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Glycemic Management in
Type 2 Diabetes
Efficacy and Safety of
Antihyperglycemic Therapies
Introduced Since 2004
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
3
DPP-4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1.
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.
Glucose Control
with DPP-4 Inhibitors
Placebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)
Monotherapy
Placebo-adjusted
 A1C (%)
Baseline A1C (%)
Add-on to Metformin
Add-on to SU
Alo1
Lin2
Sax3
Sit4
Alo5
Lin6
Sax7
Sit8
Alo9
Lin10,*
Sax11
Sit12,†
7.9
8.0
8.0
7.5
8.1
8.2
8.6
8.4
7.8
7.9
8.5
8.3
-0.72
-0.74
0
-0.2
-0.4
-0.6
-0.8
-1
-0.5
-0.57
-0.69
-0.65
-0.67‡
-0.53
-0.64
-0.65
-0.62
-0.83
*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;63:13951406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.
Weight Change
with DPP-4 Inhibitors
Absolute Change from Baseline
(Not Head-to-Head Trials)
Monotherapy
Alo1
Lin2
Sax3
Add-on to Metformin
Sit4
Alo5
Lin6
Sax7
Sit8
 Weight (kg)
1
Alo9
Lin10,*
0.68
0.5
NR
0
-0.5
Add-on to SU
-0.22
NR
-0.1
-0.3
-1
Sax11
Sit12,†
0.8
0.8
0.27
-0.4
-0.87
-1.5
-1.5
-2
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;63:13951406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.
Hypoglycemia
with DPP-4 Inhibitors
Percentage of Patients Reporting Hypoglycemia
(Not Head-to-Head Trials)
Monotherapy
Alo1
Lin2
Sax3
Add-on to Metformin
Sit4
Alo5
Lin6
Sax7
Sit8
Add-on to SU
Alo9
Patients (%)
25
Lin10,*
NR
NR
14.6
15
12.2
9.6
10
5.2
0
Sit12,†
22.7
20
5
Sax11
1.5
0.3
5.2
4.9
0
0.6
1.3
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;63:13951406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.
Safety Considerations
with DPP-4 Inhibitors
GI adverse
events
•
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
Minimal
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.
Glucose Control With Alogliptin
Monotherapy Initial Combo
26 Weeks1 w/ Pioglitazone
26 Weeks2
N
329
Treatment
Baseline A1C
(%)
PBO Alo
7.9
7.9
Add-on to
Metformin
26 Weeks3
Add-on to
Glyburide
26 Weeks4
Add-on to
Met + Pio
52 Weeks5
Add-on to
Insulin +/- Met
26 Weeks6
527
500
803
390
Pio Alo Alo +
Pio
Met Alo +
Met
Gly Alo +
Gly
Met+ Alo+
Pio Met+
Pio
8.8
8.0
8.1
655
8.8
8.8
7.9
8.1
8.1
8.3
Ins+/Met
Alo+
Ins+/Met
9.3
9.3
 A1C (%)
0.5
0.01
0
-0.02
-0.1
-0.5
-0.59
-1
-1.5
-0.13
-0.29
*
-0.6
*
-0.96
-1.15
-0.53
*
-0.7
-0.71
*
*
-1.71
-2
*
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.
Weight Change With Alogliptin
Monotherapy Initial Combo
26 Weeks1 w/ Pioglitazone
26 Weeks2
N
329
 Weight (kg)
Treatment
3.5
3
2.5
2
1.5
1
0.5
0
-0.5
PBO Alo
655
Pio Alo Alo +
Pio
Add-on to
Metformin
26 Weeks3
Add-on to
Glyburide
26 Weeks4
Add-on to
Met + Pio
52 Weeks5
Add-on to
Insulin +/- Met
26 Weeks6
527
500
803
390
Met Alo +
Met
Gly Alo +
Gly
Met+ Alo+
Pio Met+
Pio
Ins+/Met
Alo+
Ins+/Met
3.14
2.19
1.6
*
0.68
0.18
-0.22
1.1
0.6 0.6
0
-0.29
-0.3
-0.2
P<0.01 vs comparator.
1.
DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Rosenstock J, et al. Diabetes Care. 2010;33:2406–2408.
3. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55.4. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176.
5. Bosi E, et al. Diabetes Obes Metab. 2011;13:1088-1096. 6. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.
Hypoglycemia With Alogliptin
Monotherapy
26 Weeks1,2
Add-on to
Metformin
26 Weeks3
Add-on to
Glyburide
26 Weeks4
Add-on to
Met + Pio
52 Weeks5
Add-on to
Insulin +/- Met
26 Weeks6
329
527
500
803
390
N
Treatment
PBO
Alo
Met
Alo +
Met
Gly
Alo +
Gly
Met+
Pio
Alo+
Met+
Pio
Ins+/Met
Patients Reporting
Hypoglycemia (%)
30
Alo+
Ins+/Met
27.1
24
25
20
15
11.1
10
5
1.6
4.5
3
1.5
0
0
1.
9.6
1.5
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.
Alogliptin:
Warnings and Adverse Events
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.
Nesina (alogliptin) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2013.
Glucose Control With Linagliptin
Monotherapy Initial Combo Initial Combo
24 Weeks1
w/ Metformin w/ Pioglitazone
24 Weeks2
24 Weeks3
N
Treatment
Baseline A1C
(%)
 A1C (%)
0.5
Add-on to
Metformin
24 Weeks4
Add-on to
Metformin
2 Years5
Add-on to
Metformin +
SU
24 Weeks6
1055
503
791
389
700
1552
PBO Lin
Lin Met Lin + Lin +
HD Met Met
LD HD
Pio Lin +
Pio
Met Lin +
Met
Glim + Lin +
Met
Met
8.7
8.6
8.0
8.0
8.0
8.5
8.7
8.7
8.6
0.25
8.1
7.7
7.7
Met +
SU
Lin +
Met +
SU
8.1
8.2
0.15
0
-0.5
-1
-1.5
-2
-0.44
*
-0.5
-0.49
-0.56
-1.06
-1.1 -1.2
-1.6
*
*
-0.21
-0.41
-0.1
-0.72
*
†
* 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.
Weight Changes With Linagliptin
Initial Combo w/
Metformin
24 Weeks1
Initial Combo
w/ Pioglitazone
24 Weeks2
Add-on to
Metformin
24 Weeks3
Add-on to
Metformin
2 Years4
791
389
700
1552
Met Lin +
Met
Glim Lin +
+ Met Met
N
 Weight (kg)
Treatment
2.5
2
1.5
1
0.5
0
-0.5
-1
-1.5
-2
Lin
Met Lin + Lin +
HD Met Met
LD
HD
Pio
Lin +
Pio
2.3
1.3
1.2
0.2
-0.1
-0.5
-0.8
-0.5 -0.4
-1.4
*
* 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.
Hypoglycemia With Linagliptin
Monotherapy Initial Combo Initial Combo
24 Weeks1
w/ Metformin w/ Pioglitazone
24 Weeks2
24 Weeks3
N
Treatment
Add-on to
Metformin
24 Weeks4
Add-on to
Metformin
2 Years5
Add-on to
Metformin +
SU
24 Weeks6
1055
503
791
389
700
1552
PBO Lin
Lin Met Lin + Lin +
HD Met Met
LD HD
Pio Lin +
Pio
Met Lin +
Met
Glim + Lin +
Met
Met
Patients Reporting
Hypoglycemia (%)
40
Met +
SU
Lin +
Met +
SU
36
35
30
22.7
25
20
14.8
15
10
5
0
7
3.4 3.5
0.6 0.3
0
0
0 1.2
2.8
0.6
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
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.
Tradjenta (linagliptin) prescribing information. Ridgefield, CT: Boehringer Ingelheim, Inc.; 2014.
Glucose Control With Saxagliptin
Monotherapy
24 Weeks1
Initial Combo
w/ Metformin
24 Weeks2
Add-on to
Metformin
24 Weeks3
Add-on to
Metformin
18 Weeks4
Add-on to
Glyburide vs
Uptitration
24 Weeks5
Add-on to
TZD
24 Weeks6
401
1306
743
801
768
565
N
Treatment
Baseline A1C (%)
0.5
PBO
Sax
Met
Sax +
Met
Met
Sax +
Met
Sit +
Met
Sax +
Met
Gly
Sax +
Gly
TZD
Sax +
TZD
7.9
8.0
9.4
9.4
8.1
8.1
7.7
7.7
8.4
8.5
8.2
8.4
0.19
0.13
0.08
 A1C (%)
0
-0.5
-1
-1.5
-2
-2.5
-3
-0.46
-0.69
*
*
-0.62 -0.52
-0.3
-0.64
*
-0.94
*
-2
-2.5
*
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.
Weight Changes With Saxagliptin
Monotherapy
24 Weeks1
Initial Combo
w/ Metformin
24 Weeks2
Add-on to
Metformin
24 Weeks3
Add-on to
Metformin
18 Weeks4
Add-on to
Glyburide vs
Uptitration
24 Weeks5
Add-on to
TZD
24 Weeks6
401
1306
743
801
768
565
N
Weight (kg)
Treatment
PBO
2
1.5
1
0.5
0
-0.5
-1
-1.5
-2
Sax
Met
Sax +
Met
Met
Sax +
Met
Sit +
Met
Sax +
Met
Gly
Sax +
Gly
*
0.8
TZD
Sax +
TZD
1.4
0.9
0.3
-0.1
-0.4
-0.4
-0.92 -0.87
-1.4
-1.6
-1.8
*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.
Hypoglycemia With Saxagliptin
Monotherapy
24 Weeks1
Initial Combo
w/ Metformin
24 Weeks2
Add-on to
Metformin
24 Weeks3
Add-on to
Metformin
18 Weeks4
Add-on to
Glyburide vs
Uptitration
24 Weeks5
Add-on to
TZD
24 Weeks6
401
1306
743
801
768
565
N
Patients Reporting
Hypoglycemia (%)
Treatment
PBO
16
14
12
10
8
6
4
2
0
Sax
Met
Sax +
Met
Met
Sax +
Met
Sit +
Met
Sax +
Met
Gly
Sax +
Gly
TZD
Sax +
TZD
14.6
10.1
6.3
5.2
4
5
3.4
5.2
2.8
3.2
3.8
2.7
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.
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.
Glucose Control With Sitagliptin
Monotherapy
vs Glipizide
52 Weeks1
Initial Combo
w/ Metformin
24 Weeks2
Add-on to
Metformin
24 Weeks3
Add-on to
Insulin
24 Weeks4
N
1172
1091
701
641
Treatment
Glip
Sit
Met
Sit
Sit+
Met
Met
Sit+
Met
Ins
Sit+
Ins
Baseline A1C
(%)
7.5
7.5
8.7
8.9
8.8
8.0
8.0
8.6
8.7
Add-on to
Add-on to
Pioglitazone vs Rosiglitazone +
Met + Pio
Metformin
5
12 Months
54 Weeks6
151
278
Met + Sit +
Pio
Pio
8.4
8.5
Rosi + Sit +
Met Rosi +
Met
8.7
8.8
0.0
0
 A1C (%)
-0.02
-0.3
-0.5
-1
-0.7 -0.7
-0.7
-0.7
*
-1.13
-1.5
-2
-0.6
*
-1.1
-1.4 -1.4
†
-1.9
*
*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.
Weight Changes With Sitagliptin
Monotherapy Monotherapy Add-on to
24 Weeks1
52 Weeks2 Pioglitazone
24 Weeks3
N
741
Treatment
PBO
793
Sit
Glip
353
Sit
Pio
Sit +
Pio
Add-on to
Glimepiride
24 Weeks4
Add-on to
Insulin
24 Weeks5
Add-on to Pio
vs Met + Pio
12 Months6
441
641
151
Glim
Sit +
Glim
Ins
Sit +
Ins
Met +
Pio
Sit +
Pio
 Weight (kg)
3
2
1.5
1.1
1.8
0.8
1
0.1
0.1
0
-0.2
-1
-2
-3
-4
-1.1
-0.4
-1.5
*
-1.6
-2.8
†
*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.
Hypoglycemia With Sitagliptin
Sitagliptin vs
Glipizide
52 weeks1
Initial Combo
w/ Metformin
24 Weeks2
Add-on to
Metformin
24 Weeks3
Add-on to
Pioglitazone
24 Weeks4
Add-on to
Glimepiride
24 Weeks5
Add-on to
Insulin
24 Weeks6
N
793
1091
701
353
441
641
Treatment
Glip
Patients Reporting
Hypoglycemia (%)
35
Sit PBO Met
Sit +
Met
Met Sit +
Met
Pio
Sit + Glim Sit + Sit +
Pio
Glim Glim +
Met
Ins
Sit +
Ins
32
30
25
20
16.4
16.0
15
10
5
0
7.5
4.9
2.2
0.6 1.1
2.1 1.3
0
1.1
8.0
2.8
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.
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
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
25
ER, extended release; GLP-1, glucagon-like peptide 1.
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.
Glucose Control
with GLP-1 Receptor Agonists
Placebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)
Monotherapy
Placebo-adjusted
 A1C (%)
Baseline A1C (%)
Add-on to Metformin
Add-on to SU
Alb1
Exe2
Exe ER3
Lir4
Alb5
Exe6
Exe ER7
Lir8
Alb9,*
Exe10
Exe
ER11,†
Lir12
8.1
7.8
8.5
8.3
8.1
8.2
8.6
8.4
8.2
8.6
8.3
8.5
-1.5‡
-1.36
0
-0.5
-0.7
-1
-1.0
-1.5
-1.14
-1.5 ‡
‡
-0.9
-0.8
-0.9
‡
-0.98
-1.5 ‡
-1.5 ‡
-2
*Metformin with or without SU or TZD. †Metformin with or without SU. ‡Absolute change from baseline (active-controlled trial).
1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.
2. 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;375:14471456. 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.
Weight Change with GLP-1
Receptor Agonists
Absolute Change from Baseline
(Not Head-to-Head Trials)
Monotherapy
 Weight (kg)
Alb1
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
-4
Exe2
Exe ER3
Add-on to Metformin
Lir4
Alb5
Exe6
Exe ER7
Lir8
Add-on to SU
Alb9,*
Exe10
Exe
ER11,†
Lir12
-0.2
-0.6
-0.9
-1.2
-1.6
-2.0
-2.5
-3.1
-2.3
-2.6
-2.8
-3.38
*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;375:14471456. 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.
Hypoglycemia with GLP-1
Receptor Agonists
Percentage of Patients Reporting Hypoglycemia
(Not Head-to-Head Trials)
Monotherapy
Patients (%)
Alb1
40
35
30
25
20
15
10
5
0
Exe2
Exe ER3
Add-on to Metformin
Lir4
Alb5
Exe6
Exe ER7
Lir8
Add-on to SU
Alb9,*
Exe10
Exe
ER11,†
Lir12
36
4
0
5.2
10.4
8
3
5
1.0
13.0
8.1
3
*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;375:14471456. 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.
Safety Considerations
with 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.
Glucose Control With Albiglutide
Monotherapy vs
Placebo
52 Weeks1
Add-on to Metformin
104 Weeks2
Add-on to
Met +/- SU +/- TZD
32 Weeks3
Add-on to
Basal Insulin
26 Weeks4
296
1049
841
586
N
Treatment
 A1C (%)
Baseline A1C
(%)
0.4
0.2
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
PBO
Alb†
Met
8.0
8.1
8.2
Glim+ Sit+
Met Met
8.1
8.1
Alb+
Met
Lira+
Met+/SU
Alb+
Met+/SU
8.1
8.2
8.2
Lispro Alb
8.4
8.5
0.27
0.2
-0.36
-0.28
-0.63
-0.90
*
*
**
-0.66
-0.79
-0.82
-0.98
*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].
Weight Change With Albiglutide
Monotherapy vs
Placebo
52 Weeks1
Add-on to Metformin
104 Weeks2
Add-on to
Met +/- SU +/- TZD
32 Weeks3
Add-on to
Basal Insulin
26 Weeks4
296
1049
841
586
N
Treatment
PBO
Alb†
Met Glim + Sit +
Met Met
1.5
Alb +
Met
Lira+
Alb+
Met+/- Met+/SU
SU
1.17
0.8
1
 Weight (kg)
Lispro Alb
0.5
0
-0.5
-1
-1.5
-2
-2.5
-0.7
-0.90
-1
-0.64
-0.86
-0.70
*
-1.21
*
-2.19
**
*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].
Blood Pressure Change With
Albiglutide
Add-on to Metformin
104 Weeks1
Add-on to
Met +/- SU +/- TZD
32 Weeks2
1049
841
N
Treatment
 Systolic BP (mmHg)
2.5
2
Met Glim + Sit +
Met Met
Alb +
Met
Lira+ Alb+
Met+/- Met+/SU
SU
2.2
1.5
1.5
1
0.5
0.20
0
-0.5
-1
-1.5
-1
Decrease of
<1 mmHg in
both groups
*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.
Hypoglycemia With Albiglutide
Monotherapy vs
Placebo
52 Weeks1
Add-on to Metformin
104 Weeks2
Add-on to
Met +/- SU +/- TZD
32 Weeks3
Add-on to
Basal Insulin
26 Weeks4
296
1049
841
586
N
Patients with documented
symptomatic hypoglycemia (%)
Treatment
PBO
Alb†
Met Glim + Sit +
Met Met
Alb +
Met
Lira+
Alb+
Met+/- Met+/SU
SU
Lispro Alb
35
29.9
30
25
17.9
20
15.8
13.0
15
10.4
10
5
0
4.0
2.0
0.0
1.7
3.0
*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].
Albiglutide: 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*
*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
Monotherapy
24 Weeks1
Add-on to
Metformin
30 Weeks2
Add-on to
Sulfonylurea
30 Weeks3
233
336
377
N
Treatment†
Baseline A1C (%)
Add-on to TZD
Add-on to
Add-on to Met +
16 Weeks4
Metformin + SU SU vs Glargine
30 Weeks5
26 Weeks6
233
733
PBO
Exe
Met
Exe +
Met
SU
Exe +
SU
TZD
Exe +
TZD
Met +
SU
Exe +
Met +
SU
Glar +
Met +
SU
Exe +
Met +
SU
7.8
7.8
8.2
8.2
8.7
8.6
7.9
7.9
8.5
8.5
8.3
8.2
0.5
0.12
0.1
 A1C (%)
551
0.2
0.09
0
-0.5
-1
-1.5
-0.2
-0.9
*
-0.8
*
-0.86
*
-0.89
-0.9
*
*
-1.1
-1.1
*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.
Weight Reduction With Exenatide
Monotherapy
24 Weeks1
Add-on to
Metformin
30 Weeks2
Add-on to
Sulfonylurea
30 Weeks3
233
336
377
N
Treatment†
PBO
Exe
Met
Exe +
Met
SU
Add-on to TZD
Add-on to
Add-on to Met +
16 Weeks4
Metformin + SU SU vs Glargine
30 Weeks5
26 Weeks6
233
Exe +
SU
TZD
733
Exe +
TZD
Met +
SU
551
Exe +
Met +
SU
Glar +
Met +
SU
Exe +
Met +
SU
3
1.8
 Weight (kg)
2
1
0
-0.3
-1
-2
-1.4
-0.9
-1.6
-3
-4
-0.24
-0.6
-3.1
*
-2.8
*
-1.75
-1.6
*
*
*
-2.3
**
*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.
Blood Pressure Changes With
Exenatide
Monotherapy
24 Weeks
N
233
Treatment
PBO
Exe 10 μg BID
0
 Systolic BP
(mmHg)
-0.5
-0.3
-1
-1.5
-2
-2.5
-3
-3.5
-4
-3.7
*
*P<0.05 vs placebo.
Moretto TJ, et al. Clin Ther. 2008;30:1448-1460.
Hypoglycemia With Exenatide
Monotherapy
24 Weeks1
Add-on to Metformin
30 Weeks2
Add-on to
Sulfonylurea
30 Weeks3
Add-on to TZD
16 Weeks4
233
336
377
233
N
Treatment†
PBO
Exe
Met
Exe +
Met
SU
Exe +
SU
Patients Reporting
Hypoglycemia (%)
40
TZD
Exe +
TZD
36
35
30
25
20
15
10.7
10
5
4
1
5
5
7.1
3
0
†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.
Exenatide: 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
6
3
7
1
Asthenia
4
2
GERD
3
1
3
0
Hyperhidrosis
3
1
Adverse Events*
Dyspepsia
3
0
*Occurring in ≥2% of patients receiving exenatide
Byetta (exenatide) injection prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2013 .
Glucose Control With Exenatide ER
Add-on to
OAs*
30 Weeks1
Monotherapy vs
OAs
26 Weeks2
Add-on to
Metformin
26 Weeks3
Add-on to
Met +/- SU
26 Weeks4
Add-on to
OAs†
26 Weeks5
258
820
514
456
911
N
Exe Exe
BID ER
Sit
Pio
Met Exe
ER
Sit+ Pio+ Exe
Met Met ER+
Met
Baseline
A1C (%)
8.3
8.5
8.5
8.6
8.5
 A1C (%)
Treatment
8.3
8.5
8.5
8.6
Glar Exe
+
ER +
OAs OAs
8.3
8.3
Lira Exe ER
+
+
OAs OAs
8.4
8.5
0
-0.5
-1
-0.9
-1.15
-1.5
-1.20
-1.5
-1.63
-2
P<0.01
-1.90
-1.48-1.53
P<0.001
-1.3
-1.5
P<0.0001
-1.50
P=0.017
-1.28
-1.48
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.
Weight Reduction With Exenatide ER
N
 Weight (kg)
Treatment
(mg/day)
4
3
2
1
0
-1
-2
-3
-4
-5
Add-on to
OAs*
30 Weeks1
Monotherapy vs
OAs
26 Weeks2
Add-on to
Metformin
26 Weeks3
Add-on to
Met +/- SU
26 Weeks4
Add-on to
OAs†
26 Weeks5
258
820
514
456
911
Glar Exe
+ ER +
OAs OAs
Lira Exe
+ ER +
OAs OAs
Exe Exe
BID ER
Sit
Pio
Met Exe
ER
Sit+ Pio+ Exe
Met Met ER+
Met
2.8
1.5
1.4
-0.8
-0.8
-2.0 -2.0
-2.3
-3.6 -3.7
-2.6
P<0.0001
P<0.001
-2.7
-3.6
P<0.001
*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents.
†Metformin,
sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.
1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258.
3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243.
5. Buse JB, et al. Lancet. 2013;381:117-124.
Hypoglycemia With Exenatide ER
N
Patients reporting
hypoglycemia (%)
Treatment
35
30
25
20
15
10
5
0
Add-on to
OAs*
30 Weeks1
Monotherapy vs
OAs
26 Weeks2
Add-on to
Metformin
26 Weeks3
Add-on to
Met +/- SU
26 Weeks4
Add-on to
OAs†
26 Weeks5
258
820
514
456
911
Glar Exe
+ ER +
OAs OAs
Lira Exe
+ ER +
OAs OAs
Exe Exe
BID ER
Sit
Pio
Met
Exe
ER
Sit+ Pio+ Exe
Met Met ER+
Met
31.0
13.0
8.9
6.1 5.4
5.2
3.1 3.7 4.1
3.0
11.0
1.0 1.0
*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.
Exenatide Extended Release:
Adverse Events
Patients (%)
Adverse
Events*
Monotherapy
+ Met
+ Met +/- SU
Exe ER
Sit
Pio
Met
Exe ER
Sit
Pio
Exe ER
Glar
(n=248)
(n=163)
(n=163)
(n=246)
(n=160)
(n=166)
(n=165)
(n=233)
(n=233)
Nausea
11.3
3.7
4.3
6.9
24.4
9.6
4.8
12.9
1.3
Diarrhea
10.9
5.5
3.7
12.6
20.0
9.6
7.3
9.4
4.0
Injection site
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.
Glucose Control With Liraglutide
Monotherapy vs
Glimepiride
52 Weeks1
Add-on to
Metformin
26 Weeks2
Add-on to
Metformin
26 Weeks3
Add-on to
Sulfonylurea
26 Weeks4
Add-on to
Met + TZD
26 Weeks5
Add-on to
Met + SU
26 Weeks6
N
746
1091
665
1041
821
581
Treatment
Glim
Lir
Met Glim
+
Met
Lir+
Met
Sit+
Met
Lir+
Met
SU
8.4
8.3
8.4
8.4
8.5
8.4
8.4
Baseline
A1C (%)
8.4
0.5
Rosi Lir+
+
SU
SU
8.4
8.5
Rosi Lir+ Met+ Glar+ Lir+
+ Rosi+ SU Met+ Met+
Met Met
SU
SU
8.4
8.6
8.3
8.2
8.3
0.23
0.09
 A1C (%)
0
-0.5
-0.24
-0.44
-0.51
-1
-1.5
-2
-1.14
*
-0.98 -1.00
*
-0.5
-0.9
-1.09
-1.13
-1.50
**
*
**
-1.50
**
-1.33
**
***
*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.
Weight Reduction With Liraglutide
Add-on to
Metformin
26 Weeks2
Add-on to
Metformin
26 Weeks3
Add-on to
Sulfonylurea
26 Weeks4
Add-on to
Met + TZD
26 Weeks5
Add-on to
Met + SU
26 Weeks6
N
746
1091
665
1041
821
581
Treatment
Glim
 Weight (kg)
Monotherapy vs
Glimepiride
52 Weeks1
3
2
1
0
-1
-2
-3
-4
Lir
Met Glim
+
Met
Lir+
Met
Sit+
Met
Lir+
Met
SU
Rosi Lir+
+
SU
SU
Rosi Lir+ Met+ Glar+ Lir+
+ Rosi+ SU Met+ Met+
Met Met
SU
SU
***
2.10
1.60
1.00
1.10
0.60
-0.10
-0.96
-1.50
-2.50
*
-2.80
*
**
-0.20
-0.42
*
-3.38
-2.00
-1.80
*
*
*
*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.
Blood Pressure Changes
With Liraglutide
N
Treatment
Monotherapy vs
Glimepiride
52 Weeks1
Add-on to
Metformin
26 Weeks2
Add-on to
Metformin
26 Weeks3
Add-on to
Sulfonylurea
26 Weeks4,5
Add-on to
Met + TZD
26 Weeks6
Add-on to
Met + SU
26 Weeks7
746
1091
665
1041
821
581
Glim
Lir
Met Glim
+
Met
 Systolic BP
(mmHg)
1
Lir+
Met
Sit+
Met
Lir+
Met
SU
Rosi Lir+
+
SU
SU
Rosi Lir+ Met+ Glar+ Lir+
+ Rosi+ SU Met+ Met+
Met Met
SU
SU
0.5
0.4
0
-1
-0.7
-0.9 -0.7
-2
-1.8
-3
-4
-3.6
-5
*
-6
-2.3
*
-0.9
-2.3
-1.1
-2.8
-4.0
-5.6
*
†All
*
*P<0.05 vs comparator.
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
Hypoglycemia With Liraglutide
Monotherapy
52 Weeks1
Add-on to Metformin
26 Weeks2
Add-on to Metformin
26 Weeks3
Add-on to Sulfonylurea
26 Weeks4
746
1091
665
1041
N
Treatment†
Glim
Lir
Met
Glim+
Met
Lir+
Met
Sit+
Met
Lir+
Met
SU
Rosi+
SU
Lir+
SU
Patients Reporting
Hypoglycemia (%)
30
25
24
20
15
10
5
17
*
*8
3
*3
8.1
5
5
2.6
4.3
0
*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.
Liraglutide: Adverse Events
Patients (%)
Monotherapy
+ Met
+ Glim
+ Met + TZD
Adverse
Events*
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
5.1
1.1
Headache
9.1
9.3
8.2
4.6
Dyspepsia
5.3
9.0
0.9
6.6
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
SGLT2 Inhibitors
FDA-Approved Agents
• Canagliflozin
• Dapagliflozin
Key Features
• Oral administration
• Inhibit reabsorption of glucose
into the bloodstream from renal
fluid
50
SGLT2, sodium-glucose cotransporter 2.
DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14.
Glucose Control
with SGLT2 Inhibitors
Placebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)
Monotherapy
Baseline A1C (%)
Add-on to Metformin
Add-on to Insulin +/- OAs
Can1
Dap2
Can3
Dap4
Can5
Dap6
8.1
7.8
8.1
8.2
8.2
8.6
Placebo-adjusted
 A1C (%)
0
-0.2
-0.4
-0.6
-0.52*
-0.66
-0.8
-1
-1.2
-1.4
-0.4
-0.57
-0.9*
-1.2
*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.
Weight Change
with SGLT2 Inhibitors
Absolute Change from Baseline
(Not Head-to-Head Trials)
Monotherapy
 Weight (kg)
Can1
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
-4
-4.5
Dap2
Add-on to Metformin
Can3
Dap4
Add-on to Insulin +/- OAs
Can5
-1.4
-3.4
-3.2
Dap6
-1.6
-3.2
-4.0
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.
Hypoglycemia
with SGLT2 Inhibitors
Percentage of Patients Reporting Hypoglycemia
(Not Head-to-Head Trials)
Monotherapy
Can1
Dap2
Add-on to Metformin
Can3
Dap4
Add-on to Insulin +/- OAs
Can5
60
51.2
Dap6
53.6
Patients (%)
50
40
30
20
10
3.0
2.9
5.0
3.4
0
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.
Safety Considerations
with 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.
Glucose Control With Canagliflozin
Monotherapy
26 Weeks1
Add-on to
Metformin
12 Weeks2
Add-on to
Metformin
52 Weeks3
Add-on to
Metformin + SU
52 Weeks4
Add-on to
OAs +/- Insulin
in CKD*
26 Weeks5
N
584
451
1452
755
269
Treatment
(mg/day)
PBO
Can†
Met
Sit +
Met
Can +
Met
8.0
8.0
7.8
7.6
7.7
 A1C (%)
Baseline A1C
(%)
0.2
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
Glim + Can +
Met
Met
7.8
7.8
Sit+
Met+
SU
Can+
Met+
SU
Ins +
OAs
Can +
Ins +
OAs
8.1
8.1
8.0
8.0
0.14
-0.03
-0.22
-0.44
-1.03
**
**
**
-0.66
-0.74
-0.92
-0.81
-0.93
**
-1.03
‡
*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.
**P<0.001 vs placebo.
†All
‡Met
dosages shown are canaglifozin 300 mg.
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.
Weight Change With Canagliflozin
Monotherapy
26 Weeks1
Add-on to
Metformin
12 Weeks2
Add-on to
Metformin
52 Weeks3
Add-on to
Metformin + SU
52 Weeks4
Add-on to
OAs +/- Insulin
in CKD*
26 Weeks5
N
584
451
1452
755
269
Treatment
(mg/day)
PBO
Can†
Met
Sit +
Met
Can +
Met
0.7
1
 Weight (kg)
Glim + Can +
Met
Met
Sit+
Met+
SU
Can+
Met+
SU
Ins +
OAs
Can +
Ins +
OAs
0.2
0.1
0
-1
-0.5
-0.9
-0.5
-1.4
-2
-2.3
-3
-4
-3.4
-5
**
**
-3.0
**
**
-4.0
**
*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
Monotherapy
26 Weeks1
Add-on to
Metformin
12 Weeks2
Add-on to
Metformin
52 Weeks3
Add-on to
Metformin + SU
52 Weeks4
Add-on to
OAs +/- Insulin
in CKD*
26 Weeks5
N
584
451
1452
755
269
Treatment
(mg/day)
PBO
Can†
Met
Sit +
Met
Can +
Met
Glim + Can +
Met
Met
2
 Systolic BP
(mmHg)
0.4
Sit+
Met+
SU
Can+
Met+
SU
Ins +
OAs
Can +
Ins +
OAs
0.9
0.2
0
-4
-6
-8
-0.3
-1.3 -0.8
-2
-3.6
-5.0
**
-4.6
-5.1
**
-6.4
*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.
Hypoglycemia With Canagliflozin
Add-on to
Metformin
52 Weeks3
Add-on to
Metformin + SU
52 Weeks4
N
584
451
1452
755
269
Treatment
(mg/day)
PBO
Glim + Can +
Met
Met
Sit+
Met+
SU
Patients reporting
hypoglycemia (%)
Monotherapy
26 Weeks1
Add-on to
Metformin
12 Weeks2
Add-on to
OAs +/- Insulin
in CKD*
26 Weeks5
Can†
Met
Sit +
Met
Can +
Met
60
Can+
Met+
SU
Ins +
OAs
Can +
Ins +
OAs
51.2
50
40.7 43.2
40
34.0
36.4
30
20
10
0
2.6
3.0
2.0
5.0
5.0
0.0
*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.
Canagliflozin: Adverse Events
Patients (%)
Adverse Events*
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.
Glucose Control With Dapagliflozin
Initial Combo
with
Monotherapy Metformin
24 Weeks1
24 Weeks2
N
485
Treatment
(mg/day)
PBO Dap*
Baseline A1C
(%)
7.8
603
8.0
Met
Dap Dap +
Met
9.1
9.1
9.1
Add-on to
Metformin
52 Weeks3
Add-on to
Pioglitazone
24 Weeks4
814
480
Glip Dap +
+ Met Met
8.1
7.9
451
Pio Dap +
Pio
8.3
8.4
 A1C (%)
0.5
-0.23
-0.52 -0.52
-1
-0.89
-1.5
***
-2
-2.5
808
Sit+/- Dap+
Met Sit+/Met
8.7
8.7
Ins+/- Dap+
OAs Ins+/OAs
8.5
8.6
0
0
-0.5
Add-on to
Sitagliptin +/Add-on to
Metformin
insulin + OAs
24 Weeks5
24 Weeks6
-0.42
-0.50
-0.97
***
-1.44-1.45
***
-0.39
-0.96
**
-1.98
***
*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
Initial Combo
with
Monotherapy Metformin
24 Weeks1
24 Weeks2
N
485
603
Treatment
(mg/day)
PBO Dap*
Met
Dap Dap +
Met
 Weight (kg)
2
Add-on to
Metformin
52 Weeks3
Add-on to
Pioglitazone
24 Weeks4
814
480
Glip Dap +
+ Met Met
Add-on to
Sitagliptin +/Add-on to
Metformin
insulin + OAs
24 Weeks5
24 Weeks6
451
Pio Dap +
Pio
808
Sit+/- Dap+
Met Sit+/Met
Ins+/- Dap+
OAs Ins+/OAs
1.6
1.4
1
0.4
0
-0.1
-1
-3
-4
***
-1.4
-2
-0.3
-1.6
-2.1
-2.2
-3.2
-2.7
-3.3
-3.2
***
***
***
**
*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.
Blood Pressure Change With
Dapagliflozin
Initial Combo
with
Monotherapy Metformin
24 Weeks1
24 Weeks2
N
485
603
Treatment
(mg/day)
PBO Dap* Met
Dap Dap +
Met
 Systolic BP
(mmHg)
2
Add-on to
Metformin
52 Weeks3
Add-on to
Pioglitazone
24 Weeks4
814
480
Glip Dap +
+ Met Met
Add-on to
Sitagliptin +/Add-on to
Metformin
insulin + OAs
5
24 Weeks
24 Weeks6
451
Pio Dap +
Pio
808
Sit+/- Dap+
Met Sit+/Met
Ins+/- Dap+
OAs Ins+/OAs
1.3
0.8
0
-2
-4
-6
-8
-0.9
-1.2
-3.6
-4.0
-3.3
-3.4
-4.3
-3.6
-5.1
-6.0
-6.7
*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 Dapagliflozin
Initial Combo
with
Monotherapy Metformin
24 Weeks1
24 Weeks2
485
603
Treatment
(mg/day)
PBO Dap* Met
Dap Dap +
Met
Patients reporting
hypoglycemia (%)
N
Add-on to
Metformin
52 Weeks3
Add-on to
Pioglitazone
24 Weeks4
814
480
Glip Dap +
+ Met Met
Pio Dap +
Pio
Add-on to
Sitagliptin+/Add-on to
Metformin
insulin + OAs
5
24 Weeks
24 Weeks6
451
Sit+/- Dap+
Met Sit+/Met
60
808
Ins+/- Dap+
OAs Ins+/OAs
51.8 53.6
50
39.7
40
30
20
10
0
2.7
2.9
2.9 0.9
3.3
3.4
0.7 0.0
1.8 2.7
*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.
Dapagliflozin: Adverse Events
Patients (%)
Adverse Events*
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.
Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company. 2014.
Inhaled Insulin
65
Inhaled Insulin
FDA-Approved Agent
• Technosphere insulin
Key Features
• Inhaled administration
• Rapid-acting insulin
– Peak levels achieved in ~15
minutes
66
Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.
Glucose Control with
Technosphere Insulin
Add-on to Metformin and/or Other OAs
24 Weeks
Placebo
N
Technosphere insulin
353
Baseline A1C (%)
8.3
8.3
 A1C (%)
0
-0.2
*
-0.4
-0.42
-0.6
-0.8
-0.82
-1
*
*Difference from placebo (95% CI): -0.40% (-0.57% to -0.23%).
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Weight Change with
Technosphere Insulin
Add-on to Metformin and/or Other OAs
24 Weeks
Placebo
N
Technosphere insulin
353
 Weight (kg)
1
0.49
0.5
*
0
-0.5
-1
-1.5
-1.13
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Hypoglycemia with
Technosphere Insulin
Add-on to Metformin and/or Other OAs
24 Weeks
N
353
Nonsevere
Patients With
Hypoglycemia (%)
PBO
80
Severe
TI
PBO
TI
67
60
40
30
20
1.7
5.1
0
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Safety Considerations
with Technosphere Insulin
•
•
Lung disease
•
Heart failure
Hypoglycemia
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
•
Observe for signs and symptoms of fluid retention or heart failure,
especially when used with TZDs
•
Increase frequency of glucose monitoring
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Technosphere Insulin:
Adverse Events
Patients (%)
Adverse Events*
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
Glucose Reduction
DPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin
(Absolute Changes from Baseline; Not Head-to-Head Trials)
DPP-4 Inhibitors
 A1C (%)
Baseline A1C (%)
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
-1.4
-1.6
GLP-1 Receptor Agonists
SGLT2 Inhibitors
Alo1
Lin2
Sax3
Sit4
Alb5
Exe6
Exe ER7
Lir8
Can9
Dap10
7.9
8.1
8.1
8.0
8.1
8.2
8.6
8.4
7.8
7.9
-0.6
-0.5
-0.7
-0.7
-0.52
-0.63
-0.8
-0.93
-1.5
-1.5
1. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 2. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 3. DeFronzo
RA, et al. Diabetes Care. 2009;32:1649-1655. 4. . Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 5. Ahrén B, et al.
Diabetes Care. 2014 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.
Weight Reduction
DPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin
(Separate Studies; Not Head-to-Head Trials)
 Weight (kg)
DPP-4 Inhibitors
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
-4
-4.5
Alo1
Lin2
-0.3
-0.4
Sax3
GLP-1 Receptor Agonists
Sit4
Alb5
Exe6
Exe ER7
Lir8
SGLT2
Inhibitors
Can9
Dap10
NR
-0.87
-1.21
-2
-2.8
-2.8
-3.2
-4
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.
Effects of Antihyperglycemic
Therapies on Blood Pressure
Meta-analyses
Class
∆ Systolic BP, mmHg
(95% CI)
∆ Diastolic BP, mmHg
(95% CI)
-3.57
(-5.49 to -1.66)
-0.1
(-1.2 to 0.8)
-1.38
(-2.02 to -0.73)
-3.77
(-4.65 to -2.90)
-1.75
(-2.27 to -1.23)
-1.09
(-3.01 to 0.82)
-4.70
(-6.13 to -3.27)
-0.97
(-2.15 to 0.21)
-3.79
(-5.82 to -1.77)
Newer therapies
GLP-1 receptor agonists1
DPP-4 inhibitors2
SGLT2 inhibitors3
—
Older therapies
Metformin4
TZDs5
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.