Saxaslideshare

Saxagliptin in clinical practice

Mathew John, MD, DM, DNB

Endocrinologist

Providence Endocrine & Diabetes Specialty Centre

www.endocrinologydiabetes.com

Agenda

• Diabetes mellitus: current scenario

• Unmet medical needs : why we need newer therapies ?

• Drugs acting on incretin axis

• Saxagliptin: overview

efficacy trialsefficacy trials

safety trials

• Rational positioning

• Cardiovascular safety

World diabetes map 2025

http://www.oxan.com/worldnextweek/2007-11-08/Diabetesmedicaltimebomb.aspx

State of current glycemic control: NHANES

Hoerger TJ . Is Glycemic Control Improving in U.S. Adults? Diabetes Care January 2008 vol. 31 no. 1 81-86

Parameter DiabCare Asia1 DEDICOM2

Year of study 1998 2005

Total patients 2269 819

Mean age (yrs) 53 54

Nearly Half to 2/3rd of All Adult Patients With T2DM Remain Uncontrolled on Their Current Therapy

Mean age (yrs) 53 54

Mean HbA1c 8.9 NA

% having HbA1c <7% 50 38

% tested for HbA1c 7.8 13

1. Raheja BS et al. JAPI 2001;49:717-22; 2.Nagpal J et al. Diabetes Care 2006; 29:2341-8

UKPDS results of Intensive therapyRisk reduction vs. conventional therapy

Unmet needs in diabetes therapeutics

• Progressive nature of disease: beta cell failure, need to frequently modify therapy

• Hypoglycemia risk: with sulphonylureas, insulin, combinations combinations

• Weight gain: sulphonylureas, insulin, pioglitazone

• Cardiovascular disease

Normal Glucose Homeostasis: Role of Incretins1,2

β

Increased Glucose

Uptake

Glucose

In response to meals, incretin hormones (GIP and GLP-1) are increasingly released from the small intestine

Insulin Secretion

Fat1

GI Tract

DPP-4Enzymes

α

βIncretin Effect

Decreased Glucose

Production

Liver

Glucose

Homeostasis

Pancreatic cells respond to high levels of incretins

2

Glucagon Secretion

Incretins (GIP/GLP-1)

Pancreatic alpha cell

Pancreatic beta cellβ

α

GI TractPancreas

DPP-4 enzymes break down incretins

3

Indirect

suppression

of glucagon

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4.

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.

2. Drucker DJ. Cell Metab. 2006;3:153-165.

β

Impaired Glucose

Uptake

Fat

Insulin Secretion

GI Tract

DPP-4Enzymes

T2DM: Role of Incretins1,2

In adults with T2DM, incretins are released, but the incretin-mediated effects are diminished

1

Less indirect

Pancreasα

βDiminished

Incretin Effect

Increased Glucose

Production

Liver

Hyperglycemia

Glucagon Secretion

β

α

Incretins (GIP/GLP-1)

Pancreatic alpha cell

Pancreatic beta cell

GI Tract

Incretin action on pancreatic cells is reduced

2

Less indirect

suppression

of glucagon

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.

2. Drucker DJ. Cell Metab. 2006;3:153-165.

Saxagliptin

DPP 4 inhibitor

Potent, selective, reversible inhibitor

10 fold more potent that Sitagliptin and Vildagliptin

Active metabolite : M2: 2 fold less potent

Relative Selectivity of Saxagliptin

Selectivity for DPP-4 vs DPP-8/9*

DPP-4 selectivitySaxagliptin

Saxagliptin Active Metabolite

Versus DPP-8 ~400 fold ~950

* Calculated using Ki; the inhibitor concentration needed for 50% inhibition of the target enzyme; substrate-independent.

DPP=dipeptidyl peptidase.

Kirby MS et al. Poster presented at: 3rd International Conference on Dipeptidyl Peptidases and Related Proteins; April 23-25, 2008; Antwerp, Belgium.



Clinical Pharmacology: Pharmacokinetics

Absorption

• Median time to max. concentration (Tmax) following 5 mg once daily dose was 2 hrs for saxagliptin & 4 hrs for its active metabolite

• Saxagliptin may be administered with or without food

Distribution

• In vitro protein binding of saxagliptin and its active metabolite in human serum is negligible

• Changes in blood protein levels in various disease states (eg, renal or hepatic impairment) are not expected to alter the disposition of saxagliptin

Clinical Pharmacology: Pharmacokinetics

Metabolism

• Metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5)

• Major metabolite of saxagliptin is also a DPP-4 inhibitor- one-half as potent as saxagliptin

ExcretionExcretion

• Saxagliptin is eliminated by both renal & hepatic pathways

• Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively

• Following a single oral dose of Saxagliptin 5 mg to healthy subjects, mean plasma terminal half-life (t1/2) for

– saxagliptin was 2.5 hrs

– active metabolite 3.1 hs respectively

SaxagliptinStudiesStudies

Saxagliptin Has Been Proven in Well-Controlled Clinical Trials

• All Phase 3 trials were multicenter, multinational, randomized, double-

blind controlled studies

• The primary efficacy endpoint for all studies was A1C change from

baseline at 6 months

Phase 3 (6)N=4148N=4148

Monotherapy(2)Trials(N=766)

Entry A1C: 7.0%–10.0%

Initial Combo With MET (N=1306)

Entry A1C: 8.0%–12.0%

Add-On Combination (3)

Therapy Trials(N=2076)

MET=metformin; SU=sulfonylurea; TZD=thiazolidinedione.

Saxagliptin Has Been Proven in Well-Controlled Clinical Trials

Add-On CombinationTherapy Trials

(N=2076)

Add-On to a TZD (N=565)

Entry A1C: 7.0%–10.5%

Add-On to the SUGlibenclamide

(N=768)Entry A1C: 7.5%–10.0%

Add-On to MET(N=743)

Entry A1C: 7.0%–10.0%

Saxagliptin add on to MetforminMetformin24 week data

Saxagliptin 5 mg Added to MET Provided Extra Help for Adult Patients Uncontrolled on MET Plus Placebo:

A1C Results

Change in A1C at 6 Months*Change in A1C at 6 Months* Percentage of Patients Achieving A1C <7% at 6 Months

Percentage of Patients Achieving A1C <7% at 6 Months

0.2

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

Saxagliptin 5 mg + MET (n=186)

Mean baseline: 8.1 %

Placebo + MET (n=175)


Pe

rce

nta

ge o

f P

ati

en

ts (

%)

80.0

100.0

In addition to diet and exercise

P<0.0001 vs placebo + MET-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

–0.7%

+0.1%

Pe

rce

nta

ge o

f P

ati

en

ts (

%)

0.0

20.0

40.0

60.0





44%

17%

P<0.05 vs placebo + MET

80.0

*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.

DeFronzo RA The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With InadequatelyControlled Type 2 Diabetes With Metformin Alone Diabetes Care 32:1649–1655, 2009

Saxagliptin 5 mg Added to MET Provided Significant Reductions in A1C at 6 Months

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

* (%

)

-0.4

0.0

0.4

-0.2

0.2Placebo + MET

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

* (%

)

Weeks

-1.0

-0.4

BL 4 6 8 12 16 20 24LOCF

24

-0.8

-0.6

*Includes patients with a baseline and week 24 value.

Week 24 (LOCF) includes intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for

patients needing rescue. Mean change from baseline is adjusted for baseline value.

Saxa 5 mg + MET

Saxagliptin 5 mg Added to MET Provided Statistically Significant Reductions in FPG and PPG

Change in 2-Hour PPG†

at 6 Months*Change in 2-Hour PPG†

at 6 Months*Change in FPG at 6 Months*Change in FPG at 6 Months*


Mean baseline: 175 mg/dL

0

10

+1 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)







0

10

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)


-60

-50

-40

-30

-20

-10+1 mg/dL

–22 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)


–23 mg/dLGreater Reduction When Saxagliptin 5 mg Added

-70

-60

-50

-40

-30

-20

-10

–58 mg/dL

–18 mg/dL


Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

-70

*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. †As part of a 3-hour oral glucose tolerance test (OGTT).

DeFronzo RA The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With InadequatelyControlled Type 2 Diabetes With Metformin Alone Diabetes Care 32:1649–1655, 2009

Saxagliptin add on to MetforminMetformin

102 week data

HbA1c Mean Change From Baseline (LOCF) at Week 102

Baseline HbA1c: 8.0 - 8.1%

Diabetes duration: 6.3 - 6.7 years

0.0

0.4

0.2

Fro

m B

L±S

E

PBO + METSAXA 5mg + MET

-0.4

-0.2

-0.6Hb

A1c

(%)

Me

an

∆F

rom

BL

BL 4 8 2012 30 37 50 63 76 89 102

Weeks

Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009

9.0

12.0

Ad

juste

d M

ean

Ch

an

ge in

FPG

6.0

Dose

n observed=BL mean

5+MET

31179

PBO+MET

15175

SAXA (mg)

PBO + METSAXA 5mg + MET

0.0

10

-min

120-min PPG

Dose

n observed=

5+MET

46

PBO+MET

24

SAXA (mg)

50

Perc

en

tag

e o

f p

ati

en

ts A

ch

iev

ing

HbA1c <7%

40 30

Dose

n observed=

5+MET

13

PBO+MET

15

SAXA (mg)

HbA1c Mean Change From Baseline (LOCF) at Week 102

-9.0

0.0

Ad

juste

d M

ean

Ch

an

ge in

F

PG

(m

g/d

L)

±±±±SE 6.0

3.0

-3.0

-6.0

-12.0

-15.0 -11

-40

Ad

juste

d M

ean

Ch

an

ge in

120-

PP

G (

mg

/dL

)

±±±±SE -43.0

-20

-30

-50

-35

10

Perc

en

tag

e o

f p

ati

en

ts A

ch

iev

ing

Hb

A1c

<7%

(95%

CI)

12

40

30

20

0

30

SAXA: Saxagliptin; MET: Metformin; PBO: Placebo

Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009

Patients on GlibenclamideSaxagliptin add on

vs. Glibenclamide uptitrationGlibenclamide uptitration

Saxagliptin 5 mg Added to a Submaximal Dose of GLIB

Saxagliptin as Add-On Combination Therapy With GLY

Number of Patients768 adult patients with T2DM with inadequate glycemic control on a submaximal dose of the SU glibenclamide alone

A1C Entry Criteria ≥7.5%–≤10%

Duration 24 weeks


Base Therapy Submaximal dose of Glib for 2 months or greater

Lead-in TherapySingle-blind, 4-week, diet and exercise lead-in period, and placed on GlIB 7.5 mg once daily

Treatment Arms*4 arms: Saxagliptin (2.5 or 5 mg) + 7.5 mg GLIB, PBO + 10 mg GLIB

Rescue Protocol MET rescue, added on to existing study medication

*Patients who received placebo were eligible to have Glib up-titrated to a total daily dose of 15 mg. Up-titration of GLIB was not permitted in patients who

received Saxagliptin 2.5 mg or 5 mg. Dose titration of Saxagliptin was not permitted during the study.

Saxagliptin: Add on to Sulphonylurea

768 adult patientsOn 7.5 mg of Glibenclamide

Add Saxagliptin 5 mg

Glibenclamide

Uptitrate Glibenclamideto 15 mg/day

Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R. Saxagliptin Added to a Submaximal-Dose of Sulphonylurea Improves Glycaemic Control Compared With Uptitration of Sulphonylurea in Patients With Type 2 Diabetes: A Randomized Controlled Trial. Int J Clin Pract. 2009:63:1395-1406.

Saxagliptin 5 mg Added to a Submaximal Dose of GLIB: A1C Results

-0.2

0.0

0.2

Saxagliptin 5 mg + GLIB 7.5 mg (n=250)

Mean baseline: 8.5%

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)



Change in A1C at 6 Months*Change in A1C at 6 Months*

Placebo + Up-Titrated GLIB (n=264)

Mean baseline: 8.4%

+0.1%

Pe

rce

nta

ge o

f P

ati

en

ts (

%)

60.0

80.0

100.0P<0.05 vs placebo

+ up-titrated GLIB


-1.0

-0.8

-0.6

-0.4

-0.2

P<0.0001 vs placebo

+ up-titrated GLY

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

–0.6% Pe

rce

nta

ge o

f P

ati

en

ts (

%)

0.0

20.0

40.0

23%

9%


Mean baseline: 8.5%


Mean baseline: 8.4%

92% of patients in the placebo + SU group required up-

titration to the maximum SU study dose of 15 mg

*Intent-to-treat population using last observation on study prior to MET rescue therapy.

Chacra AR . Int J Clin Pract. 2009:63:1395-1406

Change in FPG at 6 Months*Change in FPG at 6 Months* Change in 2-Hour PPG†


at 6 Months*

Saxagliptin 5 mg Added to a Submaximal Dose of GLIB: FPG and PPG Results





+8 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

0

10





+1 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

0

10

+8 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

-40

-30

-20

-10

0

P<0.05 vs placebo

+ up-titrated GLIB

+1 mg/dL

–10 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

-40

-30

-20

-10

0

–10 mg/dLImprovement When Onglyza 5 mg Added

P<0.05 vs placebo + up-titrated GLIB

-50

-60

-70

-50

-60

-70

–34 mg/dL

*Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT.

Chacra AR . Int J Clin Pract. 2009:63:1395-1406

Incidence (%) of HypoglycemiaIncidence (%) of Hypoglycemia

Saxagliptin Plus GLIB: Incidence of Hypoglycemia

Saxagliptin 5 mg + GLIB 7.5 mg

Saxagliptin 2.5 mg + GLIB 7.5 mg

Placebo + Up-Titrated GLIB

Reported 14.6% 13.3% 10.1%

Add-on to the SU Glibenclamide study

Reported

Hypoglycemia*14.6% 13.3% 10.1%

Confirmed

Hypoglycemia†0.8% 2.4% 0.7%

*Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required.†Defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL.

There was no significant differences between different groups in the reported and confirmed hypoglycemia

Patients on ThiazolidinedioneSaxagliptin add on Vs. Placebo

Saxagliptin 5 mg Provided Extra Help for Patients Struggling to Gain Glycemic Control on a TZD

Saxagliptin as Add-On Combination Therapy With a TZD

Number of Patients565 adult patients with T2DM with inadequate glycemic control on TZD alone

A1C Entry Criteria ≥7%–≤10.5%

Duration 24 weeks

Base TherapyPioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or 8 mg either once daily or in two divided doses of 4 mg) for


Base Therapy daily or 8 mg either once daily or in two divided doses of 4 mg) for

at least 12 weeks

Lead-In TherapySingle-blind, 2-week, diet and exercise placebo lead-in period, during which patients received TZD at their pre-study dose for the duration of the study

Treatment Arms* 3 arms: Saxagliptin (2.5 or 5 mg) + TZD, PBO + TZD

Rescue Protocol MET added on to existing study medications

*Dose titration of Onglyza or TZD was not permitted during the study.

Saxagliptin 5 mg Provided Statistically Significant A1C Reductions When Added to

a TZD

Change in A1C at 6 Months*Change in A1C at 6 Months*

-0.2

0.0

0.2

Placebo + TZD (n=180)

Mean baseline: 8.2%

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

Saxagliptin 5 mg + TZD (n=183)

Mean baseline: 8.4%



Pe

rce

nta

ge o

f P

ati

en

ts (

%)

60.0

42%

80.0

100.0

*Intent-to-treat population using last observation on study prior to MET rescue therapy.

-1.0

-0.8

-0.6

-0.4

-0.2

P<0.0001 vs placebo + TZD

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

–0.3%

P<0.05 vs placebo + TZDP

erc

en

tag

e o

f P

ati

en

ts (

%)

0.0

20.0

40.0

42%

26%

Placebo + TZD (n=180)

Mean baseline: 8.2%


Mean baseline: 8.4%–0.9%

Saxgliptin 5 mg Added to a TZD Provided Statistically Significant Reductions in FPG

and PPG

Placebo + TZD(n=127)




Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e (

mg

/dL

)

-10

0

10

Change in FPG at 6 Months*Change in FPG at 6 Months* Change in 2-Hour PPG†


at 6 Months*

Placebo + TZD(n=181)




-10

0

10

Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e (

mg

/dL

) –3 mg/dL

Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e (

mg

/dL

)

-60

-50

-40

-30

-20

-10

–65 mg/dL

–15 mg/dL

-70P<0.05 vs placebo + TZD-60

-50

-40

-30

-20

-10

–17 mg/dL

Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e (

mg

/dL

)

–15 mg/dLGreater Reduction When

Onglyza 5 mg Added

–3 mg/dL

P<0.05 vs placebo + TZD -70

*Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT.

Saxagliptin Safety & Tolerability

35Version 1.3

Saxagliptin: Incidence of Adverse EventsOverall Incidence of Adverse Events Was Similar to Placebo

Pooled Analysis of Adverse Reactions Occurring in ≥5% of Patients and More

Commonly Than Placebo

Pooled Analysis of Adverse Reactions Occurring in ≥5% of Patients and More

Commonly Than Placebo

Saxagliptin 5 mg

(N=882)

Placebo

(N=799)

In Monotherapy and Add-On Therapy Studies*

(N=882) (N=799)

Upper respiratory tract infection

7.7% 7.6%

Urinary tract infection

6.8% 6.1%

Headache 6.5% 5.9%

*Prespecified pooled analysis of 2 monotherapy studies, the add-on to MET study, the add-on to the SU glibenclamide study,

and the add-on to a TZD study; 24-week data regardless of glycemic rescue.

36Version 1.3

Saxagliptin: Discontinuation of Therapy Due to Adverse Events

• Discontinuation of therapy due to adverse events occurred in 3.3% and 1.8%of patients receiving Saxagliptin and placebo, respectively

Most Common Adverse Events Associated With Discontinuation of Therapy*

Most Common Adverse Events Associated With Discontinuation of Therapy*

Saxagliptin 5 mg

Saxagliptin2.5 mg

Comparator

Percent of Patients

• There was a dose-related mean decrease in absolute lymphocyte count observed with Saxagliptin

5 mg (N=882)

2.5 mg(N=882)

Comparator (N=799)

Lymphopenia 0.5% 0.1% 0.0%

Rash 0.3% 0.2% 0.3%

Blood creatinine increase 0.0% 0.3% 0.0%

Blood creatine phosphokinase increase

0.2% 0.1% 0.0%

*Reported in at least 2 patients treated with Saxagliptin

37Version 1.3

Saxagliptin: Incidence of Hypoglycemia

Incidence of Reported Hypoglycemia

Across Phase 3 Clinical Trials

Incidence of Reported Hypoglycemia

Across Phase 3 Clinical Trials

Saxagliptin5 mg

Saxagliptin2.5 mg

Comparator

Add-On to MET 5.8% 7.8% 5.0%

Percent of Patients

Initial Combo With MET 3.4% — 4.0%

Add-On to the SU Glyburide 14.6% 13.3% 10.1%

Add-On to a TZD 2.7% 4.1% 3.8%

Pooled Monotherapy 5.6% 4.0% 4.1%

Cardiovascular safety

Cardiovascular safety :

MACE (Major Adverse CV Events)

Ongoing CV trials : SAVOR-TIMI 53

Multiple Analytical Methods for Relative Risk1

• 41 of CV death/MI/ stroke (MACE), 40 CEC*-adjudicated CV events, and 61 Sponsor identified acute cardiovascular events assessed by multiple analytic methods showed similar results for relative risk

• Onglyza was not associated with an increased risk of CV events in a pooled retrospective analysis of the Phase 2/3 clinical program

* Clinical Events Committee

1Frederich R et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)

Incidence Rate Ratios1

• For investigator identified CV death, MI or stroke, the results within individual studies were consistent with the pooled analysis

• Onglyza was not associated with • Onglyza was not associated with an increased risk of CV events in a pooled retrospective analysis of the Phase 2/3/ clinical program

1Frederich R et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2diabetes. Post graduate Medicine 122 (3)

Kaplan Meier Analysis1

• This Kaplan Meier analysis of MACE and all cause mortality does not suggest increased risk for CV death, MI or stroke either early or late after initiation of saxagliptin initiation of saxagliptin treatment.

1Frederich R et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)

Cardiovascular risk factors (in addition to T2D)Saxagliptin controlled Phase 2b/3 pooled population

Data on file. Not in public domain

Ongoing CV trials of Saxagliptin

• Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus" trial (SAVOR-TIMI 53)

• Multicenter, randomized, double-blind, placebo-controlled Phase 4 study, to evaluate treatment with Saxagliptin, a Phase 4 study, to evaluate treatment with Saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in adult type 2 diabetes patients with cardiovascular risk factors.

• The five-year study will follow approximately 12,000 patients with type 2 diabetes

Saxagliptin Hepatic Impairment

Renal Impairment

45Version 1.3

Saxagliptin: Renal Impairment

• Mild Impairment, creatinine clearance [CrCl] ≤50 mL/min: No dosage adjustment

• Moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). Saxagliptin 2.5 mg is recommended.recommended.

• Saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoing peritoneal dialysis.

• Assessment of renal function is recommended prior to initiation of Saxagliptin and periodically thereafter.

46Version 1.3

Saxagliptin: Hepatic Impairment

• In subjects with hepatic impairment (Child-Pugh classes A, B, and C)

• Mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin.

• The corresponding Cmax and AUC of the active metabolite • The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls.

• These differences are not considered to be clinically meaningful.

• No dosage adjustment is recommended for patients with hepatic impairment

Saxagliptin

Dosing

Convenient Once-Daily Dosing

• Standard dose : 5

mg/day

• Taken any time

Dosing Considerations for SaxagliptinDosing Considerations for Saxagliptin

Recommended Dose

or

Recommended dose once daily taken regardless of meals

Moderate-to-severe renal

5 mg once daily 2.5 mg once daily

of day, with or

without food

• 24-hour glycemic

control

Moderate-to-severe renal impairment, or ESRD requiring hemodialysis (CrCl ≤50 mL/min)

Co-administration with strong CYP3A4/5 inhibitors*

Tablets Not Actual Size.

2.5 mg once daily

*Such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin. ESRD= end-stage renal disease

FDA approval

Saxagliptin is approved for

Monotherapy in patients not controlled on diet / exercise

Add on therapy to Metformin, SU or Thiazolidinedione Add on therapy to Metformin, SU or Thiazolidinedione

AACE 2010 guidelines

HbA1c : 6.5-7.5 % HbA1c : 7.6-9 % HbA1c : > 9 %

•Metformin

•TZD

Combination therapy : 2 agents

•Metformin

Combination therapy : 3 agents

•Metformin

•DPP-4 inhibitors

•Alfa- glucosidase inhibitors

•TZD

•GLP 1 agonist

•DPP-4 inhibitors

•Glinides

•Sulphonylureas

•TZD

•GLP 1 agonist

•DPP-4 inhibitors

•Glinides

•Sulphonylureas

•Insulin

Rodbard, H., Jellinger, P., et al (2009). Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control. Endocrine Practice, 15(6), 540-559.

Algorithm

Lifestyle + MF +Basal Insulin

At diagnosisLifestyle +Metformin

Lifestyle + MF

Lifestyle + MF +Intensive insulin

Tier 1 therapies

Lifestyle + MF + SU

Lifestyle + MF + Pioglitazone

Lifestyle + MF+ GLP-1 agent

Lifestyle + MF + Pioglitazone++SU

Lifestyle + MF + Basal Insulin

Tier 2 therapies

Step 1 Step2 Step 3

Diabetes Care 32:1–11Oct 2008 e pub

Where to position Saxagliptin Evidence based

Lifestyle + MF +Basal InsulinSaxagliptinAt diagnosis

Lifestyle +MetforminSaxagliptin

Lifestyle + MF

Lifestyle + MF +Intensive insulin

Tier 1 therapies

Saxagliptin Lifestyle + MF + SU /Saxagliptin

Lifestyle + MF + Pioglitazone

Lifestyle + MF+ Saxagliptin

Lifestyle + MF + Pioglitazone+ SU

Lifestyle + MF + Basal Insulin/ Saxaglipin

Tier 2 therapies

Step 1 Step2 Step 3

Diabetes Care 32:1–11Oct 2008 e pub

Key messages

• Saxagliptin is a new potent DPP 4 inhibitor

• It is found to reduce all the key parameters of glycemic control : FBS, PPBS and HbA1c

• It improves measures of beta cell function

• It is weight neutral

• It has a safety profile similar to placebo

Thank you

Disclaimer

The material for these slides were derived from various sources

including pictures and cartoons from the world wide web. I havetried my best to acknowledge all possible sources and references.However, if I have overlooked any particular reference, it is notdone intentionally. Anyone reproducing materials from thispresentations should acknowledge the author of the original work.presentations should acknowledge the author of the original work.

Some of the slides are made by Aztra Zeneca/ Bristol Myers Squibb,the manufactures of Onglyza. However, all these data are currentlyin public domain, paid or otherwise.

Saxaslideshare

Health & Medicine

saxagliptin dpp

active metabolite saxagliptin

incretin axis saxagliptin

protein binding of saxagliptin

entry a1c

vs dpp

hrs active metabolite

a1c change