DPP4 Inhibitors: An Effective Option for Glycemic Control with Lower Hypoglycemia Risk

At clinical crossroads:
DPP4 Inhibitors
Lobna F El toony
Head Of Diabetes & Endocrinology Unit
Internal Medicine Department Assuit
University
UEDA – Aswan 2012

Growth of Diabetes Prevalence
Worldwide
Adapted from WHO. Available at: http://www.who.int/dietphysicalactivity/publications/facts/diabetes/en/print.html.
Accessed February 6, 2009.
Peoplewithdiabetes(millions)
0
100
200
400
1985
300
Year
1995 2000 2030
(projected)

Prevalence (%) estimates of diabetes (20-79 years), 2010
Middle East and North African Region

Number of people with diabetes (20-79 years), 2010 and
2030

Early Detection & Early and accurate
Intervention

8
The Incretin Defect in Type 2 Diabetes
Insulin
Resistance
Incretin
“Defect”
Relative Insulin
Deficiency
Hyperglycemia
Type 2 Diabetes
Incretin effect accounts for up to 70% of the insulin response to oral glucose
intake1
1. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J
Physiol Endocrinol Metab. 2004;287(2):E199-E206.

• Goals should be individualized based on
–Duration of diabetes
–Age/life expectancy
–Comorbid conditions
–Known CVD or advanced microvascular complications
–Hypoglycemia unawareness
Glycemic Recommendations for Adults with
Diabetes
ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.

Earlier and Appropriate Intervention May
Improve Patients’ Chances of Reaching
Goal
OAD=oral antidiabetic agent.
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355.
Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.
Published Conceptual Approach
HbA1cGoal
Mean
HbA1c
of patients
Duration of Diabetes
OAD
monotherapy
Diet and
exercise
OAD
combination
OAD
up-titration
OAD +
multiple daily
insulin
injections
OAD +
basal insulin
Conventional stepwise
treatment approach
Earlier and more aggressive
intervention approach
6
7
8
9
10

Glycemic Recommendations for Adults with Diabetes
A1C <7.0%*
Preprandial capillary plasma
glucose
70–130 mg/dl*
Peak postprandial capillary
plasma glucose†
<180 mg/dl*
*Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally
peak levels in patients with diabetes.
ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.

Primary sites of action of oral
antidiabetic agents
 Glucose
output
 Insulin resistance
Biguanides
 Insulin
secretion
Sulfonylureas/
meglitinides
 Carbohydrate
breakdown/
absorption
-glucosidase
inhibitors
 Insulin
resistance
Thiazolidinediones
Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

Incretins Modulate Insulin and Glucagon to
Decrease Blood Glucose During Hyperglycemia
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,11th ed. Philadelphia: Saunders; 2008:1329–1389; Drucker DJ. Diabetes Care 2003;26:2929–2940.
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day;
their levels increase in response to a meal.
Release of
active incretins
GLP-1 and GIPa
 Blood glucose in
fasting and
postprandial states
Ingestion
of food
 Glucagon
from alpha cells
(GLP-1)
 Hepatic
glucose
production
GI tract
DPP-4
enzyme
Inactive
GLP-1
 Insulin from
beta cells
(GLP-1 and GIP)
Glucose-dependent
Glucose-dependent
Pancreas
Inactive
GIP
Beta cells
Alpha cells
 Peripheral
glucose
uptake

Sitagliptin improves
beta-cell function
and increases insulin
synthesis and
release.1
Sitagliptin reduces HGO through
suppression of glucagon from alpha
cells.2
Metformin decreases HGO by
targeting the liver to decrease
gluconeogenesis and
glycogenolysis.4
Metformin has insulin-
sensitizing properties.3–5
(Liver > Muscle, fat)
Beta-Cell
Dysfunction
Hepatic Glucose
Overproduction (HGO)
Insulin
Resistance
1. Aschner P et al. Diabetes Care. 2006;29(12):2632–2637.
2. Data on file.
3. Abbasi F et al. Diabetes Care. 1998;21(8):1301–1305.
4. Kirpichnikov D et al. Ann Intern Med. 2002;137(1):25–33.
5. Zhou G et al. J Clin Invest. 2001;108(8):1167–1174.
Sitagliptin and Metformin Target the Core
Metabolic Defects of Type 2 Diabetes

Glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6 540-559)

N
N
N
N
N
N
N
O
O
NH2
Linagliptin
Vildagliptin
N
O
N
NH
OH
N
N
N
N
N
O
O
Alogliptin
Sitagliptin
F
F F
O
F
F
F
NH2
N
N
N
N
DPP-4 Inhibitors Differ Chemically
Saxagliptin
N
O
OH
NH2

18
H740
S630
Y547
F357
S209
R358
E205
E206
R125
H126
1. Data on file, MSD.
Sitagliptin is Highly Selective & fit for DPP4
Site
DPP-4=dipeptidyl peptidase-4.
Yellow: sitagliptin
Green: vildagliptin

DPP-4 Inhibitors Have Different Durations of Action
% Plasma
DPP-4 inhibition
Vildagliptin
40
100
80
0
60
20
Placebo
Saxagliptin (5 mg qd)
Saxagliptin
Adapted from Boulton et al
Poster 0606-P; ADA 2007
40
100
80
0
60
20
Placebo
Alogliptin (25 mg qd)
Day 14
-20
Covington et al,
Clin Ther 2008
40
100
80
0
60
20
Placebo
Linagliptin (5 mg qd)
Day 12
Heise et al,
Diab Obes Metab 2009
% Plasma
DPP-4 inhibition
0 4 8 12 16 20 24
Time (hr)
Alogliptin
Linagliptin
Sitagliptin
Bergman et al,
Clin Ther 2006
Day 10
Sitagliptin (100 mg qd)
Placebo
0 4 8 12 16 20 24
Time (hr)
0
20
40
60
80
100
Nb: No direct comparisons of degree of inhibition
attained by different inhibitors
Adapted from He et al
J Clin Pharmacol 2007
100
80
60
40
20
0
Day 1
Vilda (50 mg)
Placebo
Vilda (100 mg)

Sitagliptin is a different molecule
Sitagliptin Vildagliptin
Molecular structure
Half Life (T1/2) 12.4 hrs 2-3 hrs
DPP-4 Inhibition* post 24 hrs 100mg QD 80-97% @ 24hrs
50 mg QD: 20% @ 24 hrs
50 mg BID: >80% @ 12hrs
DPP-4 Peak Inhibition ~97% ~95%
Selectivity for DPP-IV vs. DPP-8/DPP-9*
2600 fold for DPP4 vs. DPP-8
10,000 fold for DPP4 vs. DPP-9
Metabolism ~16% metabolized
69% metabolized
mainly renal
(inactive metabolite)
Bioavailability ~87% 85%
Liver Monitoring NO YES
Elimination
Kidney (87%)
79% mostly unchanged
Kidney (85%)
23% unchanged
Liver (15%)
FDA YES NO
* All use different proprietary assays with different dilutions and therefore % DPP-4 inhibition cannot be compared across assays
HO
N
H
O
N
NC
F
F
F O
N
NH2
N N
N
CF3
Data on file, MSD

• Hypoglycaemia
•Weigh gain
Macrovascular
&
Microvascular
Risk Reduction
Tight Glycaemic
control

Efficacy and Safety of Treatment With
Sitagliptin or Glimepiride in Patients With
Type 2 Diabetes Inadequately Controlled
on Metformin Monotherapy
Diabetes Obes Metab. 2011

23
Efficacy: HbA1c reduction
“Addition of Sitagliptin or
Glimepiride in Patients
Inadequately Controlled
on Metformin“
Arechavaleta R et al. Diabetes Obes Metab -2011

Week 30
Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on
Metformin:
Study Design1
Continue stable dose of metformin
Single-blind
Placebo Run-in
Double-blind
Treatment Period
Week –2 Day 1
Patients ≥18 years of
age with T2DM on
stable dose of
metformin (≥1500
mg/day) for
≥12 weeks and HbA1c
6.5%– 9.0%
Glimepiride (n=519)
(started at 1 mg qd and up-titrated until week
18 as needed up to maximum dose of 6 mg qd)
qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Sitagliptin 100 mg qd (n=516)
Week –4
R
Screening
Period

HbA1c-Lowering Efficacy of Sitagliptin at
Week 30 Was Noninferior to That of
Glimepiride in Patients Inadequately Controlled
on Metformin1
LS=least squares; SE=standard error.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
Week
LSMean(±SE)HbA1c,%
Per-Protocol Population
6.0
6.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
8.0
0 6 12 18 24 30
 (95% CI)
0.07% (–0.03, 0.16)
Sitagliptin 100 mg + metformin (n=443)
Glimepiridea + metformin (n=436)
–0.47
–0.54

Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
Two Years extension Data
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin:
Comparable Efficacy
HbA1C
FPG
Add-on Sitagliptin With Metformina vs Glipizide With Metformin Study
aSitagliptin (100 mg/day) with metformin (≥1500 mg/day).

Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Change from Baseline in HbA1c by
Baseline HbA1c at Week 18
FAS=full analysis set; 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.
2. Data on file, MSD.
HbA1cLSMeanChange
fromBaseline,%
Baseline HbA1c,% <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11
FAS (Week 18)
P=0.009
P<0.001
P<0.001
Mean HbA1c,% 7.6 8.4 9.5 9.4 10.4 12.2
n=
–1.1
–1.6
–2.0
–2.9
–2.7
–2.1
–1.7
–1.1
–0.8
–4.0
–3.5
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0
Sitagliptin/metformin FDC
Metformin
99 95 99 11187 101 124 109 150 148
P=0.158
P=0.111
–3.6

28
Safety Of The Drug
Hypoglycemic events

Addition of Sitagliptin or Glimepiride in Patients
Inadequately Controlled on Metformin: Clinical
Assessment of Hypoglycemia Over 30 Weeks1
APaT Population
APaT=all patients as treated; CI=confidence interval.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
7
22
0
5
10
15
20
25
PatientsWith≥1
HypoglycemicEpisode,%
 (95% CI)
–15.0% (–19.3, –10.9)
(P<0.001)
Sitagliptin 100 mg
+ metformin (n=516)
Glimepiridea
+ metformin (n=518)

30
Sitagliptin With Metformin Provided Much
Lower Incidence of Hypoglycemia
aSitagliptin (100 mg/day) with metformin (≥1500 mg/day); bAll-patients-as-treated population.
Least squares mean between-group difference at Week 52 (95% CI): change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);
Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).
Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
Hypoglycemiab
P<0.001
32%
5%
0
10
20
30
40
50
Week 52
%ofPatientsWith≥OneEpisode
Sulfonylurea + metformin (n=584)
Sitagliptin + metformin (n=588)
Add-on Sitagliptin With Metformina vs Glipizideb With Metformin Study

31
Vicious circle of hypoglycemia awareness
Hypoglycemic
events
lead
hypoglycaemic
events
Frequent hypoglycemias
<60 mg/dl
Adapted from Hermanns et al. Diabetologie 2009; 4: R 93-R112
Symptoms of hypoglycemia:
- weaker
- appear later
- change
Awareness of hypoglycemia:
- more difficult
- less reliable

32
Complications and Effects of Severe
Hypoglycemia
Plasma glucose level
10
20
30
40
50
60
70
80
90
100
110
1
2
3
4
5
6
mg/dL
mmol/L
1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
2. Cryer PE. J Clin Invest. 2007;117(4):868–870.
Increased Risk of
Cardiac Arrhythmia1
Progressive
Neuroglycopenia2
Abnormal prolonged
cardiac
repolarization—
↑ QTc and QTd
Sudden death
Cognitive impairment
Unusual behavior
Seizure
Coma
Brain death

33
Severe Hypoglycemia Causes QTc
Prolongation
P=NS
P=0.0003
Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
Euglycemic clamp
(n=8)
Hypoglycemic clamp
2 weeks after
glibenclamide withdrawal
(n=13)
0
360
370
380
390
400
410
420
430
440
450
MeanQTinterval,ms
Baseline (t=0)
End of clamp (t=150 min)
ACCORD?
Significant QTc prolongation
during
hypoglycemia

34
ß-cell:
MoA:
SUs work by closing K+ATP channels

35
Heart: Glibenclamide (K+ATP closer)
leads to QTc prolongation
Najeed SA et al. Am J Cardiol 2002; 90: 1103-1106

36
Weight gain
Safety Of The Drug

37UKPDS 34. Lancet 1998:352:854–865. n=at baseline;
Changeinweight(kg)
Years from randomisation
*diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/l
0
1
5
0 3 6 9 12
8
7
6
4
3
2
Insulin (n=409)
Glibenclamide (n=277)
Metformin (n=342)
Conventional treatment (n=411)*
Insulin
SU
Conv.
Met
SU and weight gain (UPKPS 34)

Sitagliptin With Metformin Provided Weight Reduction
(vs Weight Gain)
Add-on Sitagliptin With Metformin vs Glimepride With Metformin Study
LSMeanChange(±SE)inBody
WeightFromBaseline,kg
Week
0 6 12 18 24 30
–1
0
1
2
APaT Population
Sitagliptin 100 mg + metformin
Glimepiridea + metformin
 = –2.0 kg
(P<0.001)
–0.8 kgb
1.2 kgb
APaT=all patients as treated; LS=least squares; SE=standard error.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. bLS mean body weight change at 30 weeks.

Two Years extension Data- 2010
Sitagliptin With Metformin Provided Weight Reduction
(vs Weight Gain)
Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
aSitagliptin (100 mg/day) with metformin (≥1500 mg/day);

- Blocks
+Promotes
Foley JE, et al. Vasc Health Risk Manag. 2010 Aug 9;6:541-8.
DPP-4 inhibitors have weight-neutral effect in T2D patients,
either as monotherapy and as add-on therapy to other oral agents
DPP-4
inhibitors
Some medications have a weight-neutral effect
FFA
+ Lipolysis
+ Fat oxidation
Apo B-48
Intestinal TG
absorption-

42
ADOPT: Progressive deterioration of glucose
control

Conclusions
 Initial combination of Sitagliptin & Metformin
enhanced the responsiveness of pancreatic B
cells to glucose in both fasting & post-prandial
states.
 Initial combination therapy demonstrated greater
improvements in B cell function than individual
monotherapies.
 Improvements in B cell function were maintained
over 2 years treatment period.
Diabetes, Obesity and Metabolism 14: 67–76, 2012.

45
Sitagliptin and -cell Mass
Mu J. et al. Eur J Pharm 2009; 623: 148-154

Week
LSmeanchange
frombaseline±SE
0.05
0.03
0.01
-0.01
-0.03
-0.05
0 24 52
Sitagliptin 100 mg
Glipizide
Per protocol population.
Nauck MA et al. Diabetes Obes Metab 2007;9:194–205.
Data on file, MSD________.
Sitagliptin Lowered and Glipizide Increased
the Proinsulin-to-Insulin Ratio
aSitagliptin (100 mg/day) with metformin (≥1500 mg/day

Effect of Sitagliptin in
Patients With Type 2 Diabetes and Inadequate
Glycemic Control on Insulin Therapy (Alone or
in Combination With Metformin)
Diabetes, Obesity and Metabolism 2010

Addition of Sitagliptin to Insulin Therapy: Study Design
Single-blind
placebo run-in
period
• Continue on a stable dose of
insulin with or without metformin
• Begin single-blind run-in period
Randomization Week 24
24-Week Stable Insulin Dose Period
QD=daily.
• Patients with type 2 diabetes
• Age >21 years
• Receiving insulin (including
glargine, detemir, ultralente, NPH,
lente, or premixed insulin) alone
or with metformin ≥1500 mg/day
• Not receiving premeal short-
acting insulin
• HbA1c ≥7.5% and ≤11%
Placebo (n=319)
Sitagliptin 100 mg QD (n=322)
R
Screening
visit
Week –2

0 6 12 18 24
0.1
Addition of Sitagliptin to Insulin Therapy: HbA1c Change From
Baseline Over Time
aBaseline mean HbA1c: 8.72% for sitagliptin, 8.64% for placebo
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
FAS Population (LOCF)
Placeboa
Sitagliptina
Difference = –0.56%
(P<0.001)
HbA1cLSMeanChange
FromBaseline,%(SE)
Weeks
0.0
–0.8
–0.7
–0.6
–0.5
–0.4
–0.3
–0.2
–0.1
–0.8
–0.03%
–0.59%
(n=305)
(n=312)

Sitagliptin
Placebo
Addition of Sitagliptin to Insulin Therapy: HbA1c Change From Baseline by
Insulin Type
FAS Population at 24 Weeks (LOCF)a
P-value for treatment by
subgroup interaction = 0.949
aExcluding data after initiation of rescue therapy.
HbA1cLSMeanChange
FromBaseline,%(SE)
–1.0
0.0
–0.8
–0.6
–0.4
–0.2
Receiving
Premixed
Insulin
Receiving Long- or
Intermediate-acting
Insulin
–0.58
–0.02
–0.61
–0.04
n=80
n=80
n=225
n=232
P<0.001 P<0.001
Mean baseline HbA1c, % 8.59 8.50 8.76 8.69

Addition of Sitagliptin to Insulin Therapy: HbA1c Change From Baseline by
Metformin Use
Not Receiving
Metformin
Receiving
Metformin
N=223 N=229
Sitagliptin
Placebo
P-value for treatment
by subgroup
interaction = 0.437
HbA1cLSMeanChange
FromBaseline,%(SE)
–1.0
0.4
–0.8
–0.6
–0.4
–0.2
0.2
0.0
–0.55
0.10
–0.66
–0.13
P<0.001 P<0.001
n=82 n=83 n=223 n=229
Mean baseline HbA1c, % 8.68 8.76 8.73 8.60

Addition of Sitagliptin to Insulin Therapy: Change from
Baseline 2-h PPG and FPG
–18.5
–3.5
–30
–20
–10
0
–30.9
5.2
–60
–40
–20
0
20
LSMeanChangeFrom
Baseline2-hPPG,mg/dL
LSMeanChangeFrom
BaselineFPG,mg/dL
n=310 n=313
n=240 n=257
Sitagliptin
Placebo
P<0.001
P<0.001
FAS=full analysis set; FPG=fasting plasma glucose; LOCF=last observation carried forward; LS = least squares;
PPG=postprandial glucose.
Mean baseline
PPG, mg/dL 290.9 292.1
Mean baseline
FPG, mg/dL 175.8 179.1

Sitagliptin and Hepatic
Functions
54

Diabetic Patients & Fatty Liver
• In Western countries, the prevalence of
NAFLD in the general population ranges from
15-39% (3,4). Thus, the prevalence of NAFLD
is increasing and the disease is becoming a
major target disease for treatment.
• NAFLD is considered as a hepatic
manifestation of the metabolic syndrome and
is particularly associated with insulin
resistance (IR), obesity, hypertension and
abnormalities of glucose and lipid metabolism
. However, effective drug therapy for NASH
has not been established at present.

Fatty liver among Diabetics …..
Iwasaki, et al.
www.hepato-gastroenterology.org
DOI 10.5754/hge11263
2011; 58(112): Ahead of print.

Sitagliptin Improves Hepatic Functions

The DPP -4 I in Cardiovascular
Disease

Sitagliptin
N=3415
n (%)
Nonexposed N=2724
n (%)
Between-Groups
Difference,
% (95% CI)a
Serious clinical adverse experiences ≥0.2% in any group
Coronary artery disease 5 (0.1) 7 (0.3) –0.1 (–0.4, 0.1)
Myocardial infarction 4 (0.1) 5 (0.2) –0.1 (–0.3, 0.1)
Noncardiac chest pain 4 (0.1) 9 (0.3) –0.2 (–0.5, 0.0)
Cholelithiasis 6 (0.2) 2 (0.1) 0.1 (–0.1, 0.3)
Pneumonia 4 (0.1) 5 (0.2) –0.1 (–0.3, 0.1)
aPositive differences indicate that the proportion for the sitagliptin group is higher than the proportion for the
nonexposed group.
“0.0” represents rounding for values that are slightly greater than zero.
Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central.
Incidences of Serious Adverse Events Were Generally Similar Between
Treatment Groups With or Without Sitagliptin
Sitagliptin pooled safety and tolerability analysis

Sitagliptin and Renal
Functions

Renal Function
• Although sitagliptin is eliminated mostly through the kidney , it
is tolerated well in patients with mild, moderate and severe
renal failure (including those on dialysis) (Bergman, Cote et al.
2007).
• sitagliptin is approved in patients with mild renal impairment
(creatinine clearance [CCr] ≥ 50 mL/min) However, in patients
with moderately (CCr ≥30 to < 50 mL/min) and severely (CCr <
30 mL/min) impaired renal function / end stage renal disease
(ESRD) it can be given in a reduced dose .
•
• Deacon 2011 , Tatjana Ábel National Health Center
• Hungary 2011).

Risks & Benefits
DPP-IV
inhibitors
EFFICACY
↓A1c 0.7%
(up to 1.5% if
starting A1c higher)
COST
$200 / month*
* Source – drugstore.com
SIDE EFFECTS (common)
- none
SIDE EFFECTS (putative)
- Pancreatitis
- Pharyngitis
CONTRAINDICATIONS
- h/o pancreatitis

► DPP-4 is found on the surface of lymphocytes
► It inhibits breakdown of multiple cytokines and
hormones including many involved in immune cell
regulation
BUT
► Meta-analysis of 12 Phase IIb / III trials involving
3,415 patients on sitagliptin vs. 2,724 patients on
placebo showed incidence of infections 34.5% vs.
32.9% (NS)
► Incidence of nasopharyngitis was 7.1% vs. 5.9% (NS)
Risks: Immunodeficiency
From: Williams-Herman, D et al. (2008). BMC End Dis 8(14)

► 88 cases of pancreatitis in patients on sitagliptin
have been reported to the FDA by 09/2009
BUT
► Retrospective study of 786,656 patients including
patients with h/o chronic pancreatitis and other
pancreatitis risk factors
► 15,826 patients on sitagliptin
► Incidence of pancreatitis increased in patients
with diabetes; no difference for sitagliptin
Risks: Pancreatitis
From: Garg R et al. (2010). Diabetes Care online 08/03/10

Conclusions—
DPP-4 Inhibitors
• Sitagliptin (Januvia ) have a major role in
diabetes management , both in monotherapy
and in combination therapy with metformin
(Janumet ) , glitazones, sulfonylurea, or insulin,
• It can effectively reduce fasting and
postprandial blood glucose levels and also
HbA1c value.
• Based on studies and clinical experience, they
can be tolerated very well, and they cause no
increase of body weight, hypoglycemia and

Conclusions—
Cont.
• Based on animal and in vitro studies ,they
can preserve or enhance beta cell
function.
• Ability to use in renal insufficiency, heart
failure, and hepatic disease markedly
increases therapeutic options for our
patients

DPP4 Inhibitors: An Effective Option for Glycemic Control with Lower Hypoglycemia Risk

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DPP4 Inhibitors: An Effective Option for Glycemic Control with Lower Hypoglycemia Risk