64
-1 -0.86
-0.9*
-1.2
-1.2
-1.4
*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. 64
Weight Change

0
-0.5
-1
 Weight (kg)
-1.5
-1.4
-2 -1.6
-2.5 -2.04
-2.48 -2.46
-3
-3.5 -3.2 -3.2
-3.4
-4
-4.5 -4.0
Hypoglycemia with SGLT2 Inhibitors

70
58.2
60 53.6
51.2
50
Patients (%)
40
30
20
10 3.0 2.9 5.0 3.4
<1 1.4
0
Genitourinary
• Increased incidence; patients should be monitored and treated if necessary
infection
Increased LDL-C • Small increases in LDL-C have been observed in clinical trials
• Increased incidence of bladder cancers in patients receiving dapagliflozin
Bladder cancer • 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 • Monitor kidney function during therapy, especially in patients with GFR <60
impairment mL/min/1.73 m2
• Increased incidence of bone fractures in canagliflozin and dapagliflozin clinical
Bone fractures trials
• Canagliflozin labeling includes specific warning about bone fractures
• Potentially increased risk of diabetic ketoacidosis in patients with insulin
DKA deficiency and/or those undergoing acute metabolic stress
Garber AJ, et al. Endocr Pract. 2016;22:84-113. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company.
2015. Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015. Jardiance (empagliflozin) prescribing
information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2015. Handelsman Y, et al. Endocr Pract. 2016;22:753-762. 67
Glucose Control With Canagliflozin
Add-on to
Add-on to Add-on to Add-on to OAs +/- Insulin
Monotherapy Metformin Metformin Metformin + SU in CKD†
N 584 451 1452 755 269
Treatment* PBO Can Met Sit + Can + Glim + Can + Sit+ Can+ Ins + Can +
(mg/day) Met Met Met Met Met+ Met+ OAs Ins +
SU SU 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
(%) 0.14
0.2
0
 A1C (%)
-0.2 -0.03
-0.4 -0.22
-0.6 -0.44
-0.8 -0.66 **
-0.74 -0.81
-1 -0.92 -0.93
-1.03 ** -1.03
-1.2 **
** ‡
*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. 68
Weight Change With Canagliflozin
Add-on to
N 584 451 1452 755 269
SU SU OAs
1 0.7
0.1 0.2
0
 Weight (kg)
-1 -0.5 -0.5
-0.9
-2 -1.4
-3 -2.3 **
-4 -3.4
-3.0 **
** -4.0
-5 **
**

**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. 69
Canagliflozin
Add-on to
N 584 451 1452 755 269
SU SU OAs
2 0.9
0.4 0.2
 Systolic BP
0
-0.3
(mmHg)
-2 -1.3 -0.8
-4 -3.6
-5.0 -4.6
-6 -5.1
-8
** ** -6.4

**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. 70
Hypoglycemia With Canagliflozin
Add-on to
N 584 451 1452 755 269
SU SU OAs
60
51.2
hypoglycemia (%)
Patients reporting
50
40.7 43.2
40 34.0 36.4
30
20
10 3.0 2.0
5.0 5.0
2.6 0.0
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. 71
Canagliflozin: Adverse Events
Patients (%)
Adverse Events* Canagliflozin 100 mg Canagliflozin 300 mg Placebo
(n=833) (n=834) (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. 72
Glucose Control With Dapagliflozin
Initial Combo Add-on to
with Add-on to Add-on to Sitagliptin +/- Add-on to
Monotherapy Metformin Metformin Pioglitazone Metformin insulin + OAs
N 485 603 814 480 451 808
Treatment* PBO Dap Met Dap Dap + Glip Dap + Pio Dap + Sit+/- Dap+ Ins+/- Dap+
(mg/day) Met + Met Met Pio Met Sit+/- OAs Ins+/-
Met 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
(%)
0.5
0
0
 A1C (%)
-0.5 -0.23
-0.42 -0.50 -0.39
-0.52 -0.52
-1 -0.89 -0.97 *** -0.96
-1.5 *** -1.44-1.45 *** **
-2
-1.98
-2.5
***
*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.
73
Weight Change With Dapagliflozin
N 485 603 814 480 451 808
Met OAs
2 1.4 1.6
1
 Weight (kg)
0.4
0
-0.1 -0.3
-1
-1.4
***
-2 -1.6
-2.2 -2.1
-3 -2.7
**
-3.2 -3.3 -3.2 ***
-4
*** ***
**P<0.001 vs placebo. ***P<0.0001 vs comparator.
5. Jabbour SA, et al. Diabetes Care. 2014;37:740-750. 6. Wilding JPH, et al. Ann Intern Med. 2012;156:405-415. 74
Dapagliflozin
24 Weeks1 24 Weeks2 52 Weeks3 24 Weeks4 24 Weeks 5 24 Weeks6
N 485 603 814 480 451 808
Met OAs
2 1.3
0.8
 Systolic BP
0
(mmHg)
-2 -0.9
-1.2
-4 -3.6 -3.3 -3.4 -3.6

-4.0 -4.3
-6 -5.1
-6.0
-6.7
-8

Hypoglycemia With Dapagliflozin
with Add-on to Add-on to Sitagliptin+/- Add-on to
24 Weeks1 24 Weeks2 52 Weeks3 24 Weeks4 24 Weeks 5 24 Weeks6
N 485 603 814 480 451 808
Met OAs
60
51.8 53.6
hypoglycemia (%)
Patients reporting
50
39.7
40
30
20
10 2.9 2.9 0.9 3.3 3.4
2.7 0.7 0.0 1.8 2.7
0

Dapagliflozin: Adverse Events
Patients (%)
Adverse Events*
Dapagliflozin 5 mg Dapagliflozin 10 mg Placebo
(n=1145) (n=1193) (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.
Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company. 2014. 77
Glucose Control With Empagliflozin
Add-on to Add-on to Add-on to Add-on to Add-on to
Monotherapy Metformin Metformin Met + SU Pio +/- Met MDI insulin
N 899 638 1549 669 499 563
Treatment* PBO Sit Emp Met Emp Glim Emp + Met+ Emp+ Pio+/- Emp+ Ins Emp+
(mg/day) + Met + Met Met SU Met+ Met Pio+/- Ins
SU Met
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
(%)
0.5
0.08
0
 A1C (%)
-0.13 -0.17 -0.11

-0.5
-0.66 -0.55
-0.66 -0.72
-1 -0.78 -0.77 -0.77 -0.81
** ** *** ** **
-1.5 -1.27
**
*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. 78
Weight Change With Empagliflozin
N 899 638 1549 669 499 563
SU Met
2 1.6
1 0.34 0.44
 Weight (kg)
0.18
0
-0.33 -0.39
-1 -0.45
-2 -1.47
-2.48 -2.46 -2.39 ** -2.04

-3
** ** -3.10 ** **
-4 *** ***
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. 79
Blood Pressure Change
With Empagliflozin
N 899 638 1549 669 499 563
SU Met
 Systolic BP (mm Hg)
4
2.5
2
0.7 0.4 0.72
0
-0.4
-2 -1.4
-4 -3.10 -2.9
-3.50 -3.80
*** -4.00
-6 -5.00 -5.20 ** **
** **
***
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. 80
Hypoglycemia With Empagliflozin
N 899 638 1549 669 499 563
SU Met
70
59.0 58.2
hypoglycemia (%)
Patients reporting
60
50
40
30 25.0
20
11.5
8.4
10 4.0
<1 <1 <1 0.5 1.4 1.8 2.4
0

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. 81
Empagliflozin: Adverse Events
Patients (%)
Adverse Events*
Empagliflozin 10 mg Empagliflozin 25 mg Placebo
(n=999) (n=977) (n=995)
Female genital mycotic
5.4 6.4 1.5
infections
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.
Jardiance (empagliflozin) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2014. 82
NONINSULIN AGENTS: CLASS

COMPARISONS
83
Glucose Reduction
DPP4 Inhibitors, GLP1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin
(Absolute Changes from Baseline; Not Head-to-Head Trials)
DPP4 Inhibitors GLP1 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
0
-0.2
-0.4
 A1C (%)
-0.6 -0.5 -0.52

-0.6 -0.63
-0.8 -0.7 -0.7
-0.8 -0.77
-1 -0.93
-1.2
-1.4
-1.6 -1.42
-1.5 -1.5
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. 84
Weight Reduction
DPP4 Inhibitors, GLP1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin
(Separate Studies; Not Head-to-Head Trials)
DPP4 Inhibitors GLP1 Receptor Agonists SGLT2 Inhibitors

Alo1 Lin2 Sax3 Sit4 Alb5 Dul6 Exe7 Exe ER8 Lir9 Can10 Dap11 Emp12
0
-0.3 NR
-1 -0.4
-0.9
 Weight (kg)
-1.2
-2
-2.0
-3 -2.6 -2.5
-2.8 -2.8
-3.2
-4
-4.0
-5
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. 85
Effects of Antihyperglycemic
Therapies on Blood Pressure
Meta-analyses
∆ Systolic BP, mmHg ∆ Diastolic BP, mmHg
Class
(95% CI) (95% CI)
Newer therapies
-3.57 -1.38
GLP1 receptor agonists1 (-5.49 to -1.66) (-2.02 to -0.73)
-0.1 —
DPP4 inhibitors2 (-1.2 to 0.8)
-3.77 -1.75
SGLT2 inhibitors3
(-4.65 to -2.90) (-2.27 to -1.23)
Older therapies
-1.09 -0.97
Metformin4 (-3.01 to 0.82) (-2.15 to 0.21)
-4.70 -3.79
TZDs5 (-6.13 to -3.27) (-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. 86
INHALED INSULIN
87
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. 88

Glucose Control with
Inhaled Insulin
Add-on to Metformin and/or Other OAs

24 Weeks
Placebo Inhaled insulin
N 353
Baseline A1C (%) 8.3 8.3
0
-0.2
 A1C (%)
-0.4 *
-0.42
-0.6
-0.8
-0.82
-1 *
*Difference from placebo (95% CI): -0.40% (-0.57% to -0.23%).

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014. 89
Weight Change with
Inhaled Insulin

24 Weeks
Placebo Inhaled insulin
N 353
1
0.49
 Weight (kg)
0.5
0 *
-0.5
-1
-1.13
-1.5
Hypoglycemia with
Inhaled Insulin
24 Weeks
N 353
Nonsevere Severe
PBO II PBO II
80
Hypoglycemia (%)
67
Patients With
60
40 30
20
5.1
1.7
0
II, inhaled insulin.

with Inhaled Insulin
• 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
Lung disease
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
• Observe for signs and symptoms of fluid retention or heart failure,

Heart failure
especially when used with TZDs
Hypoglycemia • Increase frequency of glucose monitoring
Inhaled Insulin:
Adverse Events
Patients (%)
Adverse Events* Inhaled insulin Placebo Active comparators
(n=1991) (n=290) (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.
GLARGINE U-300
94
Glucose Control With
Glargine U-300
Add-on to OA, Insulin- Add-on to OA, Basal-Bolus
Naive Basal Insulin Users Insulin Regimen
6 Months1 6 Months2 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

0
-0.5
 A1C (%)
-0.56 -0.57
-1 -0.83 -0.83
-1.5 -1.42
-1.46
-2
1. Bolli GB, et al. Diabetes Obes Metab. 2015;17:386-394. 2. Yki-Järvinen H, et al. Diabetes Care. 2014;37:3235-3243.
Weight Change With
Glargine U-300
N 878 811 807
1 0.9 0.9
0.8 0.71
 Weight (kg)
0.66
0.6
0.49
0.4
P=0.015
0.2
0.08
0
Hypoglycemia With
Glargine U-300
N 878 811 807
100 79.3 88.6 83.4

Overall* 71.5
52.5 46.2
50
0
Nocturnal* 100
59.7
41.6 45.3
50 23.5 30.5
17.9
0
Severe* 10
5.7 5
0.9 0.9 1.5 1
0
*Percentage of patients reporting event.
Risk of Hypoglycemia With
Glargine U-300
Pooled Analysis of Phase III Trials
(N=2496)
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 1.00 1.50
Ritzel R, et al. Diabetes Obes Metab. 2015 Apr 30. doi: 10.1111/dom.12485. [Epub ahead of print]. 98
Insulin Dose With
Glargine U-300
N 878 811 807
1.2
0.92 0.97
1 0.88
 Insulin dose
0.84
(U/kg/day)
0.8
0.62
0.6 0.53
0.4
0.2
0
Baseline dose (U/kg/day) 0 0 0.66 0.64 0.67 0.67
with Glargine U-300
• Monitor potassium levels in at-risk patients and treat as

Hypokalemia
necessary
• Observe for signs and symptoms of fluid retention or heart

Heart failure
failure, especially when used with thiazolidinediones
Toujeo (glargine U-300) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC. 100
Glargine U-300: Adverse Events
Patients (%)
Adverse Events*
Type 1 diabetes Type 2 diabetes
(n=304) (n=1242)
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. 101
DEGLUDEC
102
Insulin Degludec
• Basal insulin analog

– No pronounced peak
– Duration of action >24 hours
Moghissi E et al. Endocr Pract. 2013;19:526-535. 103

Glucose Control With Degludec
Add-on to OA,
Add-on to OA, Basal-Bolus
Basal Insulin Users or
Insulin-Naive Insulin Regimen
Insulin-Naive
52 Weeks1 52 Weeks3
26 Weeks2
N 1030 687 744
Deg Glar Deg OD Deg OD Glar Deg Glar

Treatment
Flex
Baseline A1C (%) 8.2 8.2 8.4 8.5 8.4 8.3 8.4
0
-0.2
-0.4
 A1C (%)
-0.6
-0.8
-1
-1.2 -1.06 -1.07 -1.1
-1.19 -1.18
-1.4 -1.28 -1.26
Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h intervals between doses; Glar = glargine; OD =
once daily.
1. Zinman B, et al. Diabetes Care. 2012;35:2464-2471. 2. Meneghini L, et al. Diabetes Care. 2013;36:858-864.
3. Garber AJ, et al. Lancet Endocrinol. 2012;379:1498-1507. 104
Weight Change With Degludec
Add-on to OA,
Insulin-Naive
52 Weeks1 52 Weeks3
26 Weeks2
N 1030 687 744

Treatment
Flex
5
4
4 3.6
 Weight (kg)
3 2.4
2.1
2 1.6 1.5 1.3
1
once daily.
Hypoglycemia With Degludec
Add-on to OA,
Insulin-Naive
52 Weeks1 52 Weeks3
26 Weeks2
N 1030 687 744
Treatment
Flex
† 13.63
Overall* 15 11.09
10
5 3.6 3.6 3.5
1.52 1.85
0
Nocturnal* 2 † 1.84
1.39
1 † 0.6 0.6 0.8
0.25 0.39
0
Severe* 0.1
0.06 0.05
0.05 † 0.023
0.003 2 events 2 events 2 events
0
*Events per patient-year. †P<0.05 vs glargine. Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h
intervals between doses; Glar = glargine; OD = once daily.
Insulin Dose With Degludec
Add-on to OA,
Insulin-Naive
52 Weeks1 52 Weeks3
26 Weeks2
N 1030 687 744

Treatment
Flex
0.8 0.75
0.69
0.59 0.6
 Insulin dose
0.6 0.52 0.55 0.52

(U/kg/day)
0.4
0.2
0
Baseline dose U/kg/day 0.12 0.11 0.25 0.23 0.23 0.45 0.44
once daily.
with Degludec
• Monitor potassium levels in at-risk patients and treat as

Hypokalemia
necessary
• Observe for signs and symptoms of fluid retention or heart

Heart failure failure; consider dosage reduction or discontinuation if heart
failure occurs
Tresiba (insulin degludec) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016. 108
Degludec: Adverse Events
Patients (%)
Adverse Events* Type 1 diabetes Type 2 diabetes

(n=1102) (n=2713)
Upper respiratory infection 11.9 8.4

Headache 11.8 8.8
Sinusitis 5.1 —
Gastroenteritis 5.1 —
Diarrhea — 6.3
*Occurring in ≥5% of patients receiving degludec.
Tresiba (insulin degludec) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016. 109
FIXED RATIO COMBINATIONS

OF GLP1 RAS AND BASAL
INSULIN
110
Safety Considerations with Fixed Ratio
Combinations of GLP1 RAs and Basal Insulin
Hypokalemia • Monitor potassium levels in at-risk patients and treat as necessary
• Observe for signs and symptoms of fluid retention or heart failure; consider dosage reduction or
Heart failure
discontinuation if heart failure occurs
• Common
GI adverse
• Usually dose dependent and transient
events • Usually reduced with dose titration
• Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal
relationship has been established
Pancreatitis • Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of
increased pancreatic risk with incretins vs other agents
and pancreatic • Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is
cancer suspected
• Labeling for GLP1 receptor agonists suggests consideration of other therapies for patients with a history of
pancreatitis
• Animal data showed an increased incidence of C-cell tumors with liraglutide treatment, but confirmatory
population studies are lacking
Medullary • iDegLira patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of
thyroid cancer thyroid tumors
• iDegLira is contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia
syndrome type 2
• Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea,
Renal or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. iGlarLixi
impairment should not be used in patients with ESRD. Liraglutide was found to be safe in patients with moderate renal
impairment and may confer a beneficial effect.
ESRD, end-stage renal disease.
Garber AJ, et al. Endocr Pract. 2016;22:84-113. 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. Davies MJ, et al. Diabetes Care. 2016;39:222-230. Marso SP, et al. N Engl J
Med. 2016;375:311-322. Soliqua 100/33 (insulin glargine and lixisenatide injection) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2016.
111
Xultophy® 100/3.6 (insulin degludec and liraglutide injection) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016.
Glucose Control With iGlarLixi
Add-on to OA, Add-on to Basal Insulin

Insulin-Naive ± OAs
30 Weeks1 30 Weeks2
N 1070 736
Lixi Glar* iGlarLixi Glar* iGlarLixi

Treatment
Baseline A1C (%) 8.1 8.1 8.1 8.5 8.5

0
-0.5
 A1C (%)
-0.6
-1 -0.9
-1.1
-1.5 -1.3 P<0.0001
-1.6
-2 P<0.0001
P<0.0001
Per protocol maximum dose: 60 units/day.
Glar, glargine; Lixi; lixisenatide; OAs, oral agents.
1. Rosenstock J, et al. Diabetes Care. 2016;39:2026-2035. 2. Aroda VR, et al. Diabetes Care. 2016;39:1972-1980. 112
Weight Change With iGlarLixi

30 Weeks1 30 Weeks2
N 1070 736
Lixi Glar iGlarLixi Glar iGlarLixi

Treatment
1.5 1.1
1 0.7
0.5
 Weight (kg)
0
-0.5 -0.3
-1 P<0.0001 -0.7
-1.5 P<0.0001
-2
-2.5 -2.3
Glar, glargine; Lixi; lixisenatide; OAs, oral agents.

Hypoglycemia With iGlarLixi

30 Weeks1 30 Weeks2
N 1070 736
Treatment
45 42.5
40
40
hypoglycemia* (%)
Patients reporting
35
symptomatic
30 25.6
25 23.6
20
15
10 6.4
5
0
*BG ≤70 mg/dL.

BG, blood glucose; Glar, glargine; Lixi; lixisenatide; OAs, oral agents.
Insulin Dose With iGlarLixi

30 Weeks1 30 Weeks2
N 1070 736
Treatment
60
55
50 47 47
Dose* (units)
45 40.3 39.8
40
35
30
25
20
NA
15
*Dose range: 15-60 units glargine; 5-20 g lixisenatide.

Glar, glargine; Lixi; lixisenatide; NA, not applicable; OAs, oral agents.
iGlarLixi: Adverse Events
Patients (%)
Adverse Events*
(N=834)
Nausea 10.0
Nasopharyngitis 7.0
Diarrhea 7.0
Upper respiratory tract infection 5.5
Headache 5.4
*Occurring in ≥5% of patients receiving iGlarLixi.
Soliqua 100/33 (insulin glargine and lixisenatide injection) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2016. 116
Glucose Control With iDegLira

26 Weeks1 26 Weeks2
N 1663 413
Lira Deg iDegLira Deg* iDegLira

Treatment
Baseline A1C (%) 8.3 8.3 8.3 8.8 8.7

0
-0.5
 A1C (%)
-1 -0.9
-1.5 -1.3 -1.4
-2 -1.9 -1.9
NI
-2.5 P<0.0001
P<0.0001
S
P<0.0001
*Per protocol maximum dose: 50 units/day (no maximum dose of degludec alone was specified in the insulin naïve trial).
Deg, degludec; Lira; liraglutide; NI, noninferior; S, superior.
1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. 2. Buse JB, et al. Diabetes Care. 2014;37:2926-2933 . 117
Weight Change With iDegLira

26 Weeks1 26 Weeks2
N 1663 413
Lira Deg* iDegLira Deg* iDegLira

Treatment
2 1.6
1
 Weight (kg)
0
0
-1 -0.5
P<0.0001
-2
-3 -2.7
-3
-4 P<0.0001
P<0.0001
Deg, degludec; Lira; liraglutide.

1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. 2. Buse JB, et al. Diabetes Care. 2014;37:2926-2933 . 118
Hypoglycemia With iDegLira
26 Weeks1 26 Weeks2
N 1663 413
Lira Deg* iDegLira Deg* iDegLira
Treatment
P<0.0001
P<0.0001
45
39
40
hypoglycemia* (%)
Patients reporting
35 32
confirmed
30
25 24
25
20
15
10 7
5
0
*BG <56 mg/dL regardless of symptoms.

BG, blood glucose; Deg, degludec; Lira; liraglutide.
1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. 2. Buse JB, et al. Diabetes Care. 2014;37:2926-2933. 119
Insulin Dose With iDegLira

26 Weeks1 26 Weeks2
N 1663 413
Lira Deg iDegLira Deg* iDegLira

Treatment
60
55 53
50
45 45
Dose* (units)
45 P<0.0001
40 38
35
30
25
20
NA
15
*Dose range: 16-50 units glargine; 0.58-1.8 mg lixisenatide (no maximum dose of degludec alone was specified in the insulin naïve trial).
Deg, degludec; Lira; liraglutide; NA, not applicable.
1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. 2. Buse JB, et al. Diabetes Care. 2014;37:2926-2933. 120
iDegLira: Adverse Events
Patients (%)
Adverse Events*
(N=834)
Nasopharyngitis 9.6
Headache 9.1
Nausea 7.8
Diarrhea 7.5
Increased lipase 6.7
Upper respiratory infection 5.7
*Occurring in ≥5% of patients receiving iDegLira.
Xultophy® 100/3.6 (insulin degludec and liraglutide injection) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016. 121

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Glycemic Management in

FDA-Approved Agents Key Features

Monotherapy Add-on to Metformin Add-on to SU

-0.6 -0.5 -0.53

1 0.68 0.8 0.8

NR, value not reported.

NR, value not reported.

• Potentially increased risk of congestive heart failure hospitalization with alogliptin

-0.02 -0.1 -0.13

N 401 1306 743 801 768 565

0.5 0.19 0.13 0.08

N 401 1306 743 801 768 565

*P=0.01 vs glyburide uptitration.

N 401 1306 743 801 768 565

Adverse Events* Patients (%)

Onglyza (saxagliptin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb. 2013. 19

-0.7 -0.7 -0.7 -0.7 -0.6

N 741 793 353 441 641 151

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

N 793 1091 701 353 441 641

Incidence per 100 patient-years

Williams-Herman D, et al. BMC Endocr Disord. 2010;10(7) . http://www.biomedcentral.com/1472-6823/10/7.

GLP1 RECEPTOR AGONISTS

FDA-Approved Agents Key Features

ER, extended release; GLP1, glucagon-like peptide 1.

Monotherapy Add-on to Metformin Add-on to SU

Monotherapy Add-on to Metformin Add-on to SU

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

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

-1 -0.8 -0.79 -0.79

BID, twice daily; OW, once weekly (extended release)

BID, twice daily; OW, once weekly (extended release).

N 296 1049 310 841 779 586

N 296 1049 310 841 779 586

-3 -2.22 -2.29 -2.43 -2.56

†Alldulaglutide dosages shown are 1.5 mg once weekly.

Monotherapy Monotherapy Add-on to Add-on to Add-on to Add-on to

events/patient per year

†All exenatide dosages shown are 10 μg BID.

*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents.

*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents.

Add-on to Monotherapy vs Add-on to Add-on to Add-on to

*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents.

Bydureon (exenatide extended release) injection prescribing information.

N 746 1091 665 1041 821 581

N 746 1091 665 1041 821 581

-1 -0.7 -0.9 -0.7

N 746 1091 665 1041

*P<0.01 vs active comparator.

*Noninferiority criteria met.

FDA-Approved Agents Key Features

SGLT2, sodium-glucose cotransporter 2.

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

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

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

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

*All canagliflozin dosages shown are canaglifozin 300 mg.

*All canagliflozin dosages shown are canaglifozin 300 mg.

*All canagliflozin dosages shown are canaglifozin 300 mg.

-4 -3.6 -3.3 -3.4 -3.6

*All dapagliflozin dosages shown are dapagliflozin 10 mg.

*All dapagliflozin dosages shown are dapagliflozin 10 mg.

-0.13 -0.17 -0.11

-2.48 -2.46 -2.39 ** -2.04