DPP4 inhibitors

1. DPP4- inhibitors
Amman-Sheraton Hotel
Dr.Ibrahim Tuffaha 16-feb2014

2. Introduction
Each of us—every human adult—is composed
of roughly 100 trillion individual cells. Our health
depends on effective communication between
those cells. Over time, it has become clear that
the systems that coordinate cellular activity are far
more complex than we originally believed.

3. One example is the incretin hormones, such as
GLP-1. These are rapidly secreted from the gut
following food intake. Research continues to
shed light on their role in health and disease,
causing many physicians to rethink the processes
underlying glucose metabolism and type 2
diabetes.

4. Prevalence of Diabetes
in United States
25
20
23.6
15
10
16.1
19.3
1988-94
1999-2002
5
0
2008

5. Treatment of diabetes

6. Therapeutic Options for
Type 2 DM
2008
1995
Sulfonylurea
INSULIN
–
–
–
NPH
Regular
Ultralente
Sulfonylurea
INSULIN
–
–
–
–
NPH
Regular
Insulin analogues
Inhaled
Metformin
TZDs
Alpha glucosidase inhibitors
Meglitinides
Endocannabinoid receptor Incretin mimetics
Amylin analogues
DPP IV inhibitors

9. Reduced Incretin Effect in Type 2
Diabetic Patients
Control Subjects
Incretin
effect
40
* * *
* *
*
*
20
0
30
60 90 120 150 180
TIME (min)
INSULIN ( mU/L
)
INSULIN (mU/L
)
60
0
Type 2 Diabetic Patients
80
Intravenous Glucose
Oral Glucose
60
80
40
* *
20
0
0
30
*
60 90 120 150 180
TIME (min)
Nauck M, et al. Diabetologia. 1986;29:46-52.

10. GLP-1 Modes of Action in
Man
Upon ingestion of food…
GLP-1 is secreted
from the L-cells
in the jejunum
and ileum
• Slows gastric emptying
• Reduces food intake
• Suppresses glucagon secretion
• Stimulates insulin secretion
Long term effects
demonstrated in animals…
• Increases beta-cell cell mass and
maintains beta-cell efficiency
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412
Drucker DJ. Mol Endocrinol 2003; 17:161-171

11. GLP-1 Secretion and Inactivation
Mixed
meal
Intestinal
GLP-1
release
T1/2 = 1 to 2 min
GLP-1 (7-36)
active
DPP-4
GLP-1 (9-36)
inactive
(>80% of pool)
Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131 .

12. GLP-1 Functions

13. GLP-1 Secretion and Inactivation
Mixed
meal
Intestinal
GLP-1
release
T1/2 = 1 to 2 min
GLP-1 (7-36)
active
DPP-4
GLP-1 (9-36)
inactive
(>80% of pool)
Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131 .

14. N.B
1-2 minutes only ;80%Glp-1 active ------to
GLP-1 inactive
This happened by DPP4
TO GET MORE BENEFITS OF INTERNAL
GLP-1 we have to :
1)Prolong the half life
2)Decrease the amount of inacttivity

15. THIS LEADS US TO INHIBIT THE DPP4

16. DPP4 inhibitors (gliptins) is hypoglycemic
class that inhibiting the action of DPP4
(which degrade the action of GLP-1 to
convert it to inactive form )

17. Inhibition of DPP-4 Increases Active
GLP-1
Mixed
meal
Intestinal
GLP-1
release
GLP-1 (7-36)
GLP-1 (7-36)
active
active
DPP-4
DPP-4
inhibitor
GLP-1 (9-36)
inactive
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

18. DPP 4 Inhibitors
♦ Once daily ingestion
♦ Reduce fasting and postprandial glucose,
reduce HbA1c
♦ Decrease glucagon response to ingested
meal
♦ Initial studies in combination with metformin

19. DPP4 inhibitors drugs
Drugs belonging to this class are :
Sitagliptin[5] (FDA approved 2006, marketed by Merck & Co. as
Januvia),
Vildagliptin[6] (EU approved 2007, marketed in the EU by
Novartis as Galvus),
Saxagliptin (FDA approved in 2009, marketed as Onglyza),
Linagliptin (FDA approved in 2011, marketed as Tradjenta by Eli
Lilly Co and Boehringer Ingelheim),[7]
Anagliptin (approved in Japan in 2012, marketed by Sanwa
Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.)[8]
Teneligliptin (approved in Japan in 2012[9])
Alogliptin (FDA approved 2013, marketed by Takeda
Pharmaceutical Company)
Gemigliptin (being developed by LG Life Sciences)

20. DPP-4 inhibitors (eg, sitagliptin,
saxagliptin, linagliptin) are a class of drugs
that prolong the action of incretin
hormones. DPP-4 degrades numerous
biologically active peptides, including the
endogenous incretins GLP-1 and glucosedependent insulinotropic polypeptide
(GIP).

21. Comparative Effectiveness of
Treatment Options: Intermediate
Outcomes
Glycemic control (HbA1c)
Weight
Lipids
Low-density lipoprotein (LDL)
High-density lipoprotein (HDL)
Triglyceride (TG)

22. Summary of DPP-4 Inhibition
Increases fasting and postprandial GLP-1 levels
Reduces fasting and postprandial glycemia
Improves ß-cell function
– Increases insulin secretion, reduces proinsulin/insulin ratio
– Increases beta-cell mass
Inhibits glucagon secretion
– Reduces hepatic glucose production
Increases insulin sensitivity
Reduces postprandial lipemia
No effect on gastric emptying or body weight
Reduces HbA1c by ~1%
Is safe and tolerable in short term
In renal impairment, dose decreased by 50%

23. DPP-4 inhibitors can be used as a
monotherapy or in combination with
Metformin or a TZD. They are given once
daily and are weight neutral.

24. A study shows that added to insulin (with
or without Metformin )
decrease FBS by 15 mg/dl
And decrease 2h PPBS by 36 mg /dl

25. In nephropathy it is safe to use DPP4
inhibitor as GFR >30 ml /min with halving
the dose
In ESRD linagliptin and sitagliptin only
used

26. The clinical observations that DPP4inhibitors associated with pancreatitis or
pancreatic cancer is refused by ADA
because no proofs. But they suggesting
not to use in patient who has pancreatitis

27. Clinically observed that upper respiratory
infection is related to the use of DPP4
inhibitors
. On the other hand, a meta-analysis
suggested that treatment with DPP-4
inhibitors could reduce the risk of bone
fractures.