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
400
People with diabetes (millions)

300

200

100

0
1985 1995 2000 2030
(projected)
Year
Adapted from WHO. Available at: http://www.who.int/dietphysicalactivity/publications/facts/diabetes/en/print.html.
Accessed February 6, 2009.
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
Act Now ……
Early Detection & Early and accurate
Intervention
 The Incretin Defect in Type 2 Diabetes

Incretin
“Defect”

Insulin Relative Insulin

Resistance 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. 8
Glycemic Recommendations for Adults with
Diabetes
• Goals should be individualized based on
–Duration of diabetes
–Age/life expectancy
–Comorbid conditions
–Known CVD or advanced microvascular complications
–Hypoglycemia unawareness

ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.

 Earlier and Appropriate Intervention May
Improve Patients’ Chances of Reaching
Goal
Published Conceptual Approach
OAD +
multiple daily
Diet and OAD OAD OAD OAD + insulin
exercise monotherapy up-titration combination basal insulin injections

10
9
HbA1c Goal

8
7
Mean 6
HbA1c Duration of Diabetes
of patients Conventional stepwise Earlier and more aggressive
treatment approach intervention approach
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.
 Glycemic Recommendations for Adults with Diabetes

A1C <7.0%*

Preprandial capillary plasma 70–130 mg/dl*

glucose

Peak postprandial capillary <180 mg/dl*

plasma glucose†

*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

-glucosidase Sulfonylureas/
inhibitors meglitinides Biguanides Thiazolidinediones

 Carbohydrate  Insulin  Glucose  Insulin

breakdown/ secretion output resistance
absorption  Insulin resistance

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

Glucose-dependent  Peripheral
Ingestion
of food  Insulin from glucose
beta cells uptake
Pancreas (GLP-1 and GIP)
Release of
GI tract active incretins  Blood glucose in
GLP-1 and GIPa Beta cells fasting and
Alpha cells postprandial states
DPP-4
Glucose-dependent
enzyme
 Glucagon  Hepatic
Inactive Inactive from alpha cells glucose
GLP-1 GIP (GLP-1) production

Incretin hormones GLP-1 and GIP are released by the intestine throughout the day;
their levels increase in response to a meal.

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.
 Sitagliptin and Metformin Target the Core
Metabolic Defects of Type 2 Diabetes
Beta-Cell Insulin
Dysfunction Resistance
Sitagliptin improves
beta-cell function Metformin has insulin-
and increases insulin sensitizing properties.3–5
synthesis and (Liver > Muscle, fat)
release.1

Sitagliptin reduces HGO through

suppression of glucagon from alpha Metformin decreases HGO by
cells.2 targeting the liver to decrease
Hepatic Glucose gluconeogenesis and
Overproduction (HGO) glycogenolysis.4

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.
Glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6 540-559)
 DPP-4 Inhibitors Differ Chemically

F F
NH2 O H O N
F N HO N
N N
N
Sitagliptin N
Vildagliptin
F
F OH
F
O

N
N
NH2
O
Saxagliptin
N N
N
N O N N
N N
O N N
NH2 N
Alogliptin
Linagliptin O
 18

Sitagliptin is Highly Selective & fit for DPP4

Site

H126

H740
R125
S209
E205

Yellow: sitagliptin E206 R358

Green: vildagliptin S630

Y547
F357

1. Data on file, MSD. DPP-4=dipeptidyl peptidase-4.

 DPP-4 Inhibitors Have Different Durations of Action
% Plasma
DPP-4 inhibition
100
% Plasma
Vildagliptin 80
Day 1
DPP-4 inhibition

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

Sitagliptin Vildagliptin

F FNH2O
Molecular structure N N N
F N H
N N NC O
CF3 HO
Half Life (T1/2) 12.4 hrs 2-3 hrs

50 mg QD: 20% @ 24 hrs

DPP-4 Inhibition* post 24 hrs 100mg QD 80-97% @ 24hrs
50 mg BID: >80% @ 12hrs

DPP-4 Peak Inhibition ~97% ~95%

2600 fold for DPP4 vs. DPP-8 270 fold for DPP4 vs. DPP-8
Selectivity for DPP-IV vs. DPP-8/DPP-9*
10,000 fold for DPP4 vs. DPP-9 32 fold for DPP4 vs. DPP-9

69% metabolized
Metabolism ~16% metabolized mainly renal
(inactive metabolite)

Bioavailability ~87% 85%

Liver Monitoring NO YES

Kidney (85%)
Kidney (87%)
Elimination 23% unchanged
79% mostly unchanged
Liver (15%)

FDA YES NO

* All use different proprietary assays with different dilutions and therefore % DPP-4 inhibition cannot be compared across assays
Data on file, MSD
 Tight Glycaemic
control

• Hypoglycaemia
Macrovascular
•Weigh gain
&
Microvascular
Risk Reduction
 Efficacy and Safety of Treatment With
Sitagliptin or Glimepiride in Patients With
Type 2 Diabetes Inadequately Controlled
on Metformin Monotherapy
Diabetes Obes Metab. 2011
 Efficacy: HbA1c reduction

“Addition of Sitagliptin or
Glimepiride in Patients
Inadequately Controlled
on Metformin“

Arechavaleta R et al. Diabetes Obes Metab -2011

23
 Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on
Metformin:
Study Design1

Patients ≥18 years of Sitagliptin 100 mg qd (n=516)

age with T2DM on
stable dose of
metformin (≥1500 R
mg/day) for
≥12 weeks and HbA1c Glimepiride (n=519)
6.5%– 9.0%
(started at 1 mg qd and up-titrated until week
18 as needed up to maximum dose of 6 mg qd)

Continue stable dose of metformin

Screening Single-blind Double-blind

Period Placebo Run-in Treatment Period

Week –4 Week –2 Day 1 Week 30

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

1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
 HbA1c-Lowering Efficacy of Sitagliptin at
Week 30 Was Noninferior to That of
Glimepiride in Patients Inadequately Controlled
on Metformin1
8.0
Sitagliptin 100 mg + metformin (n=443)
7.8
LS Mean (±SE) HbA1c, %

Glimepiridea + metformin (n=436)

7.6
Per-Protocol Population
7.4
7.2 –0.47
 (95% CI)
7.0 0.07% (–0.03, 0.16)
6.8 –0.54

6.6
6.4
6.2
6.0
0 6 12 18 24 30
Week
LS=least squares; SE=standard error.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Add-on Sitagliptin With Metformina vs Glipizide With Metformin Study
Two Years extension Data
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin:
Comparable Efficacy

HbA1C

FPG

aSitagliptin (100 mg/day) with metformin (≥1500 mg/day).

Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
 Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Change from Baseline in HbA1c by
Baseline HbA1c at Week 18
FAS (Week 18)
Baseline HbA1c,% <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11
Mean HbA1c,% 7.6 8.4 9.5 9.4 10.4 12.2
0
n= 87 101 124 109 99 95 99 111 150 148
–0.5
HbA1c LS Mean Change
from Baseline, %

–1.0 –0.8
–1.1 –1.1
–1.5
P=0.158 –1.6 –1.7
–2.0
–2.0 –2.1
P=0.009
–2.5
P=0.111
–2.7
–3.0 –2.9

–3.5 P<0.001
Sitagliptin/metformin FDC –3.6
–4.0
Metformin P<0.001
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.
Safety Of The Drug

Hypoglycemic events

28
 Addition of Sitagliptin or Glimepiride in Patients
Inadequately Controlled on Metformin: Clinical
Assessment of Hypoglycemia Over 30 Weeks1
APaT Population

 (95% CI)
–15.0% (–19.3, –10.9)
(P<0.001)
Hypoglycemic Episode, %

25 22
Patients With ≥1

Sitagliptin 100 mg
20 + metformin (n=516)
Glimepiridea
15 + metformin (n=518)
10 7
5
0

APaT=all patients as treated; CI=confidence interval.

aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Add-on Sitagliptin With Metformina vs Glipizideb With Metformin Study

Sitagliptin With Metformin Provided Much

Lower Incidence of Hypoglycemia
Hypoglycemiab
50

% of Patients With ≥ One Episode

40
32%
30 P<0.001

20

10 5%

0
Week 52
Sulfonylurea + metformin (n=584)
Sitagliptin + metformin (n=588)

(100 mg/day) with metformin (≥1500 mg/day); bAll-patients-as-treated population.

aSitagliptin

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).
30
Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
 Vicious circle of hypoglycemia awareness

Hypoglycemic
Frequent hypoglycemias Symptoms of hypoglycemia:
events
<60 mg/dl - weaker
lead
- appear later
hypoglycaemic
events - change

Awareness of hypoglycemia:
- more difficult
- less reliable

31
Adapted from Hermanns et al. Diabetologie 2009; 4: R 93-R112
 Complications and Effects of Severe
Hypoglycemia
Plasma glucose level

110
6

100

5 90 Increased Risk of Progressive

80 Cardiac Arrhythmia1 Neuroglycopenia2
4
70 Abnormal prolonged Cognitive impairment
60 cardiac Unusual behavior
3
50 repolarization— Seizure
40 ↑ QTc and QTd
2 Coma
30 Sudden death
Brain death
1 20
mmol/L

10
mg/dL

1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307. 32

2. Cryer PE. J Clin Invest. 2007;117(4):868–870.
 Severe Hypoglycemia Causes QTc
Prolongation

450 P=0.0003
440
Mean QT interval, ms

430
420 P=NS

410
400
390
380 Significant QTc prolongation
370 during
360 hypoglycemia
0
Euglycemic clamp Hypoglycemic clamp
(n=8) 2 weeks after
glibenclamide withdrawal
Baseline (t=0) (n=13)
End of clamp (t=150 min)
ACCORD?
33
Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
 MoA:
SUs work by closing K+ATP channels

ß-cell:

34
 Heart: Glibenclamide (K+ATP closer)
leads to QTc prolongation

Najeed SA et al. Am J Cardiol 2002; 90: 1103-1106 35

Safety Of The Drug
Weight gain

36
 SU and weight gain (UPKPS 34)

8
7 Insulin
Change in weight (kg)

6
5
4 SU
3
2 Conv.
1 Met
0 Conventional treatment (n=411)*
Insulin (n=409)
0 3 6 9 12 Glibenclamide (n=277)
Years from randomisation Metformin (n=342)

*diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/l
UKPDS 34. Lancet 1998:352:854–865. n=at baseline; 37
 Add-on Sitagliptin With Metformin vs Glimepride With Metformin Study

Sitagliptin With Metformin Provided Weight Reduction

(vs Weight Gain)

APaT Population

Sitagliptin 100 mg + metformin

LS Mean Change (±SE) in Body

2
Glimepiridea + metformin
Weight From Baseline, kg

1.2 kgb
1

 = –2.0 kg
0 (P<0.001)

–0.8 kgb
–1
0 6 12 18 24 30

Week
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.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
 Add-on Sitagliptin With Metformina vs Glipizide With Metformin Study

Two Years extension Data- 2010

Sitagliptin With Metformin Provided Weight Reduction
(vs Weight Gain)

aSitagliptin (100 mg/day) with metformin (≥1500 mg/day);

Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
Some medications have a weight-neutral effect

DPP-4 inhibitors have weight-neutral effect in T2D patients,

either as monotherapy and as add-on therapy to other oral agents

Intestinal TG
Apo B-48 - absorption

DPP-4
inhibitors + Lipolysis

FFA

+ Fat oxidation

- Blocks
+Promotes

Foley JE, et al. Vasc Health Risk Manag. 2010 Aug 9;6:541-8.
Beta-cell function

41
ADOPT: Progressive deterioration of glucose
control

42
 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.
 Sitagliptin and -cell Mass

Mu J. et al. Eur J Pharm 2009; 623: 148-154 45

46
Add-on Sitagliptin With Metformina vs Glipizide With Metformin Study

Sitagliptin Lowered and Glipizide Increased

the Proinsulin-to-Insulin Ratio

0.05 Sitagliptin 100 mg

Glipizide
0.03
from baseline ± SE
LS mean change

0.01

-0.01

-0.03

-0.05

0 24 52
aSitagliptin (100 mg/day) with metformin (≥1500 mg/day
Per protocol population.
Week
Nauck MA et al. Diabetes Obes Metab 2007;9:194–205.
Data on file, MSD________.
 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

• Patients with type 2 diabetes

• Age >21 years
24-Week Stable Insulin Dose Period
• Receiving insulin (including
glargine, detemir, ultralente, NPH,
lente, or premixed insulin) alone
or with metformin ≥1500 mg/day
• Not receiving premeal short-
acting insulin Sitagliptin 100 mg QD (n=322)
• HbA1c ≥7.5% and ≤11%

R
• Continue on a stable dose of
insulin with or without metformin
• Begin single-blind run-in period Placebo (n=319)

Single-blind
placebo run-in
period

Screening Week –2 Randomization Week 24

visit
QD=daily.
Diabetes, Obesity and Metabolism 12: 167–177, 2010.
 Addition of Sitagliptin to Insulin Therapy: HbA1c Change From
Baseline Over Time

FAS Population (LOCF)

0.1
0.0 –0.03%
HbA1c LS Mean Change
From Baseline, % (SE)

–0.1 (n=312)
–0.2
Difference = –0.56%
–0.3
(P<0.001)
–0.4
–0.5
–0.6 –0.59%

–0.7 (n=305)

–0.8 Sitagliptina
0 6 12 18 24 Placeboa
Weeks
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.
Diabetes, Obesity and Metabolism 12: 167–177, 2010.
 Addition of Sitagliptin to Insulin Therapy: HbA1c Change From Baseline by
Insulin Type

FAS Population at 24 Weeks (LOCF)a

Receiving Receiving Long- or
Premixed Intermediate-acting
Insulin Insulin
Mean baseline HbA1c, % 8.59 8.50 8.76 8.69
0.0 n=80
n=80
n=225
n=232
HbA1c LS Mean Change
From Baseline, % (SE)

–0.2 –0.04
–0.02
Sitagliptin
–0.4 Placebo

–0.6
P-value for treatment by
subgroup interaction = 0.949

–0.8 –0.61
–0.58

–1.0 P<0.001 P<0.001

aExcluding data after initiation of rescue therapy.
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
Diabetes, Obesity and Metabolism 12: 167–177, 2010.
 Addition of Sitagliptin to Insulin Therapy: HbA1c Change From Baseline by
Metformin Use

FAS Population at 24 Weeks (LOCF)a

Not Receiving Receiving
Metformin Metformin
Mean baseline HbA1c, % 8.68 8.76 8.73 8.60
0.4 0.10
0.2
HbA1c LS Mean Change
From Baseline, % (SE)

0.0 Sitagliptin
n=82 n=83 n=223 n=229
N=223 N=229 Placebo
–0.2
–0.13
–0.4
P-value for treatment
by subgroup
–0.6 interaction = 0.437

–0.8 –0.55 –0.66

–1.0 P<0.001 P<0.001

aExcluding data after initiation of rescue therapy.
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
Diabetes, Obesity and Metabolism 12: 167–177, 2010.
 Addition of Sitagliptin to Insulin Therapy: Change from
Baseline 2-h PPG and FPG

FAS Population at 24 Weeks (LOCF)a

Mean baseline Mean baseline
PPG, mg/dL 290.9 292.1 FPG, mg/dL 175.8 179.1
20 5.2 0
n=310 n=313
Baseline 2-h PPG, mg/dL

LS Mean Change From

LS Mean Change From

Baseline FPG, mg/dL

0 n=240 n=257
–10
–3.5
–20

–20
–40
–30.9
–18.5

–60 P<0.001 –30

Sitagliptin P<0.001
aExcluding data after initiation of rescue therapy. Placebo
FAS=full analysis set; FPG=fasting plasma glucose; LOCF=last observation carried forward; LS = least squares;
PPG=postprandial glucose.
Diabetes, Obesity and Metabolism 12: 167–177, 2010.
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
Sitagliptin Improves Hepatic Functions
The DPP -4 I in Cardiovascular
Disease
Sitagliptin pooled safety and tolerability analysis

Incidences of Serious Adverse Events Were Generally Similar Between

Treatment Groups With or Without Sitagliptin
Nonexposed N=2724 Between-Groups
Sitagliptin n (%) Difference,
N=3415 % (95% CI)a

n (%)
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.
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

EFFICACY
↓A1c 0.7% COST
(up to 1.5% if $200 / month*
starting A1c higher)

DPP-IV
inhibitors
SIDE EFFECTS (common) SIDE EFFECTS (putative)
- none - Pancreatitis
- Pharyngitis

CONTRAINDICATIONS
- h/o pancreatitis

* Source – drugstore.com
 Risks: Immunodeficiency

► 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)

From: Williams-Herman, D et al. (2008). BMC End Dis 8(14)

 Risks: Pancreatitis

► 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

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
Pay Me Now

or
Pay Me Later
Thank You ….

Lobna