Are All DPP-4i the same?

1
Are All DPP-4i the same?

 Incretins and DPP-4 Inhibition

 DPP-4 Inhibitors: Pharmacologic Profile
 Clinical Profile for Sitagliptin
 Safety Profile for Sitagliptin
 Summary and Conclusion

2
 A Brief History of Incretins

Incretin effect shown to DPP-4 identified as an

First definition of First description of
be reduced in patients enzyme that inactivates
incretins3 DPP-46
with type 2 diabetes7 GIP and GLP-19,10

1902 1932 1964 1966 1973 1986 1987 1995

First observation of
Demonstration of the GIP identified as a GLP-1 identified as a
intestinal effect on
incretin effect1,4,5 human incretin1 human incretin8
pancreatic secretion1,2

DPP-4 = dipeptidyl peptidase-4; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1.
1. Creutzfeldt W. Regul Pept. 2005;128:87–91. 2. Bayliss WM et al. J Physiol. 1902;28:325–353. 3. La Barre J. Bull Acad R Med Belg. 1932;120:620–634. 4. McIntyre N et al. Lancet.
1964;284:20–21. 5. Elrick H et al. J Clin Endocr. 1964;24:1076–1082. 6. Hopsu-Havu VK et al. Histochemie. 1966;7:197–201. 7. Nauck M et al. Diabetologia. 1986;29:46–52.
8. Kreymann B et al. Lancet. 1987;330:1300–1304. 9. Kieffer TJ et al. Endocrinology. 1995;136;3585–3596. 10. Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952–957. 3
 Incretin Hormones Have Key Roles in
Glucose Homeostasis

GLP-1 GIP
 Is released from L cells in ileum  Is released from K cells in duodenum1,2
and colon1,2
 Stimulates insulin response from beta
 Stimulates insulin response from beta cells in a glucose-dependent manner1
cells in a glucose-dependent manner1
 Does not affect gastric emptying2
 Inhibits glucagon secretion from
 Has no significant effects on satiety
alpha cells in a glucose-dependent
or body weight2
manner1
 Inhibits gastric emptyinga,1,2
 Reduces food intake and body weighta,2

aEffectsoccur only with pharmacologic levels of GLP-1.

GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1.
1. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 2. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. 4
 GLP-1 and GIP Have Short Half-Lives
Due to Inactivation by DPP-4
DPP-4 cleavage of GLP-11 DPP-4 cleavage of GIP1
t1/2 ~2 min t1/2 = 5-7 min2,a
7
HA– –NH2
9 42
1
YA–
–NH2
36 3
Agonist, active Agonist, active
DPP-4
7 –NH2
9 DPP-4 42

–NH2 1
36 3
Inactive Inactive
a5 minutes in T2DM and 7 minutes in healthy patients.2
DPP-4 = dipeptidyl peptidase-4; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1.
1. Drucker DJ. Diabetes Care. 2003; 26:2929–2940. 2. Deacon CF et al. J Clin. Endocrinol. Metab. 2000;85:3575–3581. 5
 Therapeutic Strategies to Enhance Incretin
Action1,2

 GLP-1 receptor agonists

(GLP-1 receptor activators; incretin mimetics)
Purpose: Raise agonist plasma concentrations into the pharmacologic range
– DPP-4-resistant GLP-1 mimetics
– GLP-1 analogues with delayed absorption

 DPP-4 inhibitors
(incretin enhancers)
Purpose: Prevent degradation of endogenously released incretin hormones
to elevate plasma levels of the active incretins

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1.

1. Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952–957. 2. Brubaker PL. Trends Endocrinol Metab. 2007;18:240–245. 6
 DPP-4 Inhibition Increases
Concentrations of Active Incretins1–4
Adipose Skeletal
tissue muscle
Ingestion
of food
Pancreatic islet  Peripheral
glucose uptake

Active GIPa
Glucose-
β-cell dependent
Insulin Glucose
Active GLP-1a FPG, PPG
Glucose-
α-cell dependent
GI tract
DPP-4 Glucagon
Sitagliptin
(DPP-4 inhibitor) X  Hepatic
glucose
production
Liver
Inactive Inactive
GLP-1 GIP
Adapted with permission from Drucker D.4
aIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal.

GI = gastrointestinal; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1; DPP-4 = dipeptidyl peptidase-4; FPG = fasting plasma glucose;
PPG = postprandial plasma glucose.
1. Ahrén B. Curr Diabetes Rep. 2003;3:365–372. 2. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 3. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
4. Drucker D. J Clin Invest. 2007;117:24–32. 7
 Sitagliptin Has Effects on Active Incretins, Insulin,
Glucagon, and Blood Glucose1
Randomized, placebo-controlled, 4-period, crossover study in T2DM (N=24)
Effects of sitagliptin vs placebo on OGTT (75 g)
↑GLP-1 ↑Insulin
↓Glucose
↑GIP ↓Glucagon
20 100
Active GLP-1a 80
C-peptidea
15
60 Glucosea
pmol/L

ng/mL
10 300
40
250
5 20

mg/dL
200
0 0
–60 0 60 120 180 240 60 0 60 120 180 240 150
70
60 Active GIPa 50 Glucagona 100
50 40 –60 0 60 120 180 240
pmol/L

pg/mL

40 30 Minutes
30
20
20
10 10 Placebo
0 0
–60 0 60 120 180 240 –60 0 60 120 180 240 Sitagliptin (100 mg)
Minutes Minutes
Adapted with permission from Aulinger BA et al.1
Data are expressed as mean ± SEM.
aP<0.05 sitagliptin vs placebo for incremental AUC values after OGTT.

T2DM = type 2 diabetes mellitus; OGTT = oral glucose tolerance test; GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic peptide; SEM = Standard error of the mean.
1. Aulinger BA et al. Diabetes. 2014;63:1079–1092. 8
 Sitagliptin Effects May Occur via GLP-1–
Dependent and Independent Mechanisms1
Randomized, placebo-controlled, 4-period, crossover study in T2DM (N=24)
with infusion of either the GLP-1 receptor antagonist exendin (9-39) or saline

Incremental C-Peptide AUC Over 240 Minutes Following 75-g OGTT

 In the presence of exendin (9-39):
12

C-peptide AUC, μg/mL·240 minc

– Glucose-lowering effect of 8.5a
sitagliptin was reduced by ~50% 10
6.0a,b
– Insulinotropic effect of sitagliptin 8 5.7
was reduced by ~50% 4.6b
6 GLP-1-
– Glucagon-suppressing effect of independent
sitagliptin was abolished 4
 GLP-1-independent effects of 2
sitagliptin on insulin and glucose are
0
likely to be mediated by GIP Placebo Sitagliptin Placebo Sitagliptin
Saline IV GLP-1 Receptor Antagonist
Adapted with permission from Aulinger BA et al. 1 Exendin (9-39) IV
aP<0.001 for sitagliptin vs placebo.
bP<0.01 for exendin (9-39) vs saline.
cMean ±standard error of the mean.

GLP-1 = glucagon-like peptide-1; T2DM = type 2 diabetes mellitus; AUC = area under the concentration/time curve; SEM = standard error of the mean; OGTT = oral glucose tolerance test;
IV = intravenous.
1. Aulinger BA et al. Diabetes. 2014;63:1079–1092. 9
 Sitagliptin Partially Restores Insulin Secretory
Response to GIP in T2DM
Randomized, placebo-controlled study in patients with T2DM after treatment with sitagliptin
(n=12) or placebo (n=13) as add-on to metformin1
P<0.05 P<0.05
35 P=0.004
Insulin AUC, pmol/L × 120 min

30 GIP

25 Saline

20

15

10

0
Sitagliptin Placebo Sitagliptin Placebo
Week 1 Week 12

Treatment with sitagliptin for 12 weeks partially restored the insulin

secretory response to GIP1 that is absent in T2DM2,3
GIP = glucose-dependent insulinotropic peptide; T2DM = type 2 diabetes mellitus; AUC = area under the concentration/time curve.
1. Aaboe K et al. Diabetes, Obesity and Metabolism. 2015;17:74–81. 2. Nauck MA et al. J Clin Invest. 1993;91:301–307. 3. Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88:4897–4903. 10
DPP-4 Inhibitors: Focus on Sitagliptin

 Incretins and DPP-4 Inhibition

 DPP-4 Inhibitors: Pharmacologic Profile
 Clinical Profile for Sitagliptin
 Safety Profile for Sitagliptin
 Summary and Conclusion

11
 DPP-4 Inhibitors Differ in Molecular Structures and
Pharmacologic Propertiesa
Chemical
Class β-Phenethylamines1 Cyanopyrrolidines5,7 Aminopiperidine9 Xanthine3
Generic
Name
Sitagliptin2 Vildagliptin6 Saxagliptin8 Alogliptin10 Linagliptin12

H O
Molecular F F NH2 O H NH2 O CN N N
N N H 3C N N
Structure3 F N N N N N
H N
N N NC O NC O O N O N N
HO HO NH2
CF3
NH 2

DPP-4
Inhibitory
Activity
~18 nM1 5.3 nM4 3.4 nM4 6.9 nM11 ~1 nM3
(IC50)
2.5 h (parent)8 Effective t1/2 ~12 h12
Half-life 12.4 h2 ~2–3 h6 21 h10
3.1 h (metabolite)8 Terminal t1/2 >100 h12

aPharmacodynamic studies were performed in different assay systems and should not be compared.

DPP-4 = dipeptidyl peptidase-4.

1. Kim D et al. J Med Chem. 2005;48:141–151. 2. EUSPC for JANUVIA. 3. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182. 4. Matsuyama-Yokono A et al. Biochem Pharmacol.
2008;76:98–107. 5. Villhauer EB et al. J Med Chem. 2003;46:2774–2789. 6. EUSPC for Galvus. 7. Augeri DJ et al. J Med Chem. 2005;48:5025–5037. 8. EUSPC for Onglyza. 9. Feng J et al.
J Med Chem. 2007;50:2297–2300. 10. EUSPC for Vipidia. 11. Lee B et al. Eur J Pharmacol. 2008;589:306–314. 12. EUSPC for Trajenta. 12
 Pharmacokinetic Properties of DPP-4 Inhibitorsa

Half-life (t1/2)
Absorption at Clinically
tmax (median) Bioavailability Relevant Dose Distribution Metabolism Elimination
Sitagliptin 1–4 h ~87% 12.4 h 38% protein bound ~16% metabolized Renal 87%
(Merck)1 (79% unchanged)
Vildagliptin 1.7 h 85% ~2–3 h 9.3% protein bound 69% metabolized Renal 85%
(Novartis)2 mainly renal (23% unchanged)
(inactive metabolite)
Saxagliptin 2 h (4 h for ≥75%4 2.5 h (parent) Low protein binding Hepatic Renal 75%
(BMS/AZ)3 active 3.1 h (metabolite) (active metabolite) (24% as parent; 36%
metabolite) CYP3A4/5 as active metabolite)

Alogliptin 1–2 h 100% ~21 h 20–30% protein binding <7% metabolized Renal 76%
(Takeda)5 (60–70% unchanged)
Linagliptin 1.5 h ~30% Effective t1/2 ~12 h Concentration-dependent ~13% metabolized Feces 80%
(BI)6 Terminal t1/2 >100 h protein binding: Renal 5%
1 nM: 99% (DPP-4)
≥30 nM: 75%–89%

aPharmacokinetic studies were performed in different assay systems and should not be compared.

DPP-4 = dipeptidyl peptidase-4.

1. EUSPC for JANUVIA. 2. EUSPC for Galvus. 3. EUSPC for Onglyza. 4. EPAR for Onglyza. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/001039/WC500044319.pdf. Accessed November 3, 2016. 5. EUSPC for Vipidia. 6. EUSPC for Trajenta. 13
 DPP-4 Is a Member of a Family of Closely
Related Proteases1

DPP-9

DPP-8

DPP-4 FAP
Gene DPP-4
Family
DPP-6

PEP

QPP/DPPII
Other Proline-
Specific APP
Peptidases Prolidase

Adapted with permission from Drucker DJ et al.1

APP = aminopeptidase P; DPP = dipeptidyl peptidase; FAP = fibroblast activation protein; PEP = prolyl endopeptidase; QPP = quiescent cell proline dipeptidase.
1. Drucker DJ et al. Diabetes Care. 2007;30:1335–1343. 14
 Select Pharmacodynamic Properties of
DPP-4 Inhibitorsa

DPP-4 Peak IC50 for DPP-8 IC50 for DPP-9 IC50 for FAP
Inhibition IC50 for DPP-4, nM (DPP-8/DPP-4), nM (DPP-9/DPP-4), nM (FAP/DPP-4), nM
Sitagliptin 48,000 >100,000 >100,000
97% ~18
(Merck)1–3 (~2,700) (>5,000) (>5,000)
Vildagliptin 1,112 66.2 73,000
~95% 5.3
(Novartis)3–5 (210) (13) (>10,000)
Saxagliptin 244 104 >1,000
80% 3.4
(BMS/AZ)3,6,7 (72) (31) (300)
Alogliptin >100,000 >100,000 >100,000
≥95% 6.9
(Takeda)3,8 (>10,000) (>10,000) (>10,000)
Linagliptin 40,000 >10,000 89
(BI)7,9 92% ~1
(~40,000) (>10,000) (~89)

Adapted with permission from Alba M et al. 1

aPharmacodynamic studies were performed in different assay systems and should not be compared.

DPP-4 = dipeptidyl peptidase-4; FAP = fibroblast activation protein α.

1. Alba M et al. Curr Med Res Opin. 2009;25:2507–2514. 2. Kim D et al. J Med Chem. 2005;48:141–151. 3. Lee B et al. Eur J Pharmacol. 2008;589:306–314.
4. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–107. 5. He YL et al. J Clin Pharmacol. 2007;47:633–641. 6. European Public Assessment Report for Onglyza.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed November 3, 2016. 7. Thomas L et al.
J Pharmacol Exp Ther. 2008;325:175–182. 8. Covington R et al. Clin Ther. 2008;30:499 –512. 9. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 15
 Rationale for Once-Daily Dosing of Sitagliptin
Based on DPP-4 Inhibition1
Single-dose study in healthy subjects (n=6)

100

80
DPP-4 Inhibition, %a

60

40

20 Sitagliptin 100 mg qd

0
0 1 2 4 6 8 12 16 24
Hours Postdose

Adapted with permission from Alba M et al.1

aDPP-4 inhibition corrected for sample assay dilution.

DPP-4 = dipeptidyl peptidase-4.

1. Alba M et al. Curr Med Res Opin. 2009;25:2507–2514. 16
 DPP-4 Inhibition in Patients With Type 2 Diabetes Treated With
Sitagliptin, Saxagliptin, or Vildagliptin: Predosea DPP-4 Inhibition
Levels Days 1–51

Primary end point: % trough DPP-4 inhibition on day 5, 24 hours postdose

100
% Inhibition of DPP-4 (mean ±SE)

90
80
70
60
50
40
30
20
10
0
–10
Day 1 Day 2 Day 3 Day 4 Day 5
Placebo once daily (n=17) Vildagliptin 50 mg twice daily (n=17) Vildagliptin 50 mg once daily (n=18)
Sitagliptin 100 mg once daily (n=17) Saxagliptin 5 mg once daily (n=20)

This study did not evaluate glycemic efficacy (ie, HbA1c)

Adapted with permission from Tatosian DA et al. 1
The dashed horizontal line indicates 94% inhibition, the maximum level of DPP-4 inhibition that was quantifiable under the assay conditions used in this study.
aBefore the morning dose for vildagliptin twice daily group.

DPP-4 = dipeptidyl peptidase-4; HbA1C = hemoglobin A1C; SE = standard error.

1. Tatosian DA et al. Diabetes Ther. 2013;4:431–442. 17
 DPP-4 Inhibition in Patients With Type 2 Diabetes:
Primary End Point1

DPP-4 Inhibition (%) at 24 Hours After Final Morning Dose

Treatment n LS Meana (95% CI)
Saxagliptin once daily 20 73.5 (66.6, 79.0)
Sitagliptin once daily 17 91.7 (91.4, 92.1)
Vildagliptin once daily 18 28.9 (17.9, 38.4)
Vildagliptin twice daily 17 90.6 (88.9, 92.1)
Placebo once daily 17 3.5 (–0.7, 7.5)

Adapted with permission from Tatosian DA et al. 1

aBack-transformed from a log scale.

DPP-4 = dipeptidyl peptidase-4; LS = least-squares; CI = confidence interval.

1. Tatosian DA et al. Diabetes Ther. 2013;4:431–442. 18
 DPP-4 Inhibition in Patients With Type 2 Diabetes:
DPP-4 Inhibition Levels After Final Morning Dose on Day 51

100
% Inhibition of DPP-4 (mean ±SE)

90
80
70
60
50
40
30
20
10
0
–10
12 Hoursa 24 Hoursb 36 Hours 48 Hours 96 Hours

Placebo once daily (n=17) Vildagliptin 50 mg twice daily (n=17) Vildagliptin 50 mg once daily (n=18)
Sitagliptin 100 mg once daily (n=17) Saxagliptin 5 mg once daily (n=20)

Adapted with permission from Tatosian DA et al. 1

The dashed horizontal line indicates 94% inhibition, the maximum level of DPP-4 inhibition that was quantifiable under the assay conditions used in this study.
aThe Day 5 morning dose was at 0 hours. The final dose of vildagliptin (twice daily) was administered at 12 hours.
bPrimary end point.

DPP-4 = dipeptidyl peptidase-4; SE = standard error.

1. Tatosian DA et al. Diabetes Ther. 2013;4:431–442. 19
 DPP-4 Inhibition in Patients With Type 2 Diabetes: Comparison of
DPP-4 Inhibition at 24 Hours After Final Morning Dose1

Comparison Differencea (90% CI) P Value

Sitagliptin vs saxagliptin 18.2 (15.0, 21.7) <0.001
Sitagliptin vs vildagliptin once daily 62.9 (58.2, 67.7) <0.001
Sitagliptin vs vildagliptin twice daily 1.1 (–0.1, 2.3) 0.128
Saxagliptin vs vildagliptin once daily 44.6 (34.5, 55.2) <0.001
Saxagliptin vs vildagliptin twice daily –17.1 (–21.2, –13.3) <0.001
Vildagliptin once vs twice daily –61.8 (–68.8, –55.2) <0.001

Adapted with permission from Tatosian DA et al. 1

aBetween-treatment differences in percent inhibition; positive values favor the first treatment listed.

DPP-4 = dipeptidyl peptidase-4; CI = confidence interval.

1. Tatosian DA et al. Diabetes Ther. 2013;4:431–442. 20
 Rationale for Once-Daily Dosing of Alogliptin
Based on DPP-4 Inhibition1

Day 1 of a 14-day study in patients with type 2 diabetes

100

80
Plasma DPP-4 Inhibition, %

60
Alogliptin 25 mg (n=15)
40 Placebo (n=11)

20

–20
0 4 6 8 12 16 24
Time After Dosing, h

Adapted with permission from Covington R et al..1

DPP-4 = dipeptidyl peptidase-4.
1. Covington R et al. Clin Ther. 2008;30:499–512. 21
 Rationale for Once-Daily Dosing of Linagliptin
Based on DPP-4 Inhibition1

Day 1 of a 12-day study in patients with type 2 diabetes

100

80
DPP-4 Inhibition, %

60

40
Linagliptin 5 mg (n=8)
20 Placebo (n=12)

0
0 4 6 8 12 16 24
Time, h

Adapted with permission from Heise T et al.1

DPP-4 = dipeptidyl peptidase-4.
1. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 22
 Rationale for Twice-Daily Dosing of Vildagliptin
Based on DPP-4 Inhibition1
Single oral dose study in patients with type 2 diabetes
100

80
DPP-4 Inhibition, %

Placebo
60 Vildagliptin 100 mg (n=15)
Vildagliptin 50 mg (n=16)
40

20

0
0 4 6 8 12 16 24
Day 1
Time postdose, h

Adapted with permission from He YL et al.1

DPP-4 = dipeptidyl peptidase-4.
1. He YL et al. J Clin Pharmacol. 2007;47:633–641. 23
 Rationale for Once-Daily Dosing of Saxagliptin
Based on DPP-4 Inhibition1
Single oral dose study in patients with type 2 diabetes

100
Plasma DPP-4 Inhibition, %

80

60

40

Saxagliptin 2.5 mg (n=6)

20
Saxagliptin 5 mg (n=5 or 6)

0
0 4 6 8 12 16 24
Day 1
Time postdose, h

Adapted with permission from Tahrani AA et al.1

DPP-4 = dipeptidyl peptidase-4.
1. Tahrani AA et al. Adv Ther. 2009;26:249–262. 24
 GLP-1 and GIP Excretion Profiles Are Similar After
Sitagliptin or Vildagliptin Administration1
Mixed Mixed
16 Meal Difference between 16 Meal
GLP-1 intact, pmol/L

GLP-1 total, pmol/L

14 treatment groups: P<0.0001 14
12 12
10 a aa a a a a a a
10
a a
8 a aa a a a a a a a a 8 Difference between
6 6 treatment groups: P=0.69
4 4
2 2
0 0
0 60 120 180 240 0 60 120 180 240
60 Difference between 60
treatment groups: P<0.0001 Difference between
GIP intact, pmol/L

50 50

GIP total, pmol/L

treatment groups: P=0.16
40 40
30 30
20 20
10 a aa a a a a a a a a
10
a a a a a a a a
0 0
0 60 120 180 240 0 60 120 180 240
Minutes Minutes
Sitagliptin Vildagliptin Placebo

Adapted with permission from Baranov O et al. 1

aTime points where P<0.05 for difference between treatment group and placebo.

GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1.

1. Baranov O et al. Diabetes Obes Metab. 2016. doi: 10.1111/dom.12706. 25
 Insulin and Glucagon Excretion Profiles Are Similar After
Sitagliptin and Vildagliptin Administration1
Difference between treatment Difference between treatment
550 groups: P=0.60 80 2.0 groups: P=0.71
1.8

Insulin Secretion Rate,

500 70
Insulin, pmol/L

450 1.6

pmol.kg–1/min0–1
400 60 1.4
350 50 1.2

mU/L
300 40 1.0
250 0.8
200 30
150 0.6
20 0.4
100
50 10 0.2
0 0 0
0 60 120 180 240 0 60 120 180 240
Minutes Minutes
16 Difference between treatment 55
groups: P=0.36
14 50
45
Glucagon, pmol/L

12
40 Sitagliptin
10 35

mg/L
8 30 Vildagliptin
6 25 Placebo
20
4
Mixed 15
2 Meal 10
0 0
0 60 120 180 240
Minutes
Adapted with permission from Baranov O et al. 1
1. Baranov O et al. Diabetes Obes Metab. 2016. doi: 10.1111/dom.12706. 26
DPP-4 Inhibitors: Focus on Sitagliptin

 Incretins and DPP-4 Inhibition

 DPP-4 Inhibitors: Pharmacologic Profile
 Clinical Profile for Sitagliptin
 Safety Profile for Sitagliptin
 Summary and Conclusion

27
 Addition of Sitagliptin or Glipizide in Patients
Inadequately Controlled on Metformin: Study Design1,2

 Multinational, randomized, double-blind study compared sitagliptin with glipizide in patients with T2DM with
inadequate glycemic control on metformin
 Noninferiority design (for primary hypothesis at week 52)

Continue/start Week –2: Glipizide: 5 mg/day increased to 20 mg/day

metformin Eligible if HbA1c (held if premeal fingerstick glucose <6.1 mmol/L
monotherapy ≥6.5% to ≤10% or hypoglycemia)

Day 1
Randomization Week 104
Screening Metformin monotherapy Double-blind treatment period:
period run-in period glipizide or sitagliptin 100 mg qd

Single-blind
placebo Week 52
Primary End Point
Metformin (stable dose ≥1,500 mg/day)

 Mean glipizide titrated dose was 9.2 mg/day for the per-protocol population

qd = once daily; T2DM = type 2 diabetes mellitus.

1. Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205. 2. Seck T et al. Int J Clin Pract. 2010;64:562–576. 28
 Sitagliptin Was Noninferior to Glipizide in
Reducing HbA1c at Week 52 (Primary End Point)1
Per-Protocol Population
LS mean change from baseline at 52 weeks (for both groups): –0.7%

8.2 Sulfonylureaa + metformin (n=411 at 52 weeks)

8.0 Sitagliptinb + metformin (n=382 at 52 weeks)
Achieved primary
7.8 hypothesis of
HbA1c (±SE), %

7.6 noninferiority to
7.4 sulfonylurea
7.2
7.0
6.8
6.6
6.4
6.2
0 6 12 18 24 30 38 46 52
Weeks

Adapted with permission from Nauck MA et al. 1

aSpecifically glipizide ≤20 mg/day.
bSitagliptin 100 mg/day with metformin (≥1,500 mg/day).

LS = least-squares; SE = standard error.

1. Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205. 29
 Sitagliptin and Glipizide Provided Similar and
Sustained HbA1c Reductions Over 104 Weeks1
2-Year Per-Protocol Population (Patients Inadequately Controlled on Metformin)
LS mean change from baseline at 104 weeks (for both groups): –0.5%

8.0 Sulfonylureaa + metformin (n=256 at 104 weeks)

7.8 Sitagliptinb + metformin (n=248 at 104 weeks)
7.6
HbA1c (±SE), %

7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
0 6 12 18 24 30 38 46 52 60 69 78 91 104
Weeks

Adapted with permission from Seck T et al.1

aSpecifically glipizide ≤20 mg/day.
bSitagliptin 100 mg/day with metformin (≥1500 mg/day).

LS = least-squares; SE = standard error.

1. Seck T et al. Int J Clin Pract. 2010;64:562–576. 30
 Sitagliptin vs Metformin in Type 2 Diabetes
Mellitus: Study Design1

Sitagliptin 100 mg qd (n=528)

T2DM, 18–78 y,
drug-naive or off
OHA ≥4 mo, R
HbA1c 6.5%–9.0%
Metformin 2000 mg (n=522)a

Screening Single-blind placebo Active Treatment Period

period run-in period

1 week 2 weeks
Screening Day 1 Week 24
Randomization
 Primary end point: HbA1c change from baseline at 24 weeks for the per-protocol
populationb (noninferiority analysis)

aTitrated upto 1000 mg bid over 3–5 weeks.

bConsisted of patients who completed the study and did not have any reasons for exclusion from this population, including absence of baseline or on-treatment data at the week 24 visit or
major protocol violations (eg, drug compliance <75%, addition of non-study antihyperglycemic agent or incorrect double-blind study medication).
OHA = oral antihyperglycemic agent; qd = once daily; T2DM = type 2 diabetes mellitus.
1. Aschner P et al. Diabetes Obes Metab. 2010;12:252–261. 31
 Sitagliptin vs Metformin in Type 2 Diabetes
Mellitus: Sitagliptin Is Noninferior to Metformin1

Per-Protocol Population (Week 24)

Mean baseline HbA1c, % 7.2 7.2

0
Change From Baseline, %

–0.2
HbA1c LS Mean

–0.4

–0.43
–0.6
–0.57 Sitagliptin 100 mg qd (n=455)

Metformin (n=439)
–0.8
Between-groups difference=0.14 (0.06, 0.21)a

aPrespecified noninferiority margin=0.40%.

LS = least-squares; qd = once daily.
1. Aschner P et al. Diabetes Obes Metab. 2010;12:252–261. 32
 Sitagliptin Efficacy Is Similar Regardless of Renal
Function (1-Year Data)
HbA1c Reductions in 3 Active-Controlled Clinical Trials

GFR >50 mL/min GFR >30 mL/min to <50 mL/min ESRD on Dialysis

Sitagliptin 100 mg Sitagliptin 50 mg Sitagliptin 25 mg

0.1 0.1 once daily2 0.1 once daily3
Change in HbA1c From Baseline, %

Change in HbA1c From Baseline, %

Change in HbA1c From Baseline, %

once daily1
–0.1 –0.1 –0.1

–0.3 –0.3 –0.3

–0.5 –0.5 –0.5

–0.7 –0.7 –0.7

–0.7 –0.7
–0.9 –0.9 –0.8 –0.9

–1.1 –1.1 –1.1

–1.3 –1.3 –1.3

–1.5 52 weeks –1.5 54 weeks –1.5 54 weeks

SU (glipizide) HbA1c reduction: –0.7 SU (glipizide) HbA1c reduction: –0.6 SU (glipizide) HbA1c reduction: –0.9

ESRD = end-stage renal disease; GFR = glomerular filtration rate; SU = sulfonylurea.

1. Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205. 2. Arjona Ferreira JC et al. Diabetes Care. 2013;36:1067–1073. 3. Arjona Ferreira JC et al. Am J Kidney Dis. 2013;61:579–587. 33
 Safety of Sitagliptin in Patients With Type 2 Diabetes and
End-Stage Renal Disease on Dialysis1
APaT, Excluding Data After Initiation of Glycemic Rescue Therapy

Sitagliptin Glipizide
(n=64) (n=65)
n (%) n (%)
With one or more AEs 53 (82.8) 52 (80.0)
With drug-relateda AEs 10 (15.6) 13 (20.0)
With serious AEs 23 (35.9) 21 (32.3)
With serious drug-related AEs 0 (0.0) 0 (0.0)
Who died 4 (6.3) 6 (9.2)
Discontinuedb due to an AE 7 (10.9) 8 (12.3)
Discontinued due to a drug-related AE 1 (1.6) 2 (3.1)
Discontinued due to a serious AE 6 (9.4) 6 (9.2)
Discontinued due to a serious drug-related AE 0 (0.0) 0 (0.0)

Adapted with permission from Arjona Ferreira JC et al.1

APaT = all patients as treated; AE = adverse event.
aDetermined by the investigator to be related to the drug.
bStudy medication withdrawn.

1. Arjona Ferreira JC et al. Am J Kidney Dis. 2013;61:579–587. 34

DPP-4 Inhibitors: Focus on Sitagliptin

 Incretins and DPP-4 Inhibition

 DPP-4 Inhibitors: Pharmacologic Profile
 Clinical Profile for Sitagliptin
 Safety Profile for Sitagliptin
 Summary and Conclusion

35
 Sitagliptin Pooled Safety Analysis:
Background and Objective

Background
 In earlier pooled safety analyses of 19 double-blind, randomized, controlled studies
in 10,246 patients with type 2 diabetes, the safety and tolerability of sitagliptin were
generally comparable to those of placebo or other treatments1,2

Objective
 To examine the safety and tolerability of sitagliptin 100 mg/d in patients with
type 2 diabetes by pooling the results of 25 double-blind, randomized, controlled
studies with 14,611 patients, including 7,726 on sitagliptin3

1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7. 2. Engel SS et al. Int J Clin Pract. 2010;64:984–990. 3. Engel SS et al. Diabetes Ther. 2013;4:119–145. 36
 Sitagliptin Pooled Safety Analysis: Design1

 25 double-blind, randomized, controlled clinical studies of up to

2 years’ durationa
– Sitagliptin as monotherapy
– Sitagliptin in initial combination with MET or PIO
– Sitagliptin in combination with MET, PIO, SU (±MET), insulin (±MET), or
MET (+PIO or ROSI)
– Patients included in the nonexposed group received the following: placebo, MET,
PIO, SU (±MET), insulin (±MET), or MET (+PIO or ROSI)
 Exclusions included:
– Studies conducted only in Japan
– Patients with moderate-to-severe renal insufficiency

aStudies with results available as of December 2011.

MET = metformin; PIO = pioglitazone; ROSI = rosiglitazone; SU = sulfonylurea.
1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 37
 Sitagliptin Pooled Safety Analysis:
Summary of Adverse Events1
Incidence Rate per 100 Patient-Yearsa
Sitagliptin Nonexposed Between-Groups
Adverse Event (n=7,726) (n=6,885) Difference (95% CI)b
1 or more AEs 142.8 151.1 –7.6 (–13.9, –1.3)
Drug-related AEsc 19.1 25.5 –5.9 (–7.8, –4.1)
Serious AEs 7.3 6.9 0.4 (–0.6, 1.4)
Serious drug-related AEsc 0.4 0.2 0.1 (–0.1, 0.4)
Died 0.3 0.4 –0.1 (–0.4, 0.1)
Discontinued due to AEs 4.5 4.9 –0.5 (–1.3, 0.3)
Discontinued due to drug-related AEsc 1.6 2.2 –0.5 (–1.0, –0.0)
Discontinued due to serious AEs 1.7 1.4 0.2 (–0.2, 0.7)
Discontinued due to serious drug-related AEsc 0.2 0.1 0.1 (–0.0, 0.3)

Adapted with permission from Engel SS et al.1

a100 × (number of patients with ≥1 event)/person-years of follow-up time.
bBetween-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the

nonexposed group. "0.0" and "–0.0" represent rounding for values that were slightly greater and slightly less than zero, respectively.
cConsidered by the investigator to be drug-related.

AE = adverse event; CI = confidence interval.

1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 38
 Sitagliptin Pooled Safety Analysis: Adverse
Events by System Organ Class1
Incidence Rate per 100 Patient-Yearsa
Sitagliptin Nonexposed Between-Groups
System Organ Class (n=7,726) (n=6,885) Difference (95% CI)b
Blood and lymphatic system disorders 1.2 0.9 0.2 (–0.1, 0.6)
Cardiac disorders 3.7 3.8 –0.2 (–0.9, 0.5)
Congenital, familial, and genetic disorders 0.2 0.2 –0.0 (–0.2, 0.1)
Ear and labyrinth disorders 1.6 1.9 –0.4 (–0.9, 0.1)
Endocrine disorders 0.3 0.4 –0.2 (–0.4, 0.0)
Eye disorders 3.8 3.9 –0.1 (–0.9, 0.6)
Gastrointestinal disorders 24.3 24.6 0.3 (–1.7, 2.3)
General disorders and administration site conditions 8.3 9.2 –0.9 (–2.1, 0.2)
Hepatobiliary disorders 1.2 0.9 0.2 (–0.1, 0.6)
Immune system disorders 0.9 0.9 –0.1 (–0.4, 0.3)
Infections and infestations 45.5 45.7 0.3 (–2.5, 3.1)
Injury, poisoning, and procedural complications 8.8 8.8 0.3 (–0.9, 1.4)
Investigations 14.0 14.9 –1.3 (–2.7, 0.2)

Adapted with permission from Engel SS et al.1

a100 ×(number of patients with ≥1 event)/person-years of follow-up time.
bBetween-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the

nonexposed group. "0.0" and "–0.0" represent rounding for values that were slightly greater and slightly less than zero, respectively.
CI = confidence interval.
1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 39
 Sitagliptin Pooled Safety Analysis: Adverse
Events by System Organ Class1,2 (continued)
Incidence Rate per 100 Patient-Yearsa
Sitagliptin Nonexposed Between-Groups
System Organ Class (n=7,726) (n=6,885) Difference (95% CI)b
Metabolism and nutrition disorders 11.1 17.5 –6.4 (–7.9, –4.9)
Musculoskeletal and connective tissue disorders 19.3 18.5 0.7 (–1.0, 2.4)
Neoplasms benign, malignant, and unspecified 2.0 1.5 0.5 (0.0, 1.0)
Nervous system disorders 15.1 14.7 0.3 (–1.1, 1.8)
Pregnancy, puerperium, and perinatal conditions 0 0.1 –0.0 (–0.1, 0.1)
Psychiatric disorders 4.3 4.5 –0.1 (–0.9, 0.6)
Renal and urinary disorders 2.8 2.6 0.1 (–0.5, 0.7)
Reproductive system and breast disorders 2.6 2.8 –0.2 (–0.8, 0.4)
Respiratory, thoracic, and mediastinal disorders 7.9 8.0 –0.1 (–1.2, 0.9)
Skin and subcutaneous tissue disorders 7.8 6.7 1.1 (0.1, 2.1)
Social circumstances 0 0 –0.0c
Surgical and medical procedures 0 0 0.0c
Vascular disorders 5.4 5.3 –0.1 (–1.0, 0.7)

Adapted with permission from Engel SS et al.1

a100 × (number of patients with ≥1 event)/person-years of follow-up time.
bBetween-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the

nonexposed group. "0.0" and "–0.0" represent rounding for values that were slightly greater and slightly less than zero, respectively.
c95% CI were not computed for events that occurred in fewer than 4 patients in both groups, because CI would necessarily have included 0.

CI = confidence interval.
1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 2. Engel SS et al. Diabetes Ther. 2013;4:487. 40
 Sitagliptin Pooled Safety Analysis: Summary of
Selected Composite Adverse Events of Interest1

Incidence Rate per 100 Patient-Yearsa

Sitagliptin Nonexposed Between-Groups
Adverse Event (n=7,726) (n=6,885) Difference (95% CI)b
Acute renal failure (narrow SMQ) 0.2 0.1 0.0 (–0.1, 0.2)
Acute renal failure (broad SMQ) 2.1 1.6 0.4 (–0.1, 0.9)
Proteinuria 0.5 0.4 0.1 (–0.2, 0.3)
Atrial fibrillation/flutter 0.4 0.2 0.2 (–0.0, 0.4)
Bronchitis 4.0 3.5 0.5 (–0.2, 1.2)
Pneumonia 0.9 0.8 0.2 (–0.2, 0.5)
Upper respiratory infection 8.2 8.9 –0.6 (–1.7, 0.5)
Urinary tract infection 4.4 4.8 –0.3 (–1.1, 0.4)
Rash 1.7 1.1 0.6 (0.2, 1.1)

Adapted with permission from Engel SS et al.1

a100 × (number of patients with ≥1 event)/person-years of follow-up time.
bBetween-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the

nonexposed group. "0.0" and "–0.0" represent rounding for values that were slightly greater and slightly less than zero, respectively.
CI = confidence interval; SMQ = Standardized MedDRA Queries; MedDRA = Medical Dictionary for Regulatory Activities.
1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 41
 Sitagliptin Pooled Safety Analysis: Summary

 In this pooled analysis of >14,000 patients from 25 randomized controlled studies of

up to 2 years’ duration, sitagliptin has been shown to be generally well tolerated1
– Sitagliptin was administered at the 100 mg/day dose; patients with moderate-to-severe
renal insufficiency (ie, requiring reduced sitagliptin doses) were excluded from
the analysis1
– Results are similar to those from earlier pooled-safety analyses2,3
 The incidence rates of serious AEs, death, and AEs leading to discontinuation were
similar between the sitagliptin and nonexposed groups1
 The incidences of patients reporting ≥1 AE, ≥1 drug-relateda AE, and drug-related
AEs leading to discontinuation were higher in the nonexposed group, primarily due
to the greater incidence of drug-related hypoglycemia1

aConsidered by the investigator to be related to study drug.

AE = adverse event; MACE = major adverse cardiovascular event.
1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 2. Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. 3. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7. 42
 Sitagliptin Pooled Safety Analysis:
Summary (continued)1

 Sitagliptin therapy was associated with increased incidences of acne,

atrial fibrillationa, chest discomfort, constipation, dermatitis contact,
dyspepsia, Gilbert’s syndrome, hepatomegaly, ischemic
cardiomyopathy, lipoma, micturition urgency, ovarian cyst,
periodontitis, rash macular, rash vesicular, tibia fracture, and vaginal
hemorrhage
 Postmarketing adverse events reported for sitagliptin will continue to
be monitored

aWhen atrial fibrillation and atrial flutter were combined, the between‐groups difference (95% CI) was 0.2 (–0.0, 0.4). Incidence rates for atrial flutter were 0.0 and 0.1 for the sitagliptin
and the nonexposed groups, respectively, with a between‐groups difference (95% CI) of –0.1 (–0.2, 0.0).
AE = adverse event; MACE = major adverse cardiovascular event.
1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 43
 Sitagliptin Pooled Safety Analysis: Limitations1

 Results are from patients in randomized, controlled clinical trials, and

may not be fully reflective of use in the general population
 Studies included in the pooled analysis are only up to 2 years in
duration, and may not be reflective of safety after prolonged use
 Analysis focused on sitagliptin 100 mg/day, the usual clinical dose
 Multiple comparisons were made without adjusting for multiplicity,
which increased the chances for spurious findings

1. Engel SS et al. Diabetes Ther. 2013;4:119–145. 44

 TECOS CV Safety Trial:
Summary of Study Design1,2

 Continue metformin and/or

Patients aged ≥50
Sitagliptinb + Usual Care pioglitazone and/or sulfonylurea,
years with T2DM, (n=7,332) and/or insulin
pre-existing CVD, and  Additional AHA or insulin
HbA1c 6.5%–8.0% and R (other than GLP-1 receptor
dose-stable for ≥3 agonists and DPP-4 inhibitors)
months on other AHA
therapya
Placebo + Usual Care added according to usual care to
target HbA1c, according to current
(n=7,339) guidelines (eg, ADA)

Study continued until 1,300 patients experienced a confirmed primary composite CV event (time from randomization
to first confirmed CV-related death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina)

Adapted with permission from Green JB et al.1

aMono- or dual therapy with metformin, sulfonylurea, or pioglitazone, or insulin alone or in combination with metformin.
bIf eGFR is ≥50 mL/min/1.73 m2, dose of sitagliptin = 100 mg/d; if eGFR is 30 to <50 mL/min/1.73 m2, dose of sitagliptin = 50 mg/d; if eGFR is <30 mL/min/1.73 m2 during the study,

dose reduced to 25 mg/d.

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; R = randomization;
AHA = antihyperglycemic agent; GLP-1 = glucagon-like peptide-1; DPP-4 = dipeptidyl peptidase-4; ADA = American Diabetes Association;
eGFR = estimated glomerular filtration rate.
1. Green JB et al. Am Heart J. 2013;166:983–989.e7. 2. Green JB et al. N Engl J Med. 2015;373:232–242. 45
 TECOS CV Safety Trial: Met Primary Composite
CV Outcome of Noninferiority1
Primary Composite CV Outcome: Intention-to-Treat Population
100 Placebo
11.6% (n=851)
15
80
Patients with Event, %

10 Sitagliptin
60 11.4% (n=839)

5
40
HR (95% CI) 0.98 (0.89, 1.08)
0
20 0 4 8 12 18 24 30 36 42 48

0
0 4 8 12 18 24 30 36 42 48
No. at Risk Month
Sitagliptin 7332 7131 6937 6777 6579 6386 4525 3346 2058 1248
Placebo 7339 7146 6902 6751 6512 6292 4411 3272 2034 1234

Between-group difference (ITT) was not statistically significant for superiority: P=0.65
Between-group difference (PP) was statistically significant for noninferiority: P<0.001a
Adapted with permission from Green JB et al.1
aNoninferiority P-value for a margin of 1.30 in hazard ratio.

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; ITT = intention-to-treat; PP = per protocol; HR = hazard ratio; CI =
confidence interval.
1. Green JB et al. N Engl J Med. 2015;373:232–242. 46
 TECOS CV Safety Trial:
Hospitalizations for Heart Failure (ITT)1
Hospitalizations for Heart Failure: Intention-to-Treat Population
100

5
Placebo
Patients with Event, %

80
4 229 (3.1%)

60 3
Sitagliptin
2 228 (3.1%)
40 1
HR (95% CI) 1.00 (0.83, 1.20)
0
20 0 4 8 12 18 24 30 36 42 48

0
0 4 8 12 18 24 30 36 42 48
Month
No. at Risk
Sitagliptin 7332 7189 7036 6917 6780 6619 4728 3515 2175 1324
Placebo 7339 7204 7025 6903 6712 6549 4599 3443 2131 1315

Between group difference was not statistically significant (P=0.98)

Adapted with permission from Green JB et al.1

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; HR = hazard ratio; CI = confidence interval; ITT = intention-to-treat.
1. Green JB et al. N Engl J Med. 2015;373:232–242. 47
 TECOS CV Safety Trial: CV Safety Outcome in
Select Patient Subgroup Analyses
Subject Group at Baseline n Hazard Ratio 95% CI

Primary Outcome (CV Death, Nonfatal MI, Nonfatal Stroke, Hospitalization for UA)

Overall1 14,671 0.98 0.89, 1.08

Female2 4297 0.94 0.78, 1.14

Male2 10,374 1.00 0.89, 1.11

Age ≥75 years3 2004 1.10 0.89, 1.36

History of heart failure1 2643 0.97 0.80, 1.17

≥90 mL/min/1.73 m2 eGFR4 3325 0.88 0.71, 1.09

60–89 mL/min/1.73 m2 eGFR4 7879 1.05 0.92, 1.21

45–59 mL/min/1.73 m2 eGFR4 2538 0.94 0.77, 1.14

30–44 mL/min/1.73 m2 eGFR4 783 0.97 0.70, 1.35

Use of insulin5 3408 1.01 0.84, 1.21

0.0 0.5 1.0 1.5 2.0

Favors Sitagliptin Favors Placebo

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CI=confidence interval; CV = cardiovascular; MI = myocardial infarction; UA = unstable angina; eGFR = estimated glomerular filtration rate.
1. Green JB et al. N Engl J Med. 2015;373:232–242. 2. Green JB et al. Sex differences in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Poster presented at: EASD 2016; September 12–
16, 2016; Munich, Germany. Poster 1141. 3. Bethel MA et al. Assessing the safety of sitagliptin in elderly participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabet Med Basic Clin
Sci Posters Type 2 Diabetes. 2016;33:86. Poster presented at the ADA 2016, June 10–14, New Orleans, LA. 4. Cornel JH et al. Diabetes Care. 2016 [Epub ahead of print]. 5. Bethel MA et al. Impact of sitagliptin on
cardiovascular and safety-related outcomes in insulin-treated type 2 diabetes: the TECOS experience. Poster presented at: EASD 2016; September 12–16, 2016; Munich, Germany. Poster 774. 48
 TECOS CV Safety Trial: CV Safety Outcome in
Select Patient Subgroup Analyses (continued)
Subject Group at Baseline n Hazard Ratio 95% CI

Hospitalization for Heart Failure

Overall1 14,671 1.00 0.83, 1.19

Female2 4297 0.99 0.69, 1.43

Male2 10,374 0.99 0.80, 1.22

Age ≥75 years3 2004 0.99 0.65, 1.49

History of heart failure1 2643 1.03 0.77, 1.36

≥90 mL/min/1.73 m2 eGFR4 3325 0.68 0.41, 1.13

60–89 mL/min/1.73 m2 eGFR4 7879 1.03 0.79, 1.35

45–59 mL/min/1.73 m2 eGFR4 2538 1.15 0.79, 1.69

30–44 mL/min/1.73 m2 eGFR4 783 0.94 0.58, 1.52

Use of insulin5 3408 0.81 0.59, 1.12

0.0 0.5 1.0 1.5 2.0

Favors Sitagliptin Favors Placebo

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CI=confidence interval; CV = cardiovascular; MI = myocardial infarction; UA = unstable angina; eGFR = estimated glomerular filtration rate.
1. McGuire DK et al. JAMA Cardiol. 2016;1:126–135. 2. Green JB et al. Sex differences in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Poster presented at: EASD 2016; September 12–
16, 2016; Munich, Germany. Poster 1141. 3. Bethel MA et al. Assessing the safety of sitagliptin in elderly participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabet Med Basic Clin
Sci Posters Type 2 Diabetes. 2016;33:86. Poster presented at the ADA 2016, June 10–14, New Orleans, LA. 4. Cornel JH et al. Diabetes Care. 2016 [Epub ahead of print]. 5. Bethel MA et al. Impact of sitagliptin on
cardiovascular and safety-related outcomes in insulin-treated type 2 diabetes: the TECOS experience. Poster presented at: EASD 2016; September 12–16, 2016; Munich, Germany. Poster 774. 49
 TECOS CV Safety Trial: Key Non-CV Outcomes
and Serious Adverse Events (ITT)1,2
Non-CV outcomesa
n (%); rate per 100 patient-years Sitagliptin (N=7,332) Placebo (N=7,339) HR (95% CI) P-value
Acute pancreatitis 23 (0.3); 0.11 12 (0.2); 0.06 1.93 (0.96, 3.88) 0.07
Charter-defined cancer 268 (3.7); 1.25 290 (4.0); 1.37 0.91 (0.77, 1.08) 0.27
Pancreatic cancer 9 (0.1);0.04 14 (0.2);0.07 0.66 (0.28, 1.51) 0.32
Severe hypoglycemia 160 (2.2); 0.78 143 (1.9); 0.70 1.12 (0.89, 1.40) 0.33

Adverse Events Reported in ≥1% of Patients in Either Study Group According to System Organ Class

Serious Adverse Events Sitagliptin (N=7,332) Placebo (N=7,339)

Patients; n (%) Events Patients; n (%) Events
Benign, malignant or unspecified neoplasms 341 (4.7) 405 371 (5.1) 470
Injury, poisoning, or procedural complications 146 (2.0) 165 133 (1.8) 153
Gastrointestinal disorders 130 (1.8) 143 102 (1.4) 121
Musculoskeletal and connective-tissue disorders 118 (1.6) 136 93 (1.3) 102
Respiratory, thoracic, or mediastinal disorders 66 (0.9) 81 77 (1.0) 95
Adapted with permission from Green JB et al.1
aITT population.

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; ITT = intention-to-treat; HR = hazard ratio; CI = confidence interval.
1. Green JB et al. N Engl J Med. 2015;373:232–242. 2. Green JB et al. N Engl J Med. 2015;373:58.
50
 TECOS CV Safety Trial: Fracture Sensitivity
Analysis (ITT)1

3.0
2.6
2.5
Observed Rate of Fracture, %

2.5 Sitagliptin (N=7,332) Placebo (N=7,339)

2.0

1.5
1.0 1.0
1.0

0.5 0.3
0.2
n=189 n=186 n=75 n=71 n=18 n=16
0.0
Overall Fracture Major Osteoporotic Fracture Hip Fracture
Adjusteda rate of fracture
8.7 8.6 3.5 3.3 0.8 0.7
per 1,000 person-years
HR (95% CI): 1.04 (0.84, 1.27); P=0.745 1.07 (0.77, 1.49); P=0.673 1.11 (0.57, 2.18); P=0.761

Unadjusted HR (95% Cl) 1.01 (0.82, 1.23); P=0.944 1.05 (0.76, 1.45); P=0.779 1.12 (0.57, 2.19); P=0.747
aAdjusted for age, sex, white race, diastolic blood pressure, current smoker, diabetes duration, diabetic neuropathy, and use of metformin, sulfonylurea,
thiazolidinedione, and insulin.
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; ITT = intention-to-treat; HR = hazard ratio; CI = confidence interval.
1. Josse RG et al. Diabetes Obes Metab. 2016. [Epub ahead of print] 51
 DPP-4 Inhibitor CV Safety Trials
Agent Saxagliptin1 Alogliptin2 Sitagliptin3-6 Linagliptin7 Vildagliptin
Trial SAVOR-TIMI 53 EXAMINE TECOS CARMELINA
N 16,492 5,380 14,671 8,300

CV death, CV death, CV death, CV death,

Primary end point nonfatal MI, nonfatal MI, nonfatal MI, nonfatal MI,
nonfatal stroke nonfatal stroke nonfatal stroke, UA nonfatal stroke, UA No CVST
Established Pre-existing CVD + planned
Established
vascular albuminuria or
CV risk ACS vascular
complications impaired renal
complications
or ≥2 risk factors function
Completed Completed Completed Estimated
Year
2013 2013 2015 2018
Safety analyses
No No Yes No
in CKD patients?
DPP-4 = dipeptidyl peptidase-4; CV = cardiovascular; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial
Infarction; MI = myocardial infarction; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome;
ACS = acute coronary syndrome; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; UA = unstable angina; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study
With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk; CVD = cardiovascular disease; CVST = cardiovascular safety trial; CKD = chronic kidney disease.
1. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 2. White WB et al. N Engl J Med. 2013;369:1327–1335. 3. Green JB et al. Am Heart J. 2013;166:983–989.e7. 4. Green JB et al.
N Engl J Med. 2015;373:232–242. 5. Cornel JH et al. Diabetes Care. 2016. doi:10.2337/dc16-1415/-/DC1. 6. Engel SS et al. Assessing the safety of sitagliptin in patients with type 2 diabetes and
chronic kidney disease in the TECOS Trial. Presented at the 2016 American Diabetes Association Scientific Sessions. June 10–14, 2016. New Orleans, Louisiana. 7. CARMELINA: Cardiovascular and
renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. https://clinicaltrials.gov/ct2/show/NCT01897532. Accessed
October 5, 2016. 52
DPP-4 Inhibitors: Focus on Sitagliptin

 Incretins and DPP-4 Inhibition

 DPP-4 Inhibitors: Pharmacologic Profile
 Clinical Profile for Sitagliptin
 Safety Profile for Sitagliptin
 Summary and Conclusion

53
 Summary and Conclusion

 Incretins are rapidly degraded by DPP-4

– DPP-4 inhibition increases the concentration of active incretins, thereby
increasing insulin release and decreasing circulating glucagon levels in a
glucose-dependent manner
 Sitagliptin has a favorable PK/PD profile
 Sitagliptin monotherapy and combination therapy with metformin
provided substantial and statistically significant glucose-lowering
efficacy in patients with normal and impaired renal function
 Sitagliptin has an established safety profile based on a pooled safety
analysis of 25 clinical trials and a CV safety study (TECOS)

DPP-4 = dipeptidylpeptidase; PK = pharmacokinetic; PD = pharmacodynamics; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular;
ITT = intention-to-treat; HR = hazard ratio; CI = confidence interval. 54