glycemic management in type 2 diabetes efficacy and safety of antihyperglycemic therapies introduced...
TRANSCRIPT
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Glycemic Management in Type 2 Diabetes
Efficacy and Safety of Antihyperglycemic Therapies
Introduced Since 2004
1
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*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..
A
1C (
%)
Glucose Control With Sitagliptin: Selected Mono and Combination Therapy Studies
-2-1.8-1.6-1.4-1.2
-1-0.8-0.6-0.4-0.2
0
-0.67 -0.66-0.67
-1.13
-0.02
0
-1.4
-0.3
-1.9
-0.67 -0.6
-1.4
-1.1
Monotherapyvs 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 Sit Glip Sit Met Sit+Met
Met Sit+Met
Ins Sit+Ins
Met +Pio
Sit +Pio
Rosi + Met
Sit +Rosi
+Met
Baseline A1C (%)
7.5 7.5 8.9 8.7 8.8 8.0 8.0 8.6 8.7 8.4 8.5 8.7 8.8
*
* *†
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*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: Selected Mono and Combination Therapy Studies
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
†
*
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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 Sitagliptin:Selected Studies
0
5
10
15
20
25
30
35
4.9
0.62.8
32
1.1 2.10
7.5 8.0
2.2 1.3 1.1
16.4 16.0
Sitagliptin vs Glipizide
52 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 Sit Glip PBO Met Sit +Met
Met Sit +Met
Pio Sit +Pio
Glim Sit +Glim
Sit +Glim +
Met
Ins Sit +Ins
Pat
ient
s R
epor
ting
Hyp
ogly
cem
ia (
%)
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Incidence of 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.
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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:Mono and Combination Therapy
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
*
A
1C (
%)
*
*
**
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*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: Mono and Combination Therapy
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
*
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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:Mono and Combination TherapyMonotherapy
24 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
Pat
ient
s R
epor
ting
Hyp
ogly
cem
ia (
%)
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Incidence of Adverse Events With Saxagliptin
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. 2011.
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* 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:Mono and Combination Therapy
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
A
1C (
%)
*
**
*
†
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Weight Changes With LinagliptinInitial 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
W
eigh
t (kg
)
* P<0.0001 vs comparator.
HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily).
1. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 2. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661.3. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 4. Gallwitz B, et al. Lancet. 2012;380:475-483.
*
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Hypoglycemia With Linagliptin:Mono and Combination Therapy
Pat
ient
s R
epor
ting
Hyp
ogly
cem
ia (
%)
0
5
10
15
20
25
30
35
40
0.63.4
02.8
36
14.8
0.33.5
1.2 0.6
7
22.7
0 0
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
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.
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Incidence of Adverse Events With Linagliptin
Tradjenta (linagliptin) prescribing information. Ridgefield, CT: Boehringer Ingelheim, Inc.; 2012.
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.
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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:Mono and Combination Therapy
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
A
1C (
%)
* * * *
*
*
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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
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
)
*
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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
Monotherapy26 Weeks1,2
Add-on to Metformin26 Weeks3
Add-on to Glyburide26 Weeks4
Add-on toMet + Pio52 Weeks5
Add-on to Insulin +/- 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 (
%)
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Incidence of Adverse Events With Alogliptin
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.
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A
1C (
%)
Glucose Control With Exenatide With/Without Oral Agents
*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.
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
-0.2
0.1 0.12 0.090.2
-1.1
-0.9-0.8 -0.86 -0.89 -0.9
-1.1
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 (%) 8.2 8.2 8.7 8.6 7.9 7.9 8.5 8.5 8.3 8.2
* * ***
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W
eigh
t (kg
) Weight Reduction With Exenatide: Mono
and Dual Combination Therapy
*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
** **
***
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*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
Monotherapy24 Weeks
N 233
Treatment PBO Exe 10 μg BID
*
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†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:Mono and Dual Combination Therapy
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
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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. San Diego, CA: Amylin Pharmaceuticals, Inc. 2011 .
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*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 Liraglutide With/Without Oral Agents
A
1C (
%)
-1.6-1.4-1.2
-1-0.8-0.6-0.4-0.2
00.20.4
-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
Lira +Met
Sit +Met
Lira +Met
SU Rosi +
SU
Lira +SU
Rosi +
Met
Lira +Rosi +
Met
Met +SU
Glar +Met +
SU
Lira +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
*** ***
*******
*
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*P<0.0001 vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU.†All liraglutide dosages shown are 1.8 mg QD.
1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230.
6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.
-4
-3
-2
-1
0
1
2
3
1.10 1.00
-0.96
2.10
0.60
1.60
-2.50 -2.80-3.38
-0.20
-2.00 -1.80-1.50
-0.10-0.42
W
eigh
t (kg
) Weight Reduction With Liraglutide: Mono
and Dual Combination Therapy
* ****
*
*
***
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
Lira +Met
Sit +Met
Lira +Met
SU Rosi +
SU
Lira +SU
Rosi +
Met
Lira +Rosi +
Met
Met +SU
Glar +Met +
SU
Lira +Met +
SU
*
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Blood Pressure Changes With Liraglutide
-6
-5
-4
-3
-2
-1
0
1
-0.7
0.4
-0.9 -0.9 -1.1
0.5
-3.6
-2.3
-0.7
-2.8
-5.6
-4.0
-1.8-2.3
S
ysto
lic B
P
(mm
Hg)
**
**
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
Lira +Met
Sit +Met
Lira +Met
SU Rosi +
SU
Lira +SU
Rosi +
Met
Lira +Rosi +
Met
Met +SU
Glar +Met +
SU
Lira +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
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*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:Mono and Dual Combination Therapy
Monotherapy52 Weeks1
Add-on to Metformin26 Weeks2
Add-on to Metformin26 Weeks3
Add-on to Sulfonylurea26 Weeks4
N 746 1091 665 1041
Treatment† Glim Lira Met Glim +Met
Lira +Met
Sit +Met
Lira +Met
SU Rosi +SU
Lira +SU
*
Pat
ient
s R
epor
ting
Hyp
ogly
cem
ia (
%)
**
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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. 2012.
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*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 ER
A1C
(%
)
Add-on toOAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin26 Weeks3
Add-on toMet +/- SU26 Weeks4
Add-on toOAs†
26 Weeks5
N 258 820 514 456 911
Treatment Exe BID
Exe ER
Sit Pio Met Exe ER
Sit Pio Exe ER
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
P<0.001 P<0.0001P<0.01P=0.017 P=0.02
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*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents.†Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.
1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258.3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243.
5. Buse JB, et al. Lancet. 2013;381:117-124.
Add-on toOAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin26 Weeks3
Add-on toMet +/- SU26 Weeks4
Add-on toOAs†
26 Weeks5
N 258 820 514 456 911
Treatment (mg/day)
Exe BID
Exe ER
Sit Pio Met Exe ER
Sit Pio Exe ER
Glar +
OAs
Exe ER + OAs
Lira +
OAs
Exe ER + OAs
P<0.0001
W
eigh
t (kg
)
Weight Reduction With Exenatide ER
P<0.001P<0.001
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*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.
0
5
10
15
20
25
30
35
6.1 3.7 3.0
31.0
8.95.4 4.1
1.0
13.011.0
3.15.2
1.0
Add-on toOAs*
30 Weeks1
Monotherapy vs OAs
26 Weeks2
Add-on to Metformin26 Weeks3
Add-on toMet +/- SU26 Weeks4
Add-on toOAs†
26 Weeks5
N 258 820 514 456 911
Treatment Exe BID
Exe ER
Sit Pio Met Exe ER
Sit Pio Exe ER
Glar +
OAs
Exe ER + OAs
Lira +
OAs
Exe ER + OAs
Pat
ient
s re
port
ing
hypo
glyc
emia
(%
)
Hypoglycemia With Exenatide ER
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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.San Diego, CA: Amylin Pharmaceuticals, Inc. 2012.
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*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.
**P<0.001 vs placebo. ***P<0.05 vs placebo.†Met criteria for noninferiority and superiority (upper limit of confidence interval <0.0%).
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.3. Schernthaner G, et al. Diabetes Care. 2013;April 5 epub ahead of print. 4. 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
0
0.2
0.40.14
-0.74 -0.66
-0.03
-0.77 -0.76
-1.03
-0.33
-1.03-0.92
-0.44
-0.22
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on toMetformin + SU
52 Weeks3
Add-on toOAs +/- Insulin in
CKD*26 Weeks4
N 584 451 755 269
Treatment (mg/day)
PBO Can 100
Can 300
PBO Sit Can 100
Can 300
Sit Can 300
PBO Can 100
Can 300
Baseline A1C (%)
8.0 8.1 8.0 7.8 7.6 7.8 7.7 8.1 8.1 8.0 7.9 8.0
****
******
†
*****
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*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.
**P<0.001 vs placebo. †P<0.001 vs sitagliptin.
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.3. Schernthaner G, et al. Diabetes Care. 2013;April 5 epub ahead of print. 4. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473.
Weight Change With Canagliflozin
-4-3.5
-3-2.5
-2-1.5
-1-0.5
00.5
-0.5 -0.5
0.1 0.2
-2.5-2.3 -2.3
-1.2
-3.4-3.0
-1.4-0.9
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on toMetformin + SU
52 Weeks3
Add-on toOAs +/- Insulin in
CKD*26 Weeks4
N 584 451 755 269
Treatment (mg/day)
PBO Can 100
Can 300
PBO Sit Can 100
Can 300
Sit Can 300
PBO Can 100
Can 300
**
****
** † W
eigh
t (kg
)
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*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.
**P<0.001 vs comparator.
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.3. Schernthaner G, et al. Diabetes Care. 2013;April 5 epub ahead of print. 4. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473.
Blood Pressure Change With Canagliflozin
-7-6-5-4-3-2-1012
0.4
-0.8
0.9
-0.3
-3.3
1.0
-5.1-6.1
-5.0
-3.6
-6.4
-1.3
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on toMetformin + SU
52 Weeks3
Add-on toOAs +/- Insulin
in CKD*26 Weeks4
N 584 451 755 269
Treatment (mg/day)
PBO Can 100
Can 300
PBO Sit Can 100
Can 300
Sit Can 300
PBO Can 100
Can 300
S
ysto
lic B
P
(mm
Hg)
**
**
**
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*Estimated glumerular filtration rate 30-50 mL/min/1.73 m2.
**P<0.001 vs placebo. ***P<0.05 vs placebo.†Met criteria for noninferiority and superiority (upper limit of confidence interval <0.0%).
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.3. Schernthaner G, et al. Diabetes Care. 2013;April 5 epub ahead of print. 4. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473.
Hypoglycemia With Canagliflozin
0
10
20
30
40
50
60
35
4136
4 2
43
53
30
51
2
Monotherapy26 Weeks1
Add-on toMetformin12 Weeks2
Add-on toMetformin + SU
52 Weeks3
Add-on toOAs +/- Insulin in
CKD*26 Weeks4
N 584 451 755 269
Treatment (mg/day)
PBO Can 100
Can 300
PBO Sit Can 100
Can 300
Sit Can 300
PBO Can 100
Can 300
Pat
ient
s re
port
ing
hypo
glyc
emia
(%
)
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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. 2013.