glycemic management in type 2 diabetes
DESCRIPTION
Glycemic Management in Type 2 Diabetes. Efficacy and Safety of Antihyperglycemic Therapies Introduced Since 2004. DPP-4 Inhibitors. DPP-4 Inhibitors. FDA-Approved Agents Alogliptin Linagliptin Saxagliptin Sitagliptin. Key Features Oral administration - PowerPoint PPT PresentationTRANSCRIPT
Glycemic Management in Type 2 Diabetes
Efficacy and Safety of Antihyperglycemic Therapies
Introduced Since 2004
1
DPP-4 Inhibitors
2
FDA-Approved Agents• Alogliptin• Linagliptin• Saxagliptin• Sitagliptin
Key Features• Oral administration• Increase endogenous GLP-1
and GIP levels• Increase glucose-dependent
insulin secretion• Suppress glucagon production
DPP-4 Inhibitors
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 SUAlo1 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 SUAlo1 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 SUAlo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†
Hypoglycemiawith 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
1.6 3
11.1
1.5
24
1.5 0
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:Warnings and 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
Wei
ght (
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 LinagliptinP
atie
nts
Rep
ortin
g H
ypog
lyce
mia
(%)
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:Warnings and 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
00.5 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
00.5
11.5
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
3.45.2
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 5.9Upper 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
0.80.1
-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 NonexposedConstipation 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
FDA-Approved Agents• Albiglutide• 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
GLP-1 Receptor Agonists
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 SUAlb1 Exe2 Exe ER3 Lir4 Alb5 Exe6 Exe ER7 Lir8 Alb9,* Exe10 Exe
ER11,†Lir12
Baseline A1C (%) 8.1 7.8 8.5 8.3 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 -0.9-0.8-0.7
-0.9 -0.98
-1.5 -1.5 -1.5
-1.14
-1.5-1.36
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. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 3. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 4. Garber A, et al. Lancet. 2009;373:473-481. 5. Ahrén B, et al. Diabetes Care. 2014 Jun 4. pii: DC_140024. [Epub ahead of print]. 6. DeFronzo RA et
al. Diabetes Care. 2005;28:1092-1100. 7. Bergenstal RM, et al. Lancet. 2010;376:431-439. 8. Pratley RE, et al. Lancet. 2010;375:1447-1456. 9. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 10. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 11. Diamant M, et al. Lancet. 2010;375:2234-2243. 12. Marre M, et al. Diabet Med. 2009;26:268-278.
Pla
cebo
-adj
uste
d
A1C
(%)
‡
‡
‡ ‡
‡
‡
Monotherapy Add-on to Metformin Add-on to SUAlb1 Exe2 Exe ER3 Lir4 Alb5 Exe6 Exe ER7 Lir8 Alb9,* Exe10 Exe
ER11,†Lir12
Weight Change with GLP-1 Receptor Agonists
-4-3.5
-3-2.5
-2-1.5
-1-0.5
0
-0.9-1.2
-0.6
-3.1-2.8
-1.6-2.0
-2.3-2.6-2.5
-3.38
-0.2
*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. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 3. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 4. Garber A, et al. Lancet. 2009;373:473-481. 5. Ahrén B, et al. Diabetes Care. 2014 Jun 4. pii: DC_140024. [Epub ahead of print]. 6. DeFronzo RA et
al. Diabetes Care. 2005;28:1092-1100. 7. Bergenstal RM, et al. Lancet. 2010;376:431-439. 8. Pratley RE, et al. Lancet. 2010;375:1447-1456. 9. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 10. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 11. Diamant M, et al. Lancet. 2010;375:2234-2243. 12. 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 SUAlb1 Exe2 Exe ER3 Lir4 Alb5 Exe6 Exe ER7 Lir8 Alb9,* Exe10 Exe
ER11,†Lir12
Hypoglycemia with GLP-1 Receptor Agonists
05
10152025303540
03
10.4
4 5
36
5.21.0
13.08
38.1
*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. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 3. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 4. Garber A, et al. Lancet. 2009;373:473-481. 5. Ahrén B, et al. Diabetes Care. 2014 Jun 4. pii: DC_140024. [Epub ahead of print]. 6. DeFronzo RA et
al. Diabetes Care. 2005;28:1092-1100. 7. Bergenstal RM, et al. Lancet. 2010;376:431-439. 8. Pratley RE, et al. Lancet. 2010;375:1447-1456. 9. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 10. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 11. Diamant M, et al. Lancet. 2010;375:2234-2243. 12. 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 extenatide 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 Metformin104 Weeks2
Add-on toMet +/- SU +/- TZD
32 Weeks3
Add-on toBasal Insulin
26 Weeks4
N 296 1049 841 586
Treatment PBO Alb† Met Glim+Met
Sit+Met
Alb+ Met
Lira+ Met+/-
SU
Alb+ Met+/-
SU
Lispro Alb
Baseline A1C (%)
8.0 8.1 8.2 8.1 8.1 8.1 8.2 8.2 8.4 8.5
*P<0.0001 vs placebo. **P<0.001 vs active compatators.†All albiglutide dosages shown are 50 mg once weekly.
1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.2. Ahrén B, et al. Diabetes Care. 2014 Jun 4. pii: DC_140024. [Epub ahead of print]. 3. Pratley RE, et al. Lancet Diabetes Endocrinol.
2014;2:289-297. 4. Rosenstock J, et al. Diabetes Care. 2014 Jun 4. pii: DC_140001. [Epub ahead of print].
Glucose Control With Albiglutide
A1C
(%)
-1.2-1
-0.8-0.6-0.4-0.2
00.20.4
0.2
-0.36
-0.98
-0.66
-0.90
-0.28
-0.79 -0.82
0.27
-0.63
* ***
Monotherapy vsPlacebo
52 Weeks1
Add-on to Metformin104 Weeks2
Add-on toMet +/- SU +/- TZD
32 Weeks3
Add-on toBasal Insulin
26 Weeks4
N 296 1049 841 586
Treatment PBO Alb† Met Glim +Met
Sit +Met
Alb + Met
Lira+ Met+/-
SU
Alb+ Met+/-
SU
Lispro Alb
*P<0.0001 vs glimepiride or lispro. **P<0.0001 vs albiglutide.†All albiglutide dosages shown are 50 mg once weekly.
1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB.2. Ahrén B, et al. Diabetes Care. 2014 Jun 4. pii: DC_140024. [Epub ahead of print]. 3. Pratley RE, et al. Lancet Diabetes Endocrinol.
2014;2:289-297. 4. Rosenstock J, et al. Diabetes Care. 2014 Jun 4. pii: DC_140001. [Epub ahead of print].
Weight Change With Albiglutide
Wei
ght (
kg)
-2.5-2
-1.5-1
-0.50
0.51
1.5
-0.7
1.17
-2.19
0.8
-0.90 -0.86-0.64 -0.70
-1-1.21
*
**
*
Add-on to Metformin104 Weeks1
Add-on toMet +/- SU +/- TZD
32 Weeks2
N 1049 841
Treatment Met Glim +Met
Sit +Met
Alb + Met
Lira+ Met+/-
SU
Alb+ Met+/
-SU
*P<0.0001 vs glimepiride or lispro. **P<0.0001 vs albiglutide.†All albiglutide dosages shown are 50 mg once weekly.
1. Ahrén B, et al. Diabetes Care. 2014 Jun 4. pii: DC_140024. [Epub ahead of print].2. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297.
Blood Pressure Change With Albiglutide
S
ysto
lic B
P (m
mH
g)
-1.5-1
-0.50
0.51
1.52
2.5 2.2
1.5
0.20
-1
Decrease of <1 mmHg in both groups
Monotherapy vsPlacebo
52 Weeks1
Add-on to Metformin104 Weeks2
Add-on toMet +/- SU +/- TZD
32 Weeks3
Add-on toBasal Insulin
26 Weeks4
N 296 1049 841 586
Treatment PBO Alb† Met Glim +Met
Sit +Met
Alb + Met
Lira+ Met+/-
SU
Alb+ Met+/-
SU
Lispro Alb
*P<0.0001 vs glimepiride or lispro. **P<0.0001 vs albiglutide.†All albiglutide dosages shown are 50 mg once weekly.
1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB.2. Ahrén B, et al. Diabetes Care. 2014 Jun 4. pii: DC_140024. [Epub ahead of print]. 3. Pratley RE, et al. Lancet Diabetes Endocrinol.
2014;2:289-297. 4. Rosenstock J, et al. Diabetes Care. 2014 Jun 4. pii: DC_140001. [Epub ahead of print].
Hypoglycemia With AlbiglutideP
atie
nts
with
doc
umen
ted
sym
ptom
atic
hyp
ogly
cem
ia (%
)
0
5
10
15
20
25
30
35
2.0
17.9
13.0
29.9
0.01.7
10.4
15.8
4.0 3.0
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 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
Series105
10152025303540
15
37.1
4 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 911Treatment Exe
BIDExe 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 911Treatment (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 911Treatment Exe
BIDExe 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
05
101520253035
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
rting
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.
-4-3-2-10123
1.10 1.00
-0.96
2.10
0.601.60
-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
-6-5-4-3-2-101
-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
3024
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
49
FDA-Approved Agents• Canagliflozin• Dapagliflozin
Key Features• Oral administration• Inhibit reabsorption of glucose
into the bloodstream from renal fluid
SGLT2 Inhibitors
50SGLT2, 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 +/- OAsCan1 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 +/- OAsCan1 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)
Hypoglycemiawith 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 +/- OAsCan1 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
*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.**P<0.001 vs placebo.
†All dosages shown are canaglifozin 300 mg.‡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
** ****
‡
**
*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.**P<0.001 vs comparator.
†All dosages shown are canaglifozin 300 mg.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 269Treatment (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)
*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.**P<0.001 vs comparator.
†All dosages shown are canaglifozin 300 mg.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 269Treatment (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)
*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.†All dosages shown are canaglifozin 300 mg.
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
3.0 0.05.0
43.251.2
2.0Pat
ient
s re
porti
ng
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 dosages shown are dapaglifozin 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 dosages shown are dapaglifozin 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 dosages shown are dapaglifozin 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
0.8 1.3
-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 dosages shown are dapaglifozin 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 DapagliflozinP
atie
nts
repo
rting
hy
pogl
ycem
ia (%
)
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.
Inhaled Insulin
65
FDA-Approved Agent• Technosphere insulin
Key Features• Inhaled administration• Rapid-acting insulin
– Peak levels achieved in ~15 minutes
Inhaled Insulin
66
Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.
Glucose Control with Technosphere 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 Technosphere 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 with Technosphere Insulin
Add-on to Metformin and/or Other OAs24 Weeks
Placebo Technosphere 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 with Technosphere Insulin
Add-on to Metformin and/or Other OAs24 Weeks
N 353
Nonsevere Severe
PBO TI PBO TI
01020304050607080
30
1.7
67
5.1Pat
ient
s W
ith
Hyp
ogly
cem
ia
(%)
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Safety Considerationswith Technosphere Insulin
Lung disease
• Contraindicated in asthma, COPD, and other chronic lung diseases• Perform spirometry to assess lung function before initiating technosphere
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.
Technosphere Insulin:Adverse Events
Adverse Events*Patients (%)
Technosphere 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 technosphere insulin.
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Class Comparisons
Noninsulin Agents
72
DPP-4 Inhibitors GLP-1 Receptor Agonists SGLT2 InhibitorsAlo1 Lin2 Sax3 Sit4 Alb5 Exe6 Exe ER7 Lir8 Can9 Dap10
Baseline A1C (%) 7.9 8.1 8.1 8.0 8.1 8.2 8.6 8.4 7.8 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 -0.63-0.8
-1.5 -1.5
-0.93
-0.52
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 Jun 4. pii: DC_140024. [Epub ahead of print]. 6. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 7. . Bergenstal RM, et al. Lancet. 2010;376:431-439. 8. Pratley RE, et al. Lancet. 2010;375:1447-1456. 9. Cefalu WT, et al.
Lancet. 2013;382:941-950. 10. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022.
A
1C (%
)
DPP-4 Inhibitors GLP-1 Receptor AgonistsSGLT2
InhibitorsAlo1 Lin2 Sax3 Sit4 Alb5 Exe6 Exe ER7 Lir8 Can9 Dap10
Weight Reduction
-4.5-4
-3.5-3
-2.5-2
-1.5-1
-0.50
-0.3 -0.4-0.87
-1.21
-2.8
-2
-2.8
-4
-3.2
DPP-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 Jun 4. pii: DC_140024. [Epub ahead of print]. 6. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 7. . Bergenstal RM, et al. Lancet. 2010;376:431-439. 8. Pratley RE, et al. Lancet. 2010;375:1447-1456. 9. Cefalu WT, et al.
Lancet. 2013;382:941-950. 10. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022.
W
eigh
t (kg
)
NR
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