GLP-1

GLP-1 is produced by the L-cells of the gut after

food intake in two biologically active forms
It is rapidly degraded by DPP-4

Food intake
Glucose
Insulin uptake
Gut Pancreas
Beta cells
Alpha cells
Glucose
homeostasis
GLP-1 & GIP

DPP-4 Glucagon Glucose

release
DPP-4
inhibitors X
Physiologicaleffectsofincretinhormones
Bone Brain
formation
Memory
Bone
Memory
Food intake

Insulin Insulin
Pancreas
GIP Beta-cell mass Beta-cell GLP-1
mass
Glucagon Glucagon

Fat GI tract Heart

Gastric
Gastric emptying
Fat acid Cardioprotection
accumulation secretion
Cardiac output
YabeD,SeinoY.Progress in Biophysics and Molecular Biology 2011;107:248-56.
 Impairedincretinresponseintype2diabetesmaybe
duetodecreasedlevelsofGLP-1followingmeals

20
*****
* Plasma GLP-1 concentrations

15 * in type 2 diabetes patients (

were significantly (P<0.05)
)
GLP-1 (pmol/l)

decreased compared with

normal glucose tolerant ( ) and
impaired glucose tolerant ( )
10
subjects. Meal was started

* at time 0 and finished

in the 10-15 minute period.

*P<0.05 between Type 2 diabetes and normal groups

0
0 60 120 180 240
min

AdaptedfromToft-NielsenMB,etal.J Clin Endocrinol Metabl 2001;86:37173723

 GLP-1reducesliverglucoseproduction
andincreasesperipheralglucoseuptake
Muscle glucose
uptake

Insulin secretion

Glucagon
Liver
secretion
-cell -cell glucose
production

Nauck MA. Am J Med 2009;122:S3-S10

 The incretin system as a
target for T2D therapy
TheimpairmentoftheincretinsysteminT2Daffectsinsulinsecretionandenhances
glucagonsecretion.

NativeGLP-1in vivo israpidlymetabolizedbytheserineproteasedipeptidyl-peptidase-

IV(DPP-IV).
Two strategies to increase GLP-1

Inhibition of DPP-IV GLP-1 Receptor Agonists

Sitagliptin Exenatide
Saxagliptin Exenatide LAR
Vildagliptin Liraglutide
Linagliptin Lixisenatide
Alogliptin Albiglutide
DPP-IV
INHIBITORS INCRETINS
DicembriniIetal.E.ExDiabRes2011.
 DPP-4inhibitors:mechanismofaction
Food intake Increases and prolongs
GLP-1 and GIP effect on
DPP-4 inhibitor -cells:
-cells
Insulin release
Stomach
Pancreas Net effect:
DPP-4 Blood glucose
Incretins
GI tract
Increases and prolongs
-cells GLP-1 effect on -cells:
Glucagon secretion
Intestine

Kulasa K, Edelman S, et al. Core Evidence 2010;5:2337

 Vomiting
Increasing plasma GLP-1 concentrations

Diarrhoea
Nausea
Abdominal pain GLP-1 level during
treatment with
incretin mimetics

Appetite
Food intake
Weight loss

Gastric emptying

Insulin secretion
Plasma glucose
Glucagon secretion

GLP-1 level during

GLP-1 effects
treatment with
Madsbad S. Lancet 2009;373:438-439 incretin enhancers
 alogliptin significantly increases active GLP-1
and decreases glucagon levels in Type 2
diabetes patients
GLP-1 levels Glucagon levels
14 alogliptin 25mg
*** *** *** 25
Placebo
Mean (+ SE) GLP-1 at

12

Mean (+ SE) glucagon

Week 16 (pmol/L)

20
***

at Week 16 (ng/)L
10

8 15
*** *
6 *** *** ***
** 10 ** ** ***
4 **
5
2

0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (h) Time (h)
*P<0.05; **P<0.01; ***P<0.001 compared to placebo
Statistically significant differences in postprandial active GLP-1 (increased) and glucagon (decreased)
vs placebo after 16 weeks of treatment in type 2 diabetes patients.

1. Adapted from Eliasson B, et al. Diabetalogia. 2012;55:915925

 DPP-4inhibitorsaddressmultiple
pathologiesofType2diabetes
Insulin secretion

Glucose production Glucagon secretion

DPP-4
Glucose uptake inhibitors
Incretin effect

Neurotransmitter Lipolysis
dysfunction
Glucose reabsorption

1.Vipidia(alogliptin)SPC.Availableat:
www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002182/human_med_001696.jsp&mid=WC0b01ac058001d124[Accessed
January2014];2.FigureadaptedfromDeFronzoRA.AmJMed.2010;123(3suppl):s38s48
 ClinicalbenefitsofDPP-4inhibitors

Glycaemic control:
Asaclass,DPP-4inhibitorshaveextensiveevidenceforefficacyinreducingHbA1cinpatients
withType2diabetes
ReductionsinHbA1c-0.5to0.8%1
ReductionsareadditivewhenDPP-4inhibitorsareusedtogetherwithinsulin,thiazolidinediones,
metforminandsulphonylureas1

Tolerability:
DPP-4inhibitorsaregenerallywelltoleratedasmonotherapyandincombinationwithother
agents
Lowriskofhypoglycaemia1
Notassociatedwithgastrointestinalsideeffects1
Generallysuitableforpatientswithrenalinsufficiency(withappropriatedosereductions) 1

Weight-neutral effects:
Couldincreasepatientadherencetotherapy1

DAlessio D. Peak Issues. 2009. Available at: http://www.webbasedcme.com/resources/docs/PPG-Issue-2.

 Differentiatingfactorsofavailable
DPP-4inhibitors

DPP-4
DPP-4 Distribution
Chemistry
inhibition

Potential for
Metabolism & Selectivity drug-to-drug
Excretion interactions

Use in special
Safety & Glycaemic
populations
tolerability efficacy

Deacon CF. Diabetes, Obesity and Metabolism 2011;13:718

 Pharmacokineticdifferencesofavailable
DPP-4inhibitors
Alogliptin1-4 Linagliptin1-3,5 Saxagliptin1-3 Sitagliptin1-3 Vildagliptin1-3
Molecular
Structure

Modified -amino acid-

Chemistry Xanthine-based Cyanopyrrolidine Cyanopyrrolidine
pyrimidinedione based
Therapeutic
12.5 25 5 5 100 2 x 50
dose (mg/day)
Oral
~100% ~30% ~67% ~87% 85%
Bioavailability
Protein
20% Extensive Negligible 38% 10%
Binding
Metabolism No No CYP450 3A4/5 No Hydrolysis
Elimination Renal Biliary Renal Renal Renal
Half life, hours 1221 1040 24 (parent) 824 1.54.5
37 (active metabolite)
Drug-to-drug
No No Yes No No
interactions

1. Deacon CF. Diabetes Obes Metab. 2011;13:7-18. 2. Scheen AJ. Diabetes Obes Metab 2010;12:648-658. 3. Golighty LK, et al. Clin Pharmacokinet 2012;51:501-514. 4. Ndefo
UA, et al. Am J Health Syst Pharm 2014;71:103-109. 5. Trajenta (linagliptin) SPC 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002110/WC500115745.pdf [Accessed July 2014]
 UseofDPP-4inhibitorsin
specialpopulations
Alogliptin Linagliptin Saxagliptin Sitagliptin Vildagliptin
Elderly1-5 No restriction <80 years No restriction Caution in No restriction
patients
75 years
Hepatic Insufficiency6,7
Mild Yes Yes7 Yes Yes No
Moderate Yes Yes7 Yes Yes No
Severe No Yes7 No No No
Hepatic Function
No No No No Yes
Monitoring
Renal Insufficiency*6,7
Mild Yes Yes Yes Yes Yes
Moderate Reduced dose Yes Reduced dose Reduced dose Reduced dose
Severe/ESRD Reduced dose Yes Reduced dose Reduced dose Reduced dose
Renal Function
Yes No Yes Yes Yes
Monitoring
*Renal insufficiency: Mild: CrCl 50 mL/min, Moderate: CrCl 30<50 mL/min, Severe/ESRD: CrCl <30 mL/min
CrCl=creatinine clearance; ESRD=end-stage renal disease; EU=Europe; min=minute; NR=not recommended
1. Vipidia (alogliptin) Summary of Product Characteristics (SmPC) 2014. 2. Trajenta (linagliptin) SmPC 2013. 3. Onglyza (saxagliptin)
SmPC 2014. 4. Januvia (sitagliptin) SmPC 2014. 5. Galvus (vildagliptin) SmPC 2014. 6. Deacon CF. Diabetes Obes Metab. 2011;13:7-18.
7. Deacon CF, et al. Expert Opin Pharmacother. 2013;14:2047-2058.
 ComparativeEfficaciesofDPP-4s
Placebo-correctedchangefrombaselineinHbA1c-Monotherapy
Alogliptin1 Linagliptin2 Saxagliptin3 Sitagliptin4 Vildagliptin5
12.5mg25mg 5mg5mg 5mg5mg 100mg100mg 50mgBID50mg
7.9%7.9% 8.1%8.0% 7%-10%8.0% 8.0%8.0% 8.6%8.4%

-0.1

-0.2

-0.3

-0.4
-0.4
-0.5
HbA1c(%)

-0.5
-0.6 -0.56
-0.59 -0.6 -0.6 -0.6
-0.7
-0.7 -0.7
-0.8
-0.8
-0.9

-1.0

-1.1 ThecurrentDPP-4shavecomparativeefficacy
-1.2

1. DeFronzo R, et al. Diabetes Care 2008;31:2315-2317. 2. Linagliptin Prescribing Information. 3. Saxagliptin Prescribing
Information. 4. Sitagliptin Prescribing Information. 5. Vildagliptin Summary of Product Characteristics.
 Targeting the kidney to treat type 2 diabetes
Normal renal glucose handling

Thekidneyfiltersapproximately180Lofplasmaeachday,whichcontainsabout162gofglucose.

SGLT2mediatesglucosetransportintheS1segmentandabsorbsabout80%to90%offilteredglucose.

SGLT1hashighaffinitybutlowcapacityforglucosetransportandmediatesglucosetransportintheS3
segmentandreabsorbstheremaining10%to20%offilteredglucose.

Majority of glucose is
reabsorbed by SGLT2
(90%)

Proximal tubule
SGLT2
Remaining glucose
Glucose is reabsorbed by Minimal to no
SGLT1 (10%) glucose
excretion
Glucose
filtration

WrightEM.Am J Physiol Renal Physiol2001;280:F1018;2.LeeYJ,et al.Kidney Int Suppl2007;106:S2735;

HummelCS,et al.Am J Physiol Cell Physiol2011;300:C1421.
 SGLT2
INHIBITORS

Gliflozin offers an insulin-independent mechanism to lower blood glucose levels by inhibiting

SGLT2.
Pro: TheinhibitionofSGLT2resultsindailyurinaryglucoseexcretionofapproximately70g
providing:
SignificantandsustainedHbA1creductionsversusplacebowhenaddedtometformin
Secondarybenefits:
1)weightloss(duetothelossofcaloriesintotheurine)
2)loweringbloodpressure(duetofluidandsodiumdepletion)

SGLT2
Gliflozins

Con:
Increasedriskofurinary Proximal tubule

tractinfections.
Gliflozin
Increasedriskofbladder SGLT2 Glucose
filtration
cancer(?) Glucose Increased urinary
glucose excretion

Abdul-GhaniMA.CurrDiabRep201212:230238
ParkinsonC.Newtreatmentoptions.DownloadedonNov2014
 TheKidneysPlayanImportant
RoleinGlucoseControl
NormalRenalGlucosePhysiology
180gofglucoseisfilteredeachday
Virtuallyallglucosereabsorbedintheproximal
tubules&reentersthecirculation
SGLT2reabsorbsabout90%oftheglucose
SGLT1reabsorbsabout10%oftheglucose
Virtuallynoglucoseexcretedinurine
Mather,A&Pollock,C.Kidney International.2011;79:S1-S6.
 RationaleforSGLT2Inhibitors
SGLT2isalow-affinity,highcapacityglucose
transporterlocatedintheproximaltubuleandis
responsiblefor90%ofglucosereabsorption
SelectiveSGLT2inhibitorshaveanovel&unique
mechanismofactionreducingbloodglucoselevelsby
increasingrenalexcretionofglucose
Decreasedglycemiawilldecreaseglucosetoxicity
leadingtofurtherimprovementsinglucosecontrol
SelectiveSGLT2inhibition,wouldalsocauseurineloss
ofthecaloriesfromglucose,potentiallyleadingto
weightloss
BrooksAM,ThackerSM.Ann Pharmacother. 2009;42(7):1286-1293.
 SGLT2Inhibitorsin
Phase3Development

Empagliflozin

Canagliflozin

Dapagliflozin

Ipragliflozin
 Empagliflozin:ChangeinA1C
Randomized,double-blind,12weektrialcomparing
empagliflozinandopen-labelmetformin

*
*

*P.001vs.placebo
500mgBIDforfourweeks,then1000mgBIDorthemaximumtoleratedose

FerranniniE,etal.Abstract877.EASD2010.
 Empagliflozin:ChangeinPlasma
GlucoseintheFastingState
Randomized,double-blind,12weektrialcomparing
empagliflozinandopen-labelmetformin

*
*
*P.001vs.placebo
500mgBIDforfourweeks,then1000mgBIDorthemaximumtoleratedose
FerranniniE,etal.Abstract877.EASD2010.
 Canagliflozin
Metformin+CanagliflozinDose-RangingStudy
MeanBaseline
A1C(%)
7.718.017.817.577.707.717.62

*
*
*

*
*
RosenstockJ,etal.Abstract77-OR.ADA2010. *P.001vs.placebocalculatedusingLSmeans
 Canagliflozin
SGLT2InhibitionforType2Diabetes:
Metformin+CanagliflozinDose-RangingStudy
MeanBaseline
Weight(kg)
85.587.587.787.787.886.387

*
* *

* *

RosenstockJ,etal.Abstract77-OR.ADA2010. *P.001vs.placebocalculatedusingLSmeans
 CanagliflozinTrials
Symptomaticgenitalinfectionsin3-8%canagliflozin
arms
2%placebo
2%SITA
Urinarytractinfectionsin3-9%canagliflozinarms
6%placebo
2%SITA
Hypoglycemiain0-6%canagliflozinarms
2%placebo
5%SITA

RosenstockJ,etal.Abstract77-OR.ADA2010.
 ChangesfromBaselineinA1C
inPhase3DapagliflozinStudies
PlaceboDapa2.5mgDapa5mgDapa10mg

WildingJPH,etal.Abstract78-OR.ADA2010;StrojekK,etal.Abstract870.EASD2010;
FerranniniE,etal.Diabetes Care. 2010;33(10):2217-2224;BaileyCJ,etal.Lancet. 2010;375(9733):2223-2233.
 ChangesfromBaselineinBodyWeight
inPhase3DapagliflozinStudies
PlaceboDapa2.5mgDapa5mgDapa10mg

WildingJPH,etal.Abstract78-OR.ADA2010;StrojekK,etal.Abstract870.EASD2010;
FerranniniE,etal.Diabetes Care. 2010;33(10):2217-2224;BaileyCJ,etal.Lancet. 2010;375(9733):2223-2233.
 PerspectivesonSGLT2Inhibition
Potentialadvantages Concerns
InsulinIndependence Polyuria
Weightloss(75gurine Electrolytedisturbances
glucose=300kcal/day) Bacterialurinarytract
Lowriskofhypoglycemia infections
Bloodpressure Fungalgenitalinfections
lowering? Malignancies