1Version 1.3
Dr Mohan K Rao MD
Fellowship in diabetes & Endocrinology
(UTSW Medical Center, Dallas, USA)
Consultant endocrinologist
Sagar Center for Diabetes
Sagar Hospitals
2Version 1.3
India: World Diabetic Capital
Country/Territory
2010 Millions
Country/Territory
1 India
50.8
1 India
2 China
43.2
2 China
3 USA
26.8
3 USA
4 Russian federation
9.6
2030 Millions
4 Pakistan
5 Brazil
6
5 Brazil
Recent NEJM 7.6
Publication,
March 2010
China has the highest number
of Adult
diabetics: 92.4 million
Germany
7.5
6 Indonesia
87
62.6
36
13.8
12.7
12
7 Pakistan
7.1
7 Mexico
11.9
8 Japan
7.1
8 Bangladesh
10.4
9 Russian federation
10.3
9 Indonesia
10 Mexico
7
6.8
10 Egypt
8.6
Number of people with diabetes (20-79 years), 2010 and 2030
Adapted from: The International Diabetes Federation, Diabetes Atlas Fourth Edition (2009). Available at: http://www.eatlas.idf.org/. Accessed: March 09, 2010
Overview
 Which glycemic prameters to control?
 Challenges of Hypoglycemia, Weight gain & Patient
adherence to therapy?
 Which hormonal abnormalities to control?
 Evidence for Saxagliptin in comprehensive glycemic control
in Type 2 DM
HbA1c reflects both fasting and postprandial
hyperglycaemia
Plasma glucose
(mmol/L)
15.0
10.0
(mg/dL)
300
Postprandial
hyperglycaemia
200
Fasting
hyperglycaemia
5.0
100
Normal
0
0
0600
1200
1800
Time of day
Riddle MC. Diabetes Care. 1990;13:676-86.
2400
0600
Achieving HbA1c target requires an action
on both FPG and PPG
HbA1c=
Fasting
Glucose
+
Postprandial
Glucose
FPG influenced by:
PPG influenced by:
› Hepatic glucose
production
› Hepatic sensitivity
to insulin
› Exercise during the
previous
day
› Meal from the previous
night
› Alcohol
› Obstructive sleep apnoea
› Nocturnal hypoglycaemia
›
›
›
›
›
Pre-prandial glucose
Glucose load from meal
Incretin level
Insulin secretion
Insulin sensitivity in
peripheral tissues
› Decrease in glucagon suppression
IDF. International Diabetes Foundation. Diabetes Atlas. Third Edition.
http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 26 Jan, 2009.
Hazard ratio
DECODE Study: Relative Risk of Mortality
Increased with Increasing 2-Hr Glucose Level
2
1
0
>11.1
7.8-11.0
<7.8
<6.1
6.1-6.9
DECODE Study Group. Lancet 1999;354:617-621.
>7.0
7Version 1.3
Appropriate A1C Management Should Consider Both
FPG and PPG Levels
Approximate Contribution
to A1C (%)
PPG
FPG
A1C (%)
30%†
70%*†
<7.3
47%‡
53%‡
7.3–8.4
55%
45%
40%*
30%*
8.5–9.2
60%
9.3–10.2
70% >10.2
 FPG and PPG contributions to A1C
differ as A1C levels change
 PPG is the major contributor
to A1C in patients with A1C
<7.3%
 FPG is the major contributor
to A1C in patients with A1C
≥9.3%
FPG and PPG concentrations were measured in 290 patients with T2DM. Patients were divided into quintiles of A1C and these values were used to
calculate the relative contribution that each made to the patient’s overall diurnal hyperglycemia. The results were compared across quintiles.
*Significant difference was observed between FPG and PPG.
†Significantly different from all other quintiles.
‡Significantly different from >10.2 quintile.
All percentages are approximated.
Monnier L et al. Diabetes Care. 2003;26:881-885.
Different measures provide varying insights
 HbA1c as an indicator of glycaemic control
 Haemoglobin A1c (HbA1c) is an effective measure to evaluate the overall
control of diabetes and risk of complications
AACE 2010
Along with HbA1c,
complications2
 HbA1c is the preferred
measurefasting
accordingand
to international
guidelinesglucose
Consideration
of both
post-prandial
(e.g. ESC/EASD)3
levels as end points
 HbA1c levels can be directly correlated to glucose levels1 and
 FPG and PPG as measures of glycaemic control
 Measuring FPG and PPG allows daily variations in glucose levels to
be assessed,
compared
with HbA1c4
Hence,
Comprehensive
Glycemic
 PPG should be measured 2 hours after a meal as part of SMBG
Control is Important in all Type 2 DM
monitoring4
 PPG correlates with CV risk5,6

.
Acute glucose variations detected postprandially may be an important
indicator of oxidative stress7,8
1. Nathan DN, et al. Diabetologia. 2007;50:2239-44. 2. DCCT Study. Diabetes. 1995;44:968-83. 3. Rydén L, et al. Eur Heart J.
2007;28:88-136. 4. International Diabetes Foundation. Available at: http://www.idf.org. Accessed: 29 Jun, 2009. 5. DECODE Study
Group. Lancet. 1999;354:617-21. 6. Hanefeld M, et al. Diabetologia. 1996;39:1577-83. 7. Monnier L, et al. JAMA. 2006;295:1681-7.
8. Brownlee M. Diabetes. 2005;54:1615-25.
Risk for Retinopathy in Conventional and
Intensive Treatment Subgroups of the DCCT
Conventional
Intensive
The DCCT Study
Group: Diabetes
44:968-83, 1995
Postprandial hyperglycemia and the risk for
diabetic complications
Hence, Postprandial glycemic
....mean HbA1c
is not the most
completeis
expression
of the degree
of
excursions
Control
Important
in all
hyperglycaemia. Other features of diabetic control, which are not reflected
Type
DM
by HbA1c may add to or modify the
risk for2complications.
For example, the
risk for complications may be more highly dependent on the extent of
postprandial glycaemic excursions....
DCCT Study Group, Diabetes 1995
ADOPT: Treatment effect on primary
outcome
N=4351
Hazard ratio (95% CI)
Rosiglitazone vs metformin, 0.68 (0.55–0.85), P<0.001
Rosiglitazone vs glyburide, 0.37 (0.30–0.45), P<0.001
40
Glyburide
Hence,
Sustained comprehensive glycemic
30
Control is Important in all Type 2 DM
Cumulative
incidence
of monotherapy
failure*
(%)
Metformin
20
Rosiglitazone
10
0
0
1
*Time to FPG >180 mg/dL
Kahn SE et al. N Engl J Med. 2006;355:2427-2443.
2
3
Years
4
5
Hypoglycaemia – a major predictor of
cardiovascular death in the VADT study
Hazard Ratio
P Value
(HR lower CL,
HR upper CL)
Hypoglycaemia
0.01
HbA1c
4.042
(1.449,11.276)
1.213 (1.038,1.417)
HDL
0.699 (0.536, 0.910)
0.01
Age
2.090 (1.518, 2877)
<0.01
Prior event
3.116 (1.744, 5567)
<0.01
0
2
4
6
8
10
Duckworth W.(VADT): results. 2008. Available from
http://webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?
type=0&lid=3853, Accessed: 20 Oct 2009.
12
0.02
Recent hypoglycaemia is associated with
a higher risk of MI in diabetes patients
• Risk of MI associated with episodes of hypoglycaemia
within a given prior period
Cases
of MI
(%)
Controls
(%)
Adjusted risk of MI
(95% CI)
Index date or day before
2.9
0.1
—
Prior 2 weeks
1.1
0.3
1.65 (1.50–1.81)
Previous 5.5 months
6.0
2.5
1.20 (1.15–1.25)
Previous 6 months
4.8
2.1
1.11 (1.06–1.15)
Previous year
9.6
4.2
1.12 (1.08–1.16)
Any hypoglycaemia
in specific periods
Miller DR, et al. Poster Presentation at 45th EASD. Sep 29 – 2 Oct 2009, Vienna, Austria.
Hypoglycaemia and CV events
• In the ACCORD study and VADT, a clear association between
severe hypoglycaemia and CV events was found1,2
(although no cause-effect relationship was proven)
•
Hence, avoidance of hypoglycemia is very
important consideration
• Hypoglycaemia may be of particular concern in:
• Obese patients
• Individuals with a long duration of type 2 diabetes – such
as elderly patients, especially those with previous CV
events3,4
1. Byington RP for the ACCORD Study Group. Accessed: 9 Oct 2009. 2. Duckworth W, et al. N Engl J Med. 2009;360:12939. 3. Del Prato S. Diabetologia. 2009;52:1219-26. 4. Mannucci E, et al. Nutr Metab Cardiovasc Dis. 2009;19:604-612.
Obesity and insulin resistance
 FFAs thought to:
 stimulate glucose production by
the liver
 interfere with its ability to
remove and respond to insulin
 high levels of FFAs toxic to
pancreatic β-cells (lipotoxicity)
 TNF-α thought to:
 influence insulin resistance by
promotion of lipolysis, leading to
increased FFA levels
Influence of FFAs on the liver
Lipotoxicity
Long-term exposure to high levels of FFAs increases destruction of β-cells
Effect enhanced by hyperglycaemia
Most current therapies result in weight gain
over time
UKPDS: up to 8 Kg in 12 years1
8
100
7
Treatment difference (95% CI)
Rosiglitazone vs metformin
6.9 (6.3 to 7.4); P<0.001
Rosiglitazone vs glibenclamide,
2.5 (2.0 to 3.1); P<0.001
Insulin (n=409)
6
96
Hence, avoidance of Weight gain is very
Glibenclamide (n=277)
important consideration
5
Weight (Kg)
Change in weight (Kg)
ADOPT: up to 4.8 Kg in 5 years2
4
3
2
92
88
1
Metformin (n=342)
0
0
3
6
9
12
0
0
1
Years from randomisation
Conventional treatment (n=411); diet initially then
sulphonylureas, insulin and/or metformin if FPG >15
mmol/L
n=at baseline1
1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65.
2. Kahn SE, et al (ADOPT). N Engl J Med. 2006;355:2427-43.
2
3
4
5
Years
Annualised slope (95% CI)
Rosiglitazone, 0.7 (0.6 to 0.8)
Metformin, -0.3 (-0.4 to -0.2)**
Glibenclamide, -0.2 (-0.3 to 0.0)**
Frequency of daily doses affects
concordance
Percentage of people with type 2 diabetes with optimal
self-reported concordance with oral glucose-lowering agents
(no omission) according to the frequency of daily doses
80
Optimal concordance (%)
Hence, therapies with once daily dosing
improve ease of administration, patient
adherence and overall glycemic control
60
*
**
40
20
Once-daily
Twice-daily
Three-timesdaily
*P<0.05; **P<0.01 vs once-daily administration
Guillausseau PJ. Treat Endocrinol. 2005;4:167-75.
Emergence of Diabetes as a Multihormonal
Disorder: A Historical Perspective
Hence, all hormonal abnormalities needed
to be targeted to achieve glycemic
control
b cells
a cells
L cells
1925
1950
1975
2000
Adapted from Hirsch IB. NEJM. 2005;352:174-183; Drucker DJ. Cell Metab. 2006; 3:153-165; Singh-Franco D et al. Clin Ther. 2007;29:535-562.
Wish List
A drug that can be used for
 Sustained comprehensive glycemic control with lower
postprandial glycemic excursions
 Safer: Low hypoglycemic risk & Weight neutral
 Improves patient adherence
 Targets all hormonal abnormalities of diabetes
pathophysiology
AACE 2010
Goals as priorities in the selection of
medications
 Inclusion of major classes of FDA-approved glycemic medication,
incretin-based therapies
Hence, our Wish list matches
Minimizing risk and severity of hypoglycemia
with AACE 2010 criteria for selection of medications
Minimizing risk and magnitude of weight gain
Consideration of both fasting and postprandial glucose
including



levels as end points
 In many cases, delaying pharmacotherapy to allow for lifestyle modifications
is inappropriate because these interventions are usually not adequate
 Consideration of
total cost of therapy to the individual and society
at large, including costs related to medications, glucose monitoring
requirements, hypoglycemic events, drug-related adverse events, and
treatment of diabetes-associated complications
 The major cost is related to the treatment of the complications of diabetes. We
believe that identification of the safest and most efficacious agents is essential.
Normal Glucose Homeostasis: Role of
Incretins1,2
1
In response to meals, incretin
hormones (GIP and GLP-1)
are increasingly released from
the small intestine
Fat
22Version 1.3
Increased
Glucose
Uptake
Insulin Secretion
DPP-4
Enzymes
β
GI Tract
Incretin Effect
Pancreas
α
Indirect
suppression
of glucagon
Glucagon Secretion
Incretins (GIP/GLP-1)
2
Pancreatic cells
respond to high
levels of incretins
3
DPP-4 enzymes
break down
incretins
β Pancreatic beta cell
α
Pancreatic alpha cell
Liver
Decreased
Glucose
Production
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.
Glucose
Homeostasis
23Version 1.3
T2DM: Role of Incretins1,2
1
In adults with T2DM,
incretins are released,
but the incretin-mediated
effects are diminished
Fat
Insulin Secretion
DPP-4
Enzymes
Diminished
Incretin Effect
Impaired
Glucose
Uptake
β
GI Tract
Pancreas
α
Less indirect
suppression
of glucagon
Hyperglycemia
Glucagon Secretion
Incretins (GIP/GLP-1)
β
Pancreatic beta cell
α
Pancreatic alpha cell
1. Kim W et al. Pharmacol Rev. 2008;60:470-512.
2. Drucker DJ. Cell Metab. 2006;3:153-165.
2
Incretin action on
pancreatic cells is
reduced
Liver
Increased
Glucose
Production
24Version 1.3
Saxagliptin, a DPP-4 Inhibitor, Enhances
the Body’s Natural Response to Food1,2
1
Saxagliptin, a DPP-4 inhibitor,
sustains the effects of
incretins in adults with T2DM
Increased
Glucose
Uptake
Fat
Insulin Secretion
O
DPP-4
Enzymes
β
GI Tract
Incretin Effect
Pancreas
α
Glucose
Homeostasis
Indirect
suppression
of glucagon
Glucagon Secretion
O
Saxagliptin
Incretins (GIP/GLP-1)
β
Pancreatic beta cell
α
Pancreatic alpha cell
1. Kim W et al. Pharmacol Rev. 2008;60:470-512.
2. Drucker DJ. Cell Metab. 2006;3:153-165.
2
Saxagliptin lowers FPG and PPG
in a glucose dependant manner
Pancreatic cells
respond to higher
levels of incretins
Liver
Decreased
Glucose
Production
25Version 1.3
A Review of the Evidence
A Proven Partner to Improve Glycemic Control
Indication and Important Limitations of Use
GLP1 is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes
mellitus.
should not be used for the treatment of type 1 diabetes
mellitus or diabetic ketoacidosis.
Please see full Indian Prescribing Information available at this presentation.
Chemical Structure of DPP4 Inhibitors
F
F
HO
H2N
HO
N
O
CN
Saxagliptin
Ki = 1.3 nM
•
•
•
N
H
O
O
NH2 O
N
Vildagliptin
Ki = 13 nM
F
N
Sitagliptin
Ki = 18 nM
O
N
N
N
CN
Me
N
N
CF3
CN
N
AlogliptinNH2
Ki = 13 nM
Vildagliptin’s nitrile group interacts with ser630 in the DPP4 active site
Sitagliptin and alogliptin interact with glu205/glu206 in the DPP4 active site
Saxagliptin’s compact structure fits more tightly into the DPP4 active site
- Provides extended binding at 37°C
- Strong interactions with ser630, tyr547, and glu205/glu206 in the DPP4
active site
- Most potent DPP4 inhibitor
BYETTA/ LIRAGLUTIDE
27Version 1.3
GLP1/DPP IV Along With Diet and Exercise
Provided Improved
Comprehensive Glycemic Control
28Version 1.3
GLP1/ DPP 1V Has Been Proven in WellControlled Clinical Trials
Add-On Combination
Therapy Trials
(N=2076)
Add-On to MET
(N=743)
Entry A1C: 7.0%–10.0%
Add-On to the SU
Glibenclamide
Add-On to a TZD
(N=768)
Entry A1C: 7.0%–10.5%
Entry A1C: 7.5%–10.0%
(N=565)
ANOLOGUE INSULINS




RAPID ACTING INSULINS
HUMOLOG PLAIN/ HUMALOG MIX 25/75 HUMALOG MIX
50/50
USEFUL IN CLINICAL SETTINGS LIKE IN-PATIENT/
PREGNANCY/ RENAL FAILURE/OUT-PATIENT CARE
MORE PHYSIOLOGICAL
BETTER PPBG CONTROL, LESS HYPOGLYCAEMIA
CONCLUSION
FBS/PPBS/HBA1C ALL NEEDS TO BE CONTROLLED
HYPOGLYCEMIA/ WEIGHT GAIN EQUALLY DANGEROUS
MULTI-HORMONAL APPROACH
ANOLOGUE INSULINS RESULTED IN MORE PHYSIOLOGICAL
REDUCTION IN BLOOD SUGARS
 INCRETIN BASED THERAPY IS VERY USEFUL




THANK YOU
32Version 1.3
Introducing Shanti, Currently on MET Therapy
Shanti
Age:
45y
Race/Ethnicity: Indian Abd circum :90 cm
Current Chart
Height:
Latest Blood Glucose Values
•
Occupation: Teacher
•A1C: 8
•
Diagnosed with T2DM 5 years ago
•FPG: 150 mg/dl
•
Current MET dose 1500 mg/day
•PPG: 210 mg/dl
•
Hypertensive
•
Sedentary lifestyle
•
Non proliferative retinopathy
Discussion questions
• What action would you take?
Not actual patient
150 cm Weight: 65 kg
In addition to diet and
exercise
33Version 1.3
Saxagliptin 5 mg Added to MET Provided Extra Help
for Adult Patients Uncontrolled on MET Plus Placebo
Saxagliptin as Add-On Combination Therapy With MET
Number of Patients
A1C Entry Criteria
Duration
Base Therapy
Lead-in Therapy
Treatment Arms*
Rescue Protocol
743 adult patients with T2DM and inadequate
glycemic control on MET alone
7%– 10%
24 weeks
MET (1500 mg to 2550 mg daily) for at least 8
weeks
Single-blind, 2-week, diet and exercise placebo
(PBO) lead-in period, during which patients
received MET at their prestudy dose, up to 2500
mg daily, for the duration of the study
4 arms: Saxa 2.5 mg + MET, Saxa 5 mg + MET,
saxagliptin 10 mg + MET, PBO + MET
Pioglitazone added on to existing study
medications
*Dose titrations of Saxagliptin and MET were not permitted.
In addition to diet and exercise
34Version 1.3
Saxagliptin 5 mg Added to MET Provided Extra
Help for Adult Patients Uncontrolled on MET
Plus Placebo: A1C Results
Percentage of Patients Achieving
A1C <7% at 6 Months
Mean Change From Baseline (%)
Saxagliptin 5 mg + MET Placebo + MET
0.2
(n=186)
(n=175)
Mean baseline: 8.1 %
Mean baseline: 8.1 %
0.0
+0.1%
-0.2
-0.4
-0.6
-0.8
Percentage of Patients (%)
Change in A1C at 6 Months*
100.0
80.0
60.0
40.0
17%
20.0
0.0
–0.7%
-1.0
P<0.0001 vs placebo + MET
44%
Saxagliptin 5 mg + MET Placebo + MET
(n=186)
(n=175)
Mean baseline: 8.1 %
Mean baseline: 8.1 %
P<0.05 vs placebo + MET
*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.
In addition to diet and exercise
35Version 1.3
Saxagliptin 5 mg Added to MET Provided
Significant Reductions in A1C at 6 Months
Mean Change From Baseline* (%)
0.4
0.2
Placebo + MET
0.0
-0.2
-0.4
-0.6
Saxa 5 mg + MET
-0.8
-1.0
BL
4
6
8
12
16
Weeks
20
24
24
LOCF
*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.
In addition to diet and exercise
36Version 1.3
Saxagliptin 5 mg Added to MET Provided
Statistically Significant Reductions in
FPG and PPG
Change in 2-Hour PPG†
at 6 Months*
Saxagliptin 5 mg + MET
Placebo + MET
Saxagliptin 5 mg + MET
(n=187)
(n=176)
(n=155)
(n=135)
Mean baseline: 179 mg/dL
Mean baseline: 175 mg/dL
Mean baseline: 296 mg/dL
Mean baseline: 295 mg/dL
10
0
+1 mg/dL
-10
-20
-30
–22 mg/dL
-40
-50
–23 mg/dL
-60
Greater Reduction When
Saxagliptin 5 mg Added
-70
P<0.05 vs placebo + MET
Mean Change From Baseline (mg/dL)
Mean Change From Baseline (mg/dL)
Change in FPG at 6 Months*
10
Placebo + MET
0
-10
-20
–18 mg/dL
-30
-40
-50
-60
-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).
–58 mg/dL
P<0.05 vs placebo + MET
37Version 1.3
HbA1c Mean Change From Baseline (LOCF)
at Week 102
SAXA 5mg + MET
HbA1c (%) Mean Δ From BL±SE
0.4
PBO + MET
Baseline HbA1c: 8.0 - 8.1%
Diabetes duration: 6.3 - 6.7 years
0.2
Saxagliptin when used for early addition
0.0
provides sustained comprehensive
-0.2
glycemic control
-0.4
-0.6
BL 4 8 12
20
30
37
50
63
Weeks
Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009
76
89
102
38Version 1.3
HbA1c Mean Change From Baseline (LOCF) at
Week 102
SAXA 5mg + MET
FPG
Dose
n observed=
BL mean
SAXA (mg)
5+MET
31
179
120-min PPG
Dose
PBO+MET
n observed=
15
175
12.0
PBO+MET
Dose
24
n observed=
6.0
3.0
0.0
-3.0
-6.0
-9.0
-12.0
-11
SAXA (mg)
5+MET
13
PBO+MET
15
50
0.0
3.0
-4
-20
-30
-40
-35
Percentage of patients Achieving
HbA1c <7% (95% CI)
Adjusted Mean Change in 120-min
PPG (mg/dL) ± SE
Adjusted Mean Change in
FPG (mg/dL) ± SE
SAXA (mg)
5+MET
46
HbA1c <7%
10
9.0
-15.0
PBO + MET
-50
SAXA: Saxagliptin; MET: Metformin; PBO: Placebo
Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009
40
30
30
20
10
0
12
Saxagliptin plus metformin leads to more
balanced glycaemic control
 Combination of Saxa plus
metformin leads to more
balanced glucose control
 Saxa plus metformin as
first-line therapy for
treatment-naïve patients
with uncontrolled type 2
diabetes may lead to fewer
glucose excursions, that
result in hypo- or
Saxagliptin reduces postprandial glycemic
excursions
hyperglycaemia
Glucose excursion profiles at baseline and week 24
In addition to diet and exercise
40Version 1.3
Saxagliptin 5 mg Together With MET Gave
Medication-Naive Adult Patients Greater Glycemic
Control vs MET Plus Placebo
Saxagliptin as Initial Combination With MET
Number of Patients
1306 treatment-naive adult patients with T2DM
with inadequate glycemic control on diet and
exercise alone
A1C Entry Criteria
8% to 12%
Duration
24 weeks
Base Therapy
N/A (patients were treatment-naive)
Lead-in Therapy
Treatment Arms*
Rescue Protocol
Single-blind, 1-week, dietary and exercise
placebo lead-in period
4 arms: Saxagliptin 5 mg + MET, saxagliptin 10
mg + MET, saxagliptin 10 mg + PBO, MET +
PBO
Pioglitazone rescue as add-on therapy
*The MET dose was up-titrated weekly in 500 mg/day increments, as tolerated, to a maximum of 2000 mg/day based on FPG.
In addition to diet and exercise
41Version 1.3
Saxagliptin Together With MET Gave MedicationNaive Adult Patients Greater Glycemic Control
Percentage of Patients Achieving
A1C <7% at 6 Months
Saxagliptin 5 mg + MET
MET + Placebo
(n=306)
(n=313)
Mean baseline: 9.4%
Mean baseline: 9.4%
0
-0.5
-1.0
-1.5
-2.0
-2.5
–2.0%
–2.5%
80.0
60%
60.0
41%
40.0
20.0
0.0
-3.0
-3.5
100.0
Percentage of Patients (%)
Mean Change From Baseline (%)
Change in A1C at 6 Months*
Saxagliptin 5 mg + MET
P<0.0001 vs MET + placebo
(n=314)
Mean baseline: 9.4%
Mean baseline: 9.4%
P<0.05 vs MET + placebo
*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.
Metformin was initiated at a starting dose of 500 mg daily, up-titrated to 1000 mg at Week 1, and
thereafter up-titrated as tolerated to a maximum of 2000 mg daily based on FPG through Week 5.
MET + Placebo
(n=307)
42Version 1.3
In addition to diet and exercise
Saxagliptin With MET as Initial Combination
Delivered Statistically Significant Reductions in
FPG and PPG
Change in 2-Hour PPG†
at 6 Months*
Change in FPG at 6 Months*
20
(n=315)
(n=320)
Mean baseline: 199 mg/dL
Mean baseline: 199 mg/dL
0
-20
-40
-60
–60 mg/dL
–47 mg/dL
-80
-100
-120
-140
P<0.05 vs MET + placebo
Saxagliptin 5 mg + MET MET + Placebo
Mean Change From Baseline (mg/dL)
Mean Change From Baseline (mg/dL)
Saxagliptin 5 mg + MET MET + Placebo
20
(n=146)
(n=141)
Mean baseline: 340 mg/dL
Mean baseline: 355 mg/dL
0
-20
-40
-60
-80
-100
–97 mg/dL
-120
P<0.05 vs MET + placebo
-140
*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.
†As part of a 3-hour OGTT.
–138 mg/dL
43Version 1.3
Introducing Leela, Currently on SU Therapy
Leela
Age:
45y
Race/Ethnicity: Indian Abd circum :70 cm
Height:
150 cm Weight:
Current Chart
Latest Blood Glucose Values
•
Occupation: School teacher
• A1C: 8.1
•
Diagnosed with T2DM 5 years ago
• FPG: 148 mg/dl
•
Lean
• PPG: 228 mg/dl
•
Currently on 7.5 mg glibenclamide daily
•
Sedentary lifestyle
•
Non proliferative retinopathy
Discussion questions
• What would you do now? Up-titrate GlIB? Add a second agent?
• What other factors would you consider in her treatment?
Not actual patient
52 kg
In addition to diet and exercise
44Version 1.3
Saxagliptin 5 mg Added to a Submaximal Dose of GLIB
Saxagliptin as Add-On Combination Therapy With GLY
Number of Patients
768 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 Therapy
Treatment Arms*
Rescue Protocol
Single-blind, 4-week, diet and exercise lead-in period,
and placed on GlIB 7.5 mg once daily
4 arms: Saxagliptin (2.5 or 5 mg) + 7.5 mg GLIB,
PBO + 10 mg GLIB
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.
In addition to diet and exercise
45Version 1.3
Saxagliptin 5 mg Added to a Submaximal Dose
of GLIB: A1C Results
Percentage of Patients Achieving
A1C <7% at 6 Months
0.2
Saxagliptin 5 mg +
GLIB 7.5 mg (n=250)
Placebo + Up-Titrated
GLIB (n=264)
Mean baseline: 8.5%
Mean baseline: 8.4%
0.0
+0.1%
-0.2
-0.4
-0.6
-0.8
-1.0
–0.6%
P<0.0001 vs placebo
+ up-titrated GLY
100.0
Percentage of Patients (%)
Mean Change From Baseline (%)
Change in A1C at 6 Months*
P<0.05 vs placebo
+ up-titrated GLIB
80.0
60.0
40.0
23%
20.0
9%
0.0
92% of patients in the
placebo + SU group required uptitration to the maximum SU
study dose of 15 mg
*Intent-to-treat population using last observation on study prior to MET rescue therapy.
Saxagliptin 5 mg + Placebo + Up-Titrated
GLIB (n=264)
GLIB 7.5 mg (n=250)
Mean baseline: 8.5%
Mean baseline: 8.4%
In addition to diet and exercise
46Version 1.3
Saxagliptin 5 mg Added to a Submaximal Dose of GLIB:
FPG and PPG Results
Change in 2-Hour PPG†
at 6 Months*
10
Saxagliptin 5 mg +
GLIB 7.5 mg (n=252)
Placebo + Up-Titrated
GLIB (n=265)
Mean baseline: 175 mg/dL
Mean baseline: 174 mg/dL
0
-10
-20
+1 mg/dL
–10 mg/dL
-30
–10 mg/dL
-40
Improvement When
Onglyza 5 mg Added
-50
-60
-70
P<0.05 vs placebo
+ up-titrated GLIB
Mean Change From Baseline (mg/dL)
Mean Change From Baseline (mg/dL)
Change in FPG at 6 Months*
*Intent-to-treat population using last observation on study prior to MET rescue therapy.
†As part of a 3-hour OGTT.
10
Saxagliptin 5 mg +
GLIB 7.5 mg (n=202)
Placebo + Up-Titrated
GLIB (n=206)
Mean baseline: 315 mg/dL
Mean baseline: 323 mg/dL
0
+8 mg/dL
-10
-20
-30
-40
-50
-60
-70
–34 mg/dL
P<0.05 vs placebo
+ up-titrated GLIB
In addition to diet and exercise
47Version 1.3
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 Patients
565 adult patients with T2DM with inadequate
glycemic control on TZD alone
A1C Entry Criteria
7%–10.5%
Duration
24 weeks
Base Therapy
Pioglitazone (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 at least 12 weeks
Lead-In Therapy
Single-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.
In addition to diet and exercise
48Version 1.3
Saxgliptin 5 mg Added to a TZD Provided
Statistically Significant Reductions in FPG and PPG
Change in 2-Hour PPG†
at 6 Months*
Change in FPG at 6 Months*
Saxagliptin 5 mg + TZD
Placebo + TZD
(n=185)
(n=181)
Mean baseline: 160 mg/dL
Mean baseline: 162 mg/dL
10
0
–3 mg/dL
-10
-20
–17 mg/dL
-30
-40
–15 mg/dL
-50
Greater Reduction When
Onglyza 5 mg Added
Mean Change From
Baseline (mg/dL)
Mean Change From
Baseline (mg/dL)
10
Saxagliptin 5 mg + TZD
-60
-70
P<0.05 vs placebo + TZD
*Intent-to-treat population using last observation on study prior to MET rescue therapy.
†As part of a 3-hour OGTT.
Placebo + TZD
(n=134)
(n=127)
Mean baseline: 303 mg/dL
Mean baseline: 291 mg/dL
0
-10
-20
–15 mg/dL
-30
-40
-50
-60
-70
P<0.05 vs placebo + TZD
–65 mg/dL
In addition to diet and exercise
49Version 1.3
Saxagliptin 5 mg Provided Statistically Significant
A1C Reductions When Added to a TZD
Percentage of Patients Achieving
A1C <7% at 6 Months
Mean Change From Baseline (%)
Saxagliptin 5 mg + TZD
0.2
Placebo + TZD
(n=183)
(n=180)
Mean baseline: 8.4%
Mean baseline: 8.2%
0.0
-0.2
–0.3%
-0.4
-0.6
Percentage of Patients (%)
Change in A1C at 6 Months*
80.0
60.0
42%
40.0
–0.9%
P<0.0001 vs placebo + TZD
26%
20.0
0.0
-0.8
-1.0
100.0
Saxagliptin 5 mg + TZD
(n=180)
Mean baseline: 8.4%
Mean baseline: 8.2%
P<0.05 vs placebo + TZD
*Intent-to-treat population using last observation on study prior to MET rescue therapy.
Placebo + TZD
(n=184)
Summary of Efficacy
• Saxagliptin 5 mg provides consistent, clinically meaningful and statistically
significant reductions in
• HbA1c
• FPG
• PPG
• Saxagliptin 5 mg provides significant blood glucose lowering efficacy in
addition to metformin or Sulphonylureas or Thiazolidinediones over 24
weeks
• The addition of saxagliptin 5 mg to metformin provided sustained clinically
meaningful glycaemic improvements over 102 weeks
• Saxagliptin 5 mg also provides significant blood glucose lowering efficacy
in monotherapy and in initial combination with metformin over 24 weeks
Source: Approved India PI
51Version 1.3
Review of Safety and Tolerability
Please see full Indian Prescribing Information available at this presentation.
52Version 1.3
Saxagliptin: Incidence of Adverse Events
Overall Incidence of Adverse Events Was Similar to Placebo
Pooled Analysis of Adverse Reactions
Occurring in ≥5% of Patients and More
Commonly Than Placebo
In Monotherapy and Add-On Therapy Studies*
Percent of Patients
Saxagliptin
5 mg
(N=882)
Placebo
(N=799)
 Adverse reactions reported in ≥2% of
patients treated with Saxagliptin 5 mg
or Saxagliptin 2.5 mg and ≥1% more
frequently compared to placebo,
respectively, included:




Upper
respiratory
tract infection
7.7%
7.6%
Urinary tract
infection
6.8%
6.1%
Headache
6.5%
5.9%
Sinusitis: 2.6% and 2.9% vs 1.6%, respectively
Abdominal pain: 1.7% and 2.4% vs 0.5%
Gastroenteritis: 2.3% and 1.9% vs 0.9%
Vomiting: 2.3% and 2.2% vs 1.3%
 Hypersensitivity-related events (such
as urticaria and facial edema) were
reported in 1.5%, 1.5%, and 0.4% of
patients who received Saxagliptin 5
mg, Saxagliptin 2.5 mg, and placebo,
respectively
*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.
53Version 1.3
Incidence of Adverse Events in Initial
Combination With MET
Adverse Reaction Occurring in ≥5%
Patients and More Commonly Than
MET Plus Placebo
In Initial Combination With MET Study*
Percent of Patients
Saxagliptin
5 mg
+ MET
(N=320)
MET +
Placebo
(N=328)
Headache
7.5%
5.2%
Nasopharyngi
tis
6.9%
4.0%
*Metformin
 In the initial combination with
MET, the overall incidence of
adverse events was 55% for
Saxagliptin 5 mg plus MET
vs 59% for MET plus placebo
was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily.
Jadzinsky M et al. Diabetes Obes Metab. 2009;11:611-622.
54Version 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
There was a dose-related mean decrease in absolute lymphocyte count observed with Saxagliptin
Most Common Adverse Events Associated
With Discontinuation of Therapy*
Percent of Patients
Saxagliptin Saxagliptin
Comparato
5 mg
2.5 mg
r (N=799)
Lymphopenia
Rash
Blood creatinine increase
Blood creatine
phosphokinase increase
*Reported in at least 2 patients treated with Saxagliptin
(N=882)
(N=882)
0.5%
0.3%
0.0%
0.1%
0.2%
0.3%
0.0%
0.3%
0.0%
0.2%
0.1%
0.0%
55Version 1.3
Saxagliptin: Incidence of Hypoglycemia
Incidence of Reported Hypoglycemia
Across Phase 3 Clinical Trials
Percent of Patients
Saxaglipti Saxaglipti
n
n
5 mg
2.5 mg
Comparat
or
Add-On to MET
5.8%
7.8%
5.0%
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%
Saxagliptin Plus GLIB: Incidence of
Hypoglycemia
56Version 1.3
Incidence (%) of Hypoglycemia
Add-on to the SU Glibenclamide study
Saxagliptin 5
mg +
GLIB 7.5 mg
Saxagliptin 2.5
mg +
GLIB 7.5 mg
Placebo +
Up-Titrated
GLIB
0.8%
2.4%
0.7%
Saxagliptin has minimal risk of
14.6% hypoglycemia
13.3%
10.1%
Reported
Hypoglycemia*
Confirmed
Hypoglycemia†
• Use with Medications Known to Cause Hypoglycemia: Insulin
secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a
lower dose of the insulin secretagogue may be required to reduce the
risk of hypoglycemia when used in combination with Saxagliptin
*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.
Pivotal Phase 3 Studies – ST Period Excluding RT
Mean Change from Baseline in Body Weight
at Week 24 (LOCF)
kg
SAXA 2.5 mg
SAXA 5 mg
SAXA 10 mg
PBO
-1.22
-0.05
-0.13
-1.35
Monotherapy
(-011)
(-038)
Saxagliptin
is weight
neutral
-0.3
-0.9
-1.3
Add-on Combination
+ MET (-014)
-1.43
-0.87
-0.53
+ SU (-040)
0.7
0.8
0.3
+ TZD (-013)
1.3
1.4
.9
SAXA 5 mg SAXA 10 mg
+ MET
+ MET
SAXA 10 mg
Initial Combination
with MET (-039)
-1.8
-1.4
-1.1
DeFronzo RA. Diabetes Care. 2009;32:1649-55
Hollander P. J Clin Endocrinol Metab. 2009;94(12):4810-19
Jadzinsky M. Diabetes, Obesity and Metabolism.2009;11:611-22
-0.92
MET
-1.6
58Version 1.3
Add onto Metformin Trial
Most Frequent AEs by Treatment (Week 102)
AEa
SAXA 2.5 mg SAXA 5 mg SAXA 10 mg
+ MET
+ MET
+ MET
n=192
n=191
n=181
Influenza
20 (10.4)
22 (11.5)
23 (12.7)
Nasopharyngitis
25 (13.0)
21 (11.0)
25 (13.8)
PBO
+ MET
n=179
23 (12.8)
19 (10.6)
Bronchitis
12 (6.3)
18 (9.4)
9 (5.0)
11 (6.1)
URTI
23 (12.0)
17 (8.9)
19 (10.5)
14 (7.8)
Headache
26 (13.5)
17 (8.9)
22 (12.2)
20 (11.2)
UTI
19 (9.9)
15 (7.9)
17 (9.4)
12 (6.7)
Back pain
15 (7.8)
15 (7.9)
9 (5.0)
16 (8.9)
Diarrhea
27 (14.1)
14 (7.3)
17 (9.4)
23 (12.8)
aValues
are expressed as n (%).
Five most frequent AEs by dose highlighted.
URTI = upper respiratory tract infection; UTI = urinary tract infection.
59Version 1.3
Warnings and Precautions
 Use with Medications Known to Cause Hypoglycemia: Insulin
secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a
lower dose of the insulin secretagogue may be required to reduce the
risk of hypoglycemia when used in combination with Saxagliptin
 Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction with
Saxagliptin or any other antidiabetic drug
60Version 1.3
Drug Interactions and Use in Specific Populations
Drug Interactions
Saxagloptin should be limited to 2.5 mg when coadministered with a strong
CYP3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and
telithromycin).
Use in Specific Populations
Pregnant and Nursing Women: There are no adequate and well-controlled
studies in pregnant women. Saxagliptin, like other antidiabetic medications,
should be used during pregnancy only if clearly needed. It is not known
whether saxagliptin is secreted in human milk. Because many drugs are
secreted in human milk, caution should be exercised when Saxagliptin is
administered to a nursing woman.
Pediatric Patients: Safety and effectiveness of Saxagliptin in pediatric
patients have not been established.
61Version 1.3
Saxagliptin: Renal safety
 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.
 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.
62Version 1.3
Saxagliptin: Hepatic safety
 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 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

63Version 1.3
Cardiovascular risk factors (in addition to T2D)
Saxagliptin controlled Phase 2b/3 pooled population
Number (%) of subjects
SAXA
2.5 mg
n = 937
SAXA
5 mg
n = 1,269
SAXA
10 mg
n = 1,000
All SAXA3
n = 3,356
Control
n = 1,251
777 (83)
1,015 (80)
803 (80)
2,724 (81)
1,035 (83)
Hypertension
519 (55)
655 (52)
510 (51)
1,750 (52)
688 (55)
Hypercholesterolaemia1
471 (50)
565 (45)
353 (35)
1,475 (44)
566 (45)
Smoking history
383 (41)
449 (35)
393 (39)
1,301 (39)
471 (38)
First degree family
member with premature
coronary heart disease
190 (20)
248 (20)
186 (19)
677 (20)
265 (21)
118 (13)
150 (12)
118 (12)
404 (12)
165 (13)
Subjects with at least one CV
risk factor
in addition to T2D
Patients with
prior CV disease2
SAXA: Saxagliptin; CV: Cardiovascular.
1. Includes mixed dyslipidaemia
2. Prior CV disease defined as previous myocardial infarction, congestive heart failure, hospitalisation for unstable angina, stable
angina, percutaneous coronary intervention, coronary artery bypass graft, coronary artery disease, cerebrovascular disease, peripheral
vascular disease
3. Includes contribution from 20–100 mg saxagliptin in Phase 2b study.
Data on file. AstraZeneca/Bristol-Myers
Squibb Alliance.
64Version 1.3
Cardiovascular events: Saxagliptin controlled
Phase 2b/3 pooled population
Time to onset of first primary Major Adverse Cardiovascular Event (MACE)*
First adverse event (%)
5
4
3
Control
2
1
All saxagliptin
0
0
Patients at risk
Control
1,251
All
3,356
saxagliptin
*
24
37
50
63
76
89
Weeks
102
115
128
935
860
774
545
288
144
123
102
57
2,615
2,419
2,209
1,638
994
498
436
373
197
Primary MACE was defined as was defined as stroke (cerebrovascular accidents), MI, and CV death
Data on file. AstraZeneca/Bristol-Myers Squibb Alliance.
Summary of Efficacy and Safety
 Saxagliptin
 Provides meaningful benefits across key glycemic parameters (HbA1c,
PPG and FPG)
 Provides a favourable safety and tolerability profile (low risk of
hypoglycaemia, no or minimal differences in weight change compared
with control, etc)
 Provides reassurance of CV safety – no CV safety signal has been
identified
 Offers a treatment option with a favourable benefit/risk profile for
people with type 2 diabetes not at glycaemic goal.
Source: Approved India PI
In addition to diet and exercise
66Version 1.3
Convenient Once-Daily Dosing
Dosing Considerations for Saxagliptin
Recommended Dose
or
5 mg once daily 2.5 mg once daily
2.5 mg once daily
Recommended dose
once daily taken
regardless of meals
Moderate-to-severe
renal impairment,
or ESRD requiring
hemodialysis
(CrCl ≤50 mL/min)
Co-administration with
strong CYP3A4/5
inhibitors*
Tablets Not Actual Size.

Taken any time of day, with or without food

24-hour glycemic control

Single, one-step dose adjustment in moderate-
to-severe renal impairment or ESRD requiring
hemodialysis on Saxagliptin 5 mg

Dose of Saxagliptin should be limited to 2.5 mg
when co-administered with a strong CYP3A4/5
inhibitor*

No dosage adjustment based on gender, race,
weight, or hepatic impairment
Saxagliptin has not been studied in patients
undergoing peritoneal dialysis. Assessment
of renal function is recommended prior to
initiation of Saxagliptin and periodically
thereafter
*Such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, ritonavir, saquinavir, and telithromycin.
ESRD= end-stage renal disease
Saxagliptin
can be used for
 Early Intervention
 Early addition
 Sustained comprehensive glycemic control with lower postprandial
glycemic excursions
 Safer: Low hypoglycemic risk & Weight neutral
 Targets all hormonal abnormalities of diabetes pathophysiology
68Version 1.3
Saxagliptin: A Proven Partner for the
Ongoing Struggle With T2DM
 Improved glycemic control by significantly reducing A1C and its key
contributors—FPG & PPG
 Provided significant A1C reductions when partnered with key OAD
agents
 Metformin, Glibenclamide, or a TZD
 Overall incidence of adverse events similar to placebo
 Weight and lipid neutral
 Convenient, once-daily dosing
THANKS
70Version 1.3
Please see full US Prescribing Information available at this presentation
Pharmacology
DPP-8/9 Inhibition and AEs:
No Definitive Conclusions can be Drawn
 A preclinical study in rats and dogs has led to controversy concerning the
possibility of nonselective inhibition of DPP-8/9 enzymes increasing the
potential for AEs1
 Subsequent preclinical studies offered contradictory evidence, thus there is
no conclusive evidence of a relationship between DPP-8/9 inhibition and AEs
in animals2,3
 DPP-8/9 are widely expressed enzymes. Research in animal cell models
indicate localization in the digestive and immune systems4
 Given contradictory animal data, limitation of extrapolating animal data to
humans, and the limited clinical data, no definitive conclusions can be drawn
about a link between AEs and DPP-8/9 inhibition in humans5
1.
2.
3.
4.
5.
AE=adverse event; DPP=dipeptidyl peptidase.
Lankas GR et al. Diabetes. 2005;54:2988-2994.
Burkey BF et al. Diabetes Obes Metab. 2008;10:1057-1061.
Rosenblum JS et al. Poster presented at: American Diabetes Association; June 22-26, 2007; Chicago, IL.
Yu DMT et al. J Histochem Cytochem. 2009. doi:10.1369/jhc.2009.953760.
Barnett A. Int J Clin Pract. 2006;60(11):1454-1470.
 What Effect Does Saxagliptin Have on
Lymphocyte Counts and Infection
Rates?
Changes in Lymphocyte Counts With
Daily Dosing of Saxagliptin
• Mean baseline absolute lymphocyte count: ~2200 cells/µL
Change from Baseline in Absolute Lymphocyte Counts (%)
2 Placebo-Controlled
Trials*
Lymphocyte Percent Changes
From Baseline (%)
5 Placebo-Controlled Trials
10
Saxagliptin 5 mg
Placebo
5
0
-5
Weeks
-10
BL 6 12
24
37
50
63
76
89
102
115
128
• There was a dose-related mean decrease in absolute lymphocyte count
observed with saxagliptin
* From Weeks 76 to 128, the two placebo-controlled trials included Fixed-Dose Monotherapy and Add-On to Metformin.
Data combine short-term data (Week 24) and the most recently assessed long-term data (Week 128).
Bristol-Myers Squibb Company. NDA 22-350. Available
at:http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148109.pdf. Published March 2, 2009. Accessed March 10, 2010.
Adverse
Reactions
Adverse Events: Lymphocyte and Infections
 Decreases in lymphocyte count were not associated with clinically
relevant adverse reactions1,2
 Clinical significance of this decrease in lymphocyte count relative
to placebo is not known1,2
 No difference in pattern of infection-related AEs for saxagliptin-
treated subjects with lymphocyte count decreases as compared
with saxagliptin-treated subjects in the overall population2
 The effect of saxagliptin on lymphocyte counts in patients with
lymphocyte abnormalities (eg, human immunodeficiency virus) is
unknown1
AE=adverse event.
1. Onglyza [package insert]. India.
2. Bristol-Myers Squibb Company. NDA 22-350. Available at:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148109.pdf. Published March 2, 2009. Accessed Mar 10,
2010
 What Skin-Related Adverse Events
Have Been Seen With Saxagliptin
Treatment?
Nonclinical Toxicology
Adverse
Reactions
 Saxagliptin produced adverse skin changes in the extremities of
cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum,
and/or nose)
 Skin lesions were reversible at >20 times the MRHD but in some cases
were irreversible and necrotizing at higher exposures
 Adverse skin changes were not observed at exposures similar to
(1 to 3 times) the MRHD of 5 mg
 Clinical correlates to skin lesions in monkeys have not been observed in
human clinical trials of saxagliptin
MRHD=maximum recommended human dose.
Source: Approved India PI
 What is the Effect of Saxagliptin on
the Incidence of Pancreatitis?
Adverse Reactions
Adverse Events of Pancreatitis in the Phase IIb/III
Pooled Population1,2
Saxagliptin 2.5
mg*
n=937
All AEs of
Pancreatitis║
Saxagliptin 5
mg*
n=1269
Saxagliptin 10
mg†
n=1066
All
Saxagliptin‡
n=3422
Comparator§
n=1251
1 (0.1%)
3 (0.2%)
2 (0.2%)
6 (0.2%)
2 (0.2%)
Pancreatitis PT
0
2 (0.2%)
1 (0.1%)
3 (0.1%)
1 (0.1%)
Acute
Pancreatitis PT
0
1 (0.1%)
1 (0.1%)
2 (0.1%)
0
Chronic
Pancreatitis PT
1 (0.1%)
0
0
1 (<0.1%)
1 (0.1%)
 Of the six patients with pancreatitis in the saxagliptin treatment groups, five patients had at least one
known risk factor for pancreatitis (alcohol use, cholelithiasis, prior history of hypertriglyceridemia, or
prior history of pancreatitis). One patient, in the saxagliptin
5 mg + MET group, had no known risk factors for pancreatitis
*
Includes subjects who were later uptitrated in the monotherapy dose-regimen study.
Includes the Open Label cohort in the monotherapy fixed-dose study.
‡
Includes data from higher dose groups in the Phase IIb dose-ranging study; therefore, numbers across the rows are not additive.
§
Combined placebo groups from all Phase IIb/III studies, including the MET monotherapy group from the initial combination with MET study.
║
Includes rescue therapy.
AE=adverse event; PT=preferred term; MET=metformin.
Data combine short-term data (24 weeks) and the most recently assessed long-term data. Long-term phase for each study varies from 2 to 4 years.
1. Bristol-Myers Squibb Company-AstraZeneca. Saxagliptin BMS-477118. Part Two. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM149589.pdf. Published May 8 2009. Accessed November 05, 2009.
2. Bristol-Myers Squibb Company. NDA 22-350. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148109.pdf. Published March 2, 2009. Accessed November 5, 2009.
†
422US09PSM41201
278438
Dermatological safety –overview
 Multi-focal reversible skin lesions (erosions and ulcers) observed in
cynomolgus monkeys exposed to saxagliptin
 Phase 3 safety monitoring included investigator training, supplemental data
collection with special case-report forms
 Analyses performed based on pre-defined Medical Dictionary for Regulatory
Activities (MedDRA) preferred terms similar to non-clinical findings in monkeys
 Terms included skin ulcer, erosion, and necrosis
 Events infrequent – none led to study drug discontinuation
 None considered to be related to study drug
 Based on the clinical programme, no evidence was observed for human
clinical data correlating to monkey skin findings
Saxagliptin, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting:
NDA 22-350. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. Accessed:
Mar 10, 2010.
Lymphocyte count analyses – overview
 Dose-dependent reductions in lymphocyte count were observed in Phase 1 and
2b studies at higher doses
 In Phase 3 studies, a small dose-dependent reduction in mean absolute
lymphocyte count was observed with the
5 and 10 mg doses
 Decline with 5 mg dose approximately 100 c/µL relative to PBO from
baseline mean lymphocyte count of approximately 2200 c/µL
 Decreases were non-progressive with daily dosing of saxagliptin up to 128
weeks
 Lymphocyte decreases not associated with clinical adverse consequences
 In subjects with low lymphocyte counts, the types of infections observed
were similar to those in the general population (i.e. no unusual
opportunistic infections)
 Comparable infection-related AE rates were observed for saxagliptin 5 mg
and placebo without signal for opportunistic events in the overall population
Saxagliptin, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting:
NDA 22-350. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. Accessed:
Mar 10, 2010
Saxagliptin 5 mg as Recommended Usual
Clinical Dose
 Consistent efficacy benefit observed for saxagliptin 5 mg versus 2.5 mg as
monotherapy, and add-on treatment (MET, TZD, SU)

Results consistent with observations of greater DPP4 inhibition at
trough with 5 mg versus 2.5 mg dose
 No evidence for incremental efficacy benefit for 10 mg versus 5 mg dose
in key glycemic parameters
 Given the comparable safety profile of the 2.5 and 5 mg doses, saxagliptin
5 mg is the proposed usual clinical dose
Source: Approved India PI
Difference from Placebo in Adjusted Mean
Change from Baseline in A1C
Phase 2b/3 Monotherapy Studies
Post-hoc Pooled Analysis (Wk 12)
Pooled
SAXA
2.5 mg
Pooled
SAXA 5
mg
0.0
 A1C (%) with 95%
CI
SAXA + MET
(014)
2.5 mg 5 mg
SAXA + TZD
(013)
2.5 mg 5 mg
SAXA + SU
(040)
2.5 mg 5 mg
0.0
-0.2
-0.2
-0.4
-0.6
Phase 3 Add-on Combination Studies
ST Period (Wk 24)
-0.4
-0.36
-0.51
-0.61
-0.6
-0.63
-0.8
-0.8
-0.72
-0.73
-0.83
-1.0
-1.2
Source: Approved India PI
-1.0
-1.2
-0.62