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HR 0.44
3 (95% CI 0.24-0.82)
41 total events
Control
2
All Saxa
0
BL 24 37 50 63 76 89 102 115 128
Weeks
Patients at
Risk
Control 1251 935 860 774 545 288 144 123 102 57
All Saxa 3356 2615 2419 2209 1638 994 498 436 373 197
Frederich R, et al. Postgraduate Medicine 2010;122(3). doi: 10.3810/pgm.2010.05.2138.
Primary Objective
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Trial Organization
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Definition of High Risk for CV Disease
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Established CV Disease
Placebo Saxagliptin
(N = 8,212) (N = 8,280)
Age 65 yr 65 yr
Female (%) 33 33
Established CVD n=12,959 79 78
Multiple Risk Factors n=3,533 21 22
Cardiac Risk Factors (%)
Dyslipidemia 71 71
HTN 82 81
Prior MI 38 38
Prior CHF 13 13
Prior Coronary Revasc. 43 43
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Baseline Medications
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Placebo Saxagliptin
(N = 8,212) (N = 8,280)
Cardiovascular Medications (%)
Aspirin 75 76
Statin 78 78
ACEi 55 54
ARB 28 28
Beta Blocker 62 62
Diabetic Medications (%)
Insulin 41 42
Sulfonylurea 40 41
TZD 6 6
Metformin 69 70
None 5 4
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Glycemic Indices Over Time
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
40
*
38.4
*
40.0
*
8.0 *
7.9 *
7.8
*
7.9
36.2
8 30.0
HbA1c (%)
6 0
Rand 1 year 2 year EoT Rand 1 year 2 year EoT
These changes were in the context of:
• 23% in the intensification of anti-hyperglycemic medications with saxagliptin
compared to control (p<0.001), and
• 30% in the initiation of insulin therapy for more than 3 months with saxagliptin
compared to control (p<0.001).
Primary Endpoint
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
14
CV Death, MI or Ischemic CVA (%)
HR 1.00
12
95% CI 0.89-1.12
p<0.001 (non-inferiority)
10
p=0.99 (superiority) 2y KM
Saxagliptin 7.3%
8
6
Placebo 7.2%
4
6 12 18 24
Months
Placebo 8212 7983 7761 7267 4855
2y KM
14 Saxagliptin 12.8%
Hosp for UA, CHF or Revasc (%)
HR 1.02
12
CV Death, MI, Ischemic CVA,
95% CI 0.94-1.11
p<0.001 (non-inferiority) Placebo 12.4%
10
p=0.66 (superiority)
8
6 12 18 24
Months
Placebo 8212 7843 7502 6926 4602
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Sub-Group Analysis
TIMI STUDY GROUP / HADASSAH MEDICAL ORG Primary Endpoint
0.2 0.5 1 2
Favors Saxagliptin Favors Placebo
0.2 0.5 1 2
Favors Saxagliptin Favors Placebo
p>0.05 for all interactions between treatment and subgroups
Changes in
TIMI STUDY GROUP / HADASSAH MEDICAL ORG Microalbuminuria
Shift from baseline category
(<3.4, ≥3.4 - ≤33.9, or >33.9 mg/mmol)
Saxagliptin Placebo
global p<0.001
20
16%
15 13%
(%) 11%
10 9%
0
Worsened Improved
End of Treatment
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Hypoglycemia
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Saxagliptin Placebo
p<0.001
p=0.002
15.3%
15 14.2%
13.4%
12.5%
10
(%)
p=0.047
5 p=0.33
2.1% 1.7%
0.6% 0.5%
0
Any Minor Major Requiring
Hospitalization
Major – required assistance to actively intervene
Minor – symptoms, but recovered by themselves within 30 minutes,
or glucose level < 54 mg/dl, regardless of symptoms.
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Endpoints of Special Interest
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Placebo Saxagliptin
p value
(N=8,212) (N=8,280)
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Pancreatic Events
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Placebo Saxagliptin p
(N=8,212) (N=8,280) value
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Baseline NT-pro BNP and
TIMI STUDY GROUP / HADASSAH MEDICAL ORG Hospitalization for Heart Failure
Preliminary data (N=12,397 patients; 387 HF events)
Saxagliptin Placebo p=0.024 for Q4
10.9%
10%
Hosp. for Heart Failure (%)
8.9%
4%
2.2% 2.0%
2%
1.1%
0.3%
0.1% 0.1%
0%
Q1 Q2 Q3 Q4
(5 - 64) (65 - 140) (141 - 332) (333 - 46,627)
Quartiles of NT-proBNP (pg/ml)
Caveats
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Conclusions
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Conclusions
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
• In addition, saxagliptin:
– Improved glycemic control
– Decreased the need for insulin and other
diabetes medications
– Increased hypoglycemic events, but not
hospitalization for hypoglycemia
– Prevented progression of microalbuminuria
– Did not increase risk of pancreatitis or
pancreatic cancer
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
Conclusions (Heart Failure)
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.
For Full Details, Please Go to
TIMI STUDY GROUP / HADASSAH MEDICAL ORG www.NEJM.org
Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.