glycemic management in type 2 diabetes efficacy and safety of modern antihyperglycemic therapies 1
TRANSCRIPT
Glycemic Management in Type 2 Diabetes
Efficacy and Safety of Modern Antihyperglycemic Therapies
1
DPP-4 INHIBITORS
2
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
3DPP-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.
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
(%
)
‡
Monotherapy Add-on to Metformin Add-on to SU
Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†
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.
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.
W
eigh
t (kg
) NR NR
Monotherapy Add-on to Metformin Add-on to SU
Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†
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.
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.
Pat
ient
s (%
) NR NR
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
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents
• 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.
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 (
%)
* * * *
*
*
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
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
W
eigh
t (kg
)
*
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 to Metformin26 Weeks3
Add-on to Glyburide26 Weeks4
Add-on toMet + Pio52 Weeks5
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 (
%)
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.
Monotherapy24 Weeks1
Initial Combo w/ Metformin
24 Weeks2
Initial Combow/ Pioglitazone
24 Weeks3
Add-on to Metformin24 Weeks4
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 (
%)
*
**
*
†
Initial Combo w/ Metformin24 Weeks1
Initial Combow/ Pioglitazone
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.
HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily).
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.
*
Monotherapy24 Weeks1
Initial Combo w/ Metformin
24 Weeks2
Initial Combow/ Pioglitazone
24 Weeks3
Add-on to Metformin24 Weeks4
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
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.
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.
Monotherapy24 Weeks1
Initial Combow/ Metformin
24 Weeks2
Add-on to Metformin24 Weeks3
Add-on to Metformin18 Weeks4
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 (
%)
*
*
**
Monotherapy24 Weeks1
Initial Combow/ Metformin
24 Weeks2
Add-on to Metformin24 Weeks3
Add-on to Metformin18 Weeks4
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
*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*
Monotherapy24 Weeks1
Initial Combow/ Metformin
24 Weeks2
Add-on to Metformin24 Weeks3
Add-on to Metformin18 Weeks4
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
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 (
%)
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.
*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
Initial Combow/ Metformin
24 Weeks2
Add-on to Metformin24 Weeks3
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
*
* *†
*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
Monotherapy24 Weeks1
Monotherapy52 Weeks2
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
†
*
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
Initial Combow/ Metformin
24 Weeks2
Add-on to Metformin24 Weeks3
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
(%
)
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.
GLP-1 RECEPTOR AGONISTS
24
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
25ER, extended release; GLP-1, glucagon-like peptide 1.
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.
Monotherapy Add-on to Metformin Add-on to SU
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
Placebo-Adjusted Change from Baseline(Not Head-to-Head Trials)
*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
(%
)
‡
‡
‡ ‡
‡
‡
‡
‡
Monotherapy Add-on to Metformin Add-on to SU
Alb1 Dul2 Exe3 Exe ER4
Lir5 Alb6 Dul7 Exe8 Exe ER9
Lir10 Alb11,* Exe12 Exe ER13,†
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
)
Absolute Change from Baseline(Not Head-to-Head Trials)
Monotherapy Add-on to Metformin Add-on to SU
Alb1 Dul2 Exe3 Exe ER4
Lir5 Alb6 Dul7 Exe8 Exe ER9
Lir10 Alb11,* Exe12 Exe ER13,†
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.
Percentage of Patients Reporting Hypoglycemia(Not Head-to-Head Trials)
Pat
ient
s (%
)
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
• 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• Labeling for GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of
pancreatitis
Pancreatic cancer
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents
• 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.
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
**** *
Weight Change With Albiglutide
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
-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.
†
Add-on to Metformin104 Weeks1
Add-on toMet +/- SU +/- TZD
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
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.
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
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.
Glucose Control With Dulaglutide
35
*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.
Monotherapy52 Weeks1
Monotherapy52 Weeks2
Add-on to Metformin26 Weeks3
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
*****
****
***
Weight Reduction With Dulaglutide
36
*P<0.05 vs glargine. **P<0.001 vs sitagliptin.†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.
Monotherapy26 Weeks1
Monotherapy26 Weeks2
Add-on to Metformin26 Weeks3
Add-on toPio + Met26 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
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
**
**
Blood Pressure Change With Dulaglutide
37
†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.
Monotherapy52 Weeks1
Monotherapy52 Weeks2
Add-on to Metformin26 Weeks3
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
Hypoglycemia With Dulaglutide
38
†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.
Monotherapy52 Weeks1
Monotherapy52 Weeks2
Add-on to Metformin26 Weeks3
Add-on toPio + Met26 Weeks4
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
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.
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.
Monotherapy24 Weeks1
Add-on to Metformin30 Weeks2
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* * ***
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.
Monotherapy24 Weeks1
Add-on to Metformin30 Weeks2
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
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
** **
***
*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
*
Monotherapy24 Weeks1
Add-on to Metformin30 Weeks2
Add-on to Sulfonylurea
30 Weeks3
Add-on to TZD16 Weeks4
N 233 336 377 233
Treatment† PBO Exe Met Exe +Met
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
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 .
*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 to Metformin26 Weeks3
Add-on toMet +/- SU26 Weeks4
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
*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.
Add-on toOAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin26 Weeks3
Add-on toMet +/- SU26 Weeks4
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
*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.
Add-on toOAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin26 Weeks3
Add-on toMet +/- SU26 Weeks4
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 (
%)
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.
*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
Add-on to Metformin26 Weeks2
Add-on to Metformin26 Weeks3
Add-on to Sulfonylurea
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
*** ***
*******
*
Monotherapy vs Glimepiride52 Weeks1
Add-on to Metformin26 Weeks2
Add-on to Metformin26 Weeks3
Add-on to Sulfonylurea
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
*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
* ****
*
*
***
*
Blood Pressure Changes With Liraglutide
Monotherapy vs Glimepiride52 Weeks1
Add-on to Metformin26 Weeks2
Add-on to Metformin26 Weeks3
Add-on to Sulfonylurea26 Weeks4,5
Add-on toMet + TZD26 Weeks6
Add-on toMet + SU
26 Weeks7
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
*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)
**
**
*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
Monotherapy52 Weeks1
Add-on to Metformin26 Weeks2
Add-on to Metformin26 Weeks3
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 (
%)
**
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.
SGLT2 INHIBITORS
54
SGLT2 Inhibitors
FDA-Approved Agents
• Canagliflozin• Dapagliflozin• Empagliflozin
Key Features
• Oral administration• Inhibit reabsorption of
glucose into the bloodstream from renal fluid
55SGLT2, sodium-glucose cotransporter 2.
DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14.
Glucose Controlwith SGLT2 Inhibitors
Placebo-Adjusted Change from Baseline(Not Head-to-Head Trials)
*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. Cefalu WT, et al. Lancet. 2013;382:941-950. 4. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022.5. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 6. Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs
Can1 Dap2 Can3 Dap4 Can5 Dap6
Baseline A1C (%) 8.1 7.8 8.1 8.2 8.2 8.6
-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
Pla
cebo
-adj
uste
d
A1C
(%
)
*
*
Weight Changewith SGLT2 Inhibitors
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.3. Cefalu WT, et al. Lancet. 2013;382:941-950. 4. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022.5. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 6. Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs
Can1 Dap2 Can3 Dap4 Can5 Dap6
-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
W
eigh
t (kg
)
Absolute Change from Baseline(Not Head-to-Head Trials)
Hypoglycemia with SGLT2 Inhibitors
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.3. Cefalu WT, et al. Lancet. 2013;382:941-950. 4. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022.5. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 6. Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs
Can1 Dap2 Can3 Dap4 Can5 Dap6
0
10
20
30
40
50
60
3.0 5.0
51.2
2.9 3.4
53.6
Pat
ient
s (%
)
Percentage of Patients Reporting Hypoglycemia(Not Head-to-Head Trials)
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.
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on to Metformin52 Weeks3
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
****
**‡
**
*All canagliflozin dosages shown are canaglifozin 300 mg.†Estimated glomerular filtration rate 30-50 mL/min/1.73 m2.
**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
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on to Metformin52 Weeks3
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
-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)
*All canagliflozin dosages shown are canaglifozin 300 mg.†Estimated glomerular filtration rate 30-50 mL/min/1.73 m2.
**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
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on to Metformin52 Weeks3
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
-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)
*All canagliflozin dosages shown are canaglifozin 300 mg.†Estimated glomerular filtration rate 30-50 mL/min/1.73 m2.
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
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on to Metformin52 Weeks3
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
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
(%
)
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.
Monotherapy24 Weeks1
Initial Combo with
Metformin24 Weeks2
Add-on toMetformin52 Weeks3
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 dapagliflozindosages 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 *****
***
***
***
Monotherapy24 Weeks1
Initial Combo with
Metformin24 Weeks2
Add-on toMetformin52 Weeks3
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
*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.
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
*****
***
*** ***
Monotherapy24 Weeks1
Initial Combo with
Metformin24 Weeks2
Add-on toMetformin52 Weeks3
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
*All dapagliflozin dosages shown are dapagliflozin 10 mg.
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.
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
Monotherapy24 Weeks1
Initial Combo with
Metformin24 Weeks2
Add-on toMetformin52 Weeks3
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
*All dapagliflozin dosages shown are dapagliflozin 10 mg.
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.
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
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
Urinary tract infections 5.7 4.3 3.7
Back pain 3.1 4.2 3.2
Increased urination 2.9 3.8 1.7
Male genital mycotic infections 2.8 2.7 0.3
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.
Monotherapy24 Weeks1
Add-on toMetformin24 Weeks2
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
**
******** ***
Monotherapy24 Weeks1
Add-on toMetformin24 Weeks2
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
*All empagliflozin dosages shown are empagliflozin 25 mg.
**P<0.001 vs placebo. ***P<0.0001 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.
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
-2.48
**
********
******
Monotherapy24 Weeks1
Add-on toMetformin24 Weeks2
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
*All empagliflozin dosages shown are empagliflozin 25 mg.
**P<0.05 vs placebo. ***P<0.001 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.
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
******
***
*****
Monotherapy24 Weeks1
Add-on toMetformin24 Weeks2
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
*All empagliflozin dosages shown are empagliflozin 25 mg.
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
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)
Urinary tract infections 9.3 7.6 7.6
Female genital mycotic infections 5.4 6.4 1.5
Upper respiratory tract infection 3.1 4.0 3.8
Increased urination 3.4 3.2 1.0
Dyslipidemia 3.9 2.9 3.4
Arthralgia 2.4 2.3 2.2
Male genital mycotic infections 3.1 1.6 0.4
Nausea 2.3 1.1 1.4
*Adverse events occurring in ≥2% of patients receiving empagliflozin at rates greater than placebo.
INHALED INSULIN
75
Inhaled Insulin
• Inhaled administration• Rapid-acting insulin
– Peak levels achieved in ~15 minutes
76
Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.
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
Weight Change withInhaled Insulin
Add-on to Metformin and/or Other OAs24 Weeks
Placebo Inhaled insulin
N 353
*
-1.5
-1
-0.5
0
0.5
1
-1.13
0.49
W
eigh
t (kg
)
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Hypoglycemia withInhaled Insulin
Add-on to Metformin and/or Other OAs24 Weeks
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.
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
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
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
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.
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
CLASS COMPARISONSNoninsulin Agents
82
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 Reduction
-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
DPP-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 (
%)
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
)
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