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.
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 .
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
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).
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.
Notas del editor
The incretin effect is the increased magnitude of insulin secretion in response to an oral glucose load compared to the insulin secretion in response to intravenous glucose administration. The incretin effect is now known to be a direct result of gut hormones secreted in response to oral intake which have a salutary effect on nutrient handling. These hormones are collectively known as incretin hormones and the two main human incretin hormones are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Exendin 4 has 50% homology with GLP-1.
The incretin effect is blunted in individuals with Type 2 DM.
Quickly after it’s release GLP-1 is converted to it’s inactive form by an enzyme dipeptidyl peptidase 4.
Quickly after it’s release GLP-1 is converted to it’s inactive form by an enzyme dipeptidyl peptidase 4.
Comparative Effectiveness of Treatment Options: Intermediate Outcomes
Intermediate clinical outcomes were the most frequently evaluated outcomes. There were 121 relevant articles with data from only randomized controlled trials that addressed either HbA1c, body weight, or lipids. Fifty-one of the studies had also been included in the 2007 CER.
References:
Bennett WL, Wilson LM, Bolen S, et al. Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update. Comparative Effectiveness Review No. 27. (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-0018.) AHRQ Publication No. 11-EHC038-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2011. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=644.
Bolen S, Wilson L, Vassy J, et al. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults With Type 2 Diabetes. Comparative Effectiveness Review No. 8. (Prepared by Johns Hopkins Evidence-based Practice Center under Contract No. 290-02-0018.) Rockville, MD: Agency for Healthcare Research and Quality. July 2007. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=40.