DPP4- inhibitorsDPP4- inhibitors
Amman-Sheraton HotelAmman-Sheraton Hotel
Dr.Ibrahim Tuffaha 16-feb-Dr.Ibrahim Tuffaha 16-feb-20142014
IntroductionIntroduction
Each of us—every human adult—is composedEach of us—every human adult—is composed
of roughly 100 trillion individual cells. Our healthof roughly 100 trillion individual cells. Our health
depends on effective communication betweendepends on effective communication between
those cells. Over time, it has become clear thatthose cells. Over time, it has become clear that
the systems that coordinate cellular activity are farthe systems that coordinate cellular activity are far
more complex than we originally believed.more complex than we originally believed.
One example is the incretin hormones, such asOne example is the incretin hormones, such as
GLP-1. These are rapidly secreted from the gutGLP-1. These are rapidly secreted from the gut
following food intake. Research continues tofollowing food intake. Research continues to
shed light on their role in health and disease,shed light on their role in health and disease,
causing many physicians to rethink the processescausing many physicians to rethink the processes
underlying glucose metabolism and type 2underlying glucose metabolism and type 2
diabetes.diabetes.
16.1 19.3
23.6
0
5
10
15
20
25
1988-94 1999-2002 2008
Prevalence of DiabetesPrevalence of Diabetes in United States in United States
Treatment of diabetesTreatment of diabetes
Therapeutic Options forTherapeutic Options forType 2 DMType 2 DM
19951995SulfonylureaSulfonylureaINSULININSULIN– NPHNPH– RegularRegular– UltralenteUltralente
20082008SulfonylureaSulfonylureaINSULININSULIN– NPHNPH– RegularRegular– Insulin analoguesInsulin analogues– InhaledInhaled
MetforminMetforminTZDsTZDsAlpha glucosidase inhibitorsAlpha glucosidase inhibitorsMeglitinidesMeglitinidesEndocannabinoid receptor -Endocannabinoid receptor -Incretin mimeticsIncretin mimeticsAmylin analoguesAmylin analoguesDPP IV inhibitorsDPP IV inhibitors
Reduced Incretin Effect in Type 2 Reduced Incretin Effect in Type 2 Diabetic PatientsDiabetic Patients
00
2020
4040
6060
8080
INS
UL
IN (
INS
UL
IN (
mU
/Lm
U/L ))
00 3030 6060 9090 120120 150150 180180TIME (min)TIME (min)
Control SubjectsControl Subjects
Intravenous GlucoseIntravenous Glucose
Oral GlucoseOral Glucose
**** **
**** ** **
00
2020
4040
6060
8080
INS
UL
IN (
INS
UL
IN (
mU
/Lm
U/L ))
00 3030 6060 9090 120120 150150 180180TIME (min)TIME (min)
Type 2 Diabetic PatientsType 2 Diabetic Patients
****
**
Nauck M, et al. Diabetologia. 1986;29:46-52.
Incretin effect
GLP-1 Modes of Action in GLP-1 Modes of Action in ManMan
GLP-1 Modes of Action in GLP-1 Modes of Action in ManMan
GLP-1 is secretedfrom the L-cells
in the jejunumand ileum
GLP-1 is secretedfrom the L-cells
in the jejunumand ileum
• Stimulates insulin secretion• Stimulates insulin secretion
• Suppresses glucagon secretion• Suppresses glucagon secretion
• Slows gastric emptying• Slows gastric emptying
Long term effectsdemonstrated in animals…Long term effectsdemonstrated in animals…• Increases beta-cell cell mass and maintains beta-cell efficiency• Increases beta-cell cell mass and maintains beta-cell efficiency
• Reduces food intake• Reduces food intake
Upon ingestion of food…Upon ingestion of food…
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171
Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.
GLP-1 Secretion and InactivationGLP-1 Secretion and Inactivation
IntestinalGLP-1
release
GLP-1 (7-36)active
Mixed meal
GLP-1 (9-36)inactive
(>80% of pool)
DPP-4
T1/2 = 1 to 2 min
GLP-1 FunctionsGLP-1 Functions
Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.
GLP-1 Secretion and InactivationGLP-1 Secretion and Inactivation
IntestinalGLP-1
release
GLP-1 (7-36)active
Mixed meal
GLP-1 (9-36)inactive
(>80% of pool)
DPP-4
T1/2 = 1 to 2 min
N.BN.B
1-2 minutes only ;80%Glp-1 active ------to 1-2 minutes only ;80%Glp-1 active ------to GLP-1 inactiveGLP-1 inactive
This happened by DPP4This happened by DPP4
TO GET MORE BENEFITS OF INTERNAL TO GET MORE BENEFITS OF INTERNAL GLP-1 we have to :GLP-1 we have to :
1)Prolong the half life1)Prolong the half life
2)Decrease the amount of inacttivity 2)Decrease the amount of inacttivity
THIS LEADS US TO INHIBIT THE DPP4THIS LEADS US TO INHIBIT THE DPP4
DPP4 inhibitors (gliptins) is hypoglycemic DPP4 inhibitors (gliptins) is hypoglycemic class that inhibiting the action of DPP4 class that inhibiting the action of DPP4 (which degrade the action of GLP-1 to (which degrade the action of GLP-1 to convert it to inactive form )convert it to inactive form )
Inhibition of DPP-4 Increases Active Inhibition of DPP-4 Increases Active GLP-1GLP-1
GLP-1 (9-36)inactive
IntestinalGLP-1
release
Mixed meal
GLP-1 (7-36)active
DPP-4
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
DPP-4inhibitor
GLP-1 (7-36)active
DPP 4 InhibitorsDPP 4 Inhibitors
♦ Once daily ingestionOnce daily ingestion♦ Reduce fasting and postprandial glucose, Reduce fasting and postprandial glucose,
reduce HbA1creduce HbA1c♦ Decrease glucagon response to ingested Decrease glucagon response to ingested
mealmeal♦ Initial studies in combination with metforminInitial studies in combination with metformin
DPP4 inhibitors drugsDPP4 inhibitors drugs
Drugs belonging to this class are :Drugs belonging to this class are :SitagliptinSitagliptin[5][5] (FDA approved 2006, marketed by (FDA approved 2006, marketed by Merck & Co.Merck & Co. as as
Januvia),Januvia),VildagliptinVildagliptin[6][6] (EU approved 2007, marketed in the EU by (EU approved 2007, marketed in the EU by
NovartisNovartis as Galvus), as Galvus),SaxagliptinSaxagliptin (FDA approved in 2009, marketed as Onglyza), (FDA approved in 2009, marketed as Onglyza),LinagliptinLinagliptin (FDA approved in 2011, marketed as Tradjenta by Eli (FDA approved in 2011, marketed as Tradjenta by Eli
Lilly Co and Lilly Co and BoehringerBoehringer Ingelheim Ingelheim),),[7][7]AnagliptinAnagliptin (approved in Japan in 2012, marketed by Sanwa (approved in Japan in 2012, marketed by Sanwa
Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.)[8]Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.)[8]Teneligliptin (approved in Japan in 2012[9])Teneligliptin (approved in Japan in 2012[9])Alogliptin (FDA approved 2013, marketed by Takeda Alogliptin (FDA approved 2013, marketed by Takeda
Pharmaceutical Company)Pharmaceutical Company)Gemigliptin (being developed by LG Life Sciences)Gemigliptin (being developed by LG Life Sciences)
DPP-4 inhibitors (eg, sitagliptin, DPP-4 inhibitors (eg, sitagliptin, saxagliptin, linagliptin) are a class of drugs saxagliptin, linagliptin) are a class of drugs that prolong the action of incretin that prolong the action of incretin hormones. DPP-4 degrades numerous hormones. DPP-4 degrades numerous biologically active peptides, including the biologically active peptides, including the endogenous incretins GLP-1 and glucose-endogenous incretins GLP-1 and glucose-dependent insulinotropic polypeptide dependent insulinotropic polypeptide (GIP). (GIP).
Glycemic control (HbA1c)Glycemic control (HbA1c) WeightWeight Lipids Lipids
Low-density lipoprotein (LDL)Low-density lipoprotein (LDL) High-density lipoprotein (HDL)High-density lipoprotein (HDL) Triglyceride (TG)Triglyceride (TG)
Comparative Effectiveness of Comparative Effectiveness of Treatment Options: Intermediate Treatment Options: Intermediate
OutcomesOutcomes
Summary of DPP-4 InhibitionSummary of DPP-4 Inhibition
Increases fasting and postprandial GLP-1 levelsIncreases fasting and postprandial GLP-1 levels
Reduces fasting and postprandial glycemiaReduces fasting and postprandial glycemia
Improves Improves ß-cell functionß-cell function– Increases insulin secretion, reduces proinsulin/insulin ratioIncreases insulin secretion, reduces proinsulin/insulin ratio– Increases beta-cell massIncreases beta-cell mass
Inhibits glucagon secretionInhibits glucagon secretion– Reduces hepatic glucose productionReduces hepatic glucose production
Increases insulin sensitivityIncreases insulin sensitivity
Reduces postprandial lipemiaReduces postprandial lipemia
No effect on gastric emptying or body weightNo effect on gastric emptying or body weight
Reduces HbA1c by Reduces HbA1c by ~~1%1%
Is safe and tolerable in short termIs safe and tolerable in short term
In renal impairment, dose decreased by 50%In renal impairment, dose decreased by 50%
DPP-4 inhibitors can be used as a DPP-4 inhibitors can be used as a monotherapy or in combination with monotherapy or in combination with Metformin or a TZD. They are given once Metformin or a TZD. They are given once daily and are weight neutral.daily and are weight neutral.
A study shows that added to insulin (with A study shows that added to insulin (with or without Metformin ) or without Metformin )
decrease FBS by 15 mg/dldecrease FBS by 15 mg/dl
And decrease 2h PPBS by 36 mg /dlAnd decrease 2h PPBS by 36 mg /dl
In nephropathy it is safe to use DPP4 In nephropathy it is safe to use DPP4 inhibitor as GFR >30 ml /min with halving inhibitor as GFR >30 ml /min with halving the dose the dose
In ESRD linagliptin and sitagliptin only In ESRD linagliptin and sitagliptin only used used
The clinical observations that DPP4-The clinical observations that DPP4-inhibitors associated with pancreatitis or inhibitors associated with pancreatitis or pancreatic cancer is refused by ADA pancreatic cancer is refused by ADA because no proofs. But they suggesting because no proofs. But they suggesting not to use in patient who has pancreatitisnot to use in patient who has pancreatitis
Clinically observed that upper respiratory Clinically observed that upper respiratory infection is related to the use of DPP4 infection is related to the use of DPP4 inhibitorsinhibitors
. On the other hand, a meta-analysis . On the other hand, a meta-analysis suggested that treatment with DPP-4 suggested that treatment with DPP-4 inhibitors could reduce the risk of bone inhibitors could reduce the risk of bone fractures.fractures.
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