Saxagliptin and evidence, Medical slides, efficacy, safety and trials

1. Saxagliptin usage in T2DM: focus on CV and Renal effects

2. After a two year visit to the United States , Michelangelo's
David is returning to Italy . . .

3. His Proud Sponsors were:

4. MR. HP
 46-year-old machinist
 Shift worker
 Diagnosed with T2DM 3 years ago
 Current medications: metformin 1000 mg bid,
telmisartan 80mg, amlodipine 10 mg, HCTZ 25 mg,
atorvastatin 20 mg, rabeprazole 20 mg
 History of hypertension, hypercholesterolemia and
gastric reflux
 Has private drug plan

5. MR. HP: EXAMINATION
 BP: 135-80; HR 80
 BMI: 32
 Weight: 93.4 kg, obese
 Mild edema 1+
 Mild non-proliferative retinopathy

6. MR. HP: LAB RESULTS
 A1C = 9.6%
 eGFR > 60 mL/min
 FPG: 10.4 mmol/L
 Total Cholesterol = 4.8 mmol/L
 HDL = 0.8 mmol/L
 Triglycerides = 5.1 mmol/L
 ACR = 4.7 mg/mmol

7. DIABETIC COMPLICATIONS
Stroke
2- to 4-fold increase in
cardiovascular mortality
and stroke3
Cardiovascular
Disease
8/10 diabetic patients
die from CV events4
Diabetic Neuropathy
Leading cause of non-
traumatic lower
extremity amputations5
Diabetic
Retinopathy
Leading cause of
blindness in working-
age adults1
Diabetic
Nephropathy
Leading cause of
end-stage renal
disease2
1. Fong DS et al. Diabetes Care 2003;26(Suppl 1):S99-S102. 2. Molitch ME et al. Diabetes Care 2003;26 (Suppl 1):S94-S98. 3. Kannel WB et al. Am J Heart 1990;120:672-6.
4. Gray RP and Yudkin JS. In: Textbook of Diabetes. 1997. 5. Mayfield JA, et al. Diabetes Care 2003;26(Suppl 1):S78-S79.

8. INDIVIDUALIZING A1C TARGETS
Adapted from CDA Guidelines 2013
> 7%
≤ 7%
6.0%
MOST PATIENTS
WITH TYPE 1
AND TYPE 2
DIABETES
Consider 7.1-8.5% if:
• Limited life expectancy
• High level of functional dependency
• Extensive coronary artery disease at high risk
of ischemic events
• Multiple co-morbidities
• History of recurrent severe hypoglycemia
• Hypoglycemia unawareness
• Longstanding diabetes for whom it is difficult to
achieve an A1C ≤ 7%, despite effective doses of
multiple anthyperglycemic agents, including
intensified basal-bolus insulin therapy
A target A1C ≤ 6.5% may
be considered in some
patients with type 2
diabetes to further lower
the risk of nephropathy
and retinopathy which
must be balanced
against the risk of
hypoglycemia
8.5%
7%

9. SU
GLP1
TZD
DPP4
Insulin
Glucosidase
Inhibitor
Orlistat
Now we have choices - What next?
SGLT2

11. DURABILITY WITH SU THERAPY?
Adapted from Defronzo RA.. Diabetes 2009;58(4):773-95.
Time (years)
-2
-1
0
1
Change
in
A1C
(%)
0 1 2 3 4 5 6 10
Hanefeld (n=250)
Tan (n=297)
Chicago (n=230)
ADOPT (n=1,441)
UKPDS (n=1,573)
PERISCOPE (n=181)
Glimepiride
Glyburide Glyburide
Glyburide
Gliclazide
Glyburide

12. Network Meta-analysis Comparing Antihyperglycemic Drugs as Add-on to Metformin:
Results Compared to Placebo
Change in A1C (%)
Change in Body
Weight (kg)
Overall
Hypoglycemia
Mean
Diff.
Mean
Diff.
OR
Sulfonylureas -0.82* 2.17* 8.86*
Meglitinides -0.71* 1.40* 10.51*
TZDs -0.82* 2.46* 0.45
AGIs -0.66* -1.01* 0.40
DPP-4 Inhibitors -0.69* 0.23 1.13
GLP-1R agonists -1.02* -1.66* 0.92
Basal insulin -0.88* 1.38* 4.77*
Premixed insulin -1.07* 3.41* 17.78*
* significant vs PBO
Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820. 12

13. Network Meta-analysis Comparing Antihyperglycemic Drugs as Add-on to Metformin:
Results Compared to Placebo
Change in A1C (%)
Change in Body
Weight (kg)
Overall
Hypoglycemia
Mean
Diff.
Mean
Diff.
OR
Sulfonylureas -0.82* 2.17* 8.86*
Meglitinides -0.71* 1.40* 10.51*
TZDs -0.82* 2.46* 0.45
AGIs -0.66* -1.01* 0.40
DPP-4 Inhibitors -0.69* 0.23 1.13
GLP-1R agonists -1.02* -1.66* 0.92
Basal insulin -0.88* 1.38* 4.77*
Premixed insulin -1.07* 3.41* 17.78*
* significant vs PBO
Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820. 13

14. Network Meta-analysis Comparing Antihyperglycemic Drugs as Add-on to Metformin:
Results Compared to Placebo
Change in A1C (%)
Change in Body
Weight (kg)
Overall
Hypoglycemia
Mean
Diff.
Mean
Diff.
OR
Sulfonylureas -0.82* 2.17* 8.86*
Meglitinides -0.71* 1.40* 10.51*
TZDs -0.82* 2.46* 0.45
AGIs -0.66* -1.01* 0.40
DPP-4 Inhibitors -0.69* 0.23 1.13
GLP-1R agonists -1.02* -1.66* 0.92
Basal insulin -0.88* 1.38* 4.77*
Premixed insulin -1.07* 3.41* 17.78*
* significant vs PBO
Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820. 14

15. DPP-4 INHIBITORS

16. Insulin Glucagon
GLP-1
Incretin

17. Incretin Hormones
GLP-1 = glucagon-like peptide-1
α-Cell
 Glucagon
β-Cell
 Insulin
Pancreatic
Islet
Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940; and Wang Q, et al. Diabetologia.
2004;47(3):478-487.
GLP-1
Incretin
DPP4

18. Saxagliptin efficacious across patient types
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Mono plus Met plus SU plus TZD plus INS
%
HbA1c
Drop
from
baseline

19. -3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
A1c<8% A1c 8-9% A1c 9-10% A1c >10%
%
HbA1c
Drop
from
baseline
Saxagliptin efficacious across HbA1c
levels*
* When Saxagliptin in used with metformin as initial combination

20. Impact of treatment with
saxagliptin on glycemic
stability and β-cell function in
the SAVOR-TIMI-53 study
1Hadassah University Hospital, Jerusalem, Israel; 2TIMI Study Group, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3AstraZeneca Research and
Development, Wilmington, DE, USA; 4Bajcsy-Zsilinszky Hospital, Budapest, Hungry;
5Taichung Veterans General Hospital, Taiwan; 6Hospital Universitario La Paz, Bolivia
Presented at the 74th Scientific Sessions of the American Diabetes Association (ADA), San
Francisco, CA, USA, June 13–17, 2014
G Leibowitz,1 O Mosenzon,1 DL Bhatt,2 B Hirshberg,3 C
Wei,3 A Cahn,1 G Jermendy,4 W H-H Sheu,5 JL
Sendon,6 BM Scirica,2 I Raz1
126-LB

21. Glycemic instability Definition
1. HbA1C increase ≥0.5% post-randomization,
2. Initiation of new anti-diabetic medications for ≥3 months, or
3. Increase in dose of oral anti-diabetic medication or ≥25% increase in
insulin dose for ≥3 months.
β-Cell function was assessed by calculating fasting HOMA-2β at baseline and at
year 2 in patients not treated with insulin

22. 23.7
5.5
29.3
7.8
0
5
10
15
20
25
30
35
Change in Additional Antidiabetic Therapies
22
Addition/increase in
antihyperglycemic medication
Initiation of insulin therapy
for >3 months
Patients
Changing
Therapy
(%)
P<0.001
P<0.001
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
Saxagliptin Placebo

23. Saxagliptin reduces glucose instability compare to standard
anti-diabetic therapy
-40
-35
-30
-25
-20
-15
-10
-5
0
Glycemic Instability A1c worsening
Risk reduction compare to Placebo
P<0.0001

24. Saxagliptin effects on fasting HOMA-2β
-5
-4
-3
-2
-1
0
1
2
Standard Care Saxagliptin
Changes in HOMA
P<0.0001

25. Results
25

26. Take Home
• Compared to placebo, treatment with saxagliptin improved glycemic
indices and attenuated glycemic instability over time, irrespective of
baseline anti-hyperglycemic regimens.
• Saxagliptin minimized the deterioration of β-cell function observed in
placebo-treated patients; in patients not taking any oral anti-diabetic
drugs or when added to other oral anti-diabetic drugs.
• These findings suggest that inhibition of DPP-4 with saxagliptin may
slow the natural progression of T2D, as reflected by a slower decline in
β-cell function.
26

27. AZT-ONGL-11001
ON-SL-TW1105002
Sustainable - Saxagliptin added to metformin
102 Weeks: HbA1c mean change from baseline
Baseline HbA1c: 8.0 - 8.1%
Diabetes duration: 6.3 - 6.7 years
0.0
-0.4
-0.2
0.4
0.2
-0.6
HbA
1c
(%)
Mean
Δ
From
BL±SE
BL 4 8 20
12 30 37 50 63 76 89 102
Weeks
Patients:
SAXA 5mg + MET
PBO + MET
191
179
146
111
116
72
99
60
25
15
89
52
70
33
58
25
PBO + MET
SAXA 5mg + MET
DeFronzo RA, et al. Diabetes. 2009; 58 (suppl 1):A147, Abstract 547

29. 2007
2007
Safety Concerns About Antihyperglycemic Agents

30. 6 million patients using it

32. Phung OJ, et al. Diabetic Medicine 2013;30:1160-1171.
In a meta-analysis of 33 studies (12 RCTs, 17 cohort, 4 case-control) representing 1,345,446 patients, SUs
were associated with a significantly increased risk of CV death and of a CV composite compared with
other oral diabetes drugs
n = the total number of comparisons for that analysis one study may contribute more than one comparison to
the analysis CV composite = MI, stroke, CV-related hospitalization or CV death
SUs May Increase CV Risk in Patients with T2D: Meta-analysis of 33 Studies
32

33. FDA Guidance for Industry to Evaluate CV Risk
in New Antihyperglycemic Medications1
• July 2008: In order to establish the safety of a new antihyperglycemic medication to
treat T2DM, FDA’s Endocrinologic and Metabolic Drugs Advisory
Committee provided guidance on risk assessment
– Effects on CV risk to be more thoroughly addressed during antihyperglycemic medication
development
– Recommendation to demonstrate that therapy will not result
in unacceptable increase in CV risk
– Key areas to be addressed by study sponsors (inclusion of patients with a higher risk of CV events
[eg, patients with advanced
CV disease, elderly patients, and patients with impaired renal function], study duration ≥2 years)
1- Center for Drug Evaluation and Research. Guidance for Industry:
Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. December 2008.
http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed September 12, 2014.
T2DM = type 2 diabetes mellitus; CV = cardiovascular.

34. Non-Inferiority Comparison
Standard of Care (Placebo)
New Drug

35. Non-Inferiority Comparison
Standard of Care (Placebo)
New Drug

36. Type 2 Diabetes: UKPDS

37. A1C Same

38. Ongoing CV Outcome Trials:
DPP-4 Inhibitors
•Adapted from:
1. Golden SH. Am J Cardiol 2011; 108(Suppl):59B-67B. 2. Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B. 3.
www.clinicaltrials.gov
Trial Therapies # Population Primary endpoint End Date
EXAMINE Alogliptin/Pl
acebo
5400 ACS 15-90 days
before
Non-inferiority: time to
occurrence of MACE
PUBLISHED
SAVOR Saxagliptin/
Placebo
16,500 CVD or ≥ 2 RF Superiority efficacy,
non-inferiority safety:
composite CV death, NF
MI, NF stroke
PUBLISHED
CARMELINA Linagliptin/P
lacebo
8,300 High risk of CV
events
Time to first occurrence of
composite CV outcome
Jan 2018
CAROLINA Linagliptin/
Glimepiride
6000 CVD or ≥ 2 RF Non-inferiority: time to
first occurrence of any
component of MACE
composite outcome
Sept 2018
TECOS Sitagliptin/
Placebo
14,000 Established CVD Non-inferiority: time to
first occurrence of
composite CV outcome
Dec 2014

39. SAVOR-TIMI 53, EXAMINE, TECOS & ELIXA
ACS, acute coronary syndrome; CVD, cardiovascular disease; ELIXA, Evaluation of LIXisenatide in Acute Coronary Syndrome;
EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; MI, mhyocardial infarction;
R, randomization; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus –Thrombolysis in Myocardial Infarction 53; TECOS, Trial Evaluating
Cardiovascular Outcomes with Sitagliptin; UA, unstable angina.
SAVOR-TIMI 53: Scirica BM et al. N Engl J Med. 2013;369:1317-26; EXAMINE: White WB et al. N Engl J Med. 2013;369:1327-35; TECOS: Bethel MA et al. Diabetes Obes Metab. 2015;17:395-402;
TECOS: Green JB et al. N E J Med .2015 doi: 10.1056/NEJMoa1501352; ELIXA: Bentley-Lewis R et al. Am Heart J. 2015;169:631-638.; Pfeffer MA et al. The Evaluation of Lixisenatide in Acute
Coronary Syndrome — The Results of ELIXA. American Diabetes Association, 75th Scientific Sessions, June 5 – 9, 2015, Boston, MA.
Median Duration of Follow-up
CV death, Nonfatal MI,
Nonfatal stroke, or UA
requiring hospitalization
Randomization Up to Year 4
Year 3
Year 2
Year 1
R
Saxagliptin
Placebo
6.5–12.0
A1C , % Primary End point
Duration of Treatment
(as part of usual care)
CV death, Nonfatal MI,
Nonfatal stroke, or UA
requiring hospitalization
CV death, Nonfatal MI, or
Nonfatal stroke
CV death, Nonfatal MI, or
Nonfatal stroke
Established CVD
and/or multiple risk factors
ACS within
15 to 90 days
ACS within
180 days
Preexisting CVD
R
Alogliptin
Placebo
6.5–11.0
R
Sitagliptin
Placebo
6.5–8.0
R
Lixisenatide
Placebo
5.5-11.0
Median
2.1 years
Median
1.5 years
Median
2.1 years
Median
3.0 years

40. SAVOR1,2 TECOS3 EXAMINE4,5
DPP-4i Saxagliptin Sitagliptin Alogliptin
Study size 16,492 14,671 5380
Mean age 65.1 66 61
Duration of
diabetes
10.3 years 11.6 years 7.2 years
Follow-up period 2.1 years 3.0 years 18 months
HbA1C Baseline
6.5 – 12% 6.5 - 8% 6.5 - 11%
Baseline use of
Insulin
41% 23%
Insulin was included after a
protocol change
30%
Mean eGFR 72.5 mL/min
> 50 mL/min: 84.4% (13,916)
30-50 mL/min: 13.6% (2,240)
<30 mL/min: 2.0% (336)
74.9 mL/min
eGFR <30 mL/min as
baseline exclusion
criteria.
71.2 mL/min
≥60 mL/min: 71% (3,815)
<60 mL/min: 22.5%
(1,565)
DPP-4i Cardiovascular Outcomes Trials
1. Mosenzon O, et al. Diabetes Metab Res Rev 2013; 29:417–426; 2. Scirica BM, et al. N Engl J Med 2013;369:1317–1326;
3. Green JB, et al. New Engl J Med 2015; E-pub ahead of print; 4. White WB, et al. N Engl J Med 2013;369:1327–1335;
5. Zannad F, et al. Lancet 2015;385:2067–2076

41. DPP-4i Cardiovascular Outcomes Trials
1. Mosenzon O, et al. Diabetes Metab Res Rev 2013; 29:417–426; 2. Scirica BM, et al. N Engl J Med 2013;369:1317–1326;
3. Green JB, et al. New Engl J Med 2015; E-pub ahead of print; 4. White WB, et al. N Engl J Med 2013;369:1327–1335;
5. Zannad F, et al. Lancet 2015;385:2067–2076
ACS, acute coronary syndrome; CHF, congestive heart failure; CV, cardiovascular; hHF, hospitalization for heart failure; MACE, major adverse cardiovascular events; MI, myocardial infarction; UA,
unstable angina;
SAVOR1,2 TECOS3 EXAMINE4,5
Baseline CV risk
factors
Primary and secondary
prevention
1/3 multiple risk factors
2/3 established CV disease
Secondary prevention
only, pre-existing
vascular disease
Secondary
prevention only, ACS
15–90 days prior to
randomization
Primary composite
endpoint
CV death, non-fatal MI,
non-fatal stroke
CV death, non-fatal MI,
non-fatal stroke, UA
requiring hospitalization
CV death, non-fatal
MI, non-fatal stroke
Secondary
composite endpoint
or single secondary
endpoints
1.Primary endpoint + hosp.
for UA, hosp. for revasc.,
or hHF
2. All-cause mortality
1.Composite of MACE
2. Individual components
of primary endpoint
3. All-cause mortality
4. Hosp. for CHF
Primary endpoint +
hosp. for urgent
revasc. due to UA

42. Representativeness of DPP-4i Cardiovascular Outcomes Trials
Peters AL, et al. Presented at the American Diabetes Association 75th Scientific Sessions, Boston, MA, 5–9 June 2015
NHANES, National Health and Nutrition Examination Survey
4.26%
21.36%
4.48%
8.95%
0.17%
0
5
10
15
20
25
30
TECOS SAVOR CAROLINA CARMELINA EXAMINE
%
of
T2DM
Patients
Eligible
CVOT
Analysis of the US NHANES database

43. Still comparisons cant be avoided
Parameter SAVOR TECOS
CV safe- primary endpoint CV
death, MI Stroke
Non Inferiority proven
CV Superiority- Not achieved
Hospitalization for Heart Failure Signal found No concern
Acute Pancreatitis No concern Signal found
Changes in Renal function
parameter
Renal Safe/ May be reno-
protective
Safe or may harm?
Reduction in eGFR
Requirement of additional drugs Significantly reduces requirement for new drug or up-
titrating drug

44. DPP4i and hHF: how much is the concern?

45. SAVOR-TIMI 53
Temporal Rates for Hospitalization for Heart
Failure
HR =, hazard ratio; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus –Thrombolysis in
Myocardial Infarction 53.
Scirica BM et al. Circulation. 2014;130(18):1579-88.
Saxagliptin Placebo
4%
3%
2%
1%
0%
0
Hospitalization
for
Heart
Failure
(%)
180 360 540 720
0.6%
1.1%
1.3%
Placebo
Saxagliptin
4959
4978
7389
7375
7856
7867
8036
8064
8212
8280
Days from Randomization
1.9%
2.8%
3.5%
(1.07-1.51)
P=0.007
HR 1.27
(1.29-1.55)
P=0.001
HR 1.80 (1.15-1.88)
P=0.002
HR 1.46

46. 46
Events 2.8% per year
N= 12000
Events =1040
5 years – min 3 yrs follow up
(Am Heart J 2011;162:818-825.e6.)

47. 47
Events 2.8% per year
N= 12000
Events =1040
5 years – min 3 yrs follow up
Events 2.1% per year
N= 11,314
Add 4500 Only CV Disease Patient
N=16492
Stopped 2 years
Event Rate 7.3% for 2 years
Event Rate 3.65% per year

48. Italy database: 282 000 patients treated with antidiabetic drugs:
• New Heart Failure (HF): 7212
• Hospitalisations for HF: 14 613
• Hospital re-admissions: 1727
Conclusions: DPP-4i is not associated with an increased risk of HF

49. Risk of Hospitalization for Heart Failure with Dipeptidyl
Peptidase-4 Inhibitors vs. Sulfonylureas and with
Saxagliptin vs. Sitagliptin in a U.S. Claims Database
Alex Z. Fu, PhD1, Stephen S. Johnston, MA2, John Sheehan, PhD, RPh3,
Ameen Ghannam, PhD3, Katherine Tsai, PhD, MPH4,
Katherine Cappell, PhD2, Robert Fowler, MS2, Iftekhar Kalsekar, PhD3
1Georgetown University Medical Center
2Truven Health Analytics
3AstraZeneca
4MedImmune
Presented at the 75th Scientific Sessions of the American Diabetes
Association, Boston, MA, June 5–9th, 2015
164-LB

50. Patient Characteristics: Saxa and Sita Cohorts after Propensity Score
Matchinga (1 of 2)
Baseline CVD No Baseline CVD
SAXA
N=13 042
SITA
N=13 042
SAXA
N=43 402
SITA
N=43 042
Age, yrs, mean (SD) 63.2 (11.3) 63.3 (11.4) 54.8 (10.7) 54.9 (10.8)
Male, % 61.4 61.2 54.1 54.1
Hospitalization in 30 days pre-index, % 3.9 3.6 0.7 0.6
Hospitalization in 31–365 days pre-index, % 20.7 20.1 3.9 3.9
Cardiologist visit during baseline, % 64.1 64.4 8.5 8.5
CKD (excluding ESRD), % 6.2 6.4 1.9 1.9
ESRD, % 5.2 5.2 0.9 0.9
Hyperlipidemia or lipid disorder 58.1 57.8 45.4 45.3
Hypertension, % 75.9 76.2 55.9 55.7
Microvascular complications of diabetes, %
Nephropathy
Peripheral neuropathy
Retinopathy
4.4
14.5
9.5
4.4
14.1
9.2
2.2
7.2
6.2
2.2
7.3
6.2
Heart failure, % 12.0 11.9 0.0 0.0
Hospitalized heart failure, % 1.0 1.1 0.0 0.0
Fu A, et al. ADA 2015 Poster 164-LB
aMean range (absolute) value of the standardized differences for all listed covariates was: 0.48% (0% to 1.5%) for patients with baseline CVD;
0.34% (0% to 1.2%) for patients with no CVD
CKD, chronic kidney disease; CVD, cardiovascular disease; ESRD, end stage renal disease; SAXA, saxagliptin; SD, standard deviation; SITA,
sitagliptin

51. Patient Characteristics: Saxa and Sita Cohorts after Propensity Score
Matchinga (2 of 2)
Baseline CVD No Baseline CVD
SAXA
N=13 042
SITA
N=13 042
SAXA
N=43 402
SITA
N=43 042
Acute myocardial infarction, % 3.6 3.5 0.0 0.0
Other ischemic heart disease, % 54.3 54.6 0.0 0.0
Other heart disease, % 57.2 57.5 0.0 0.0
Stroke (narrow), % 1.2 1.1 0.0 0.0
Stroke (broad), % 16.9 16.5 0.0 0.0
Peripheral artery disease, % 10.5 10.5 0.0 0.0
Coronary revascularization procedures, %
Coronary artery bypass graft
Percutaneous coronary intervention
1.3
4.3
1.2
4.2
0.0
0.0
0.0
0.0
Medication use (180 days pre-index)
Any anti-diabetes medication, %
Number of anti-diabetes medication classes, mean (SD)
Any anti-hypertensive medication, %
Lipid-lowering medications, %
Digoxin (cardiac glycoside)
83.6
2.5 (0.9)
88.1
76.5
5.0
83.7
2.5 (0.9)
88.1
76.6
5.2
81.6
2.5 (0.8)
71.4
60.7
0.3
81.4
2.5 (0.8)
71.8
60.7
0.3
Fu A, et al. ADA 2015 Poster 164-LB
aMean range (absolute) value of the standardized differences for all listed covariates was: 0.48% (0% to 1.5%) for patients with baseline CVD;
0.34% (0% to 1.2%) for patients with no CVD
CVD, cardiovascular disease; SAXA, saxagliptin; SD, standard deviation; SITA, sitagliptin

52. hHF Hazard Ratios for for Saxagliptin Relative to Sitagliptin
Fu A, et al. ADA 2015 Poster 164-LB CI, confidence interval; CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; hHF, hospitalization for heart failure; SU, sulfonylurea

53. Composite Cardiovascular Outcomea Hazard Ratios for or Saxagliptin
Relative to Sitagliptin
Fu A, et al. ADA 2015 Poster 164-LB
aComposite of hospitalization for acute myocardial infarction, hospitalization for stroke, hospitalization for unstable angina, coronary
revascularization, and hHF
bReference category for hazard ratio; hazard ratio <1 indicates lower risk for DPP-4i or saxagliptin
CI, confidence interval; CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; hHF, hospitalization for heart failure; SU, sulfonylurea

54. • What about Renal Protection?

55. What is Renal safety?
1. Renal Safety: Drug which will not harm kidney i.e. increasing S.Cr. or
reducing eGFR
2. Dose Flexibility: Drug which is excreted by Kidney, dose needs to be
adjusted. Drug excreted via non-renal route dose adjustment is not required.
No correlation to renal safety
3. Reno-Protection: Drug which protect Kidney by improving renal parameters
i.e. reducing proteinuria, improving ACR or eGFR etc.

56. STAGES OF DIABETIC NEPHROPATHY
Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(S1):S1-S212.
Note: change in definition of microalbuminuria
ACR ≥2.0 mg/mmol
2013
56

57. 57
Is Albuminuria Preventable?
IRMA-2
RENAAL
IDNT
Ruggenenti P, et al. N Engl J Med 2004; 351: 1941-51.
ADA. Diabetes Care 2004; 27(Suppl. 1): S79-S83.
ESRD
Normoalbuminuria Macroalbuminuria
Microalbuminuria
20-199 200
UAE (µg/min) <20 >
_

58. 58
What We Know: Glycemic Control
Prevents Microvascular Complications
Percent reduction compared with control
0 10 20 30 40 50 60 70 80
ADVANCE
Major Micro
Renal
Eye
ACCORD
Microalbumin
Macroalbuminuria
Retinopathy 3-step
UKPDS
Metformina
Insulin/SUa
Final A1C values
6.5% vs. 7.3%
6.4% vs. 7.5%
7.0% vs. 7.9%
*
aUKPDS results shown are for cumulative microvascular endpoints (renal failure or death; vitreous hemorrhage; retinal photocoagulation)
in the respective treatment arms of the glucose control study.
*Statistically significant.
*
*
*
*
*

59. SAVOR patient as per GFR categories
16492
Total population
GFR>50
N= 13916
GFR 30-
50ml/min
N= 2240
GFR<30 ml/min
N= 336
Udell JA et al. Diabetes Care; DOI: 10.2337/dc14-1850
GFR: Glomerular filtration rate

60. Does Saxagliptin improve renal outcome in
CKD patients? Results from SAVOR study
Jacob A. Udell et al; Saxagliptin in DM Patients and Renal Impairment; Diabetes Care, DOI: 10.2337/dc14-1850,
published online January 12, 2015
775
94
547
134
758
73
519
166
0
100
200
300
400
500
600
700
800
900
Total Improved No Change Worsened
Saxagliptin Placebo
5380
559
4139
682
5241
448
4008
790
0
1000
2000
3000
4000
5000
6000
Total Improved No Change Worsened
Saxagliptin Placebo
110
17
76
17
96
11
72
13
0
20
40
60
80
100
120
Total Improved No Change Worsened
Saxagliptin Placebo
eGFR >50 mL/min/1.73 m2
eGFR 30-50 mL/min/1.73 m2 eGFR <30mL/min/1.73 m2
p <0.0001
p= 0.61 (NS)
p =0.037
(n= 1,533)
(n= 10,621)
(n= 206)
Frequency of progressive
microalbuminuria by completion of
follow-up according to renal function
(n=12,360)

61. 11.8
11.1
10.7
9.6
9.2
8.7
0
2
4
6
8
10
12
14
16
18
Year 1 Year 2 End of treatment
9.4
12.4
13.3
11.4
14.2
15.9
0
2
4
6
8
10
12
14
16
18
Year 1 Year 2 End of treatment
Changes in Microalbuminuria
61
Worsening* microalbuminuria Improved* microalbuminuria
Patients
With
Worsening
Microalbuminuria
(%)
Patients
With
Improved
Microalbuminuria
(%)
Saxagliptin
Placebo
*Treatment difference in the number and proportion of patients with albumin/creatinine ratios that worsened, did
not change, or improved is defined as a shift from baseline category (<3.4, ≥3.4 to ≤33.9, or >33.9 mg/mmol).
†P<0.001 vs placebo; ‡P = 0.0058 vs placebo.
Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
†
†
†
†
‡
‡

62. 20
22
24
26
28
30
32
Saxa Placebo
Reversing Microalbuminuria to normal
P<0.0001
Saxagliptin reverses Micro-albuminurea to
normal
Standard antidiabetic
drug

63. 63
Author | 00 Month Year
Set area descriptor | Sub level 1

64. Clinical implications of SAVOR Study: renal
impairment subgroup observations
1. Largest cohort in prospective study with any diabetic medicine studied to
evaluate safety and efficacy
2. Saxagliptin is a CV safe drug and did not increased chances of AE in
moderately or severly decreased GFR patients
3. Study shows sign of nephroprotective effect of saxagliptin by reversing
microalbuminuria in about one third of study population
4. These data needs to be further validated in future clinical trials.

66. Multiple Organ Damage
Multiple Defects
STENO 2
BP, Lipids, Glycemic Control
Hypoglycemia
SU Rotation
Saxa – Renal Benefits,
Reduced Medications Add on