The document reviews type 2 diabetes mellitus (T2DM) and discusses the combination therapy of sitagliptin and metformin as an effective initial treatment for patients with T2DM. It highlights the burden of diabetes globally, potential healthcare costs, and clinical efficacy regarding earlier intervention strategies to improve glycemic control. The findings suggest that earlier application of combined therapy can lead to better patient outcomes, including a more rapid achievement of HbA1c goals.

1. SUITABLE AND COMBINATION THERAPY
OF T2DM WITH SITAGLIPTIN
ID-PM-MSD-JANUME-SD-HCP-000007
dr. Wahyuddin, M.Kes SpPD FINASIM

2. Outline
2
• Overview of Diabetes Burden
• Rationale for Earlier Combination Use of Sitagliptin
and Metformin
• Clinical Efficacy and Safety of Sitagliptin Therapy in
Newly- diagnosed Patients as Initial Treatment in
Combination With Metformin

3. Overview of Diabetes Burden
%
2.8%
6.4%
8.8%
9.3%
10.2%
25% 51%
10.9%
0%
5%
10%
15%
2000 2010 2015 2019 2030 2045
90% of all diabetes cases are
T2DM
WORLD
PREVALENCE
Diabetes is associated with increasing healthcare costs
Western-Pacific region
Global High-income countries
• 2019: US$760 bill • US$294 bill
• 2045: US$845 bill 11.2% Middle-income
countries
• US$160.20 bill
Low-income countries
• 2019: US$162 bill
• 2045: US$185 bill 14% • US$0.95
bill
DIRECT*1
INDIRECT** (2015)1,2
*Direct costs due to diabetes are regardless of whether this expenditure is born by
patients
3
themselves or by private or public payers or by government.
**Indirect costs due to diabetes include loss of production resulting from labour-force drop
out (from
disability), mortality, absenteeism, and presenteeism (reduced productivity when at work).
References: 1. International Diabetes Federation (IDF) Diabetes Atlas, 9th Edition 2019. 2. Ogurtsova K, et al. Diabetes Res Clin Pract. 2017;128:40-50. 3. Wild S, et al. Diabetes
Care
2004;27:1047–1053.

4. Overview of Diabetes Burden
2
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a
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ibutable to d
i
a
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Diabetes Report 2000 – 2045
Reference: International Diabetes Federation (IDF) Diabetes Atlas, 10th Edition
2021
4

5. 5
Earlier and Appropriate Intervention May Improve Patients’
Chances of Reaching HbA1c Goal1–3
A Retrospective Analysis From the UK CPRD Database (2004–2006; Follow-up to 2011)
Highlighting Median Time to Intensification and Mean HbA1c at Intensification in Patients With
T2DM Treated With 1 or 2 OADs With Intensification to 2 OADs or Insulin, Respectively
HbA
1c
,
%
10
9
8
7
6
OAD dual
combination
OAD
monotherapy
OAD triple
combination Insulin
8.7% 9.1% 9.7%
8.5%
2.9 years 7.2 years
6.7 years
Time
For patients with HbA1c
7%
≥ Conventional stepwise
treatment approach (actual
data)
Earlier and more aggressive
intervention approach (conceptual
data)
Reproduced with permission from Khunti et al.1
This model was derived using conceptual approach developed by Del Prato et al.3
CPRD = Clinical Practice Research Datalink; T2DM = type 2 diabetes mellitus; OAD = oral antidiabetic drug.
1. Khunti K et al. Prim Care Diabetes. 2017;11:3‒12. 2. Khunti K et al. Diabetes Care. 2013;36:3411‒3417. 3. Del Prato S et al. Int J Clin Pract. 2005;59:1345–
1355.

6. Immediate Treatment Intensification Improves Glycemic Control
in Patients With T2DM1
A Retrospective Analysis From the UK CPRD Database of Patients With T2DM (2000–2014)
Highlighting Decrease in HbA1c 1 Year Post Index Datea and Proportion of Patients Achieving HbA1c
<7%b
–1.1
0.26
0.16
–
1.2
–
0.8
–
0.4
0.0
0.4
Change
in
HbA
1c
Post
Index
Date
a
,
%
Immediate
Intensification
n=2,647
Delayed
Intensification
n=2,452
Never
Intensified
n=1,611
45.8
6
19.1
0
10
20
30
40
50
Patients
Achieving
HbA
1c
<7%
b
,
%
Immediate
intensification
n=2,647
Delayed
intensification
n=2,452
aIndex date defined as first HbA1c result 7%
≥ post 90 days of metformin monotherapy (considered treatment
failure).
bPatients who did not receive treatment intensification never reached the HbA1c target
<7%. T2DM = type 2 diabetes mellitus; CPRD = Clinical Practice Research Datalink.
1. Watson L et al. Curr Med Res Opin. 2016;32:1465–1475.

7. Delay in Treatment Intensification Despite Suboptimal
Glycemic Control1
A Retrospective Analysis From the UK CPRD Database of Patients With T2DM (2004–2006; Follow-up to
2011)
Time to treatment intensification after reaching HbA1c cutoff in patients receiving monotherapy
2.9
1.9
1.6
2.2
1.5
1.1
Median
Time
to
Intensification,
Years
≥7.0%
n=35,988
≥7.5%
n=31,375
≥8.0%
n=25,096
Intensification with OAD
Intensification with OAD or
insulin
7
Percentage of patients
who intensified therapy 65% 72% 67% 75% 67% 76%
4.0
3.0
2.0
1.0
0.0
Cutoff HbA1c
CPRD = Clinical Practice Research Datalink; T2DM = Type 2 Diabetes Melitus; OAD = Oral Antidiabetes
Drug.
1. Khunti K et al. Diabetes Care. 2013;36:3411–3417.

8. Poor Glycemic Control Due to a Delay in Treatment Intensification Is
Associated With Increased Risk of Diabetic Retinopathy1
A Retrospective Cohort Study Conducted at a University-based Hospital in Thailand
Using Medical Records of Patients With T2DM (2010–2014)
New or progression of DR:
OR 4.78, 95% CI 1.10, 20.90; P=0.038
20
15
10
5
0
8
Incidence
rate
of
new
or
progressive
DR
(±
95%
CI),
cases
per
1000
person
months
10
(6, 16.4)
2.2
(0.5, 9.1)
HbA1c at baseline
HbA1c change at end of studya
P=0.0003
P<0.001
Clinical inertia
(n=67)
10.01±0.97
–1.46±1.85
Non-inertia
(n=31)
10.92±1.40
–3.04±1.76
aMedian study follow-up time 29.5 months (interquartile range 16–42 months).
T2DM = type 2 diabetes mellitus; DR = diabetic retinopathy; OR = odds ratio; CI = confidence
interval.
1. Osataphan S et al. J Diabetes. 2017;9:267–274.

9. Multiple Factors Contribute to Clinical Inertia1
30%
50%
20%
Healthcare System-Related
Patient-Related
• Underestimation of
patient’s need for therapy
• Uncertainty regarding the
reality of poor
disease control and the
need to intervene
Physician-Related
Relative
Contributions
Factors
1. Reach G et al. Diabetes Metab. 2017;43:501–511.
9
• Failure to set and/or monitor progress
toward treatment goals
• Time and resource constraints
• Concerns relating to avoidance of
treatment
side effects
• Low health literacy
• Poor physician–patient communication
• Lack of acknowledgment of disease
severity
• Reluctance to have treatments intensified
• Side effects from medications
• Inability to follow complex treatment
regimens
• No clinical
guidelines
• No visit planning
• No decision
support
• No disease registry
• Poor communication between physician and
staff
• No active outreach to patients
• No team approach to care
Adapted with permission from Reach G et
al.

10. 10
Outline
T2DM = type 2 diabetes
• Overview of Diabetes Burden
• Rationale for Earlier Combination Use of Sitagliptin and
Metformin
• Clinical Efficacy and Safety of Sitagliptin Therapy in
Newly- diagnosed Patients as Initial Treatment in
Combination With Metformin

11. T2DM Treatment Algorithm from PERKENI, 2021
11

12. Potential Advantages of Earlier Combination Therapy
12
• Use of lower doses of individual agents1
• More rapid achievement of glycemic control1,2
• Targeting multiple core defects with complementary
modes of action1
1. Bailey CJ et al. Int J Clin Pract. 2005;59:1309–1316. 2. Pantalone KM et al. Diabetes Care. 2016;39:1527–
1534.

13. Sitagliptin and Metformin Target Multiple Metabolic Defects of
Type 2 Diabetes
Sitagliptin improves
markers of beta-cell
function and increases
insulin synthesis and
release1,2
Sitagliptin reduces HGO
through suppression of
glucagon from alpha
cells6
Metformin decreases
HGO by targeting the
liver to decrease
gluconeogenesis and
glycogenolysis3
Metformin has insulin-
sensitizing
properties3–5 (Liver >
Muscle)
Beta-Cell Dysfunction
Hepatic Glucose
Overproduction
(HGO)
Insulin
Resistance
Sitagliptin increases
intact GLP-1 levels1
Metformin
increases total
GLP-1 levels1
13
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.

14. Sitagliptin Suppresses the Glucagon Response to a Meal1
In a 6-week Randomized Trial With Sitagliptin (100 mg/Day; n=25) or Placebo (n=22) in Patients With T2DM,
Sitagliptin
Suppressed the Glucagon Response to a Meal Compared With Predosing Levels and Placebo
Sitagliptin Placebo
30
40
50
60
70
80
90
20
–60 –
30
0 30 60 90 120 150 180 210 240 270
300
Plasma
Glucagon
(±
SD),
pg/mL
Time, min
MTT T2DM pre-
sitagliptin T2DM
post-sitagliptin
90
80
70
60
50
40
30
20
–60 –30
0
30 60 90 120 150 180 210 240 270
300
Plasma
Glucagon
(±
SD),
pg/mL
MTT
Control
T2DM pre-placebo
T2DM post-
placebo
Adapted with permission from Muscelli E et al.1
T2DM = type 2 diabetes mellitus; MTT = meal tolerance test.
1. Muscelli E et al. J Clin Endocrinol Metab. 2012;97:2818–2826.
14

15. Complementary Effects of Sitagliptin and Metformin on
Active GLP-1, Glucagon, and EGP in Patients With T2DM1
0
20
40
60
80
0 60 120 180 240 300 360
Bioactive
GLP-1,
pmol/L
SITA+METb
SITAb
MET
PBO
Time, min
60
80
100
120
40
0 60 120 180 240 300
360
Plasma
Glucagon
a
,
pg/mL
Time, min
SITA+METc
SITAc
MET
PBO
0.5
1.0
1.5
2.0
2.5
0.0
0 60 120 180 240 300
360
EGPa,
mg/kg·min
Time,
min
SITA+METd
SITAd
15
METd
PBO
Changes in Bioactive GLP-1, Plasma Glucagon, and EGP During a
MTT
Adapted with permission from Solis-Herrera C et
al.1 aResponses to a 6-hour meal tolerance test.
bP<0.01 vs placebo and metformin at baseline;
P<0.001 vs placebo and metformin post MTT.
cP<0.05 vs placebo and metformin (0-120 min).
dP<0.01 vs placebo.
GLP-1 = glucagon-like peptide 1; EGP =
endogenous glucose production; T2DM = type 2
diabetes mellitus; MTT = meal tolerance test; SITA
= sitagliptin; MET =metformin; PBO = placebo.

16. 16
Outline
T2DM = type 2 diabetes
• Overview of Diabetes Burden
• Rationale for Earlier Combination Use of Sitagliptin
and Metformin
• Clinical Efficacy and Safety of Sitagliptin Therapy in
Newly-diagnosed Patients as Initial Treatment in
Combination With Metformin

17. 17
Initial Therapy With Sitagliptin/Metformin FDC vs Metformin
Monotherapy: Study Design1
Day 1
Randomization
Week 44
Screening
period
Screening Week 18
T2DM, aged 18–
78
years, OHA naive,
HbA1c 7.5%
≥
R
Glycemic rescue criteria FPG criteria
to week 18
>16.7 mmol/L
Day 1 to Week
6
>14.4 mmol/L
Week 6 to Week
12
>12.8 mmol/L
Week 12 to Week
18
Sitagliptin/metformin FDC 50/1,000 mg bida (n=625)
Metformin 1,000 mg bidb (n=621)
Phase A Phase B
1 week 18 weeks 26 weeks
Adapted with permission from Reasner C et al.1
bid = twice daily; FDC = fixed-dose combination; FPG = fasting plasma glucose; OHA = oral antihyperglycemic agent; R = randomization; T2DM = type 2 diabetes
mellitus.
aSitagliptin/metformin FDC was initiated at 50/500 mg bid and uptitrated to the full dose over 4 weeks.
bMetformin was initiated at 500 mg bid and titrated up to 1000 mg bid over 4 weeks.
1. Reasner C et al. Diabetes Obes Metab. 2011;13:644–652.

18. 18
Significantly Greater HbA1c Reductions at Week 18 With
Sitagliptin/Metformin FDC vs Metformin Monotherapy1
LS mean difference:
–0.6 (–0.8, –0.4);
P<0.001
LS
Mean
(±SE)
Change
in
HbA
1c
From
Baseline,
%
Week
–
3
–
2
–
1
0
0 6 12 18
–
2.4
–
1.8
FAS Popa
ulationa
Sitagliptin/metformin FDC 50/1,000 mg bid
(n=559) 1c
Mean baseline HbA = 9.9%
Metformin 1,000 mg bid
(n=564) Mean baseline HbA1c =
9.8%
Primary End Point:
1c
Change in HbA
from
baseline to week
18
Adapted with permission from Reasner C et al. 1
bid = twice a day; FAS = full analysis set; FDC = fixed-dose combination; LS = least-squares; SE = standard
error.
aExcludes data obtained after initiation of additional antihyperglycemic agents.
1. Reasner C et al. Diabetes Obes Metab. 2011;13:644–652.

19. Similar Overall Incidence of AEs Over 18 Weeks With
Sitagliptin/Metformin FDC vs Metformin Monotherapy1
APaT Populationa
Clinical AEsa
Sitagliptin/metformin
FDC 50/1,000 mg bid
(n=625)
n (%)
Metformin
(n=621)
n (%)
With one or more AEs 271 (43.4) 301 (48.5)
With no AEs 354 (56.6) 320 (51.5)
With drug-related AEs 109 (17.4) 116 (18.7)
With serious AEs 13 (2.1) 20 (3.2)
With serious drug-related AEs 1 (0.2) 1 (0.2)
Who died 1 (0.2) 1 (0.2)
Who were discontinued due to AEs 25 (4.0) 25 (4.0)
Who were discontinued due to drug-related AEs 18 (2.9) 16 (2.6)
Who were discontinued due to serious AEs 6 (1.0) 5 (0.8)
Who were discontinued due to serious drug-related AEs 1 (0.2) 1 (0.2)
19
APaT
Population
Adapted with permission from Reasner C et al.1
aExcluding data after initiation of an additional antihyperglycemic agent.
AE = adverse experience; APaT = all patients as treated; bid = twice a day; FDC = fixed-dose
combination.
1. Reasner C et al. Diabetes Obes Metab. 2011;13:644–652.

20. Maintenance of Glycemic Control at Week 44 With Sitagliptin/
Metformin FDC vs Metformin Monotherapy (Phase B)1
FAS Population
Including data after initiation of additional OHA
therapy
Primary End Point:
Change in HbA1c
from baseline at
week 44
–
3
–
2
–
1
0
0 6 12
18
31 44
Weeks
Metformin 1,000 mg bid
(n=569)
Mean baseline HbA1c = 9.8%
Sitagliptin/metformin FDC 50/1,000 mg bid
(n=560) Mean baseline HbA1c = 9.9%
20
HbA
1c
Over
Time
(LS
Mean
±SE),
%
LS mean
differenc
e
–0.5;
P<0.001
LS mean change from baseline
–2.3; 95% CI (–2.4, –2.1)
LS mean change from baseline
–1.8; 95% CI (–1.9, –1.6)
Adapted with permission from Olansky L et al.1
FDC = fixed-dose combination; bid = twice daily; FAS = full-analysis-set; LS = least-squares; OHA = oral antihyperglycemic agent; SE = standard
error.
1. Olansky L et al. Diabetes Obes Metab. 2011;13:841–849.

21. 21
Similar Overall Incidence of AEs Over 44 Weeks With
Sitagliptin/Metformin FDC vs Metformin Monotherapy1
APaT Population
Including data after initiation of additional OHA
therapy
Clinical AEs
Sitagliptin/metformin FDC
50/1,000 mg bid
(N=625)
n (%)
Metformin
1,000 mg bid
(N=621)
n (%)
With one or more AEs 358 (57.3) 380 (61.2)
With drug-related AEsa 127 (20.3) 136 (21.9)
With serious AEs 28 (4.5) 38 (6.1)
With serious drug-related AEsa 3 (0.5) 1 (0.2)
Who died 1 (0.2) 2 (0.3)
Who were discontinued due to AEs 27 (4.3) 32 (5.2)
Who were discontinued due to drug-related AEsa 19 (3.0) 19 (3.1)
Who were discontinued due to serious AEs 6 (1.0) 5 (0.8)
Who were discontinued due to serious drug-related
AEsa
2 (0.3) 1 (0.2)
Adapted with permission from Olansky L et al.1
aDetermined by the investigator to be related to the
drug.
AE = adverse event; APaT = all-patients-as-treated; bid

22. Initial Combination Therapy With Sitagliptin Plus Metformin vs
Either Agent Alone: Study Design
FPG criteria
to week 24
HbA1c >8%
to week 54
HbA1c >7.5%
to week 104
Week –2
Glycemic rescue criteria
Day 1 Week 54 Week 104
Week 24
Screenin
g
period
If on OHA,
discontinue therapy
Single-
blind
placebo
run-in
period
Diet and
exercise run-
in period
50-week
extension study3
24-week phase1 with
30-week continuation phase2
6–12 weeks
Eligible if
HbA1c 7.5%–
11%
Patients with T2DM not
on therapy or on mono-
or low-dose combo-OHA
R
Metformin 500 mg bid
Metformin 1,000 mg bid
Sitagliptin 100 mg qd
Sitagliptin 50 mg bid + metformin 1,000 mg bid
Placebo Metformin 1,000 mg bid
Sitagliptin 50 mg bid + metformin 500 mg bid
bid = twice daily; FPG = fasting plasma glucose; OHA = oral antihyperglycemic agent; qd = once daily; R = randomization; T2DM = type 2 diabetes mellitus.
1. Goldstein B et al. Diabetes Care. 2007;30:1979–1987. 2. Williams-Herman D et al. Curr Med Res Opin. 2009;25:569–583. 3. Williams-Herman D et al. Diabetes Obes Metab. 2010;12:442–451.
22

23. 23
Initial Combination Therapy With Sitagliptin Plus Metformin:
HbA1c Reductions at 24 Weeks1
Placebo-adjusted
HbA
1c
Change,
%
0.5
0.0
–
0.5
–
1.0
–
1.5
–
2.0
–
2.5
–
3.0
–
3.5
–0.8a
–1.0a
–1.3a
–1.6a
–2.1a
Placebo group results at 24 weeks:
+0.2%
24-Week placebo-adjusted results
Mean baseline HbA1c = 8.8%
n=178 n=177 n=183 n=178
n=175
24-Week open-label results
Mean baseline HbA1c = 11.2%
–2.9b
n=117
APT Population—HbA1c Reductions at 24
Weeks
Primary End Point:
Change in HbA1c
from baseline at 24
weeks
Metformin 1,000 mg bid
Sitagliptin 50 mg bid + metformin 1,000 mg
bid
Sitagliptin 100 mg qd Metformin 500 mg
bid Sitagliptin 50 mg bid + metformin 500 mg bid
aP 0.001
≤ vs placebo.
bLS mean change from baseline without adjustment for placebo.
APT = all-patients-treated; bid = twice daily; LS = least-squares; qd = once
daily.
1. Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987.

24. Significantly Greater Proportion of Patients at HbA1c Goal at Week 24 With
Initial Combination Therapy of Sitagliptin Plus Metformin vs Either Agent Alone1
APT Population—Percentage of Patients Achieving HbA1c <6.5% and <7% at 24
Weeks
Patients
at
Goal,
%
70
60
50
40
30
20
10
0 n=165 n=175 n=178 n=177 n=183 n=178
HbA1c <6.5%
n=165 n=175 n=178 n=177 n=183
n=178
HbA1c <7%
38
23
20
9
66a
43a
Mean Baseline HbA1c = 8.8%
Sitagliptin 100 mg qd Metformin 500 mg bid Metformin 1,000 mg bid Placebo
Sitagliptin 50 mg bid + metformin 500 mg bid Sitagliptin 50 mg bid + metformin 1,000
mg bid
aP<0.01 vs monotherapy.
APT = all patients treated; bid = twice a day; qd = once a
day.
1. Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987. 24

25. Summary
Combination Therapy With Sitagliptin Plus Metformin
25
• Evidence suggests that earlier combination therapy for
appropriate patients with T2DM may be a viable strategy1
• Sitagliptin and metformin have complementary
mechanisms of action2–6
• Initial combination therapy with sitagliptin and metformin for
the treatment of T2DM substantially improved glycemic
control and was generally well tolerated in patients whose
diabetes was inadequately controlled on diet and exercise7–
11diet and exercise7–11
1. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. 2. Abbasi F et al. Diabetes Care. 1998;21:1301–1305. 3. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 4. Zhou G et al. J Clin
Invest.
2001;108:1167–1174. 5. Migoya EM. Clin Pharmacol Ther. 2010;88:801–808. 6. Solis-Herrera C et al. Diabetes Care. 2013;36:2756–2762. 7. Goldstein BJ et al. Diabetes Care. 2007;30:1979–
1987.
8. Williams-Herman D et al. Diabetes Obes Metab. 2010;12:442–451. 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. Williams-Herman D et al. Curr Med Res Opin. 2009;25:569–583.