Early Combination of Sitagliptin/Metformin

in Type 2 Diabetes Mellitus

Agus Yuwono MD,PhD
 TOPIC

–Diabetes T2 Pathophysiology
–Comprehensive Approach is
Pathophysiology Based
–Modern Management type 2 DM
–Therapy with DPP-4 Inhibitor
–Combination Therapy
2
 The Pathophysiology of Type 2 Diabetes Involves
Multiple Organ Systems
Pancreatic
Peripheral Tissues Beta Cells
Liver Decreased
Decreased Increased Increased
Glucose Uptake Lipolysis insulin secretion
Glucose Production

Pancreatic
Alpha Cells
Excessive
glucagon secretion
Insulin Islet cell
resistance dysfunction

Combined islet cell dysfunction incretin

and insulin resistance effect

HYPERGLYCEMIA
?
3
Adapted with permission from Inzucchi SE. JAMA 2002;287:360–372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247–254.
 TOPIC

–Diabetes Pathophysiology
–Comprehensive Approach is
Pathophysiology Based
–Modern Management type 2 DM
–Therapy with DPP-4 Inhibitor
–Combination Therapy
4
 Comprehensive Approach is Pathophysiology
Based 1–6
Pancreas
incretin DPP IV inhibitor
effect Impaired insulin
GLP 1 RA
secretion
Muscle, fat,
Sulfonylureas and liver
Liver
Biguanides Meglitinides
TZDs Insulin
resistance
↓Glucose level
Hepatic glucose
overproduction TZDs
Biguanides
Gut Kidneys

Glucose Renal glucose

absorption reabsorption
α-Glucosidase
inhibitors SGLT2 inhibitors
Biguanides
DPP-4 = dipeptidyl peptidase-4; TZDs = thiazolidinediones.
1. DeFronzo RA. Ann Intern Med. 1999;131:281–303. 2. Buse JB et al. In: Williams Textbook of Endocrinology, 11th ed. Philadelphia: Saunders; 2008:1329–1389.
3. Inzucchi SE. JAMA. 2002;287:360–372. 4. Porte D et al. Clin Invest Med. 1995;18:247–254. 5. Chao EC et al. Nat Rev. 2010;9:551–559. 6. JANUVIATM (sitagliptin) [Summary of
product characteristics]. Merck. 2016.
 TOPIC

–Diabetes Pathophysiology
–Comprehensive Approach is
Pathophysiology Based
–Modern Management type 2 DM
–Therapy with DPP-4 Inhibitor
–Combination Therapy
6
Modern Management of Type 2 Diabetes
Hormones involved
In glucose regulation
• Insulin
Incretin base
• Glucagon Theraphy
• Incretins

Insulin Resistance
islet cell
skeletal muscle Biguanid
adipose tissue
liver
7
 Earlier and Appropriate Intervention May
Improve Patients’ Chances of Reaching Goal1
Published Conceptual Approach

OAD +
multiple daily
Diet and OAD OAD OAD OAD + insulin
exercise monotherapy up-titration combination basal insulin injections

10

9
HbA1c,%

7 HbA1c
goal of
7%
Mean HbA1c 6
Duration of Diabetes
of patients Conventional stepwise Earlier and proactive
treatment approach intervention approach
Adapted with permission from Del Prato S et al.1
OAD = oral antidiabetic agent.
1. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
9
 Metformin: mechanism of action
1. Intestine:
glucose absorption
 Anaerobic glucose
metabolism
3. Muscle and adipose
tissue: glucose uptake
Metformin  glucose
utilization

5. Liver: hepatic Blood

glucose output glucose
 2.Insulin resistance

Insulin 4. Pancreas:
resistance insulin secretion

www.diabetesclinic.ca
Incretins Modulate Insulin and Glucagon to Decrease
Blood Glucose During Hyperglycemia

Meal

Peripheral
Increased insulin Muscle
glucose
(beta cells) Adipose uptake
Glucose tissue
GIP Dependent
Gut
GLP-1 Pancreas Physiologic
Glucose
Glucose Control
Dependent

Decreased glucagon
(alpha cells) Liver
Glucose
production

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

Brubaker PL et al. Endocrinology 2004;145:2653–2659; Zander M et al. Lancet 2002;359:824–930; Ahren B. Curr Diab Rep 2003;3:365–372;
Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Drucker DJ. Diabetes Care 11
2003;26:2929–2940.
 Sitagliptin and Metformin Target Multiple Metabolic Defects
of Type 2 Diabetes
Beta-Cell
Dysfunction
Sitagliptin increases Metformin increases
intact GLP-1 levels1 total GLP-1 levels1

Metformin decreases Sitagliptin improves

HGO by targeting the markers of beta-cell
liver to decrease function and increases
gluconeogenesis and insulin synthesis and
glycogenolysis3 release1,2

Sitagliptin reduces
HGO through Metformin has insulin-
suppression of sensitizing properties3–5
glucagon from alpha (Liver > Muscle)
cells6
Hepatic Glucose
Insulin Resistance
Overproduction (HGO)
1. Vardarli I et al. Diabetes. 2014;63:663–674. 2. Aschner P et al. Diabetes Care. 2006;29:2632–2637. 3. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 4. Abbasi F et al. Diabetes
Care. 1998;21:1301–1305. 5. Zhou G et al. J Clin Invest. 2001;108:1167–1174. 6. Solis-Herrera et al. Diabetes Care. 2013;36:2756–2762.
 TOPIC

–Diabetes Pathophysiology
–Comprehensive Approach is
Pathophysiology Based
–Modern Management type 2 DM
–Incretin base Theraphy
–Combination Therapy
13
 The Incretin Effect Is Diminished
in Individuals With Type 2 Diabetes
Control Subjects Patients With Type 2 Diabetes
(n=8) (n=14)
Normal Incretin Effect 0.6 Diminished Incretin Effect 0.6
80 80

0.5 0.5
IR Insulin, mU/L

IR Insulin, mU/L
60 60
0.4 0.4

nmol/L

nmol/L
40 0.3 40 0.3

0.2 0.2
20 20
0.1 0.1

0 0 0 0

0 60 120 180 0 60 120 180

Time, min Time, min
Oral glucose load Intravenous (IV) glucose infusion
IR = immunoreactive
Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag.
14
Vilsbøll T, Holst JJ. Diabetologia 2004;47:357–366.
 DPP-4 Inhibitors Improve Glucose Control by
Increasing Incretin Levels in Type 2 Diabetes
Ingestion
of food Glucose dependent
 Insulin Insulin
from beta cells increases
(GLP-1 and GIP) peripheral
glucose
GI tract Release of Pancreas uptake
incretins from
the gut
β-cells
α-cells Improved
Hyperglycemia
Physiologic
Glucose Control

X
DPP-4
Enzyme  Glucagon
↑insulin and
↓glucagon
from alpha cells reduce hepatic
DPP-4 (GLP-1)Glucose glucose
Inhibitor dependent output
Inactive
incretins DPP-4 = dipeptidyl peptidase 4

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr
15
Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
 Sitagliptin Lowers Post-meal Glucose
Excursion and Enhances Insulin Secretion
P<0.05 for between group difference
Japanese Monotherapy Study 70
Placebo Sitagliptin 100 mg qd
60

Plasma Insulin (µU/mL)

Baseline Baseline
50
Week 12 Week 12
320 40
Plasma Glucose (mg/dL)

30

280 11.7 20
mg/dL
10
-69.2
240 mg/dL 0
0 0.5 1.0 2.0 0 0.5 1.0 2.0
Time (hr)
200

Insulinogenic Index (µU/mg)

0.5 Placebo
0.4 Sitagliptin 100 mg qd
160 Placebo Sitagliptin 100 mg qd
0.3

0.2
120
0 0.5 1.0 2.0 0 0.5 1.0 2.0 0.1

Time (hr) 0
P<0.001 for difference in change from baseilne in 2-hr PPG Week 0 Week 12
Between group difference (P<0.001)
Insulinogenic index = ∆ I30 / ∆ G30
16
Nonaka K et al. A201. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.
 Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily
Dosing in Monotherapy
18-Week study 24-Week study Japanese study
Change vs
-0.6% -0.79% -1.05%
placebo*
(P<.001) (P<.001) 8.4 (P<.001)
8.4 8.4

8.0
8.0 8.0
A1C (%)

A1C (%)
A1C (%)

7.6

7.6 7.6
7.2

Placebo (n=74) Placebo (n=244) Placebo (n=75)

7.2 Sitagliptin 100 mg (n=168) 7.2 6.8
Sitagliptin 100 mg (n=229) Sitagliptin 100 mg (n=75)

6 18 0 5 10 15 20 24 0 8 12
0 12 4
Time (wk) Time (wk) Time (wk)
*Between group difference in LS means.
Raz I et al; PN023; Aschner P et al. PN021; Nonaka K et al; A201. Abstracts presented at: 66 th Scientific Sessions of the American
17
Diabetes Association; June 9-13, 2006; Washington, DC.
 Sitagliptin in Patients With Type 2 Diabetes:
HbA1c Results by Baseline HbA1c1
Full Analysis Set
Baseline HbA1c Subgroups
<8% ≥8% to <9% ≥9%
Mean baseline HbA1c , % 7.4 8.4 9.4
0
n=68 n=20 n=13
Placebo-adjusted LS Mean

–0.5
–0.5
HbA1c Change, %a

Sitagliptin

–1.0 –0.9

–1.5
–1.6
P=0.043, treatment by subgroup interaction.
–2.0
LS = least-squares.
1. Barzilai N et al. Curr Med Res Opin. 2011;27:1049–1058.
 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

aSpecificallyglipizide ≤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.
 Sitagliptin Improved Markers of Beta-Cell
Function: 24-Week Monotherapy Study

Proinsulin/insulin ratio HOMA-β

0.48 75
p< 0.001* p< 0.001*
0.46 70

0.44 65

0.42 60

0.4 55

0.38 50

0.36 45

0.34 40

0.32 35

0.3 30
Placebo Sitagliptin Placebo Sitagliptin
Hatched = Baseline
∆ from baseline = 0.078
Solid = Week 24
∆ from baseline = 13.2 +/- 3.3
(95% CI -0.114, -0.023) (95% CI 3.9, 21.9)
vs pbo vs pbo 20
Aschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.
 Sitagliptin

 Sitagliptin is a potent, highly selective once-daily oral

therapy.1
 Sitagliptin enhances incretin levels through inhibition of
DPP-4.1
 Sitagliptin is a DPP-4 inhibitor that is not covalently
bound.2 It rapidly dissociates and has a prolonged half-life
that supports once- daily dosing.1
 Sitagliptin 100 mg has shown near maximal and
sustained DPP-4 inhibition over 24 hours, resulting in
increases in active GLP-1 and GIP.3,4

1. Data on file, MSD.

2. Wallace MB et al. Bioorg Med Chem Lett. 2008;18:2362–2367.
3. Herman GA et al. J Clin Endocrinol Metab. 2006;91(11):4612–4619. 21
4. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: 10.1185/03007990902109514.
 Characteristics of an Ideal Therapy

 Characteristics of an ideal antidiabetic agent

– Lowers HbA1c to normal levels
– Decreases insulin resistance and hepatic glucose
production and increases or preserves beta-cell mass
while restoring first-phase insulin response
– Does not cause weight gain
– Does not increase risk of hypoglycemia
– Does not cause edema or congestive heart failure

22
23
 TOPIC

–Diabetes Pathophysiology
–Comprehensive Approach is
Pathophysiology Based
–Modern Management type 2 DM
–Therapy with DPP-4 Inhibitor
–Combination Therapy
24
 Initial Combination Therapy with Sitagliptin and
Metformin: Effective and Durable Glycemic Control
Over 1 Year in Patients With T2DM
Proportion of patients
achieving an A1C target of <7% Proportion of patients achieving an A1C target
90
of <7% at Week 24 remaining at <7% at Week 54
77 90 85
80
79 80
67 80
Proportion of patients (%)

70

Proportion of patients (%)

63 70
57 70
60
59
48 60
50 44
41
50
40 35
40
23 25
30
30
20
20
10
10
0
APT Week 54 Completers 0
Sitagliptin 100 mg qd (n=106/58)
Sitagliptin 100 mg qd (n=33)
Metformin 500 mg bid (n=117/77)
Metformin 500 mg bid (n=34)
Metformin 1000 mg bid (n=134/101)
Metformin 1000 mg bid (n=63)
Sitagliptin 50 mg + metformin 500 mg bid (n=147/106)
Sitagliptin 50 mg + metformin 500 mg bid (n=65)
Sitagliptin 50 mg + metformin 1000 mg bid (n=153/124)
Sitagliptin 50 mg + metformin 1000 mg bid (n=96)
25
Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.
Sitagliptin Add-on to Metformin Improved 24-Hour Glucose
Profile in Patients With Type 2 Diabetes

Post Prandial

Fasting/Pre-Prandial 26
 Sitagliptin Added to Ongoing Metformin Therapy: Sustained
Glycemic Control Over
54-weeks With Weight Loss
A1C (%) Weight (kg)
Phase A Phase A
7.9 2.0

LS mean chance from baseline

7.7 LS mean change from
LS mean change from baseline 1.0 baseline at week 54

in body weight (kg)

7.5 at week 54
Mean A1C (%)

-0.6 kg (95% CI: -1.5, -0.2)

-0.7% (95% CI: -0.8, -0.6)
7.3
0.0
7.1

6.9 -1.0

6.7

6.5 -2.0
0 6 12 18 24 30 38 46 54 0 12 24 38 54
Weeks
Weeks

27
Karasik A et al. Poster presented at 2007 ADA Annual Meeting.
 Initial Combination Therapy with Sitagliptin and Metformin: Change
From Baseline in A1C at Week 54 by Baseline A1C Subgroups*

<8% 8% and <9% 9% and <10% 10%

(mean 7.6%) (mean 8.4%) (mean 9.4%) (mean 10.4%)
0.0 0.0
HbA1C Change from baseline

-0.5 -0.5
at Week 54 (%)

-1.0 -1.0

-1.5 -1.5

-2.0 Sitagliptin 100 mg (28/43/19/16) -2.0

Metformin 500 mg bid (32/39/30/16)
-2.5 -2.5
Metformin 1000 mg bid (40/53/33/8)
-3.0 Sitagliptin 50 mg + metformin 500 mg bid (39/49/38/21) -3.0
Sitagliptin 50 mg + metformin 1000 mg bid (33/60/43/17)
-3.5 -3.5

*Mean change  SE: APT Population. 28

Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.
 Effect of FDC Sitagliptin/Metformin on A1C Reduction Is
Higher Than Monotherapy
Placebo-Subtracted Data in 24-Week Study
Combination Combination
Sitagliptin Metformin Sita 50 mg/ Sitagliptin Metformin Sita 50 mg/
100 mg qd 500 mg bid Met 500 mg bid 100 mg qd 1000 mg bid Met 1000 mg bid
A1C reduction from baseline (%)

-0

-0.5

-1.0 -0.8 -0.8

-1
-1.5 -1.3
-1.6
-2.0
Additive to 89%
P<.001 -2.1
1.6/(0.8 + 1.0)89%
-2.5
P<.001
Additive to 100%
2.1/(0.8 + 1.3)=100%
FDC=fixed-dose combination. 29
Williams-Herman D et al. Presented at: 19th World Diabetes Congress (IDF) in South Africa, 2006.
 24-Week Add-on Therapy to Metformin Study

Incidence of Hypoglycemia With Sitagliptin With

Metformin Was Similar to Placebo With Metformin

5.0 Placebo + metforminb (n=237)

Sitagliptina + metforminb (n=464)
4.0
Patients (%)

3.0

2.1%
2.0
1.3%
1.0

0.0

Patients with at least one episode of hypoglycemia over 24 weeks

All-patients-as-treated population
aSitagliptin 100 mg/day; bMetformin ≥1500 mg/day

30
Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.
 24-Week Add-on Therapy to Metformin Study

Sitagliptin With Metformin Provided Weight Loss

Similar to Placebo With Metformin at Week 24
0

-0.1
Change in Body Weighta

-0.2
from baseline (kg)b

-0.3
Placebo + metformind (n=169)
-0.4 Sitagliptinc + metformind (n=399)

-0.5

-0.6
–0.6
P=0.017
-0.7 vs baseline
–0.7
P<0.001
-0.8 vs baseline

aExcluding data after initiation of glycemic rescue therapy; bleast squares means;
cSitagliptin 100 mg/day; dMetformin ≥1500 mg/day
31
Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.
 Combination Therapy Offers Advantages
Over Monotherapy
 Combination therapy may provide more glycemic control
than the individual monotherapies
 Combination therapy may provide more comprehensive
coverage of the key pathophysiologies of type 2 diabetes
than monotherapy
 An appropriately chosen combination therapy may help
more patients achieve their HbA1c goal without increasing
side effects1
 Sitagliptin and metformin have complementary
mechanisms of action3–8
1. Khunti K et al. Diabetes Care. 2013;36:3411–3417. 2. Pantalone KM et al. Diabetes Care. 2016;39:1527–1534. 3. Vardarli I et al. Diabetes. 2014;63:663–674. 4. Aschner P et al.
Diabetes Care. 2006;29:2632–2637. 5. Solis-Herrera et al. Diabetes Care. 2013;36:2756–2762. 6. Abbasi F et al. Diabetes Care. 1998;21:1301–1305. 7. Kirpichnikov D et al. Ann
Intern Med. 2002;137:25–33. 8. Zhou G et al. J Clin Invest. 2001;108:1167–1174. 9. Reasner C et al. Diabetes Obes Metab. 2011;13:644–652. 10. Olansky L et al. Diabetes Obes
Metab. 2011;13:841–849. 11. Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987. 12. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160–168. 13. Barzilai N et al. Curr
Med Res Opin. 2011;27:1049–1058. 14. Engel SS et al. Diabetes Ther. 2013;4:119–145. 15. JANUVIA SPC. 16. Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205. 17. Seck
T et al. Int J Clin Pract. 2010;64:562–576. 18. Seck TL et al. Diab Res Clin Pract. 2011;93:e15–7. 19. Arjona Ferreira JC et al. Diabetes Care. 2013;36:1067–1073. 20. Arjona
Ferreira JC et al. Am J Kidney Dis. 2013;61:579–587. 32
 Initial Fixed-Dose Combination Therapy With JANUMET™
vs Metformin Monotherapy: Conclusions

Compared with metformin alone, in patients with

type 2 diabetes and moderate to severe hyperglycemia
on diet and exercise initial combination therapy with
sitagliptin/metformin FDC (JANUMET) provided1,2
• Superior glycemic improvements resulting in more patients
achieving HbA1c goal
• A similar incidence of hypoglycemia, and lower incidences of
abdominal pain and diarrhea compared with metformin alone

FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
33
2. Data on file, MSD.
 Conclusions

 Treatment to achieve glycemic control early is important to help

reduce complications of type 2 diabetes1
 Many patients on current monotherapies do not achieve glycemic
control2
 Combination therapy with a DPP-4 inhibitor and metformin offers
opportunity for improved glycemic efficacy, complementary
mechanisms of action, and a low risk of hypoglycemia without weight
gain
 Sitagliptin/metformin provides a more comprehensive approach for
addressing the key pathophysiologies of type 2 diabetes

34
 Sitagliptin Was Associated with a Low Incidence of
Hypoglycemia and No Weight Gain1
APaT, Excluding Data After Initiation of Glycemic Rescue Therapy
1.5 LS Mean Between-Group Difference LS Mean Between-Group Difference

Patients With ≥1 Episode of Symptomatic

(95% CI) (95% CI):
12 –4.5% (–15.3, 5.6); P=0.3
1 –1.0 (–2.8, 0.9) 0.8 Sitagliptina
LS Mean Body Weight Change From

(–0.5, 2.1) 10.8

Hypoglycemia Over 54 Weeks, %

(n=64)
10
Glipizideb
Baseline at Week 54,

0.5 (n=65)
8

0 6.3
6
–0.2
-0.5 (–1.4, 1.1) Sitagliptina
(n=45) 4

Glipizideb
-1 (n=41) 2

-1.5 0
Baseline, kg 69.8 68.2
APaT = All Patients as Treated; LS = least squares; CI = confidence interval.
a25 mg once daily. bMean dose of glipizide was 5.3 mg per day. Glipizide was initiated at 2.5 mg/day and titrated to a maximum of 20 mg/day.

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

 Rationale for Dose Reduction of Sitagliptin in
Patients With Renal Impairment
Single-dose (50 mg), open-label pharmacokinetic study in participants
without diabetes with varying degrees of renal function compared
Sitagliptin Clearance Decreases with Worsening Renal Function, Increasing Exposure
Sitagliptin Clearance, mL/min

339 19.8

Sitagliptin Exposure:
16.6
242
9.96

AUC, μM · h
126 7.09
60.2 4.40
N/A

CrCl, mL/min CrCl, mL/min

*Hemodialysis at 48 h postdose in subjects with ESRD

Dose adjustment of sitagliptin for patients with moderate to severe renal

impairment or ESRD is recommended to achieve plasma concentrations
comparable to those in patients with normal renal function, and not based
CrCl = creatinine
onclearance;
a risk AUC of
= areaadverse
under the curve; ESRD = end-stage
effects orrenalrenal
disease. toxicity1,2
1. Bergman AJ et al. Diabetes Care. 2007;30:1862–1864. 2. Evans M et al. Diabetes Ther. 2015;6:1–5.
 Incidence of Adverse Events Over 18 Weeks
(APaT Population)1
Sitagliptin
100 mg qd Placebo
Event, n (%) n=352 n=178
One or more AEs 82 (23.3) 27 (15.2)
Drug-related AEsa 10 (2.8) 3 (1.7)
SAEs 6 (1.7) 2 (1.1)
Drug-related SAEsa 1 (0.3) 1 (0.6)
Discontinued because of AEs 5 (1.4) 2 (1.1)
Discontinued because of drug-related AEsa 2 (0.6) 1 (0.6)

 A small increase (0.6 kg) in mean body weight occurred in the

sitagliptin group (APaT population) at 18 weeks; none occurred in the
placebo group
 There were no reports of hypoglycemia in either treatment group over
18 weeks
Adapted with permission from Mohan V for
et al. the APaT population
1

AE = adverse event; APaT = all-patients-as-treated; qd = once daily; SAE = serious adverse event.
aDetermined by the investigator to be possibly, probably, or definitely drug related.

1. Mohan V et al. Diabetes Res Clin Pract. 2009;83:106–116.

 Sitagliptin Pooled Safety Analysis:
Prespecified Adverse Events of Interest1

 Hypoglycemia  Other composite end points of interest

– Pancreatitis – Bronchitis
 Gastrointestinal
– Pancreatic cancer – Pneumonia
 MACE – Acute renal failure – Upper respiratory infection
 Neoplasms – Proteinuria – Urinary tract infection
– Atrial fibrillation/flutter– Rash
 Angioedema
 Laboratory abnormalities (alanine
aminotransferase, aspartate
aminotransferase, serum creatinine)

MACE = major adverse cardiovascular events.

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