GLP-1R agonists lower glycated haemoglobin by about 0.6–1% and induce weight loss. DPP-4 inhibitors reduce glycated haemoglobin by 0.5–0.6% and have no effect on weight. The GLP-1–related drugs arrived in clinical practice with much fanfare and anticipation. DPP- 4 enzyme is a ubiquitous cell-membrane protein, expressed in many tissues, including lymphocytes, which has raised some concerns about the long-term effects of DPP-4 inhibitors, especially on immune function. Data consistent with case reports and animal studies indicate an increased risk for pancreatitis with GLP-1-based therapy and also raise caution about the potential long-term actions of these drugs to promote pancreatic and thyroid cancers. This lecture will review the incretin-based therapies with focus on their benefits and their potential transient and serious side effects.

1. Incretin-Based Therapies for the
Treatment of Type 2 Diabetes:
Update on the Benefits and Risks
Dr. Abdulameer Abdullah Al-ashbal
Ass.Prof. ; Consultant Diabetologist
Almustansiriya medical college ,
Department of Medicine ;
Alyermouk Teaching Hospital

2. No financial relationships with
any commercial interests

3. The gastrointestinal tract
has a crucial role in the control of
energy homeostasis
through its role in
the digestion,
absorption,
and assimilation
of ingested nutrients.
Dr. Abdulameer Abdullah Al-ashbal
Ass.Prof. ; Consultant Diabetologist

4. The role of
Insulin
in
glucose homeostasis
is a firmly established concept and
forms the cornerstone of
discussions of the pathophysiolgy
of diabetes.
Dr. Abdulameer Abdullah Al-ashbal
Ass.Prof. ; Consultant Diabetologist

5. However,
how
glucose enters the blood stream
has profound effects on
magnitude of stimulatory effect of
glucose
on insulin secetrion.
Dr. Abdulameer Abdullah Al-ashbal
Ass.Prof. ; Consultant Diabetologist

6. The observation that in response to
hyperglycemic stimuli,1.E
En lrick
do
cri H, e
•M 19 nol M t al. J
oral glucose19 cInty 64; 2 etab Clin
64
; 2 re N 4: 10
:2
0– , et al 76–1
elicits a greater insulin response than
21
. . Lan 082.
cet
intravenous glucose,
is termed
“The Incretin Effect “
, which accounts for up to 60% of postprandial
insulin release in healthy people

7. The incretin effect
Energy administeration
The gut via
The parenteral
route
Glucose Glucose
+
(Insulin secretagogue)
(Insulin secretagogue)
Gut-derived signals
(Potent insulin secretagogues)
Insulin release Insulin release

8. Plasma Insulin (µU/mL) The incretin effect*
Time (min)
* Perley MI,et al. J Clin Invest. 1967; 46:1954-1962.

9. And
this finding
m
L
m
U
P
µ
u
n
a
I
s
(
/
i
l)
Time (min)
firmly implicated
gastrointestinal factors*
as important mediators of
insulin secretion after oral glucose
* Mcintyre N, et al. J Clin Endocrinol Metab , 1965 25:1317–1324.

10. These factors have come to be termed
“Incretins“
(INtestine seCRETtion Insulin)
and
their role on glucose homeostasis has led to
Zunz E, et al. Arch Int Physiol Biochim 1929; 31:
20–44.
a novel class of
incretin-based
antihyperglycemic agents
based on the function and physiology of
two endogenous dominant incretin hormones

11. These two native incretin hormones are :
Glucagon-like peptide-1
(GLP-1)
1. Bell GI, et al. Nature 1983 ;
302 :716 -718
2. Heinrich C. et al. Endocrinology
1984: 115:2176-2181
3. Mojsov S, et al. I Biol Chem
1986; 261:11880-11889
4. Novak U, et al. European Journal
of Biochemistry 1987;
164:553-558
5. Holst JJ, et al. FEBS Lett 1987;
211:169-174
6. Kreymann B, et al. Lancet.
1987;2:1300-4
7. Ørskov C ,et al . Endocrinology
1986 ;119 :1467-1475
8. Mojsov S ,et al . J Clin Invest
1987; 79 :616-619
that principally responsible for the incretin effect 1-8.

12. (K-cells of the intestinal mucosa)

* Takeda J, et al.Proc Natl Acad Sci U S A 1987; 84:7005–7008

13. (L-cells of the intestinal mucosa)


* Orskov C, et al. En-docrinology 1986; 119:1467—1475.

14.  GLP-1 -secreting enteroendocrine
L-cells are located predominantly in
the ileum and colon1-3.
 GIP-secreting enteroendocrine
K-cells are concentrated in 1. Bell GI,et al. Nature
1983; 302: 716–718.
the duodenum and proximal jejunum1-6.
2. Schmidt WE,et al.
Diabetologia 1985; 28:
1. JF et al. Diabetes Metab 704–707.
2005;31:233-242 3. Kreymann B, et al.
2. Drucker DJ.Diabetes Care Lancet 1987; 2: 1300–
1304.
These native hormones are secreted
2003; 26:1929-2940
3. Orskov C,et al. Diabetes
Insulin
1994 ;43:535-53
4. Damholt, et al.
at low basal levels in the fasting
1. Inagaki N, et al. Mol
m
P
Endocrinology 1999 ;140,
a
s
l
Endocrinol 1989; 3: 1014–
4800-4808
n
a
o
r
e
c
s
1021.
t
i
5. Holst, J. J. Physiol. Rev. 87:
state and their circulating levels
2. Takeda J, et al. Proc Natl
1409-1439 2007;
doi:10.1152/physrev.00034.2006
Acad Sci USA 1987; 84: GLP-1
7005–7008.
3. Brown JC, et al. J Physiol
increase rapidly and transiently
m
P
1970; 209: 57–64.
a
s
l
4. Dupre J, et al. J Clin
n
a
o
r
e
c
s
t
i
Endocrinol Metab 1973;
following food ingestion1-5 . 5.
37: 826–828.
Adrian TE,et al.
Diabetologia 1978; 14:
GIP
m
P
a
s
413–417.
l
n
a
o
r
e
c
6. Taminato T, et al. Diabetes
s
t
i
1977; 26: 480–484.
Hours

15. Interactions between
nutrients and GIP and GLP- 1
On a rapid time scale, typically occurring when a
meal is digested and absorbed,
nutrients
and
the incretin hormones,GLP-1 and GIP,
Synergize
in the acute stimulation of insulin secretion
(exocytosis of insulin secretory granules) *
*Jia X, et al . Am J Physiol 1995 ;268: E645–E651

16. Incretin Receptors (GIP Receptors)
The human gipr gene 1-4
 is localized to chromosome 19, band
1.
q13.3. Usd
i
End n TB, e
o
286 crinolo al.
t
 is expressed in both α and β cells in
2. 1 g
Yas -2870. y ,199
u 3; 1
Biop da K, e 33:
hy s t al .
3. 1994;2 Res C Bioch
pancreatic islets, McI
Phy
0 o
ntos 5: 1556 mmun m
h
siol CH, e 1562.
-
e
,
4. 361-36 Scand t al. Ac
 And in other tissues: GI tract, adipose tissue,
Yip 5
R G, .
, 19 t
96; 1 a
E nd 57:
ocri et al.
adrenal cortex, pituitary, heart, testis, endothelium of major blood
400 n
4-40 ology
07. , 199
8; 13
vessels, bone, trachea, spleen, thymus, lung, kidney, thyroid, and 9:
several brain areas.

17. Incretin Receptors (glp-1 Receptors)
The human glp-1r gene 1-5
is located on chromosome 6p21.
1.
Its genetic expression:2 42Stoffel M
. :
Th 1215 , et a
o
3. U S rens -1218 l. Dia
Th A , 1 B . Pr . bet
es,
 may be almost exclusively restricted to the β cells and is
4.
ore
199 ns 992;8 oc Na
B,
199
3;
Tib 3; 42 et a 9: 86 tl Aca
present in cells lining the pancreatic ducts
Ch aduiz : 167 l. Di 41-86 d Sc
e 8 a i
5. 377 m, 2 a EC, -168 betes 45.
 in a variety of other tissues: thyroid C cells, kidney, lung,
0
Dil 87-3 01; 2 et al. .
lon 779 76: J B
2 ,
199 3 io l
3 ; 1 J S, e t .
heart, gastrointestinal track, skin, pituitary, and multiple regions
33: al.
190 End
of the peripheral and central nervous system. 7-1 ocri
910 nol
. ogy
,

18. Molecular mechanisms underlying the insulinotropic
effects of GIP and GLP-1 on Pancreatic beta cell*
GIPR GLP-1R
Insulin
* Seino Y et al .J Diabetes Invest 2010,2040-1124)

19. Glucose-dependency of the insulin stimulatory
effect of glucagon-like peptide-1
10 mmol/L Glucose
2.8 mmol/L Glucose
Insulin Release (% of total content)
10 mmol/L Glucose
2.8 mmol/L Glucose
GLP-1 (7-36) amide (pmol/L)
*Goke R, et al. Res Exp Med (Berl). 1993; 193:97-103

21. Dipeptidyl-peptidase -IV (DPP -IV ) enzyme
A subset of prolyl oligopeptidases, including
dipeptidyl-peptidase IV (DPP IV ) or CD26,
specifically cleave off
N-terminal dipeptides
from substrates having
proline or alanine in amino acid position 2.

22. Dipeptidyl-peptidase - 4
*DPP -IV ) enzyme)
In 1993 it was demonstrated that
( Dipeptidyl-peptidase - 4 (DPP -IV
enzyme mediates the inactivation of
GLP-1 and GIP
by removing the two N-terminal amino
acids of the hormones.
* Mentlein R, et al. Eur J Biochem 1993; 214:829–35.
Bruckley D, et al Regul. Pept. 1992, 40, 117

23. Endocrine pathway for the actions of GLP- 1*
Nutrients Incretin Secretion
in the gut lumen L-cells- intestinal villus
100% of the GLP- 1
Luminal
Endothelial cells
DPP-IV** enzyme
Portal circulation (Liver)
25% of the GLP- 1
Soluble plasma
DPP-IV enzyme
Systemic circulation
10—15% of the GLP- 1
Soluble plasma
DPP-IV enzyme
The pancreas and the brain
10—15% or less of the GLP- 1
Holst J J,et al.Diabetologia 2005 48: 612-615 **DPP-IV:Dipeptidyl peptidase-IV

24. Inactivation of GLP-1 and GIP by
Dipeptidyl peptidase-IV (DPP-IV) enzyme((1-11
1.
Na
u
2. 46– ck M
Me 5 2 . , et
al.
3. 214 ntlein Di a
:82 R, b et
Vil 9 – 3 et a olo
200 sbøll 5. l. E gia
(Half-life of 7 min)
4. ur 198
(Half-life of 1-1.5 min) De 3; 8 T,e JB 6; 2
aco 8: 2 t al ioc 9:
5. Me 2 .J h em
tab n CF, 0–4. Clin 199
De 20 et En
6. 271 acon 00; 8 al. J doc
rin
3;
C
Bru :E45 CF,et 5:357 lin E ol M
8
7. 117 ckley -E46 al. A 5-358 ndoc et a
b
D, 4 mJ 1 rin
De . et a Ph y ol
aco lR sio
8. 112 n C eg u l 1
Kie 6-113 , et a l. P 996
9. 199 ffer 1. l. D ep t ;
TJ, i ab . 19
The inactivation enzyme
De 5;136 et et e
s1 92,
a 40,
10. Me con C , 358 al. En 995
; 44
De tab19 F, et 5-359 docri ,
a nol
11. 172 con, 95; 80 al. Cl 6. ogy
, 3 5 C. F , 95 in.
DPP-IV
Me 5 ,e 2 En
214 ntlein -362 t al . -957 docri
829 : R, J.E nol
–35 Et ndo
. al . c ri n
Eu ol 2
rJ 002
Bio
che ;
m1
993
;
(Half-life of 4-5 min) (Half-life of 17 min)

25. GLP-1 (yellow) released by enteroendocrine L-cells,
diffuses to the capillaries, where it is inactivated by
DPP-4 enzyme (red)*
-IV
DPP
GLP-1 GLP-1
DP P-IV
* Histochemistry by C. Ørskov, the Panum Institute

26. The incretin hormones and
Pathophysiology of Type 2 DM 1-12
In type 2 diabetes
1.
2. Na
19 uck
3. Ra 93;9 MA
19 chm 1:3 , et
The secretion of 5.
4. The glucose-lowering
Ah 96;4 an 01– al. J
20 re´ 5:1 J,et 307 Clin
Vil 04;3 n B, 524 al. D In
ve
61 sbø 6:8 et a –153 iab
actions of
st
3J ll T 67 l. ete
6. Cli , e –8 Ho 0 s
37 n En t a 76 rm
7. J C 23. doc l. D Me
22 lin rin ia b tab
8. 4. En ol ete Re
9. D do Me s2 s
Cli iab cri tab 00
10 n et no 20 1;
11 . Re . Inv Me lM
eta 01 50
:6
. Me l.g u es d 2 ;8
6: 09
Vil ta Pe t. 00 b2 37 –
12
. 11 el sb bo pt 199 0;1 00
3; 17
li 1 3; 7 –
Na 11 – l T, sm.1 994 91: :713 88
:2
19 uc 11 et 98 ;5 30 –7 20
1
93 k M 19. al.D 7; 3 :63 1–30 19 –
;3 A, iab 6: -74 7.
GIP GLP-1
6:
74 et a eto 677 .
GIP GLP-1 1– l.D
74 iab
4 eto
log -68
ia 2
20 .
Normal
log 02
much weaker
ia ;4
preserved
5:
or increased reduced
or absent
(resistance)

27. The incretin hormones and Pathophysiology
of Type 2 DM
Consequently in patients with Type 2 diabetes,
the incretin effect is either
severely
reduced*
abolished or (From normal 60%
to < 10%)**
resulting in
inappropriately low insulin secretion following oral ingestion
of nutrients*.
.Tronier B, et al . Diabetes Clin Pract1985;]Suppl 1[:S568 * ** Mentlein R, et al. Eur J Biochem 1993; 214: 829–35.
Nauck M , et al. Diabetologia 1986;29:46-52. Rask E, et al. Metabolism 2004; 53 : 624 –631.
Diabet Med 2000;17:713–719.

28. Pathophysiological changes in Type 2 diabetes1-6
1.
2. Degr
Increased Increased glucagon
3.
Sh on
20 age zo R
01 P, Deranged adipocyte
A ;85 et A. D
hepatic glucose secretion
37 hfen :805 al. I iabe
4. :19 B, 3
Le 86 et -805 lin E es Re
Ro -11 al.
C t
biology
6 8. nd v19
5. C)8S ek D 13. Diab
production 19
Ni
els - 13S m
6. 98; on M .
.A
JM
eto
log
ia
ocr
ino 98 ;9
l M :97
eta 7–2
Vi 22 B, ed 20 b 6.
lsg :11 20 02
ell 37 et al. 02 ;
T, -11 D ;11
et i
al. 43. abete 3(
Su
Di sC pp
ab l
Increased ete
s2
00
2;8
are
0:5
Insulin 09
-51
resistance Type 2 diabetes 3.
Increased
gastric-emptying
rate
Impaired incretin effect
Decreased insulin 2.Decreased secretion of GLP-1
secretion 3.Impaired response to GIP

29. The unique antidiabetic effects of
Glucagon-like peptide-1
The lost efficacy of GIP
precludes
its application as a therapeutic agent.
While
the preserved effect of GLP- 1
has inspired attempts
to treat Type 2 diabetes with it *
‫٭‬Hoist II, et al ? Bio Drugs 2002; 16:175-181

30. Approaches to enhance incretin effects
The preserved effects of GLP- 1 has inspired attempts to
treat Type 2 diabetes with it 1-4
Because 1.M
e
GLP-1 is rapidly inactivated9byein R
19 ntl
2.D 9; 8
eac 5:9 . Reg
the enzyme DPP-4, Endo on CE -24. ul Pep
DPP-4 c
80 ri ,e t
3. V :952- nol M t al.
modulating its ils 957 eta Clin
En boll . b1
Level & activity doc T. J 995
2 0 0 ri n ;
4.E 3;82 ol M Clin
g 7 e
En an JM 06 -2 tab ,
has become a major focus of investigation
d
200 ocrin ,. J Cl 13.
7
2 ; 8 o l M in
for treating type 2 diabetes by
7:3
768 etab
-37
73.
one of major three approaches, which are known as
GLP-1 - based therapies
or
incretin - based therapies

31. The current approaches to enhance incretin
action in patients with type 2 diabetes
1) GLP-1 receptor agonists *:
as Exendin -4 or DDP-4
degradation-resistant and
Exenatide
can produce GLP-1
(Half-life of 2-4 h)
levels that are more than
(synthetic exendin-4)
(Byetta ®)
5 times a patient's
physiologic levels.
2) GLP-1 analogues *:
as liraglutide
(Half-life of 12-14 h)
by conjugation of GLP-1
Incretin mimetics
(used by SC
to circulating albumin
injection)
(Victoza ®)
• * Amori RE, et al.JAMA.2007;298:194-206
• Liraglutide: Blonde L., et al. Can J Diabetes. 2008;32 (Supp):A107

32. GLP-1 analogue, exendin-4,
first found in the saliva of the Gila monster Lizard
The Gila Monster Lizard
-4
en din
Ex

33. The current approaches to enhance incretin
action in patients with type 2 diabetes
• Inhibitors of DPP-IV *: augment the concentration of
endogenously released
Sitagliptin (Januvia ®) both GIP and GLP-1 and
normalize GLP-1 level in type 2
,Viltagliptin (Galvus ®) diabetes and can result in an
approximate 2-fold increase in
saxagliptin (Onglyza ®) GLP-1 levels.
Linagliptin (Tradjenta ®)
Alogliptin (Nesina ® ) Incretin
enhancers
* Pospisilik JA, et al . Diabetes 2002; 51: 2677-2683 (Gliptins)
Fonseca VA ,et al. Am J Med.2010; 123(7):S2 -S10.
(used Orally)

34. Effects of GLP-1 R agonists (Gliptins)
on glucose metabolism1-10
GLP-1 receptor agonist
Pancreatic
islet cells
1. Brubaker PL . Trends Endocrinol
Metab,2007; 18:240–245
Decreased food Prolonged gastric Increased insulin Decreased glucagon
2. Lovshin JA, et al. Nat Rev Endocrinol.
2009; 5:262–269
intake emptying secretion
3. Brubaker PL. Trends Endocrinolsecretion
Metab ,2007;18:240–245
4. Lovshin JA, et al. Nat Rev Endocrinol ,
2009;5:262–269
5. Drucker DJ,et al. Lancet 2006; 368:
1696–705.
6. Willms B, et al. J Clin Endocrinol Metab
1996; 81: 327–32.
7. Nauck MA, et al. Am J Physiol 1997;
Weight loss 273: E981–8.
8. Maljaars J, et al.Aliment Pharmacol Ther
Decreased blood glucose
2007; 26 (Suppl. 2): 241–50.
9. Gutniak M, et al. N Engl J Med 1992;
326:1316-22.
↓ ( 0.6 – 0.8%HbA1c)
10. Degn KB, et al.Diabetes 2004; 53: 1187–
94.
Increased insulin
sensitivity

35. Current incretin mimetics
(GLP-1 R agonists; GLP-1 analogues) used by
injection for type 2 diabetes 1-10
1.
2. Am
Ex o r
et enti i RE
Exendin-4
ZP-1O 3.
Li al. L de L , et (Natural GLP-1 ) ;
rag an A al. 2002
CJC-1131 4. Dia lut ce R ( JAM
Albugon ® 5.
G be id t 2 O
Exenatide
{S runb tes. e: B 008 nce .20
A
2 l ;37 we 07
Cl uppl erge 008 ond (Synthetic exendin-4 )
2 ek ;29
AVE-0010 54 lan 1[ r G ;32 e L :1(Byetta ®) : ly
6.
A u ]S d J S3 , e (S ., e 240- ):D 8 19
L 1 t 1 ru 4
u SCt once or twice/d
Albiglutide ® 7. ]S less ppl 1 , et 8: N al.D pp): al. C 250 cke -206
u i a an . rD
Bo ppl T, e [ S l. D o. 7 iabe A10 ;2005 J J,
1 3 i 8 t 7
Lixisenatide 8. 54]S ll G, [ S3 t al. 18:N abet 8. olog
GLP-1 R agonist; 9. ]Sup r
Ra up et 19 Dia o. olo
tne pl al. :N be 78 gia (Liraglutide) ia
20
11
1[ D o . to l 7 . 20 ;54
SC once / d ; Ro pl RE S iab 78 og 11 (Victoza ®)
]S sen 1[ , et 316 eto 9. ia 2
10 up s S3 a ;
(Naturally occurring
2010 . D pl toc 17 l> : N logi 01
1; GLP-1 analogue) ;
]S ahm 1[ k J, :N Diab o.78 a 20 54
LY 2189265 (LY) up
pl s J S 31 et o. 7 eto 4. 11 SC once or twice / d
1[ , e 7 al. 85 lo ;
;2010
GLP-1 analogue; S 3 t al. : No Dia . gia
1 9 D ia . 7 be 20
SC once-weekly ; : N be 86. tolo 11
;5
2011) ITCA 650 tolog o. gia 4 Exenatide
79 20
(Exentide 0. a 20 VRS-859 LAR ®
i 11
;54
Taspoglutide ® Albiglutide Cont. SC delivery
11
(GLP-1 R agonist
;5 4 (Bydureon
(GLP-1 analogue; for 3 months ; SC monthly ;
SC once-weekly; once-weekly 2011 ) 2011)
(exenatide extended-release),
SC once-weekly );
2011) 2012

36. Photographs of pancreatic tissue sections in rats
treated with exendin-4 and controls*
Exendin-4-treated patients:
a Vascular thickening (arrow) was
seen in exocrine pancreas.
Lumen patency was
significantly increased with
exendin-4 vs controls and more
inflammatory cells were
present in the adventitia.
b Acinar structure disruption and
pyknotic nuclei at arrows. No
significant damage in islets of
Langerhans.
c More severe acinar structure
disruption involving large
acinar section.
d Severe acinar destruction and
fibrosis.
Controls :
e, f No damage, acinar pancreas and
islets of Langerhans
(Exocrine and endocrine pancreas)
* Nachnani J S et al. Diabetologia (2010) 53:153–159.

37. Exenatide (Byetta®) and liraglutide(Victoza®) and
*Acute pancreatitis warning
 Postmarketing data have shown an increase in acute
pancreatitis, including fatal and nonfatal hemorrhagic
or necrotizing pancreatitis.
 In August 2008, the FDA described 36 patients with
pancreatitis related to exenatide use.
 Pancreatitis was also seen in clinical studies of the
GLP-1 agonist liraglutide.
* 1. Byetta. ]Package Insert[. San Diego, CA: Amylin Pharmaceuticals, Inc. 2009.
2. FDA alert. Available at:
http://www.fda.gov/Drugs/DrugSafety/ostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm. Updated August
2008.
• Cure P, et al. N Engl J Med. 2008;358:1969–1972.
• Buse JB, et al.(LEAD-6). Lancet 2009; 374: 39– 47

38. GLP-1 Receptor Agonists Activate Rodent Thyroid C-Cells
Causing Calcitonin Release and C-Cell Proliferation
Liraglutide stimulates C-
cells in rodents, causing
an increase in calcitonin
and there were few cases
of medullary thyroid
cancer in these animals
and not in humans*.
* Bjerre Knudsen L et al. Endocrinology 2010;151:1473-1486

39. Exenatide (Byetta®) and liraglutide (Victoza®)
and medullary thyroid cancer (MTC) concerns*
 Previous studies with rat thyroid C-cell lines and
thyroid tissues have shown that activation of the
GLP-1 receptor leads to calcitonin secretion*.
 Plasma calcitonin is a specific biomarker for both
C-cell activation and increased C-cell number **,
and changes in calcitonin levels are used in the
diagnosis of C-cell disease in humans ***.
* Crespel A, et al. Endocrinology 1996;137:3674–3680
Lamari Y, et al. FEBS Lett 1996;393:248–252
Vertongen P, et al. Endocrinology 1996;135:1537–1542
** Kurosawa M, et al. Arch Gerontol Geriatr 1988;7:229–238
*** Wolfe HJ, et al. N Engl J Med 1973;289:437–441

40. Exenatide (Byetta®) and liraglutide (Victoza®)
and medullary thyroid cancer (MTC) concerns*
 Hence, potentially sustained use of Liraglutide
might increase the risk for medullary thyroid
cancer in human which it did in rodents.
 Long-term clinical studies of sufficient size and
duration regarding cancer and incretin
therapeutics have not yet been completed.
 Patients should be counseled regarding the
risk and symptoms of MTC.

41. Overview of current DPP-4 inhibitors (Gliptins) used
orally for type 2 diabetes 1-4
1.
PSN 9301 2.
M
85 entle Sitagliptin;
Sitagliptin
De :9 -2 in R
En aco 4. . R
eg
Januvia ® 2007
3. 80 doc n CE ul
Ile- :95 rin , Pe
thiazolidide
Vi 2
4. M lsbo -95 Me l.
Eg etab ll T 7.
ol et a
tab Cli
Sitagliptin +metformin
pt
19
99
19 n ;
M an J , 20 . J C
eta M 03 li
b 2 ,. J ;82 n E
00 Cl 70 nd
95
; Janumet ® 2007
Valine 2;8 in 6 - oc
pyrrolidide
7:3 En 271 rino
76 doc 3. l
8 - ri n
Sitagliptin +simvastatin
37 ol
73
. Juvisync ® 2011
NVP DPP728
Vildagliptin;
Galvus ® 2008
Dutogliptin;
Melagliptin;
Saxagliptin;
Alogliptin Linagliptin; Onglyza ® 2009
(Nesina ® 2012 ) (Tradjenta ®2012)
®2012
Denagliptin;

42. Effects of DPP-IV inhibitors (Gliptins)
on glucose metabolism 1-6
DPP-IV inhibitors (Gliptins)  GLP-1
1.
Wi
llm
Na
2. sB Pancreatic
uck ,e
3. 19 M Me t al. islet cells
Ma 97; 2 A, tab 1 J Cli
Ph ljaar : E 73 et a 99 n E
l. 6; nd
4. 2): arma s J, e 981– Am 81: ocri
32 no
Gu 241– col T t al.A 8. J Phy 7– l
Decreased food Prolonged gastrick 50. her 2 lime
tn
5. 1992 ia M Increased insulin
sio 32.
l
De ; 3 , et
00 nt
7; Decreased glucagon
intake* 6. 118 *
emptying7gn KB26:131 al. N secretion 26
(Su secretion
Ric –9 , et 6-2 En pp
Da hter 4. al. 2.
Di
gl
JM
l.
tab B,
CD as abe ed
00 e S et al. tes
20
67
39 yst R Coch 04
;5
. ev ran 3:
20 e
08
;?
???
?:
Weight loss
Decreased blood glucose
(HbA1c↓ 0.7% ] 0.5 – 0.6%[ )
* Potential effects to slow gastric emptying and increase satiety probably
contribute littleIncreased insulin efficacy of DPP-4 inhibitors , therefore they
to the therapeutic
are weight-neutralsensitivity
or may cause slight gains in weight

44. Summary of adverse events in patients with type 2 diabetes
treated with GLP-1 analogues (Exenatide and Liraglutide)*
GLP-1 analogues Control
Adverse events Risk Ratio (95% CI),
Incretin Mean % (95% CI) Mean % (95% CI)
vs. Control Achieving Control Achieving Control
Hypoglycemia
Exenatide vs. Placebo Injection (1.08-4.88) 2.30 (8.1-29.1) 10.0 (4.0-12.0) 7.0
Exenatide vs. Insulin (1.46-2.26) 1.02 (1.3-4.1) 2.3 (1.3-4.0) 2.3
Nausea
All GLP-1 analoques vs. Comparator (2.02-4.24) 1.92 (25.4-41.4) 32.9 (9.0-17.3) 12.6
Exenatide vs. Comparator (2.16-4.64) 3.17 (36.4-47.7) 41.9 (9.5-18.5) 13.4
Liraglutide vs. Placebo Injection (0.27-3.01) 0.89 (3.1-10.1) 5.6 (1.8-16.2) 5.7
Vomiting
All GLP-1 analoques vs. Comparator (2.51-4.41) 3.32 (9.1-14.6) 11.6 (3.1-5.1) 4.0
Exenatide vs. Comparator (2.64-4.70) 3.52 (12.5-15.9) 14.1 (3.1-5.1) 4.0
Liraglutide vs. Placebo Injection (0.13-2.91) 0.62 (1.1-4.7) 2.3 (0.9-13.4) 3.6
Diarrhea
All GLP-1 analoques vs. Comparator (1.72-2.89) 2.23 (7.9-13.0) 10.2 (3.7-6.6) 4.9
Exenatide vs. Comparator (1.75-2.94) 2.27 (8.8-13.6) 11.0 (3.6-6.7) 4.9
DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval
* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis.
JAMA. 2007;298:194-206.

45. Summary of adverse events in patients with type 2 diabetes
treated with DDP-4 inhibitors (Sitagliptin and Vildagliptin)*
DDP-4 inhibitors Control
Risk Ratio (95% CI),
Adverse events Incretin
Mean % (95% CI) Mean % (95% CI)
Achieving Control Achieving Control
vs. Control
Hypoglycemia
All DDP4 inhibitors vs comparator (0.50-1.86)0.97 1.6 (0.7-3.2) 1.4 (0.6-3.4)
Sitagliptin vs comparator (0.30-2.87) 0.92 (0.9-3.3) 1.8 (0.2-8.5) 1.5
Vildagliptin vs comparator (0.50-1.19) 0.84 0.4-4.8) 1.4) (0.3-5.7) 1.2
Nausea
All DDP4 inhibitors vs comparator 0.89 (0.58-1.36) 2.7 (2.1-3.4) 3.1 (2.0-4.7)
Sitagliptin vs comparator 1.46 (0.88-2.43) 2.1 (1.4-3.0) 1.4 (0.7-2.4)
Vildagliptin vs comparator 0.57 (0.37-0.88) (2.6-4.6) 3.4 5.2 (3.6-7.4)
Vomiting
All DDP4 inhibitors vs comparator (0.42-1.15) 0.69 1.3 (0.8-2.2) 1.5 (0.9-2.6)
Sitagliptin vs comparator (0.45-1.65) 0.86 1.1 (0.6-2.0) 1.2 (0.8-1.9)
Vildagliptin vs comparator 0.49 (0.21-1.1.11) NR NR
Diarrhea
All DDP4 inhibitors vs comparator 0.80 (0.42-1.54) (2.8-5.1) 3.8 4.0 (1.8-4.6)
Sitagliptin vs comparator 1.21 (0.81-1.80) 3.6 (2.5-5.1) 2.8 (1.8-4.6)
Vildagliptin vs comparator 0.34 (0.14-0.80) 4.0 (2.0-8.0) 9.9 (2.7-30.7)
DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval
* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.

46. Long-term effects of DPP-4 inhibitors on
immune function of patients with type 2 diabetes*
 DPP- 4 is a ubiquitous cell-membrane protein, expressed in
many tissues, including lymphocytes, which has raised some
concerns about the long-term effects of DPP4 inhibitors,
especially on
immune function.
 DPP-4 inactivates many peptides and is identical to the T cell
activation antigen CD26, so its inhibition potentially
can affect many pathways. Thus, long term safety is unknown.
* Drucker DJ, et al. Lancet. 2006;368(9548):1696-1705
Fleicher B. Immunol Today 1994 ;15 :180 –184
Kieffer TJ, et al. Endocrinology 1995 ;136 :3585 –3596
Marguet D, et al. Proc Natl Acad Sci U S A 2000 97 :6874 –6879

47. Other adverse events in patients with type 2 diabetes
treated with DPP4 inhibitors (i.e. Sitagliptin:Januvia)*
 Studies analysis showed an increased risk of infections.
 Post-marketing reports of anaphylaxis, angioedema, rash,
urticaria and exfoliative skin conditions such as Stevens-
Johnson syndrome have occurred with sitagliptin (Januvia),
up to 3 months after starting treatment.
 It has also been suggested that immunomodulatory effects of
DPP-4 inhibition might increase risk for all cancers
including pancreatic and thyroid cancer**.
* Drucker DJ, et al. Lancet. 2006;368(9548):1696-1705.
** Havre PA, et al. Front Biosci 2008;13:1634–1645.
Matteucci E, Giampietro O. Curr Med Chem 2009;16:2943–2951.

48. Adverse events in patients with type 2 diabetes treated
with DDP-4 inhibitors (Sitagliptin and Viltagliptin)*
DDP-4 inhibitors Control
Adverse events Risk Ratio (95% CI),
Mean % (95% CI) Mean % (95% CI)
Incretin
vs. Control Achieving Control Achieving Control
Abdominal pain
All DDP4 inhibitors vs comparator 0.73 (0.36-1.45) 2.4 (1.8-3.2) 3.2 (1.7-5.7)
Sitagliptin vs comparator 0.92 (0.47-1.80) 2.5 (1.8-3.3) 2.6 (1.7-3.9)
Vildagliptin vs comparator 0.32 (0.16-0.66) NR NR
Couph
All DDP4 inhibitors vs comparator 1.07 (0.65-1.78) 2.9 (2.1-4.0) 2.4 (1.7-3.5)
Sitagliptin vs comparator 0.95 (0.54-1.78) 2.5 (1.7-3.5) 2.6 (1.8-3.9)
Vildagliptin vs comparator 1.86 (0.57-6.11) 4.8 (2.6-8.6) 1.7 (0.7-4.1)
Influenza
All DDP4 inhibitors vs comparator 0.87 (0.64-1.19) 4.1 (3.3-5.1) 4.4 (3.4-5.8)
Sitagliptin vs comparator 0.95 (0.65-1.39) 4.0 (3.1-5.1) 5.3 (3.7-7.4)
Vildagliptin vs comparator 0.73 (0.42-1.27) 4.2 (2.5-7.1) 6.1 (5.0-7.4)
Nasopharyngitis
All DDP4 inhibitors vs comparator 1.17 (0.98-1.40) 6.4 (5.1-7.8) 4.5 (3.0-6.7)
Sitagliptin vs comparator 1.38 (1.06-1.81) (3.5-7.9) 5.3 7.3 (6.0-8.9)
Vildagliptin vs comparator 1.02 (0.80-1.29) (5.8-9.3) 7.3 6.4 (4.9-8.4)
DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval
* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.

49. Adverse events in patients with type 2 diabetes
treated with DDP-4 inhibitors (Sitagliptin and Viltagliptin)*
DDP-4 inhibitors Control
Adverse events Risk Ratio (95% CI),
Mean % (95% CI) Mean % (95% CI)
Incretin
vs. Control Achieving Control Achieving Control
Upper respiratory tract infection
All DDP4 inhibitors vs comparator 0.99 (0.81-1.21) 6.3 (5.1-7.7) 6.4 (4.9-8.4)
Sitagliptin vs comparator 1.09 (0.84-1.43) 5.7 (4.0-8.0) 4.7 (2.8-8.0)
Vildagliptin vs comparator 0.88 (0.65-1.18) 6.8 (5.3-8.6) 8.0 (6.5-9.8)
Sinusitis
All DDP4 inhibitors vs comparator 0.61 (0.34-1.12) 2.0 (1.3-3.1) 3.4 (2.4-4.8)
Sitagliptin vs comparator 0.81 (0.41-1.58) 2.2 (1.4-3.4) 2.5 (1.6-3.9)
Vildagliptin vs comparator 0.20 (0.05-0.78) 1.2 (0.3-4.1) 5.4 (3.1-9.2)
Urinary tract infection
All DDP4 inhibitors vs comparator 1.52 (1.04-2.21) 3.2 (2.3-4.5) 2.4 (1.8-3.2)
Sitagliptin vs comparator 1.42 (0.95-2.11) 3.1 (2.1-4.6) 2.6 (1.9-3.5)
Vildagliptin vs comparator 2.72 (0.85-8.68) 3.6 (1.5-8.3) 1.3 (0.5-3.3)
Headache
All DDP4 inhibitors vs comparator 1.38 (1.10-1.72) 5.1 (4.1-6.4) 3.9 (3.1-4.8)
Sitagliptin vs comparator 1.24 (0.82-1.87) 3.6 (2.9-4.5) 3.1 (1.9-4.9)
Vildagliptin vs comparator 1.47 (1.12-1.94) 6.3 (5.0-8.0) 4.4 (3.4-5.6)
DPP4: dipeptidyl peptidase 4 ; Comparator :placebo ororal hypoglycemic agent or insulin; CI :confidence interval
* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.

50. Representative images of increased exocrine pancreatic
ductal cell replication in HIP* Rats treated with sitagliptin
**Januvia” for 12 weeks”
Increased ductal cell
turnover and ductal
metaplasia are well-
characterized risk factors for
pancreatic ductal cancer and
pancreatitis 1-4 .
•Parsa I, et al. Cancer Res 1985; 45: 1285– 1290
•Wagner M, et al. Genes Dev 2001; 15: 286– 293
•Wagner M, et al. Gastroenterology 2002; 122: 1898– 1912
•Lowenfels AB, et al. N Engl J Med 1993; 328: 1433– 1437.
* HIP:Human Islet amyloid Polypeptide transgenic rats, a model for type 2 diabetes
** Matveyenko AV et al.Diabetes 2009 ;58 : 1604-1615.

51. Necrotizing pancreatitis in a HIP rat treated
with sitagliptin “Januvia” for 12 weeks*
*Matveyenko AV et al. Diabetes 2009 ;58 : 1604-1615.

52. Sitagliptin or sitagliptin/metformin
marketed as Januvia and Janumet))
Acute pancreatitis warning
 In 2009, FDA has completed a review of 88 cases of
acute pancreatitis in patients using sitagliptin or
sitagliptin/metformin. The cases were reported to FDA’s Adverse
Event Reporting System (AERS) between October 2006 and
February 2009.
 Hospitalization: 66% of the patients, 4 to the intensive care unit.
Two cases of hemorrhagic or necrotizing pancreatitis.
 21% of pancreatitis cases occurred within 30 days of starting
sitagliptin, sitagliptin/metformin.
 The most common adverse events were abdominal pain, nausea and
vomiting.
FDA , U.S. Food and Drug Adminstration

53. Odds ratio of test vs control events (pancreatitis
pancreatic and thyroid cancer, or any cancer) for
.*exenatide, sitagliptin, and other therapies
 These data are consistent with
case reports and animal studies
and indicating an increased risk
for pancreatitis with GLP-1- of Interest
Conflicts
based therapy. The authors disclose no
 The findings also raise caution
conflicts.
about the potential long-term
actions of these drugs toFunding
promote pancreatic cancer.by the Larry L.
Supported
Hillblom Foundation.
* Elashoff R, et al. Gastroenterology.2011 Jul;141(1):150-6.
Source : Larry L. Hillblom Islet Research Center at David Geffen School of Medicine
and Department of Biomathematics, University of California

54. Considerations for Healthcare Professionals
regarding the use of sitagliptin and sitagliptin/metformin
(Januvia and Janumet)
In 2009, FDA has asked the manufacturer
of these products to revise the prescribing
information to include:
 post-marketing reports of acute pancreatitis.
 Patients should carefully be monitored for
pancreatitis after initiation or dose increases
of these drugs.
 These drugs should be used with caution in patients
with a history of pancreatitis.

55. Considerations for Healthcare Professionals
regarding the use of sitagliptin and sitagliptin/metformin
(Januvia and Janumet)
 Be aware of the signs and symptoms of pancreatitis such
as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes
radiating to the back.
 Discontinue these drugs if pancreatitis is suspected.
 If pancreatitis is suspected in a patient, supportive
medical care should be instituted. The patient should
be monitored closely with appropriate laboratory studies such as serum
and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium,
glucose, and lipase.
 Inform patients of the signs and symptoms of acute
pancreatitis.

56. Drug surveillance and a real world approach for drugs
 Many side effects, drug interactions, and effectiveness can not
be detected when drugs are approved. They may be found only
after drugs have been used by millions of people and for a
long time.
 In addition, available reports were sponsored by
pharmaceutical companies and arguably have a limited
capacity to detect adverse outcomes*.
 Drug regulatory agencies are unlikely to receive data on drug
safety (i.e. an administrative, healthcare database.) that are
independent of industry ties.
 Moreover, university-based medicine institutions have not viewed
the problem of drug surveillance as a worthy academic pursuit.
 Until surveillance tools devoid ofindustry influence have been established
to provide more robust data, such dilemmas of uncertainty regarding
adverse effects will remain unsolved.”
* Dore DD, et al. Curr Med Res Opin 2009;25:1019–1027.
Williams-Herman D,et al. BMC Endocr Disord 2008;8:14.

57. Comparison between
GLP-1 analogs and DDP-IV inhibiters
Specificity
The effects of GLP-analogs are strictly Specific
while
the DDP-IV inhibiters lack specificity

58. Undesirable side effects due to other
potential endogenous
DPP-IV substrates identified in kinetic studies
Among the additional substrates identified in kinetic
studies* are a number of neuropeptides, including:
 Pituitary adenylylate cyclase–activating polpeptide (PACAP),
 Vasoactive intestinal polypeptide (VIP),
 Gastrin-releasing peptide (GRP),
 Neuropeptide Y (NPY), and
 Growth hormone–releasing hormone (GHRH),
 Other regulatory peptides (such as GLP-2 and peptide YY
[PYY]),
 A number of chemokines and cytokines.
*Lambeir AM, et al. Crit Rev Clin Lab Sci,2003 40 :209 -294

59. Unanswered questions
GLP-1R agonists and DPP-IV inhibitors
Furthermore, GLP-1R agonists exhibit <100% amino acid
identity with the native peptide.
The immunogenic potential raises the specter of
immunoneutralizing antibodies
in some patients, which may lead to reduction in
therapeutic efficacy or potential exacerbation of diabetes
if the
antibodies cross-react
with endogenous GLP-1

60. Unanswered questions
GLP-1R agonists and DPP-IV inhibitors
DPP-IV, is activated by external stimuli and modulates T-cell
activation, producing pleiotropic effects in experimental
inflammatory and neoplastic disorders.
Global genetic inactivation of CD26 in mice is associated with subtle
but detectable abnormalities in cytokine and immunoglobulin
secretion *.
Whether highly selective inhibition of of DPP-IV will adversely
perturb immune-related activity in human subjects is unclear;
hence,
the long-term safety of sustained DPP-IV inhibition
merits careful scrutiny.

61.  DPP-4 inhibitors have some theoretical
advantages over existing therapies with
oral antidiabetic compounds but should
currently be restricted to individual
patients.
* Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic
Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2

62.  Long-term data especially on
cardiovascular outcomes and safety are
urgently needed before widespread use
of these agents.
* Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic
Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2

63.  More information on the benefit-risk
ratio of DPP-4 inhibitor treatment is
necessary especially analysing adverse
effects on parameters of immune
function.
* Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic
Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2

64.  Also, long-term data are needed
investigating patient-oriented
parameters like health related quality
of life, diabetic complications and all
cause mortality.
* Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic
Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2

65. Physician relationships with the industry
“Conflict implies that there is a problem or
argument, and I don’t believe that these
relationships are a conflict at all,”
 Transparency
 Conflicts of interest
 Harm to:
- Professional reputations
(prescribing and professional behavior )
- Scientific research
- Guideline credibility
- Patients (patient care ).

66. Physician relationships with the industry
Clinical practice guidelines are increasingly used in
medical malpractice cases and are forming the basis of
many of the
pay-for-performance initiatives
these relationships affect the prescribing and professional
behavior of physicians.
Continuing medical education programs sponsored by a
drug company were more likely to highlight
the drug company’s product.
A Journal of the American Medical Association review published by Wazana and colleagues in
2000

67. Physician relationships with the industry
What we have to be careful about is that
many trials are not designed to answer
a scientific question,
but rather to answer
a marketing question
Therefore
“Conflicts of interest are not universally bad, but
they’re not universally good.”

68. BMC Endocr Disord. 2010; 10: 7. Published online 2010
April 22. doi: 10.1186/1472-6823-10-7
Safety and tolerability of sitagliptin in clinical studies:
a pooled analysis of data from 10,246 patients with
Disclosures
All authors are employed by Merck Sharp &
type 2 diabetes Dohme, Corp.,
Debora Williams-Herman ; Samuel S Engel ; Elizabeth Round ; Jeremy Johnson; Gregory T Golm; Hua Guo ;
Bret J Musser ; Michael J Davies ; Keith D Kaufman: ; of Merck & Co., Inc.,
a subsidiary Barry J Goldstein
Received February 10, 2010; Accepted April manufacturer of sitagliptin
the 22, 2010.
Conclusions : In this updated stock or safety analysis of
and may have
company
pooled
data from 10,246 patients withstock options.
type 2 diabetes, sitagliptin 100
mg/day was generally well tolerated in clinical trials of
up to 2 years in duration.

69. Example of conflict of interests or Competing
interests
A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin
Drug Development Program for Type 2 Diabetes
DOI: 10.3810/pgm.2010.05.2138
No increased, riskPhD, Fred Fiedorek,
Conclusion:Conflict of Interests Statements MD, Mark Donovan, PhD, Niklas Berglind, BSc,
Robert Frederich MD,
of CV death/MI/stroke was observed MD are employed by Bristol-Myers Squibb.
Roland Chen, MD, and Robert Wolf,
in patients randomly assigned is employed by AstraZeneca.
Susan Harris, MS
saxagliptin across a broad drug , MD, MHS, FACC provided consulting or other services, and received honoraria from,
John H. Alexander
development program. Although this Ingelheim, Bristol-Myers Squibb, CSL Behring, Duke Private
AstraZeneca, Boehringer
systematic overview Diagnostic Clinic, Duke Health System, and Regado Biosciences.
has inherent and
important limitations, the H. support a
Johndata Alexander also received research grant or contract funding from Bristol-Myers
Squibb, Duke with
potential reduction in CV eventsHealth System, Medtronic Japan, Merck and Company, National Institutes of Health, Pfizer, and Regado
Biosciences.
saxagliptin. The hypothesis of CV protection , MD provided consulting or other services, received honoraria, or received
Kenneth W. Mahaffey
with saxagliptin willresearch grant or contract funding from, or provided educational activities or lectures for, Adolor Corp, Alexion,
be tested prospectively in
a large randomized clinical Inc., Amylin Inc., Argolyn, AstraZeneca, Bayer HealthCare, Boehringer
Amgen outcome trial
evaluating saxagliptin compared with standard Hospital, Bristol-Myers Squibb, CardioKinetix Inc.,
Ingelheim, Brigham & Women’s
of care in patients with type 2 diabetes at Sankyo, Duke University School of Medicine, Edwards
Cierra, Cordis, Daiichi
increased risk for CV events. Eli Lilly, Elsevier (AHJ), Forest Laboratories, Genentech,
Lifesciences,
GlaxoSmithKline, Guidant Corporation, Innocoll Pharmaceuticals, Johnson & Johnson,
KCI Medical, Luitpold Pharmaceutical, Medtronic Inc., Merck and Company, Momenta Pharmaceutical, Novartis, Pfizer,
Portola Pharmaceutical, Proctor and Gamble, Pozen, Regado Biosciences, sanofi-aventis, Schering-Plough Corp., Scios
Inc., The Medicines Company, WebMD, and William Beaumont Hospital.

70. Example of conflict of interests or
Competing interests
Sitagliptin: review of preclinical and clinical data
regarding incidence of pancreatitis
S S Engel, D E Williams-Herman, G T Golm, R J Clay, S V Machotka, K D Kaufman, and B J Goldstein
Int J Clin Pract. 2010 June; 64(7): 984–990.
Disclosures
All authors are
Conclusions employees of Merck & Co., Inc.,
Preclinical the manufacturerdata with sitagliptin to date
and clinical trial of sitagliptin and
may have stock or stock options
do not indicate an the company. of pancreatitis in
in increased risk
patients with T2DM treated with sitagliptin.
Received February 2010;
Accepted February 2010.

71. Example of conflict of interests or
Competing interests
Use of a claims-based active drug safety surveillance system to assess the
risk of acute pancreatitis with exenatide or sitagliptin compared to
metformin or glyburide.
Dore DD, et al. Current Medical Research and Opinion. 2009;25 :1019-1027.
Declaration of interest:
CONCLUSIONS:
Funding for this research was provided to i3 Drug
data do not
Thesesafety by Amylin Pharmaceuticals, , Inc.,for an has
provide evidence which
association of agreement with Eli Lilly and Company toof
a global acute pancreatitis among initiators
collaborate on the development and
exenatide or sitagliptinof exentide. D.D.D., J. D.S. and
commercialization
compared to met/gly initiators.
These results are limited by the data available in an
K.A.C. are employees of i3 Drug Safety.
administrative, healthcare database.

72. Example of conflict of interests or
Competing interests
Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or
Sitagliptin
A retrospective observational pharmacy claims analysis
•Rajesh Garg MD1,
•William Chen, PHD, MPH2 and Declaration of interest:
•Merri Pendergrass MD, PHD2
No potential conflicts of
Garg R, et al. Diabetes Care November 2010 vol. 33 :2349-2354
interest relevant to
CONCLUSIONSarticle were reported.
this Our study demonstrated increased incidence of acute
pancreatitis in diabetic versus nondiabetic patients but did not find an
association between the use of exenatide or sitagliptin and acute pancreatitis. The
limitations of this observational claims-based analysis cannot exclude the
possibility of an increased risk.
Despite these limitations, these data provide valuable information for practicing clinicians
weighing potential reported benefits versus risks, including the FDA warning of increased
pancreatitis.

73. Although, the GLP-1–based
therapies arrived in clinical
practice with much fanfare
and anticipation*,
**
* Butler PC, et al. Diabetologia (2010) 53:1–6.
Animal studies:
** Nachnani JS, et al. Diabetologia 2009; doi:10.1007/s00125-009
Matveyenko AV, et al .Diabetes 2009;58:1604–1615

74. Theoretical model to explain currently available observations with increased risks for
d ecr ed
ease acute pancreatitis and pancreatic cancer in individuals with reas
d Obesity & Type 2 diabetes inc
Metformin Rx(insulin Rx) GLP-1 Rx ?
1.
Va
i
of c nio H
con anc , Bi
er anc
2. Fra trol an preve hini F
Pol nce d p ntio . IA
edn : IAR hysic n. Vo RC h 08.
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75. Conclusions
 Glucagon-like peptide-1-based therapy is gaining widespread use
for type 2 diabetes, although there are concerns about risks for
pancreatitis and pancreatic and thyroid cancers.
 DPP-4 inhibitors have some theoretical advantages over existing
therapies with oral antidiabetic compounds but should currently
be restricted to individual patients.
 There are also concerns that DPP-4 inhibitors could cause cancer,
given their effects on immune function.
 No data are yet available on whether these new agents affect
hard endpoints such as cardiovascular disease, morbidity, and
mortality.

76. Januvia
Potentially extremely
Dangerous and Januvia
expensive Mildly effective in
some patients
Janus
Jan
The image of the Roman god,
Janus
whose prime characteristic of facing in two directions,
seems very appropriate for the similarly named drug
Januvia,

77. Suggested seven deadly sins of drug prescription
And
• toWe control the marketare the first,we neither
Never be better (‘Never be the first,
assume that new drugs for products that
or the last, to use sin is to assume that:
this a new drug.’ consume,
pay for nor )
or the last,
•
new drugs are are experienced by
and
better
to use pharmaceuticals to treat a non-pharmaceutical problem;
whose unwanted consequences drug
•
• to use a peoplenew
to repeat prescriptions that serve no rational purpose;
to use one drug to counter the side effects produced by another;
other
• to overestimate the benefits of your intervention;
• to pursue the mirage of longevity beyond the realms of common sense; and
• to reduce the quality of the life you are trying to improve.

78. Thank you